Journal articles
Ford J, Kafetsouli D, Wilson H, Udeh-Momoh C, Politis M, AhmadiAbhari S, Rabiner I, Middleton LT (2022). At a Glance: an Update on Neuroimaging and Retinal Imaging in Alzheimer's Disease and Related Research.
J Prev Alzheimers Dis,
9(1), 67-76.
Abstract:
At a Glance: an Update on Neuroimaging and Retinal Imaging in Alzheimer's Disease and Related Research.
Neuroimaging serves a variety of purposes in Alzheimer's disease (AD) and related dementias (ADRD) research - from measuring microscale neural activity at the subcellular level, to broad topological patterns seen across macroscale-brain networks, and everything in between. In vivo imaging provides insight into the brain's structure, function, and molecular architecture across numerous scales of resolution; allowing examination of the morphological, functional, and pathological changes that occurs in patients across different AD stages (1). AD is a complex and potentially heterogenous disease, with no proven cure and no single risk factor to isolate and measure, whilst known risk factors do not fully account for the risk of developing this disease (2). Since the 1990's, technological advancements in neuroimaging have allowed us to visualise the wide organisational structure of the brain (3) and later developments led to capturing information of brain 'functionality', as well as the visualisation and measurement of the aggregation and accumulation of AD-related pathology. Thus, in vivo brain imaging has and will continue to be an instrumental tool in clinical research, mainly in the pre-clinical disease stages, aimed at elucidating the biological complex processes and interactions underpinning the onset and progression of cognitive decline and dementia. The growing societal burden of AD/ADRD means that there has never been a greater need, nor a better time, to use such powerful and sensitive tools to aid our understanding of this undoubtedly complex disease. It is by consolidating and reflecting on these imaging advancements and developing long-term strategies across different disciplines, that we can move closer to our goal of dementia prevention. This short commentary will outline recent developments in neuroimaging in the field of AD and dementia by first describing the historical context of AD classification and the introduction of AD imaging biomarkers, followed by some examples of significant recent developments in neuroimaging methods and technologies.
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Wilson H, Pagano G, Yousaf T, Polychronis S, De Micco R, Giordano B, Niccolini F, Politis M (2022). Correction to: Predict cognitive decline with clinical markers in Parkinson's disease (PRECODE-1).
J Neural Transm (Vienna),
129(10).
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de Natale ER, Wilson H, Politis M (2022). Predictors of RBD progression and conversion to synucleinopathies.
Curr Neurol Neurosci Rep,
22(2), 93-104.
Abstract:
Predictors of RBD progression and conversion to synucleinopathies.
PURPOSE OF REVIEW: Rapid eye movement (REM) sleep behaviour disorder (RBD) is considered the expression of the initial neurodegenerative process underlying synucleinopathies and constitutes the most important marker of their prodromal phase. This article reviews recent research from longitudinal research studies in isolated RBD (iRBD) aiming to describe the most promising progression biomarkers of iRBD and to delineate the current knowledge on the level of prediction of future outcome in iRBD patients at diagnosis. RECENT FINDINGS: Longitudinal studies revealed the potential value of a variety of biomarkers, including clinical markers of motor, autonomic, cognitive, and olfactory symptoms, neurophysiological markers such as REM sleep without atonia and electroencephalography, genetic and epigenetic markers, cerebrospinal fluid and serum markers, and neuroimaging markers to track the progression and predict phenoconversion. To-date the most promising neuroimaging biomarker in iRBD to aid the prediction of phenoconversion is striatal presynaptic striatal dopaminergic dysfunction. There is a variety of potential biomarkers for monitoring disease progression and predicting iRBD conversion into synucleinopathies. A combined multimodal biomarker model could offer a more sensitive and specific tool. Further longitudinal studies are warranted to iRBD as a high-risk population for early neuroprotective interventions and disease-modifying therapies.
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Wilson H, de Natale ER, Politis M (2022). Recent Advances in Neuroimaging Techniques to Assist Clinical Trials on Cell-Based Therapies in Neurodegenerative Diseases.
Stem Cells,
40(8), 724-735.
Abstract:
Recent Advances in Neuroimaging Techniques to Assist Clinical Trials on Cell-Based Therapies in Neurodegenerative Diseases.
Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are progressive disorders for which curative therapy is still lacking. Cell-based therapy aims at replacing dysfunctional cellular populations by repairing damaged tissue and by enriching the microenvironment of selective brain areas, and thus constitutes a promising disease-modifying treatment of neurodegenerative diseases. Scientific research has engineered a wide range of human-derived cellular populations to help overcome some of the logistical, safety, and ethical issues associated with this approach. Open-label studies and clinical trials in human participants have used neuroimaging techniques, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), to assess the success of the transplantation, to evaluate the functional integration of the implanted tissue into the host environment and to understand the pathophysiological changes associated with the therapy. Neuroimaging has constituted an outcome measure of large, randomized clinical trials, and has given answers to clarify the pathophysiology underlying some of the complications linked with this therapy. Novel PET radiotracers and MRI sequences for the staging of neurodegenerative diseases and to study alterations at the molecular level significantly expands the translational potential of neuroimaging to assist pre-clinical and clinical research on cell-based therapy in these disorders. This concise review summarizes the current use of neuroimaging in human studies of cell-based replacement therapy and focuses on the future applications of PET and MRI techniques to evaluate the pathophysiology and treatment efficacy, as well as to aid patient selection and as an outcome measure to improve treatment success.
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Chandra A, Farrell C, Wilson H, Dervenoulas G, De Natale ER, Politis M (2021). Aquaporin-4 polymorphisms predict amyloid burden and clinical outcome in the Alzheimer's disease spectrum. Neurobiology of Aging, 97, 1-9.
King-Robson J, Wilson H, Politis M, Alzheimer’s Disease Neuroimaging Initiative (2021). Associations Between Amyloid and Tau Pathology, and Connectome Alterations, in Alzheimer's Disease and Mild Cognitive Impairment.
J Alzheimers Dis,
82(2), 541-560.
Abstract:
Associations Between Amyloid and Tau Pathology, and Connectome Alterations, in Alzheimer's Disease and Mild Cognitive Impairment.
BACKGROUND: the roles of amyloid-β and tau in the degenerative process of Alzheimer's disease (AD) remain uncertain. [18F]AV-45 and [18F]AV-1451 PET quantify amyloid-β and tau pathology, respectively, while diffusion tractography enables detection of their microstructural consequences. OBJECTIVE: Examine the impact of amyloid-β and tau pathology on the structural connectome and cognition, in mild cognitive impairment (MCI) and AD. METHODS: Combined [18F]AV-45 and [18F]AV-1451 PET, diffusion tractography, and cognitive assessment in 28 controls, 32 MCI, and 26 AD patients. RESULTS: Hippocampal connectivity was reduced to the thalami, right lateral orbitofrontal, and right amygdala in MCI; alongside the insula, posterior cingulate, right entorhinal, and numerous cortical regions in AD (all p
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Fletcher B, Chappell LC, Lavallee L, Wilson HM, Stevens R, Mackillop L, McManus RJ, Tucker KL (2021). Changes to management of hypertension in pregnancy, and attitudes to self-management: an online survey of obstetricians, before and following the first wave of the COVID-19 pandemic.
Pregnancy Hypertens,
26, 54-61.
Abstract:
Changes to management of hypertension in pregnancy, and attitudes to self-management: an online survey of obstetricians, before and following the first wave of the COVID-19 pandemic.
OBJECTIVE: This study aimed to understand the views and practice of obstetricians regarding self-monitoring for hypertensive disorders of pregnancy (blood pressure (BP) and proteinuria), the potential for self-management (including actions taken on self-monitored parameters) and to understand the impact of the COVID-19 pandemic on such views. DESIGN: Cross-sectional online survey pre- and post- the first wave of the COVID-19 pandemic. SETTING AND SAMPLE: UK obstetricians recruited via an online portal. METHODS: a survey undertaken in two rounds: December 2019-January 2020 (pre-pandemic), and September-November 2020 (during pandemic) RESULTS: 251 responses were received across rounds one (150) and two (101). Most obstetricians considered that self-monitoring of BP and home urinalysis had a role in guiding clinical decisions and this increased significantly following the first wave of the COVID-19 pandemic (88%, (132/150) 95%CI: 83-93% first round vs 96% (95%CI: 92-94%), (97/101), second round; p = 0.039). Following the pandemic, nearly half were agreeable to women self-managing their hypertension by using their own readings to make a pre-agreed medication change themselves (47%, 47/101 (95%CI: 37-57%)). CONCLUSIONS: a substantial majority of UK obstetricians considered that self-monitoring had a role in the management of pregnancy hypertension and this increased following the pandemic. Around half are now supportive of women having a wider role in self-management of hypertensive treatment. Maximising the potential of such changes in pregnancy hypertension management requires further work to understand how to fully integrate women's own measurements into clinical care.
