Apathy progression is associated with brain atrophy and white matter damage in Parkinson’s disease

Apathy is a prevalent non-motor symptom that significantly impacts the quality of life in Parkinson's disease (PD) patients. Although previous studies have investigated the neural correlates of apathy in PD, the longitudinal relationships between regional brain atrophy, white matter hyperintensities (WMHs), and apathy progression remain underexplored. Using longitudinal, multisite data of <i>de novo</i> PD patients from the Parkinson's Progression Markers Initiative (PPMI), the present study aims to investigate these relationships. We used T1-weighted magnetic resonance imaging (MRI) and clinical data from 445 participants. Apathy was assessed as part of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I. We applied deformation-based morphometry (DBM) to quantify grey matter atrophy and used the Brain tISsue segmentatiON (BISON) algorithm to segment WMHs from T1-weighted images. Using linear regression models, we performed cross-sectional analyses to identify the associations between baseline brain measurements (DBM and WMH) and apathy severity. Longitudinal analyses utilized linear mixed-effects models to investigate whether baseline brain measurements were associated with future apathy progression over time, accounting for covariates such as age, sex, motion artefacts, Hoehn and Yahr stage, levodopa-equivalent daily dose (LEDD), Total Intracranial Volume (TIV) and baseline apathy. Hypothesis-based and exploratory analyses were conducted to confirm the results previously reported in the literature and explore potential new associations. No cross-sectional regional associations survived multiple comparison corrections. Longitudinal hypothesis-based models confirmed that baseline atrophy in regions such as the bilateral nucleus accumbens area, superior parietal, putamen, insula, left precuneus, right precentral and cerebellum grey matter was significantly associated with future apathy progression. Exploratory longitudinal analyses identified additional regions, including the bilateral lingual, parahippocampal, basal forebrain, ventral diencephalon, isthmus cingulate, thalamus, hippocampus, left middle temporal, right inferior temporal, pericalcarine, medial orbitofrontal, cuneus, where baseline atrophy was correlated with progression of apathy severity. Moreover, greater WMH burden, particularly in the frontal lobe, was associated with worsening apathy. These results highlight the influence of both grey matter atrophy and WMHs on apathy progression in PD.