Greater cortical thinning and microstructural integrity loss in myotonic dystrophy type 1 compared to myotonic dystrophy type 2.

BACKGROUND: Myotonic dystrophy is a multisystem disorder characterized by widespread organic involvement including central nervous system symptoms. Although myotonic dystrophy disease types 1 (DM1) and 2 (DM2) cover a similar spectrum of symptoms, more pronounced clinical and brain alterations have been described in DM1. Here, we investigated brain volumetric and white matter alterations in both disease types and compared to healthy controls (HC). METHODS: MRI scans were obtained from 29 DM1, 27 DM2, and 56 HC. We assessed macro- and microstructural brain changes by surface-based analysis of cortical thickness of anatomical images and tract-based spatial statistics of fractional anisotropy (FA) obtained by diffusion-weighted imaging, respectively. Global MRI measures were related to clinical and neuropsychological scores to evaluate their clinical relevance. RESULTS: Cortical thickness was reduced in both patient groups compared to HC, showing similar patterns of regional distribution in DM1 and DM2 (occipital, temporal, frontal) but more pronounced cortical thinning for DM1. Similarly, FA values showed a widespread decrease in DM1 and DM2 compared to HC. Interestingly, FA was significantly lower in DM1 compared to DM2 within most parts of the brain. CONCLUSION: Comparisons between DM1 and DM2 indicate a more pronounced cortical thinning of grey matter and a widespread reduction in microstructural integrity of white matter in DM1. Future studies are required to unravel the underlying and separating mechanisms for the disease courses of the two types and their neuropsychological symptoms.

Linking white matter hyperintensities to regional cortical thinning, amyloid deposition, and synaptic density loss in Alzheimer's disease.

INTRODUCTION: We investigated the association between white matter hyperintensities (WMH) and regional cortical thickness, amyloid and tau deposition, and synaptic density in the WMH-connected cortex using multimodal images. METHODS: We included 107 participants (59 with Alzheimer's disease [AD]; 27 with mild cognitive impairment; 21 cognitively normal controls) with amyloid beta (Aß) positivity on amyloid positron emission tomography (PET). The cortex connected to WMH was identified using probabilistic tractography. RESULTS: We found that WMH connected to the cortex with more severe regional degeneration as measured by cortical thickness, Aß and tau deposition, and synaptic vesicle glycoprotein 2 A (SV2A) density using 18F-SynVesT-1 PET. In addition, higher ratios of Aß in the deep WMH-connected versus WMH-unconnected cortex were significantly related to lower cognitive scores. Last, the cortical thickness of WMH-connected cortex reduced more than WMH-unconnected cortex over 12 months. DISCUSSION: Our results suggest that WMH may be associated with AD-intrinsic processes of degeneration, in addition to vascular mechanisms. HIGHLIGHTS: We studied white matter hyperintensities (WMHs) and WMH-connected cortical changes. WMHs are associated with more severe regional cortical degeneration. Findings suggest WMHs may be associated with Alzheimer's disease-intrinsic processes of degeneration.

The hippocampus as a structural and functional network epicentre for distant cortical thinning in neurocognitive aging.

Alterations in grey matter (GM) and white matter (WM) are associated with memory impairment across the neurocognitive aging spectrum and theorised to spread throughout brain networks. Functional and structural connectivity (FC,SC) may explain widespread atrophy. We tested the effect of SC and FC to the hippocampus on cortical thickness (CT) of connected areas. In 419 (223 F) participants (agemean=73 ±â€¯8) from the Alzheimer's Disease Neuroimaging Initiative, cortical regions associated with memory (Rey Auditory Verbal Learning Test) were identified using Lasso regression. Two structural equation models (SEM), for SC and resting-state FC, were fitted including CT areas, and SC and FC to the left and right hippocampus (LHIP,RHIP). LHIP (ß=-0.150,p=<.001) and RHIP (ß=-0.139,p=<.001) SC predicted left temporopolar/rhinal CT; RHIP SC predicted right temporopolar/rhinal CT (ß=-0.191,p=<.001). LHIP SC predicted right fusiform/parahippocampal (ß=-0.104,p=.011) and intraparietal sulcus/superior parietal CT (ß=0.101,p=.028). Increased RHIP FC predicted higher left inferior parietal CT (ß=0.132,p=.042) while increased LHIP FC predicted lower right fusiform/parahippocampal CT (ß=-0.97; p=.023). The hippocampi may be epicentres for cortical thinning through disrupted connectivity.