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Sakhneny L, Mueller L, Schonblum A, Azaria S, Burganova G, Epshtein A, Isaacson A, Wilson H, Spagnoli FM, Landsman L, et al (2021). The postnatal pancreatic microenvironment guides β cell maturation through BMP4 production.
Dev Cell,
56(19), 2703-2711.e5.
Abstract:
The postnatal pancreatic microenvironment guides β cell maturation through BMP4 production.
Glucose homeostasis depends on regulated insulin secretion from pancreatic β cells, which acquire their mature phenotype postnatally. The functional maturation of β cells is regulated by a combination of cell-autonomous and exogenous factors; the identity of the latter is mostly unknown. Here, we identify BMP4 as a critical component through which the pancreatic microenvironment regulates β cell function. By combining transgenic mouse models and human iPSCs, we show that BMP4 promotes the expression of core β cell genes and is required for proper insulin production and secretion. We identified pericytes as the primary pancreatic source of BMP4, which start producing this ligand midway through the postnatal period, at the age β cells mature. Overall, our findings show that the islet niche directly promotes β cell functional maturation through the timely production of BMP4. Our study highlights the need to recapitulate the physiological postnatal islet niche for generating fully functional stem-cell-derived β cells for cell replacement therapy for diabetes.
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Cozzitorto C, Mueller L, Ruzittu S, Mah N, Willnow D, Darrigrand J-F, Wilson H, Khosravinia D, Mahmoud A-A, Risolino M, et al (2020). A Specialized Niche in the Pancreatic Microenvironment Promotes Endocrine Differentiation.
Dev Cell,
55(2), 150-162.e6.
Abstract:
A Specialized Niche in the Pancreatic Microenvironment Promotes Endocrine Differentiation.
The interplay between pancreatic epithelium and the surrounding microenvironment is pivotal for pancreas formation and differentiation as well as adult organ homeostasis. The mesenchyme is the main component of the embryonic pancreatic microenvironment, yet its cellular identity is broadly defined, and whether it comprises functionally distinct cell subsets is not known. Using genetic lineage tracing, transcriptome, and functional studies, we identified mesenchymal populations with different roles during pancreatic development. Moreover, we showed that Pbx transcription factors act within the mouse pancreatic mesenchyme to define a pro-endocrine specialized niche. Pbx directs differentiation of endocrine progenitors into insulin- and glucagon-positive cells through non-cell-autonomous regulation of ECM-integrin interactions and soluble molecules. Next, we measured functional conservation between mouse and human pancreatic mesenchyme by testing identified mesenchymal factors in an iPSC-based differentiation model. Our findings provide insights into how lineage-specific crosstalk between epithelium and neighboring mesenchymal cells underpin the generation of different pancreatic cell types.
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Carotenuto A, Wilson H, Giordano B, Caminiti SP, Chappell Z, Williams SCR, Hammers A, Silber E, Brex P, Politis M, et al (2020). Impaired connectivity within neuromodulatory networks in multiple sclerosis and clinical implications.
Journal of Neurology,
267(7), 2042-2053.
Abstract:
Impaired connectivity within neuromodulatory networks in multiple sclerosis and clinical implications
AbstractThere is mounting evidence regarding the role of impairment in neuromodulatory networks for neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease. However, the role of neuromodulatory networks in multiple sclerosis (MS) has not been assessed. We applied resting-state functional connectivity and graph theory to investigate the changes in the functional connectivity within neuromodulatory networks including the serotonergic, noradrenergic, cholinergic, and dopaminergic systems in MS. Twenty-nine MS patients and twenty-four age- and gender-matched healthy controls performed clinical and cognitive assessments including the expanded disability status score, symbol digit modalities test, and Hamilton Depression rating scale. We demonstrated a diffuse reorganization of network topography (P < 0.01) in serotonergic, cholinergic, noradrenergic, and dopaminergic networks in patients with MS. Serotonergic, noradrenergic, and cholinergic network functional connectivity derangement was associated with disease duration, EDSS, and depressive symptoms (P < 0.01). Derangements in serotonergic, noradrenergic, cholinergic, and dopaminergic network impairment were associated with cognitive abilities (P < 0.01). Our results indicate that functional connectivity changes within neuromodulatory networks might be a useful tool in predicting disability burden over time, and could serve as a surrogate endpoint to assess efficacy for symptomatic treatments.
