International Multicenter Analysis of Brain Structure Across Clinical Stages of Parkinson's Disease.

BACKGROUND: Brain structure abnormalities throughout the course of Parkinson's disease have yet to be fully elucidated. OBJECTIVE: Using a multicenter approach and harmonized analysis methods, we aimed to shed light on Parkinson's disease stage-specific profiles of pathology, as suggested by in vivo neuroimaging. METHODS: Individual brain MRI and clinical data from 2357 Parkinson's disease patients and 1182 healthy controls were collected from 19 sources. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effects models. Patients grouped according to Hoehn and Yahr stage were compared with age- and sex-matched controls. Within the patient sample, we investigated associations with Montreal Cognitive Assessment score. RESULTS: Overall, patients showed a thinner cortex in 38 of 68 regions compared with controls (dmax  = -0.20, dmin  = -0.09). The bilateral putamen (dleft  = -0.14, dright  = -0.14) and left amygdala (d = -0.13) were smaller in patients, whereas the left thalamus was larger (d = 0.13). Analysis of staging demonstrated an initial presentation of thinner occipital, parietal, and temporal cortices, extending toward rostrally located cortical regions with increased disease severity. From stage 2 and onward, the bilateral putamen and amygdala were consistently smaller with larger differences denoting each increment. Poorer cognition was associated with widespread cortical thinning and lower volumes of core limbic structures. CONCLUSIONS: Our findings offer robust and novel imaging signatures that are generally incremental across but in certain regions specific to disease stages. Our findings highlight the importance of adequately powered multicenter collaborations. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

C9orf72 promoter hypermethylation is neuroprotective: Neuroimaging and neuropathologic evidence.

OBJECTIVE: To use in vivo neuroimaging and postmortem neuropathologic analysis in C9orf72 repeat expansion patients to investigate the hypothesis that C9orf72 promoter hypermethylation is neuroprotective and regionally selective. METHODS: Twenty patients with a C9orf72 repeat expansion participating in a high-resolution MRI scan and a clinical examination and a subset of patients (n = 11) were followed longitudinally with these measures. Gray matter (GM) density was related to C9orf72 promoter hypermethylation using permutation-based testing. Regional neuronal loss was measured in an independent autopsy series (n = 35) of C9orf72 repeat expansion patients. RESULTS: GM analysis revealed that hippocampus, frontal cortex, and thalamus are associated with hypermethylation and thus appear to be relatively protected from mutant C9orf72. Neuropathologic analysis demonstrated an association between reduced neuronal loss and hypermethylation in hippocampus and frontal cortex. Longitudinal neuroimaging revealed that hypermethylation is associated with reduced longitudinal decline in GM regions protected by hypermethylation and longitudinal neuropsychological assessment demonstrated that longitudinal decline in verbal recall is protected by hypermethylation. CONCLUSIONS: These cross-sectional and longitudinal neuroimaging studies, along with neuropathologic validation studies, provide converging evidence for neuroprotective properties of C9orf72 promoter hypermethylation. These findings converge with prior postmortem studies suggesting that C9orf72 promoter hypermethylation may be a neuroprotective target for drug discovery.