Journal articles
Smith RG, Pishva E, Shireby G, Smith AR, Roubroeks JAY, Hannon E, Wheildon G, Mastroeni D, Gasparoni G, Riemenschneider M, et al (In Press). A meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex.
Abstract:
A meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex
ABSTRACTEpigenome-wide association studies of Alzheimer’s disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer’s disease (N=1,453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N=1,408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further > 600 unique donors. The meta-analysis summary statistics are available in our online data resource (www.epigenomicslab.com/ad-meta-analysis/).
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Chong JR, Chai YL, Xing H, Herr DR, Wenk MR, Francis PT, Ballard C, Aarsland D, Silver DL, Chen CP, et al (2023). Decreased DHA-containing phospholipids in the neocortex of dementia with Lewy bodies are associated with soluble Aβ42 , phosphorylated α-synuclein, and synaptopathology.
Brain PatholAbstract:
Decreased DHA-containing phospholipids in the neocortex of dementia with Lewy bodies are associated with soluble Aβ42 , phosphorylated α-synuclein, and synaptopathology.
Docosahexaenoic acid (DHA) is an essential omega-3 polyunsaturated fatty acid implicated in cognitive functions by promoting synaptic protein expression. While alterations of specific DHA-containing phospholipids have been described in the neocortex of patients with Alzheimer's disease (AD), the status of these lipids in dementia with Lewy bodies (DLB), known to manifest aggregated α-synuclein-containing Lewy bodies together with variable amyloid pathology, is unclear. In this study, post-mortem samples from the parietal cortex of 25 DLB patients and 17 age-matched controls were processed for phospholipidomics analyses using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) platform. After controlling for false discovery rate, six out of the 46 identified putative DHA-phospholipid species were significantly decreased in DLB, with only one showing increase. Altered putative DHA-phospholipid species were subsequently validated with further LC-MS/MS measurements. of the DHA-containing phospholipid (DCP) species showing decreases, five negatively correlated with soluble beta-amyloid (Aβ42) levels, whilst three also correlated with phosphorylated α-synuclein (all p
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Chai YL, Lee JH, Chong JR, Ballard C, Francis PT, Kennedy BK, Arumugam TV, Chen CP, Aarsland D, Lai MKP, et al (2023). Inflammatory panel cytokines are elevated in the neocortex of late-stage Alzheimer's disease but not Lewy body dementias.
J Neuroinflammation,
20(1).
Abstract:
Inflammatory panel cytokines are elevated in the neocortex of late-stage Alzheimer's disease but not Lewy body dementias.
BACKGROUND: Chronically dysregulated neuroinflammation has been implicated in neurodegenerative dementias, with separate studies reporting increased brain levels of inflammatory mediators and gliosis in Alzheimer's disease (AD) as well as in Lewy body dementias (LBD). However, it is unclear whether the nature and extent of neuroinflammatory responses in LBD are comparable to those in AD. In this study, we performed head-to-head measurements of a panel of cytokines in the post-mortem neocortex of AD versus the two major clinical subtypes of LBD, namely, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). METHODS: Post-mortem tissues from the mid-temporal cortex (Brodmann area 21) of a cohort of neuropathologically well-defined AD, PDD and DLB patients were processed and measured for a comprehensive range of cytokines (IL-1α, IL-1Ra, IL-8, IL-10, IL-12p70, IL-13, IFN-γ, GM-CSF and FGF-2) using a multiplex immunoassay platform. Associations between inflammation markers and neuropathological measures of neuritic plaques, neurofibrillary tangles as well as Lewy bodies were also performed. RESULTS: We found IL-1α, IFN-γ, GM-CSF and IL-13 to be elevated in the mid-temporal cortex of AD patients. In contrast, none of the measured cytokines were significantly altered in either DLB or PDD. Similar cytokine changes were observed in two other neocortical areas of AD patients. Furthermore, increases of IL-1α, IFN-γ, GM-CSF, IL-10 and IL-13 associated with moderate-to-severe neurofibrillary tangle burden, but not with neuritic plaques or Lewy bodies. Our findings of elevated neocortical pro- and anti-inflammatory cytokines in AD, but not in DLB or PDD, suggest that neuroinflammatory responses are strongly linked to neurofibrillary tangle burden, which is higher in AD compared to LBD. In conclusion, neuroinflammation may not play a prominent role in the pathophysiology of late-stage LBD.
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Henderson C, Knapp M, Stirling S, Shepstone L, High J, Ballard C, Bentham P, Burns A, Farina N, Fox C, et al (2022). Cost-effectiveness of mirtazapine for agitated behaviors in dementia: findings from a randomized controlled trial.
International Psychogeriatrics,
34(10), 905-917.
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Cost-effectiveness of mirtazapine for agitated behaviors in dementia: findings from a randomized controlled trial
ABSTRACTObjectives:To examine the costs and cost-effectiveness of mirtazapine compared to placebo over 12-week follow-up.Design:Economic evaluation in a double-blind randomized controlled trial of mirtazapine vs. placebo.Setting:Community settings and care homes in 26 UK centers.Participants:People with probable or possible Alzheimer’s disease and agitation.Measurements:Primary outcome included incremental cost of participants’ health and social care per 6-point difference in CMAI score at 12 weeks. Secondary cost-utility analyses examined participants’ and unpaid carers’ gain in quality-adjusted life years (derived from EQ-5D-5L, DEMQOL-Proxy-U, and DEMQOL-U) from the health and social care and societal perspectives.Results:One hundred and two participants were allocated to each group; 81 mirtazapine and 90 placebo participants completed a 12-week assessment (87 and 95, respectively, completed a 6-week assessment). Mirtazapine and placebo groups did not differ on mean CMAI scores or health and social care costs over the study period, before or after adjustment for center and living arrangement (independent living/care home). On the primary outcome, neither mirtazapine nor placebo could be considered a cost-effective strategy with a high level of confidence. Groups did not differ in terms of participant self- or proxy-rated or carer self-rated quality of life scores, health and social care or societal costs, before or after adjustment.Conclusions:On cost-effectiveness grounds, the use of mirtazapine cannot be recommended for agitated behaviors in people living with dementia. Effective and cost-effective medications for agitation in dementia remain to be identified in cases where non-pharmacological strategies for managing agitation have been unsuccessful.
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Shireby G, Dempster EL, Policicchio S, Smith RG, Pishva E, Chioza B, Davies JP, Burrage J, Lunnon K, Seiler Vellame D, et al (2022). DNA methylation signatures of Alzheimer’s disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types.
Nature Communications,
13(1).
Abstract:
DNA methylation signatures of Alzheimer’s disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types
AbstractAlzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the progressive accumulation of amyloid-beta and neurofibrillary tangles of tau in the neocortex. We profiled DNA methylation in two regions of the cortex from 631 donors, performing an epigenome-wide association study of multiple measures of AD neuropathology. We meta-analyzed our results with those from previous studies of DNA methylation in AD cortex (total n = 2013 donors), identifying 334 cortical differentially methylated positions (DMPs) associated with AD pathology including methylomic variation at loci not previously implicated in dementia. We subsequently profiled DNA methylation in NeuN+ (neuronal-enriched), SOX10+ (oligodendrocyte-enriched) and NeuN–/SOX10– (microglia- and astrocyte-enriched) nuclei, finding that the majority of DMPs identified in ‘bulk’ cortex tissue reflect DNA methylation differences occurring in non-neuronal cells. Our study highlights the power of utilizing multiple measures of neuropathology to identify epigenetic signatures of AD and the importance of characterizing disease-associated variation in purified cell-types.
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Chua XY, Chong JR, Cheng AL, Lee JH, Ballard C, Aarsland D, Francis PT, Lai MKP (2022). Elevation of inactive cleaved annexin A1 in the neocortex is associated with amyloid, inflammatory and apoptotic markers in neurodegenerative dementias.
Neurochem Int,
152Abstract:
Elevation of inactive cleaved annexin A1 in the neocortex is associated with amyloid, inflammatory and apoptotic markers in neurodegenerative dementias.
Inflammation is usually a tightly regulated process whose termination by mediators including Annexin A1 (AnxA1) results in the resolution of inflammatory responses. In neurodegenerative dementias, chronic neuroinflammation, along with accumulation of aggregated β-amyloid (Aβ) peptides and apoptosis, has long been recognized to be a pathological hallmark; but it is unclear whether a failure of inflammation resolution contributes to this pathophysiological process. In this study, we measured AnxA1 immunoreactivities in postmortem neocortex (Brodmann areas BA9 and BA40) of well characterized Alzheimer's disease (AD), Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) patients as well as aged controls. Inactive cleaved AnxA1 was found to be elevated in AD and DLB in BA40. Levels of cleaved AnxA1 also positively correlated with amyloidogenic brain Aβ, anti-inflammatory markers such as IL10 and IL13, as well as with the pro-apoptotic marker cleaved caspase-3 in BA40. Our findings suggest that elevated cleaved AnxA1 in neurodegenerative dementias may reflect a failure of inflammation resolution in certain regions of the diseased brain, and also support a mechanistic link between AnxA1 and amyloid pathology, neuroinflammation and apoptosis.
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Pihlstrøm L, Shireby G, Geut H, Henriksen SP, Rozemuller AJM, Tunold J-A, Hannon E, Francis P, Thomas AJ, Love S, et al (2022). Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology.
Nature Communications,
13(1).
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Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology
AbstractParkinson’s disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2, SFMBT2, AKAP6 and PHYHIP. Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.
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Gelegen C, Cash D, Ilic K, Sander M, Kim E, Simmons C, Bernanos M, Lama J, Randall K, Brown JT, et al (2022). Relevance of sleep and associated structural changes in GBA1 mouse to human rapid eye movement behavior disorder.
Scientific Reports,
12(1).
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Relevance of sleep and associated structural changes in GBA1 mouse to human rapid eye movement behavior disorder
AbstractRapid eye movement (REM) sleep behaviour disorder (RBD) is a REM parasomnia that often predicts the later occurrence of alpha-synucleinopathies. Variants in the gene encoding for the lysosomal enzyme glucocerebrosidase, GBA, strongly increase the risk of RBD. In a GBA1-mouse model recently shown to mimic prodromal stages of α-synucleinopathy, we now demonstrate striking REM and NREM electroencephalographic sleep abnormalities accompanied by distinct structural changes in the more widespread sleep neurocircuitry.
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Smith RG, Pishva E, Shireby G, Smith AR, Roubroeks JAY, Hannon E, Wheildon G, Mastroeni D, Gasparoni G, Riemenschneider M, et al (2021). A meta-analysis of epigenome-wide association studies in Alzheimer's disease highlights novel differentially methylated loci across cortex.
Nat Commun,
12(1).
Abstract:
A meta-analysis of epigenome-wide association studies in Alzheimer's disease highlights novel differentially methylated loci across cortex.
Epigenome-wide association studies of Alzheimer's disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer's disease (N = 1453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N = 1408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further >600 unique donors. The meta-analysis summary statistics are available in our online data resource ( www.epigenomicslab.com/ad-meta-analysis/ ).
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Alakbarzade V, French JM, Howlett DR, Attems J, Francis PT, Stratton S, Clark CN, Pereira AC, Hainsworth AH (2021). Cerebral amyloid angiopathy distribution in older people: a cautionary note.
Alzheimers Dement (N Y),
7(1).
Abstract:
Cerebral amyloid angiopathy distribution in older people: a cautionary note.
INTRODUCTION: Radiolabeled ligands for fibrillar amyloid beta (Aβ) peptides are used in positron emission tomography (PET) for dementia diagnosis. Current ligands do not discriminate parenchymal amyloid plaques from cerebral amyloid angiopathy (CAA). METHODS: We undertook neuropathological examination of 65 older people (81.6 ± 7.96 (mean ± SD) years, 27F/38M): 15 with neuropathological diagnosis of AD, 25 with neuropathological diagnosis of other neurodegenerative dementias (Lewy body dementia and Parkinson disease dementia), and 25 without significant neurodegenerative pathology. RESULTS: We observed CAA in non-Alzheimer's dementia (non-AD dementia) and control brains, of comparable extent to those with neuropathologically confirmed AD. Aβ-positive vessel density did not differ significantly between non-AD dementia and control groups. Across all subjects there was a highly significant correlation between vessel Aβ40 density and vessel Aβ42 density (Spearman rho = 0.855, P <. 001). CAA was absent or sparse in subcortical white matter across all patient groups. CONCLUSION: Our data indicate that CAA can be abundant in non-AD brains and raise a cautionary note regarding interpretation of amyloid PET imaging.
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McAleese KE, Colloby SJ, Thomas AJ, Al-Sarraj S, Ansorge O, Neal J, Roncaroli F, Love S, Francis PT, Attems J, et al (2021). Concomitant neurodegenerative pathologies contribute to the transition from mild cognitive impairment to dementia.
Alzheimers Dement,
17(7), 1121-1133.
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Concomitant neurodegenerative pathologies contribute to the transition from mild cognitive impairment to dementia.
INTRODUCTION: the aged brain frequently exhibits multiple pathologies, rather than a single hallmark pathology (pure pathology [PurP]), ranging from low/intermediate levels of additional pathology (LowP) to mixed severe pathology (mixed SevP). We investigated the frequency of PurP, LowP, and mixed SevP, and the impact of additional LowP on cognition. METHODS: Data came from 670 cases from the Brains for Dementia research program. Cases were categorized into PurP, mixed SevP, or a main disease with additional LowP; 508 cases had a clinical dementia rating. RESULTS: 69.9% of cases had LowP, 22.7% had PurP, and 7.5% had mixed SevP. Additional LowP increased the likelihood of having mild dementia versus mild cognitive impairment (MCI) by almost 20-fold (odds ratio = 19.5). DISCUSSION: Most aged individuals have multiple brain pathologies. The presence of one additional LowP can significantly worsen cognitive decline, increasing the risk of transitioning from MCI to dementia 20-fold. Multimorbidity should be considered in dementia research and clinical studies.
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Alić I, Goh PA, Murray A, Portelius E, Gkanatsiou E, Gough G, Mok KY, Koschut D, Brunmeir R, Yeap YJ, et al (2021). Correction: Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.
Mol Psychiatry,
26(10).
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Lawingco T, Chaudhury S, Brookes KJ, Guetta-Baranes T, Guerreiro R, Bras J, Hardy J, Francis P, Thomas A, Belbin O, et al (2021). Genetic variants in glutamate-, Aβ−, and tau-related pathways determine polygenic risk for Alzheimer's disease.
Neurobiology of Aging,
101, 299.e13-299.e21.
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Genetic variants in glutamate-, Aβ−, and tau-related pathways determine polygenic risk for Alzheimer's disease
Synapse loss is an early event in late-onset Alzheimer's disease (LOAD). In this study, we have assessed the capacity of a polygenic risk score (PRS) restricted to synapse-encoding loci to predict LOAD. We used summary statistics from the International Genetics of Alzheimer's Project genome-wide association meta-analysis of 74,046 patients for model construction and tested the “synaptic PRS” in 2 independent data sets of controls and pathologically confirmed LOAD. The mean synaptic PRS was 2.3-fold higher in LOAD than that in controls (p < 0.0001) with a predictive accuracy of 72% in the target data set (n = 439) and 73% in the validation data set (n = 136), a 5%–6% improvement compared with the APOE locus (p < 0.00001). The model comprises 8 variants from 4 previously identified (BIN1, PTK2B, PICALM, APOE) and 2 novel (DLG2, MINK1) LOAD loci involved in glutamate signaling (p = 0.01) or APP catabolism or tau binding (p = 0.005). As the simplest PRS model with good predictive accuracy to predict LOAD, we conclude that synapse-encoding genes are enriched for LOAD risk-modifying loci. The synaptic PRS could be used to identify individuals at risk of LOAD before symptom onset.
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Khan Z, Da Silva MV, Nunez K-M, Kalafatis C, Nowicki S, Walker Z, Testad I, Francis P, Ballard C (2021). Investigating the effects of impairment in non-verbal communication on neuropsychiatric symptoms and quality of life of people living with dementia.
Alzheimers Dement (N Y),
7(1).
Abstract:
Investigating the effects of impairment in non-verbal communication on neuropsychiatric symptoms and quality of life of people living with dementia.
INTRODUCTION: People living with dementia in nursing homes have complex needs; impairments in cognition, communication, and daily function; neuropsychiatric symptoms (NPS); and poor quality of life (QoL). The current study examines impairments in non-verbal communication as a potential driver of NPS and QoL. METHODS: One hundred nursing home residents with dementia were assessed using the Emory Dyssemia Index (EDI), Neuropsychiatric Inventory Nursing Home version (NPI-NH), Quality of Life in Alzheimer's Disease (QoL-AD) at baseline, 12-, and 24-week follow-up. RESULTS: the quantile regression (0.5) model indicated that impairment of non-verbal communication was independently associated with the severity of NPS (P = .001) and proxy reported QoL (P
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Low CYB, Lee JH, Lim FTW, Lee C, Ballard C, Francis PT, Lai MKP, Tan MGK (2021). Isoform‐specific upregulation of FynT kinase expression is associated with tauopathy and glial activation in Alzheimer's disease and Lewy body dementias.
Brain Pathology,
31(2), 253-266.
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Isoform‐specific upregulation of FynT kinase expression is associated with tauopathy and glial activation in Alzheimer's disease and Lewy body dementias
AbstractCumulative data suggest the involvement of Fyn tyrosine kinase in Alzheimer's disease (AD). Previously, our group has shown increased immunoreactivities of the FynT isoform in AD neocortex (with no change in the alternatively spliced FynB isoform) which associated with neurofibrillary degeneration and reactive astrogliosis. Since both the aforementioned neuropathological features are also variably found in Lewy Body dementias (LBD), we investigated potential perturbations of Fyn expression in the post‐mortem neocortex of patients with AD, as well as those diagnosed as having one of the two main subgroups of LBD: Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). We found selective upregulation of FynT expression in AD, PDD, and DLB which also correlated with cognitive impairment. Furthermore, increased FynT expression correlated with hallmark neuropathological lesions, soluble β‐amyloid, and phosphorylated tau, as well as markers of microglia and astrocyte activation. In line with the human post‐mortem studies, cortical FynT expression in aged mice transgenic for human P301S tau was upregulated and further correlated with accumulation of aggregated phosphorylated tau as well as with microglial and astrocytic markers. Our findings provide further evidence for the involvement of FynT in neurodegenerative dementias, likely via effects on tauopathy and neuroinflammation.
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Alić I, Goh PA, Murray A, Portelius E, Gkanatsiou E, Gough G, Mok KY, Koschut D, Brunmeir R, Yeap YJ, et al (2021). Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.
Molecular Psychiatry,
26(10), 5766-5788.
Abstract:
Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain
A population of more than six million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21 organoids secrete increased proportions of Aβ-preventing (Aβ1–19) and Aβ-degradation products (Aβ1–20 and Aβ1–34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.
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Wasserman D, Bindman D, Nesbitt AD, Cash D, Milosevic M, Francis PT, Chaudhuri KR, Leschziner GD, Ferini-Strambi L, Ballard C, et al (2021). Striatal Dopaminergic Deficit and Sleep in Idiopathic Rapid Eye Movement Behaviour Disorder: an Explorative Study.
Nat Sci Sleep,
13, 1-9.
Abstract:
Striatal Dopaminergic Deficit and Sleep in Idiopathic Rapid Eye Movement Behaviour Disorder: an Explorative Study.
INTRODUCTION: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is increasingly recognised as an important precursor disease state of alpha-synucleinopathies. This parasomnia is characterized by a history of recurrent nocturnal dream enactment behaviour, loss of skeletal muscle atonia, and increased phasic muscle activity during REM sleep. Neuroimaging studies of striatal dopamine transporter uptake tracer signaling suggest increasing dopaminergic deficit across the continuum of the alpha-synucleinopathies, with early sleep dysfunction suggestive of early caudate dysfunction. Henceforth, we set out to investigate the relationship between early sleep changes and the striatal dopaminergic availability in iRBD. METHODS: Twelve patients with iRBD, who had undergone a video polysomnography and a neuroimaging assessment of striatal dopamine transporter (DaT) uptake tracer signaling, and 22 matched controls who had similarly undergone a video polysomnography were retrospectively identified. Data were statistically analyzed to identify altered sleep parameters and correlate them with striatal dopamine transporter uptake tracer signaling. RESULTS: the iRBD patients exhibited an increased number of periodic limb movements during sleep (P=0.001), compared to 22 age-matched healthy subjects. In addition, several significant links were found between regional DaT-uptakes and sleep architecture. Correlational analyses suggested a strong positive association between sleep fragmentation and dopamine deficiency in left caudate (r=-0.630, P=0.028), whilst an increased uptake in the whole striatum was strongly linked to the sleep efficiency, and to a lesser degree to the length of sleep duration. DISCUSSION: to the best of our knowledge, this is the first demonstration of a close relationship between dopaminergic availability in striatum and the quality of sleep in iRBD. Taken together, our exploratory findings suggest that subtle but functionally significant striatal changes in early stages of iRBD may contribute to the further shaping of sleep architecture.
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Banerjee S, High J, Stirling S, Shepstone L, Swart AM, Telling T, Henderson C, Ballard C, Bentham P, Burns A, et al (2021). Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial.
Lancet,
398(10310), 1487-1497.
Abstract:
Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial.
BACKGROUND: Agitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this care is not effective. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed the efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia. METHODS: This parallel-group, double-blind, placebo-controlled trial-the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD)-was done in 26 UK centres. Participants had probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of 45 or more. They were randomly assigned (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo. The primary outcome was reduction in CMAI score at 12 weeks. This trial is registered with ClinicalTrials.gov, NCT03031184, and ISRCTN17411897. FINDINGS: Between Jan 26, 2017, and March 6, 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants receiving mirtazapine and participants receiving placebo (adjusted mean difference -1·74, 95% CI -7·17 to 3·69; p=0·53). The number of controls with adverse events (65 [64%] of 102 controls) was similar to that in the mirtazapine group (67 [66%] of 102 participants receiving mirtazapine). However, there were more deaths in the mirtazapine group (n=7) by week 16 than in the control group (n=1), with post-hoc analysis suggesting this difference was of marginal statistical significance (p=0·065). INTERPRETATION: This trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.
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Hartl D, May P, Gu W, Mayhaus M, Pichler S, Spaniol C, Glaab E, Bobbili DR, Antony P, Koegelsberger S, et al (2020). A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease.
Molecular Psychiatry,
25(3), 629-639.
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A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease
Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, UK, and USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 alpha-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aß formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD.
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Hannon E, Shireby GL, Brookes K, Attems J, Sims R, Cairns NJ, Love S, Thomas AJ, Morgan K, Francis PT, et al (2020). Genetic risk for Alzheimer’s disease influences neuropathology via multiple biological pathways.
Brain Communications,
2(2).
Abstract:
Genetic risk for Alzheimer’s disease influences neuropathology via multiple biological pathways
Abstract
. Alzheimer’s disease is a highly heritable, common neurodegenerative disease characterized neuropathologically by the accumulation of β-amyloid plaques and tau-containing neurofibrillary tangles. In addition to the well-established risk associated with the APOE locus, there has been considerable success in identifying additional genetic variants associated with Alzheimer’s disease. Major challenges in understanding how genetic risk influences the development of Alzheimer’s disease are clinical and neuropathological heterogeneity, and the high level of accompanying comorbidities. We report a multimodal analysis integrating longitudinal clinical and cognitive assessment with neuropathological data collected as part of the Brains for Dementia Research study to understand how genetic risk factors for Alzheimer’s disease influence the development of neuropathology and clinical performance. Six hundred and ninety-three donors in the Brains for Dementia Research cohort with genetic data, semi-quantitative neuropathology measurements, cognitive assessments and established diagnostic criteria were included in this study. We tested the association of APOE genotype and Alzheimer’s disease polygenic risk score—a quantitative measure of genetic burden—with survival, four common neuropathological features in Alzheimer’s disease brains (neurofibrillary tangles, β-amyloid plaques, Lewy bodies and transactive response DNA-binding protein 43 proteinopathy), clinical status (clinical dementia rating) and cognitive performance (Mini-Mental State Exam, Montreal Cognitive Assessment). The APOE ε4 allele was significantly associated with younger age of death in the Brains for Dementia Research cohort. Our analyses of neuropathology highlighted two independent pathways from APOE ε4, one where β-amyloid accumulation co-occurs with the development of tauopathy, and a second characterized by direct effects on tauopathy independent of β-amyloidosis. Although we also detected association between APOE ε4 and dementia status and cognitive performance, these were all mediated by tauopathy, highlighting that they are a consequence of the neuropathological changes. Analyses of polygenic risk score identified associations with tauopathy and β-amyloidosis, which appeared to have both shared and unique contributions, suggesting that different genetic variants associated with Alzheimer’s disease affect different features of neuropathology to different degrees. Taken together, our results provide insight into how genetic risk for Alzheimer’s disease influences both the clinical and pathological features of dementia, increasing our understanding about the interplay between APOE genotype and other genetic risk factors.
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Liu KY, Reeves S, McAleese KE, Attems J, Francis P, Thomas A, Howard R (2020). Neuropsychiatric symptoms in limbic-predominant age-related TDP-43 encephalopathy and Alzheimer's disease.
Brain,
143(12), 3842-3849.
Abstract:
Neuropsychiatric symptoms in limbic-predominant age-related TDP-43 encephalopathy and Alzheimer's disease.
There is clinical overlap between presentations of dementia due to limbic-predominant age-related TDP-43 encephalopathy (LATE) and Alzheimer's disease. It has been suggested that the combination of Alzheimer's disease neuropathological change (ADNC) and LATE neuropathological changes (LATE-NC) is associated with greater neuropsychiatric symptom burden, compared to either pathology alone. Longitudinal Neuropsychiatric Inventory and psychotropic medication prescription data from neuropathologically diagnosed pure ADNC (n = 78), pure LATE-NC (n = 14) and mixed ADNC/LATE-NC (n = 39) brain bank donors were analysed using analysis of variance and linear mixed effects regression models to examine the relationship between diagnostic group and neuropsychiatric symptom burden. Nearly all donors had dementia; three (two pure LATE-NC and one pure ADNC) donors had mild cognitive impairment and another two donors with LATE-NC did not have dementia. The mixed ADNC/LATE-NC group was older than the pure ADNC group, had a higher proportion of females compared to the pure ADNC and LATE-NC groups, and had more severe dementia versus the pure LATE-NC group. After adjustment for length of follow-up, cognitive and demographic factors, mixed ADNC/LATE-NC was associated with lower total Neuropsychiatric Inventory and agitation factor scores than pure ADNC, and lower frontal factor scores than pure LATE-NC. Our findings indicate that concomitant LATE pathology in Alzheimer's disease is not associated with greater neuropsychiatric symptom burden. Future longitudinal studies are needed to further investigate whether mixed ADNC/LATE-NC may be protective against agitation and frontal symptoms in dementia caused by Alzheimer's disease or LATE pathology.
Abstract.
Author URL.
Rajkumar AP, Bidkhori G, Shoaie S, Clarke E, Morrin H, Hye A, Williams G, Ballard C, Francis P, Aarsland D, et al (2020). Postmortem Cortical Transcriptomics of Lewy Body Dementia Reveal Mitochondrial Dysfunction and Lack of Neuroinflammation.
American Journal of Geriatric Psychiatry,
28(1), 75-86.
Abstract:
Postmortem Cortical Transcriptomics of Lewy Body Dementia Reveal Mitochondrial Dysfunction and Lack of Neuroinflammation
Objective: Prevalence of Lewy body dementias (LBD) is second only to Alzheimer's disease (AD) among people with neurodegenerative dementia. LBD cause earlier mortality, more intense neuropsychiatric symptoms, more caregivers’ burden, and higher costs than AD. The molecular mechanisms underlying LBD are largely unknown. As advancing molecular level mechanistic understanding is essential for identifying reliable peripheral biomarkers and novel therapeutic targets for LBD, the authors aimed to identify differentially expressed genes (DEG), and dysfunctional molecular networks in postmortem LBD brains. Methods: the authors investigated the transcriptomics of postmortem anterior cingulate and dorsolateral prefrontal cortices of people with pathology-verified LBD using next-generation RNA-sequencing. The authors verified the identified DEG using high-throughput quantitative polymerase chain reactions. Functional implications of identified DEG and the consequent metabolic reprogramming were evaluated by Ingenuity pathway analyses, genome-scale metabolic modeling, reporter metabolite analyses, and in silico gene silencing. Results: the authors identified and verified 12 novel DEGs (MPO, SELE, CTSG, ALPI, ABCA13, GALNT6, SST, RBM3, CSF3, SLC4A1, OXTR, and RAB44) in LBD brains with genome-wide statistical significance. The authors documented statistically significant down-regulation of several cytokine genes. Identified dysfunctional molecular networks highlighted the contributions of mitochondrial dysfunction, oxidative stress, and immunosenescence toward neurodegeneration in LBD. Conclusion: Our findings support that chronic microglial activation and neuroinflammation, well-documented in AD, are notably absent in LBD. The lack of neuroinflammation in LBD brains was corroborated by statistically significant down-regulation of several inflammatory markers. Identified DEGs, especially down-regulated inflammatory markers, may aid distinguishing LBD from AD, and their biomarker potential warrant further investigation.
Abstract.
Shireby GL, Davies JP, Francis PT, Burrage J, Walker EM, Neilson GWA, Dahir A, Thomas AJ, Love S, Smith RG, et al (2020). Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex.
Brain,
143(12), 3763-3775.
Abstract:
Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex.
Human DNA methylation data have been used to develop biomarkers of ageing, referred to as 'epigenetic clocks', which have been widely used to identify differences between chronological age and biological age in health and disease including neurodegeneration, dementia and other brain phenotypes. Existing DNA methylation clocks have been shown to be highly accurate in blood but are less precise when used in older samples or in tissue types not included in training the model, including brain. We aimed to develop a novel epigenetic clock that performs optimally in human cortex tissue and has the potential to identify phenotypes associated with biological ageing in the brain. We generated an extensive dataset of human cortex DNA methylation data spanning the life course (n = 1397, ages = 1 to 108 years). This dataset was split into 'training' and 'testing' samples (training: n = 1047; testing: n = 350). DNA methylation age estimators were derived using a transformed version of chronological age on DNA methylation at specific sites using elastic net regression, a supervised machine learning method. The cortical clock was subsequently validated in a novel independent human cortex dataset (n = 1221, ages = 41 to 104 years) and tested for specificity in a large whole blood dataset (n = 1175, ages = 28 to 98 years). We identified a set of 347 DNA methylation sites that, in combination, optimally predict age in the human cortex. The sum of DNA methylation levels at these sites weighted by their regression coefficients provide the cortical DNA methylation clock age estimate. The novel clock dramatically outperformed previously reported clocks in additional cortical datasets. Our findings suggest that previous associations between predicted DNA methylation age and neurodegenerative phenotypes might represent false positives resulting from clocks not robustly calibrated to the tissue being tested and for phenotypes that become manifest in older ages. The age distribution and tissue type of samples included in training datasets need to be considered when building and applying epigenetic clock algorithms to human epidemiological or disease cohorts.
Abstract.
Author URL.
O'Brien J, Taylor JP, Ballard C, Barker RA, Bradley C, Burns A, Collerton D, Dave S, Dudley R, Francis P, et al (2020). Visual hallucinations in neurological and ophthalmological disease: pathophysiology and management.
J Neurol Neurosurg Psychiatry,
91(5), 512-519.
Abstract:
Visual hallucinations in neurological and ophthalmological disease: pathophysiology and management.
Visual hallucinations are common in older people and are especially associated with ophthalmological and neurological disorders, including dementia and Parkinson's disease. Uncertainties remain whether there is a single underlying mechanism for visual hallucinations or they have different disease-dependent causes. However, irrespective of mechanism, visual hallucinations are difficult to treat. The National Institute for Health Research (NIHR) funded a research programme to investigate visual hallucinations in the key and high burden areas of eye disease, dementia and Parkinson's disease, culminating in a workshop to develop a unified framework for their clinical management. Here we summarise the evidence base, current practice and consensus guidelines that emerged from the workshop.Irrespective of clinical condition, case ascertainment strategies are required to overcome reporting stigma. Once hallucinations are identified, physical, cognitive and ophthalmological health should be reviewed, with education and self-help techniques provided. Not all hallucinations require intervention but for those that are clinically significant, current evidence supports pharmacological modification of cholinergic, GABAergic, serotonergic or dopaminergic systems, or reduction of cortical excitability. A broad treatment perspective is needed, including carer support. Despite their frequency and clinical significance, there is a paucity of randomised, placebo-controlled clinical trial evidence where the primary outcome is an improvement in visual hallucinations. Key areas for future research include the development of valid and reliable assessment tools for use in mechanistic studies and clinical trials, transdiagnostic studies of shared and distinct mechanisms and when and how to treat visual hallucinations.
Abstract.
Author URL.
Clarke E, Jantrachotechatchawan C, Buhidma Y, Broadstock M, Yu L, Howlett D, Aarsland D, Ballard C, Francis PT (2019). Age-related neurochemical and behavioural changes in D409V/WT GBA1 mouse: Relevance to lewy body dementia.
Neurochem Int,
129Abstract:
Age-related neurochemical and behavioural changes in D409V/WT GBA1 mouse: Relevance to lewy body dementia.
Heterozygous mutations in GBA1, the gene which encodes the lysosomal enzyme glucocerebrosidase (GCase), are a strong genetic risk factor for the development of Lewy body dementia (LBD). Until this point however, recapitulation of the symptoms and pathology of LBD has been limited to a homozygous GBA1 mouse model which genetically and enzymatically reflects the lysosomal storage disorder Gaucher's disease. This study reports for the first time cognitive impairment by two independent behavioural tests in heterozygous GBA1 mutant mice (D409V/WT) which demonstrate significant cognitive impairment by the age of 12 months. Furthermore, reductions in GBA1 GCase enzyme activity within the brain reflects levels seen in sporadic and GBA1 mutant LBD patients. While there is no overt deposition of Lewy bodies within the hippocampus, alterations to cholinergic machinery and glial proliferation are evident, both pathological features of LBD. Interestingly, we also describe the novel finding of significantly reduced GBA2 GCase enzyme activity specifically within the hippocampus. This suggests that reduced GBA1 GCase enzyme activity dis-equilibrates the finely balanced glycosphingolipid metabolism pathway and that reductions in GBA2 GCase enzyme could contribute to the pathological and behavioural effects seen. Overall, this study presents evidence to suggest that pathological hallmarks associated with LBD specifically affecting brain regions intrinsically linked with cognition are present in the D409V/WT mice. In the absence of Lewy body deposition, the D409V/WT mice could be considered an early pre-clinical model of LBD with potential for drug discovery. Since few robust pre-clinical models of LBD currently exist, with further characterization, the mouse model described here may contribute significantly to developments in the LBD field.
Abstract.
Author URL.
Chaudhury S, Brookes KJ, Patel T, Fallows A, Guetta-Baranes T, Turton JC, Guerreiro R, Bras J, Hardy J, Francis PT, et al (2019). Alzheimer’s disease polygenic risk score as a predictor of conversion from mild-cognitive impairment.
Translational Psychiatry,
9(1).
Abstract:
Alzheimer’s disease polygenic risk score as a predictor of conversion from mild-cognitive impairment
Mild-cognitive impairment (MCI) occurs in up to one-fifth of individuals over the age of 65, with approximately a third of MCI individuals converting to dementia in later life. There is a growing necessity for early identification for those at risk of dementia as pathological processes begin decades before onset of symptoms. A cohort of 122 individuals diagnosed with MCI and followed up for a 36-month period for conversion to late-onset Alzheimer’s disease (LOAD) were genotyped on the NeuroChip array along with pathologically confirmed cases of LOAD and cognitively normal controls. Polygenic risk scores (PRS) for each individual were generated using PRSice-2, derived from summary statistics produced from the International Genomics of Alzheimer’s Disease Project (IGAP) genome-wide association study. Predictability models for LOAD were developed incorporating the PRS with APOE SNPs (rs7412 and rs429358), age and gender. This model was subsequently applied to the MCI cohort to determine whether it could be used to predict conversion from MCI to LOAD. The PRS model for LOAD using area under the precision-recall curve (AUPRC) calculated a predictability for LOAD of 82.5%. When applied to the MCI cohort predictability for conversion from MCI to LOAD was 61.0%. Increases in average PRS scores across diagnosis group were observed with one-way ANOVA suggesting significant differences in PRS between the groups (p < 0.0001). This analysis suggests that the PRS model for LOAD can be used to identify individuals with MCI at risk of conversion to LOAD.
Abstract.
Francis PT, Hayes GM, Costello H, Whitfield DR (2019). Brains for Dementia Research: the Importance of Cohorts in Brain Banking.