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Wilson H, Pagano G, de Natale ER, Mansur A, Caminiti SP, Polychronis S, Middleton LT, Price G, Schmidt KF, Gunn RN, et al (2020). Mitochondrial Complex 1, Sigma 1, and Synaptic Vesicle 2A in Early Drug-Naive Parkinson's Disease.
Mov Disord,
35(8), 1416-1427.
Abstract:
Mitochondrial Complex 1, Sigma 1, and Synaptic Vesicle 2A in Early Drug-Naive Parkinson's Disease.
BACKGROUND: Dysfunction of mitochondrial energy generation may contribute to neurodegeneration, leading to synaptic loss in Parkinson's disease (PD). The objective of this study was to find cross-sectional and longitudinal changes in PET markers of synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1 in drug-naive PD patients. METHODS: Twelve early drug-naive PD patients and 16 healthy controls underwent a 3-Tesla MRI and PET imaging to quantify volume of distribution of [11 C]UCB-J, [11 C]SA-4503, and [18 F]BCPP-EF for synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1, respectively. Nine PD patients completed approximately 1-year follow-up assessments. RESULTS: Reduced [11 C]UCB-J volume of distribution in the caudate, putamen, thalamus, brain stem, and dorsal raphe and across cortical regions was observed in drug-naive PD patients compared with healthy controls. [11 C]UCB-J volume of distribution was reduced in the locus coeruleus and substantia nigra but did not reach statistical significance. No significant differences were found in [11 C]SA-4503 and [18 F]BCPP-EF volume of distribution in PD compared with healthy controls. Lower brain stem [11 C]UCB-J volume of distribution correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale part III and total scores. No significant longitudinal changes were identified in PD patients at follow-up compared with baseline. CONCLUSIONS: Our findings represent the first in vivo evidence of mitochondrial, endoplasmic reticulum, and synaptic dysfunction in drug-naive PD patients. Synaptic dysfunction likely occurs early in disease pathophysiology and has relevance to symptomatology. Mitochondrial complex 1 and sigma 1 receptor pathology warrants further investigations in PD. Studies in larger cohorts with longer follow-up will determine the validity of these PET markers to track disease progression. © 2020 the Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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Wilson H, Politis M, Rabiner EA, Middleton LT (2020). Novel PET Biomarkers to Disentangle Molecular Pathways across Age-Related Neurodegenerative Diseases.
Cells,
9(12), 2581-2581.
Abstract:
Novel PET Biomarkers to Disentangle Molecular Pathways across Age-Related Neurodegenerative Diseases
There is a need to disentangle the etiological puzzle of age-related neurodegenerative diseases, whose clinical phenotypes arise from known, and as yet unknown, pathways that can act distinctly or in concert. Enhanced sub-phenotyping and the identification of in vivo biomarker-driven signature profiles could improve the stratification of patients into clinical trials and, potentially, help to drive the treatment landscape towards the precision medicine paradigm. The rapidly growing field of neuroimaging offers valuable tools to investigate disease pathophysiology and molecular pathways in humans, with the potential to capture the whole disease course starting from preclinical stages. Positron emission tomography (PET) combines the advantages of a versatile imaging technique with the ability to quantify, to nanomolar sensitivity, molecular targets in vivo. This review will discuss current research and available imaging biomarkers evaluating dysregulation of the main molecular pathways across age-related neurodegenerative diseases. The molecular pathways focused on in this review involve mitochondrial dysfunction and energy dysregulation; neuroinflammation; protein misfolding; aggregation and the concepts of pathobiology, synaptic dysfunction, neurotransmitter dysregulation and dysfunction of the glymphatic system. The use of PET imaging to dissect these molecular pathways and the potential to aid sub-phenotyping will be discussed, with a focus on novel PET biomarkers.
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Wilson H, Pagano G, Niccolini F, Muhlert N, Mehta MA, Searle G, Gunn RN, Rabiner EA, Foltynie T, Politis M, et al (2020). The role of phosphodiesterase 4 in excessive daytime sleepiness in Parkinson's disease.
Parkinsonism and Related Disorders,
77, 163-169.
