Abstract WP416: Comparison of Ex-vivo Human Leptomeningeal Arteriole Function in Cognitively Normal and Dementia Disorders From Rapid Autopsy Brain Donors

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Vascular dysfunction is increasingly recognized in the pathophysiology of dementia disorders such as Alzheimer’s disease (AD). We showed that exposure to β-amyloid (Aβ) and medin (aging-associated amyloid) cause cerebrovascular endothelial dysfunction which may be involved with cognitive dysfunction. We aim to test the hypotheses that patients with AD, mild cognitive impairment (MCI) and vascular dementia (VD) differ in cerebrovascular arteriole function and have worse vascular response to amyloid proteins when compared to cognitively normal (CN) patients.Methods: Under a Brain Donation Rapid Autopsy Program, leptomeningeal arterioles were isolated from 44 donors (89.6±1.4 years), cannulated, pressurized and baseline endothelium-dependent dilation (EDD, acetylcholine max 10-4M) and smooth muscle dilation (SMD, papaverine or DETA-Nonoate) were measured and compared among CN, MCI, AD and VD subjects. % change from baseline responses were also measured following 1 hour exposure to Aβ42 (0.5 or 2 μM) or medin (5 μM).Results: There was no difference in baseline EDD and SMD among the groups (Fig. A,B). Overall, Aβ caused reduction in EDD (46.2±3.8 vs. 75.3±3.5% baseline, p<0.001) and SMD (83.6±2.8 vs. 90.7±2.6% baseline, p=0.02). Medin caused similar reduction in EDD (35.7±4.7 vs. 77.5±4% baseline, p<0.001) and SMD (70.9±5.4 vs. 89.3±3% baseline, p=0.006). Dilator responses to Aβ and medin did not differ among the groups (Fig. C-F).Conclusions: Contrary to our hypotheses, leptomeningeal arteriole function did not differ among CN, MCI, AD and VD patients. Aβ and medin caused endothelium and smooth muscle dysfunction, but the degree of dysfunction was not different among the groups. The results may point to the importance of duration/degree of exposure to vasculogenic amyloid proteins (the ‘milieu’) rather than intrinsic differences in arteriole properties in accounting for vascular dysfunction leading to cognitive dysfunction in dementia disorders.

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