Vascular and neurodegenerative contributions to cognitive decline and multidomain progression in de novo Parkinsons disease

INTRODUCTION: Cognitive decline in Parkinsons disease (PD) may reflect interacting neurodegenerative and cerebrovascular processes, but their distinct temporal contributions remain unclear. METHODS: Newly diagnosed, untreated PD participants from the PPMI who were cognitively normal at baseline and had at least three years of cognitive follow-ups were included. Linear mixed-effects models examined longitudinal atrophy, white matter hyperintensity (WMH), and clinical trajectories. Mixed-effects models also examined the associations between baseline WMHs and a decline-related atrophy pattern expression score with subsequent multidomain clinical progression. RESULTS: 58 participants experienced cognitive decline and 292 remained cognitively stable. Converters showed faster decline across all cognitive domains, accompanied by faster worsening of motor, gait, neuropsychiatric, sleep-related, and functional symptoms. Converters further showed higher baseline WMH burden without accelerated accumulation, alongside accelerated limbic and subcortical atrophy. Greater baseline WMH burden was associated with differential longitudinal progression in converters across eleven clinical outcomes, including cognition, gait, and functional independence (all q<0.05). Baseline atrophy pattern expression showed similar converter-dependent associations with longitudinal progression across eight outcomes, with the strongest interaction for MoCA (q<0.001). In joint models, atrophy pattern expression retained broader associations with cognitive and motor progression, whereas WMH burden retained more selective associations with neuropsychiatric symptoms and functional independence. DISCUSSION: Cognitive decline in PD was characterized by accelerated neurodegeneration occurring against a background of WMH-related cerebrovascular vulnerability rather than accelerated WMH accumulation, supporting distinct temporal patterns and complementary clinical associations of neurodegenerative and vascular processes with cognitive impairment and broader disease progression in PD.