Abstract:
The role of phosphodiesterase 4 in excessive daytime sleepiness in Parkinson's disease
Introduction: Preclinical studies suggest a link between cAMP/PKA signalling, phosphodiesterase 4 (PDE4) expression and excessive daytime sleepiness (EDS). Here, we investigated in vivo the association between PDE4 expression and EDS in Parkinson's disease (PD) patients using [11C]rolipram PET and MR imaging. Methods: Eighteen participants, 12 PD and 6 healthy controls, underwent one [11C]rolipram PET and a multi-modal MRI scan. Probabilistic tractography was performed on subjects’ diffusion data to functionally parcellate the striatum according with projections to limbic cortical areas. The severity of EDS was assessed using the Epworth Sleepiness Scale (ESS). To assess PDE4 expression in PD patients with EDS, the PD cohort was divided according to the presence (n = 5) or absence (n = 7) of EDS, defined using validated cut-off of score ≥10 on the ESS as score ≥10 on the ESS. Results: PD patients with EDS showed significantly increased [11C]rolipram volume of distribution (VT) in the caudate (P = 0.029), hypothalamus (P = 0.013), hippocampus (P = 0.036) and limbic striatum (P = 0.030) compared to patients without EDS. Furthermore, higher ESS scores correlated with increased [11C]rolipram VT in the caudate (r = 0.77; P = 0.003), hypothalamus (r = 0.84; P = 0.001), hippocampus (r = 0.81; P = 0.001) and limbic subdivisions of the striatum (r = 0.80; P = 0.003). Conclusion: Our findings translate into humans preclinical data indicating that EDS is associated with elevated PDE4 in regions regulating sleep. The severity of EDS in PD was associated with elevated PDE4 expression; thus, suggesting a role of PDE4 in the pathophysiology of EDS in PD.
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Carotenuto A, Giordano B, Dervenoulas G, Wilson H, Veronese M, Chappell Z, Polychronis S, Pagano G, Mackewn J, Turkheimer FE, et al (2020). [18F]Florbetapir PET/MR imaging to assess demyelination in multiple sclerosis.
Eur J Nucl Med Mol Imaging,
47(2), 366-378.
Abstract:
[18F]Florbetapir PET/MR imaging to assess demyelination in multiple sclerosis.
PURPOSE: We evaluated myelin changes throughout the central nervous system in Multiple Sclerosis (MS) patients by using hybrid [18F]florbetapir PET-MR imaging. METHODS: We included 18 relapsing-remitting MS patients and 12 healthy controls. Each subject performed a hybrid [18F]florbetapir PET-MR and both a clinical and cognitive assessment. [18F]florbetapir binding was measured as distribution volume ratio (DVR), through the Logan graphical reference method and the supervised cluster analysis to extract a reference region, and standard uptake value (SUV) in the 70-90 min interval after injection. The two quantification approaches were compared. We also evaluated changes in the measures derived from diffusion tensor imaging and arterial spin labeling. RESULTS: [18F]florbetapir DVRs decreased from normal-appearing white matter to the centre of T2 lesion (P
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Pagano G, Niccolini F, Wilson H, Yousaf T, Khan NL, Martino D, Plisson C, Gunn RN, Rabiner EA, Piccini P, et al (2019). Comparison of phosphodiesterase 10A and dopamine transporter levels as markers of disease burden in early Parkinson's disease.
Movement Disorders,
34(10), 1505-1515.
Abstract:
Comparison of phosphodiesterase 10A and dopamine transporter levels as markers of disease burden in early Parkinson's disease
Background: Recent work has shown loss of phosphodiesterase 10A levels in middle-stage and advanced treated patients with PD, which was associated with motor symptom severity. Objectives: to assess phosphodiesterase 10A levels in early PD and compare with loss of dopamine transporter as markers of disease burden. Methods: Seventy-eight subjects were included in this study (17 early de novo, 15 early l-dopa–treated, 24 moderate-advanced l-dopa–treated patients with PD, and 22 healthy controls). All participants underwent [11C]IMA107 PET, [11C]PE2I PET, and 3-Tesla MRI scan. Results: Early de novo PD patients showed loss of [11C]IMA107 and of [11C]PE2I binding in caudate and putamen (P < 0.001); early l-dopa–treated PD patients showed additional loss of [11C]IMA107 in the caudate (P < 0.001; annual decline 3.6%) and putamen (P < 0.001; annual decline 2.8%), but loss of [11C]PE2I only in the putamen (P < 0.001; annual decline 6.8%). Lower [11C]IMA107 correlated with lower [11C]PE2I in the caudate (rho = 0.51; P < 0.01) and putamen (rho = 0.53; P < 0.01). Longer disease duration correlated with lower [11C]IMA107 in the caudate (rho = –0.72; P < 0.001) and putamen (rho = –0.48; P < 0.01), and with lower [11C]PE2I only in the putamen (rho = –0.65; P < 0.001). Higher burden of motor symptoms correlated with lower [11C]IMA107 in the caudate (rho = –0.42; P < 0.05) and putamen (rho = –0.41; P < 0.05), and with lower [11C]PE2I only in the putamen (rho = –0.69; P < 0.001). Conclusion: Our findings demonstrate loss of phosphodiesterase 10A levels very early in the course of PD and is associated with the gradual and progressive increase of motor symptoms. Phosphodiesterase 10A imaging shows similar potential with dopamine transporter imaging to follow disease progression. © 2019 International Parkinson and Movement Disorder Society.