Neurosci Bull,
35(2), 289-294.
Author URL.
Chaudhury S, Brookes KJ, Patel T, Fallows A, Guetta-Baranes T, Turton JC, Guerreiro R, Bras J, Hardy J, Francis PT, et al (2019). Correction: Alzheimer's disease polygenic risk score as a predictor of conversion from mild-cognitive impairment.
Transl Psychiatry,
9(1).
Abstract:
Correction: Alzheimer's disease polygenic risk score as a predictor of conversion from mild-cognitive impairment.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Abstract.
Author URL.
Bereczki E, Branca RM, Francis PT, Pereira JB, Baek J-H, Hortobagyi T, Winblad B, Ballard C, Lehtio J, Aarsland D, et al (2019). Corrigendum: Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach (vol 141, pg 582, 2018). Brain, 142
Chai YL, Chong JR, Weng J, Howlett D, Halsey A, Lee JH, Attems J, Aarsland D, Francis PT, Chen CP, et al (2019). Lysosomal cathepsin D is upregulated in Alzheimer's disease neocortex and may be a marker for neurofibrillary degeneration.
Brain Pathology,
29(1), 63-74.
Abstract:
Lysosomal cathepsin D is upregulated in Alzheimer's disease neocortex and may be a marker for neurofibrillary degeneration
Alzheimer's disease (AD) is characterized by accumulation of β-amyloid plaques (AP) and neurofibrillary tangles (NFT) in the cortex, together with synaptic loss and amyloid angiopathy. Perturbations in the brain lysosomal system, including the cathepsin family of proteases, have been implicated in AD where they may be involved in proteolytic clearance of misfolded and abnormally aggregated peptides. However, the status of cathepsin D (catD) is unclear in Lewy body dementia, the second most common form of neurodegenerative dementia after AD, and characterized by Lewy bodies (LB) containing aggregated α-synuclein. Furthermore, earlier reports of catD changes in AD have not been entirely consistent. We measured CatD immunoreactivities in the temporal (Brodmann area BA21) and parietal (BA40) cortices of well characterized AD brains as well as two clinical subtypes of Lewy body dementia, namely Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB), known to show varying degrees of concomitant AD pathology. Increased catD immunoreactivities in AD were found for both neocortical regions measured, where they also correlated with neuropathological NFT scores and phosphorylated pSer396 tau burden, and appeared to co-localize at least partly to NFT-containing neurons. In contrast, catD was increased only in BA40 in DLB and not at all in PDD, did not correlate with LB scores, and did not appreciably co-localize with α-synuclein inclusions. Our study suggests that catD upregulation may be an adaptive response to AD-related processes leading to neurofibrillary degeneration, but may not be directly associated with formation of α-synuclein inclusions in Lewy body dementia.
Abstract.
Thubron EB, Rosa HS, Hodges A, Sivaprasad S, Francis PT, Pienaar IS, Malik AN (2019). Regional mitochondrial DNA and cell-type changes in post-mortem brains of non-diabetic Alzheimer's disease are not present in diabetic Alzheimer's disease.
Sci Rep,
9(1).
Abstract:
Regional mitochondrial DNA and cell-type changes in post-mortem brains of non-diabetic Alzheimer's disease are not present in diabetic Alzheimer's disease.
Diabetes increases the risk of Alzheimer's disease (AD), and mitochondrial dysfunction is implicated in both diseases, however the impact of both diabetes and AD on brain mitochondria is not known. We measured mitochondrial DNA (mtDNA), an indicator of mitochondrial function, in frontal, parietal, and cerebellar regions of post-mortem human brains (n = 74) from non-cognitively impaired controls (NCI), mild-cognitively impaired (MCI) and AD cases. In a subset of parietal cortices, we measured mRNAs corresponding to cell types and mitochondrial function and semi-automated stereological assessment was performed on immune-staining of parietal cortex sections. mtDNA showed significant regional variation, highest in parietal cortex, and lowest in cerebellum. Irrespective of cognitive status, all brain regions had significantly higher mtDNA in diabetic cases. In the absence of diabetes, AD parietal cortices had decreased mtDNA, reduced MAP2 (neuronal) and increased GFAP (astrocyte) mRNA, relative to NCI. However, in the presence of diabetes, we did not observe these AD-related changes, suggesting that the pathology observed in diabetic AD may be different to that seen in non-diabetic AD. The lack of clear functional changes in mitochondrial parameters in diabetic AD suggest different cellular mechanisms contributing to cognitive impairment in diabetes which remain to be fully understood.
Abstract.
Author URL.
Whitfield DR, Francis PT, Ballard C, Williams G (2018). Associations between ZnT3, tau pathology, agitation, and delusions in dementia.
Int J Geriatr Psychiatry,
33(8), 1146-1152.
Abstract:
Associations between ZnT3, tau pathology, agitation, and delusions in dementia.
OBJECTIVE: Neuropsychiatric symptoms such as agitation and delusions occur frequently in Lewy body dementia and Alzheimer's disease and represent significant burden and unmet treatment need. The underlying aetiology remains poorly understood. METHODS: We used a multidimensional linear model to look for associations between measurements of agitation, delusions, amyloid, tau and α-synuclein pathology, and synaptic proteins (ZnT3, PSD95, synaptophysin, and β-III-tubulin) across multiple brain regions in post-mortem tissue from a cohort of 130 Lewy body dementia and Alzheimer's disease patients and non-demented controls. RESULTS: We found both agitations and delusions to be significantly associated with increased tau pathology and decreased levels of ZnT3. ZnT3 packages Zn2+ into synaptic vesicles to be released as a long-term modulator of synaptic activity. CONCLUSIONS: Our finding adds to the evidence that zinc modulating compounds are of interest for treatment or symptomatic relief in these dementias.
Abstract.
Author URL.
Francis PT, Costello H, Hayes GM (2018). Brains for Dementia Research: Evolution in a Longitudinal Brain Donation Cohort to Maximize Current and Future Value.
Journal of Alzheimer's Disease,
66(4), 1635-1644.
Abstract:
Brains for Dementia Research: Evolution in a Longitudinal Brain Donation Cohort to Maximize Current and Future Value
Brain banking has a long and distinguished past, contributing greatly to our understanding of human neurological and psychiatric conditions. Brain banks have been operationally diverse, collecting primarily end stage disease, with variable quality clinical data available, yet it is now recognized the most informative brain donations are from those in longitudinally studied cohorts. The Brains for Dementia Research (BDR) cohort and program was for planned brain donation across five UK brain banks and one donation point, with standardized operating procedures, following longitudinal clinical and psychometric assessments for people with no cognitive impairment as well as those with dementia. Lay representatives with experience of dementia were involved from inception of BDR and 74.5% of all enquiries about participation came through routes that were directly attributable to or influenced by lay representatives. Ten years after inception, this ongoing project has received over 700 brain donations from the recruited cohort of 3,276 potential brain donors. At cohort census for this paper, 72.2% of the living cohort have no cognitive impairment by assessment, whereas only 28.3% of the donated cohort were without cognitive impairment. It is important that brain banks are agile and reflect the changing needs of the research community, given that 'big data', readiness cohorts, and GWAS demand large sample numbers of highly characterized individuals to facilitate new approaches and understanding of pathological processes in dementia.
Abstract.
Costello H, Hayes GM, Francis PT (2018). Factors affecting withdrawal and donation attrition in the brains for dementia research cohort.
International Journal of Geriatric Psychiatry,
33(12), 1709-1716.
Abstract:
Factors affecting withdrawal and donation attrition in the brains for dementia research cohort
Objectives: to measure two forms of attrition in a cohort of volunteer brain donors: Withdrawal during life and non-donation at death. To test whether cognitive impairment independently predicts attrition. Method: Attrition rates were calculated for all registered participants and for all brain donors who had completed a baseline and follow-up assessment of cognition, health, and lifestyle. Attrition reasons were described, and attrition rates were compared by gender, age group, and cognitive status. Multivariate logistic regression was used to identify the factors which independently predicted during life and at death. Results: a total of 3276 brain donors registered and 2307 (70.4%) remained in the cohort. Attrition rate overall was 5.9% for withdrawal and 13.8% for donation. Family disagreement and the brain bank not being informed of participant death were the most common reasons for withdrawal and donation attrition. Withdrawal was associated with having cognitive impairment (OR 2.0 95% CI 1.1-3.5), increased age (OR 3.1 95% CI 1.4-6.9), and lower education (OR 1.8 95% CI 1.2-2.8). Participants exhibiting cognitive decline between assessments were more likely to withdraw (OR 4.9 95% CI 1.7-13.6). Participants living alone were almost twice as likely to die without donating (OR 1.9 95% CI 1.1-3.3). Conclusions: Attrition rates were relatively low, and consistent with other studies cognitive impairment, increased age, and less education predicted study withdrawal. Deaths of participants living alone were less likely to result in donation. Tailored, regular retention practices aimed at resolving family disagreement regarding donation decisions are required.
Abstract.
Brookes KJ, McConnell G, Williams K, Chaudhury S, Madhan G, Patel T, Turley C, Guetta-Baranes T, Bras J, Guerreiro R, et al (2018). Genotyping of the Alzheimer's Disease Genome-Wide Association Study Index Single Nucleotide Polymorphisms in the Brains for Dementia Research Cohort.
Journal of Alzheimer's Disease,
64(2), 355-362.
Abstract:
Genotyping of the Alzheimer's Disease Genome-Wide Association Study Index Single Nucleotide Polymorphisms in the Brains for Dementia Research Cohort
The Brains for Dementia Research project is a recently established longitudinal cohort which aims to provide brain tissue for research purposes from neuropathologically defined samples. Here we present the findings from our analysis on the 19 established GWAS index SNPs for Alzheimer's disease, in order to demonstrate if the BDR sample also displays association to these variants. A highly significant association of the APOE ϵ4 allele was identified (p = 3.99×10 -12). Association tests for the 19 GWAS SNPs found that although no SNPs survive multiple testing, nominal significant findings were detected and concordance with the Lambert et al. GWAS meta-analysis was observed.
Abstract.
Creese B, Bell E, Johar I, Francis P, Ballard C, Aarsland D (2018). Glucocerebrosidase mutations and neuropsychiatric phenotypes in Parkinson's disease and Lewy body dementias: Review and meta-analyses.
Am J Med Genet B Neuropsychiatr Genet,
177(2), 232-241.
Abstract:
Glucocerebrosidase mutations and neuropsychiatric phenotypes in Parkinson's disease and Lewy body dementias: Review and meta-analyses.
Heterozygous mutations in glucocerebrosidase gene (GBA) are a major genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Recently, there has been a considerable focus on the relationship between GBA mutations and emergence of cognitive impairment and neuropsychiatric symptoms in these diseases. Here, we review the literature in this area, with a particular focus, including meta-analysis, on the key neuropsychiatric symptoms of cognitive impairment, psychosis, and depression in Parkinson's disease. Our meta-analysis demonstrated that GBA mutations are associated with a 2.4-fold increased risk of cognitive impairment. In addition, our novel meta-analyses of psychosis and depression showed a 1.8- and 2.2-fold increased risk respectively associated with GBA mutations, although due to possible bias and heterogeneity the depression findings should be interpreted with caution. While the precise mechanisms which increase susceptibility to neurodegeneration in GBA carriers are not known, evidence of greater cortical Lewy body pathology, reduced patterns of cortical activation, and hippocampal pathology in animal models are all consistent with a direct effect of GBA mutations on these symptoms. Extension of this work in DLB and individuals without neurodegeneration will be important in further characterizing how GBA mutations increase risk for PD and DLB and influence disease course.
Abstract.
Author URL.
Ferrero H, Larrayoz IM, Martisova E, Solas M, Howlett DR, Francis PT, Gil-Bea FJ, Martínez A, Ramírez MJ (2018). Increased Levels of Brain Adrenomedullin in the Neuropathology of Alzheimer’s Disease.
Molecular Neurobiology,
55(6), 5177-5183.
Abstract:
Increased Levels of Brain Adrenomedullin in the Neuropathology of Alzheimer’s Disease
Alzheimer’s disease (AD) is characterized by the loss of synaptic contacts caused in part by cytoskeleton disruption. Adrenomedullin (AM) is involved in physiological functions such as vasodilation, hormone secretion, antimicrobial activity, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins, causing microtubule destabilization. Here, we describe the relationships between AM and other signs of AD in clinical specimens. Frontal cortex from AD patients and controls were studied for AM, acetylated tubulin, NCAM, Ox-42, and neurotransmitters. AM was increased in AD compared with controls, while levels of acetylated tubulin, NCAM, and neurotransmitters were decreased. Interestingly, increases in AM statistically correlated with the decrease in these markers. Furthermore, Ox42 overexpression in AD correlated with levels of AM. It is proposed that AD patients may have neural cytoskeleton failure associated with increase of AM levels, resulting in axon transport collapse and synaptic loss. These observations suggest that reducing AM expression may constitute a new avenue to prevent/treat AD.
Abstract.
Chappell S, Patel T, Guetta-Baranes T, Sang F, Francis PT, Morgan K, Brookes KJ (2018). Observations of extensive gene expression differences in the cerebellum and potential relevance to Alzheimer's disease.
BMC Research Notes,
11(1).
Abstract:
Observations of extensive gene expression differences in the cerebellum and potential relevance to Alzheimer's disease
Objectives: in order to determine how gene expression is altered in disease it is of fundamental importance that the global distribution of gene expression levels across the disease-free brain are understood and how differences between tissue types might inform tissue choice for investigation of altered expression in disease state. The aim of this pilot project was to use RNA-sequencing to investigate gene expression differences between five general areas of post-mortem human brain (frontal, temporal, occipital, parietal and cerebellum), and in particular changes in gene expression in the cerebellum compared to cortex regions for genes relevant to Alzheimer's disease, as the cerebellum is largely preserved from disease pathology and could be an area of interest for neuroprotective pathways. Results: General gene expression profiles were found to be similar between cortical regions of the brain, however the cerebellum presented a distinct expression profile. Focused exploration of gene expression for genes associated with Alzheimer's disease suggest that those involved in the immunity pathway show little expression in the brain. Furthermore some Alzheimer's disease associated genes display significantly different expression in the cerebellum compared with other brain regions, which might indicate potential neuroprotective measures.
Abstract.
Bereczki E, Branca RM, Francis PT, Pereira JB, Baek JH, Hortobágyi T, Winblad B, Ballard C, Lehtiö J, Aarsland D, et al (2018). Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach.
Brain,
141(2), 582-595.
Abstract:
Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach
See Attems and Jellinger (doi:10.1093/brain/awx360) for a scientific commentary on this article. Cognitive changes occurring throughout the pathogenesis of neurodegenerative diseases are directly linked to synaptic loss. We used in-depth proteomics to compare 32 post-mortem human brains in the prefrontal cortex of prospectively followed patients with Alzheimer's disease, Parkinson's disease with dementia, dementia with Lewy bodies and older adults without dementia. In total, we identified 10 325 proteins, 851 of which were synaptic proteins. Levels of 25 synaptic proteins were significantly altered in the various dementia groups. Significant loss of SNAP47, GAP43, SYBU (syntabulin), LRFN2, SV2C, SYT2 (synaptotagmin 2), GRIA3 and GRIA4 were further validated on a larger cohort comprised of 92 brain samples using ELISA or western blot. Cognitive impairment before death and rate of cognitive decline significantly correlated with loss of SNAP47, SYBU, LRFN2, SV2C and GRIA3 proteins. Besides differentiating Parkinson's disease dementia, dementia with Lewy bodies, and Alzheimer's disease from controls with high sensitivity and specificity, synaptic proteins also reliably discriminated Parkinson's disease dementia from Alzheimer's disease patients. Our results suggest that these particular synaptic proteins have an important predictive and discriminative molecular fingerprint in neurodegenerative diseases and could be a potential target for early disease intervention.
Abstract.
Ghumatkar P, Peshattiwar V, Patil S, Muke S, Whitfield D, Howlett D, Francis P, Sathaye S (2018). The effect of phloretin on synaptic proteins and adult hippocampal neurogenesis in a (1-42)-injected male Wistar rats.
JOURNAL OF PHARMACY AND PHARMACOLOGY,
70(8), 1022-1030.
Author URL.
Hayes G, Costello H, Nurock S, Cornwall A, Francis P (2018). Ticking boxes or meaningful partnership - the experience of lay representation, participant and study partner involvement in Brains for Dementia Research.
DEMENTIA-INTERNATIONAL JOURNAL OF SOCIAL RESEARCH AND PRACTICE,
17(8), 1023-1034.
Author URL.
Patel T, Brookes KJ, Turton J, Chaudhury S, Guetta-Baranes T, Guerreiro R, Bras J, Hernandez D, Singleton A, Francis PT, et al (2018). Whole-exome sequencing of the BDR cohort: evidence to support the role of the PILRA gene in Alzheimer's disease.
Neuropathology and Applied Neurobiology,
44(5), 506-521.
Abstract:
Whole-exome sequencing of the BDR cohort: evidence to support the role of the PILRA gene in Alzheimer's disease
Aim: Late-onset Alzheimer's disease (LOAD) accounts for 95% of all Alzheimer's cases and is genetically complex in nature. Overlapping clinical and neuropathological features between AD, FTD and Parkinson's disease highlight the potential role of genetic pleiotropy across diseases. Recent genome-wide association studies (GWASs) have uncovered 20 new loci for AD risk; however, these exhibit small effect sizes. Using NGS, here we perform association analyses using exome-wide and candidate-gene-driven approaches. Methods: Whole-exome sequencing was performed on 132 AD cases and 53 control samples. Exome-wide single-variant association and gene burden tests were performed for 76 640 nonsingleton variants. Samples were also screened for known causative mutations in familial genes in AD and other dementias. Single-variant association and burden analysis was also carried out on variants in known AD and other neurological dementia genes. Results: Tentative single-variant and burden associations were seen in several genes with kinase and protease activity. Exome-wide burden analysis also revealed significant burden of variants in PILRA (P = 3.4 × 10 −5 ), which has previously been linked to AD via GWAS, hit ZCWPW1. Screening for causative mutations in familial AD and other dementia genes revealed no pathogenic variants. Variants identified in ABCA7, SLC24A4, CD33 and LRRK2 were nominally associated with disease (P
Abstract.
Costello H, Hayes GM, Highton-Williamson E, Nurock S, Hanbury D, Francis PT (2017). A pilot study of potential brain donor satisfaction and attitudes towards telephone assessment.
International Journal of Geriatric Psychiatry,
32(12), 1247-1256.
Abstract:
A pilot study of potential brain donor satisfaction and attitudes towards telephone assessment
Objective: Test the feasibility of assessing cognition, psychiatric symptoms and daily living skills of potential brain donors by telephone and compare satisfaction and attitudes across telephone and face-to-face assessment. Method: Data were collected from 108 healthy participants from the Brains for Dementia Research cohort. Purposive sampling was used to assess feasibility and a randomised control trial design compared satisfaction and attitudes towards telephone and face-to-face assessment. Non-parametric tests were conducted to compare groups, and logistic regression was performed to assess the relationship between satisfaction and participant characteristics. Results: of the 80 participants offered telephone assessment, 67 (83.8%) agreed, 2 (2.5%) had a significant hearing impairment, 4 (5.0%) had potential memory problems and 7 (8.7%) declined. On average, telephone assessments lasted 38 min and duration was negatively associated with Telephone Interview of Cognitive Status-Modified scores (p = 0.001) and positively associated with age (p = 0.040), Neuropsychiatric Inventory scores (p = 0.019), Geriatric Depression Scale (p = 0.035) and Global Deterioration Scale (p = 0.022). Satisfaction was high in respect to organisational and personal aspects; ratings did not differ significantly across telephone and face-to-face assessment groups and were not related to socio-demographic characteristics. Participants undergoing telephone assessment were significantly more likely to hold positive attitudes towards this mode of assessment. Conclusions: Telephone assessment is feasible, time-efficient and acceptable to healthy, potential brain donors. When used with other assessment modes and within the context of established contact, telephone assessment offers greater flexibility to researchers and participants and represents an effective mechanism for overcoming the challenges of growing, ageing cohorts and uncertain resources. Copyright © 2016 John Wiley & Sons, Ltd.
Abstract.
Datta A, Chai YL, Tan JM, Lee JH, Francis PT, Chen CP, Sze SK, Lai MKP (2017). An iTRAQ-based proteomic analysis reveals dysregulation of neocortical synaptopodin in Lewy body dementias.
Molecular brain,
10(1).
Abstract:
An iTRAQ-based proteomic analysis reveals dysregulation of neocortical synaptopodin in Lewy body dementias
Lewy body dementias are the second most common cause of neurodegenerative dementia in the elderly after Alzheimer's disease (AD). The two clinical subgroups of Lewy body dementias, namely, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), are differentiated by the chronology of cognitive symptoms relative to parkinsonism. At present, there remains a debate on whether DLB and PDD are separate disease entities, or fall within the same spectrum of Lewy body dementias. In this study, we compared the detergent-soluble proteome via an 8-plex isobaric tag for relative and absolute quantitation (iTRAQ) analysis of pooled lysates from the prefrontal cortex (BA9) of DLB (n = 19) and PDD (n = 21) patients matched a priori for amyloid (total Aβ42) burden, semi-quantitative scores for Lewy bodies and neurofibrillary tangles together with age-matched control (n = 21) subjects. A total of 1914 proteins were confidently identified by iTRAQ (false discovery rate = 0%). None of the proteins showed a significant yet opposite regulation in between DLB and PDD when compared to aged controls in the proteomic data set as well as following immunoblot analysis of the pooled and individual lysates involving all 61 subjects. The postsynaptic protein, synaptopodin (SYNPO) was significantly down-regulated in both DLB and PDD subgroups, suggesting a defective synaptic transmission in the demented patients. In conclusion, the largely similar proteome of DLB and PDD matched for amyloid burden suggests that variations in concomitant AD-related pathology, abnormal post-translational modifications or protein-protein interactions, defective intracellular trafficking or misfolding of proteins could play a part in driving the clinically observed differences between these two subgroups of Lewy body dementias. This further indicates that amyloid-targeting therapeutic strategies may show different efficacies in DLB versus PDD.
Abstract.
Lanctôt KL, Agüera-Ortiz L, Brodaty H, Francis PT, Geda YE, Ismail Z, Marshall GA, Mortby ME, Onyike CU, Padala PR, et al (2017). Apathy associated with neurocognitive disorders: Recent progress and future directions.
Alzheimer's and Dementia,
13(1), 84-100.
Abstract:
Apathy associated with neurocognitive disorders: Recent progress and future directions
Introduction Apathy is common in neurocognitive disorders (NCDs) such as Alzheimer's disease and mild cognitive impairment. Although the definition of apathy is inconsistent in the literature, apathy is primarily defined as a loss of motivation and decreased interest in daily activities. Methods the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) Neuropsychiatric Syndromes Professional Interest Area (NPS-PIA) Apathy workgroup reviewed the latest research regarding apathy in NCDs. Results Progress has recently been made in three areas relevant to apathy: (1) phenomenology, including the use of diagnostic criteria and novel instruments for measurement, (2) neurobiology, including neuroimaging, neuropathological and biomarker correlates, and (3) interventions, including pharmacologic, nonpharmacologic, and noninvasive neuromodulatory approaches. Discussion Recent progress confirms that apathy has a significant impact on those with major NCD and those with mild NCDs. As such, it is an important target for research and intervention.
Abstract.
Kassaar O, Pereira Morais M, Xu S, Adam EL, Chamberlain RC, Jenkins B, James TD, Francis PT, Ward S, Williams RJ, et al (2017). Corrigendum: Macrophage Migration Inhibitory Factor is subjected to glucose modification and oxidation in Alzheimer's Disease.
Sci Rep,
7 Author URL.
Hussain AA, Lee Y, Zhang JJ, Francis PT, Marshall J (2017). Disturbed Matrix Metalloproteinase Pathway in Both Age-Related Macular Degeneration and Alzheimer's Disease.
Journal of Neurodegenerative Diseases,
2017Abstract:
Disturbed Matrix Metalloproteinase Pathway in Both Age-Related Macular Degeneration and Alzheimer's Disease
Purpose. Abnormal protein deposits including β-amyloid, found in ageing Bruch's membrane and brain, are susceptible to degradation by matrix metalloproteinases (MMPs). In ageing Bruch's membrane, these MMPs become less effective due to polymerisation and aggregation reactions (constituting the MMP Pathway), a situation much advanced in age-related macular degeneration (AMD). The likely presence of this MMP Pathway in brain with the potential to compromise the degradation of β-amyloid associated with Alzheimer's disease (AD) has been investigated. Methods. Presence of high molecular weight MMP species (HMW1 and HMW2) together with the much larger aggregate termed LMMC was determined by standard zymographic techniques. Centrigugation and gel filtration techniques were used to separate and quantify the distribution between bound and free MMP species. Results. The MMP Pathway, initially identified in Bruch's membrane, was also present in brain tissue. The various MMP species displayed bound-free equilibrium and in AD samples, the amount of bound HMW1 and pro-MMP9 species was significantly reduced (p
Abstract.
Gatt A, Ekonomou A, Somani A, Thuret S, Howlett D, Corbett A, Johnson M, Perry E, Attems J, Francis P, et al (2017). Importance of Proactive Treatment of Depression in Lewy Body Dementias: the Impact on Hippocampal Neurogenesis and Cognition in a Post-Mortem Study.
Dement Geriatr Cogn Disord,
44(5-6), 283-293.
Abstract:
Importance of Proactive Treatment of Depression in Lewy Body Dementias: the Impact on Hippocampal Neurogenesis and Cognition in a Post-Mortem Study.
OBJECTIVE: to examine the impact of selective serotonin reuptake inhibitors (SSRIs) and depression on neurogenesis and cognition in dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD). METHODS: Late-stage progenitor cells were quantified in the subgranular zone (SGZ) of the hippocampal dentate gyrus of DLB/PDD patients (n = 41) and controls without dementia (n = 15) and compared between treatment groups (unmedicated, SSRIs, acetyl cholinesterase inhibitors [AChEIs], combined SSRIs and AChEIs). RESULTS: DLB/PDD patients had more doublecortin-positive cells in the SGZ compared to controls. The doublecortin-positive cell count was higher in the SGZ of patients treated with SSRIs and correlated to higher cognitive scores. CONCLUSION: SSRI treatment was associated with increased hippocampal neurogenesis and preservation of cognition in DLB/PDD patients.
Abstract.
Author URL.
Chong JR, Chai YL, Lee JH, Howlett D, Attems J, Ballard CG, Aarsland D, Francis PT, Chen CP, Lai MKP, et al (2017). Increased transforming growth factor β2 in the neocortex of Alzheimer's disease and dementia with lewy bodies is correlated with disease severity and soluble Aβ<inf>42</inf> load.
Journal of Alzheimer's Disease,
56(1), 157-166.
Abstract:
Increased transforming growth factor β2 in the neocortex of Alzheimer's disease and dementia with lewy bodies is correlated with disease severity and soluble Aβ42 load
Background: of the three transforming growth factor (TGF)-β isoforms known, TGFβ1 deficits have been widely reported in Alzheimer's disease (AD) and studied as a potential therapeutic target. In contrast, the status of TGFβ2, which has been shown to mediate amyloid-β (Aβ)-mediated neuronal death, are unclear both in AD and in Lewy body dementias (LBD) with differential neuritic plaque and neurofibrillary tangle burden. Objective: to measure neocortical TGFβ2 levels and their correlations with neuropathological and clinical markers of disease severity in a well-characterized cohort of AD as well as two clinical subtypes of LBD, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), known to manifest relatively high and low Aβ plaque burden, respectively. Methods: Postmortem samples from temporal cortex (BA21) were measured for TGFβ2 using a Luminex-based platform, and correlated with scores for neuritic plaques, neurofibrillary tangles, α-synuclein pathology, dementia severity (as measured by annual decline of Mini-Mental State Examination scores) as well as soluble and total fractions of brain Aβ42. Results: TGFβ2 was significantly increased in AD and DLB, but not in PDD. TGFβ2 also correlated with scores for neurofibrillary tangles, Lewy bodies (within the LBD group), dementia severity, and soluble Aβ42 concentration, but not with neuritic plaque scores, total Aβ42, or monomeric α-synuclein immunoreactivity. Conclusions: TGFβ2 is increased in the temporal cortex of AD and DLB, and its correlations with neuropathological and clinical markers of disease severity as well as with soluble Aβ42 load suggest a potential pathogenic role in mediating the neurotoxicity of non-fibrillar Aβ. Our study also indicates the potential utility of targeting TGFβ2 in pharmacotherapeutic approaches to AD and DLB.
Abstract.
Kassaar O, Morais MP, Xu S, Adam EL, Chamberlain RC, Jenkins B, James T, Francis PT, Ward S, Williams RJ, et al (2017). Macrophage Migration Inhibitory Factor is subjected to glucose modification and oxidation in Alzheimer's Disease.
Scientific Reports,
7Abstract:
Macrophage Migration Inhibitory Factor is subjected to glucose modification and oxidation in Alzheimer's Disease
Glucose and glucose metabolites are able to adversely modify proteins through a non-enzymatic reaction called glycation, which is associated with the pathology of Alzheimer's Disease (AD) and is a characteristic of the hyperglycaemia induced by diabetes. However, the precise protein glycation profile that characterises AD is poorly defined and the molecular link between hyperglycaemia and AD is unknown. In this study, we define an early glycation profile of human brain using fluorescent phenylboronate gel electrophoresis and identify early glycation and oxidation of macrophage migration inhibitory factor (MIF) in AD brain. This modification inhibits MIF enzyme activity and ability to stimulate glial cells. MIF is involved in immune response and insulin regulation, hyperglycaemia, oxidative stress and glycation are all implicated in AD. Our study indicates that glucose modified and oxidised MIF could be a molecular link between hyperglycaemia and the dysregulation of the innate immune system in AD.
Abstract.
Chai YL, Xing H, Chong JR, Francis PT, Ballard CG, Chen CP, Lai MKP (2017). Mitochondrial Translocase of the Outer Membrane Alterations May Underlie Dysfunctional Oxidative Phosphorylation in Alzheimer's Disease.
Journal of Alzheimer's Disease,
61(2), 793-801.
Abstract:
Mitochondrial Translocase of the Outer Membrane Alterations May Underlie Dysfunctional Oxidative Phosphorylation in Alzheimer's Disease
The translocase of the outer membrane (TOM) is a vital mitochondrial transport system facilitating the importation of nuclear encoded proteins into the organelle. While mitochondrial dysfunction, including perturbation of oxidative phosphorylation (OXPHOS) complex, is evident in Alzheimer's disease (AD), it remains unclear whether the observed OXPHOS deficits may be associated with TOM alterations. Objectives: to correlate TOM subunits with OXPHOS complex proteins in AD. Methods: Postmortem neocortex (BA40) fromADand age-matched controls were processed to obtain mitochondrial enriched homogenates for the measurement of Tom20, Tom22, Tom40, and Tom70 as well as components of OXPHOS complex I-V by immunoblotting.Results: Tom20 and Tom70 immunoreactivities were significantly reduced in AD, as were components of OXPHOS complex I and III. Both Tom20 and Tom70 positively correlated with complex III and V, while Tom20 also correlated with complex IV. Conclusion: Reductions in certain TOMsubunits and their correlations with specific OXPHOS complex proteins suggest that an impaired mitochondrial transportation system may contribute to previously observed oxidative phosphorylation deficits in AD. Follow-up studies are needed to corroborate the present correlative study.
Abstract.
Alghamdi A, Vallortigara J, Howlett DR, Broadstock M, Hortobágyi T, Ballard C, Thomas AJ, O'Brien JT, Aarsland D, Attems J, et al (2017). Reduction of RPT6/S8 (a Proteasome Component) and Proteasome Activity in the Cortex is Associated with Cognitive Impairment in Lewy Body Dementia.
J Alzheimers Dis,
57(2), 373-386.
Abstract:
Reduction of RPT6/S8 (a Proteasome Component) and Proteasome Activity in the Cortex is Associated with Cognitive Impairment in Lewy Body Dementia.
Lewy body dementia is the second most common neurodegenerative dementia and is pathologically characterized by α-synuclein positive cytoplasmic inclusions, with varying amounts of amyloid-β (Aβ) and hyperphosphorylated tau (tau) aggregates in addition to synaptic loss. A dysfunctional ubiquitin proteasome system (UPS), the major proteolytic pathway responsible for the clearance of short lived proteins, may be a mediating factor of disease progression and of the development of α-synuclein aggregates. In the present study, protein expression of a key component of the UPS, the RPT6 subunit of the 19S regulatory complex was determined. Furthermore, the main proteolytic-like (chymotrypsin- and PGPH-) activities have also been analyzed. The middle frontal (Brodmann, BA9), inferior parietal (BA40), and anterior cingulate (BA24) gyrus' cortex were selected as regions of interest from Parkinson's disease dementia (PDD, n = 31), dementia with Lewy bodies (DLB, n = 44), Alzheimer's disease (AD, n = 16), and control (n = 24) brains. Clinical and pathological data available included the MMSE score. DLB, PDD, and AD were characterized by significant reductions of RPT6 (one-way ANOVA, p
Abstract.
Author URL.
Ferrero H, Solas M, Francis PT, Ramirez MJ (2017). Serotonin 5-HT<inf>6</inf> Receptor Antagonists in Alzheimer’s Disease: Therapeutic Rationale and Current Development Status.
CNS Drugs,
31(1), 19-32.
Abstract:
Serotonin 5-HT6 Receptor Antagonists in Alzheimer’s Disease: Therapeutic Rationale and Current Development Status
Alzheimer’s disease (AD) is the most common cause of dementia in elderly people. Because of the lack of effective treatments for this illness, research focused on identifying compounds that restore cognition and functional impairments in patients with AD is a very active field. Since its discovery in 1993, the serotonin 5-HT6 receptor has received increasing attention, and a growing number of studies supported 5-HT6 receptor antagonism as a target for improving cognitive dysfunction in AD. This article reviews the rationale behind investigations into the targeting of 5-HT6 receptors as a symptomatic treatment for cognitive and/or behavioral symptoms of AD. In addition to describing the available clinical evidence, this article also describes the purported biochemical and neurochemical mechanisms of action by which 5-HT6 receptor antagonists could influence cognition, and the preclinical data supporting this therapeutic approach to AD. A large number of publications describing the development of ligands for this receptor have come to light and preclinical data indicate the procognitive efficacy of 5-HT6 receptor antagonists. Subsequently, the number of patents protecting 5-HT6 chemical entities has continuously grown. Some of these compounds have successfully undergone phase I clinical studies and have been further evaluated in clinical phase II trials with variable success. Phase II studies have also revealed the potential of combining 5-HT6 receptor antagonism and cholinesterase inhibition. Two of these antagonists, idalopirdine and RVT-101, have been further developed into ongoing phase III clinical trials. Overall, 5-HT6 receptor antagonists can reasonably be regarded as potential drug candidates for the treatment of AD.
Abstract.
Hortobagyi T, Alghamdi A, Vallortigara J, Whitfield D, Howlett D, Broadstock M, Ballard C, Attems J, Aarsland D, Francis PT, et al (2017). [P1–235]: RELATIONSHIP BETWEEN PATHOLOGY SCORES, CLINICAL DATA AND EXPRESSION LEVELS OF PROTEASOME SUB‐UNITS IN ALZHEIMER's DISEASE AND LEWY BODY DEMENTIAS. Alzheimer's & Dementia, 13(7S_Part_7).
Lee JH, Koh SQ, Guadagna S, Francis PT, Esiri MM, Chen CP, Wong PTH, Dawe GS, Lai MKP (2016). Altered relaxin family receptors RXFP1 and RXFP3 in the neocortex of depressed Alzheimer's disease patients.
Psychopharmacology,
233(4), 591-598.
Abstract:
Altered relaxin family receptors RXFP1 and RXFP3 in the neocortex of depressed Alzheimer's disease patients
Rationale: the G-protein-coupled relaxin family receptors RXFP1 and RXFP3 are widely expressed in the cortex and are involved in stress responses and memory and emotional processing. However, the identification of these receptors in human cortex and their status in Alzheimer's disease (AD), which is characterized by both cognitive impairments and neuropsychiatric behaviours, have not been reported. Objectives: in this study, we characterized RXFP receptors for immunoblotting and measured RXFP1 and RXFP3 immunoreactivities in the postmortem neocortex of AD patients longitudinally assessed for depressive symptoms. Methods: RXFP1 and RXFP3 antibodies were characterized by immunoblotting with lysates from transfected HEK cells and preadsorption with RXFP3 peptides. Also, postmortem neocortical tissues from behaviourally assessed AD and age-matched controls were processed for immunoblotting with RXFP1 and RXFP3 antibodies. Results: Compared to controls, putative RXFP1 immunoreactivity was reduced in parietal cortex of non-depressed AD patients but unchanged in depressed patients. Furthermore, putative RXFP3 immunoreactivity was increased only in depressed AD patients. RXFP1 levels in the parietal cortex also correlated with severity of depression symptoms. In contrast, RXFP1 and RXFP3 levels did not correlate with dementia severity or β-amyloid burden. Conclusion: Alterations of RXFP1 and RXFP3 may be neurochemical markers of depression in AD, and relaxin family receptors warrant further preclinical investigations as possible therapeutic targets for neuropsychiatric symptoms in dementia.
