Machine learning nominates the inositol pathway and novel genes in Parkinson's disease.

There are 78 loci associated with Parkinson's disease in the most recent genome-wide association study (GWAS), yet the specific genes driving these associations are mostly unknown. Herein, we aimed to nominate the top candidate gene from each Parkinson's disease locus and identify variants and pathways potentially involved in Parkinson's disease. We trained a machine learning model to predict Parkinson's disease-associated genes from GWAS loci using genomic, transcriptomic and epigenomic data from brain tissues and dopaminergic neurons. We nominated candidate genes in each locus and identified novel pathways potentially involved in Parkinson's disease, such as the inositol phosphate biosynthetic pathway (INPP5F, IP6K2, ITPKB and PPIP5K2). Specific common coding variants in SPNS1 and MLX may be involved in Parkinson's disease, and burden tests of rare variants further support that CNIP3, LSM7, NUCKS1 and the polyol/inositol phosphate biosynthetic pathway are associated with the disease. Functional studies are needed to further analyse the involvements of these genes and pathways in Parkinson's disease.

Neuropsychological Changes in Isolated REM Sleep Behavior Disorder: A Systematic Review and Meta-analysis of Cross-sectional and Longitudinal Studies.

The aim of this meta-analysis is twofold: (a) to assess cognitive impairments in isolated rapid eye movement (REM) sleep behavior disorder (iRBD) patients compared to healthy controls (HC); (b) to quantitatively estimate the risk of developing a neurodegenerative disease in iRBD patients according to baseline cognitive assessment. To address the first aim, cross-sectional studies including polysomnography-confirmed iRBD patients, HC, and reporting neuropsychological testing were included. To address the second aim, longitudinal studies including polysomnography-confirmed iRBD patients, reporting baseline neuropsychological testing for converted and still isolated patients separately were included. The literature search was conducted based on PRISMA guidelines and the protocol was registered at PROSPERO (CRD42021253427). Cross-sectional and longitudinal studies were searched from PubMed, Web of Science, Scopus, and Embase databases. Publication bias and statistical heterogeneity were assessed respectively by funnel plot asymmetry and using I2. Finally, a random-effect model was performed to pool the included studies. 75 cross-sectional (2,398 HC and 2,460 iRBD patients) and 11 longitudinal (495 iRBD patients) studies were selected. Cross-sectional studies showed that iRBD patients performed significantly worse in cognitive screening scores (random-effects (RE) model = -0.69), memory (RE model = -0.64), and executive function (RE model = -0.50) domains compared to HC. The survival analyses conducted for longitudinal studies revealed that lower executive function and language performance, as well as the presence of mild cognitive impairment (MCI), at baseline were associated with an increased risk of conversion at follow-up. Our study underlines the importance of a comprehensive neuropsychological assessment in the context of iRBD.

Mitochondrial function-associated genes underlie cortical atrophy in prodromal synucleinopathies.

Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson's disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49-87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41-88) years; 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain's structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer's disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain's structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer's disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks.

Differentially targeted seeding reveals unique pathological alpha-synuclein propagation patterns.