Accelerated Cortical Thinning in Schizophrenia Is Associated With Rare and Common Predisposing Variation to Schizophrenia and Neurodevelopmental Disorders.

BACKGROUND: Schizophrenia is a highly heritable disorder characterized by increased cortical thinning throughout the life span. Studies have reported a shared genetic basis between schizophrenia and cortical thickness. However, no genes whose expression is related to abnormal cortical thinning in schizophrenia have been identified. METHODS: We conducted linear mixed models to estimate the rates of accelerated cortical thinning across 68 regions from the Desikan-Killiany atlas in individuals with schizophrenia compared with healthy control participants from a large longitudinal sample (ncases = 169 and ncontrols = 298, ages 16-70 years). We studied the correlation between gene expression data from the Allen Human Brain Atlas and accelerated thinning estimates across cortical regions. Finally, we explored the functional and genetic underpinnings of the genes that contribute most to accelerated thinning. RESULTS: We found a global pattern of accelerated cortical thinning in individuals with schizophrenia compared with healthy control participants. Genes underexpressed in cortical regions that exhibit this accelerated thinning were downregulated in several psychiatric disorders and were enriched for both common and rare disrupting variation for schizophrenia and neurodevelopmental disorders. In contrast, none of these enrichments were observed for baseline cross-sectional cortical thickness differences. CONCLUSIONS: Our findings suggest that accelerated cortical thinning, rather than cortical thickness alone, serves as an informative phenotype for neurodevelopmental disruptions in schizophrenia. We highlight the genetic and transcriptomic correlates of this accelerated cortical thinning, emphasizing the need for future longitudinal studies to elucidate the role of genetic variation and the temporal-spatial dynamics of gene expression in brain development and aging in schizophrenia.

Distinct spatiotemporal patterns of cortical thinning in Alzheimer's disease-type cognitive impairment and subcortical vascular cognitive impairment.

Previous studies on Alzheimer's disease-type cognitive impairment (ADCI) and subcortical vascular cognitive impairment (SVCI) has rarely explored spatiotemporal heterogeneity. This study aims to identify distinct spatiotemporal cortical atrophy patterns in ADCI and SVCI. 1,338 participants (713 ADCI, 208 SVCI, and 417 cognitively unimpaired elders) underwent brain magnetic resonance imaging (MRI), amyloid positron emission tomography, and neuropsychological tests. Using MRI, this study measures cortical thickness in five brain regions (medial temporal, inferior temporal, posterior medial parietal, lateral parietal, and frontal areas) and utilizes the Subtype and Stage Inference (SuStaIn) model to predict the most probable subtype and stage for each participant. SuStaIn identifies two distinct cortical thinning patterns in ADCI (medial temporal: 65.8%, diffuse: 34.2%) and SVCI (frontotemporal: 47.1%, parietal: 52.9%) patients. The medial temporal subtype of ADCI shows a faster decline in attention, visuospatial, visual memory, and frontal/executive domains than the diffuse subtype (p-value < 0.01). However, there are no significant differences in longitudinal cognitive outcomes between the two subtypes of SVCI. Our study provides valuable insights into the distinct spatiotemporal patterns of cortical thinning in patients with ADCI and SVCI, suggesting the potential for individualized therapeutic and preventive strategies to improve clinical outcomes.

Longitudinal brain structure changes in Parkinson's disease: A replication study.

