Abstract A108: Small Vessel And Glymphatic Dysfunction In Asymptomatic Intracranial Atherosclerosis Relates To Cognition And Predicts Decline

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Background: Asymptomatic intracranial atherosclerotic stenosis (aICAS) is linked to cognitive impairment, yet the pathogenic pathways remain unresolved. Small-vessel injury and dysfunction of perivascular/glymphatic clearance are leading candidates. We characterized this burden with multiple complementary imaging indicators and integrated plasma biomarkers to evaluate associations with cognition, and examine prognostic value for subsequent decline. 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, Fig 1 ). 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 ( Fig 2 ). 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, Fig 3 ). Conclusions: In aICAS, imaging indicators of small-vessel and glymphatic dysfunction were associated with worse cognition. Lipid-related injury exerted an indirect effect through small-vessel/glymphatic pathways, and baseline ALPS predicted near-term cognitive decline. These findings address the unresolved 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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