Abstract.
Lee C, Low CYB, Francis PT, Attems J, Wong PT-H, Lai MKP, Tan MGK (2016). An isoform-specific role of FynT tyrosine kinase in Alzheimer's disease.
J Neurochem,
136(3), 637-650.
Abstract:
An isoform-specific role of FynT tyrosine kinase in Alzheimer's disease.
Alzheimer's disease (AD) is the leading cause of dementia in old age and is characterized by the accumulation of β-amyloid plaques and neurofibrillary tangles (NFT). Recent studies suggest that Fyn tyrosine kinase forms part of a toxic triad with β-amyloid and tau in the disease process. However, it is not known whether Fyn is associated with the pathological features of AD in an isoform-specific manner. In this study, we identified selective up-regulation of the alternative-spliced FynT isoform with no change in FynB in the AD neocortex. Furthermore, gene ontology term enrichment analyses and cell type-specific localization of FynT immunoreactivity suggest that FynT up-regulation was associated with neurofibrillary degeneration and reactive astrogliosis. Interestingly, significantly increased FynT in NFT-bearing neurons was concomitant to decreased FynB immunoreactivity, suggesting an involvement of alternative splicing in NFT formation. Furthermore, cultured cells of astrocytic origin have higher FynT to FynB ratio compared to those of neuronal origin. Lastly, primary rat mixed neuron-astrocyte cultures treated with Aβ25-35 showed selective up-regulation of FynT expression in activated astrocytes. Our findings point to an isoform-specific role of FynT in modulating neurofibrillary degeneration and reactive astrogliosis in AD. Fyn kinase is known to interact with β-amyloid and tau, and contributes to Alzheimer's disease pathogenesis. In this study, it is shown that the alternatively spliced FynT isoform is specifically up-regulated in the AD neocortex, with no change in FynB isoform. The increased FynT correlated with markers of neurofibrillary degeneration and reactive astrogliosis. In primary mixed cultures, treatment with amyloid peptides specifically up-regulated FynT in activated astrocytes. This study points to altered alternative splicing as a potential pathogenic mechanism in AD.
Abstract.
Author URL.
Vallortigara J, Whitfield D, Quelch W, Alghamdi A, Howlett D, Hortobágyi T, Johnson M, Attems J, O'Brien JT, Thomas A, et al (2016). Decreased Levels of VAMP2 and Monomeric Alpha-Synuclein Correlate with Duration of Dementia.
Journal of Alzheimer's Disease,
50(1), 101-110.
Abstract:
Decreased Levels of VAMP2 and Monomeric Alpha-Synuclein Correlate with Duration of Dementia
Alpha-synuclein (β-syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), but are also frequently present in Alzheimer's disease (AD). Much remains unknown about the role of β-syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key 'SNAP (Soluble N-ethylmaleimide Sensitive Factor Attachment Protein) Receptor' (SNARE) proteins as a consequence of alterations in the aggregation state of β-syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition.We have studied a large cohort (n = 130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric β-syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p < 0.001). This correlated to the final MMSE score before death (p = 0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p = 0.0004) and monomeric β-syn (p = 0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological β-syn.
Abstract.
Gatt AP, Duncan OF, Attems J, Francis PT, Ballard CG, Bateman JM (2016). Dementia in Parkinson's disease is associated with enhanced mitochondrial complex I deficiency.
Movement Disorders,
31(3), 352-359.
Abstract:
Dementia in Parkinson's disease is associated with enhanced mitochondrial complex I deficiency
Background: Dementia is a common feature of Parkinson's disease (PD), but the neuropathological changes associated with the development of Parkinson's disease dementia (PDD) are only partially understood. Mitochondrial dysfunction is a hallmark of PD but has not been studied in PDD. Methods: Molecular and biochemical approaches were used to study mitochondrial activity and quantity in postmortem prefrontal cortex tissue. Tissues from pathologically confirmed PD and PDD patients and from age-matched controls were used to analyze the activity of mitochondrial enzyme complex nicotinamide adenine dinucleotide:ubiquinone oxidoreductase, or complex I (the first enzyme in the mitochondrial respiratory chain), mitochondrial DNA levels, and the expression of mitochondrial proteins. Results: Complex I activity was significantly decreased (27% reduction; analysis of variance with Tukey's post hoc test; P
Abstract.
Xing H, Lim YA, Chong JR, Lee JH, Aarsland D, Ballard CG, Francis PT, Chen CP, Lai MKP (2016). Increased phosphorylation of collapsin response mediator protein-2 at Thr514 correlates with β-amyloid burden and synaptic deficits in Lewy body dementias.
Molecular Brain,
9(1).
Abstract:
Increased phosphorylation of collapsin response mediator protein-2 at Thr514 correlates with β-amyloid burden and synaptic deficits in Lewy body dementias
Collapsin response mediator protein-2 (CRMP2) regulates axonal growth cone extension, and increased CRMP2 phosphorylation may lead to axonal degeneration. Axonal and synaptic pathology is an important feature of Lewy body dementias (LBD), but the state of CRMP2 phosphorylation (pCRMP2) as well as its correlations with markers of neurodegeneration have not been studied in these dementias. Hence, we measured CRMP2 phosphorylation at Thr509, Thr514 and Ser522, as well as markers of β-amyloid (Aβ), tau-phosphorylation, α-synuclein and synaptic function in the postmortem neocortex of a longitudinally assessed cohort of LBD patients characterized by low (Parkinson's disease dementia, PDD) and high (dementia with Lewy bodies, DLB) burden of Alzheimer type pathology. We found specific increases of pCRMP2 at Thr514 in DLB, but not PDD. The increased CRMP2 phosphorylation correlated with fibrillogenic Aβ as well as with losses of markers for axon regeneration (β-III-tubulin) and synaptic integrity (synaptophysin) in LBD. In contrast, pCRMP2 alterations did not correlate with tau-phosphorylation or α-synuclein, and also appear unrelated to immunoreactivities of putative upstream kinases glycogen synthase kinase 3β and cyclin-dependent kinase 5, as well as to protein phosphatase 2A. In conclusion, increased pCRMP2 may underlie the axonal pathology of DLB, and may be a novel therapeutic target. However, antecedent signaling events as well as the nature of pCRMP2 association with Aβ and other neuropathologic markers require further study.
Abstract.
Lee JH, Francis PT, Ballard CG, Aarsland D, Kalaria RN, Wong PTH, Chen CP, Lai MKP (2016). Muscarinic M1 Receptor Coupling to G-protein is Intact in Parkinson's Disease Dementia.
Journal of Parkinson's Disease,
6(4), 733-739.
Abstract:
Muscarinic M1 Receptor Coupling to G-protein is Intact in Parkinson's Disease Dementia
Background: Postsynaptic cholinergic deficits, including reduced cortical muscarinic M1 receptor coupling to G-proteins, are neurochemical findings postulated to underlie the limited efficacy of presynaptically-targeted cholinergic replacement therapies in Alzheimer's disease (AD). While the loss of M1-G-protein coupling has been associated with β-amyloid (Aβ) burden in AD, the status of M1 coupling to G-proteins in Parkinson's disease-related or mixed dementias is unclear. Objective: to test the hypothesis that M1 receptor uncoupling is correlated with Aβ burden, we aimed to study muscarinic M1 neurochemical parameters in neurodegenerative dementias characterized by low and high Aβ loads. Methods: M1 receptors, M1 coupling to G-proteins as well as Aβ were measured in postmortem frontal cortex of a cohort of longitudinally assessed patients with Parkinson's Disease Dementia (PDD, low Aβ load) and AD with significant subcortical cerebrovascular disease (AD CVD, high Aβ load). Results: We found unchanged levels of M1 receptors in both dementia groups, while M1 coupling was reduced only in AD CVD (p
Abstract.
Tajeddinn W, Persson T, Calvo-Garrido J, Ahmed MS, Maioli S, Vijayaraghavan S, Kazokoglu MS, Parrado-Fernandez C, Yoshitake T, Kehr J, et al (2016). Pharmacological Modulations of the Serotonergic System in a Cell-Model of Familial Alzheimer's Disease.
JOURNAL OF ALZHEIMERS DISEASE,
53(1), 349-361.
Author URL.
Bereczki E, Francis PT, Howlett D, Pereira JB, Höglund K, Bogstedt A, Cedazo-Minguez A, Baek JH, Hortobágyi T, Attems J, et al (2016). Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia.
Alzheimer's and Dementia,
12(11), 1149-1158.
Abstract:
Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia
Introduction Our objective was to compare the levels of three synaptic proteins involved in different steps of the synaptic transmission: Rab3A, SNAP25, and neurogranin, in three common forms of dementia: Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia. Methods a total of 129 postmortem human brain samples were analyzed in brain regional specific manner exploring their associations with morphologic changes and cognitive decline. Results We have observed robust changes reflecting synaptic dysfunction in all studied dementia groups. There were significant associations between the rate of cognitive decline and decreased levels of Rab3 in DLB in the inferior parietal lobe and SNAP25 in AD in the prefrontal cortex. of particular note, synaptic proteins significantly discriminated between dementia cases and controls with over 90% sensitivity and specificity. Discussion Our findings suggest that the proposition that synaptic markers can predict cognitive decline in AD, should be extended to Lewy body diseases.
Abstract.
Baek JH, Whitfield D, Howlett D, Francis P, Bereczki E, Ballard C, Hortobágyi T, Attems J, Aarsland D (2016). Unfolded protein response is activated in Lewy body dementias.
Neuropathology and Applied Neurobiology,
42(4), 352-365.
Abstract:
Unfolded protein response is activated in Lewy body dementias
Aim: the unfolded protein response (UPR) is a pro-survival defence mechanism induced during periods of endoplasmic reticulum stress, and it has recently emerged as an attractive therapeutic target across a number of neurodegenerative conditions, but has not yet been studied in synuclein disorders. Methods: the level of a key mediator of the UPR pathway, glucose-regulated protein 78 (GRP78), also known as binding immunoglobulin protein (BiP), was measured in post mortem brain tissue of patients with dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) in comparison with Alzheimer's disease (AD) and age-matched controls using Western blot. The UPR activation was further confirmed by immunohistochemical detection of GRP78/BiP and phosphorylated protein kinase RNA-like endoplasmic reticulum (ER) kinase (p-PERK). Results: GRP78/BiP was increased to a greater extent in DLB and PDD patients compared with AD and control subjects in cingulate gyrus and parietal cortex. However, there were no changes in the prefrontal and temporal cortices. There was a significant positive correlation between GRP78/BiP level and α-synuclein pathology in the cingulate gyrus, while AD-type pathology showed an inverse correlation relationship in the parietal cortex. Conclusion: Overall, these results give emphasis to the role of UPR in Lewy body dementias, and suggest that Lewy body degeneration, in combination with AD-type pathologies, is associated with increased UPR activation to a greater extent than AD alone, possibly as a consequence of the increasing load of ER proteins. This work also highlights a novel opportunity to explore the UPR as a therapeutic target in synuclein diseases.
Abstract.
Tajeddinn W, Persson T, Maioli S, Calvo-Garrido J, Parrado-Fernandez C, Yoshitake T, Kehr J, Francis P, Winblad B, Hoglund K, et al (2015). 5-HT1B and other related serotonergic proteins are altered in APPswe mutation.
NEUROSCIENCE LETTERS,
594, 137-143.
Author URL.
Whitfield DR, Vallortigara J, Alghamdi A, Hortobágyi T, Ballard C, Thomas AJ, O'Brien JT, Aarsland D, Francis PT (2015). Depression and synaptic zinc regulation in alzheimer disease, dementia with lewy bodies, and parkinson disease dementia.
American Journal of Geriatric Psychiatry,
23(2), 141-148.
Abstract:
Depression and synaptic zinc regulation in alzheimer disease, dementia with lewy bodies, and parkinson disease dementia
Objective Depression is a common symptom in dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), and Alzheimer disease (AD), yet its molecular basis remains unclear and current antidepressants do not appear to be effective. Cerebral zinc has been implicated in depression and synaptic dysfunction. We investigated the relationship between synaptic zinc regulation (for which zinc transporter 3 [ZnT3] is responsible) and depression in a large clinicopathologic study. Methods We examined brains from people with PDD (N = 29), DLB (N = 27), and AD (N = 15) and comparison subjects without depression or dementia (N = 24). Individuals were categorized according to the presence and severity of depression (on a scale of 0-3) based on standardized assessments during life (principally Neuropsychiatric Inventory). Western blotting was used to determine ZnT3 levels in Brodmann area 9 (BA9), and regression analysis was used to determine the relationship between ZnT3 and depression. Results Reductions in ZnT3 in BA9 were significantly associated with elevated depression scores in the study cohort (β = -0.351, df = 93, t = -3.318 p = 0.0004). This association remained when only individuals with DLB, PDD, and no dementia or depression were examined (β = -0.347, df = 78, t = -3.271, p = 0.002) or only individuals with AD and no dementia or depression were examined (β = -0.433, df = 37, t = -2.924, p = 0.006). Conclusion Although decreased zinc levels have been implicated in the genesis of depression in animal models and in major depressive disorder in humans, this study provides the first evidence of a role for zinc in depression in people with dementia and highlights zinc metabolism as a therapeutic target.
Abstract.
Cox CJ, Choudhry F, Peacey E, Perkinton MS, Richardson JC, Howlett DR, Lichtenthaler SF, Francis PT, Williams RJ (2015). Dietary (-)-epicatechin as a potent inhibitor of βγ-secretase amyloid precursor protein processing.
Neurobiol Aging,
36(1), 178-187.
Abstract:
Dietary (-)-epicatechin as a potent inhibitor of βγ-secretase amyloid precursor protein processing.
Flavonoids, a group of dietary polyphenols have been shown to possess cognitive health benefits. Epidemiologic evidence suggests that they could play a role in risk reduction in dementia. Amyloid precursor protein processing and the subsequent generation of amyloid beta (Aβ) are central to the pathogenesis of Alzheimer's disease, as soluble, oligomeric Aβ is thought to be the toxic species driving disease progression. We undertook an in vitro screen to identify flavonoids with bioactivity at βγ-mediated amyloid precursor protein processing, which lead to identification of a number of flavonoids bioactive at 100 nM. Because of known bioavailability, we investigated the catechin family further and identified epigallocatechin and (-)-epicatechin as potent (nanomolar) inhibitors of amyloidogenic processing. Supporting this finding, we have shown reduced Aβ pathology and Aβ levels following short term, a 21-day oral delivery of (-)-epicatechin in 7-month-old TASTPM mice. Further, in vitro mechanistic studies suggest this is likely because of indirect BACE1 inhibition. Taken together, our results suggest that orally delivered (-)-epicatechin may be a potential prophylactic for Alzheimer's disease.
Abstract.
Author URL.
Mohamed N-E, Lee JH, Francis PT, Esiri MM, Chen CP, Lai MKP (2015). Differential alterations of neocortical GluN receptor subunits in patients with mixed subcortical ischemic vascular dementia and Alzheimer's disease.
J Alzheimers Dis,
44(2), 431-437.
Abstract:
Differential alterations of neocortical GluN receptor subunits in patients with mixed subcortical ischemic vascular dementia and Alzheimer's disease.
BACKGROUND: Glutamatergic deficits are well-established neurochemical findings in Alzheimer's disease (AD) and are thought to underlie both cognitive and behavioral symptoms of the disease. However, it is unclear whether subcortical ischemic vascular dementia (SIVD) and mixed SIVD/AD (MixD) manifest similar changes in the glutamatergic system. OBJECTIVE: to measure the immunoreactivities of NMDA receptor GluN1, GluN2A, and GluN2B subunits in SIVD and MixD. METHODS: Postmortem neocortical tissues from a cohort of well-characterized, longitudinally followed-up patients with SIVD and MixD, together with age-matched controls, were processed for immunoblotting with GluN subunit-specific antibodies. RESULTS: There was a significant reduction of GluN1 only in MixD, while significant increases of GluN2A and GluN2B were found only in SIVD. Furthermore, GluN1 loss and GluN2A/2B upregulation was associated respectively with higher Braak stages and lacunar infarct scores. CONCLUSIONS: Our data suggest that the differential alterations of GluN subunits in SIVD and MixD may result from separate, interacting disease processes, and point to the potential utility of glutamatergic approaches for pharmacotherapy.
Abstract.
Author URL.
Howlett DR, Whitfield D, Johnson M, Attems J, O'Brien JT, Aarsland D, Lai MKP, Lee JH, Chen C, Ballard C, et al (2015). Regional Multiple Pathology Scores Are Associated with Cognitive Decline in Lewy Body Dementias.
Brain Pathology,
25(4), 401-408.
Abstract:
Regional Multiple Pathology Scores Are Associated with Cognitive Decline in Lewy Body Dementias
Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by the presence of α-synuclein-containing Lewy bodies and Lewy neurites. However, both dementias also show variable degrees of Alzheimer's disease (AD) pathology (senile plaques and neurofibrillary tangles), particularly in areas of the cortex associated with higher cognitive functions. This study investigates the contribution of the individual and combined pathologies in determining the rate of cognitive decline. Cortical α-synuclein, phosphorylated tau (phosphotau) and Aβ plaque pathology in 34 PDD and 55 DLB patients was assessed semi-quantitatively in four regions of the neocortex. The decline in cognition, assessed by Mini Mental State Examination, correlated positively with the cortical α-synuclein load. Patients also had varying degrees of senile Aβ plaque and phosphotau pathology. Regression analyses pointed to a combined pathology (Aβ plaque plus phosphotau plus α-synuclein-positive features), particularly in the prefrontal cortex (BA9) and temporal lobe neocortex with the superior and middle temporal gyrus (BA21, 22), being a major determining factor in the development of dementia. Thus, cognitive decline in Lewy body dementias is not a consequence of α-synuclein-induced neurodegeneration alone but senile plaque and phosphorylated tau pathology also contribute to the overall deficits.
Abstract.
Howlett DR, Attems J, Francis PT (2015). Spreading pathologies precede cognitive decline in Alzheimer's disease.
Biol Psychiatry,
77(8), 678-679.
Author URL.
Ekonomou A, Savva GM, Brayne C, Forster G, Francis PT, Johnson M, Perry EK, Attems J, Somani A, Minger SL, et al (2015). Stage-specific changes in neurogenic and glial markers in Alzheimer's disease.
Biological Psychiatry,
77(8), 711-719.
Abstract:
Stage-specific changes in neurogenic and glial markers in Alzheimer's disease
BACKGROUND: Reports of altered endogenous neurogenesis in people with Alzheimer's disease (AD) and transgenic AD models have suggested that endogenous neurogenesis may be an important treatment target, but there is considerable discrepancy among studies. We examined endogenous neurogenesis and glia changes across the range of pathologic severity of AD in people with and without dementia to address this key question. METHODS: Endogenous neurogenesis and glia in the subventricular zone and dentate gyrus neurogenic niches were evaluated using single and double immunohistochemistry and a validated antibody selection for stage-specific and type-specific markers in autopsy tissue from a representative cohort of 28 participants in the Medical Research Council Cognitive Function and Ageing Study. Immunopositive cells were measured blinded to diagnosis using bright-field and fluorescent microscopy. RESULTS: the number of newly generated neurons significantly declined only in the dentate gyrus of patients with severe tau pathology. No other changes in other neurogenic markers were observed in either of the neurogenic niches. Alterations in astrocytes and microglia were also observed in the dentate gyrus across the different stages of tau pathology. No change in any of the markers was observed in individuals who died with dementia compared with individuals who did not die with dementia. CONCLUSIONS: Alterations in endogenous neurogenesis appeared to be confined to a reduction in the generation of new neurons in the dentate gyrus of patients with AD and severe neurofibrillary tangle pathology and were accompanied by changes in the glia load. These data suggest that intervention enhancing endogenous neurogenesis may be a potential therapeutic target in AD.
Abstract.
Whitfield DR, Vallortigara J, Alghamdi A, Howlett D, Hortobágyi T, Johnson M, Attems J, Newhouse S, Ballard C, Thomas AJ, et al (2014). Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer's disease: Association with cognitive impairment.
Neurobiology of Aging,
35(12), 2836-2844.
Abstract:
Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer's disease: Association with cognitive impairment
The loss of zinc transporter 3 (ZnT3) has been implicated in age-related cognitive decline in mice, and the protein has been associated with plaques. We investigated the levels of ZnT3 and postsynaptic density protein 95 (PSD95), a marker of the postsynaptic terminal, in people with Parkinson's disease dementia (PDD, n= 31), dementia with Lewy bodies (DLB, n= 44), Alzheimer's disease (AD, n= 16), and controls (n= 24), using semiquantitative western blotting and immunohistochemistry in 3 cortical regions. Standardized cognitive assessments during life and semiquantitative scoring of amyloid β (Aβ), tau, and α-synuclein at postmortem were used to investigate the relationship between ZnT3 and PSD95, cognition and pathology. Associations were observed between ZnT3 and PSD95 levels in prefrontal cortex and cognitive impairment (p= 0.001 and p= 0.002, respectively) and between ZnT3 levels in the parietal cortex and cognitive impairment (p= 0.036). Associations were also seen between ZnT3 levels in cingulate cortex and severity of Aβ (p= 0.003) and tau (p= 0.011) pathologies. DLB and PDD were characterized by significant reductions of PSD95 (p < 0.05) and ZnT3 (p < 0.001) in prefrontal cortex compared with controls and AD. PSD95 levels in the parietal cortex were found to be decreased in AD cases compared with controls (p= 0.02) and PDD (p= 0.005). This study has identified Zn2+ modulation as a possible novel target for the treatment of cognitive impairment in DLB and PDD and the potential for synaptic proteins to be used as a biomarker for the differentiation of DLB and PDD from AD.
Abstract.
Gatt AP, Jones EL, Francis PT, Ballard C, Bateman JM (2014). Corrigendum to Association of a polymorphism in mitochondrial transcription factor a (TFAM) with Parkinson's disease dementia but not dementia with Lewy bodies [Neurosci. Lett. 557, (2013), 177-180]. Neuroscience Letters, 563
Mohamed NE, Howlett DR, Ma L, Francis PT, Aarsland D, Ballard CG, McKeith IG, Chen CP, Lai MKP (2014). Decreased immunoreactivities of neocortical AMPA receptor subunits correlate with motor disability in Lewy body dementias.
Journal of Neural Transmission,
121(1), 71-78.
Abstract:
Decreased immunoreactivities of neocortical AMPA receptor subunits correlate with motor disability in Lewy body dementias
Dementia with Lewy bodies and Parkinson's disease dementia are different clinical phenotypes of Lewy body dementias differentiated by the temporal relationship between parkinsonism and dementia onset. At present, it is unclear whether the glutamatergic system is affected in these disorders. In this study, we measured α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA subunits in the postmortem neocortex of a cohort of prospectively studied Lewy body dementia cases, as well as age-matched controls by immunoblotting. We found losses of GluA2/3/4 immunoreactivities in Lewy body dementias which correlated with higher pre-death Hoehn and Yahr scores and with longer Parkinson's disease duration before dementia onset, but not with dementia severity, cortical Lewy body burden, or amyloid plaque and neurofibrillary tangle burden. Our study suggests that GluA2/3/4 losses may be a neurochemical marker of motor disability in Lewy body dementias. © 2013 Springer-Verlag Wien.
Abstract.
Tan MGK, Lee C, Lee JH, Francis PT, Williams RJ, Ramírez MJ, Chen CP, Wong PT-H, Lai MKP (2014). Decreased rabphilin 3A immunoreactivity in Alzheimer's disease is associated with Aβ burden.
Neurochem Int,
64, 29-36.
Abstract:
Decreased rabphilin 3A immunoreactivity in Alzheimer's disease is associated with Aβ burden.
Synaptic dysfunction, together with neuritic plaques, neurofibrillary tangles and cholinergic neuron loss is an established finding in the Alzheimer's disease (AD) neocortex. The synaptopathology of AD is known to involve both pre- and postsynaptic components. However, the status of rabphilin 3A (RPH3A), which interacts with the SNARE complex and regulates synaptic vesicle exocytosis and Ca(2+)-triggered neurotransmitter release, is at present unclear. In this study, we measured RPH3A and its ligand Rab3A as well as several SNARE proteins in postmortem neocortex of patients with AD, and found specific reductions of RPH3A immunoreactivity compared with aged controls. RPH3A loss correlated with dementia severity, cholinergic deafferentation, and increased β-amyloid (Aβ) concentrations. Furthermore, RPH3A expression is selectively downregulated in cultured neurons treated with Aβ25-35 peptides. Our data suggest that presynaptic SNARE dysfunction forms part of the synaptopathology of AD.
Abstract.
Author URL.
Mulugeta E, Vallortigara J, Francis PT, Hye A, Kalaria RN, Perry EK, Lovestone S, Ballard CG (2014). Dynamin protein in stroke and vascular dementia.
Neuroscience Letters,
563, 118-122.
Abstract:
Dynamin protein in stroke and vascular dementia
Damage to sub-cortical white matter is a key substrate of vascular dementia (VaD) leading to deficits in executive function and cognitive processing speed. Dynamin1 is a 100. kDa protein, accounting for 0.4% of the total brain protein, and has a central role in many intracellular processes such as synaptic vesicle trafficking and recycling. In this study, we examined the status of Dynamin1 in the white matter from frontal cortex area. In order to measure the levels of Dynamin1, we isolated cortical white matter from a total of 34 post-mortem brains derived from controls (N= 11), mixed Alzheimer's disease (AD) and VaD (N= 8), VaD (N= 7), and stroke no dementia (SND, N= 8) subjects. A commercial ELISA kit was then used to determine the level of Dynamin1. In comparison to controls, Dynamin1 was elevated in patients SND (+400%) and reduced in patients with mixed VaD (-50%). Furthermore, levels of Dynamin1 were significantly associated with preserved cognition as indicated by the MMSE and CAMCOG and upregulation of vesicular glutamate transporter 1. This work indicates that Dynamin1 is associated with both preserved cognition and regenerative responses in older people with cerebrovascular disease and may represent a novel treatment target. © 2014.
Abstract.
Vallortigara J, Rangarajan S, Whitfield D, Alghamdi A, Howlett D, Hortobágyi T, Johnson M, Attems J, Ballard C, Thomas A, et al (2014). Dynamin1 concentration in the prefrontal cortex is associated with cognitive impairment in Lewy body dementia.
F1000Research,
3Abstract:
Dynamin1 concentration in the prefrontal cortex is associated with cognitive impairment in Lewy body dementia
Dementia with Lewy Bodies (DLB) and Parkinson's Disease Dementia (PDD) together, represent the second most common cause of dementia, after Alzheimer's disease (AD). The synaptic dysfunctions underlying the cognitive decline and psychiatric symptoms observed throughout the development of PDD and DLB are still under investigation. In this study we examined the expression level of Dynamin1 and phospho-CaMKII, key proteins of endocytosis and synaptic plasticity respectively, as potential markers of molecular processes specifically deregulated with DLB and/or PDD. In order to measure the levels of these proteins, we isolated grey matter from post-mortem prefrontal cortex area (BA9), anterior cingulated gyrus (BA24) and parietal cortex (BA40) from DLB and PDD patients in comparison to age-matched controls and a group of AD cases. Clinical and pathological data available included the MMSE score, neuropsychiatric history, and semi-quantitative scores for AD pathology (plaques - tangles) and for α-synuclein (Lewy bodies). Changes in the expression of the synaptic markers, and correlates with neuropathological features and cognitive decline were predominantly found in the prefrontal cortex. On one hand, levels of Dynamin1 were significantly reduced, and correlated with a higher rate of cognitive decline observed in cases from three dementia groups. On the other hand, the fraction of phospho-CaMKII was decreased, and correlated with a high score of plaques and tangles in BA9. Interestingly, the correlation between the rate of cognitive decline and the level of Dynamin1 remained when the analysis was restricted to the PDD and DLB cases, highlighting an association of Dynamin1 with cognitive decline in people with Lewy Body dementia.
Abstract.
Ballard C, Aarsland D, Francis P, Corbett A (2014). Erratum to: Neuropsychiatric symptoms in patients with dementias associated with cortical Lewy bodies: Pathophysiology, clinical features, and pharmacological management (Drugs Aging (2013) 30, (603-611) DOI: 10.1007/s40266-013-0092-x). Drugs and Aging, 31(8).
Datta A, Qian J, Chong R, Kalaria RN, Francis P, Lai MKP, Chen CP, Sze SK (2014). Novel pathophysiological markers are revealed by iTRAQ-based quantitative clinical proteomics approach in vascular dementia.
JOURNAL OF PROTEOMICS,
99, 54-67.
Author URL.
Ballard C, Francis P, Corbett A (2014). Randomized controlled trial of mibampator for behavioral and psychological symptoms of dementia: comments on the trial and thoughts for future studies - ADDENDUM.
Int Psychogeriatr Author URL.
Ramirez MJ, Lai MKP, Tordera RM, Francis PT (2014). Serotonergic therapies for cognitive symptoms in Alzheimer's disease: rationale and current status.
Drugs,
74(7), 729-736.
Abstract:
Serotonergic therapies for cognitive symptoms in Alzheimer's disease: rationale and current status.
Alzheimer's disease (AD) is the most common cause of dementia in elderly people. Research focused on identifying compounds that restore cognition and memory in AD patients is a very active investigational pursuit. Cholinesterase inhibitors for the symptomatic treatment of cognitive decline in AD have been in use for more than a decade but provide only modest benefits in most patients. Preclinical research is constantly providing new information on AD. The involvement of the serotonergic system in higher cognitive processes such as memory and learning has been widely described and extensive serotonergic denervation has been reported in AD. This review aims to explain the rationale behind testing serotonergic therapies for AD in terms of current knowledge about the pathophysiology of the disease. Based on preclinical studies, certain serotonin (5-HT) receptor ligands have been suggested to have the ability to modify or improve memory/cognition, specifically 5-HT receptors acting at 5-HT1A, 5-HT4 and 5-HT6 receptors. This article summarizes the pharmacology, efficacy, safety and tolerability data for the various serotonergic agents currently in clinical development for AD.
Abstract.
Author URL.
Gatt AP, Jones EL, Francis PT, Ballard C, Bateman JM (2013). Association of a polymorphism in mitochondrial transcription factor a (TFAM) with Parkinson's disease dementia but not dementia with Lewy bodies.
Neuroscience Letters,
557(PB), 177-180.
Abstract:
Association of a polymorphism in mitochondrial transcription factor a (TFAM) with Parkinson's disease dementia but not dementia with Lewy bodies
The single nucleotide polymorphism (SNP) a > G rs2306604 in the gene encoding mitochondrial transcription factor a (TFAM) has been associated with Alzheimer's disease, with the a allele being recognised as a risk factor, but has not been studied in other types of dementia. We hypothesised that TFAM SNP rs2306604 might also be associated with Lewy body dementias. To test this hypothesis rs2306604 genotype was determined in 141 controls and 135 patients with dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD). rs2306604 genotype frequencies were significantly different to controls in PDD (p = 0.042), but not in DLB (p = 0.529). The a allele was also associated with PDD (p = 0.024, OR = 2.092), but not DLB (p = 0.429, OR = 1.308). Moreover, the a allele was strongly associated with PDD in males (p = 0.001, OR = 5.570), but not in females (p = 0.832, OR = 1.100). Mitochondrial DNA copy number in the prefrontal cortex was also significantly reduced in PDD patients, but this reduction was not associated with rs2306604 genotype. These data show that the TFAM SNP rs2306604 a allele may be a risk factor for PDD, particularly in males, but not for DLB. Therefore, the genetic factors that predispose individuals to develop dementia may differ in PDD and DLB. © 2013 Elsevier Ireland Ltd.
Abstract.
Solas M, Francis PT, Franco R, Ramirez MJ (2013). CB2 receptor and amyloid pathology in frontal cortex of Alzheimer's disease patients.
Neurobiol Aging,
34(3), 805-808.
Abstract:
CB2 receptor and amyloid pathology in frontal cortex of Alzheimer's disease patients.
The cannabinoid system seems to play an important role in various neurodegenerative diseases including Alzheimer's disease (AD). The relationship of cannabinoid receptors (CB(1)R and CB(2)R) to cognitive function and neuropathological markers in AD remains unclear. In the present study, postmortem cortical brain tissues (Brodmann area 10) from a cohort of neuropathologically confirmed AD patients and age-matched controls were used to measure CB(1)R and CB(2)R by immunoblotting. Correlational analyses were performed for the neurochemical and cognitive data. CB(1)R expression was significantly decreased in AD. Levels of CB(1)R correlated with hypophagia, but not with any AD molecular marker or cognitive status (Mini Mental State Examination score). The level of CB(2)R was significantly higher (40%) in AD. Increases in the expression of the glial marker glial fibrillar acidic protein were also found. CB(2)R expression did not correlate with cognitive status. Interestingly, expression levels of CB(2)R correlated with two relevant AD molecular markers, Aβ(42) levels and senile plaque score. These results may constitute the basis of CB(2)R-based therapies and/or diagnostic approaches.
Abstract.
Author URL.
Howlett DR, Hortobágyi T, Francis PT (2013). Clusterin associates specifically with Aβ40 in Alzheimer's disease brain tissue.
Brain Pathol,
23(6), 623-632.
Abstract:
Clusterin associates specifically with Aβ40 in Alzheimer's disease brain tissue.
Genome-wide association studies have pointed to clusterin (apolipoprotein J) as being linked to the occurrence of Alzheimer's disease (AD); studies have identified the protein as a possible biomarker. The association between clusterin and senile plaques in AD brain is well known, and clusterin levels in AD brain are 40% higher than that in control subjects. The present study investigates, immunohistochemically, the association between clusterin and Aβ peptides in AD and control cortex. A unique and specific association between clusterin and Aβ40 was observed in plaques in the cerebral cortex from AD subjects in that only plaques that contained Aβ40 showed clusterin immunoreactivity, while the many plaques with Aβ42 alone lacked clusterin labeling. Cerebrovascular Aβ in AD brain generally lacked Aβ42 but was positively labeled by both the Aβ40 and the clusterin antibodies. In control subjects, however, Aβ40 was absent from plaques, although very occasional plaques were found to be labeled by both the Aβ42 and the clusterin antibodies. Overall, in AD, but not aged control brain, clusterin was associated specifically with the Aβ40 form of Aβ in the brain. The lack of clusterin in association with Aβ42 may be a significant feature in neuronal loss and neurodegeneration in the disease state.
Abstract.
Author URL.
Bajic N, Jenner P, Ballard CG, Francis PT (2013). Erratum: Proteasome inhibition leads to early loss of synaptic proteins in neuronal culture (Journal of Neural Transmission (2012) 119 (1467-1476) DOI:10.1007/s00702-012-0816-9). Journal of Neural Transmission, 120(7).
Ballard C, Aarsland D, Francis P, Corbett A (2013). Neuropsychiatric Symptoms in Patients with Dementias Associated with Cortical Lewy Bodies: Pathophysiology, Clinical Features, and Pharmacological Management. Drugs & Aging, 30(8), 603-611.
Geda YE, Schneider LS, Gitlin LN, Miller DS, Smith GS, Bell J, Evans J, Lee M, Porsteinsson A, Lanctôt KL, et al (2013). Neuropsychiatric symptoms in Alzheimer's disease: Past progress and anticipation of the future.
Alzheimer's and Dementia,
9(5), 602-608.
Abstract:
Neuropsychiatric symptoms in Alzheimer's disease: Past progress and anticipation of the future
Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer's first case, Frau Auguste D. presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer's Association convened a research roundtable on the topic of NPS in AD. A major outcome of the roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer's Research and Treatment (ISTAART). The NPS-PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome-specific synthetic reviews and recommendations prepared by NPS-PIA workgroups on depression, apathy, sleep, agitation, and psychosis. © 2013 the Alzheimer¢s Association. All rights reserved.
Abstract.
Ballard C, Francis P, Corbett A (2013). Randomized controlled trial of mibampator for behavioral and psychological symptoms of dementia: comments on the trial and thoughts for future studies.
International Psychogeriatrics,
25(5), 687-689.