CONTEXT: An existing major challenge in Parkinson's disease (PD) research is the identification of biomarkers of disease progression. While magnetic resonance imaging is a potential source of PD biomarkers, none of the magnetic resonance imaging measures of PD are robust enough to warrant their adoption in clinical research. This study is part of a project that aims to replicate 11 PD studies reviewed in a recent survey (JAMA neurology, 78(10) 2021) to investigate the robustness of PD neuroimaging findings to data and analytical variations. OBJECTIVE: This study attempts to replicate the results in Hanganu et al. (Brain, 137(4) 2014) using data from the Parkinson's Progression Markers Initiative (PPMI). METHODS: Using 25 PD subjects and 18 healthy controls, we analyzed the rate of change of cortical thickness and of the volume of subcortical structures, and we measured the relationship between structural changes and cognitive decline. We compared our findings to the results in the original study. RESULTS: (1) Similarly to the original study, PD patients with mild cognitive impairment (MCI) exhibited increased cortical thinning over time compared to patients without MCI in the right middle temporal gyrus, insula, and precuneus. (2) The rate of cortical thinning in the left inferior temporal and precentral gyri in PD patients correlated with the change in cognitive performance. (3) There were no group differences in the change of subcortical volumes. (4) We did not find a relationship between the change in subcortical volumes and the change in cognitive performance. CONCLUSION: Despite important differences in the dataset used in this replication study, and despite differences in sample size, we were able to partially replicate the original results. We produced a publicly available reproducible notebook allowing researchers to further investigate the reproducibility of the results in Hanganu et al. (2014) when more data is added to PPMI.

Rates of cortical thinning in Alzheimer's disease signature regions associate with vascular burden but not with ß-amyloid status in cognitively normal adults at age 70.

BACKGROUND: Consistent patterns of reduced cortical thickness have been identified in early Alzheimer's disease (AD). However, the pathological factors that influence rates of cortical thinning within these AD signature regions remain unclear. METHODS: Participants were from the Insight 46 substudy of the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort), a prospective longitudinal cohort study. Linear regression was used to examine associations of baseline cerebral ß-amyloid (Aß) deposition, measured using florbetapir positron emission tomography, and baseline white matter hyperintensity volume (WMHV) on MRI, a marker of cerebral small vessel disease, with subsequent longitudinal changes in AD signature cortical thickness quantified from baseline and repeat MRI (mean [SD] interval 2.4 [0.2] years). RESULTS: In a population-based sample of 337 cognitively normal older white adults (mean [SD] age at baseline 70.5 [0.6] years; 48.1% female), higher global WMHV at baseline related to faster subsequent rates of cortical thinning in both AD signature regions (~0.15%/year faster per 10 mL additional WMHV), whereas baseline Aß status did not. Among Aß positive participants (n=56), there was some evidence that greater global Aß standardised uptake value ratio at baseline related to faster cortical thinning in the AD signature Mayo region, but this did not reach statistical significance (p=0.08). CONCLUSIONS: Cortical thinning within AD signature regions may develop via cerebrovascular pathways. Perhaps reflecting the age of the cohort and relatively low prevalence of Aß-positivity, robust Aß-related differences were not detected. Longitudinal follow-up incorporating additional biomarkers will allow assessment of how these relationships evolve closer to expected dementia onset.

Personalized brain MRI revealed distinct functional and anatomical disruptions in Creutzfeldt-Jakob disease and Alzheimer's disease.

AIMS: Creutzfeldt-Jakob disease (CJD) is a lethal neurodegenerative disorder, which leads to a rapidly progressive dementia. This study aimed to examine the cortical alterations in CJD, changes in these brain characteristics over time, and the differences between CJD and Alzheimer's disease (AD) that show similar clinical manifestations. METHODS: To obtain reliable, subject-specific functional measures, we acquired 24 min of resting-state fMRI data from each subject. We applied an individual-based approach to characterize the functional brain organization of 10 patients with CJD, 8 matched patients with AD, and 8 normal controls. We measured cortical atrophy as well as disruption in resting-state functional connectivity (rsFC) and then investigated longitudinal brain changes in a subset of CJD patients. RESULTS: CJD was associated with widespread cortical thinning and weakened rsFC. Compared with AD, CJD showed distinct atrophy patterns and greater disruptions in rsFC. Moreover, the longitudinal data demonstrated that the progressive cortical thinning and disruption in rsFC mainly affected the association rather than the primary cortex in CJD. CONCLUSIONS: CJD shows unique anatomical and functional disruptions in the cerebral cortex, distinct from AD. Rapid progression of CJD affects both the cortical thickness and rsFC in the association cortex.

