RESUMO
OBJECTIVE: To test the hypothesis that white matter hyperintensities (WMH) in behavioral-variant frontotemporal dementia (bvFTD) and Alzheimer disease (AD) are associated with disease variables such as disease severity, cortical atrophy, and cognition, we conducted a cross-sectional brain MRI study with volumetric and voxel-wise analyses. METHODS: A total of 129 patients (64 bvFTD, 65 AD) and 66 controls underwent high-resolution brain MRI and clinical and neuropsychological examination. Genetic screening was conducted in 124 cases (54 bvFTD, 44 AD, 26 controls) and postmortem pathology was available in 18 cases (13 bvFTD, 5 AD). WMH were extracted using an automated segmentation algorithm and analyses of total volumes and spatial distribution were conducted. Group differences in total WMH volume and associations with vascular risk and disease severity were examined. Syndrome-specific voxel-wise associations between WMH, cortical atrophy, and performance across different cognitive domains were assessed. RESULTS: Total WMH volumes were larger in patients with bvFTD than patients with AD and controls. In bvFTD, WMH volumes were associated with disease severity but not vascular risk. Patients with bvFTD and patients with AD showed distinct spatial patterns of WMH that mirrored characteristic patterns of cortical atrophy. Regional WMH load correlated with worse cognitive performance in discrete cognitive domains. WMH-related cognitive impairments were shared between syndromes, with additional associations found in bvFTD. CONCLUSION: Increased WMH are common in patients with bvFTD and patients with AD. Our findings suggest that WMH are partly independent of vascular pathology and associated with the neurodegenerative process. WMH occur in processes independent of and related to cortical atrophy. Furthermore, increased WMH in different regions contributes to cognitive deficits.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Afinamento Cortical Cerebral/diagnóstico por imagem , Demência Frontotemporal/diagnóstico por imagem , Leucoencefalopatias/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Atrofia , Espessura Cortical do Cérebro , Proteína C9orf72/genética , Estudos de Casos e Controles , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Afinamento Cortical Cerebral/fisiopatologia , Feminino , Demência Frontotemporal/genética , Demência Frontotemporal/fisiopatologia , Humanos , Leucoencefalopatias/genética , Leucoencefalopatias/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tamanho do Órgão , Progranulinas/genética , Índice de Gravidade de Doença , Análise Espacial , Substância Branca/patologia , Proteínas tau/genéticaRESUMO
Importance: Many psychiatric disorders can be conceptualized as disorders of brain maturation during childhood and adolescence. Discovering the neurobiological underpinnings of brain maturation may elucidate molecular pathways of vulnerability and resilience to such disorders. Objective: To investigate the underlying neurobiological mechanisms of age-associated cortical thinning during maturation and their implications for psychiatric disorders. Design, Setting, and Participants: This multicohort analysis used data from 3 community-based studies. The Saguenay Youth Study provided data from 1024 adolescents who were recruited at a single site in Quebec, Canada. The IMAGEN cohort provided data from 1823 participants who were recruited in 8 European cities. The Brazil High Risk Cohort Study for the Development of Childhood Psychiatric Disorders provided data from 815 participants who were recruited in 2 Brazilian cities. Cortical thickness was estimated from the results of magnetic resonance imaging (MRI) scans, and age-associated cortical thinning was estimated in 34 cortical regions. Gene expression from the Allen Human Brain Atlas was aligned with the same regions. Similarities in the interregional profiles of gene expression and the profiles of age-associated cortical thinning were measured. The involvement of dendrites, dendritic spines, and myelin was tested using 3 gene panels. Enrichment for genes associated with psychiatric disorders was tested among the genes associated with thinning and their coexpression networks. Data analysis was conducted between March and October 2019. Main Outcomes and Measures: MRI-derived estimates of age-associated cortical thinning and gene expression in 34 cortical regions. Results: A total of 3596 individuals aged 9 to 21 years were included in this study. Of those, 1803 participants (50.1%) were female, and the mean (SD) age was 15.2 (2.6) years. Interregional profiles of age-associated cortical thinning were associated with interregional gradients in the expression of genes associated with dendrites, dendritic spines, and myelin; the variance in thinning explained by the gene panels across different points ranged from 0.45% to 10.55% for the dendrite panel, 0.00% to 9.98% for the spine panel, and 0.19% to 26.39% for the myelin panel. These genes and their coexpression networks were enriched for genes associated with several psychiatric disorders. Conclusions and Relevance: In this study, genetic similarity between interregional variation in cortical thinning during maturation and multiple psychiatric disorders suggests overlapping molecular underpinnings. This finding adds to the understanding of the neurodevelopmental mechanisms of psychiatric disorders.