Abstract:
Randomized controlled trial of mibampator for behavioral and psychological symptoms of dementia: comments on the trial and thoughts for future studies
Behavioral and psychological symptoms of dementia (BPSD) frequently arise in people with Alzheimer's disease (AD) and other dementias. They cause significant distress and confer risk to the person and others, in addition to presenting a complex clinical challenge for treatment (Ballard et al. 2009b). There is good evidence for the value of first-line management strategies such as psychological interventions and treatment of concurrent medical conditions, particularly pain, which are known to be effective (Ballard et al. 2009b). However, there are limited pharmacological treatment options for severe aggression, which causes significant risk, and for other severe BPSD which do not respond to first-line approaches. The only pharmacological intervention with an adequate evidence base is the prescription of atypical antipsychotics, where 18 placebo-controlled trials have evaluated the effect of treatment over 6–12 weeks. The literature indicates modest but significant benefits in the treatment of aggression and psychosis with risperidone and aripiprazole (Cohen's d standardized effect size of 0.2), uncertain benefits with olanzapine, and no benefits with quetiapine (Ballard and Howard, 2006; Schneider et al. 2006a; Ballard et al. 2009b; Corbett et al. 2012). Unfortunately, the benefits of longer term prescribing are more limited (Schneider et al. 2006b; Ballard et al. 2008) and there have been increasing concerns regarding the potential for serious adverse outcomes, including accelerated cognitive decline, stroke, and death (Schneider et al. 2006b; Ballard et al. 2009a). There is therefore an urgent imperative to identify more effective pharmacological treatments for severe BPSD which have a better safety profile, particularly for long-term treatment and prophylaxis. Despite this urgency, there has been very little effort toward developing or evaluating potential novel therapies for the treatment of key symptoms such as aggression, psychosis, restlessness, and apathy.
Abstract.
Corbett A, Francis P, Ballard C (2013). Safety and efficacy of memantine extended-release in the management of alzheimer's disease.
Clinical Medicine Insights: Therapeutics,
5, 95-102.
Abstract:
Safety and efficacy of memantine extended-release in the management of alzheimer's disease
Alzheimer's disease (AD) affects the majority of the 35 million people with dementia worldwide. Four pharmacological treatment options are available for this patient group, of which memantine is licensed for treatment of people with moderate to severe stages of the condition. Memantine acts through its function as an NMDA-glutamate receptor blocker and has an established safety profile. The evidence supporting its efficacy in people with AD includes a number of large randomized clinical trials showing benefit to cognition, function, and overall clinical outcome. Additional favorable health economics analyses have confirmed the clinical and cost-effectiveness of this drug. More recently an extended-release formulation has been developed. This review outlines the key evidence base supporting memantine as a treatment for moderate to severe AD, in addition to discussing the conditions under which it may provide additional value in combination with other drugs. The review also discusses the use of memantine to address behavioral and psychological symptoms of dementia (BPSD) arising in people with AD and the limited evidence around its use in AD in people with Down's syndrome. Finally the review considers the potential value of the extended release formulation in AD. © the author(s), publisher and licensee Libertas Academica Ltd.
Abstract.
Vagnoni A, Perkinton MS, Gray EH, Francis PT, Noble W, Miller CCJ (2012). Calsyntenin-1 mediates axonal transport of the amyloid precursor protein and regulates Aβ production.
Hum Mol Genet,
21(13), 2845-2854.
Abstract:
Calsyntenin-1 mediates axonal transport of the amyloid precursor protein and regulates Aβ production.
Understanding the mechanisms that control processing of the amyloid precursor protein (APP) to produce amyloid-β (Aβ) peptide represents a key area of Alzheimer's disease research. Here, we show that siRNA-mediated loss of calsyntenin-1 in cultured neurons alters APP processing to increase production of Aβ. We also show that calsyntenin-1 is reduced in Alzheimer's disease brains and that the extent of this reduction correlates with increased Aβ levels. Calsyntenin-1 is a ligand for kinesin-1 light chains and APP is transported through axons on kinesin-1 molecular motors. Defects in axonal transport are an early pathological feature in Alzheimer's disease and defective APP transport is known to increase Aβ production. We show that calsyntenin-1 and APP are co-transported through axons and that siRNA-induced loss of calsyntenin-1 markedly disrupts axonal transport of APP. Thus, perturbation to axonal transport of APP on calsyntenin-1 containing carriers induces alterations to APP processing that increase production of Aβ. Together, our findings suggest that disruption of calsyntenin-1-associated axonal transport of APP is a pathogenic mechanism in Alzheimer's disease.
Abstract.
Author URL.
Hanney M, Prasher V, Williams N, Jones EL, Aarsland D, Corbett A, Lawrence D, Yu L-M, Tyrer S, Francis PT, et al (2012). Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial.
LANCET,
379(9815), 528-536.
Author URL.
Guadagna S, Bundgaard C, Hovelsø N, Volbracht C, Francis PT, Egebjerg J, Sotty F (2012). Memantine potentiates hippocampal θ oscillations at a therapeutic dose in anesthetized mice: a mechanistic link to its cognitive-enhancing properties.
Neuropharmacology,
62(7), 2208-2218.
Abstract:
Memantine potentiates hippocampal θ oscillations at a therapeutic dose in anesthetized mice: a mechanistic link to its cognitive-enhancing properties.
Memantine is an uncompetitive, low-affinity NMDA receptor antagonist clinically used for the treatment of cognitive deficits in moderate to severe Alzheimer's disease. Both neurophysiological and behavioral studies in rodents have suggested a beneficial effect of memantine on synaptic plasticity and learning performances. In the present study, we investigated the effect of memantine on pedonculopontine-elicited theta oscillations in the hippocampus of urethane anesthetized mice, a model shown to be sensitive to several pharmacological agents exhibiting cognitive-enhancing properties. We found that a low dose of memantine potentiated elicited theta power while a high dose was disruptive. The low dose of memantine used was shown to yield an unbound brain concentration well within the range of therapeutic concentrations reported in rodent brain extracellular fluid and human cerebrospinal fluid. For further comparison, the effect of another uncompetitive NMDA receptor antagonist with higher affinity, i.e. MK-801, was also investigated. MK-801 was at a low dose devoid of effect on elicited theta power, while a high dose, within the range of doses reported to induce cognitive deficits in a variety of hippocampal-dependent learning paradigms in mice, was found disruptive on elicited theta waves. Taken together, our results suggest that clinically relevant doses of memantine promote neuronal network synchronization in the hippocampus, which may represent an underlying mechanism for the reported cognitive-enhancing properties in both preclinical and clinical studies.
Abstract.
Author URL.
Choudhry F, Howlett DR, Richardson JC, Francis PT, Williams RJ (2012). Pro-oxidant diet enhances β/γ secretase-mediated APP processing in APP/PS1 transgenic mice.
Neurobiol Aging,
33(5), 960-968.
Abstract:
Pro-oxidant diet enhances β/γ secretase-mediated APP processing in APP/PS1 transgenic mice.
The etiology of Alzheimer's disease (AD) is complex with oxidative stress being a possible contributory factor to pathogenesis and disease progression. TASTPM transgenic mice expressing familial AD-associated amyloid precursor protein (APPswe) and presenilin transgenes (PS1M146V) show increased brain amyloid beta (Aβ) levels and Aβ plaques from 3 months. We tested if enhancing oxidative stress through diet would accelerate Aβ-related pathology. TASTPM were fed a pro-oxidant diet for 3 months resulting in increased brain levels of protein carbonyls, increased Nrf2, and elevated concentrations of glutathione (GSH). The diet increased both amyloid precursor protein (APP) and Aβ in the cortex of TASTPM but did not alter Aβ plaque load, presenilin 1, or β-secretase (BACE1) expression. TASTPM cortical neurons were cultured under similar pro-oxidant conditions resulting in increased levels of APP and Aβ likely as a result of enhanced β/γ secretase processing of APP. Thus, pro-oxidant conditions increase APP levels and enhance BACE1-mediated APP processing and in doing so might contribute to pathogenesis in AD.
Abstract.
Author URL.
Bajic N, Jenner P, Ballard CG, Francis PT (2012). Proteasome inhibition leads to early loss of synaptic proteins in neuronal culture.
Journal of Neural Transmission,
119(12), 1467-1476.
Abstract:
Proteasome inhibition leads to early loss of synaptic proteins in neuronal culture
A dysfunctional ubiquitin proteasome system may be a mediating factor of disease progression in Lewy body dementia (LBD). The effects of proteasome inhibition using lactacystin and epoxomicin in primary neuronal culture were studied to assess the validity of this model to reflect the cortical pathology of LBD. Treatment of primary cortical neurons with 5 μM lactacystin for 24 h led to a 38 % reduction in the levels of β-III-tubulin (p < 0.05), a 48 % reduction in the levels of synaptophysin (p < 0.05) and a 74 % reduction in the levels of drebrin (p < 0.01), when compared to controls. Results for epoxomicin were similar. The loss of neuronal protein occurred prior to any loss of mitochondrial activity or cell death. The results are reflective of the loss of synapses and the synaptic changes observed in LBD, which may be an early event in the neurodegeneration of LBD. The similarities with the pathological changes in LBD highlight the possibility that this model can potentially provide a platform to test novel treatments. © 2012 Springer-Verlag.
Abstract.
Francis PT, Parsons CG, Jones RW (2012). Rationale for combining glutamatergic and cholinergic approaches in the symptomatic treatment of Alzheimer's disease.
Expert Rev Neurother,
12(11), 1351-1365.
Abstract:
Rationale for combining glutamatergic and cholinergic approaches in the symptomatic treatment of Alzheimer's disease.
A total of 40 years of biochemical, clinical and neuropathological research have revolutionized our understanding of the pathophysiology of Alzheimer's disease, yet at the present moment the only drugs licensed for treatment are targeted essentially at symptoms. Some disease-modifying drugs remain in clinical trials, but many that have used similar approaches have failed. It is therefore of considerable interest to examine the optimal way of using existing medications for the benefit of patients. This article looks at the rationale behind the combined use of acetylcholinesterase inhibitors and the N-methyl-D-aspartate-receptor antagonist, memantine, from both preclinical and clinical perspectives.
Abstract.
Author URL.
Broadstock M, Lewinsky R, Jones EL, Mitchelmore C, Howlett DR, Francis PT (2012). Synaptic protein expression is regulated by a pro-oxidant diet in APPxPS1 mice.
J Neural Transm (Vienna),
119(4), 493-496.
Abstract:
Synaptic protein expression is regulated by a pro-oxidant diet in APPxPS1 mice.
Dietary factors may play a role in Alzheimer's disease (AD) pathogenesis. In an effort to recapitulate some of the synaptic protein changes observed in the disease, AD transgenic and wild-type mice were fed either a normal or pro-oxidant diet for 3 months from three months of age. Pro-oxidant diet treatment resulted in altered expression of vesicular glutamate transporter-1 and glutamine synthetase, suggesting changes in glutamatergic synaptic function, and increased expression of urokinase plasminogen activator receptor, possibly reflecting oxidative stress.
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Author URL.
Guadagna S, Esiri MM, Williams RJ, Francis PT (2012). Tau phosphorylation in human brain: relationship to behavioral disturbance in dementia.
Neurobiol Aging,
33(12), 2798-2806.
Abstract:
Tau phosphorylation in human brain: relationship to behavioral disturbance in dementia.
Agitation and aggressive behavior are common symptoms of Alzheimer's disease (AD), and tangle density in frontal cortex is a possible regional substrate of these behaviors. To investigate this further, 16 AD patients, 8 patients with non-AD dementia, and 13 age-matched control subjects for frontal cortex and, respectively, 21, 7, and 6 patients for parietal cortex were analyzed for tau and phospho-tau by enzyme-linked immunosorbent assay (ELISA). Agitation/aggression was determined by the Present Behavioural Examination. In a subset of cases, glycogen synthase kinase-3β (GSK-3β) phosphorylation and protein phosphatase 2A (PP2A) expression were measured. Phospho-tau and the phospho-tau/total tau ratio were elevated in AD in both cortical regions. In keeping with our hypothesis, the phospho-tau/total tau ratio was elevated in the frontal cortex of those patients with agitation/aggression during life, and there was a significant correlation (p = 0.024) between these behaviors and the phospho-tau/total tau ratio in the cortex. PP2A expression was lower (p < 0.01) in the frontal cortex of patients with high tau phosphorylation. This study confirms a link between tau phosphorylation and agitation/aggression and suggests that reducing tau phosphorylation may provide symptomatic relief.
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Author URL.
Burns A, Perry E, Holmes C, Francis P, Morris J, Howes MJR, Chazot P, Lees G, Ballard C (2011). A double-blind placebo-controlled randomized trial of melissa officinalis oil and donepezil for the treatment of agitation in Alzheimer's disease.
Dementia and Geriatric Cognitive Disorders,
31(2), 158-164.
Abstract:
A double-blind placebo-controlled randomized trial of melissa officinalis oil and donepezil for the treatment of agitation in Alzheimer's disease
Background/Aims: Behavioural and psychological symptoms (BPSD) are frequent in people with Alzheimer's disease and cause considerable stress to patients and their carers. Antipsychotics have been widely used as a first-line treatment, resulting in an estimated 1,800 excess strokes and 1,600 excess deaths in the UK alone. Safe and effective alternatives are urgently needed. Based upon preliminary evidence from clinical trials, aromatherapy with melissa oil may be such an alternative, but initial studies have been modest in size, and adequate blinding has been problematic. Our objective was to assess the efficacy of melissa aromatherapy in the treatment of agitation in people with Alzheimer's disease in an adequately powered and robustly blinded randomized controlled trial comparing it with donepezil, an anticholinesterase drug used with some benefit to treat BPSD. Methods and Findings: the study was a double-blind parallel-group placebo-controlled randomized trial across 3 specialist old age psychiatry centres in England. Participants had probable or possible Alzheimer's disease, were resident in a care home, had clinically significant agitation (defined as a score of 39 or above on the Cohen Mansfield Agitation Inventory) and were free of antipsychotics and/or anticholinesterase for at least 2 weeks. Participants were allocated to 1 of 3 groups: placebo medication and active aromatherapy; active medication and placebo aromatherapy or placebo of both. Main Outcome: the primary outcome measure was reduction in agitation as assessed by the Pittsburgh Agitation Scale (PAS) at 4 weeks. This is an observational scale, and raters were required to wear nose clips to ensure that full blinding was maintained. The PAS, Neuropsychiatric Inventory (NPI; another measure of BPSD) and other outcome measures were completed at baseline, 4-week and 12-week follow-ups. 114 participants were randomized, of whom 94 completed the week 4 assessment and 81 completed the week 12 assessment. Aromatherapy and donepezil were well tolerated. There were no significant differences between aromatherapy, donepezil and placebo at week 4 and week 12, but importantly there were substantial improvements in all 3 groups with an 18% improvement in the PAS and a 37% improvement in the NPI over 12 weeks. Conclusion: When assessed using a rigorous design which ensures blinding of treatment arms, there is no evidence that melissa aromatherapy is superior to placebo or donepezil, in the treatment of agitation in people with Alzheimer's disease. However, the sizeable improvement in the placebo group emphasizes the potential non-specific benefits of touch and interaction in the treatment of agitation in people with Alzheimer's disease. Copyright © 2011 S. Karger AG, Basel.
Abstract.
Clarke NA, Hartmann T, Jones EL, Ballard CG, Francis PT (2011). Antipsychotic medication is associated with selective alterations in ventricular cerebrospinal fluid Aβ 40 and tau in patients with intractable unipolar depression.
International Journal of Geriatric Psychiatry,
26(12), 1283-1291.
Abstract:
Antipsychotic medication is associated with selective alterations in ventricular cerebrospinal fluid Aβ 40 and tau in patients with intractable unipolar depression
Objective Alterations in plasma and in lumbar cerebrospinal fluid amyloid-B peptide (Aβ) levels have been reported in Alzheimer's disease. Studies have also suggested similar changes in depressed patients. No information is available on the impact of psychotropic drugs on this in patients with depression. We therefore quantified Aβ in ventricular cerebrospinal fluid (CSF) in a population of patients with treatment-resistant depression, with and without antipsychotic medication. Method a cross-sectional study of 32 patients undergoing subcaudate tractotomy for major (unipolar) depressive disorder. Ventricular CSF concentrations of Aβ peptide 1-40 and 1-42, also p-tau and total tau were determined by Western blotting or enzyme-linked immunosorbent assay. Results Patients taking antipsychotic medication in the 2 weeks prior to surgery demonstrated significantly higher levels of Aβ 1-40 (mean ± SD: 727.3 ± 382.3 vs. 440.9 ± 337.2 pg/ml; p = 0.032, Student's t-test) but unaltered Aβ 1-42 (mean 72.1 ± 67.5 vs. 60.0 ± 56.7 pg/ml; p = 0.587) compared to a matched sample not treated with antipsychotic drugs. The same group demonstrated elevated total tau (mean 945.0 ± 422.2 vs. 534.3 ± 388.3 pg/ml; p = 0.010) but not p-tau (mean 98.6 ± 71.5 vs. 88.1 ± 70.5 pg/ml; p = 0.694). No similar effect was found with lithium, antidepressants, carbamazepine or benzodiazepines. Conclusions This preliminary study suggests antipsychotic drugs, widely used in patients with severe depression across all age ranges, may be associated with alteration of Aβ 1-40 and total tau, indices strongly linked with progressive organic brain disease. Further confirmatory work is needed. Copyright © 2011 John Wiley & Sons, Ltd.
Abstract.
Kooi E-J, Prins M, Bajic N, Beliën JAM, Gerritsen WH, van Horssen J, Aronica E, van Dam A-M, Hoozemans JJM, Francis PT, et al (2011). Cholinergic imbalance in the multiple sclerosis hippocampus.
Acta Neuropathol,
122(3), 313-322.
Abstract:
Cholinergic imbalance in the multiple sclerosis hippocampus.
Hippocampal pathology was shown to be extensive in multiple sclerosis (MS) and is associated with memory impairment. In this post-mortem study, we investigated hippocampal tissue from MS and Alzheimer's disease (AD) patients and compared these to non-neurological controls. By means of biochemical assessment, (immuno)histochemistry and western blot analyses, we detected substantial alterations in the cholinergic neurotransmitter system in the MS hippocampus, which were different from those in AD hippocampus. In MS hippocampus, activity and protein expression of choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme, was decreased, while the activity and protein expression of acetylcholinesterase (AChE), the acetylcholine degrading enzyme, was found to be unaltered. In contrast, in AD hippocampus both ChAT and AChE enzyme activity and protein expression was decreased. Our findings reveal an MS-specific cholinergic imbalance in the hippocampus, which may be instrumental in terms of future treatment options for memory problems in this disease.
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Author URL.
Palmer AM, Sims NR, Francis PT (2011). David Bowen, 1940-2011 OBITUARY.
JOURNAL OF NEUROCHEMISTRY,
119(5), 1151-1153.
Author URL.
Lai MKP, Tsang SW, Esiri MM, Francis PT, Wong PT-H, Chen CP (2011). Differential involvement of hippocampal serotonin1A receptors and re-uptake sites in non-cognitive behaviors of Alzheimer's disease.
Psychopharmacology (Berl),
213(2-3), 431-439.
Abstract:
Differential involvement of hippocampal serotonin1A receptors and re-uptake sites in non-cognitive behaviors of Alzheimer's disease.
RATIONALE: Previous studies have shown extensive serotonergic deficits in the hippocampus of Alzheimer's disease (AD) patients. However, it is unclear whether such deficits play a role in non-cognitive, neuropsychiatric behaviors that occur frequently in AD and cause significant caregiver distress. OBJECTIVES: in this study, we aimed to correlate serotonergic markers in the AD hippocampus with neuropsychiatric behaviors. METHODS: Using postmortem hippocampal homogenates from aged controls as well as a cohort of longitudinally assessed AD patients, measurements of 5-HT(1A) receptors, 5-HT(2A) receptors, and serotonin re-uptake (5-HTT) sites were performed by binding with (3)H-labeled 8-OH-DPAT, ketanserin, and citalopram, respectively. RESULTS: Alterations of 5-HT(1A) receptors and 5-HTT were found to be differentially involved in neuropsychiatric behaviors, with loss of 5-HT(1A) receptors specifically correlated with depressive symptoms, while 5-HTT sites were preserved or up-regulated in patients with aggressive behaviors. CONCLUSIONS: Our data suggest that neuropsychiatric behaviors in AD share certain neurochemical features with psychiatric disorders like major depression and that serotonergic drugs used in psychiatric disorders may also be efficacious against behavioral symptoms in AD.
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Author URL.
Jones EL, Kalaria RN, Sharp SI, O'Brien JT, Francis PT, Ballard CG (2011). Genetic associations of autopsy-confirmed vascular dementia subtypes.
Dementia and Geriatric Cognitive Disorders,
31(4), 247-253.
Abstract:
Genetic associations of autopsy-confirmed vascular dementia subtypes
Background/Aims: Genetic risk factors have not been clearly established for vascular dementias (VaD) related to stroke and cerebrovascular disease. Methods: Samples were genotyped for APOE, MTHFR and ICAM. Aβ levels and choline acetyltransferase (ChAT) activities were assayed in controls and individuals with VaD. Results: Associations were found between the APOE-ε4 allele and mixed dementia, infarct/stroke dementia and subcortical ischemic vascular dementia (SIVD), and higher Aβ1-42 levels and decreased ChAT activity. MTHFR was more associated with SIVD, mixed dementia, and lower ChAT activity. Conclusions: the study demonstrates important differences in the genetic associations of VaD and begins to clarify the genetic basis of key pathological substrates. Copyright © 2011 S. Karger AG, Basel.
Abstract.
Öhrfelt A, Zetterberg H, Andersson K, Persson R, Secic D, Brinkmalm G, Wallin A, Mulugeta E, Francis PT, Vanmechelen E, et al (2011). Identification of novel α-synuclein isoforms in human brain tissue by using an online NanoLC-ESI-FTICR-MS method.
Neurochemical Research,
36(11), 2029-2042.
Abstract:
Identification of novel α-synuclein isoforms in human brain tissue by using an online NanoLC-ESI-FTICR-MS method
Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are neurodegenerative diseases that are characterized by intra-neuronal inclusions of Lewy bodies in distinct brain regions. These inclusions consist mainly of aggregated α-synuclein (α-syn) protein. The present study used immunoprecipitation combined with nanoflow liquid chromatography (LC) coupled to high resolution electrospray ionization Fourier transform ion cyclotron resonance tandem mass spectrometry (ESI-FTICR-MS/MS) to determine known and novel isoforms of α-syn in brain tissue homogenates. N-terminally acetylated full-length α-syn (Ac-α-syn 1-140) and two N-terminally acetylated C-terminally truncated forms of α-syn (Ac-α-syn 1-139 and Ac-α-syn 1-103) were found. The different forms of α-syn were further studied by Western blotting in brain tissue homogenates from the temporal cortex Brodmann area 36 (BA36) and the dorsolateral prefrontal cortex BA9 derived from controls, patients with DLB and PD with dementia (PDD). Quantification of α-syn in each brain tissue fraction was performed using a novel enzyme-linked immunosorbent assay (ELISA). © 2011 the Author(s).
Abstract.
Gaeta A, Molina-Holgado F, Kong XL, Salvage S, Fakih S, Francis PT, Williams RJ, Hider RC (2011). Synthesis, physical-chemical characterisation and biological evaluation of novel 2-amido-3-hydroxypyridin-4(1H)-ones: Iron chelators with the potential for treating Alzheimer's disease.
Bioorg Med Chem,
19(3), 1285-1297.
Abstract:
Synthesis, physical-chemical characterisation and biological evaluation of novel 2-amido-3-hydroxypyridin-4(1H)-ones: Iron chelators with the potential for treating Alzheimer's disease.
A novel class of 2-amido-3-hydroxypyridin-4-one iron chelators is described. These compounds have been designed to behave as suitable molecular probes which will improve our knowledge of the role of iron in neurodegenerative conditions. Neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson disease (PD), can be considered as diverse pathological conditions sharing critical metabolic processes such as protein aggregation and oxidative stress. Interestingly, both these metabolic alterations seem to be associated with the involvement of metal ions, including iron. Iron chelation is therefore a potential therapeutic approach. The physico-chemical (pK(a), pFe(3+) and logP) and biological properties (inhibition of iron-containing enzymes) of these chelators have been investigated in order to obtain a suitable profile for the treatment of neurodegenerative conditions. Studies with neuronal cell cultures confirm that the new iron chelators are neuroprotective against β-amyloid-induced toxicity.
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Author URL.
Tsang SW, Keene J, Hope T, Spence I, Francis PT, Wong PT-H, Chen CP, Lai MK (2010). A serotoninergic basis for hyperphagic eating changes in Alzheimer's disease.
J Neurol Sci,
288(1-2), 151-155.
Abstract:
A serotoninergic basis for hyperphagic eating changes in Alzheimer's disease.
Hyperphagia and associated eating changes occur frequently in Alzheimer's disease (AD) and lead to considerable morbidity. However, the neurochemical basis for these neuropsychiatric behaviours is at present unclear. In this study, we measured serotonin transporters, 5-HT(1A), 5-HT(2A), and 5-HT(4) receptors using radioligand binding assays in the postmortem temporal cortex of a cohort of controls and AD patients longitudinally assessed for hyperphagia. We found significant decreases in 5-HT(4) receptor densities in the hyperphagic, but not normophagic, AD group. Our data suggest that 5-HT(4) receptor deficits may be a specific neurochemical correlate of hyperphagia, and point to the potential pharmacotherapeutic utility of 5-HT(4) agonists for these behaviours in AD.
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Author URL.
Aisa B, Gil-Bea FJ, Solas M, García-Alloza M, Chen CP, Lai MK, Francis PT, Ramírez MJ (2010). Altered NCAM expression associated with the cholinergic system in Alzheimer's disease.
J Alzheimers Dis,
20(2), 659-668.
Abstract:
Altered NCAM expression associated with the cholinergic system in Alzheimer's disease.
Neurotransmitter system dysfunction and synapse loss have been recognized as hallmarks of Alzheimer's disease (AD). Our hypothesis is that specific neurochemical populations of neurons might be more vulnerable to degeneration in AD due to particular deficits in synaptic plasticity. We have studied, in postmortem brain tissue, the relationship between levels of synaptic markers (NCAM and BDNF), neurochemical measurements (cholinacetyltransferase activity, serotonin, dopamine, GABA, and glutamate levels), and clinical data (cognitive status measured as MMSE score). NCAM levels in frontal and temporal cortex from AD patients were significantly lower than control patients. Interestingly, these reductions in NCAM levels were associated to an ApoE4 genotype. Levels of BDNF were also significantly reduced in both frontal and temporal regions in AD patients. The ratio between plasticity markers and neurochemical measurements was used to study which of the neurochemical populations was particularly associated to plasticity changes. In both the frontal and temporal cortex, there was a significant reduction in the ChAT/NCAM ratio in AD samples compared to controls. None of the ratios to BDNF were different between control and AD samples. Furthermore, Pearson's product moment showed a significant positive correlation between MMSE score and the ChAT/NCAM ratio in frontal cortex (n=19; r=0.526*; p=0.037) as well as in temporal cortex (n=19; r=0.601*; p=0.018) in AD patients. Altogether, these data suggest a potential involvement of NCAM expressing neurons in the cognitive deficits in AD.
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Author URL.
Thambisetty M, Simmons A, Velayudhan L, Hye A, Campbell J, Zhang Y, Wahlund L-O, Westman E, Kinsey A, Güntert A, et al (2010). Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease.
Arch Gen Psychiatry,
67(7), 739-748.
Abstract:
Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease.
CONTEXT: Blood-based analytes may be indicators of pathological processes in Alzheimer disease (AD). OBJECTIVE: to identify plasma proteins associated with AD pathology using a combined proteomic and neuroimaging approach. DESIGN: Discovery-phase proteomics to identify plasma proteins associated with correlates of AD pathology. Confirmation and validation using immunodetection in a replication set and an animal model. SETTING: a multicenter European study (AddNeuroMed) and the Baltimore Longitudinal Study of Aging. PARTICIPANTS: Patients with AD, subjects with mild cognitive impairment, and healthy controls with standardized clinical assessments and structural neuroimaging. MAIN OUTCOME MEASURES: Association of plasma proteins with brain atrophy, disease severity, and rate of clinical progression. Extension studies in humans and transgenic mice tested the association between plasma proteins and brain amyloid. RESULTS: Clusterin/apolipoprotein J was associated with atrophy of the entorhinal cortex, baseline disease severity, and rapid clinical progression in AD. Increased plasma concentration of clusterin was predictive of greater fibrillar amyloid-beta burden in the medial temporal lobe. Subjects with AD had increased clusterin messenger RNA in blood, but there was no effect of single-nucleotide polymorphisms in the gene encoding clusterin with gene or protein expression. APP/PS1 transgenic mice showed increased plasma clusterin, age-dependent increase in brain clusterin, as well as amyloid and clusterin colocalization in plaques. CONCLUSIONS: These results demonstrate an important role of clusterin in the pathogenesis of AD and suggest that alterations in amyloid chaperone proteins may be a biologically relevant peripheral signature of AD.
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Author URL.
Lee JH, Agacinski G, Williams JH, Wilcock GK, Esiri MM, Francis PT, Wong PT-H, Chen CP, Lai MKP (2010). Intact cannabinoid CB1 receptors in the Alzheimer's disease cortex.
Neurochem Int,
57(8), 985-989.
Abstract:
Intact cannabinoid CB1 receptors in the Alzheimer's disease cortex.
The cannabinoid CB1 receptor has gained much attention as a potential pharmacotherapeutic target in various neurodegenerative diseases including Alzheimer's disease (AD). However, the relation of CB1 receptors to cognitive function in AD is at present unclear. In this study, postmortem brain tissues from a cohort of prospectively assessed, neuropathologically confirmed AD patients and aged controls were used to measure CB1 receptors by immunoblotting, and a subset of subjects also had [(3)H]SR141716A binding. Correlational analyses were then performed for the neurochemical and cognitive data. We found that CB1 receptor levels in were unchanged AD in the brain regions assessed (frontal cortex, anterior cingulate gyrus, hippocampus, caudate nucleus). Within the AD group, frontal cortical CB1 immunoreactivity correlated with cognitive scores assessed within a year of death. Our study suggests that CB1 receptors are intact in AD and may play a role in preserving cognitive function. Therefore, CB1 receptors should be further assessed as a potential therapeutic target in AD.
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Author URL.
Francis PT, Ramírez MJ, Lai MK (2010). Neurochemical basis for symptomatic treatment of Alzheimer's disease.
Neuropharmacology,
59(4-5), 221-229.
Abstract:
Neurochemical basis for symptomatic treatment of Alzheimer's disease.
Neuron and synapse loss together with neurotransmitter dysfunction have, along with Abeta deposition and neurofibrillary tangles, been recognized as hallmarks of Alzheimer's disease (AD). Furthermore, clinical and preclinical studies point to neuronal loss and associated neurochemical alterations of several transmitter systems as a main factor underlying both cognitive and neuropsychiatric symptoms. Treatment for the cognitive decline in AD, based on early findings of a cholinergic deficit, has been in the clinic for more than a decade but provides only modest benefit in most patients. Therefore there is still considerable scope for new treatments that demonstrate greater efficacy against cognitive dysfunction in spite of the fact that the mainstays of current treatments, the cholinesterase inhibitors Aricept, Exelon and Reminyl (Razadyne) will become generic over the next few years. However, the most important area for drug development is for the treatment of behavioural disturbance in AD since many existing treatments have limited efficacy and have potentially life-threatening side effects. This review examines the neurochemical underpinning of both cognitive and neuropsychiatric symptoms in dementia and provides some basis for rational drug development.
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Author URL.
Ash ES, Alavijeh MS, Palmer AM, Mitchelmore C, Howlett DR, Francis PT, Broadstock M, Richardson JC (2010). Neurochemical changes in a double transgenic mouse model of Alzheimer's disease fed a pro-oxidant diet.
Neurochem Int,
57(5), 504-511.
Abstract:
Neurochemical changes in a double transgenic mouse model of Alzheimer's disease fed a pro-oxidant diet.
Oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD) causing neurodegeneration and decreased monoamine neurotransmitters. We investigated the effect of administration of a pro-oxidant diet on the levels of monoamines and metabolites in the brains of wildtype and transgenic mice expressing mutant APP and PS-1 (TASTPM mice). Three-month-old TASTPM and wildtype (C57BL6/J) mice were fed either normal or pro-oxidant diet for 3 months. The neocortex, cerebellum, hippocampus and striatum were assayed for their monoamine and monoamine metabolite content using HPLC with electrochemical detection. Striatal tyrosine hydroxylase (TOH) levels were analysed by Western blotting. In the striatum, female TASTPM mice had higher levels of DOPAC and male TASTPM mice had higher levels of 5-HIAA compared to wildtype mice. Administration of pro-oxidant diet increased striatal MHPG, turnover of NA and 5-HT levels in female TASTPM mice compared to TASTPM mice fed control diet. The pro-oxidant diet also decreased DOPAC levels in female TASTPM mice compared to those fed control diet. Striatal TOH did not depend on diet, gender or genotype. In the neocortex, the TASTPM genotype increased levels of 5-HIAA in male mice fed control diet compared to wildtype mice. In the cerebellum, the TASTPM genotype led to decreased levels of HVA (male mice only) and also decreased turnover of DA (female mice only) compared to wildtype mice. These data suggest a sparing of monoaminergic neurones in the cortex, striatum and hippocampus of TASTPM mice fed pro-oxidant diet and could be indicative of increased activity in corticostriatal circuits. The decreased cerebellar levels of HVA and turnover of DA in TASTPM mice hint at possible axonal degeneration within this subregion.
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Author URL.
Kirvell SL, Elliott MS, Kalaria RN, Hortobágyi T, Ballard CG, Francis PT (2010). Vesicular glutamate transporter and cognition in stroke: a case-control autopsy study.
Neurology,
75(20), 1803-1809.
Abstract:
Vesicular glutamate transporter and cognition in stroke: a case-control autopsy study
Objectives: Vascular dementia (VaD) accounts for approximately 15%-20% of all dementias, but the relationship of progressive cognitive impairment to neurochemical changes is poorly understood. We have therefore investigated glutamatergic synaptic markers in VaD. Methods: We used homogenates prepared from gray matter from 2 neocortical regions (Brodmann area [BA] 9 and BA 20) and Western blotting to determine the concentrations of key components of the glutamatergic neurotransmitter system, vesicular glutamate transporter 1 (VGLUT1) and excitatory amino acid transporter EAAT2 (GLT-1), and the ubiquitous synaptic protein, synaptophysin, in 73 individuals-48 patients with cerebrovascular disease with and without dementia, 10 patients with AD, and 15 controls-in a case-control design. Results: VGLUT1 concentrations in BA 20 and BA 9 were correlated with CAMCOG total (Rs 0.525, p = 0.018, n = 20; Rs 0.560, p = 0.002, n = 27) and CAMCOG memory scores (Rs 0.616, p = 0.004, n = 20; Rs 0.675, p = 0.000, n = 27). VGLUT1 concentration in BA 9 differed between the different dementia groups and the stroke no dementia group (1-way analysis of variance F = 6.69, p = 0.001 and Bonferroni p < 0.01 in each case), with subjects with stroke who did not develop dementia exhibiting the highest mean value for VGLUT1. Conclusions: These data suggest that loss of glutamatergic synapses is a feature of VaD and Alzheimer disease but the preservation of synapses, in particular glutamatergic synapses, in the frontal cortex against the temporal cortex plays a role in sustaining cognition and protecting against dementia following a stroke. Copyright © 2010 by AAN Enterprises, Inc.
Abstract.
Ballard C, Jones EL, Londos E, Minthon L, Francis P, Aarsland D (2010). α-synuclein antibodies recognize a protein present at lower levels in the CSF of patients with dementia with Lewy bodies.
International Psychogeriatrics,
22(2), 321-327.
Abstract:
α-synuclein antibodies recognize a protein present at lower levels in the CSF of patients with dementia with Lewy bodies
Background: Dementia with Lewy bodies (DLB) accounts for 15-20% of the millions of people worldwide with dementia. Accurate diagnosis is essential to avoid harm and optimize clinical management. There is therefore an urgent need to identify reliable biomarkers. Methods: Mass spectrometry was used to determine the specificity of antibody α-synuclein (211) for α-synuclein. Using gel electrophoresis we measured protein levels detected by α-synuclein specific antibodies in the cerebrospinal fluid (CSF) of DLB patients and compared them to age matched controls. Results: a 24 kDa band was detected using α-synuclein specific antibodies which was significantly reduced in the CSF of DLB patients compared to age matched controls (p < 0.05). Further analysis confirmed that even DLB patients with mild dementia showed significant reductions in this protein in comparison to controls. Conclusions: the current study emphasizes the necessity for further studies of CSF α-synuclein as a biomarker of DLB and extends our previous knowledge by establishing a potential relationship between α-synuclein and the severity of cognitive impairment. The identification of this 24 kDa protein is the next important step in these studies. © International Psychogeriatric Association 2009.