Disease Progression Patterns of Brain Morphology in Schizophrenia: More Progressed Stages in Treatment Resistance.

BACKGROUND AND HYPOTHESIS: Given the heterogeneity and possible disease progression in schizophrenia, identifying the neurobiological subtypes and progression patterns in each patient may lead to novel biomarkers. Here, we adopted data-driven machine-learning techniques to identify the progression patterns of brain morphological changes in schizophrenia and investigate the association with treatment resistance. STUDY DESIGN: In this cross-sectional multicenter study, we included 177 patients with schizophrenia, characterized by treatment response or resistance, with 3D T1-weighted magnetic resonance imaging. Cortical thickness and subcortical volumes calculated by FreeSurfer were converted into z scores using 73 healthy controls data. The Subtype and Stage Inference (SuStaIn) algorithm was used for unsupervised machine-learning analysis. STUDY RESULTS: SuStaIn identified 3 different subtypes: (1) subcortical volume reduction (SC) type (73 patients), in which volume reduction of subcortical structures occurs first and moderate cortical thinning follows, (2) globus pallidus hypertrophy and cortical thinning (GP-CX) type (42 patients), in which globus pallidus hypertrophy initially occurs followed by progressive cortical thinning, and (3) cortical thinning (pure CX) type (39 patients), in which thinning of the insular and lateral temporal lobe cortices primarily happens. The remaining 23 patients were assigned to baseline stage of progression (no change). SuStaIn also found 84 stages of progression, and treatment-resistant schizophrenia showed significantly more progressed stages than treatment-responsive cases (P = .001). The GP-CX type presented earlier stages than the pure CX type (P = .009). CONCLUSIONS: The brain morphological progressions in schizophrenia can be classified into 3 subtypes, and treatment resistance was associated with more progressed stages, which may suggest a novel biomarker.

Spatial patterns of gray and white matter compromise relate to age of seizure onset in temporal lobe epilepsy.

OBJECTIVE: Temporal Lobe Epilepsy (TLE) is frequently a neurodevelopmental disorder, involving subcortical volume loss, cortical atrophy, and white matter (WM) disruption. However, few studies have addressed how these pathological changes in TLE relate to one another. In this study, we investigate spatial patterns of gray and white matter degeneration in TLE and evaluate the hypothesis that the relationship among these patterns varies as a function of the age at which seizures begin. METHODS: Eighty-two patients with TLE and 59 healthy controls were enrolled. T1-weighted images were used to obtain hippocampal volumes and cortical thickness estimates. Diffusion-weighted imaging was used to obtain fractional anisotropy (FA) and mean diffusivity (MD) of the superficial WM (SWM) and deep WM tracts. Analysis of covariance was used to examine patterns of WM and gray matter alterations in TLE relative to controls, controlling for age and sex. Sliding window correlations were then performed to examine the relationships between SWM degeneration, cortical thinning, and hippocampal atrophy across ages of seizure onset. RESULTS: Cortical thinning in TLE followed a widespread, bilateral pattern that was pronounced in posterior centroparietal regions, whereas SWM and deep WM loss occurred mostly in ipsilateral, temporolimbic regions compared to controls. Window correlations revealed a relationship between hippocampal volume loss and whole brain SWM disruption in patients who developed epilepsy during childhood. On the other hand, in patients with adult-onset TLE, co-occurring cortical and SWM alterations were observed in the medial temporal lobe ipsilateral to the seizure focus. SIGNIFICANCE: Our results suggest that although cortical, hippocampal and WM alterations appear spatially discordant at the group level, the relationship among these features depends on the age at which seizures begin. Whereas neurodevelopmental aspects of TLE may result in co-occurring WM and hippocampal degeneration near the epileptogenic zone, the onset of seizures in adulthood may set off a cascade of SWM microstructural loss and cortical atrophy of a neurodegenerative nature.

