Vascular and neurodegenerative contributions to cognitive decline and multidomain progression in de novo Parkinsons disease
- 1University of Montreal
Abstract
INTRODUCTIONCognitive decline in Parkinsons disease (PD) may reflect interacting neurodegenerative and cerebrovascular processes, but their distinct temporal contributions remain unclear.
METHODSNewly 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.
RESULTS58 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.
DISCUSSIONCognitive 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.
HighlightsO_LIPD converters showed accelerated limbic and subcortical gray matter atrophy. C_LIO_LIWMH burden was higher in future PD converters. C_LIO_LIBaseline atrophy pattern expression predicted cognitive and motor progression. C_LIO_LIWMH burden was selectively associated with neuropsychiatric symptoms and functional independence C_LIO_LIVascular and neurodegenerative markers provided complementary prognostic information. C_LI
Research in ContextO_ST_ABSSystematic reviewC_ST_ABSThe authors reviewed peer-reviewed literature on cognitive decline in Parkinsons 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.
InterpretationWhile 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 directionsIndependent 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.
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BibTeX
@misc{moqadam2026vascular,
title = {{Vascular and neurodegenerative contributions to cognitive decline and multidomain progression in de novo Parkinsons disease}},
author = {R. Moqadam and H. Azizi and S. Raeesi and Y. Zeighami and M. Dadar},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.09.26362673},
url = {https://www.medrxiv.org/content/10.64898/2026.09.09.26362673v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Vascular and neurodegenerative contributions to cognitive decline and multidomain progression in de novo Parkinsons disease
AU - R. Moqadam
AU - H. Azizi
AU - S. Raeesi
AU - Y. Zeighami
AU - M. Dadar
PY - 2026
DA - 2026/09/09
PB - medRxiv
DO - 10.64898/2026.09.09.26362673
UR - https://www.medrxiv.org/content/10.64898/2026.09.09.26362673v1
AB - INTRODUCTIONCognitive decline in Parkinsons disease (PD) may reflect interacting neurodegenerative and cerebrovascular processes, but their distinct temporal contributions remain unclear. METHODSNewly 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. RESULTS58 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. DISCUSSIONCognitive 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. HighlightsO_LIPD converters showed accelerated limbic and subcortical gray matter atrophy. C_LIO_LIWMH burden was higher in future PD converters. C_LIO_LIBaseline atrophy pattern expression predicted cognitive and motor progression. C_LIO_LIWMH burden was selectively associated with neuropsychiatric symptoms and functional independence C_LIO_LIVascular and neurodegenerative markers provided complementary prognostic information. C_LI Research in ContextO_ST_ABSSystematic reviewC_ST_ABSThe authors reviewed peer-reviewed literature on cognitive decline in Parkinsons 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. InterpretationWhile 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 directionsIndependent 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.
ER -