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Wilson H, Niccolini F, Pellicano C, Politis M (2019). Cortical thinning across Parkinson's disease stages and clinical correlates.
JOURNAL OF THE NEUROLOGICAL SCIENCES,
398, 31-38.
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Wilson H, Pagano G, Politis M (2019). Dementia spectrum disorders: lessons learnt from decades with PET research.
JOURNAL OF NEURAL TRANSMISSION,
126(3), 233-251.
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Wilson H, Dervenoulas G, Pagano G, Tyacke RJ, Polychronis S, Myers J, Gunn RN, Rabiner EA, Nutt D, Politis M, et al (2019). Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson's disease: an in vivo11C-BU99008 PET study.
Brain,
142(10), 3116-3128.
Abstract:
Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson's disease: an in vivo11C-BU99008 PET study.
Astroglia are multifunctional cells that regulate neuroinflammation and maintain homeostasis within the brain. Astroglial α-synuclein-positive cytoplasmic accumulations have been shown post-mortem in patients with Parkinson's disease and therefore astroglia may play an important role in the initiation and progression of Parkinson's disease. Imidazoline 2 binding sites are expressed on activated astroglia in the cortex, hippocampus, basal ganglia and brainstem; therefore, by measuring imidazoline 2 binding site levels we can indirectly evaluate astrogliosis in patients with Parkinson's disease. Here, we aimed to evaluate the role of astroglia activation in vivo in patients with Parkinson's disease using 11C-BU99008 PET, a novel radioligand with high specificity and selectivity for imidazoline 2 binding sites. Twenty-two patients with Parkinson's disease and 14 healthy control subjects underwent 3 T MRI and a 120-min 11C-BU99008 PET scan with volume of distribution (VT) estimated using a two-tissue compartmental model with a metabolite corrected arterial plasma input function. Parkinson's disease patients were stratified into early (n = 8) and moderate/advanced (n = 14) groups according to disease stage. In early Parkinson's disease, increased 11C-BU99008 VT uptake was observed in frontal (P = 0.022), temporal (P = 0.02), parietal (P = 0.026) and occipital (P = 0.047) cortical regions compared with healthy controls. The greatest 11C-BU99008 VT increase in patients with early Parkinson's disease was observed in the brainstem (52%; P = 0.018). In patients with moderate/advanced Parkinson's disease, loss of 11C-BU99008 VT was observed across frontal (P = 0.002), temporal (P < 0.001), parietal (P = 0.039), occipital (P = 0.024), and insula (P < 0.001) cortices; and in the subcortical regions of caudate (P < 0.001), putamen (P < 0.001) and thalamus (P < 0.001); and in the brainstem (P = 0.018) compared with healthy controls. In patients with Parkinson's disease, loss of 11C-BU99008 VT in cortical regions, striatum, thalamus and brainstem correlated with longer disease duration (P < 0.05) and higher disease burden scores, measured with Movement Disorder Society Unified Parkinson's Disease Rating Scale (P < 0.05). In the subgroup of patients with moderate/advanced Parkinson's disease, loss of 11C-BU99008 VT in the frontal (r = 0.79; P = 0.001), temporal (r = 0.74; P = 0.002) and parietal (r = 0.89; P < 0.001) cortex correlated with global cognitive impairment. This study demonstrates in vivo the role of astroglia in the initiation and progression of Parkinson's disease. Reactive astroglia observed early in Parkinson's disease could reflect a neuroprotective compensatory mechanisms and pro-inflammatory upregulation in response to α-synuclein accumulation. However, as the disease progresses and significant neurodegeneration occurs, astroglia lose their reactive function and such loss in the cortex has clinical relevance in the development of cognitive impairment.