Basal Forebrain Atrophy, Cortical Thinning, and Amyloid-ß Status in Parkinson's disease-Related Cognitive Decline.

BACKGROUND: Degeneration of the cortically-projecting cholinergic basal forebrain (cBF) is a well-established pathologic correlate of cognitive decline in Parkinson's disease (PD). In Alzheimer's disease (AD) the effect of cBF degeneration on cognitive decline was found to be mediated by parallel atrophy of denervated cortical areas. OBJECTIVES: To examine whether the association between cBF degeneration and cognitive decline in PD is mediated by parallel atrophy of cortical areas and whether these associations depend on the presence of comorbid AD pathology. METHODS: We studied 162 de novo PD patients who underwent serial 3 T magnetic resonance imaging scanning (follow-up: 2.33 ± 1.46 years) within the Parkinson's Progression Markers Initiative. cBF volume and regional cortical thickness were automatically calculated using established procedures. Individual slopes of structural brain changes and cognitive decline were estimated using linear-mixed models. Associations between longitudinal cBF degeneration, regional cortical thinning, and cognitive decline were assessed using regression analyses and mediation effects were assessed using nonparametric bootstrap. Complementary analyses assessed the effect of amyloid-ß biomarker positivity on these associations. RESULTS: After controlling for global brain atrophy, longitudinal cBF degeneration was highly correlated with faster cortical thinning (PFDR < 0.05), and thinning in cBF-associated cortical areas mediated the association between cBF degeneration and cognitive decline (rcBF-MoCA = 0.30, P < 0.001). Interestingly, both longitudinal cBF degeneration and its association with cortical thinning were largely independent of amyloid-ß status. CONCLUSIONS: cBF degeneration in PD is linked to parallel thinning of cortical target areas, which mediate the effect on cognitive decline. These associations are independent of amyloid-ß status, indicating that they reflect proper features of PD pathophysiology. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cortical morphological changes in multiple sclerosis patients: a study of cortical thickness, sulcal depth, and local gyrification index.

PURPOSE: Multiple sclerosis (MS) is a disease that progresses not only with demyelination but also with neurodegeneration. One of the goals of drug treatment in MS is to prevent neurodegeneration. Cortical thickness (CT), sulcal depth (SD), and local gyrification index (LGI) are indicators related to neurodegeneration. The aim of this study is to investigate changes in CT, SD, and LGI in patients with relapsing-remitting MS (RRMS). METHODS: T1 images of 74 RRMS patients and 65 healthy controls were used. T1 hypointense areas in RRMS patients were corrected using fully automated methods. CT, SD, and LGI were calculated for each patient. RESULTS: RRMS patients showed widespread cortical thinning, especially in bilateral temporoparietal areas, decreased SD in bilateral supramarginal gyrus, superior temporal gyrus, postcentral gyrus, and transverse temporal gyrus, and decreased LGI, especially in the left posterior cingulate gyrus and insula. The decrease in cortical thickness was associated with the number of attacks and lesion volume. EDSS was related to CT in the right lingual, inferior temporal, and fusiform gyrus. The LGI was correlated with T2 lesion volume in bilateral insula, with EDSS in the right insula and transverse and superior temporal gyri, and with the number of attacks in the right paracentral gyrus and pre-cuneus. However, SD did not show any correlation with EDSS, T2 lesion volume, or the number of attacks. CONCLUSION: Our results demonstrate widespread cortical thinning, decreased sulcal depth in local areas, and decreased gyrification in folds in RRMS patients, which are related to clinical parameters.

Gene transcriptional expression of cortical thinning during childhood and adolescence.

