Project Summary: Vascular dementia is the second most common cause of dementia. Therapies aim to control risk factors (e.g. hypertension, hyperlipidemia, and diabetes mellitus) to prevent development or worsening of disease. Recent studies show that viral infections are potentially modifiable risk factors for dementia. Amongst all pathogens, varicella zoster virus (VZV) is the most likely contributor to vascular dementia. VZV is a neurotropic DNA virus that is latent in >95% of Americans and reactivates to produce herpes zoster (shingles) in 50% by 85 years of age. Despite the availability of zoster vaccines, there are still >1 mil cases of zoster annually. Recent studies reveal zoster increases dementia risk and treatment (vaccines, antivirals) reduces risk. Importantly, a recent FinnGen and U.K. biobank study showed VZV was specifically associated with an increased risk of vascular dementia. VZV likely contributes to vascular dementia risk through its well-established ability to produce vascular pathology leading to ischemic or hemorrhagic stroke (VZV vasculopathy). VZV directly infects cerebral arteries and causes a vasculitis, as well as induces a prothrombotic state triggering cerebral thrombosis. A notable feature is the involvement of soluble factors that promote vasculitis or thrombosis distal from the site of rash. We recently showed that plasma exosomes isolated from acute zoster patients contained significantly elevated prothrombotic and proinflammatory proteins including thrombospondin-1, caveolae-associated protein 2, coagulation factors V and XIIIA1, calmodulin 1, and transthyretin compared to matched controls. These exosomes were non-infectious but induced IL-6 and IL-8 secretion when applied to naïve primary human brain vascular adventitial fibroblasts, activated donor platelets, and induced platelet-leukocyte aggregations supporting a proinflammatory and prothrombotic state. Importantly, these exosomes persist for at least 3 months post-zoster, well after rash clearance and detectable viremia. Overall, we hypothesize that circulating exosomes during zoster and in subsequent months will promote vasculitis and thrombosis, thus providing a mechanistic basis for the increased vascular dysfunction risk preceding vascular dementia. To test this hypothesis, we will isolate plasma exosomes from individuals during acute zoster and at 7 days, 1 month, 3 months, 6 months, and 12 months post-zoster, as well as isolate exosomes from matched control individuals during a single clinic visit. Aim 1 will analyze exosome content for known vascular damaging proteins/miRNAs from matched control and zoster individuals over a 12-month period. Aim 2 will determine the mechanism(s) in which non-infectious zoster exosomes promote vascular dysfunction. Understanding how long-lasting pathogenic exosomes promote cerebrovascular disease during and after zoster, thereby accelerating vascular dementia risk, is significant because it will potentially change cli...