Parkinson's disease is a progressive neurodegenerative disorder characterized by the intracellular accumulation of insoluble alpha-synuclein aggregates into Lewy bodies and neurites. Increasing evidence indicates that Parkinson's disease progression results from the spread of pathologic alpha-synuclein through neuronal networks. However, the exact mechanisms underlying the propagation of abnormal proteins in the brain are only partially understood. The objective of this study was first to describe the long-term spatiotemporal distributions of Lewy-related pathology in mice injected with alpha-synuclein preformed fibrils and then to recreate these patterns using a computational model that simulates in silico the spread of pathologic alpha-synuclein. In this study, 87 2-3-month-old non-transgenic mice were injected with alpha-synuclein preformed fibrils to generate a comprehensive post-mortem dataset representing the long-term spatiotemporal distributions of hyperphosphorylated alpha-synuclein, an established marker of Lewy pathology, across the 426 regions of the Allen Mouse Brain Atlas. The mice were injected into either the caudoputamen, nucleus accumbens or hippocampus, and followed over 24 months with pathologic alpha-synuclein quantified at seven intermediate time points. The pathologic patterns observed at each time point in this high-resolution dataset were then compared to those generated using a Susceptible-Infected-Removed (SIR) computational model, an agent-based model that simulates the spread of pathologic alpha-synuclein for every brain region taking simultaneously into account the effect of regional brain connectivity and Snca gene expression. Our histopathological findings showed that differentially targeted seeding of pathological alpha-synuclein resulted in unique propagation patterns over 24 months and that most brain regions were permissive to pathology. We found that the SIR model recreated the observed distributions of pathology over 24 months for each injection site. Null models showed that both Snca gene expression and connectivity had a significant influence on model fit. In sum, our study demonstrates that the combination of normal alpha-synuclein concentration and brain connectomics contributes to making brain regions more vulnerable to the pathological process, providing support for a prion-like spread of pathologic alpha-synuclein. We propose that this rich dataset and the related computational model will help test new hypotheses regarding mechanisms that may alter the spread of pathologic alpha-synuclein in the brain.

Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression.

Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% male) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e. a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the computational model recreated cortical thinning (r = 0.51, P = 0.0007) and tissue deformation (r = 0.52, P = 0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive function and can be recreated using the dynamics of agent-based modelling, structural connectivity and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodromal synucleinopathies. Therefore, the agent-based Susceptible-Infected-Removed model may be a useful tool for testing hypotheses underlying neurodegenerative diseases and new therapies aimed at slowing or stopping the spread of alpha-synuclein pathology.

A Prodromal Brain-Clinical Pattern of Cognition in Synucleinopathies.

OBJECTIVE: Isolated (or idiopathic) rapid eye movement sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Biomarkers are lacking to predict conversion to a dementia or a motor-first phenotype. Here, we aimed at identifying a brain-clinical signature that predicts dementia in iRBD. METHODS: A brain-clinical signature was identified in 48 patients with polysomnography-confirmed iRBD using partial least squares between brain deformation and 27 clinical variables. The resulting variable was applied to 78 patients with iRBD followed longitudinally to predict conversion to a synucleinopathy, specifically DLB. The deformation scores from patients with iRBD were compared with 207 patients with PD, DLB, or prodromal DLB to assess if scores were higher in DLB compared to PD. RESULTS: One latent variable explained 31% of the brain-clinical covariance in iRBD, combining cortical and subcortical deformation and subarachnoid/ventricular expansion to cognitive and motor variables. The deformation score of this signature predicted conversion to a synucleinopathy in iRBD (p = 0.036, odds ratio [OR] = 2.249; 95% confidence interval [CI] = 1.053-4.803), specifically to DLB (OR = 4.754; 95% CI = 1.283-17.618, p = 0.020) and not PD (p = 0.286). Patients with iRBD who developed dementia had scores similar to clinical and prodromal patients with DLB but higher scores compared with patients with PD. The deformation score also predicted cognitive performance over 1, 2, and 4 years in patients with PD. INTERPRETATION: We identified a brain-clinical signature that predicts conversion in iRBD to more severe/dementing forms of synucleinopathy. This pattern may serve as a new biomarker to optimize patient care, target risk reduction strategies, and administer neuroprotective trials. ANN NEUROL 2021;89:341-357.

Sex effects on brain structure in de novo Parkinson's disease: a multimodal neuroimaging study.