The cognitive and behavioral development of children and adolescents is closely related to the maturation of brain morphology. Although the trajectory of brain development has been depicted in detail, the underlying biological mechanism of normal cortical morphological development in childhood and adolescence remains unclear. By combining the Allen Human Brain Atlas dataset with two single-site magnetic resonance imaging data including 427 and 733 subjects from China and the United States, respectively, we performed partial least squares regression and enrichment analysis to explore the relationship between the gene transcriptional expression and the development of cortical thickness in childhood and adolescence. We found that the spatial model of normal cortical thinning during childhood and adolescence is associated with genes expressed predominantly in astrocytes, microglia, excitatory and inhibitory neurons. Top cortical development-related genes are enriched for energy-related and DNA-related terms and are associated with psychological and cognitive disorders. Interestingly, there is a great deal of similarity between the findings derived from the two single-site datasets. This fills the gap between early cortical development and transcriptomes, which promotes an integrative understanding of the potential biological neural mechanisms.

Multiple sclerosis optic neuritis and trans-synaptic pathology on cortical thinning in people with multiple sclerosis.

BACKGROUND: The multi-order visual system represents an excellent testing site regarding the process of trans-synaptic degeneration. The presence and extent of global versus trans-synaptic neurodegeneration in people with multiple sclerosis (pwMS) is not clear. OBJECTIVE: To explore cross-sectional and longitudinal relationships between retinal, thalamic and cortical changes in pwMS with and without MS-related optic neuritis (pwMSON and pwoMSON) using MRI and optical coherence tomography (OCT). METHODS: 162 pwMS and 47 healthy controls (HCs) underwent OCT and brain MRI at baseline and 5.5-years follow-up. Peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell inner plexiform layer (mGCIPL) thicknesses were determined. Global volume measures of brain parenchymal volume (BPV)/percent brain volume change (PBVC), thalamic volume and T2-lesion volume (LV) were derived using standard analysis protocols. Regional cortical thickness was determined using FreeSurfer. Cross-sectional and longitudinal relationship between the retinal measures, thalamic volume and cortical thickness were assessed using age, BPV/PBVC and T2-LV adjusted correlations and regressions. RESULTS: After age, BPV and T2-LV adjustment, the thalamic volume explained additional variance in the thickness of pericalcarine (R2 increase of 0.066, standardized ß = 0.299, p = 0.039) and lateral occipital (R2 increase of 0.024, standardized ß = 0.299, p = 0.039) gyrii in pwMSON. In pwoMSON, the thalamic volume was a significant predictor only of control (frontal) regions of pars opercularis. There was no relationship between thalamic atrophy and cortical thinning over the follow-up in both pwMS with and without MSON. While numerically lower in the pwMSON group, the inter-eye difference was not able to predict the presence of MSON. CONCLUSIONS: MSON can induce a measurable amount of trans-synaptic pathology on second-order cortical regions.

Determinants of cognitive and brain resilience to tau pathology: a longitudinal analysis.

Mechanisms of resilience against tau pathology in individuals across the Alzheimer's disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We used a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicentre study, we included 366 amyloid-ß-positive individuals with mild cognitive impairment or Alzheimer's disease dementia with baseline 18F-flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stßinteraction = -0.062, P = 0.032), higher education level (Stßinteraction = -0.072, P = 0.011) and higher intracranial volume (Stßinteraction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer's disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.

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.

Cerebral cortical thinning in Parkinson's disease depends on the age of onset.

Patients with older-onset Parkinson's disease (PD) have more severe motor symptoms, faster progression, and a worse prognosis. The thinning of the cerebral cortex is one of the causes of these issues. Patients with older-onset PD manifest more extended neurodegeneration associated with α-synuclein deposition in the cerebral cortex; however, the cortical regions that undergo thinning are unclear. We aimed to identify cortical regions with different thinning depending on the age of onset in patients with PD. Sixty-two patients with PD were included in this study. Patients with PD onset at <63 years old were included in the early or middle-onset PD group, and those with PD onset at >63 years old were included in the late-onset PD (LOPD) group. Brain magnetic resonance imaging data of these patients were processed using FreeSurfer to measure their cortical thickness. The LOPD group displayed less cortical thickness in the superior frontal gyrus, middle frontal gyrus, precentral gyrus, postcentral gyrus, superior temporal gyrus, temporal pole, paracentral lobule, superior parietal lobule, precuneus, and occipital lobe than the early or middle-onset PD group. Compared with patients with early and middle-onset PD, elderly patients displayed extended cortical thinning with disease progression. Differences in the clinical manifestations of PD according to the age of onset were partly due to variations in the morphological changes in the brain.