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Wilson H, Dervenoulas G, Pagano G, Koros C, Yousaf T, Picillo M, Polychronis S, Simitsi A, Giordano B, Chappell Z, et al (2019). Serotonergic pathology and disease burden in the premotor and motor phase of A53T alpha-synuclein parkinsonism: a cross-sectional study.
LANCET NEUROLOGY,
18(8), 748-759.
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Niccolini F, Wilson H, Giordano B, Diamantopoulos K, Pagano G, Chaudhuri KR, Politis M (2019). Sleep disturbances and gastrointestinal dysfunction are associated with thalamic atrophy in Parkinson's disease.
BMC Neuroscience,
20(1).
Abstract:
Sleep disturbances and gastrointestinal dysfunction are associated with thalamic atrophy in Parkinson's disease
Background: Non-motor symptoms are common aspects of Parkinson's disease (PD) occurring even at the prodromal stage of the disease and greatly affecting the quality of life. Here, we investigated whether non-motor symptoms burden was associated with cortical thickness and subcortical nuclei volume in PD patients. Methods: We studied 41 non-demented PD patients. Non-motor symptoms burden was assessed using the Non-Motor Symptoms Scale grading (NMSS). Cortical thickness and subcortical nuclei volume analyses were carried out using Free-Surfer. PD patients were divided into two groups according to the NMSS grading: Mild to moderate (NMSS: 0-40) and severe (NMSS: ≥ 41) non-motor symptoms. Results: Thalamic atrophy was associated with higher NMSQ and NMSS total scores. The non-motor symptoms that drove this correlation were sleep/fatigue and gastrointestinal tract dysfunction. We also found that PD patients with severe non-motor symptoms had significant thalamic atrophy compared to the group with mild to moderate non-motor symptoms. Conclusions: Our findings show that greater non-motor symptom burden is associated with thalamic atrophy in PD. Thalamus plays an important role in processing sensory information including visceral afferent from the gastrointestinal tract and in regulating states of sleep and wakefulness.
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Pagano G, Yousaf T, Wilson H, Niccolini F, Polychronis S, Chaudhuri KR, Politis M (2018). Constipation is not associated with dopamine transporter pathology in early drug-naïve patients with Parkinson's disease.
European Journal of Neurology,
25(2), 307-312.
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Constipation is not associated with dopamine transporter pathology in early drug-naïve patients with Parkinson's disease
Background and purpose: Constipation is a common non-motor symptom of Parkinson's disease (PD). Deposition of α-synuclein inclusions that spread from the gut to the substantia nigra through the vagus nerve has recently been speculated to be a pre-motor and early stage of PD. The aim of the study was to investigate whether constipation is associated with dopaminergic pathology on dopamine transporter (DAT) single-photon emission computed tomography in early drug-naïve patients with PD. Our hypothesis was that constipation is associated with other signs of pre-motor PD and is independent of DAT pathology. We then investigated for associations with motor and non-motor symptoms, and with cerebrospinal fluid biomarkers of PD pathology. Methods: Using the Parkinson's Progression Markers Initiative database, we investigated the prevalence of constipation and the association between constipation and clinical features, striatal [123I]Ioflupane uptake and non-imaging (cerebrospinal fluid and serum) biomarkers. Constipation was evaluated using Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I item 1.11. Results: One third (132/398) of de-novo patients with PD had constipation. Higher severity of constipation correlated with older age (r = 0.728, P < 0.001), higher MDS-UPDRS total score (r = 0.285, P < 0.001), worse postural instability (r = 0.190, P = 0.012), rapid eye movement sleep behaviour disorder (r = 0.228, P < 0.0001) and depression (r = 0.187, P = 0.024). No correlation was found with cerebrospinal fluid, serum and imaging markers of PD pathology. Conclusions: Constipation was not associated with DAT pathology but with rapid eye movement sleep behaviour disorder and depression, which are speculated to be pre-motor symptoms of PD. This confirms the hypothesis that constipation may be a pre-motor sign of PD due to an impairment of non-dopaminergic pathways.
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Pagano G, Polychronis S, Wilson H, Giordano B, Ferrara N, Niccolini F, Politis M (2018). Diabetes mellitus and Parkinson disease.
NEUROLOGY,
90(19), E1654-E1662.
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Niccolini F, Wilson H, Hirschbichler S, Yousaf T, Pagano G, Whittington A, Caminiti SP, Erro R, Holton JL, Jaunmuktane Z, et al (2018). Disease-related patterns of in vivo pathology in Corticobasal syndrome.