Abstract.
Francis PT (2009). Altered glutamate neurotransmission and behaviour in dementia: evidence from studies of memantine.
Curr Mol Pharmacol,
2(1), 77-82.
Abstract:
Altered glutamate neurotransmission and behaviour in dementia: evidence from studies of memantine.
Behavioural symptoms are a significant problem in Alzheimer's disease (AD). Symptoms including agitation/aggression and psychosis reduce patient quality of life, significantly increase caregiver burden, and often trigger nursing home placement. Underlying changes in the serotonergic, noradrenergic and cholinergic systems have been linked to some behavioural problems, however, the use of antipsychotics in this population has been associated with significant safety concerns. A role for the glutamate system in schizophrenia, as well as in anxiety and depression, has been suggested, and evidence is emerging for a role for dysfunctional glutamate neurotransmission (via N-methyl-D-aspartate (NMDA) receptors) in certain behavioural changes in dementia. For example, the NMDA receptor antagonist, memantine has been shown to improve cognition, function (activities of daily living, ADLs) and, more recently, agitation/aggression, and delusions in AD patients. To date, little information is available regarding the neurochemical basis of agitation/aggression. However, the frontal and cingulate cortices--specifically, the formation of neurofibrillary tangles in glutamatergic pyramidal neurones of these areas--are proposed as regional substrates of these behaviours. Given that memantine displays a favourable tolerability profile, it is relevant to investigate the underlying mechanism linking memantine with the behavioural elements of AD. One hypothesis proposes that memantine corrects dysfunctional glutamatergic neurotransmission in the frontal and cingulate cortices, thereby normalising pathways responsible for causing agitation. An alternative hypothesis is based on the observation that increased tangle formation is associated with agitation, and on recent studies where memantine has been shown to reduce tau phosphorylation via glycogen synthase kinase (GSK)-3 or activation of protein phosphatase (PP)-2A, which might subsequently lead to reduced agitation.
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Author URL.
Jones EL, Hanney M, Francis PT, Ballard CG (2009). Amyloid β concentrations in older people with Down syndrome and dementia.
Neuroscience Letters,
451(2), 162-164.
Abstract:
Amyloid β concentrations in older people with Down syndrome and dementia
People with Down syndrome develop Alzheimer's disease with an early age of onset. Plasma amyloid beta (Aβ) levels were measured in individuals with Down syndrome who were over the age of 40. No associations between age and Aβ1-40 and Aβ1-42 concentrations were found and nor were Aβ1-40 and Aβ1-42 levels found to vary between those with Alzheimer's-type dementia and those without dementia. The APOE genotype was not found to have an impact upon Aβ1-40 or Aβ1-42 concentrations. These data suggest that other factors play important roles in determining the onset and progression of dementia in the Down syndrome population. © 2008 Elsevier Ireland Ltd. All rights reserved.
Abstract.
Francis PT (2009). Biochemical and pathological correlates of cognitive and behavioural change in DLB/PDD.
J Neurol,
256 Suppl 3, 280-285.
Abstract:
Biochemical and pathological correlates of cognitive and behavioural change in DLB/PDD.
Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are second only to Alzheimer's disease (AD) in frequency. In particular it is evident that up to 80% of people with PD will develop dementia towards the end of their life. While the neurobiology of movement disorder has been well studied in PD, much less attention has been given to mechanisms underlying the cognitive and behavioural symptoms associated with DLB and PDD. To date, the best correlate of cognitive impairment appears to be cortical Lewy bodies; however, new emphasis has been placed on small aggregates of synuclein. Furthermore, very few studies have attempted to investigate the neurochemical correlates of behavioural disorders in DLB/PDD and whether these are similar or distinct from AD. Aggregated alpha-synuclein forms the core component of Lewy bodies, a major pathological feature of Parkinson's-related conditions. The 26S proteasome is an ATP-dependent protease that catalyses the breakdown of alpha-synuclein. Previous studies have implicated alterations in the proteasome in PD. Furthermore, proteasome inhibitors have been reported to induce alpha-synuclein aggregation and Lewy body-like inclusions, resulting in neuronal loss both in vitro and in vivo. Our preliminary results indicate that selective alterations in the expression of proteosome sub-units are a feature of both DLB and PDD, while changes in activity are restricted to PDD. Depression is a common symptom in DLB/PDD, yet the evidence base for standard treatment with SSRIs is limited. In contrast to previous studies of AD, our results indicate that there is no association between depression and the 5-HT transporter, while there was a significant increase in the number of 5-HT1A receptors in those DLB/PDD patients with depression. These data may provide an insight into the lack of success of current treatments and suggest alternative approaches.
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Author URL.
Sharp SI, Francis PT, Elliott MSJ, Kalaria RN, Bajic N, Hortobagyi T, Ballard CG (2009). Choline acetyltransferase activity in vascular dementia and stroke.
Dementia and Geriatric Cognitive Disorders,
28(3), 233-238.
Abstract:
Choline acetyltransferase activity in vascular dementia and stroke
Background/Aim: Alterations in cholinergic activity have not been systematically studied in types of cerebrovascular disease. We examined cholinergic function at postmortem, focussing on stroke and vascular dementia (VaD). Methods: Post-mortem brain tissue was studied from 61 patients with stroke or VaD (13 infarct dementia; 8 stroke/no dementia; 11 sub-cortical ischaemic VaD, SIVD; 29 VaD and concurrent Alzheimer's disease, AD), 12 patients with AD and 23 controls. Choline acetyltransferase (ChAT) was measured in Brodmann areas (BA) 9 and 20/21. Results: There were significant reductions in ChAT activity in patients with VaD and concurrent AD compared to age-matched controls (BA9: t = 2.7, p = 0.009; BA20/21: t = 4.67, p = 0.000). In patients with infarct dementia, there was a significant 27% increase in ChAT activity in BA9 (t = 2.1, p = 0.047), but not in BA20/21 (t = 1.67, p = 0.106), compared to the age-matched control group. There was no relationship between ChAT activity and cognition in the VaD patients. Conclusions: Loss of cholinergic function is only evident in VaD patients with concurrent AD. A novel increase in cholinergic activity was identified in patients with infarct dementia, which may create important new treatment opportunities. © 2009 S. Karger AG, Basel.
Abstract.
Huang L, Abuhamdah S, Howes MJR, Dixon CL, Elliot MSJ, Ballard C, Holmes C, Burns A, Perry EK, Francis PT, et al (2009). Erratum: Pharmacological profile of essential oils derived from Lavandula angustifolia and Melissa officinalis with anti-agitation properties: Focus on ligand-gated channels (Journal of Pharmacy and Pharmacology (2008) 59 (1515-1522)). Journal of Pharmacy and Pharmacology, 61(2).
Elliott MSJ, Ballard CG, Kalaria RN, Perry R, Hortobágyi T, Francis PT (2009). Increased binding to 5-HT1A and 5-HT2A receptors is associated with large vessel infarction and relative preservation of cognition.
Brain,
132(Pt 7), 1858-1865.
Abstract:
Increased binding to 5-HT1A and 5-HT2A receptors is associated with large vessel infarction and relative preservation of cognition.
Vascular dementia accounts for approximately 15-20% of all dementias. In addition, a significant subset of people with Alzheimer's disease have concurrent cerebrovascular disease. Vascular dementia is caused by different cerebrovascular morphological abnormalities including large artery territory infarction (multi-infarct vascular dementia) and sub-cortical ischaemic vascular dementia. Despite this distinction, there is a lack of studies examining the neurochemistry of individual vascular dementia subtypes. Serotonin is believed to play an important role in cognition, and serotonin receptors may provide a novel target for future anti-dementia therapeutics. This study aimed to determine levels of two serotonin receptors in subtypes of vascular dementia and relate any changes to cognition. We have determined, using saturation radioligand binding, the binding parameters (affinity and maximal binding) of ((3)H)-WAY 100635 binding to 5-HT(1A) receptors and ((3)H)-ketanserin binding to 5-HT(2A) receptors in post-mortem tissue from the frontal and temporal cortices of patients with either multi-infarct vascular dementia, sub-cortical ischaemic vascular dementia, mixed Alzheimer's disease/vascular dementia or stroke no dementia (SND). 5-HT(1A) and 5-HT(2A) receptor binding was significantly increased in the temporal cortex of patients with either multi-infarct vascular dementia or SND, compared to age-matched controls. 5-HT(1A) receptor maximal binding in the temporal cortex was also positively correlated with cognition as determined by Mini-Mental State Examination (MMSE) and Cambridge Assessment of Mental Health for the Elderly scores (CAMCOG). These results reveal an important distinction between the neurochemistry of multi-infarct vascular dementia/SND and sub-cortical ischaemic vascular dementia, suggesting that pharmacological manipulation of serotonin offers the possibility to develop novel therapies for stroke and multi-infarct vascular dementia patients. The results also highlight the importance of the cortical 5-HT(1A) receptor in mediating cognition.
Abstract.
Author URL.
Huang L, Abuhamdah S, Howes M-JR, Dixon CL, Elliot MSJ, Ballard C, Holmes C, Burns A, Perry EK, Francis PT, et al (2009). Pharmacological profile of essential oils derived from Lavandula angustifolia and Melissa officinalis with anti-agitation properties: focus on ligand-gated channels (vol 59, pg 1515, 2008).
JOURNAL OF PHARMACY AND PHARMACOLOGY,
61(2), 267-267.
Author URL.
Abbott JJ, Howlett DR, Francis PT, Williams RJ (2008). Abeta(1-42) modulation of Akt phosphorylation via alpha7 nAChR and NMDA receptors.
Neurobiol Aging,
29(7), 992-1001.
Abstract:
Abeta(1-42) modulation of Akt phosphorylation via alpha7 nAChR and NMDA receptors.
Elevated Abeta and its deposition as senile plaques are pathogenic features of Alzheimer's disease. Abeta has been shown to be toxic to neurons and to inhibit long-term potentiation yet, the intracellular signalling pathways underlying these actions are unknown. We report for the first time that acute exposure of primary mouse neurons to 400nM Abeta(1-42) increased Akt phosphorylation in an alpha(7) nicotinic receptor and NMDA receptor dependant manner. However, prolonged incubation resulted in Akt phosphorylation returning to baseline consistent with the action of a physiological regulator. Analysis of an APP transgenic mouse (TAS10) revealed a significant deficit in hippocampal Akt phosphorylation at 13 months. This time point corresponds to the emergence of plaque formation and memory impairments in these mice. The present study suggests that Abeta(1-42) regulates Akt phosphorylation in a complex manner. Acutely, Abeta(1-42) stimulates Akt phosphorylation however, chronic exposure to Abeta in TAS10 mice resulted in a downregulation of Akt phosphorylation consistent with abnormalities in excitatory neurotransmission in these mice and with recent reports of Abeta(1-42) driven internalisation of NMDA receptors.
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Author URL.
Sharp SI, Ballard CG, Ziabreva I, Piggott MA, Perry RH, Perry EK, Aarsland D, Ehrt U, Larsen JP, Francis PT, et al (2008). Cortical serotonin 1A receptor levels are associated with depression in patients with dementia with lewy bodies and Parkinson's disease dementia.
Dementia and Geriatric Cognitive Disorders,
26(4), 330-338.
Abstract:
Cortical serotonin 1A receptor levels are associated with depression in patients with dementia with lewy bodies and Parkinson's disease dementia
Background: Serotonin 1A receptors (5-HT1A) have not been studied in dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD) patients with depression. Aim: to examine 5-HT1A in DLB and PDD postmortem in relation to depression. Methods: [3H]8-hydroxy-2- dipropylaminotetralin binding to 5-HT1A was determined in temporal cortex (Brodmann areas, BA20 and BA36) from 10 DLB patients, 17 PDD patients and 9 controls. Results: 5-HT1A density was significantly higher in BA36 in combined DLB/PDD patients with depression, but was unaltered in BA20. Conclusion: Higher BA36 5-HT1A density in PDD and DLB patients than in control is dependent on whether the patient had experienced depression during life, not DLB/PDD diagnosis. A 5-HT1A antagonist adjuvant may improve treatment of depression in dementia. Copyright © 2008 S. Karger AG.
Abstract.
Francis PT (2008). Glutamatergic approaches to the treatment of cognitive and behavioural symptoms of Alzheimer's disease.
Neurodegener Dis,
5(3-4), 241-243.
Abstract:
Glutamatergic approaches to the treatment of cognitive and behavioural symptoms of Alzheimer's disease.
The glutamatergic system has long been recognised for its role in learning and memory and recent studies indicate an early loss of glutamatergic synapses in Alzheimer's disease (AD). Efforts to produce drugs which address changes in the glutamatergic system in AD are well advanced (e.g. memantine and drugs in development such as ampakines). Much less is known about the possible role of glutamate in non-cognitive behavioural changes; however, recent data from clinical trials suggest that memantine reduces agitation and aggressive behaviour in AD patients. In this context, it is important to help identify new treatment approaches to replace the use of antipsychotics in this vulnerable population.
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Author URL.
Bowen DM, Procter AW, Mann DMA, Snowden JS, Esiri MM, Neary D, Francis PT (2008). Imbalance of a serotonergic system in frontotemporal dementia: implication for pharmacotherapy.
Psychopharmacology (Berl),
196(4), 603-610.
Abstract:
Imbalance of a serotonergic system in frontotemporal dementia: implication for pharmacotherapy.
RATIONALE: Information is sparse on neurotransmitter deficiencies in frontotemporal dementia (FTD), in particular with reference to distinct histological subgroups and Alzheimer's disease (AD). OBJECTIVES: to evaluate in FTD with the major histologies, and compare with AD and controls, neurotransmission indices, as these may help in developing treatment. MATERIALS AND METHODS: Post-mortem grey matter from Brodmann Area 21, 9 and 7 of 51 brains was assayed for ten neurochemical parameters indexing neurotransmission. Repeated measures analyses of variance were carried out for each parameter comparing groups (FTD vs AD vs control) at each anatomical site. RESULTS: in FTD only the indices of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid, serotonin (5-HT)(1A) and 5-HT(2A) receptors were significantly reduced from control values. of the ten parameters only 5-HT(1A) receptors showed significant group x site interaction. This reflected disproportionate reduction in frontal and temporal compared to parietal cortex. In FTD three other receptors (muscarinic, M(1), N-methyl-D: -aspartate, NMDA, and kainate), choline acetyltransferase (ChAT) activity, 5-HT and 5-hydroxyindoleacetic acid content and 5-HT reuptake site values were not significantly reduced from control values. Only 5-HT, 5-HT reuptake site and ChAT values were significantly higher in FTD than AD. NMDA receptor and ChAT values were significantly reduced from control only in AD. CONCLUSIONS: Neurochemical results in FTD indicate degeneration and loss of pyramidal neurones in frontotemporal neocortex, yet 5-HT afferents and 5-HT concentration, which are inhibitory on pyramidal neurones, were relatively preserved. This could lead to an excess of extraneural 5-HT causing underactivity of surviving pyramidal neurones. Pharmacotherapy with a 5-HT(1A) receptor antagonist may be indicated.
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Author URL.
Mulugeta E, Molina-Holgado F, Elliott MS, Hortobagyi T, Perry R, Kalaria RN, Ballard CG, Francis PT (2008). Inflammatory mediators in the frontal lobe of patients with mixed and vascular dementia.
Dement Geriatr Cogn Disord,
25(3), 278-286.
Abstract:
Inflammatory mediators in the frontal lobe of patients with mixed and vascular dementia.
Vascular dementia (VaD) accounts for about 20% of all dementias, and vascular risk is a key factor in more than 40% of people with Alzheimer's disease (AD). Little is known about inflammatory processes in the brains of these individuals. We have examined inflammatory mediators (interleukin (IL)-1beta, IL-1alpha, IL-6 and tumour necrosis factor alpha) and chemokines (macrophage inflammatory protein 1, monocyte chemo-attractant protein (MCP)-1 and granulocyte macrophage colony-stimulating factor) in brain homogenates from grey and white matter of the frontal cortex (Brodmann area 9) from patients with VaD (n = 11), those with concurrent VaD and AD (mixed dementia; n = 8) and from age-matched controls (n = 13) using ELISA assays. We found a dramatic reduction of MCP-1 levels in the grey matter in VaD and mixed dementia in comparison to controls (55 and 66%, respectively). IL-6 decreases were also observed in the grey matter of VaD and mixed dementia (72 and 71%, respectively), with a more modest decrease (30%) in the white matter of patients with VaD or mixed dementia. In the first study to examine the status of inflammatory mediators in a brain region severely affected by white-matter lesions, our findings highlight - in contrast to previous reports in AD - that patients at the later stage of VaD or mixed dementia have a significantly attenuated neuro-inflammatory response.
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Author URL.
Marcos B, García-Alloza M, Gil-Bea FJ, Chuang TT, Francis PT, Chen CP, Tsang SWTY, Lai MKP, Ramirez MJ (2008). Involvement of an altered 5-HT -{6} receptor function in behavioral symptoms of Alzheimer's disease.
J Alzheimers Dis,
14(1), 43-50.
Abstract:
Involvement of an altered 5-HT -{6} receptor function in behavioral symptoms of Alzheimer's disease.
We studied the hypothesis that disturbances in 5-HT_{6} receptor function in the temporal cortex may contribute to clinical symptoms of Alzheimer's disease (AD). 5-HT_{6} density and 5-HT levels were significantly decreased in a cohort of AD patients prospectively assessed for cognitive/behavioral symptoms. cAMP formation after stimulation with the selective 5-HT_{6} receptor agonist E-6801 was significantly lower (p
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Author URL.
Tsang SWY, Francis PT, Esiri MM, Wong PTH, Chen CPLH, Lai MKP (2008). Loss of [3H]4-DAMP binding to muscarinic receptors in the orbitofrontal cortex of Alzheimer's disease patients with psychosis.
Psychopharmacology (Berl),
198(2), 251-259.
Abstract:
Loss of [3H]4-DAMP binding to muscarinic receptors in the orbitofrontal cortex of Alzheimer's disease patients with psychosis.
RATIONALE: Neuropsychiatric behaviours in Alzheimer's disease (AD) patients have been associated with neocortical alterations of presynaptic cholinergic and muscarinic M2 receptor markers. In contrast, it is unclear whether non-M2 muscarinic receptors have a role to play in AD behavioural symptoms. OBJECTIVES: to correlate the alterations of neocortical postsynaptic muscarinic receptors with clinical features of AD. MATERIALS AND METHODS: [(3)H]4-DAMP were used in binding assays with lysates of Chinese hamster ovary (CHO) cells stably transfected with M1-M5 receptors. [(3)H]4-DAMP was further used to measure muscarinic receptors in the postmortem orbitofrontal cortex of aged controls and AD patients longitudinally assessed for cognitive decline and behavioural symptoms. RESULTS: [(3)H]4-DAMP binds to human postmortem brain homogenates and M1-, M3-, M4- and M5-transfected CHO lysates with subnanomolar affinity. Compared to the controls, the [(3)H]4-DAMP binding density is reduced only in AD patients with significant psychotic symptoms. The association between reduced [(3)H]4-DAMP binding and psychosis is independent of the effects of dementia severity or neurofibrillary tangle burden. CONCLUSIONS: This study suggests that the loss of non-M2 muscarinic receptors in the orbitofrontal cortex may be a neurochemical substrate of psychosis in AD and provides a rationale for further development of muscarinic receptor ligands in AD pharmacotherapy.
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Molina-Holgado F, Gaeta A, Francis PT, Williams RJ, Hider RC (2008). Neuroprotective actions of deferiprone in cultured cortical neurones and SHSY-5Y cells.
J Neurochem,
105(6), 2466-2476.
Abstract:
Neuroprotective actions of deferiprone in cultured cortical neurones and SHSY-5Y cells.
Alzheimer's disease (AD) is a common neurodegenerative disorder, but the initiating molecular processes contributing to neuronal death are not well understood. AD is associated with elevated soluble and aggregated forms of amyloid beta (Abeta) and with oxidative stress. Furthermore, there is increasing evidence for a detrimental role of iron in the pathogenic process. In this context, iron chelation by compounds such as 3-hydroxypyridin-4-one, deferiprone (Ferriprox) may have potential neuroprotective effects. We have evaluated the possible neuroprotective actions of deferiprone against a range of AD-relevant insults including ferric iron, H(2)O(2) and Abeta in primary mouse cortical neurones. We have investigated the possible neuroprotective actions of deferiprone (1, 3, 10, 30 or 100 microM) in primary neuronal cultures following exposure to ferric iron [ferric nitrilotriacetate (FeNTA); 3 and 10 microM], H(2)O(2) (100 microM) or Abeta1-40 (3, 10 and 20 microM). Cultures were treated with deferiprone or vehicle either immediately or up to 6 h after the insult in a 24-well plate format. In order to elucidate a possible neuroprotective action of deferiprone against Parkinson's disease relevant insults another group of experiments were performed in the human neuroblastoma catecholaminergic SHSY-5Y cell line. SHSY-5Y cells were treated with MPP(+) iodide, the active metabolite of the dopaminergic neurotoxin MPTP and the neuroprotective actions of deferiprone evaluated. Cytotoxicity was assessed at 24 h by lactate dehydrogenase release, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide turnover (FeNTA and hydrogen peroxide) and morphometric analysis of cell viability by Hoechst 33324/propidium iodide (FeNTA, Abeta and MPP(+)) or 6-carboxyfluorescein diacetate and annexin V-Cy3 (Abeta). The present study demonstrates that deferiprone protects against FeNTA, hydrogen peroxide, MPP(+) and Abeta1-40-induced neuronal cell death in vitro, which is consistent with previous in vitro and in vivo studies that have demonstrated similar protection with other iron chelators.
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Author URL.
Abuhamdah S, Huang L, Elliott MSJ, Howes MJR, Ballard C, Holmes C, Burns A, Perry EK, Francis PT, Lees G, et al (2008). Pharmacological profile of an essential oil derived from Melissa officinalis with anti-agitation properties: Focus on ligand-gated channels.
Journal of Pharmacy and Pharmacology,
60(3), 377-384.
Abstract:
Pharmacological profile of an essential oil derived from Melissa officinalis with anti-agitation properties: Focus on ligand-gated channels
A dual radioligand binding and electrophysiological study, focusing on a range of ligand-gated ion channels, was performed with a chemically-validated essential oil derived from Melissa officinalis (MO), which has shown clinical benefit in treating agitation. MO inhibited binding of [35S] t-butylbicyclophosphorothionate (TBPS) to the rat forebrain gamma-aminobutyric acid (GABA)A receptor channel (apparent IC50 0.040±0.001 mg mL-1), but had no effect on N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropianate (AMPA) or nicotinic acetylcholine receptors. Electrophysiological analyses with primary cultures of rat cortical neurons demonstrated that MO reversibly inhibited GABA-induced currents in a concentration-dependent manner (0.01-1 mg mL-1), whereas no inhibition of NMDA- or AMPA-induced currents was noted. Interestingly, MO elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission, with a net depressant effect on neurotransmission (in contrast to the classical GABAA antagonist picrotoxinin which evoked profound epileptiform burst firing in these cells). The anti-agitation effects in patients and the depressant effects of MO in in-vitro we report in neural membranes are unlikely to reflect a sedative interaction with any of the ionotropic receptors examined here. © 2008 the Authors.
Abstract.
Huang L, Abuhamdah S, Howes MJR, Elliot MSJ, Ballard C, Holmes C, Burns A, Perry EK, Francis PT, Lees G, et al (2008). Pharmacological profile of essential oils derived from Lavandula angustifolia and Melissa officinalis with anti-agitation properties: Focus on ligand-gated channels.
Journal of Pharmacy and Pharmacology,
60(11), 1515-1522.
Abstract:
Pharmacological profile of essential oils derived from Lavandula angustifolia and Melissa officinalis with anti-agitation properties: Focus on ligand-gated channels
Both Melissa officinalis (Mo) and Lavandula angustifolia (La) essential oils have putative anti-agitation properties in humans, indicating common components with a depressant action in the central nervous system. A dual radioligand binding and electrophysiological study, focusing on a range of ligand-gated ion channels, was performed with a chemically validated essential oil derived from La, which has shown clinical benefit in treating agitation. La inhibited [35S] TBPS binding to the rat forebrain gamma aminobutyric acid (GABA)A receptor channel (apparent IC50 = 0.040 ± 0.001 mg mL-1), but had no effect on N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or nicotinic acetylcholine receptors. A 50:50 mixture of Mo and La essential oils inhibited [3H] flunitrazepam binding, whereas the individual oils had no significant effect. Electrophysiological analyses with rat cortical primary cultures demonstrated that La reversibly inhibited GABA-induced currents in a concentration-dependent manner (0.01-1 mg mL-1), whereas no inhibition of NMDA- or AMPA-induced currents was noted. La elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission, with a net depressant effect on neurotransmission (in contrast to the classic GABAA antagonist picrotoxin which evoked profound epileptiform burst firing in these cells). These properties are similar to those recently reported for Mo. The anti-agitation effects in patients and the depressant effects of La we report in neural membranes in-vitro are unlikely to reflect a sedative interaction with any of the ionotropic receptors examined here. These data suggest that components common to the two oils are worthy of focus to identify the actives underlying the neuronal depressant and anti-agitation activities reported. © 2008 the Authors.
Abstract.
Lai MKP, Tan MGK, Kirvell S, Hobbs C, Lee J, Esiri MM, Chen CP, Francis PT (2008). Selective loss of P2Y<inf>2</inf> nucleotide receptor immunoreactivity is associated with Alzheimer's disease neuropathology.
Journal of Neural Transmission,
115(8), 1165-1172.
Abstract:
Selective loss of P2Y2 nucleotide receptor immunoreactivity is associated with Alzheimer's disease neuropathology
The uridine nucleotide-activated P2Y2, P2Y4 and P2Y6 receptors are widely expressed in the brain and are involved in many CNS processes, including those which malfunction in Alzheimer's disease (AD). However, the status of these receptors in the AD neocortex, as well as their putative roles in the pathogenesis of neuritic plaques and neurofibrillary tangles, remain unclear. In this study, we used immunoblotting to measure P2Y2, P2Y4 and P2Y6 receptors in two regions of the postmortem neocortex of neuropathologically assessed AD patients and aged controls. P2Y2 immunoreactivity was found to be selectively reduced in the AD parietal cortex, while P2Y4 and P2Y6 levels were unchanged. In contrast, all three receptors were preserved in the occipital cortex, which is known to be minimally affected by AD neuropathology. Furthermore, reductions in parietal P2Y2 immunoreactivity correlated both with neuropathologic scores and markers of synapse loss. These results provide a basis for considering P2Y2 receptor changes as a neurochemical substrate of AD, and point towards uridine nucleotide-activated P2Y receptors as novel targets for disease-modifying AD pharmacotherapeutic strategies. © 2008 Springer-Verlag.
Abstract.
Sharp SI, Ballard CG, Chen CPLH, Francis PT (2007). Aggressive behavior and neuroleptic medication are associated with increased number of alpha1-adrenoceptors in patients with alzheimer disease.
American Journal of Geriatric Psychiatry,
15(5), 435-437.
Abstract:
Aggressive behavior and neuroleptic medication are associated with increased number of alpha1-adrenoceptors in patients with alzheimer disease
OBJECTIVE:: Aggressive behavior in dementia is a major clinical management problem. METHOD:: Postmortem brain tissue was obtained from 24 patients with Alzheimer disease (AD) and 25 comparison cases. [3H] Prazosin binding to α1-AdR was determined. RESULTS:: Aggressive behavior was significantly correlated with α1-adrenoceptor number in patients with AD (Rs=0.454, N=24). Furthermore, patients receiving ongoing neuroleptics had significantly higher Bmax for [ 3H] prazosin (21 ± 2, N=9) than those who were not (16 ± 1, N=15). CONCLUSIONS:: Upregulation of α1-AdR is associated with aggressive behavior and chronic treatment with neuroleptic medication. © 2007 American Association for Geriatric Psychiatry.
Abstract.
Francis PT, Perry EK (2007). Cholinergic and other neurotransmitter mechanisms in Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies.
Mov Disord,
22 Suppl 17, S351-S357.
Abstract:
Cholinergic and other neurotransmitter mechanisms in Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies.
It is now 30 years since the beginning of intensive efforts to understand the neurotransmitter biochemistry of dementia as exemplified by Alzheimer's disease and such studies have led to the development of rational treatment strategies, which are continuing to benefit patients. However, as studies became more sophisticated and clinicians rediscovered an interest in dementia, because of the potential for symptomatic treatment, it has become clear that there are several different neurodegenerative conditions that gives rise to dementia syndromes and that each has distinct neurochemical pathology. This has important treatment implications since what works for one may not work for another or at the extreme, may make matters worse. Therefore it is clear that a detailed understanding of the neurotransmitter function in each condition is not merely academic but can lead to rationale drug design and treatment strategies appropriate for that group of patients. Dementia with Lewy bodies (DLB) has clinico-pathological features, which overlap with either AD or Parkinson's disease (PD) as well as features that help to distinguish it, such as fluctuations in cognitive impairment and a higher prevalence of visual hallucinations. On this basis, it would be expected that the neurochemistry would have some similarities with both disorders.
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Author URL.
Kirvell SL, Esiri M, Francis PT (2007). Down-regulation of vesicular glutamate transporters precedes cell loss and pathology in Alzheimer's disease. (vol 98, pg 939, 2006).
JOURNAL OF NEUROCHEMISTRY,
100(6), 1713-1713.
Author URL.
Holmes C, McCulley M, Nicoll JAR, Alder JT, Chen CPL-H, Francis PT (2007). Genetic variation in the 5-HT2A receptor and altered neocortical [3H] ketanserin binding in Alzheimer's disease.
Neurosci Lett,
420(1), 58-60.
Abstract:
Genetic variation in the 5-HT2A receptor and altered neocortical [3H] ketanserin binding in Alzheimer's disease.
A common intronic single nucleotide polymorphism (T102C) in the 5-HT2A receptor gene is associated with the development of different neuropsychiatric symptoms, including hallucinations and depressive symptoms in Alzheimer's disease (AD). Differential 5-HT2A receptor binding has also been associated with the development of these symptoms in AD. However, the relationship between 5-HT2A (T102C) genotype and 5-HT2A receptor binding in AD and control human brains has not been examined. We examined the association between different 5-HT2A (T102C) genotypes and [(3)H] ketanserin binding in the temporal and frontal cortex of 20 AD and 14 control human brains. In homozygotes, but not heterozygotes, there was a significant reduction in B(max) values for [(3)H] ketanserin binding in both areas of cortex in AD compared with control subjects. This study suggests a mechanism for the generation of different neuropsychiatric symptoms in AD from a single nucleotide polymorphism with reduced receptor binding in T102C 5-HT2A receptor gene homozygotes correlating with susceptibility to depressive symptoms, whereas the relative preservation of receptor binding in heterozygotes with AD correlating with susceptibility to hallucinations.
Abstract.
Author URL.
Elliott MSJ, Abuhamdah S, Howes MJR, Lees G, Ballard CG, Holmes C, Burns A, Chazot PL, Perry EK, Francis PT, et al (2007). The essential oils from Melissa officinalis L. and Lavandula angustifolia Mill. as potential treatment for agitation in people with severe dementia.
International Journal of Essential Oil Therapeutics,
1(4), 143-152.
Abstract:
The essential oils from Melissa officinalis L. and Lavandula angustifolia Mill. as potential treatment for agitation in people with severe dementia
Agitation is a common symptom in people with severe dementia and is often treated with neuroleptic drugs which demonstrate severe side effects and limited efficacy. An encouraging alternative treatment involves the use of aromatherapy using essential oils from melissa (Melissa officinalis L.) or lavender (Lavandula angustifolia Mill.), both of which have recently been shown to reduce agitation in dementia patients. The present study has determined the receptor binding properties of essential oils from M. officinalis and L. angustifolia from four different suppliers at a number of ligand-gated and G-protein coupled receptors implicated in agitation. In addition, gas chromatography-mass spectrometry (GC-MS) analysis has been conducted to compare the chemical composition of the different oils. While both lavender and melissa oils significantly inhibited binding of radioligands to the muscarinic M1, 5-HT 2A, histamine H3 receptors and GABAA receptor channel site, melissa oil also affected binding to 5-HT1A receptors and the agonist site of the GABAA receptor. Moreover, melissa oil generally demonstrated greater potency than lavender oil with effects significant at concentrations of 0.1 mg/ml. The melissa oils obtained from different sources exhibited similar receptor binding and GC-MS profiles as did the lavender oils. This work represents the initial laboratory-based phase of a wider study examining the effectiveness of aromatherapy in the treatment of agitation in severe dementia. The purpose was to select one oil demonstrating maximum bioactivity to be used in a forthcoming clinical trial and to determine its chemical composition. With consideration given to the pharmacological and GC-MS data obtained in this study, melissa oil from Fytosan was chosen for use in the clinical trial. © Essential Oil Resource Consultants. All rights reserved.
Abstract.
Jacobs EH, Williams RJ, Francis PT (2006). Cyclin-dependent kinase 5, Munc18a and Munc18-interacting protein 1/X11alpha protein up-regulation in Alzheimer's disease.
Neuroscience,
138(2), 511-522.
Abstract:
Cyclin-dependent kinase 5, Munc18a and Munc18-interacting protein 1/X11alpha protein up-regulation in Alzheimer's disease.
Besides formation of neurofibrillary tangles and neuron loss, the Alzheimer's disease brain is characterized by neuritic plaques consisting of beta-amyloid peptide deposits and impaired neurotransmission. The proteins Munc18a, Munc18-interacting protein 1 and Munc18-interacting protein 2 mediate exocytosis and decrease beta-amyloid peptide formation. Cyclin-dependent kinase 5 and its activator p35 disrupt Munc18a-syntaxin 1 binding, thereby promoting synaptic vesicle fusion during exocytosis. We investigated protein levels of the signaling pathway: p35, cyclin-dependent kinase 5, Munc18a, syntaxin 1A and 1B, Munc18-interacting protein 1 and Munc18-interacting protein 2 in Alzheimer's disease cortex and found that this pathway was up-regulated in the Alzheimer's disease parietal and occipital cortex. In the cortex of transgenic Tg2576 mice over-expressing human beta-amyloid precursor protein with the Swedish mutation known to lead to familial Alzheimer's disease, which have substantial levels of beta-amyloid peptide but lack neurofibrillary tangles and neuron loss, no alterations of protein levels were detected. These data suggest that the pathway is enhanced in dying or surviving neurons and might serve a protective role by compensating for decreased neurotransmission and decreasing beta-amyloid peptide levels early during the progression of Alzheimer's disease.
Abstract.
Author URL.
Kirvell SL, Esiri M, Francis PT (2006). Down-regulation of vesicular glutamate transporters precedes cell loss and pathology in Alzheimer's disease.
J Neurochem,
98(3), 939-950.
Abstract:
Down-regulation of vesicular glutamate transporters precedes cell loss and pathology in Alzheimer's disease.
Alzheimer's disease (AD) is characterized pathologically by plaques, tangles, and cell and synapse loss. As glutamate is the principle excitatory neurotransmitter of the CNS, the glutamatergic system may play an important role in AD. An essential step in glutamate neurotransmission is the concentration of glutamate into synaptic vesicles before release from the presynaptic terminal. Recently a group of proteins responsible for uptake has been identified - the vesicular glutamate transporters (VGLUTs). The generation of antibodies has facilitated the study of glutamatergic neurones. Here, we used antibodies to the VGLUTs together with immunohistochemistry and western blotting to investigate the status of glutamatergic neurones in temporal, parietal and occipital cortices of patients with AD; these regions were chosen to represent severely, moderately and mildly affected regions at the end stage of the disease. There was no change in expression of the synaptic markers in relation to total protein in the temporal cortex, but a significant reduction in synaptophysin and VGLUT1 was found in both the parietal and occipital cortices. These changes were found to relate to the number of tangles in the temporal cortex. There were no correlations with either mental test score or behaviour syndromes, with the exception of depression.
Abstract.
Author URL.
Tsang SWY, Lai MKP, Kirvell S, Francis PT, Esiri MM, Hope T, Chen CPL-H, Wong PT-H (2006). Impaired coupling of muscarinic M1 receptors to G-proteins in the neocortex is associated with severity of dementia in Alzheimer's disease.
