Vascular and neurodegenerative contributions to cognitive decline and multidomain progression in de novo Parkinson’s disease
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INTRODUCTION
Cognitive decline in Parkinson’s 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.
Highlights
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PD converters showed accelerated limbic and subcortical gray matter atrophy.
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WMH burden was higher in future PD converters.
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Baseline atrophy pattern expression predicted cognitive and motor progression.
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WMH burden was selectively associated with neuropsychiatric symptoms and functional independence
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Vascular and neurodegenerative markers provided complementary prognostic information.
Research in Context
Systematic review
The authors reviewed peer-reviewed literature on cognitive decline in Parkinson’s disease (PD), emphasizing longitudinal structural MRI, white matter hyperintensities (WMH), and studies examining clinical progression. Prior work supports both neurodegenerative and vascular contributions to cognitive decline, but their longitudinal relationships with cognitive decline and multidomain progression remain incompletely characterized.
Interpretation
While both WMHs and neurodegenerative pathologies contribute to cognitive and multidomain impairments in PD, WMH burden differences precede symptomatic cognitive decline, whereas longitudinal progression of atrophy is more closely intertwined with cognitive decline.
Future directions
Independent longitudinal cohorts should examine the interactions between longitudinal progression in WMHs, neurodegeneration, molecular biomarkers, and clinical symptoms and whether their combination can improve individualized prediction of cognitive decline and subsequent progression to dementia in PD.
