Contribution of cerebrovascular lesions to neurodegeneration and cognitive decline

  1. Zhaojin Chen
  2. Shima Raeesi
  3. Amelie Metz
  4. Roqaie Moqadam
  5. Katherine Chadwick
  6. the Consortium for the early identification of Alzheimer’s disease–Quebec (CIMA-Q)
  7. Yashar Zeighami
  8. Mahsa Dadar
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Abstract

Introduction

Cerebral small vessel disease (CSVD) lesions, including white matter hyperintensities (WMHs), lacunar infarcts, cerebral microbleeds (CMBs), and enlarged perivascular spaces (PVSs) are associated with increased risk of dementia. In this study, we aimed to examine their associations with risk factors, neurodegeneration, and cognition over a follow-up period of ten years.

Methods

289 participants (183 females, mean age: 73.7 ± 5.7) with multi-modal magnetic resonance imaging (MRI) and clinical assessments from the Consortium for the Early Identification of Alzheimer’s Disease (CIMA-Q) were included. CSVD lesions and neurodegeneration were quantified using automated tools. Linear regression and mixed effects models examined the cross-sectional and longitudinal associations between lesions, risk factors, neurodegeneration, and cognitive decline.

Results

Risk factors showed the strongest cross-sectional associations with PVS number and CMB presence, and the strongest longitudinal associations with WMH and PVS volume progression (p < 0.05) . WMH and PVS volumes significantly increased over time (p < 0.01), with faster WMH progression among participants who experienced cognitive decline during study follow-ups. Higher WMH volume was associated with poorer global cognition and executive function, and presence of lacunae was associated with faster decline in executive function. Finally, both WMH and PVS were associated with longitudinal atrophy across several cortical regions.

Conclusions

Vascular risk factors were associated with CSVD burden and progression, and WMH and PVS progression were further associated with cortical atrophy and cognitive decline, underscoring the interconnected contributions of vascular risk, CSVD, and neurodegeneration to cognitive aging and dementia risk.

HIGHLIGHT

  • White matter hyperintensities (WMHs) and perivascular spaces (PVS) showed significant longitudinal increases over up to 10 years of study follow-ups.

  • Vascular risk factors were associated with CSVD burden (PVSs, cerebral microbleeds, and WMHs) and progression (PVSs and WMHs).

  • Greater WMH burden was associated with poorer global cognition and executive function, while lacunar infarcts were associated with faster longitudinal decline in executive function.

  • WMH and PVS progression were associated with longitudinal cortical atrophy, linking CSVD progression with neurodegenerative changes.

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  1. Version published to 10.64898/2026.10.04.26364698 on medRxiv