Neurobiol Aging,
27(9), 1216-1223.
Abstract:
Impaired coupling of muscarinic M1 receptors to G-proteins in the neocortex is associated with severity of dementia in Alzheimer's disease.
Impaired transmission of acetylcholine-mediated signaling by postsynaptic muscarinic M1 receptors has been postulated to underlie the limited efficacy of cholinergic replacement therapies in Alzheimer's disease (AD). However, a clear relationship between the functionality of M1 receptors and dementia severity has not been demonstrated. The present study aims to measure M1 coupling to its nucleotide binding (G-) protein in the AD neocortex, and to correlate neurochemical findings with clinical features. A cohort of dementia patients was longitudinally assessed for cognitive decline, with postmortem neuropathological confirmation of AD diagnosis. Measures of M1 receptor density, M1/G-protein coupling and choline acetyltransferase (ChAT) activities were performed in the frontal and temporal cortex of 24 AD patients as well as in 12 age-matched controls. We found that M1 receptor densities were unchanged in AD, which contrasted with significantly reduced M1 coupling to G-proteins in severely demented AD patients. Loss of M1/G-protein coupling in the frontal cortex, but not the temporal cortex, also correlated with the rate of cognitive decline. Additionally, correlations between M1/G-protein coupling and ChAT activities were demonstrated in both regions. These results suggest that defective coupling of neocortical M1 receptors to G-proteins is a neurochemical substrate of cognitive decline in AD. Based on its associations with ChAT deficits and dementia severity, we propose that M1/G-protein uncoupling may have a significant role in the disease mechanism of AD and thus may be considered to be a potential therapeutic target.
Abstract.
Author URL.
Garcia-Alloza M, Tsang SW, Gil-Bea FJ, Francis PT, Lai MK, Marcos B, Chen CP, Ramirez MJ (2006). Involvement of the GABAergic system in depressive symptoms of Alzheimer's disease.
Neurobiol Aging,
27(8), 1110-1117.
Abstract:
Involvement of the GABAergic system in depressive symptoms of Alzheimer's disease.
Cognitive and neuropsychiatric (BPSD) symptoms seen in Alzheimer's disease (AD) probably result from differential neurotransmitter alterations. The involvement of the glutamatergic and GABAergic system in cognitive and behavioral and psychological symptoms of dementia (BPSD) has been studied in post-mortem frontal and temporal cortex from AD patients who had been prospectively assessed with the Mini-Mental State Examination (MMSE) for cognitive impairment and with the Present Behavioral Examination (PBE) for BPSD. In addition to cholinergic deficits, significant decreases in gamma-amino butyric acid (GABA) content, with no changes in glutamate content, were found in frontal and temporal cortex. Both GABA levels and the glutamate/GABA ratio showed significant correlations with depression in AD. In the temporal cortex, higher densities of GABA(A)/benzodiazepine receptors also correlated with more severe depression. It can be suggested that in a situation of cholinergic deficit, such as AD, an imbalance between the excitatory glutamatergic tone and inhibitory GABAergic tone may be responsible for non-cognitive behavioral disturbances.
Abstract.
Author URL.
Lai MKP, Tsang SWY, Garcia-Alloza M, Minger SL, Nicoll JAR, Esiri MM, Wong PT-H, Chen CPL-H, Ramírez MJ, Francis PT, et al (2006). Selective effects of the APOE epsilon4 allele on presynaptic cholinergic markers in the neocortex of Alzheimer's disease.
Neurobiol Dis,
22(3), 555-561.
Abstract:
Selective effects of the APOE epsilon4 allele on presynaptic cholinergic markers in the neocortex of Alzheimer's disease.
The effects of the APOE epsilon4 allele on a range of pre- and postsynaptic cholinergic markers were studied in a cohort of community-based Alzheimer's disease (AD) patients. Compared with age-matched controls, the postmortem AD neocortex showed decreased choline acetyltransferase (ChAT) and acetyl cholinesterase activities, lower muscarinic M2, and nicotinic alpha4beta2 receptor densities, as well as reduced M1 receptor coupling to G-proteins. However, the epsilon4 allele was dose-dependently correlated only with higher losses of ChAT activities. AD patients with two epsilon4 alleles also had more beta-amyloid containing senile plaques in the temporal cortex compared to patients with 0/1 epsilon4. This study suggests that APOE epsilon4 selectively affects presynaptic cholinergic function which may contribute to the clinical and neuropathological features of AD.
Abstract.
Author URL.
Francis PT, Nordberg A, Arnold SE (2005). A preclinical view of cholinesterase inhibitors in neuroprotection: do they provide more than symptomatic benefits in Alzheimer's disease?.
Trends Pharmacol Sci,
26(2), 104-111.
Abstract:
A preclinical view of cholinesterase inhibitors in neuroprotection: do they provide more than symptomatic benefits in Alzheimer's disease?
The prevalence of Alzheimer's disease (AD), a neurodegenerative condition whose greatest risk factor is old age, is expected to rise dramatically during the next five decades, along with the trend for increased longevity. Early diagnosis and intervention with therapies that halt or slow disease progress are likely to represent an important component of effective treatment. Although much progress has been made in this area, there are currently no clinically approved interventions for AD that are classed as disease modifying or neuroprotective. Cholinesterase inhibitors are a drug class used for the symptomatic treatment of AD. Recent evidence from preclinical studies indicates that these agents can attenuate neuronal damage and death from cytotoxic insults, and therefore might affect AD pathogenesis. The mechanisms by which these actions are mediated might or might not be directly related to their primary mode of action.
Abstract.
Author URL.
Clarke NA, Francis PT (2005). Cholinergic and glutamatergic drugs in Alzheimer's disease therapy.
Expert Rev Neurother,
5(5), 671-682.
Abstract:
Cholinergic and glutamatergic drugs in Alzheimer's disease therapy.
The pathology and clinical symptoms of Alzheimer's disease are well known and include plaques, tangles, cell loss and dysfunction. The target of current treatments is to improve neuronal dysfunction and produce symptomatic benefits based on a clear understanding of neurotransmitter biochemistry. The purpose of this review is to examine the scientific background to currently available treatments, discuss the clinical experience of employing these drugs in Alzheimer's disease patients and review the socioeconomic influences on their use in the future.
Abstract.
Author URL.
Garcia-Alloza M, Gil-Bea FJ, Diez-Ariza M, Chen CPL-H, Francis PT, Lasheras B, Ramirez MJ (2005). Cholinergic-serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer's disease.
Neuropsychologia,
43(3), 442-449.
Abstract:
Cholinergic-serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer's disease.
Neuropsychiatric symptoms seen in Alzheimer's disease (AD) are not simply a consequence of neurodegeneration, but probably result from differential neurotransmitter alterations, which some patients are more at risk of than others. Therefore, the hypothesis of this study is that an imbalance between the cholinergic and serotonergic systems is related to cognitive symptoms and psychological syndromes of dementia (BPSD) in patients with AD. Cholinergic and serotonergic functions were assessed in post-mortem frontal and temporal cortex from 22 AD patients who had been prospectively assessed with the Mini-Mental State examination (MMSE) for cognitive impairment and with the Present Behavioral Examination (PBE) for BPSD including aggressive behavior, overactivity, depression and psychosis. Not only cholinergic deficits, but also the cholinacetyltransferase/serotonin ratio significantly correlated with final MMSE score both in frontal and temporal cortex. In addition, decreases in cholinergic function correlated with the aggressive behavior factor, supporting a dual role for the cholinergic system in cognitive and non-cognitive disturbances associated to AD. The serotonergic system showed a significant correlation with overactivity and psychosis. The ratio of serotonin to acetylcholinesterase levels was also correlated with the psychotic factor at least in women. It is concluded that an imbalance between cholinergic-serotonergic systems may be responsible for the cognitive impairment associated to AD. Moreover, the major findings of this study are the relationships between neurochemical markers of both cholinergic and serotonergic systems and non-cognitive behavioral disturbances in patients with dementia.
Abstract.
Author URL.
Lai MK, Tsang SW, Alder JT, Keene J, Hope T, Esiri MM, Francis PT, Chen CP (2005). Loss of serotonin 5-HT2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer's disease.
Psychopharmacology (Berl),
179(3), 673-677.
Abstract:
Loss of serotonin 5-HT2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer's disease.
RATIONALE: Previous studies have demonstrated reductions of serotonin 5-HT 2A receptors in the neocortex of Alzheimer's disease (AD) patients. However, it is unclear whether such losses play a role in the cognitive decline of AD. OBJECTIVES: to correlate neocortical 5-HT 2A receptor alterations with cognitive decline in AD. METHODS: Postmortem frontal and temporal cortical 5-HT 2A receptors were measured by [3H]ketanserin binding in aged controls as well as in a cohort of AD patients who had been longitudinally assessed for cognitive decline and behavioral symptoms. RESULTS: 5-HT 2A receptor densities in both regions were reduced in severely demented AD patients compared to age-matched controls. In the temporal cortex, this reduction also correlated with the rate of decline of Mini-Mental State Examination (MMSE) scores. The association between 5-HT 2A receptor loss and cognitive decline was independent of the effects of choline acetyltransferase (ChAT) activity and presence of behavioral symptoms. CONCLUSIONS: Our data suggest that loss of neocortical 5-HT 2A receptors may predict for faster cognitive decline in AD, and point to serotomimetics as potentially useful adjuvants to cholinergic replacement therapies.
Abstract.
Author URL.
Francis PT (2005). Neuroanatomy/pathology and the interplay of neurotransmitters in moderate to severe Alzheimer disease.
NEUROLOGY,
65(6), S5-S9.
Author URL.
Francis PT (2005). Neuroanatomy/pathology and the interplay of neurotransmitters in moderate to severe Alzheimer disease.
Neurology,
65(6 SUPPL. 3).
Abstract:
Neuroanatomy/pathology and the interplay of neurotransmitters in moderate to severe Alzheimer disease
The major neuron types affected by the degenerative process in AD are glutamatergic and cholinergic, and there is good evidence linking these systems to the characteristic cognitive impairment. The goals of AD research are to improve the function of remaining neurons and, ultimately, to prevent cell death and loss of synapses. ChEIs and memantine are able to provide symptomatic benefits during the course of the disease, and the mechanisms by which this occurs are becoming clearer. Preclinical studies suggest that memantine can offer protection to vulnerable cholinergic neurons. However, this needs to be investigated in clinical studies.
Abstract.
Sharp SI, Francis PT, Ballard CG (2005). Neurochemistry of severe dementia. Reviews in Clinical Gerontology, 15(2), 105-123.
Francis PT (2005). The Interplay of Neurotransmitters in Alzheimer's Disease.
CNS SPECTRUMS,
10(11), 6-9.
Author URL.
Francis PT (2005). The interplay of neurotransmitters in Alzheimer's disease.
CNS Spectrums,
10(11 SUPPL. 18), 6-9.
Abstract:
The interplay of neurotransmitters in Alzheimer's disease
Evidence exists for both cholinergic and glutamatergic involvement in the etiology of Alzheimer's disease. Acetylcholine (ACh), a neurotransmitter essential for processing memory and learning, is decreased in both concentration and function in patients with Alzheimer's disease. This deficit and other presynaptic cholinergic deficits, including loss of cholinergic neurons and decreased acetylcholinesterase activity, underscore the cholinergic hypothesis of Alzheimer's disease. The glutamatergic hypothesis links cognitive decline in patients with Alzheimer's to neuronal damage resulting from overactivation of N-methyl-D-aspartate (NMDA) receptors by glutamate. The sustained low-level activation of NMDA receptors, which are pivotal in learning and memory, may result from deficiencies in glutamate reuptake by astroglial cells in the synaptic cleft. This article reviews the roles of ACh and glutamate in Alzheimer's disease, with particular attention given to the overlap between cholinergic and glutamatergic pathways. In addition, the potential synergy between cholinesterase inhibitors and the NMDA receptor antagonist memantine in correcting neurologic abnormalities associated with Alzheimer's disease is addressed.
Abstract.
Francis PT (2005). The interplay of neurotransmitters in Alzheimer's disease.
CNS Spectr,
10(11 Suppl 18), 6-9.
Abstract:
The interplay of neurotransmitters in Alzheimer's disease.
Evidence exists for both cholinergic and glutamatergic involvement in the etiology of Alzheimer's disease. Acetylcholine (ACh), a neurotransmitter essential for processing memory and learning, is decreased in both concentration and function in patients with Alzheimer's disease. This deficit and other presynaptic cholinergic deficits, including loss of cholinergic neurons and decreased acetylcholinesterase activity, underscore the cholinergic hypothesis of Alzheimer's disease. The glutamatergic hypothesis links cognitive decline in patients with Alzheimer's to neuronal damage resulting from overactivation of N-methyl-d-aspartate (NMDA) receptors by glutamate. The sustained low-level activation of NMDA receptors, which are pivotal in learning and memory, may result from deficiencies in glutamate reuptake by astroglial cells in the synaptic cleft. This article reviews the roles of ACh and glutamate in Alzheimer's disease, with particular attention given to the overlap between cholinergic and glutamatergic pathways. In addition, the potential synergy between cholinesterase inhibitors and the NMDA receptor antagonist memantine in correcting neurologic abnormalities associated with Alzheimer's disease is addressed.
Abstract.
Author URL.
Ramírez MJ, Honer WG, Minger SL, Francis PT (2004). Changes in hippocampal SNAP-25 expression following afferent lesions.
Brain Res,
997(1), 133-135.
Abstract:
Changes in hippocampal SNAP-25 expression following afferent lesions.
Reductions in SNAP-25 immunohistochemistry were found after removing the glutamatergic and cholinergic inputs to the rat hippocampus. SNAP-25 levels were normalised by 1 month after afferent lesions. Surprisingly, a superimposed cholinergic lesions did not affect the return to normal SNAP-25 levels after a long-term entorhinal cortex lesion. It is concluded that changes in SNAP-25 may represent early markers of synaptic loss following afferent lesions to the hippocampus.
Abstract.
Author URL.
Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J (2004). Cholinesterase inhibitors used in the treatment of Alzheimer's disease: the relationship between pharmacological effects and clinical efficacy.
Drugs Aging,
21(7), 453-478.
Abstract:
Cholinesterase inhibitors used in the treatment of Alzheimer's disease: the relationship between pharmacological effects and clinical efficacy.
The deficiency in cholinergic neurotransmission in Alzheimer's disease has led to the development of cholinesterase inhibitors as the first-line treatment for symptoms of this disease. The clinical benefits of these agents include improvements, stabilisation or less than expected decline in cognition, function and behaviour. The common mechanism of action underlying this class of agents is an increase in available acetylcholine through inhibition of the catabolic enzyme, acetylcholinesterase. There is substantial evidence that the cholinesterase inhibitors, including donepezil, galantamine and rivastigmine, decrease acetylcholinesterase activity in a number of brain regions in patients with Alzheimer's disease. There is also a significant correlation between acetylcholinesterase inhibition and observed cognitive improvement. However, the cholinesterase inhibitors are reported to have additional pharmacological actions. Rivastigmine inhibits butyrylcholinesterase with a similar affinity to acetylcholinesterase, although it is not clear whether the inhibition of butyrylcholinesterase contributes to the therapeutic effect of rivastigmine. Based on data from preclinical studies, it has been proposed that galantamine also potentiates the action of acetylcholine on nicotinic receptors via allosteric modulation; however, the effects appear to be highly dependent on the concentrations of agonist and galantamine. It is not yet clear whether these concentrations are related to those achieved in the brain of patients with Alzheimer's disease within therapeutic dose ranges. Preclinical studies have shown that donepezil and galantamine also significantly increase nicotinic receptor density, and increased receptor density may be associated with enhanced synaptic strengthening through long-term potentiation, which is related to cognitive function. Despite these differences in pharmacology, a review of clinical data, including head-to-head studies, has not demonstrated differences in efficacy, although they may have an impact on tolerability. It seems clear that whatever the subsidiary modes of action, clinical evidence supporting acetylcholinesterase inhibition as the mechanism by which cholinesterase inhibitors treat the symptoms of Alzheimer's disease is accumulating. Certainly, as a class, the currently approved cholinesterase inhibitors (donepezil, galantamine, rivastigmine and tacrine) provide important benefits in patients with Alzheimer's disease and these drugs offer a significant advance in the management of dementia.
Abstract.
Author URL.
Garcia-Alloza M, Hirst WD, Chen CPL-H, Lasheras B, Francis PT, Ramírez MJ (2004). Differential involvement of 5-HT(1B/1D) and 5-HT6 receptors in cognitive and non-cognitive symptoms in Alzheimer's disease.
Neuropsychopharmacology,
29(2), 410-416.
Abstract:
Differential involvement of 5-HT(1B/1D) and 5-HT6 receptors in cognitive and non-cognitive symptoms in Alzheimer's disease.
Growing evidence suggests that a compromised serotonergic system plays an important role in the pathophysiology of Alzheimer's disease (AD). We assessed the expression of 5-HT(1B/1D) and 5-HT(6) receptors and cholinacetyltransferase (ChAT) activity in post-mortem frontal and temporal cortex from AD patients who had been prospectively assessed for cognitive function using the Mini-Mental State Examination (MMSE) and behavioral changes using the Present Behavioral Examination (PBE). 5-HT(1B/1D) and 5-HT(6) receptor densities were significantly reduced in both cortical areas. 5-HT(1B/1D) receptor density was correlated to MMSE decline in the frontal cortex, supporting its implication in memory impairment. The best predictor for lowered 5-HT(6) receptor density in the temporal cortex was the PBE measure of overactivity. The 5-HT(6)/ChAT ratio was related to aggression both in the frontal and temporal cortex. Therefore, antagonists acting at 5-HT(6) receptors could be useful in the treatment of non-cognitive symptoms associated to AD.
Abstract.
Author URL.
Francis PT (2003). Glutamatergic systems in Alzheimer's disease.
Int J Geriatr Psychiatry,
18(Suppl 1), S15-S21.
Abstract:
Glutamatergic systems in Alzheimer's disease.
Glutamate is the major transmitter of the brain and is involved in all aspects of cognitive function since it is the transmitter of cortical and hippocampal pyramidal neurones. Furthermore, glutamate and glutamate receptors are involved in long-term potentiation, a process believed to underlie learning and memory. Histological studies indicate loss of pyramidal neurones and their synapses in Alzheimer's disease (AD), this together with biochemical evidence suggests presynaptic (and postsynaptic) glutamatergic hypoactivity. This represents a 'double blow' as the activity of glutamatergic neurones is heavily influenced by the cholinergic system, which is also dysfunctional in AD. The clinical relevance of these changes is emphasised because glutamatergic and cholinergic dysfunction are strong correlates of cognitive decline in AD. The mechanism by which glutamatergic (and cholinergic) cells die is likely to be a combination of necrosis and apoptosis caused by a range of factors which include tangle formation and the effects of too much and too little glutamatergic neurotransmission.
Abstract.
Author URL.
Lai MKP, Tsang SWY, Francis PT, Esiri MM, Keene J, Hope T, Chen CPL-H (2003). Reduced serotonin 5-HT1A receptor binding in the temporal cortex correlates with aggressive behavior in Alzheimer disease.
Brain Res,
974(1-2), 82-87.
Abstract:
Reduced serotonin 5-HT1A receptor binding in the temporal cortex correlates with aggressive behavior in Alzheimer disease.
Previous studies have implicated brain serotonin 5-HT(1A) receptors in several CNS functions, including cognition, mood and emotional states. In Alzheimer disease (AD), cognitive impairment and behavioral symptoms are the main clinical features. However, the biochemical basis of such changes is poorly understood. Results from recent in vivo studies suggest that 5-HT(1A) receptors may be related to aggressive traits in healthy subjects. The present study investigated the state of 5-HT(1A) receptors in the postmortem neocortex of 33 AD patients prospectively assessed for cognition and behavioral symptoms, together with 20 matched controls, by saturation [(3)H]8-OH-DPAT binding assays. 5-HT(1A) receptor binding affinity (K(D)) and density (B(max)) were unchanged in the overall AD group compared with controls. Within the AD group, 5-HT(1A) receptor B(max) in the temporal cortex inversely correlated with aggression and dementia severity. However, multiple regression analyses showed that 5-HT(1A) receptor B(max) remained the best predictor for aggression, while temporal cortical neurofibrillary tangle grading was the best predictor for dementia severity. This suggests that 5-HT(1A) receptor alteration is directly related to aggression in AD, while dementia severity is more strongly related to the neurodegenerative process. Our data indicate further study of 5-HT(1A) receptors as a pharmacological target for the treatment of behavioral symptoms in AD.
Abstract.
Author URL.
Tsang SWY, Lai MKP, Francis PT, Wong PTH, Spence I, Esiri MM, Keene J, Hope T, Chen CPLH (2003). Serotonin transporters are preserved in the neocortex of anxious Alzheimer's disease patients.
NeuroReport,
14(10), 1297-1300.
Abstract:
Serotonin transporters are preserved in the neocortex of anxious Alzheimer's disease patients
Densities of serotonin transporters (5-HTT) in the postmortem neocortex of behaviorally assessed Alzheimer's disease (AD) patients and aged controls were measured by radioligand binding with [3H]citalopram. It was found that 5-HTTsites in the temporal cortex of AD patients with prominent antemortem anxiety were unaltered compared with controls, but were reduced in non-anxious AD subjects. Furthermore, homozygosity for the high activity allele of a functional polymorphism in the 5-HTT gene promoter region (5-HTTLPR) was associated with both increased [3H]citalopram binding and occurrence of anxiety in the AD subjects. Since serotonin-synthesizing neurons are known to be lost in the AD cortex, this study suggests that the preservation of 5-HTT may exacerbate serotonergic deficits and underlie anxiety symptoms in AD. © 2003 Lippincott Williams & Wilkins.
Abstract.
Tsang SWY, Lai MKP, Francis PT, Wong PT-H, Spence I, Esiri MM, Keene J, Hope T, Chen CPL-H (2003). Serotonin transporters are preserved in the neocortex of anxious Alzheimer's disease patients.
Neuroreport,
14(10), 1297-1300.
Abstract:
Serotonin transporters are preserved in the neocortex of anxious Alzheimer's disease patients.
Densities of serotonin transporters (5-HTT) in the postmortem neocortex of behaviorally assessed Alzheimer's disease (AD) patients and aged controls were measured by radioligand binding with [3H]citalopram. It was found that 5-HTT sites in the temporal cortex of AD patients with prominent antemortem anxiety were unaltered compared with controls, but were reduced in non-anxious AD subjects. Furthermore, homozygosity for the high activity allele of a functional polymorphism in the 5-HTT gene promoter region (5-HTTLPR) was associated with both increased [3H]citalopram binding and occurrence of anxiety in the AD subjects. Since serotonin-synthesizing neurons are known to be lost in the AD cortex, this study suggests that the preservation of 5-HTT may exacerbate serotonergic deficits and underlie anxiety symptoms in AD.
Abstract.
Author URL.
Lai MK, Tsang SW, Francis PT, Esiri MM, Hope T, Lai OF, Spence I, Chen CP (2003). [3H]GR113808 binding to serotonin 5-HT(4) receptors in the postmortem neocortex of Alzheimer disease: a clinicopathological study.
J Neural Transm (Vienna),
110(7), 779-788.
Abstract:
[3H]GR113808 binding to serotonin 5-HT(4) receptors in the postmortem neocortex of Alzheimer disease: a clinicopathological study.
Abnormalities in neural transmission of serotonin (5-HT) may play a role in both cognitive and neuropsychiatric features of Alzheimer disease (AD). We measured 5-HT(4) receptors in the postmortem frontal and temporal cortex of 34 AD subjects and 15 controls by radioligand binding with [3H]GR113808. Receptor binding data was then correlated with prospectively assessed cognitive (Mini-Mental State Examination, MMSE) and behavioral (Present Behavioural Examination, PBE) data. [3H]GR113808 binding affinity (K(D)) and density (B(max)) in AD were unchanged compared to controls in both cortical regions, and did not correlate with MMSE or PBE data. The binding parameters were also not related to disease duration, senile plaque and neurofibrillary tangle counts, and neuroleptic medication. We conclude that unlike other 5-HT receptors, 5-HT(4) receptor binding affinity and density do not seem to be affected in the frontal and temporal cortex in AD and may not have a direct role in the clinical features of the disease.
Abstract.
Author URL.
Lai MK, Tsang SW, Francis PT, Esiri MM, Hope T, Lai OF, Spence I, Chen CP (2003). [<sup>3</sup>H]GR113808 binding to serotonin 5-HT<inf>4</inf> receptors in the postmortem neocortex of Alzheimer disease: a clinicopathological study.
Journal of Neural Transmission,
110(7), 779-788.
Abstract:
[3H]GR113808 binding to serotonin 5-HT4 receptors in the postmortem neocortex of Alzheimer disease: a clinicopathological study
Abnormalities in neural transmission of serotonin (5-HT) may play a role in both cognitive and neuropsychiatric features of Alzheimer disease (AD). We measured 5-HT4 receptors in the postmortem frontal and temporal cortex of 34 AD subjects and 15 controls by radioligand binding with [3H]GR113808. Receptor binding data was then correlated with prospectively assessed cognitive (Mini-Mental State Examination, MMSE) and behavioral (Present Behavioural Examination, PBE) data. [3H]GR113808 binding affinity (KD) and density (Bmax) in AD were unchanged compared to controls in both cortical regions, and did not correlate with MMSE or PBE data. The binding parameters were also not related to disease duration, senile plaque and neurofibrillary tangle counts, and neuroleptic medication. We conclude that unlike other 5-HT receptors, 5-HT4 receptor binding affinity and density do not seem to be affected in the frontal and temporal cortex in AD and may not have a direct role in the clinical features of the disease.
Abstract.
Honer WG, Minger SL, Francis PT (2002). Commentary on "Synaptic pathology in prefrontal cortex is present only with severe dementia" - Response.
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY,
61(3), 295-296.
Author URL.
Honer WG, Minger SL, Francis PT (2002). Letter to the editor. Journal of Neuropathology and Experimental Neurology, 61(3).
McKeel DW, Masliah E, Hansen LA, Morris JC, Honer WG, Minger SL, Francis PT (2002). Letter to the editor (multiple letters). Journal of Neuropathology and Experimental Neurology, 61(3), 295-296.
Matthews KL, Chen CPL-H, Esiri MM, Keene J, Minger SL, Francis PT (2002). Noradrenergic changes, aggressive behavior, and cognition in patients with dementia.
Biol Psychiatry,
51(5), 407-416.
Abstract:
Noradrenergic changes, aggressive behavior, and cognition in patients with dementia.
BACKGROUND: We wished to examine the integrity of the noradrenergic system in patients with Alzheimer's disease, mixed/other dementias and controls, and possible relationships between changes in the noradrenergic system and the presence of behavioral and psychiatric signs and symptoms in dementia. METHODS: Alpha(2) adrenoceptor sites were measured by radioligand binding in three cortical regions of 46 individuals with dementia and 33 elderly normal controls together with cortical noradrenaline concentration and locus coeruleus cell and neurofibrillary tangle counts. RESULTS: the alpha(2) adrenergic receptor density was unaltered in patients with Alzheimer's disease, mixed/other dementias compared with controls; however, there was a loss of locus coeruleus cells in subjects with dementia, reaching 50% within the rostral nucleus. In addition, a significant reduction was seen in the midtemporal cortical noradrenaline concentration (31% decrease) in patients with Alzheimer's disease. In subjects with dementia, there was a positive correlation between aggressive behavior and magnitude of rostral locus coeruleus cell loss, while the reduction in noradrenaline concentration correlated with cognitive impairment. CONCLUSIONS: Subgroups of patients with Alzheimer's disease may have different neurochemical changes from patients lacking these changes. Therefore, this study may have implications for the treatment of behavioral and psychiatric signs and symptoms in dementia, particularly aggressive behavior in patients with dementia.
Abstract.
Author URL.
Lai MKP, Tsang SWY, Francis PT, Keene J, Hope T, Esiri MM, Spence I, Chen CPL-H (2002). Postmortem serotoninergic correlates of cognitive decline in Alzheimer's disease.
Neuroreport,
13(9), 1175-1178.
Abstract:
Postmortem serotoninergic correlates of cognitive decline in Alzheimer's disease.
Serotonin1A receptor density and serotonin concentration were measured in the postmortem neocortex of 17 AD patients who had been prospectively assessed every four months with the Mini-Mental State Examination (MMSE) for a mean of 2.6 years till death. In the frontal cortex, serotonin levels correlated negatively with the annual rate of MMSE decline, while serotonin1A receptor density was positively correlated with the rate of MMSE decline. Our study suggests that reduced serotonin levels and increased serotonin1A receptor density are markers for accelerated cognitive decline in AD, and provides support for the use of serotonin1A antagonists in the treatment of AD.
Abstract.
Author URL.
Cidis Meltzer C, Francis PT (2001). Brain aging research at the close of the 20th century: from bench to bedside.
Dialogues Clin Neurosci,
3(3), 167-180.
Abstract:
Brain aging research at the close of the 20th century: from bench to bedside.
Remarkable and continued growth in the field of brain aging research has been fueled by a confluence of factors. Developments in molecular biology, imaging, and genetics coupled with the imperative caused by the aging of the population has created fertile ground for improved understanding of the interaction between brain function and behavior. Aging changes in neurochemical systems may account for the spectrum of cognitive and behavioral states of successfully aged pen sons, but may also contribute to enhanced vulnerability to depressive or dementing illness. In particular, the refinement of in vivo imaging approaches to investigating the structure and function of the aging brain has provided the opportunity to strengthen our knowledge of the biological substrate of the aging brain and neuropsychiatrie disorders, and translate these into therapeutics.
Abstract.
Author URL.
Ramirez MJ, Ridley RM, Baker HF, Maclean CJ, Honer WG, Francis PT (2001). Chronic elevation of amyloid precursor protein in the neocortex or hippocampus of marmosets with selective cholinergic lesions.
J Neural Transm (Vienna),
108(7), 809-826.
Abstract:
Chronic elevation of amyloid precursor protein in the neocortex or hippocampus of marmosets with selective cholinergic lesions.
In vitro studies have consistently demonstrated a link between cholinergic neurotransmission and amyloid precursor protein metabolism, although few studies have examined such a relationship in vivo and none have been conducted in primate species. The purpose of this study was to test the hypothesis that a reduction in cholinergic activity in neocortical and hippocampal areas consequent upon destruction of ascending cholinergic projections may lead to long-term changes in levels of amyloid precursor protein in these target areas in a primate species. The status of three synaptic proteins associated with neurotransmitter release, synaptophysin, syntaxin and SNAP-25, was also been examined. Selective immunolesions of the basal forebrain cholinergic projections led to increases in amyloid precursor protein-like immunoreactivity in hippocampus and cortex, measured 8 months postlesion. Furthermore, reductions in cortical and hippocampal SNAP-25, but not syntaxin or synaptophysin, immunoreactivity were observed. These results imply that the reduced cholinergic activity characteristic of Alzheimer's disease may contribute to the continuing emergence of neuropathology in addition to the well-known association with cognitive dysfunction.
Abstract.
Author URL.
Ramirez MJ, Heslop KE, Francis PT, Rattray M (2001). Expression of amyloid precursor protein, tau and presenilin RNAs in rat hippocampus following deafferentation lesions.
Brain Res,
907(1-2), 222-232.
Abstract:
Expression of amyloid precursor protein, tau and presenilin RNAs in rat hippocampus following deafferentation lesions.
In this study, entorhinal cortex lesions and/or medial septal area cholinergic lesions were used in the rat to mimic some of the principal and earliest affects in Alzheimer's disease, namely hippocampal deafferentation. We wished to test the hypothesis that deafferentation lesions cause changes in the regulation of three proteins that are known to be important in Alzheimer's disease pathology, namely amyloid precursor protein, presenilin and tau. Expression of amyloid precursor protein mRNA was increased in several subfields of hippocampus when examined 1 week after entorhinal cortex lesion, but was reduced, compared to sham operated controls, after medial septal area cholinergic lesions. Cholinergic lesions were combined with entorhinal cortex lesions and produced no change in APP mRNA levels compared to controls. No significant changes were observed in the parietal cortex after entorhinal cortex or cholinergic lesions either alone or in combination. Tau mRNA level in hippocampus was unchanged after lesions. Presenilin-1 mRNA was expressed in the hippocampus at very low levels, and appeared to be increased following entorhinal cortex lesion. Our results support the hypothesis that amyloid precursor protein expression in hippocampal neurons is differentially affected by glutamatergic and cholinergic afferent input, and that presenilin-1, but not tau, may be subject to the same type of control in vivo.
Abstract.
Author URL.
Lai MK, Lai OF, Keene J, Esiri MM, Francis PT, Hope T, Chen CP (2001). Psychosis of Alzheimer's disease is associated with elevated muscarinic M2 binding in the cortex.
Neurology,
57(5), 805-811.
Abstract:
Psychosis of Alzheimer's disease is associated with elevated muscarinic M2 binding in the cortex.
OBJECTIVES: Results from recent drug trials suggest a role for the cholinergic system in the manifestation of neuropsychiatric symptoms in AD. To date, the status of muscarinic acetylcholine receptor subtypes in AD in relation to accompanying behavioral disturbances is unknown. This study aimed to measure alterations of muscarinic M(1) and M(2) receptor binding in the frontal and temporal cortex of AD and to correlate the neurochemical findings with clinical features. METHODS: the cognitive and behavioral features of 26 patients with AD were assessed prospectively using standardized tests. Together with 14 matched controls, the status of muscarinic M(1) and M(2) receptors in the postmortem frontal and temporal cortex of these patients were measured by radioligand binding assays and were correlated with clinical data. RESULTS: Compared with controls, M(2) receptor density was reduced only in the frontal cortex of AD, whereas M(1) was unaffected. Within the AD group, the neurochemical variables were not affected by demographic factors, disease severity, or cognition. Instead, M(2) receptor density was increased in the frontal and temporal cortex of patients with AD with psychotic symptoms compared with those without these symptoms. CONCLUSIONS: This study suggests a role for M(2) receptors in the psychosis of AD and may provide the rationale for treatment of behaviorally perturbed patients with AD with cholinomimetics and M(2) antagonists.
Abstract.
Author URL.
Minger SL, Honer WG, Esiri MM, McDonald B, Keene J, Nicoll JA, Carter J, Hope T, Francis PT (2001). Synaptic pathology in prefrontal cortex is present only with severe dementia in Alzheimer disease.
J Neuropathol Exp Neurol,
60(10), 929-936.
Abstract:
Synaptic pathology in prefrontal cortex is present only with severe dementia in Alzheimer disease.
Synaptic pathology is proposed to be integral to the clinical expression of Alzheimer disease (AD). Most studies have assessed only the vesicle protein synaptophysin as a measure of synaptic integrity. The interrelationships of synaptophysin, other presynaptic proteins, the cholinergic system, and severity of dementia in AD remain unclear. We studied the presynaptic proteins synaptophysin, syntaxin and SNAP-25, along with choline acetyltransferase (ChAT) activity in prefrontal cortex (BA 46) samples from 18 subjects with AD and 16 controls. Mean values of presynaptic protein immunoreactivities were significantly reduced, by 21%-28%, and ChAT activity was reduced by 41% in the AD groups. Synaptic protein immunoreactivity and ChAT activity were correlated with Mini-Mental State Examination scores obtained 1 yr prior to death. When AD cases were subgrouped into mild/moderate and severe illness at time of death, all differences in presynaptic proteins and ChAT activity were significant between controls and severe cases. However, no significant differences were detected in BA 46 between controls and mild/moderate cases. Considerable synaptic reserve or plasticity remains in BA 46 until the late stages of AD. Synaptophysin and ChAT appear to be more vulnerable in severe AD than are syntaxin or SNAP-25.
Abstract.
Author URL.
Clarke NA, Soininen H, Gustafson L, Minthon L, Alhainen K, Francis PT (2001). Tacrine may alter APP-like protein levels in the lumbar CSF of Alzheimer patients.
Int J Geriatr Psychiatry,
16(11), 1104-1106.
Author URL.
Minger SL, Esiri MM, McDonald B, Keene J, Carter J, Hope T, Francis PT (2000). Cholinergic deficits contribute to behavioral disturbance in patients with dementia.
Neurology,
55(10), 1460-1467.
Abstract:
Cholinergic deficits contribute to behavioral disturbance in patients with dementia.