Parkinson's disease varies in severity and age of onset. One source of this variability is sex. Males are twice as likely as females to develop Parkinson's disease, and tend to have more severe symptoms and greater speed of progression. However, to date, there is little information in large cohorts on sex differences in the patterns of neurodegeneration. Here we used MRI and clinical information from the Parkinson Progression Markers Initiative to measure structural brain differences between sexes in Parkinson's disease after regressing out the expected effect of age and sex. We derived atrophy maps from deformation-based morphometry of T1-weighted MRI and connectivity from diffusion-weighted MRI in de novo Parkinson's disease patients (149 males: 83 females) with comparable clinical severity, and healthy control participants (78 males: 39 females). Overall, even though the two patient groups were matched for disease duration and severity, males demonstrated generally greater brain atrophy and disrupted connectivity. Males with Parkinson's disease had significantly greater tissue loss than females in 11 cortical regions including bilateral frontal and left insular lobe, right postcentral gyrus, left inferior temporal and cingulate gyrus and left thalamus, while females had greater atrophy in six cortical regions, including regions in the left frontal lobe, right parietal lobe, left insular gyrus and right occipital cortex. Local efficiency of white matter connectivity showed greater disruption in males in multiple regions such as basal ganglia, hippocampus, amygdala and thalamus. These findings support the idea that development of Parkinson's disease may involve different pathological mechanisms and yield distinct prognosis in males and females, which may have implications for research into neuroprotection, and stratification for clinical trials.

Subcortical amyloid load is associated with shape and volume in cognitively normal individuals.

Amyloid-beta (Aß) deposition is one of the main hallmarks of Alzheimer's disease. The study assessed the associations between cortical and subcortical 11 C-Pittsburgh Compound B (PiB) retention, namely, in the hippocampus, amygdala, putamen, caudate, pallidum, and thalamus, and subcortical morphology in cognitively normal individuals. We recruited 104 cognitive normal individuals who underwent extensive neuropsychological assessment, PiB-positron emission tomography (PET) scan, and 3-T magnetic resonance imaging (MRI) acquisition of T1-weighted images. Global, cortical, and subcortical regional PiB retention values were derived from each scan and subcortical morphology analyses were performed to investigate vertex-wise local surface and global volumes, including the hippocampal subfields volumes. We found that subcortical regional Aß was associated with the surface of the hippocampus, thalamus, and pallidum, with changes being due to volume and shape. Hippocampal Aß was marginally associated with volume of the whole hippocampus as well as with the CA1 subfield, subiculum, and molecular layer. Participants showing higher subcortical Aß also showed worse cognitive performance and smaller hippocampal volumes. In contrast, global and cortical PiB uptake did not associate with any subcortical metrics. This study shows that subcortical Aß is associated with subcortical surface morphology in cognitively normal individuals. This study highlights the importance of quantifying subcortical regional PiB retention values in these individuals.

Subcortical amyloid relates to cortical morphology in cognitively normal individuals.

PURPOSE: Amyloid (Aß) brain deposition can occur in cognitively normal individuals and is associated with cortical volume abnormalities. Aß-related volume changes are inconsistent across studies. Since volume is composed of surface area and thickness, the relative contribution of Aß deposition on each of these metrics remains to be understood in cognitively normal individuals. METHODS: A group of 104 cognitively normal individuals underwent neuropsychological assessment, PiB-PET scan, and MRI acquisition. Surface-based cortical analyses were performed to investigate the effects of cortical and subcortical Aß burden on cortical volume, thickness, and surface area. Mediation analyses were used to study the effect of thickness and surface area on Aß-associated volume changes. We also investigated the relationships between structural metrics in clusters with abnormal morphology and regions underlying resting-state functional networks and cognitive performance. RESULTS: Cortical Aß was not associated with cortical morphology. Subcortical Aß burden was associated with changes in cortical volume, thickness, and surface area. Aß-associated volume changes were driven by cortical surface area with or without thickness but never by thickness alone. Aß-associated changes overlapped greatly with regions from the default mode network and were associated with lower performance in visuospatial abilities, episodic memory, and working memory. CONCLUSIONS: In cognitively normal individuals, subcortical Aß is associated with cortical volume, and this effect was driven by surface area with or without thickness. Aß-associated cortical changes were found in the default mode network and affected cognitive performance. Our findings demonstrate the importance of studying subcortical Aß and cortical surface area in normal ageing.