Association of Indication for Hospitalization With Subsequent Amyloid Positron Emission Tomography and Magnetic Resonance Imaging Biomarkers.

BACKGROUND: Hospitalization in older age is associated with accelerated cognitive decline, typically preceded by neuropathologic changes. We assess the association between indication for hospitalization and brain neurodegeneration. METHODS: Included were participants from the Mayo Clinic Study of Aging, a population-based longitudinal study, with ≥1 brain imaging available in those older than 60 years of age between 2004 and 2017. Primary analyses used linear mixed-effects models to assess association of hospitalization with changes in longitudinal trajectory of cortical thinning, amyloid accumulation, and white matter hyperintensities (WMH). Additional analyses were performed with imaging outcomes dichotomized (normal vs abnormal) using Cox proportional hazards regression. RESULTS: Of 2 480 participants, 1 966 had no hospitalization and 514 had ≥1 admission. Hospitalization was associated with accelerated cortical thinning (annual slope change -0.003 mm [95% confidence interval (CI) -0.005 to -0.001], p = .002), but not amyloid accumulation (0.003 [95% CI -0.001 to 0.006], p = .107), or WMH increase (0.011 cm3 [95% CI -0.001 to 0.023], p = .062). Interaction analyses assessing whether trajectory changes are dependent on admission type (medical vs surgical) found interactions for all outcomes. While surgical hospitalizations were not, medical hospitalizations were associated with accelerated cortical thinning (-0.004 mm [95% CI -0.008 to -0.001, p = .014); amyloid accumulation (0.010, [95% CI 0.002 to 0.017, p = .011), and WMH increase (0.035 cm3 [95% CI 0.012 to 0.058, p = .006). Hospitalization was not associated with developing abnormal cortical thinning (p = .407), amyloid accumulation (p = .596), or WMH/infarctions score (p = .565). CONCLUSIONS: Medical hospitalizations were associated with accelerated cortical thinning, amyloid accumulation, and WMH increases. These changes were modest and did not translate to increased risk for crossing the abnormality threshold.

Childhood maltreatment is associated with cortical thinning in people with eating disorders.

Childhood maltreatment (CM) is a non-specific risk factor for eating disorders (ED) and is associated with a greater severity in their clinical presentation and poorer treatment outcome. These data suggest that maltreated people with ED may be biologically other than clinically different from non-maltreated people. The aim of the present study was to investigate cortical thickness (CT), a possible biomarker of neurodevelopment, in people with ED with or without history of CM and in healthy women. Twenty-four healthy women, 26 with anorexia nervosa and 24 with bulimia nervosa underwent a 3T MRI scan. All participants filled in the childhood trauma questionnaire. All neuroimaging data were processed by FreeSurfer. Twenty-four participants with ED were identified as maltreated and 26 participants with ED as non-maltreated. All healthy women were non-maltreated. Compared to healthy women, maltreated people with ED showed lower CT in the left rostral anterior cingulate gyrus, while compared to people with ED without history of CM showed lower CT values in the left superior frontal and in right caudal middle frontal and superior parietal gyri. No significant differences emerged in CT measures between healthy women and people with ED without history of CM. The present findings show for the first time that in adult people with ED childhood maltreatment is associated with cortical thinning in areas implicated in the modulation of brain processes that are acknowledged to play a role in the psychopathology of ED.

Vascular burden and cognition: Mediating roles of neurodegeneration and amyloid PET.

It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aß) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity [WMH] volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aß deposition (18 F-AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or 18 F fluorodeoxyglucose PET) in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aß and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aß status. In summary, our study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive function via localized neurodegeneration. HIGHLIGHTS: Alzheimer's disease often co-exists with vascular pathology. We studied a unique cohort enriched for high white matter hyperintensities (WMH). High WMH related to cognitive impairment of semantic fluency and executive function. This relationship was mediated via temporo-parietal atrophy rather than metabolism. This relationship was, to lesser extent, serially mediated via amyloid beta and atrophy.