BACKGROUND: Noncognitive behavioral changes such as depression, aggressive behavior, psychosis, and overactivity occur frequently in patients with dementia, in addition to cognitive impairment, and often determine the need for institutionalization. The biochemical basis of such changes is poorly understood. Clinical trial data indicate that cholinomimetics improve noncognitive behaviors. This study investigated the relationship between markers of the cholinergic and dopaminergic neurotransmitter systems and noncognitive behavioral symptoms assessed during the course of dementing illness. METHOD: Brains from 46 patients with dementia (36 with AD and 10 with mixed or other dementias using Consortium to Establish a Registry for AD criteria) were examined together with 32 normal controls. The patients with dementia had been evaluated every 4 months, often over several years, for cognitive performance (Mini-Mental State Examination) and behavior (Present Behavioral Examination). Concentrations of dopamine (DA) and major metabolites, choline acetyltransferase activity (ChAT), and density (Bmax) of DA D1 receptors in frontal and temporal cortex were studied by radioligand binding protocols. None of the patients was receiving cholinomimetic drugs. RESULTS: ChAT activity, but no other neurochemical markers, was reduced in AD compared with controls. Loss of ChAT activity correlated with cognitive impairment. Lowered ChAT activity also correlated with increasing overactivity in patients with dementia in both frontal and temporal cortex whereas ChAT:DA and ChAT:D1 ratios in temporal cortex correlated negatively with aggressive behavior. CONCLUSIONS: Disturbance of the cholinergic system may underlie both cognitive and some noncognitive behavioral changes in dementia, providing a basis for rational therapy.-1467
Abstract.
Author URL.
Chen CP, Eastwood SL, Hope T, McDonald B, Francis PT, Esiri MM (2000). Immunocytochemical study of the dorsal and median raphe nuclei in patients with Alzheimer's disease prospectively assessed for behavioural changes.
Neuropathol Appl Neurobiol,
26(4), 347-355.
Abstract:
Immunocytochemical study of the dorsal and median raphe nuclei in patients with Alzheimer's disease prospectively assessed for behavioural changes.
The dorsal and median raphe nuclei were examined with immunocytochemistry to display the 5-HT neurones in 16 cases of post-mortem-proven Alzheimer's disease (AD) and 12 age and sex-matched controls. The AD cases had been prospectively assessed during life for expression of behavioural changes as well as for cognitive decline. A significant (P < 0.001) 41% reduction in density of dorsal raphe neurones was found along with a significant (P < 0.02) 29% reduction in density of median raphe neurones in AD. There were significantly more neurofibrillary tangles in both dorsal and median raphe nuclei in AD than in controls (P < 0.001). There was no correlation between reduction in neurone density in these nuclei and behavioural change, cognitive decline, neurofibrillary tangle counts in these nuclei or plaque and tangle pathology in frontal and temporal cortex. It was concluded from these findings that the raphe nuclei are significantly affected by the pathology of AD and that plasticity in the 5-HT system is the probable reason for the lack of correlation of reduced 5-HT neurone density and clinical disease parameters.
Abstract.
Author URL.
Webster MT, Amin N, Pearce B, Francis PT (1999). Glutamate toxicity in rat cultured neurones: effects on amyloid precursor-like protein 2.
Neurosci Lett,
276(2), 107-110.
Abstract:
Glutamate toxicity in rat cultured neurones: effects on amyloid precursor-like protein 2.
Amyloid precursor protein, which gives rise to the a beta polypeptide found in senile plaques in the brains of patients with Alzheimer's disease, is a member of a family of proteins which includes amyloid precursor-like protein 2 (APLP2). To date, little is known of the involvement of this protein in Alzheimer's disease or any other neurodegenerative condition. The present study set out to determine whether APLP2 expression could be modified in cultured rat cortical neurones exposed to an excitotoxic insult. Treatment of cultures with glutamate (500 microM) for 30 min resulted in increased lactate dehydrogenase liberation into the bathing medium 24 h after removal of the insult indicating neuronal damage. This was accompanied by a decrease in APLP2 recovery in the medium but no change in its intracellular level. Both the increase in LDH release and APLP2 recovery were prevented by pretreatment with the N-methyl-D-aspartate receptor antagonist MK-801. These data show that neuronal APLP2 metabolism is altered in response to an excitotoxic insult.
Abstract.
Author URL.
Procter AW, Qurne M, Francis PT (1999). Neurochemical features of frontotemporal dementia.
Dement Geriatr Cogn Disord,
10 Suppl 1, 80-84.
Abstract:
Neurochemical features of frontotemporal dementia.
This study examines neurochemical measures of cholinergic, serotonergic and glutamatergic innervation in frontal temporal and parietal cerebral cortex from 16 subjects with frontotemporal dementia (FTD) including 10 subjects with Pick pathology and 6 with dementia of frontal lobe type (DFT) together with 9 subjects with Alzheimer's disease, and 28 matched controls. In both forms of FTD there was not evidence of any cholinergic abnormality, unlike the situation in AD. Serotonin receptors were lost from frontal and temporal cortex in FTD and from temporal and parietal cortex in AD. In FTD there was no loss of kainate receptors but loss of AMPA receptors from both temporal and frontal lobes. Loss of AMPA receptors differentiated Pick-type FTD from DFT. These results are interpreted to indicate selective losses of subpopulations of cortical pyramidal neurones.
Abstract.
Author URL.
Babic T, Francis PT, Palmer AM, Snape M, Wilcock GK (1999). The cholinergic hypothesis of Alzheimer's disease: a review of progress (multiple letters) [11]. Journal of Neurology Neurosurgery and Psychiatry, 67(4).
Francis PT, Palmer AM, Snape M, Wilcock GK (1999). The cholinergic hypothesis of Alzheimer's disease: a review of progress - Reply.
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY,
67(4), 558-558.
Author URL.
Francis PT, Palmer AM, Snape M, Wilcock GK (1999). The cholinergic hypothesis of Alzheimer's disease: a review of progress.
J Neurol Neurosurg Psychiatry,
66(2), 137-147.
Abstract:
The cholinergic hypothesis of Alzheimer's disease: a review of progress.
Alzheimer's disease is one of the most common causes of mental deterioration in elderly people, accounting for around 50%-60% of the overall cases of dementia among persons over 65 years of age. The past two decades have witnessed a considerable research effort directed towards discovering the cause of Alzheimer's disease with the ultimate hope of developing safe and effective pharmacological treatments. This article examines the existing scientific applicability of the original cholinergic hypothesis of Alzheimer's disease by describing the biochemical and histopathological changes of neurotransmitter markers that occur in the brains of patients with Alzheimer's disease both at postmortem and neurosurgical cerebral biopsy and the behavioural consequences of cholinomimetic drugs and cholinergic lesions. Such studies have resulted in the discovery of an association between a decline in learning and memory, and a deficit in excitatory amino acid (EAA) neurotransmission, together with important roles for the cholinergic system in attentional processing and as a modulator of EAA neurotransmission. Accordingly, although there is presently no "cure" for Alzheimer's disease, a large number of potential therapeutic interventions have emerged that are designed to correct loss of presynaptic cholinergic function. A few of these compounds have confirmed efficacy in delaying the deterioration of symptoms of Alzheimer's disease, a valuable treatment target considering the progressive nature of the disease. Indeed, three compounds have received European approval for the treatment of the cognitive symptoms of Alzheimer's disease, first tacrine and more recently, donepezil and rivastigmine, all of which are cholinesterase inhibitors.
Abstract.
Author URL.
Chen CP, Alder JT, Bray L, Kingsbury AE, Francis PT, Foster OJ (1998). Post-synaptic 5-HT1A and 5-HT2A receptors are increased in Parkinson's disease neocortex.
Ann N Y Acad Sci,
861, 288-289.
Author URL.
Webster MT, Pearce BR, Bowen DM, Francis PT (1998). The effects of perturbed energy metabolism on the processing of amyloid precursor protein in PC12 cells.
J Neural Transm (Vienna),
105(8-9), 839-853.
Abstract:
The effects of perturbed energy metabolism on the processing of amyloid precursor protein in PC12 cells.
The mismetabolism of amyloid precursor protein (APP), favouring the production of a beta, is considered to be central to the pathogenesis of Alzheimer's disease (AD). However it remains to be established whether the causative factor is the reported toxicity of a beta or reduced production of secretory derivatives of APP which may have trophic or neuroprotective properties. One possible contributory factor to an imbalance in APP metabolism is the impaired cellular energy availability described in AD. The aim of this study was to investigate processing of APP-like proteins following inhibition of oxidative energy metabolism in PC12 cells. Under these conditions, intracellular and secreted APP-like proteins were significantly reduced. Treatment of energy perturbed cells with the lysosomotropic agent chloroquine restored intracellular concentrations of APP-like proteins to the control range, while the secretion was completely restored by activation of protein kinase C. These findings raise the possibility that energy related metabolic stress may lead to altered metabolism of APP-like proteins favouring a potentially amyloidogenic pathway. Furthermore, the observation that activation of PKC is able to overcome this potentially pathogenic process has important implications for treatment of AD with the current generation of cholinomimetic drugs, suggesting that such drugs may slow disease progression as well as improve cognitive dysfunction.
Abstract.
Author URL.
Heath PR, Chessell IP, Sanders MW, Francis PT, Bowen DM, Pearson RC (1997). Neuronal degeneration by suicide transport following injection of volkensin into rat cerebral cortex.
Exp Neurol,
147(1), 192-203.
Abstract:
Neuronal degeneration by suicide transport following injection of volkensin into rat cerebral cortex.
We have examined the time course of neurodegeneration in subcortical nuclei and other cortical areas known to project to the rat parietal cortex, following unilateral injection of the suicide transport agent, volkensin, into the cortex of one side. Degenerating neurons, visualized by Gallyas silver staining were most prominent 21 days after injection. At this time darkly staining neurons were present in nuclei and areas known to project to the injected cortical area but not in other sites. Affected subcortical nuclei included the ipsilateral ventral thalamus and intralaminar nuclei, the basal nucleus of Meynert and claustrum of the same side, and the dorsal median raphé nucleus of both sides. Within the cortex degenerating pyramidal neurons were visible in the contralateral parietal cortex and in the frontal cortex of the same side. The distribution of degenerating cells is in agreement with the conclusion that only neurons projecting to the injection site were affected. The time course of the appearance of the degeneration and its distribution are in keeping with axonal transport rather than spread by diffusion of the toxin. Neuronal counts in Nissl-stained sections of the contralateral SMI confirmed significant neuronal loss 28 days after injection. In situ hybridization studies using an oligonucleotide probe directed against GAD mRNA and counts of GAD mRNA-positive neurons in the contralateral cortex confirmed that this population of cortical interneurons, which do not project to the injection site, were unaffected.
Abstract.
Author URL.
Francis PT, Chessell IP, Bowen DM (1997). New approaches to imaging based on effects of neurotoxins.
Dement Geriatr Cogn Disord,
8(2), 117-122.
Abstract:
New approaches to imaging based on effects of neurotoxins.
Positron and single-photon emission tomography at present visualize only loss of overall brain substance, with a few exceptions. This has improved diagnostic accuracy in the clinic but further improvements could be made. By using toxins, such as volkensin, brain tissues can be produced that are deficient in various subpopulations of cortical pyramidal neurone. Experimental lesions in rats and quantitative autoradiography were used to investigate the cellular localization of receptors. Lesions were produced by intrastriatal or intracortical injections of volkensin to destroy corticofugal and corticortical pyramidal neurones respectively. Volkensin treatment caused significant loss of pyramidal neurones which was accompanied by reduced binding to certain receptors. Results are discussed in terms of the biology of cortical pyramidal neurones and in vivo imaging in Alzheimer's disease.
Abstract.
Author URL.
Chessell IP, Pearson RC, Heath PR, Bown DM, Francis PT (1997). Selective loss of cholinergic receptors following unilateral intracortical injection of volkensin.
Exp Neurol,
147(1), 183-191.
Abstract:
Selective loss of cholinergic receptors following unilateral intracortical injection of volkensin.
Experimental lesions and quantitative autoradiography were used to investigate the cellular distribution of neurotransmitter receptors in rats. Lesions were produced by intracortical injections of either volkensin or ricin. However, only the former is retrogradely transported and volkensin treatment causes significant loss of contralateral cortical pyramidal neurones. Binding of [3H]pirenzepine (muscarinic M1 receptors) and [3H]nicotine was reduced in contralateral cortex in volkensin compared with ricin and/or control (uninjected) animals. However, binding of [3H]8-hydroxy-2-(n-dipropylamino)tetralin (5-HT1A receptors), [3H]ketanserin (5-HT2A receptors), and [3H]1,3-dipropylcyclopentylxanthine (adenosine A1 receptors) was unchanged. The most likely explanation for these results is that M1 and nicotinic receptors are present in large numbers on those pyramidal neurones that are lost. The results are discussed in terms of the biology of cortical pyramidal neurones, drugs for Alzheimer's disease, and novel ligands for improving human brain scanning techniques.
Abstract.
Author URL.
Palmer AM, Francis PT (1996). Alzheimer's disease: from acetylcholine to beta-amyloid. A tribute to the work of Professor David M. Bowen.
Neurodegeneration,
5(4), 379-380.
Author URL.
Chen CPLH, Alder JT, Bowen DM, Esiri MM, McDonald B, Hope T, Jobst KA, Francis PT (1996). Presynaptic serotonergic markers in community-acquired cases of Alzheimer's disease: Correlations with depression and neuroleptic medication.
JOURNAL OF NEUROCHEMISTRY,
66(4), 1592-1598.
Author URL.
Francis PT (1996). Pyramidal neurone modulation: a therapeutic target for Alzheimer's disease.
Neurodegeneration,
5(4), 461-465.
Abstract:
Pyramidal neurone modulation: a therapeutic target for Alzheimer's disease.
It is proposed that pyramidal neurones are central to the pathogenesis and cognitive dysfunction of AD on the basis that they are the site of tangle formation and the mismetabolism of APP and degenerate, and that such cells are the focus of neurotransmitter abnormalities. Anatomical studies in animal and human brain are revealing which neurotransmitter receptors are present on populations of pyramidal neurones and a microdialysis approach has demonstrated the ability of such receptors to alter neuronal activity. Specifically, it is proposed that cholinomimetics used for the symptomatic treatment of AD may work by influencing the activity of pyramidal neurones and that this action may be potentiated by a 5-HT1A antagonist. The contribution of pyramidal neurone transmission failure to the spread of pathology in AD is the subject of continuing investigation.
Abstract.
Author URL.
Harder JA, Maclean CJ, Alder JT, Francis PT, Ridley RM (1996). The 5-HT(1A) antagonist, WAY 100635, ameliorates the cognitive impairment induced by fornix transection in the marmoset.
Psychopharmacology,
127(3), 245-254.
Abstract:
The 5-HT(1A) antagonist, WAY 100635, ameliorates the cognitive impairment induced by fornix transection in the marmoset
Fornix transection in the marmoset produces a specific pattern of cognitive deficits, notably a lack of ability to recall visuospatial tasks learnt preoperatively, and a deficit in acquiring new visuospatial tasks following transection. Previous work has shown that this learning impairment can be ameliorated by cholinergic agonists, suggesting that it occurs as a consequence of destroying the cholinergic projection from the vertical limb of the diagonal band to the hippocampus which runs through the fornix. We have now shown that this deficit in new learning can be significantly alleviated by the 5-HT(1A) antagonist, WAY 100635. This result supports the suggestion that 5-HT(1A) projections are inhibitory on the same target cells for which cholinergic projections are excitatory, and that loss of function in the target cells caused by loss of excitatory tone can be compensated by blockade of inhibitory tone. Since cholinergic loss in the hippocampus (and neocortex) occurs in association with cognitive decline in Alzheimer's disease, these results suggest that 5HT(1A) antagonists may have a role in the treatment of some of the cognitive symptoms of dementia.
Abstract.
Harder JA, Maclean CJ, Alder JT, Francis PT, Ridley RM (1996). The 5-HT1A antagonist, WAY 100635, ameliorates the cognitive impairment induced by fornix transection in the marmoset.
Psychopharmacology (Berl),
127(3), 245-254.
Abstract:
The 5-HT1A antagonist, WAY 100635, ameliorates the cognitive impairment induced by fornix transection in the marmoset.
Fornix transection in the marmoset produces a specific pattern of cognitive deficits, notably a lack of ability to recall visuospatial tasks learnt preoperatively, and a deficit in acquiring new visuospatial tasks following transection. Previous work has shown that this learning impairment can be ameliorated by cholinergic agonists, suggesting that it occurs as a consequence of destroying the cholinergic projection from the vertical limb of the diagonal band to the hippocampus which runs through the fornix. We have now shown that this deficit in new learning can be significantly alleviated by the 5-HT1A antagonist, WAY 100635. This result supports the suggestion that 5-HT1A projections are inhibitory on the same target cells for which cholinergic projections are excitatory, and that loss of function in the target cells caused by loss of excitatory tone can be compensated by blockade of inhibitory tone. Since cholinergic loss in the hippocampus (and neocortex) occurs in association with cognitive decline in Alzheimer's disease, these results suggest that 5-HT1A antagonists may have a role in the treatment of some of the cognitive symptoms of dementia.
Abstract.
Author URL.
Webster MT, Groome N, Francis PT, Pearce BR, Sherriff FE, Thinakaran G, Felsenstein KM, Wasco W, Tanzi RE, Bowen DM, et al (1995). A novel protein, amyloid precursor-like protein 2, is present in human brain, cerebrospinal fluid and conditioned media.
Biochem J,
310 ( Pt 1)(Pt 1), 95-99.
Abstract:
A novel protein, amyloid precursor-like protein 2, is present in human brain, cerebrospinal fluid and conditioned media.
A monoclonal antibody, 3B11, was raised to a novel protein, amyloid precursor-like protein 2, which did not recognize amyloid precursor protein. Multiple bands were detected in human brain fractions and cell lysate by Western blotting, indicating the presence of isoforms, 3B11 immunoreactivity was also detected in cerebrospinal fluid and conditioned medium, indicating that the protein is secreted. Immunocytochemistry revealed 3B11 immunoreactivity in sections of human brain.
Abstract.
Author URL.
Chessell IP, Francis PT, Bowen DM (1995). Changes in cortical nicotinic acetylcholine receptor numbers following unilateral destruction of pyramidal neurones by intrastriatal volkensin injection.
NEURODEGENERATION,
4(4), 415-424.
Author URL.
Dijk SN, Francis PT, Stratmann GC, Bowen DM (1995). Cholinomimetics increase glutamate outflow via an action on the corticostriatal pathway: implications for Alzheimer's disease.
J Neurochem,
65(5), 2165-2169.
Abstract:
Cholinomimetics increase glutamate outflow via an action on the corticostriatal pathway: implications for Alzheimer's disease.
Physostigmine, the acetylcholinesterase inhibitor (0.3 mg/kg, i.m.), increased extracellular glutamate but not aspartate concentrations in the striatum of anaesthetised rats, determined using microdialysis and HPLC. The rise was both tetrodotoxin and calcium dependent. In contrast, neither physostigmine (10 microM) added to the perfusion fluid nor vehicle (injected intramuscularly) affected amino acid concentrations. To obtain evidence that the action of acetylcholine was to modulate positively cortical pyramidal neurone activity via the M1 receptor, the selective M1 agonist PD 142505-0028 (10 microM) was topically applied to the frontal cortex. Like physostigmine, PD 142505-0028 rapidly increased glutamate but not aspartate concentrations in the striatum. Moreover, the effect of intramuscular physostigmine was blocked by a topically applied M1 antagonist. These new data add to our hypothesis that cholinomimetics increase pyramidal neurone function.
Abstract.
Author URL.
FRANCIS PT, DIJK SN, CHEN C, BOWEN DM (1995). METABOLIC AND FUNCTIONAL DEFICITS IN ALZHEIMER-DISEASE IN RELATION TO TREATMENT.
DEVELOPMENTAL BRAIN DYSFUNCTION,
8(1), 25-34.
Author URL.
Dijk SN, Francis PT, Stratmann GC, Bowen DM (1995). NMDA-induced glutamate and aspartate release from rat cortical pyramidal neurones: evidence for modulation by a 5-HT1A antagonist.
Br J Pharmacol,
115(7), 1169-1174.
Abstract:
NMDA-induced glutamate and aspartate release from rat cortical pyramidal neurones: evidence for modulation by a 5-HT1A antagonist.
1. We have investigated an aspect of the regulation of cortical pyramidal neurone activity. Microdialysis was used to assess whether topical application of drugs (in 10 microliter) to fill a burr hole over the frontal cortex, where part of the corticostriatal pathway originates, would change concentrations of the excitatory amino acids glutamate and aspartate in the striatum of the anaesthetized rat. 2. Topical application of N-methyl-D-aspartate (NMDA, 2 and 20 mM) dose-dependently increased glutamate and aspartate concentrations in the striatum. Coapplication of tetrodotoxin (10 microM) blocked the NMDA-evoked rise in these amino acids. A calcium-free medium, perfused through the probe also blocked the rise, indicating that it was due to an exocytotic mechanism in the striatum. 3. It was hypothesized that the rise observed was due to an increase in the activity of the corticostriatal pathway. As 5-hydroxytryptamine1A (5-HT1A) receptors are enriched on cell bodies of corticostriatal neurones, a selective 5-HT1A-antagonist (WAY 100135) was coapplied with the lower dose of NMDA. Compared to NMDA alone, coapplication of 50 microM WAY 100135 significantly increased glutamate release. This effect was sensitive to tetrodotoxin and calcium-dependent. Application of 50 microM WAY 100135 alone significantly enhanced glutamate release above baseline; this was also tested at 100 microM (not significant). 4. Compared to NMDA alone, coapplication of WAY 100135 (20 microM) significantly enhanced aspartate release; the mean value was also increased (not significantly) with 50 microM. This rise was calcium-dependent, but not tetrodotoxin-sensitive. WAY 100135 (100 microM) reduced NMDA-induced aspartate release. WAY 100135 (100 microM) reduced NMDA-induced aspartate release. Application of the drug alone had no effect on basal aspartate release.5. Coapplication of the 5-HT1A agonist, 8-OHDPAT (5 sanM) with NMDA did not affect the NMDA evoked increase in glutamate and aspartate.6. Topical application of high potassium (100 sanM) to the surface of the cortex did not result in a detectable rise in striatal glutamate or aspartate.7. Perfusion of WAY 100135 (tested at 50 microM) through the dialysis probe did not affect glutamate oraspartate concentrations.8. It was concluded that a selective 5-HT1A-antagonist can increase the activity of corticostriatal pyramidal neurones. As in Alzheimer's disease hypoactivity of pyramidal neurones almost certainly exists, a selective 5-HT1A-antagonist may be potentially useful in the treatment of the cognitive symptoms of this disease.
Abstract.
Author URL.
Qume M, Misra A, Zeman S, Boddy JL, Cross AJ, Francis PT, Procter AW, Mann DM, Bowen DM (1995). Non-serotonergic profiles of lobar atrophies.
Biochem Soc Trans,
23(4).
Author URL.
Qume M, Misra A, Zeman S, Muthu J, Cross AJ, Francis PT, Procter AW, Neary D, Bowen DM (1995). Serotonergic profiles of lobar atrophies.
Biochem Soc Trans,
23(4).
Author URL.
Chessell IP, Francis PT, Webster MT, Procter AW, Heath PR, Pearson RC, Bowen DM (1994). An aspect of Alzheimer neuropathology after suicide transport damage.
J Neural Transm Suppl,
44, 231-243.
Abstract:
An aspect of Alzheimer neuropathology after suicide transport damage.
Concentrations of APP-like immunoreactivity have been determined by western blotting in a soluble fraction and two membrane fractions of brain cortex from demented patients (14 with Alzheimer's disease and 8 with other diagnoses). The concentration of APP in the soluble fraction correlated with the number of pyramidal neurones but not astrocytes or indices of interneurones. Experimental lesions in rats and quantitative autoradiography were used to investigate the cellular localisation of receptors. Lesions were produced by intrastriatal or intracortical injections of volkensin to destroy corticofugal and corticortical pyramidal neurons respectively. Volkensin treatment caused significant loss of pyramidal neurones which was accompanied by reduced binding to muscarinic cholinergic m1 receptors. [3H] 8-OH-DPAT (serotonin 1A receptors) binding was reduced only following intrastriatal volkensin. Results from the human and rat investigations are discussed in terms of the biology of cortical pyramidal neurones and drugs for the treatment of Alzheimer's disease.
Abstract.
Author URL.
PROCTER AW, FRANCIS PT, HOLMES C, WEBSTER MT, QUME M, STRATMANN GC, DOSHI R, MANN DMA, HARRISON PJ, PEARSON RCA, et al (1994). BETA-AMYLOID PRECURSOR PROTEIN ISOFORMS SHOW CORRELATIONS WITH NEURONS BUT NOT WITH GLIA OF DEMENTED SUBJECTS.
ACTA NEUROPATHOLOGICA,
88(6), 545-552.
Author URL.
Stratmann GC, Webster MT, Francis PT, Procter AW, Bowen DM (1994). Brain membrane serine protease activity in human cortex compared with rat: implication for Alzheimer's disease.
Dementia,
5(2), 62-68.
Abstract:
Brain membrane serine protease activity in human cortex compared with rat: implication for Alzheimer's disease.
Cerebral cortex from humans and rats was extracted sequentially with detergent-containing and low-ionic-strength buffers. The resulting pellet was extracted with detergent/high-ionic-strength buffer to yield a soluble enzyme preparation. This was incubated with substrate prepared from rat cerebral cortical membranes containing amyloid precursor protein-like immunoreactivity (APPLIR) of 116 kD approximate apparent molecular mass. The effectiveness of various enzyme preparations to degrade APPLIR was: routine-post-mortem (pm)-delay human samples > rat pup > short-pm-delay human samples >> adult rat. In incubations with human samples only a 100-kD product accumulated. The activity in human brain was inhibited by phenylmethylsulphonylfluoride, insensitive to Ca2+, correlated with pyramidal neurone numbers but not those of astrocytes and was not significantly higher in Alzheimer's disease compared with controls. These data are discussed in terms of other approaches for studying proteolytic activity to explain the deposition of beta-amyloid protein in this disease.
Abstract.
Author URL.
Francis PT, Bowen DM (1994). Neuronal pathology in relation to molecular biology and treatment of Alzheimer's disease.
Mol Cell Biol Hum Dis Ser,
4, 25-54.
Author URL.
Bowen DM, Francis PT, Chessell IP, Webster MT (1994). Neurotransmission--the link integrating Alzheimer research?.
Trends Neurosci,
17(4), 149-150.
Author URL.
Webster MT, Francis PT, Procter AW, Stratmann GC, Doshi R, Mann DM, Bowen DM (1994). Postmortem brains reveal similar but not identical amyloid precursor protein-like immunoreactivity in Alzheimer compared with other dementias.
Brain Res,
644(2), 347-351.
Abstract:
Postmortem brains reveal similar but not identical amyloid precursor protein-like immunoreactivity in Alzheimer compared with other dementias.
Concentrations of amyloid precursor protein (APP)-like immunoreactivity (APPLIR) have been determined by Western blotting in a soluble fraction and two membrane fractions of two areas of brain cortex from patients with Alzheimer's disease (AD) and other dementias. There were no significant differences between AD and other cases in species with the Kunitz protease inhibitor domain. However, the total soluble APPLIR was higher in AD and it was hypothesized that this relates to cholinergic hypoactivity.
Abstract.
Author URL.
Procter AW, Francis PT, Holmes C, Webster MT, Qume M, Stratmann GC, Doshi R, Mann DMA, Harrison PJ, Pearson RCA, et al (1994). β-Amyloid precursor protein isoforms show correlations with neurones but not with glia of demented subjects.
Acta Neuropathologica,
88(6), 545-552.
Abstract:
β-Amyloid precursor protein isoforms show correlations with neurones but not with glia of demented subjects
Post-mortem cerebral cortex from 15 demented patients was specially collected to minimise autolysis and two membrane fractions and one soluble fraction were quantitatively examined for the major species of β-amyloid precursor protein (APP) of high apparent molecular mass (≥ 80 kDa) together with the major mRNA species encoding APP isoforms. The number of pyramidal neurones and astrocytes, putative biochemical indices of interneurones and pyramidal neurones, and choline acetyl transferase activity were also determined. Multiple regression analysis has been used to investigate intercorrelations of APP species with biochemical and morphometric measures, free of any effects of confounding demographic variables. Subjects with Alzheimer's disease showed a loss of cholinergic activity and d-aspartate uptake compared with patients with other causes of dementia. The major finding of the study is that measures of neurones rather than astrocytes most closely correlate with the concentration of APP. Pyramidal cell numbers were positively correlated with mRNA for APP695. APP in the soluble fraction showed a negative correlation with pyramidal cell numbers and cholinergic activity. These results indicate that neurones within the cerebral cortex are the major source of APP, and that secretion of APP is dependent upon cortical pyramidal neuronal activity and cholinergic activity. © 1994 Springer-Verlag.
Abstract.
Chessell IP, Francis PT, Bowen DM (1993). A cortical pyramidal neurone neurotransmitter receptor that may affect beta-amyloid precursor protein.
Biochem Soc Trans,
21 ( Pt 3)(3).
Author URL.
Francis PT, Pangalos MN, Stephens PH, Bartlett JR, Bridges PK, Malizia AL, Neary D, Procter AW, Thomas DJ, Bowen DM, et al (1993). Antemortem measurements of neurotransmission: possible implications for pharmacotherapy of Alzheimer's disease and depression.
J Neurol Neurosurg Psychiatry,
56(1), 80-84.
Abstract:
Antemortem measurements of neurotransmission: possible implications for pharmacotherapy of Alzheimer's disease and depression.
Aspartic acid, 5-hydroxyindoleacetic acid, glutamic acid, homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol was determined in samples of ventricular fluid from 82 subjects. Laminar distribution of the total number (Bmax value) of serotonin 1A receptors was determined on seven neurosurgical samples of neocortex. Apart from an association in a small subgroup of subjects between homovanillate concentration and corticosteroid medication, no complicating influences of treatment preceding operation were found. The content of the serotonin metabolite alone was significantly reduced in intractable depressive illness (bipolar and major depressive disorders) compared with neurological conditions subdivided into Alzheimer's disease, other dementias and other conditions. There was no other significant difference between these groups for the compounds measured. The total number of serotonin 1A receptors was highest in the superficial layers, being considerably higher than in the rat, irrespective of cortical layer. This part of the study indicated that these receptors are important for regulating activity of human corticocortical glutamatergic neurons. The results are discussed in relation to treating depression with serotonergic agents and targeting corticocortical glutamatergic neurons as well as acetylcholine in Alzheimer's disease.
Abstract.
Author URL.
CLARKE NA, WEBSTER MT, FRANCIS PT, PROCTER AW, HODGKISS AD, BOWEN DM (1993). BETA-AMYLOID PRECURSOR PROTEIN-LIKE IMMUNOREACTIVITY CAN BE ALTERED IN HUMANS BY DRUGS AFFECTING NEUROTRANSMITTER FUNCTION.
NEURODEGENERATION,
2(4), 243-248.
Author URL.
Francis PT, Sims NR, Procter AW, Bowen DM (1993). Cortical pyramidal neurone loss may cause glutamatergic hypoactivity and cognitive impairment in Alzheimer's disease: investigative and therapeutic perspectives.
J Neurochem,
60(5), 1589-1604.
Author URL.
Clarke NA, Procter AW, Webster MT, Francis PT, Hodgkiss AD, Bowen DM (1993). Effect of Li+ therapy and site of origin on cerebrospinal fluid beta-amyloid precursor protein derivatives.
Biochem Soc Trans,
21 ( Pt 3)(3).
Author URL.
Webster MT, Vekrellis K, Francis PT, Pearce BR, Bowen DM (1993). Factors affecting the beta-amyloid precursor in PC12 cells.
Biochem Soc Trans,
21 ( Pt 3)(3).
Author URL.
CHESSELL IP, FRANCIS PT, PANGALOS MN, PEARSON RCA, BOWEN DM (1993). LOCALIZATION OF MUSCARINIC (M(1)) AND OTHER NEUROTRANSMITTER RECEPTORS ON CORTICOFUGAL-PROJECTING PYRAMIDAL NEURONS.
BRAIN RESEARCH,
632(1-2), 86-94.
Author URL.
Bowen DM, Francis PT, Pangalos MN, Chessell IP (1993). Neurotransmitter receptors of rat cortical pyramidal neurones: implications for in vivo imaging and therapy.
J Reprod Fertil Suppl,
46, 131-143.
Abstract:
Neurotransmitter receptors of rat cortical pyramidal neurones: implications for in vivo imaging and therapy.
Pyramidal neurones of the neocortex have been implicated in a number of neuropsychiatric diseases, such as Alzheimer's disease. Markers that may identify these cells have been investigated using a novel technique. A subpopulation of corticifugal neocortical pyramidal neurones was destroyed by the unilateral striatal injection of volkensin, a toxin that undergoes retrograde suicide transport from the site of injection. Striatal volkensin injections produced significant reductions in the number of large pyramidal neurones of the infragranular cortical layer. The selectivity of the lesion was demonstrated by the preservation of cells containing glutamic acid decarboxylase mRNA, which are considered to be cortical interneurones. Ricin, another toxic lectin, but effective as a suicide transport agent exclusively in the PNS, produced local striatal damage but no cortical cell loss. In autoradiographic binding studies of animals treated with volkensin, binding in deep neocortical layers of [3H]8-hydroxy-2-(n-dipropylamino) tetralin ([3H]8-OH-DPAT) to 5-HT1A but not of [3H]ketanserin to 5-HT2 receptors was significantly reduced. The N-methyl-D-aspartate receptor complex was investigated using the novel glycine site antagonist [3H]L-689,560, and the muscarinic M1 receptor using [3H]pirenzepine. Significant reductions in binding of [3H]L-689,560 and [3H]pirenzepine were observed in the deep neocortical layers of the animals that had been injected with volkensin. The rank order of the ligands as effective markers for this subpopulation of pyramidal neurones was [3H]8-OH-DPAT >> [3H]pirenzepine > [3H]L-689,560 >> [3H]ketanserin. These findings are thought to have advanced the understanding of the biology of pyramidal neurones. Implications for in vivo imaging treatment of neuropsychiatric conditions such as Alzheimer's disease are discussed.
Abstract.
Author URL.
Francis PT, Webster MT, Chessell IP, Holmes C, Stratmann GC, Procter AW, Cross AJ, Green AR, Bowen DM (1993). Neurotransmitters and second messengers in aging and Alzheimer's disease.
Ann N Y Acad Sci,
695, 19-26.
Abstract:
Neurotransmitters and second messengers in aging and Alzheimer's disease.
A substantial loss of cortical cholinergic nerve endings, along with a much more circumscribed cortical degeneration of pyramidal neurons, almost certainly causes glutamatergic hypoactivity in live Alzheimer's patients. These selective pathologies are discussed in terms of therapy. An additional effect of some proposed treatments is emerging as there is evidence that processing pathways for beta-amyloid precursor proteins in cortical pyramidal neurons, a target cell for acetylcholine, are affected by neuronal activity.
Abstract.
Author URL.
Francis PT, Holmes C, Webster MT, Stratmann GC, Procter AW, Bowen DM (1993). Preliminary neurochemical findings in non-Alzheimer dementia due to lobar atrophy.
Dementia,
4(3-4), 172-177.
Abstract:
Preliminary neurochemical findings in non-Alzheimer dementia due to lobar atrophy.
Non-Alzheimer's dementia due to lobar atrophy had choline acetyltransferase activities comparable with control rather than Alzheimer's disease values, based on 3 autopsy proven cases on Pick's disease and biopsies from 3 examples of dementia of frontal lobe type. Muscarinic cholinergic receptors were relatively spared only in Alzheimer's disease. Serotonin receptors were markedly reduced (based on Pick cases) whereas measures that reflected presynaptic serotonergic activity were either not affected or increased. Cerebrospinal fluid and brain tissue measurements suggested that inhibitory interneurones and dopamine release were relatively spared. There was no in vitro evidence of hypometabolism.
Abstract.
Author URL.
Stratmann GC, Webster MT, Bhogal G, Francis PT, Bowen DM (1993). Protease "Clipsin" activity and beta-amyloid precursor protein degradation by Alzheimer brain.
Biochem Soc Trans,
21 ( Pt 3)(3).
Author URL.
Holmes C, Webster MT, Procter AW, Francis PT, Bowen DM (1993). Relationship between beta-amyloid precursor protein, pyramidal neurones and astrocytes in human neocortex.
Biochem Soc Trans,
21 ( Pt 3)(3).
Author URL.
Francis PT, Webster MT, Procter AW, Clarke NA, Bowen DM, Doshi R, Mann DM, Neary D (1993). Soluble beta-amyloid precursor protein and pyramidal neuron loss.
Lancet,
341(8842).
Author URL.