Abnormal Gray Matter Shape, Thickness, and Volume in the Motor Cortico-Subcortical Loop in Idiopathic Rapid Eye Movement Sleep Behavior Disorder: Association with Clinical and Motor Features.

Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a major risk factor for Parkinson's disease and dementia with Lewy bodies. Anatomical gray matter abnormalities in the motor cortico-subcortical loop areas remain under studied in iRBD patients. We acquired T1-weighted images and administrated quantitative motor tasks in 41 patients with polysomnography-confirmed iRBD and 41 healthy subjects. Cortical thickness and voxel-based morphometry (VBM) analyses were performed to investigate local cortical thickness and gray matter volume changes, vertex-based shape analysis to investigate shape of subcortical structures, and structure-based volumetric analyses to investigate volumes of subcortical and brainstem structures. Cortical thickness analysis revealed thinning in iRBD patients in bilateral medial superior frontal, orbitofrontal, anterior cingulate cortices, and the right dorsolateral primary motor cortex. VBM results showed lower gray matter volume in iRBD patients in the frontal lobes, anterior cingulate gyri, and caudate nucleus. Shape analysis revealed extensive surface contraction in the external and internal segments of the left pallidum. Clinical and motor impaired features in iRBD were associated with anomalies of the motor cortico-subcortical loop. In summary, iRBD patients showed numerous gray matter structural abnormalities in the motor cortico-subcortical loop, which are associated with lower motor performance and clinical manifestations of iRBD.

Patterns of cortical thinning in idiopathic rapid eye movement sleep behavior disorder.

Idiopathic rapid eye movement sleep behavior disorder is a parasomnia that is a risk factor for dementia with Lewy bodies and Parkinson's disease. Brain function impairments have been identified in this disorder, mainly in the frontal and posterior cortical regions. However, the anatomical support for these dysfunctions remains poorly understood. We investigated gray matter thickness, gray matter volume, and white matter integrity in patients with idiopathic rapid eye movement sleep behavior disorder. Twenty-four patients with polysomnography-confirmed idiopathic rapid eye movement sleep behavior disorder and 42 healthy individuals underwent a 3-tesla structural and diffusion magnetic resonance imaging examination using corticometry, voxel-based morphometry, and diffusion tensor imaging. In the patients with idiopathic rapid eye movement sleep behavior disorder, decreased cortical thickness was observed in the frontal cortex, the lingual gyrus, and the fusiform gyrus. Gray matter volume was reduced in the superior frontal sulcus only. Patients showed no increased gray matter thickness or volume. Diffusion tensor imaging analyses revealed no significant white matter differences between groups. Using corticometry in patients with idiopathic rapid eye movement sleep behavior disorder, several new cortical regions with gray matter alterations were identified, similar to those reported in dementia with Lewy bodies and Parkinson's disease. These findings provide some anatomical support for previously identified brain function impairments in this disorder.

Neural correlates of obesity across the lifespan.

Associations between brain and obesity are bidirectional: changes in brain structure and function underpin over-eating, while chronic adiposity leads to brain atrophy. Investigating brain-obesity interactions across the lifespan can help better understand these relationships. This study explores the interaction between obesity and cortical morphometry in children, young adults, adults, and older adults. We also investigate the genetic, neurochemical, and cognitive correlates of the brain-obesity associations. Our findings reveal a pattern of lower cortical thickness in fronto-temporal brain regions associated with obesity across all age cohorts and varying age-dependent patterns in the remaining brain regions. In adults and older adults, obesity correlates with neurochemical changes and expression of inflammatory and mitochondrial genes. In children and older adults, adiposity is associated with modifications in brain regions involved in emotional and attentional processes. Thus, obesity might originate from cognitive changes during early adolescence, leading to neurodegeneration in later life through mitochondrial and inflammatory mechanisms.

