Small Vessel and Glymphatic Dysfunction In Asymptomatic Intracranial Atherosclerosis Relates to Cognition and Predicts Decline
Yinxi Zou1, Weizhuang Yuan2, Anqi Cheng1, Huanyu Zhou1, Yiyang Liu1, Ningyuan Liu1, Haoyao Guo1, Linwen Liu1, Yuelun Zhang1, Hebo Wang3, Shiwen Wu4, Zhongrui Yan5, Zhibing Ai6, Mingli Li1, Caiyan Liu1, Weihai Xu1
1Peking union medical college hospital, 2The First Affiliated Hospital, Sun Yat-sen University, 3Hebei General Hospital, 4First Medical Center of Chinese PLA General Hospital, 5Jining No. 1 People's Hospital, 6Taihe Hospital, Hubei University of Medicine
Objective:
Test whether imaging indicators of small-vessel and glymphatic dysfunction biomarkers relate to cognition in asymptomatic intracranial atherosclerotic stenosis (aICAS) and predict subsequent decline.
Background:
aICAS is linked to cognitive impairment, but mechanisms remain unresolved. Small-vessel injury and impaired perivascular/glymphatic clearance are leading candidates. We quantified this burden using harmonized multimodal MRI and integrated plasma markers to evaluate cognitive associations and prognostic value.
Design/Methods:
In a multicenter cohort of aICAS patients (n=147) and matched controls (n=68), participants received 3T MRI and a standardized cognitive battery. Imaging markers included diffusion-based glymphatic index (DTI analysis along perivascular space, ALPS), white-matter free water, perivascular-space volume, and white-matter hyperintensity volume, processed with harmonized pipelines. Analyses covered group comparisons, associations with cognitive performance and plasma biomarkers, and structural equation model specified a latent CSVD/Glymphatic Burden to test mediation from an Atherogenic Lipids factor to cognition, Cox models were also used for follow-up decline.
Results:
Compared with controls, patients showed a lower ALPS index and higher global free water. In subgroup analyses, free water within stenosed perfusion territories was significantly higher in aICAS patients than in normal controls (p<0.05). Within patients, free water was also higher in stenosed compared with non-stenosed territories (p<0.01). Across the cohort, a greater glymphatic burden was associated with worse global cognitive performance and deficits in specific domain z-scores, and these associations remained robust after adjustment for demographic covariates. The CSVD/glymphatic burden mediated 58.4% of the adverse effect of atherogenic lipids on MoCA (p=0.010) and correlated with glial fibrillary acidic protein. Furthermore, baseline ALPS index is associated with subsequent cognitive decline (HR<0.01, p=0.025).
Conclusions:
Small-vessel and glymphatic dysfunction is linked to cognitive deficits in aICAS, constitutes an indirect pathway from lipids to cognition. These findings address the mechanism linking atherosclerosis to cognitive impairment and support a multi-indicator imaging-plus-plasma approach for risk stratification and mechanistic targeting.
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