Francis PT, Pangalos MN, Pearson RC, Middlemiss DN, Stratmann GC, Bowen DM (1992). 5-Hydroxytryptamine1A but not 5-hydroxytryptamine2 receptors are enriched on neocortical pyramidal neurones destroyed by intrastriatal volkensin.
J Pharmacol Exp Ther,
261(3), 1273-1281.
Abstract:
5-Hydroxytryptamine1A but not 5-hydroxytryptamine2 receptors are enriched on neocortical pyramidal neurones destroyed by intrastriatal volkensin.
Experimental lesions followed by binding of [3H]8-hydroxy-2-(n-dipropylamino)tetralin (8-OH-DPAT) and [3H]ketanserin to cryostat sections and quantitative autoradiography were used to investigate the cellular localization of 5-hydroxytryptamine1A (5-HT1A) and 5-hydroxytryptamine2 (5-HT2) receptors in the neocortex of the rat. The lesions were produced by intrastriatal injections of either volkensin (2 and 6 ng) or ricin (10 ng): both are suicide transport agents, but only the former is retrogradely transported in the central nervous system. Only animals treated with volkensin showed cortical receptor changes and these were almost exclusively confined to the 5-HT1A site. The binding of [3H]8-OH-DPAT was significantly reduced in rats receiving 2 or 6 ng volkensin in the deeper cortical layers of areas Fr1/Fr2 of neocortex ipsilateral to the striatal lesion. Quantitative histological analysis of adjacent sections had previously revealed a significant loss of large infragranular pyramidal neurones with sparing of both interneurones and supragranular pyramidal neurones. There was no significant reduction in [3H]8-OH-DPAT binding in superficial layers. In cortical areas, Par1/Par2 [3H]8-OH-DPAT binding was significantly reduced (2 and 6 ng animals) in both superficial and deeper cortical layers, but quantitative histological analysis has not been performed. The binding of [3H] ketanserin was unaffected except for the most superficial layers of Par1/Par2, where binding was significantly reduced in only the 2 ng animals. There was no reduction in [3H]8-OH-DPAT binding after intrastriatal ricin injection, which caused as much cell loss in the striatum as 2 ng of volkensin, but did not destroy cortical pyramidal neurones.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract.
Author URL.
Francis PT, Pangalos MN, Bowen DM (1992). Animal and drug modelling for Alzheimer synaptic pathology.
Prog Neurobiol,
39(5), 517-545.
Author URL.
Pangalos MN, Malizia AL, Francis PT, Lowe SL, Bertolucci PH, Procter AW, Bridges PK, Bartlett JR, Bowen DM (1992). Effect of psychotropic drugs on excitatory amino acids in patients undergoing psychosurgery for depression.
Br J Psychiatry,
160, 638-642.
Abstract:
Effect of psychotropic drugs on excitatory amino acids in patients undergoing psychosurgery for depression.
Samples of ventricular CSF were taken from 52 consecutive patients admitted for psychosurgery for intractable depression. Concentrations of asparagine, aspartate, glutamine, glutamic acid, and serine were determined. Glutamate and aspartate concentrations, implicated in excitotoxic brain damage, were not affected by various types of psychotropic drug treatment. Serine, a modulator of glutamate responses, was significantly elevated in samples from subjects receiving antidepressants. These subjects responded poorly to the operation. Psychotropic drugs are unlikely to be neurotoxic. Nevertheless, antidepressants may influence excitatory neurotransmission.
Abstract.
Author URL.
Bowen DM, Francis PT, Sims NR (1992). Letter to the editor. NeuroReport, 3(9).
PANGALOS MN, FRANCIS PT, FOSTER AC, PEARSON RCA, MIDDLEMISS DN, BOWEN DM (1992). NMDA RECEPTORS ASSESSED BY AUTORADIOGRAPHY WITH [H-3] L-689,560 ARE PRESENT BUT NOT ENRICHED ON CORTICOFUGAL-PROJECTING PYRAMIDAL NEURONS.
BRAIN RESEARCH,
596(1-2), 223-230.
Author URL.
Stratmann GC, Webster MT, Francis PT, Procter AW, Bowen DM (1992). Protease 'Clipsin' extract activity reflects demographic characteristics of human brain.
Neurosci Lett,
143(1-2), 43-47.
Abstract:
Protease 'Clipsin' extract activity reflects demographic characteristics of human brain.
'Clipsin' and other peptide bond hydrolase activities that appear to be integral membrane proteins, including two implicated in the formation of the histological hallmarks of Alzheimer's disease, were assayed in the frontal and parietal cortex from a large (n = 45) series of postmortem human brains. Tissues were extracted sequentially with detergent-containing and low ionic strength buffers. The final extracts obtained with detergent-high ionic strength buffer were assayed for peptide-bond hydrolase activity using radiolabelled casein and four chromophore-linked peptide substrates. Hydrolysis of N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide and alpha-casein showed evidence of sensitivity to the presence of Alzheimer's disease (n = 22) and some of the seven other demographic features (postmortem delay; mode of death in the case of one substrate) of the brain samples considered. By contrast, activity towards carbobenzoxy(Z)-Leu-Leu-Glu-2-naphthylamide, Z-Val-Lys-Met-4-methyl-coumaryl-7-amide and Z-Val-Lys-Lys-Arg-4-methoxy-2-naphthylamide were independent of all factors. The results are discussed in terms of damage to a sub-population of protease-containing membranes.
Abstract.
Author URL.
Bowen D, Francis P, Sims N, Cross A (1992). Protection from dementia [4]. Science, 258(5087), 1422-1423.
Procter AW, Francis PT, Stratmann GC, Bowen DM (1992). Serotonergic pathology is not widespread in Alzheimer patients without prominent aggressive symptoms.
Neurochem Res,
17(9), 917-922.
Abstract:
Serotonergic pathology is not widespread in Alzheimer patients without prominent aggressive symptoms.
Behavioural symptoms of Alzheimer's disease, such as aggression, may determine the care patients required. Most postmortem neurochemical studies have been of institutionalized patients and conclusions drawn from these may not be valid for all patients. We have shown that serotonin 2 receptors are not lost from 12 of the 13 areas of cerebral cortex examined in the patients assessed to be free of aggressive symptoms. This has been interpreted as representing the relative preservation of cortical interneurones. In contrast choline acetyltransferase activity was reduced in all areas whereas serotonin content was reduced in only 2 of the 4 areas examined.
Abstract.
Author URL.
BOWEN DM, FRANCIS PT, PANGALOS MN, STEPHENS PH, PROCTER AW, CHESSELL IP (1992). TRADITIONAL PHARMACOTHERAPY MAY SUCCEED IN ALZHEIMERS-DISEASE.
TRENDS IN NEUROSCIENCES,
15(3), 84-85.
Author URL.
Bowen DM, Francis PT, Procter AW, Young AB (1992). Treatment of Alzheimer's disease.
J Neurol Neurosurg Psychiatry,
55(4).
Author URL.
Bowen DM, Francis PT, Pangalos MN, Stephens PH, Procter AW (1992). Treatment strategies for Alzheimer's disease.
Lancet,
339(8785), 132-133.
Author URL.
Bowen DM, Francis PT, Procter AW, Halliwell JV, Mann DM, Neary D (1992). Treatment strategy for the corticocortical neuron pathology of Alzheimer's disease.
Ann Neurol,
32(1).
Author URL.
Bowen DM, Francis PT, Sims NR (1992). beta-Amyloid increased neuronal susceptibility to injury by glucose deprivation.
Neuroreport,
3(9), 733-734.
Author URL.
Bowen DM, Francis PT, Sims NR, Copani A, Koh J, Cotman CW (1992). β-Amyloid increased neuronal susceptibility to injury by glucose deprivation [1]. NeuroReport, 3(9), 733-734.
Francis PT, Procter AW, Bowen DM (1991). A glycine site as therapeutic target.
Ann N Y Acad Sci,
640, 184-188.
Author URL.
Procter AW, Stratmann GC, Francis PT, Lowe SL, Bertolucci PH, Bowen DM (1991). Characterisation of the glycine modulatory site of the N-methyl-D-aspartate receptor-ionophore complex in human brain.
J Neurochem,
56(1), 299-310.
Abstract:
Characterisation of the glycine modulatory site of the N-methyl-D-aspartate receptor-ionophore complex in human brain.
[3H]Glycine binding and glycine modulation of [3H]MK-801 binding have been used to study the glycine allosteric site associated with the N-methyl-D-aspartate receptor complex in postmortem human brain. The effect of glycine on [3H]MK-801 binding appeared sensitive to duration of terminal coma, and possibly postmortem delay. Thirty percent of the binding occurred in a subfraction of brain tissue and did not show enhancement by glycine and glutamic acid. [3H]Glycine binding to a subfraction free from this component was studied and showed high specific binding. KD and Bmax values showed considerable intersubject variability which did not appear to be due to demographic features or to tissue content of amino acids with an affinity for this site. The pharmacological characteristics of binding in this subfraction and a correlation between Bmax values and the maximal enhancement of [3H]MK-801 binding by glycine are consistent with [3H]glycine binding occurring to an N-methyl-D-aspartate receptor complex associated site. Further support for this is provided by a significantly lower Bmax value for [3H]glycine binding in subjects with Alzheimer's disease and reduced glycine enhancement of [3H]MK-801 binding. However, the effect of perimortem factors makes it difficult to confidently attribute this solely to a disease-related change in the receptor. The possible role of the glycine allosteric site in the treatment of neuropsychiatric disorders is discussed.
Abstract.
Author URL.
Chessell IP, Procter AW, Francis PT, Bowen DM (1991). D-cycloserine, a putative cognitive enhancer, facilitates activation of the N-methyl-D-aspartate receptor-ionophore complex in Alzheimer brain.
Brain Res,
565(2), 345-348.
Abstract:
D-cycloserine, a putative cognitive enhancer, facilitates activation of the N-methyl-D-aspartate receptor-ionophore complex in Alzheimer brain.
The action of D-Cycloserine (DCS) at the strychnine-insensitive glycine recognition site of the NMDA receptor-ionophore complex has been studied with membranes from inferior parietal cortex of patients with Alzheimer's disease. The maximal response of the site, measured using [3H]MK-801 binding, was 64% of that observed with glycine. Stimulation of binding induced by DCS in the presence of fixed concentrations of glycine resulted in a family of dose-response curves, consistent with the antibiotic having the property of a partial agonist at this glycine site. It is proposed that because of circumscribed glutamatergic pyramidal cell pathology DCS will have benefit for Alzheimer's patients over and above all other types of cognitive impairment.
Abstract.
Author URL.
PANGALOS MN, FRANCIS PT, PEARSON RCA, MIDDLEMISS DN, BOWEN DM (1991). DESTRUCTION OF a SUBPOPULATION OF CORTICAL-NEURONS BY SUICIDE TRANSPORT OF VOLKENSIN, a LECTIN FROM ADENIA-VOLKENSII.
JOURNAL OF NEUROSCIENCE METHODS,
40(1), 17-29.
Author URL.
Wilson K, Bowen D, Francis P, Tyrrell P (1991). Effect of central cholinergic stimulation on regional cerebral blood flow in Alzheimer's disease. British Journal of Psychiatry, 158(APR.), 558-562.
Najlerahim A, Francis PT, Bowen DM (1990). Age-related alteration in excitatory amino acid neurotransmission in rat brain.
Neurobiol Aging,
11(2), 155-158.
Abstract:
Age-related alteration in excitatory amino acid neurotransmission in rat brain.
The excitatory amino acids as neurotransmitters in the neocortex, hippocampus, striatum, thalamus, amygdala, nucleus basalis of Meynert and cerebellum from rats aged 4 months, 12 months and 24 months have been examined by measuring sodium-dependent high affinity uptake of D-[3H]-aspartate into preparations containing synaptosomes. Calcium-dependent K(+)-stimulated release of endogenous glutamate from the nucleus basalis was also measured. The hippocampus and cerebellum failed to show significant age-related changes in uptake of D-[3H]-aspartate. D-[3H]-aspartate uptake decreased significantly in the neocortex (29%), striatum (29%), nucleus basalis (26%), amygdala (19%) and thalamus (16%) in the middle-aged rats as compared to the young rats, but the changes were not progressive with age. The release of glutamate from the nucleus basalis was unaltered during the aging process.
Abstract.
Author URL.
Lowe SL, Bowen DM, Francis PT, Neary D (1990). Ante mortem cerebral amino acid concentrations indicate selective degeneration of glutamate-enriched neurons in Alzheimer's disease.
Neuroscience,
38(3), 571-577.
Abstract:
Ante mortem cerebral amino acid concentrations indicate selective degeneration of glutamate-enriched neurons in Alzheimer's disease.
There is little information about major constituents of the brain in Alzheimer's disease. In the case of amino acids most of the previous data are contradictory. These have been interpreted in an anatomic and neurotransmitter as well as a metabolic context. To help clarify this, the contents of 14 amino acids and ethanolamine were determined in samples of neocortex from diagnostic craniotomies of 15 demented patients (10 with Alzheimer's disease) and other neurosurgical procedures (57 patients, 18 with intractable depression). A comprehensive survey of the effects of possible complicating factors on the concentrations of amino acids showed that artefacts were few; this was in contrast to a post mortem series of brains (16 with Alzheimer's disease and 16 controls; six regions assayed). We have used the ante mortem data to provide the basis for an accurate comparison of amino acid values between Alzheimer and control samples. In Alzheimer's disease, the mean contents of many amino acids were slightly higher (sum of the increases of those significantly affected was 15 nmol/mg protein) whereas glutamate content alone was significantly reduced (by 16 nmol/mg protein). This was not a feature of depression or a group of patients with other dementias. Glutamate content of Alzheimer samples was related to pyramidal neuron density in cortical layer III. These alterations were detected relatively early during the course of Alzheimer's disease and are considered to be due to loss of corticocortical glutamatergic association pathways.
Abstract.
Author URL.
Procter AW, Francis PT, Lowe SL, Pangalos MN, Steele JE, Bowen DM (1990). Clinical correlations of the neurobiological changes of aging.
Ann Med Interne (Paris),
141 Suppl 1, 3-6.
Abstract:
Clinical correlations of the neurobiological changes of aging.
Increasing age is associated with increased risk of developing both dementia and depression; both conditions appear to be associated with structural changes in the cerebral cortex. In depression, there was evidence for regional alterations in cortical neurons either as a result of the disease or its treatment. In Alzheimer's disease, a key change is likely to be either shrinkage or loss of corticocortical pyramidal neurones which probably use glutamate as their transmitter. The putative pathogenic role of glutamate and energy metabolism, as well as an approach to treatment of symptoms are outlined.
Abstract.
Author URL.
Francis PT, Lowe SL, Bowen DM, Jefferys JG (1990). Lack of change in neurochemical markers during the postepileptic phase of intrahippocampal tetanus toxin syndrome in rats.
Epilepsia,
31(6), 697-701.
Abstract:
Lack of change in neurochemical markers during the postepileptic phase of intrahippocampal tetanus toxin syndrome in rats.
The chronic epileptic syndrome induced by injecting tetanus toxin into rat hippocampus causes functional changes that essentially are permanent, outlasting the period of active seizures by at least 1 year. These long-term changes have been characterized by an impaired performance on a range of behavioral tasks, which in turn have been associated with a physiologic depression of hippocampal evoked responses but not with any discernible histopathology. In the present study, we examined the hippocampi of rats in the postseizure phase of the tetanus toxin model and observed no significant changes in the concentration of neurochemical markers for six neurotransmitters. Therefore, the long-term reduction in hippocampal excitability cannot be attributed to any major loss of afferents or hippocampal neurons using aspartate, acetylcholine, gamma-aminobutyric acid (GABA), glutamate, norepinephrine (NE), or serotonin as their transmitters.
Abstract.
Author URL.
Steele JE, Bowen DM, Francis PT, Green AR, Cross AJ (1990). Spermidine enhancement of [3H]MK-801 binding to the NMDA receptor complex in human cortical membranes.
Eur J Pharmacol,
189(2-3), 195-200.
Abstract:
Spermidine enhancement of [3H]MK-801 binding to the NMDA receptor complex in human cortical membranes.
The effects of spermidine on the binding of [3H]MK-801 to the N-methyl-D-aspartate (NMDA) receptor complex was studied in human cerebral cortical membranes. [3H]MK-801 binding was increased from 56 +/- 5 fmol/mg protein (mean +/- S.E.M. n = 7) to 319 +/- 71 fmol/mg protein in the presence of 200 microM spermidine. The ED50 for spermidine stimulation of [3H]MK-801 binding was 89 +/- 22 microM (mean +/- S.E.M. n = 6). In the presence of glutamate (1 microM) plus glycine (1 microM) the ED50 was reduced to 5.5 +/- 0.7 microM. The increase in binding in the presence of spermidine was characterised by an increase in the rate of association of [3H]MK-801. In the presence of spermidine. [3H]MK-801 was inhibited by AP5. 7-chlorokynurenic acid and ifenprodil with IC50 values of 0.5 +/- 0.3 24 +/- 19 and 91 +/- 28 microM, respectively. None of these antagonists was a competitive inhibitor of the spermidine stimulation of [3H]MK-801 binding. Thus spermidine modulates the NMDA receptor complex in human brain, providing further evidence that the complex is similar in rat and human cortex.
Abstract.
Author URL.
Francis PT, Poynton A, Lowe SL, Najlerahim A, Bridges PK, Bartlett JR, Procter AW, Bruton CJ, Bowen DM (1989). Brain amino acid concentrations and Ca2+-dependent release in intractable depression assessed antemortem.
Brain Res,
494(2), 315-324.
Abstract:
Brain amino acid concentrations and Ca2+-dependent release in intractable depression assessed antemortem.
The concentrations of 3 putative neurotransmitters (glutamate, aspartate and gamma-aminobutyrate), 4 related amino acids and 5 non-transmitter-related amino acids have been measured in neurosurgical samples (frontal cortex) from patients with intractable depression and controls. In addition, the glutamate receptor agonist 2-amino-4-sulpho-butanoic acid (homocysteic acid) has been identified in human brain and measured in these samples. There were no changes in the concentrations of amino acids in depressed patients compared to control with the exception of aspartic and homocysteic acids which were elevated in a sub-group of patients with depression compared to control. The Ca2+-dependent release (K+-stimulated) of putative neurotransmitters has been demonstrated for the first time from brain tissue of depressed patients. Glutamate release was unaltered from the control value. Aspartate values showed unexplained variability but it's release and that of gamma-aminobutyrate were elevated in some depressed subjects. These results do not support the hypothesis of reduced amino acid function in depressive illness.
Abstract.
Author URL.
BOWEN DM, NAJLERAHIM A, PROCTER AW, FRANCIS PT, MURPHY E (1989). CIRCUMSCRIBED CHANGES OF THE CEREBRAL-CORTEX IN NEUROPSYCHIATRIC DISORDERS OF LATER LIFE.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,
86(23), 9504-9508.
Author URL.
Bowen DM, Francis PT, Lowe SL, Pangalos MN, Procter AW, Steele JE (1989). Pyramidal neuron loss and "glycine-site therapy": a need for an animal model and study in late-life depression.
Neurobiol Aging,
10(5), 616-618.
Abstract:
Pyramidal neuron loss and "glycine-site therapy": a need for an animal model and study in late-life depression.
Localization and other studies of glutamatergic receptors are hampered, in part, as pyramidal neurons in the neocortex cannot yet be selectively destroyed in laboratory animals. Demonstration of glutamatergic neuron dysfunction in Alzheimer's disease may allow verification of a technique suitable for the study of these cells in disorders without histopathological hallmarks. This includes Major Depressive Disorder in the elderly which has a poor prognosis.
Abstract.
Author URL.
FRANCIS PT, BOWEN DM (1989). TACRINE, a DRUG WITH THERAPEUTIC POTENTIAL FOR DEMENTIA - POST-MORTEM BIOCHEMICAL-EVIDENCE.
CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES,
16(4), 504-510.
Author URL.
Francis PT, Bowen DM (1989). Tacrine, a Drug with Therapeutic Potential for Dementia: Post-Mortem Biochemical Evidence.
Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques,
16(S4), 504-510.
Abstract:
Tacrine, a Drug with Therapeutic Potential for Dementia: Post-Mortem Biochemical Evidence
A review of biochemical findings is presented which support the idea that Alzheimer's disease represents a condition for which tetrahydroaminoacridine (tacrine) may have a beneficial effect. There is evidence that clinical and histopathologic hallmarks of the disease relate to cholinergic and serotonergic dysfunction, with less obvious abnormalities in other neurotransmitters (aspartate, dopamine, gamma-aminobutyrate, glutamate, noradrenaline and somatostatin). Clincially relevant concentrations of tacrine may ameliorate the above presynaptic deficits without producing harmful (neurotoxic) effects of aspartate and glutamate. The disease seems to be associated with an early and clinically relevant degeneration of some neurons with cortical perikarya that release these amino acid transmitters. Studies are now required on the effect of tacrine on postulated harmful peptide-bond hydrolase activity within and around such cells. © 1989, Canadian Neurological Sciences Federation. All rights reserved.
Abstract.
Francis PT, Bowen DM (1989). Tacrine, a drug with therapeutic potential for dementia: post-mortem biochemical evidence.
Can J Neurol Sci,
16(4 Suppl), 504-510.
Abstract:
Tacrine, a drug with therapeutic potential for dementia: post-mortem biochemical evidence.
A review of biochemical findings is presented which support the idea that Alzheimer's disease represents a condition for which tetrahydroaminoacridine (tacrine) may have a beneficial effect. There is evidence that clinical and histopathologic hallmarks of the disease relate to cholinergic and serotonergic dysfunction, with less obvious abnormalities in other neurotransmitters (aspartate, dopamine, gamma-aminobutyrate, glutamate, noradrenaline and somatostatin). Clinically relevant concentrations of tacrine may ameliorate the above presynaptic deficits without producing harmful (neurotoxic) effects of aspartate and glutamate. The disease seems to be associated with an early and clinically relevant degeneration of some neurons with cortical perikarya that release these amino acid transmitters. Studies are now required on the effect of tacrine on postulated harmful peptide-bond hydrolase activity within and around such cells.
Abstract.
Author URL.
Cross AJ, Stirling JM, Robinson TN, Bowen DM, Francis PT, Green AR (1989). The modulation by chlormethiazole of the GABAA-receptor complex in rat brain.
Br J Pharmacol,
98(1), 284-290.
Abstract:
The modulation by chlormethiazole of the GABAA-receptor complex in rat brain.
1. The interactions of chlormethiazole with gamma-aminobutyric acid (GABA) synthesis and release, and with ligand binding to sites associated with the GABAA-receptor complex and the GABAB-receptor have been studied in the rat. The GABAA-receptor was studied using [3H]-muscimol, [3H]-flunitrazepam was used to label the benzodiazepine modulatory site, and [35S]-butyl-bicyclophosphorothionate ([35S]-TBPS) to label the chloride channel. 2. Chlormethiazole had no effect on GABA synthesis in the cortex, hippocampus and striatum or on GABA release from cortical slices in vitro. Chlormethiazole did not displace [3H]-baclofen binding to the GABAB-receptor. 3. Chlormethiazole (IC50 = 140 microM) and pentobarbitone (IC50 = 95 microM) both inhibited [35S]-TBPS binding by increasing the rate of [35S]-TBPS dissociation. In addition, chlormethiazole caused an apparent decrease in the affinity of [35S]-TBPS binding. 4. Chlormethiazole enhanced the binding of [3H]-muscimol but had no effect on [3H]-flunitrazepam binding. In contrast, the sedative barbiturate pentobarbitone enhanced both [3H]-muscimol and [3H]-flunitrazepam binding. 5. It is concluded that the sedative and anticonvulsant effects of chlormethiazole are probably mediated through an action at the GABAA-receptor. However, chlormethiazole does not interact with the GABAA-receptor complex in an identical manner to the sedative barbiturate pentobarbitone.
Abstract.
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Palmer AM, Lowe SL, Francis PT, Bowen DM (1988). Are post-mortem biochemical studies of human brain worthwhile?.
Biochem Soc Trans,
16(4), 472-475.
Author URL.
Procter AW, Palmer AM, Francis PT, Lowe SL, Neary D, Murphy E, Doshi R, Bowen DM (1988). Evidence of glutamatergic denervation and possible abnormal metabolism in Alzheimer's disease.
J Neurochem,
50(3), 790-802.
Abstract:
Evidence of glutamatergic denervation and possible abnormal metabolism in Alzheimer's disease.
Excitatory dicarboxylic amino acids previously have been ascribed several functions in the brain. Here their total concentration and proposed neurochemical markers of neurotransmitter function have been measured in brain from patients with Alzheimer's disease (AD) and controls. Specimens were obtained antemortem (biopsy) approximately 3 years after emergence of symptoms and promptly (less than 3 h) postmortem some 10 years after onset. Early in the disease a slight elevation in aspartic acid concentration of cerebral cortex was observed in the patients with AD. A reduction in glutamic acid concentration of a similar magnitude was found. It is argued that this, together with a decrease in CSF glutamine content and lack of change in the phosphate-activated brain glutaminase activity of tissue, reflects an early metabolic abnormality. Later in the disease evidence of glutamatergic neurone loss is provided by the finding that in many regions of the cerebral cortex the Na+-dependent uptake of D-[3H]aspartic acid was almost always lowest in AD subjects compared with control when assessed by a method designed to minimise artifacts and epiphenomena. Release of endogenous neurotransmitters from human brain tissue postmortem did not appear to have the characteristics of that from human tissue antemortem and rat brain.
Abstract.
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Lowe SL, Francis PT, Procter AW, Palmer AM, Davison AN, Bowen DM (1988). Gamma-aminobutyric acid concentration in brain tissue at two stages of Alzheimer's disease.
Brain,
111 ( Pt 4), 785-799.
Abstract:
Gamma-aminobutyric acid concentration in brain tissue at two stages of Alzheimer's disease.
The concentration of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), was measured in the cerebral cortex obtained at diagnostic craniotomy from 10 patients with Alzheimer's disease of 3 yrs mean duration and 6 patients with other causes of dementia, and from 31 subjects undergoing other neurosurgical procedures (for which removal of apparently normal tissue was necessary). GABA content of 5 areas of the cerebral cortex and the cerebellar cortex was measured postmortem in the brains of 23 Alzheimer and 19 control subjects and 5 patients with other causes of dementia. Fourteen of these specimens, including 7 from patients with Alzheimer's disease of 8 yrs mean duration, were obtained within 3 h of death. These were processed in a similar manner to the neurosurgical specimens and are regarded also as fresh tissue samples. The remaining 33 specimens are regarded as conventional postmortem samples as the mean interval of death to autopsy was 21 h. GABA concentration in conventional autopsy specimens from Alzheimer subjects was not reduced as compared with controls in either cingulate or cerebellar cortex. In the inferior parietal cortex, agonal status confounded this comparison. The concentration was reduced in superior parietal, frontal and temporal cortex but there is a possibility that agonal state also confounded these comparisons. There was no deficit in GABA concentration in fresh cortical tissue from Alzheimer patients except for the temporal lobe from autopsy specimens. The content of somatostatin-like immunoreactivity was, like GABA, found to be comparable to control in some groups of Alzheimer specimens. It is argued that the deficits in autopsy samples and lack of change in surgical specimens is likely to be due to the duration of illness at the time of sampling. Losses of choline acetyltransferase activity were observed in all groups of Alzheimer specimens in all areas of brain studied. The data are consistent with other results which suggest that cholinergic under-activity is most closely related to the clinical course of Alzheimer's disease.
Abstract.
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Procter AW, Lowe SL, Palmer AM, Francis PT, Esiri MM, Stratmann GC, Najlerahim A, Patel AJ, Hunt A, Bowen DM, et al (1988). Topographical distribution of neurochemical changes in Alzheimer's disease.
J Neurol Sci,
84(2-3), 125-140.
Abstract:
Topographical distribution of neurochemical changes in Alzheimer's disease.
Biochemical indices of cortical nerve cells affected in Alzheimer's disease have been proposed (excitatory dicarboxylic amino acid, EDAA, sodium-dependent carrier; phosphate-activated glutaminase activity; serotonin type 2 recognition site; somatostatin-like immunoreactivity). These and the content of EDAAs and two related amino acids, and choline acetyltransferase (ChAT) activity have been measured in up to 13 areas of cerebral cortex and the cerebellar cortex from 16 patients with Alzheimer's disease and 17 controls. Reduction of the index of the serotonin recognition site, somatostatin content and another biochemical index of interneurones coincide and indicate a rather unexpected focal loss of such neurones from the parietal lobe. No unequivocal measure of the integrity of pyramidal neurones could be established as the content of no amino acid was reduced, the index of the EDAA carrier showed evidence of change in few brain regions and glutaminase activity was subject to unexplained variability. ChAT activity alone closely paralleled a previous report of the distribution of morphological degeneration. The results are discussed in relation to therapy and positron emission tomography.
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Palmer AM, Francis PT, Bowen DM, Benton JS, Neary D, Mann DM, Snowden JS (1987). Catecholaminergic neurones assessed ante-mortem in Alzheimer's disease.
Brain Res,
414(2), 365-375.
Abstract:
Catecholaminergic neurones assessed ante-mortem in Alzheimer's disease.
Indices of dopaminergic and noradrenergic varicosities were assayed in neocortical tissue obtained at diagnostic craniotomy from patients with Alzheimer's disease in the presenium. Dopaminergic markers (concentrations of dopamine, dihydroxyphenylacetic acid and homovanillic acid) were not significantly different from controls in either frontal or temporal cortex. In the frontal cortex, the release of endogenous dopamine and noradrenaline (in the presence of both resting and stimulating concentrations of potassium) was also unaffected whereas release of endogenous serotonin was significantly reduced. In the temporal cortex, noradrenergic markers (concentration of noradrenaline and uptake of radiolabelled noradrenaline) were significantly reduced, to at least 47% of mean control values. These deficits are interpreted as reflecting denervation and were present in patients examined only some two years after developing symptoms of dementia. The ratio of 3-methoxy-4-hydroxyphenylglycol to noradrenaline (a putative index of noradrenaline turnover) was elevated in the temporal cortex, suggesting increased activity of the remaining noradrenergic varicosities. Noradrenergic markers did not correlate with either clinical or histological indices of the severity of the disease which contrasts with presynaptic cholinergic and serotonergic markers.
Abstract.
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Palmer AM, Wilcock GK, Esiri MM, Francis PT, Bowen DM (1987). Monoaminergic innervation of the frontal and temporal lobes in Alzheimer's disease.
Brain Res,
401(2), 231-238.
Abstract:
Monoaminergic innervation of the frontal and temporal lobes in Alzheimer's disease.
Seven markers of ascending (corticopetal) dopaminergic, noradrenergic and serotonergic neurones and choline acetyltransferase activity have been studied postmortem in frontal and temporal cortex from subjects with Alzheimer's disease and compared with a matched group of controls. Dopaminergic neurones (concentrations of dopamine, dihydroxyphenylacetic acid and homovanillic acid) were not deficient but some markers of the other neurones were affected. Noradrenaline and serotonin concentrations were reduced whereas the concentrations of their metabolites were either unaltered (5-hydroxyindoleacetic acid) or increased (3-methoxy-4-hydroxyphenylglycol). All deficits were most pronounced in the temporal cortex. Severely demented subjects had evidence of generalized neuronal loss, whereas those with moderate dementia showed significant loss of only choline acetyltransferase activity. In Alzheimer subjects, a significant relationship (inverse) was found between 5-hydroxyindoleacetic acid concentration and the number of neurofibrillary tangles.
Abstract.
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PALMER AM, FRANCIS PT, BENTON JS, SIMS NR, MANN DMA, NEARY D, SNOWDEN JS, BOWEN DM (1987). PRESYNAPTIC SEROTONERGIC DYSFUNCTION IN PATIENTS WITH ALZHEIMERS-DISEASE.
JOURNAL OF NEUROCHEMISTRY,
48(1), 8-15.
Author URL.
Francis PT, Bowen DM, Lowe SL, Neary D, Mann DM, Snowden JS (1987). Somatostatin content and release measured in cerebral biopsies from demented patients.
J Neurol Sci,
78(1), 1-16.
Abstract:
Somatostatin content and release measured in cerebral biopsies from demented patients.
Somatostatin-like immunoreactivity (SLIR) has been assayed in frontal and temporal cortex obtained at diagnostic craniotomy and post-mortem from patients with histologically verified Alzheimer's disease. SLIR content was not significantly different from controls in the frontal and temporal lobes, except in the temporal cortex post-mortem. The K+-stimulated release of endogenous SLIR from tissue prisms ('mini-slices') prepared from neocortex obtained at diagnostic craniotomy from Alzheimer patients was not below the control values. Indices of cholinergic varicosities in similar samples from the frontal and temporal lobes are reduced; accordingly, somatostatin does not seem to be as prominently involved in these regions. Patients with Alzheimer's disease underwent neuropsychological assessment shortly before sampling the temporal lobe. Scores for WAIS full scale and the verbal subscale and the Token Test (measure of language comprehension) significantly correlated with the SLIR content; mean values (fmole/mg protein) were 817, 1468 and 1363 for aphasic and non-aphasic Alzheimer patients and controls, respectively. Ventricular fluid obtained from Alzheimer patients during surgery, did not have a significantly different SLIR content compared to controls. SLIR contents of ventricular fluid and neocortex from demented patients, without any specific histological changes in the sample obtained at diagnostic craniotomy, were also not significantly different from controls. Previously, we have shown that these demented patients, as well as those with histologically verified Alzheimer's disease, have a reduced SLIR content of lumbar fluid so it seems that somatostatin neurones located outside the frontal and temporal lobes are affected relatively early in the disease process.
Abstract.
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Francis PT, Carl R, Pearson A, Lowe SL, Neal JW, Stephens PH, Powell TP, Bowen DM (1987). The dementia of Alzheimer's disease: an update.
J Neurol Neurosurg Psychiatry,
50(2), 242-243.
Author URL.
Francis PT, Palmer AM, Sims NR, Bowen DM, Davison AN, Esiri MM, Neary D, Snowden JS, Wilcock GK (1985). Neurochemical studies of early-onset Alzheimer's disease. Possible influence on treatment.
N Engl J Med,
313(1), 7-11.
Abstract:
Neurochemical studies of early-onset Alzheimer's disease. Possible influence on treatment.
Multiple neurotransmitter deficits found in recent autopsy studies of patients with Alzheimer's disease may militate against the success of "simple cholinergic replacement" as treatment. To study acetylcholine synthesis, we measured the incorporation of radiolabeled glucose into the transmitter in temporal-cortex specimens obtained at diagnostic craniotomy in 17 young patients with Alzheimer's disease. Synthesis of acetylcholine was significantly correlated with cognitive impairment. These results are consistent with the view that the deficit in the presynaptic cholinergic system is a relatively early change in the development of the clinical features of the disease. Other alterations in noradrenergic cells, some cortical neurons, postsynaptic cortical receptors, and possibly serotoninergic cells may not be closely associated with Alzheimer's disease.
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Smith CC, Bowen DM, Francis PT, Snowden JS, Neary D (1985). Putative amino acid transmitters in lumbar cerebrospinal fluid of patients with histologically verified Alzheimer's dementia.
J Neurol Neurosurg Psychiatry,
48(5), 469-471.
Abstract:
Putative amino acid transmitters in lumbar cerebrospinal fluid of patients with histologically verified Alzheimer's dementia.
Concentrations of individual free amino acids were determined in lumbar cerebrospinal fluid (CSF) from patients with various complaints including histologically verified Alzheimer's dementia. Glycine and glutamine in the CSF of Alzheimer's dementia samples were lower than that of control samples. Only the concentration of glutamic acid in Alzheimer's dementia patients correlated with psychological measures. The reduction in glycine concentration was not specific for Alzheimer's dementia.
Abstract.
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FRANCIS PT, BOWEN DM, NEARY D, PALO J, WIKSTROM J, OLNEY J (1984). SOMATOSTATIN-LIKE IMMUNOREACTIVITY IN LUMBAR CEREBROSPINAL-FLUID FROM NEUROHISTOLOGICALLY EXAMINED DEMENTED PATIENTS.
NEUROBIOLOGY OF AGING,
5(3), 183-186.
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FRANCIS PT, GLADWELL RT, HOLMAN RB (1984). THE EFFECT OF TESTOSTERONE ON THE RELEASE OF ENDOGENOUS CATECHOLAMINES FROM THE HYPOTHALAMUS OF THE COCKEREL INVITRO.
PSYCHONEUROENDOCRINOLOGY,
9(1), 69-76.
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Knight PG, Francis PT, Holman RB, Gladwell RT (1982). Changes in hypothalamic monoamine concentrations accompany the progesterone-induced release of luteinizing hormone in the domestic hen.
Neuroendocrinology,
35(5), 359-362.
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