99mTc-HMPAO SPECT Perfusion Signatures Associated With Clinical Progression in Patients With Isolated REM Sleep Behavior Disorder.

BACKGROUND AND OBJECTIVES: Idiopathic/isolated REM sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies and Parkinson disease. Despite evidence of abnormal cerebral perfusion in iRBD, there is currently no pattern that can predict whether an individual will develop dementia with Lewy bodies or Parkinson disease. The objective was to identify a perfusion signature associated with conversion to dementia with Lewy bodies in iRBD. METHODS: Patients with iRBD underwent video-polysomnography, neurologic and neuropsychological assessments, and baseline 99mTc-HMPAO SPECT to assess relative cerebral blood flow. Partial least squares correlation was used to identify latent variables that maximized covariance between 27 clinical features and relative gray matter perfusion. Patient-specific scores on the latent variables were used to test the association with conversion to dementia with Lewy bodies compared with that with Parkinson disease. The signature's expression was also assessed in 24 patients with iRBD who underwent a second perfusion scan, 22 healthy controls, and 19 individuals with Parkinson disease. RESULTS: Of the 137 participants, 93 underwent SPECT processing, namely 52 patients with iRBD (67.9 years, 73% men), 19 patients with Parkinson disease (67.3 years, 37% men), and 22 controls (67.0 years, 73% men). Of the 47 patients with iRBD followed up longitudinally (4.5 years), 12 (26%) developed a manifest synucleinopathy (4 dementia with Lewy bodies and 8 Parkinson disease). Analysis revealed 2 latent variables between relative blood flow and clinical features: the first was associated with a broad set of features that included motor, cognitive, and perceptual variables, age, and sex; the second was mostly associated with cognitive features and RBD duration. When brought back into the patient's space, the expression of the first variable was associated with conversion to a manifest synucleinopathy, whereas the second was associated with conversion to dementia with Lewy bodies. The expression of the patterns changed over time and was associated with worse motor features. DISCUSSION: This study identified a brain perfusion signature associated with cognitive impairment in iRBD and transition to dementia with Lewy bodies. This signature, which can be derived from individual scans, has the potential to be developed into a biomarker that predicts dementia with Lewy bodies in at-risk individuals.

Predicting longitudinal brain atrophy in Parkinson's disease using a Susceptible-Infected-Removed agent-based model.

Parkinson's disease is a progressive neurodegenerative disorder characterized by accumulation of abnormal isoforms of alpha-synuclein. Alpha-synuclein is proposed to act as a prion in Parkinson's disease: In its misfolded pathologic state, it favors the misfolding of normal alpha-synuclein molecules, spreads trans-neuronally, and causes neuronal damage as it accumulates. This theory remains controversial. We have previously developed a Susceptible-Infected-Removed (SIR) computational model that simulates the templating, propagation, and toxicity of alpha-synuclein molecules in the brain. In this study, we test this model with longitudinal MRI collected over 4 years from the Parkinson's Progression Markers Initiative (1,068 T1 MRI scans, 790 Parkinson's disease scans, and 278 matched control scans). We find that brain deformation progresses in subcortical and cortical regions. The SIR model recapitulates the spatiotemporal distribution of brain atrophy observed in Parkinson's disease. We show that connectome topology and geometry significantly contribute to model fit. We also show that the spatial expression of two genes implicated in alpha-synuclein synthesis and clearance, SNCA and GBA, also influences the atrophy pattern. We conclude that the progression of atrophy in Parkinson's disease is consistent with the prion-like hypothesis and that the SIR model is a promising tool to investigate multifactorial neurodegenerative diseases over time.

Network connectivity and local transcriptomic vulnerability underpin cortical atrophy progression in Parkinson's disease.

