Elucidating Subtypes and Risk Factors of Brain Arteriolosclerosis

Objective: To study risk factors and arteriolar morphologies of brain arteriolosclerosis. Background: Cerebrovascular pathologies are often seen in aged brains. Here, we focus on brain arteriolosclerosis (B-ASC), i.e., degenerative thickening of cerebral arterioles. We recently reported that severe B-ASC pathology is associated with global cognitive status (PMID 26738751). Design/Methods: To study the risk factors of B-ASC, we analyzed 2,390 cases with clinical and neuropathological autopsy data from the National Alzheimer’s Coordinating Center (NACC). To address in finer detail the heterogeneous arteriolar morphologies that could be classified as B-ASC, we analyzed 74 cases from the University of Kentucky Alzheimer’s Disease Center (UKADC) and UK Pathology Department. Results: Using the NACC dataset, gender was associated with B-ASC pathology in both age at death groups after controlling for covariates including age at death, and conventional vascular risk factors: hypertension, diabetes, smoking, and hypercholesterolemia. In a subset of cases with genetic information (n = 925), the ABCC9 gene variant (rs704180), previously associated with hippocampal sclerosis, was also associated with B-ASC pathology in the ≥ 80 year-old group. Using a convenience sample of UKADC cases, the median age at death was 56.5 years with a range of 20 – 96 years. One of the subtypes of B-ASC pathology in this cohort consisted of arteriolar profiles with multiple internal lumens, which we refer to as multi-lumen vessels (MLVs, which generally have ≥ 3 lumens in a single vascular profile). In this sample, 62.1% (n = 46) of cases had ≥ 5 MLVs per brain section, as operationalized using CD34 immunohistochemistry in the frontal neocortex (Brodmann area 9). Interestingly, MLV densities increased with advanced age of death (r = 0.51; p Conclusions: We conclude that B-ASC is a complex pathologic phenotype in advanced age with both genetic and clinical risk factors, as well as morphologic subtypes, that require further study. Disclosure: Dr. Ighodaro has nothing to disclose. Dr. Abner has nothing to disclose. Dr. Monsell has nothing to disclose. Dr. Kukull has nothing to disclose. Dr. Neltner has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Fardo has nothing to disclose. Dr. Nelson has nothing to disclose.