Project Summary/Abstract Vascular contributions to cognitive impairment and dementia (VCID) is the second leading cause of dementia and a major contributor to Alzheimer’s disease (AD), the leading cause of dementia. VCID is mainly caused by cerebral small vessel disease (CSVD). Thus far, the pathophysiology underlying CSVD has not been well- understood. Vascular risk factors, including hypertension, hyperlipidemia, and diabetes mellitus, may lead to injured arterioles, impaired autoregulation, chronic hypoxia/ischemia, blood brain barrier (BBB) impairment, and neuro-inflammation. Several lines of evidence, including results from animal models, post-mortem human brain neuropathology, and systemic inflammatory biomarkers studies, implicate the independent contribution of neuroinflammation in the pathogenesis of CSVD and resulting VCID. However, direct evidence of neuroinflammation in patients with CSVD is still lacking. Sphingosine-1-phosphate receptor subtype 1 (S1PR1) is involved in cell trafficking and lymphocyte/macrophage recruitment. Previous studies have demonstrated that S1PR1 was highly expressed and colocalized with microglia and astrocytes in a mouse model of multiple sclerosis (MS). The S1P-modulator, FTY720 (fingolimod), approved by the FDA, has been widely used for treating MS due to its ability to antagonize S1P receptors functionality. An 11C-CS1P1 PET radiotracer with high affinity and selectivity for S1P1 has been recently developed and validated in animal models and post-mortem human specimens at our institution. The FDA recently approved an eIND application (IND 146548) for the first human PET imaging of this 11C-CS1P1 radiotracer. We have completed a safety and dosimetry study in normal participants, demonstrating that 11C-CS1P1 PET is safe and ready for patient studies. The goals of this exploratory study are to 1) demonstrate that S1PR1 expression is elevated and colocalize with microglia and astrocytes in post-mortem brain specimens from deceased patients with underlying CSVD. 2) Determine if neuroinflammation measured by 11C-CS1P1 uptake is independently associated with CSVD structural endpoints using in vivo PET/MR imaging. Successful completion of this study will provide both ex vivo and in vivo evidence of neuroinflammation in CSVD. This study will lay the foundation to identify patients who may benefit from therapy targeting neuroinflammation to reduce CSVD injury and dementia in the future.