Parkinson's disease pathology is hypothesized to spread through the brain via axonal connections between regions and is further modulated by local vulnerabilities within those regions. The resulting changes to brain morphology have previously been demonstrated in both prodromal and de novo Parkinson's disease patients. However, it remains unclear whether the pattern of atrophy progression in Parkinson's disease over time is similarly explained by network-based spreading and local vulnerability. We address this gap by mapping the trajectory of cortical atrophy rates in a large, multi-centre cohort of Parkinson's disease patients and relate this atrophy progression pattern to network architecture and gene expression profiles. Across 4-year follow-up visits, increased atrophy rates were observed in posterior, temporal, and superior frontal cortices. We demonstrated that this progression pattern was shaped by network connectivity. Regional atrophy rates were strongly related to atrophy rates across structurally and functionally connected regions. We also found that atrophy progression was associated with specific gene expression profiles. The genes whose spatial distribution in the brain was most related to atrophy rate were those enriched for mitochondrial and metabolic function. Taken together, our findings demonstrate that both global and local brain features influence vulnerability to neurodegeneration in Parkinson's disease.

Comprehensive Analysis of Brain Volume in REM Sleep Behavior Disorder with Mild Cognitive Impairment.

BACKGROUND: Rapid-eye-movement sleep behavior disorder (RBD) is a major risk factor for Parkinson's disease and dementia with Lewy bodies. More than a third of RBD patients have mild cognitive impairment (MCI), but their specific structural brain alterations remain poorly understood. OBJECTIVE: This study aimed to investigate the local deformation and volume of gray and white matter tissue underlying MCI in RBD. METHODS: Fifty-two idiopathic RBD patients, including 17 with MCI (33%), underwent polysomnography, neuropsychological, neurological, and magnetic resonance imaging assessments. MCI diagnosis was based on a subjective complaint, cognitive impairment on the neuropsychological battery, and preserved daily functioning. Forty-one controls were also included. Deformation-based morphometry (DBM), voxel-based morphometry (VBM), and regional volume analyses of the corpus callosum and cholinergic basal forebrain were performed. Multiple regression models were also computed using anatomical, cognitive (composite z scores), and motor parameters. RESULTS: Globally, patients with MCI displayed a widespread pattern of local deformation and volume atrophy in the cortical (bilateral insula, cingulate cortex, precuneus, frontal, temporal and occipital regions, right angular gyrus, and mid-posterior segment of the corpus callosum) and subcortical (brainstem, corona radiata, basal ganglia, thalamus, amygdala, and right hippocampus) regions compared to patients without MCI (DBM) or controls (DBM and VBM). Moreover, brain deformation (DBM) in patients were associated with lower performance in attention and executive functions, visuospatial abilities, and higher motor symptoms severity. CONCLUSION: The present study identified novel brain structural alterations in RBD patients with MCI which correlated with poorer cognitive performance. These results are consistent with those reported in patients with synucleinopathies-related cognitive impairment.

Brain atrophy progression in Parkinson's disease is shaped by connectivity and local vulnerability.

Brain atrophy has been reported in the early stages of Parkinson's disease, but there have been few longitudinal studies. How intrinsic properties of the brain, such as anatomical connectivity, local cell-type distribution and gene expression combine to determine the pattern of disease progression also remains unknown. One hypothesis proposes that the disease stems from prion-like propagation of misfolded alpha-synuclein via the connectome that might cause varying degrees of tissue damage based on local properties. Here, we used MRI data from the Parkinson Progression Markers Initiative to map the progression of brain atrophy over 1, 2 and 4 years compared with baseline. We derived atrophy maps for four time points using deformation-based morphometry applied to T1-weighted MRI from 120 de novo Parkinson's disease patients, 74 of whom had imaging at all four time points (50 Men: 24 Women) and 157 healthy control participants (115 Men: 42 Women). In order to determine factors that may influence neurodegeneration, we related atrophy progression to brain structural and functional connectivity, cell-type expression and gene ontology enrichment analyses. After regressing out the expected age and sex effects associated with normal ageing, we found that atrophy significantly progressed over 2 and 4 years in the caudate, nucleus accumbens, hippocampus and posterior cortical regions. This progression was shaped by both structural and functional brain connectivity. Also, the progression of atrophy was more pronounced in regions with a higher expression of genes related to synapses and was inversely related to the prevalence of oligodendrocytes and endothelial cells. In sum, we demonstrate that the progression of atrophy in Parkinson's disease is in line with the prion-like propagation hypothesis of alpha-synuclein and provide evidence that synapses may be especially vulnerable to synucleinopathy. In addition to identifying vulnerable brain regions, this study reveals different factors that may be implicated in the neurotoxic mechanisms leading to progression in Parkinson's disease. All brain maps generated here are available on request.

