cjavierr@hawk.iit.edu

Enlarged perivascular spaces (EPVS) have been associated with aging, increased stroke risk, decreased cognitive function and vascular dementia. However, the relationship of EPVS with age-related neuropathologies is not well understood. Therefore, the purpose of this study was two-fold: to assess the neuropathologic correlates of EPVS, and to determine the contribution of EPVS burden to cognitive decline by combining ex-vivo brain magnetic resonance images (MRI) and pathology in a community cohort of older adults.

Cerebral hemispheres were obtained from 662 participants of two longitudinal, epidemiologic clinical-pathologic cohort studies of aging. Experienced observers blinded to all pathologic and clinical data rated EPVS burden using a semiquantitative four-level scale (See Figure). Neuropathologic assessment was performed by a board-certified neuropathologist blinded to all clinical and imaging findings. Univariate and multivariate logistic regression was used to investigate the association of EPVS burden with the following age-related neuropathologies: gross and microscopic infarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, amyloid plaques, neurofibrillary tangles, hippocampal sclerosis, Lewy bodies, and TDP-43. Finally, mixed-effects models were used to evaluate EPVS burden contribution to cognitive decline in 6 domains: global, episodic, semantic, working, perceptual, and visuospatial.

Univariate analyses showed significant association of EPVS burden with gross (OR=1.59, p-value=0.002) and microscopic infarcts (OR=1.40, p-value=0.025). Multivariate logistic regression showed a significant association of EPVS burden with gross infarcts (OR=1.60, p=0.004). EPVS burden was significantly contributing to cognitive decline for all cognitive domains except working memory; and the interaction between EPVS burden and time also showed significant for global, episodic and visuospatial cognitive domains.

The results suggest: that EPVS and gross infarcts may share similar neurobiological pathways, which is in fair agreement with the literature and proposed etiologies driving these two processes, and that EPVS burden significantly contributes to cognitive decline independently from demographics and neuropathologies.

This is the biggest clinical-pathologic study up to date, and the only one to include cognitive decline in combination with EPVS.