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING,
45(13), 2413-2425.
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Yousaf T, Pagano G, Wilson H, Politis M (2018). Neuroimaging of Sleep Disturbances in Movement Disorders.
FRONTIERS IN NEUROLOGY,
9 Author URL.
Schulz J, Pagano G, Bonfante JAF, Wilson H, Politis M (2018). Nucleus basalis of Meynert degeneration precedes and predicts cognitive impairment in Parkinson's disease.
BRAIN,
141, 1501-1516.
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Pagano G, De Micco R, Yousaf T, Wilson H, Chandra A, Politis M (2018). REM behavior disorder predicts motor progression and cognitive decline in Parkinson disease.
NEUROLOGY,
91(10), E894-E905.
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Wilson H, Giordano B, Turkheimer FE, Chaudhuri KR, Politis M (2018). Serotonergic dysregulation is linked to sleep problems in Parkinson's disease.
NEUROIMAGE-CLINICAL,
18, 630-637.
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Politis M, Wilson H, Wu K, Brooks DJ, Piccini P (2017). Chronic exposure to dopamine agonists affects the integrity of striatal D-2 receptors in Parkinson's patients.
NEUROIMAGE-CLINICAL,
16, 455-460.
Author URL.
Moonga I, Niccolini F, Wilson H, Pagano G, Politis M (2017). Hypertension is associated with worse cognitive function and hippocampal hypometabolism in Alzheimer's disease.
European Journal of Neurology,
24(9), 1173-1182.
Abstract:
Hypertension is associated with worse cognitive function and hippocampal hypometabolism in Alzheimer's disease
Background and purpose: a growing body of evidence suggests that cardiovascular disease risk factors including hypertension may be linked to sporadic Alzheimer's disease (AD). It is well known that hypertension is associated with cerebrovascular disease and vascular dementia on the basis of vascular remodeling. However, the mechanisms linking hypertension and AD remain unclear. Methods: We studied 197 patients with AD (86 male; mean age ± SD: 75.8 ± 7.4 years) from the Alzheimer's Disease Neuroimaging Initiative database with (n = 97) and without (n = 100) hypertension. We explored associations between hypertension and clinical, plasma, cerebrospinal fluid and imaging markers of AD pathology in order to elucidate the underlying mechanisms that may link AD and hypertension. Results: We found that patients with AD with hypertension had worse cognitive function (Alzheimer's disease Assessment Scale-cognitive subscale, P = 0.038) and higher neuropsychiatric symptom burden (Neuropsychiatric Inventory Questionnaire, P = 0.016) compared with those without hypertension. Patients with AD with hypertension showed reduced glucose hypometabolism in the right (P < 0.001) and left (P = 0.007) hippocampus. No differences were found in magnetic resonance imaging volumetric measurements, [18F]florbetapir uptakes, plasma and cerebrospinal fluid between patients with AD with and without hypertension. Conclusions: Although hypertension is associated with worse cognitive function, behavioural symptoms and hippocampal glucose hypometabolism, it is not associated with evidence of increased amyloid or tau pathology. Effective management of hypertension may potentially have a therapeutic role in the alleviation of symptoms in AD.
Abstract.
Niccolini F, Wilson H, Pagano G, Coello C, Mehta MA, Searle GE, Gunn RN, Rabiner EA, Foltynie T, Politis M, et al (2017). Loss of phosphodiesterase 4 in Parkinson disease Relevance to cognitive deficits.
NEUROLOGY,
89(6), 586-593.
Author URL.
Wilson H, De Micco R, Niccolini F, Politis M (2017). Molecular imaging Markers to Track Huntington's Disease Pathology.
FRONTIERS IN NEUROLOGY,
8 Author URL.
Pagano G, Niccolini F, Yousaf T, Wilson H, Polychronis S, Chaudhuri KR, Politis M (2017). Urinary Dysfunction in Early De Novo Patients with Parkinson's Disease.
MOVEMENT DISORDERS,
32(6), 939-940.
Author URL.
Wilson H, Niccolini F, Haider S, Marques TR, Pagano G, Coello C, Natesan S, Kapur S, Rabiner EA, Gunn RN, et al (2016). Loss of extra-striatal phosphodiesterase 10A expression in early premanifest Huntington's disease gene carriers.
JOURNAL OF THE NEUROLOGICAL SCIENCES,
368, 243-248.
Author URL.