Brain atrophy in Parkinson's disease with polysomnography-confirmed REM sleep behavior disorder.

We aimed to investigate cortical and subcortical brain alterations in people with Parkinson's disease with polysomnography-confirmed rapid eye movement (REM) sleep behavior disorder (RBD). Thirty people with Parkinson's disease, including 15 people with RBD, were recruited and compared with 41 healthy controls. Surface-based cortical and subcortical analyses were performed on T1-weighted images to investigate thickness and shape abnormalities between groups, and voxel-based and deformation-based morphometry were performed to investigate local volume. Correlations were performed in patients to investigate the structural correlates of motor activity during REM sleep. People with RBD showed cortical thinning in the right perisylvian and inferior temporal cortices and shape contraction in the putamen compared with people without RBD. Compared with controls, people with RBD had extensive cortical thinning and volume loss, brainstem volume was reduced, and shape contraction was found in the basal ganglia and hippocampus. In comparison to controls, people without RBD showed more restricted thinning in the sensorimotor, parietal, and occipital cortices, reduced volume in the brainstem, temporal and more posterior areas, and shape contraction in the pallidum and hippocampus. In Parkinson's disease, higher tonic and phasic REM sleep motor activity was associated with contraction of the thalamic surface, extensive cortical thinning, and subtle volume reduction in the middle temporal gyrus. In Parkinson's disease, the presence of RBD is associated with extensive cortical and subcortical abnormalities, suggesting more severe neurodegeneration in people with RBD. This provides potential neuroanatomical correlates for the more severe clinical phenotype reported in people with Parkinson's disease with RBD.

Gray matter substrates of depressive and anxiety symptoms in idiopathic REM sleep behavior disorder.

INTRODUCTION: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a prodromal stage of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Depressive and anxiety symptoms are frequent features of PD, DLB and iRBD, and some studies suggest that depressive symptoms are a marker for neurodegeneration in iRBD. However, the pathophysiology of depressive and anxiety symptoms in iRBD is still unclear. This study aimed to investigate cortical and subcortical gray matter (GM) volume substrates of depressive and anxiety symptoms in iRBD patients. METHODS: Forty-six polysomnography-confirmed iRBD patients and 31 healthy controls (HC) without cognitive or mood impairment were recruited. All participants underwent 3-T magnetic resonance imaging and completed the Beck Depression Inventory Second Edition (BDI-II) and Beck Anxiety Inventory (BAI) questionnaires. Voxel-based morphometry analysis was performed to assess GM volume in cortical and subcortical structures. Between-group comparisons and regressions were performed. RESULTS: iRBD patients with depressive symptoms (BDI-II score > 13 or the use of antidepressants to treat depression) showed reduced GM volume in the caudate nucleus compared to HC and iRBD patients without depressive symptoms. Moreover, iRBD patients with anxiety symptoms (BAI score > 9 or the use of anxiolytics to treat anxiety) showed reduced GM volume in the left amygdala extending to the hippocampus compared to HC and iRBD patients without anxiety symptoms. In iRBD patients, higher BDI-II and BAI total scores were associated with lower GM volumes in these regions respectively. CONCLUSION: Depressive and anxiety symptoms in iRBD patients are related to patterns of cortical and subcortical GM volume loss.