NIH grant: Neuroinflammation in Cerebral Small Vessel Disease (1R01NS144992-01A1)

retained text

NIH grant 1R01NS144992-01A1: Neuroinflammation in Cerebral Small Vessel Disease
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Hongyu  An. Award: $618108.
Start: 2026-06-18T00:00:00.
Project Summary/Abstract
Cerebral small vessel disease (cSVD) is a leading cause of vascular contributions to cognitive impairment and
dementia (VCID), which is the 2nd leading cause of dementia and a significant contributor to Alzheimer’s disease
(AD). Thus far, the underlying pathogenesis of cSVD is poorly understood. Several lines of evidence, including
animal models, postmortem human brain pathology, and systemic inflammatory markers, demonstrated the
damaging role of chronic neuroinflammation in cSVD. Direct evidence of neuroinflammation at the tissue level
in patients with cSVD is still critically needed. The sphingosine-1-phosphate receptor 1 (S1PR1) regulates
neuroinflammation through microglial and astrocyte activation and trafficking and has emerged as a promising
target for neuroinflammation. In postmortem brains of patients with cSVD, we observed elevated S1PR1
expression and colocalization of S1PR1 with astrocytes and microglia. A novel 11C-CS1P1 PET radiotracer with
high affinity and specificity targeting S1PR1 has been recently developed and validated in animal models and
post-mortem human specimens. Under an FDA-approved eIND (IND 146548), we have successfully completed
the safety and dosimetry study in healthy participants and performed preliminary studies in patients with cSVD.
We found that 11C-CS1P1 PET uptake is significantly associated with WMH lesion burden in patients with cSVD
after controlling for age, sex, race, vascular risk factors, and amyloid deposition. We hypothesize that 11C-CS1P1
PET uptake is a tissue-level biomarker of neuroinflammation to provide insight into cSVD severity, progression,
and prognosis. We will 1) evaluate the relationship between 11C-CS1P1 PET uptake and cSVD neuroimaging
abnormalities and cognitive impairment, 2) evaluate the test-retest repeatability and longitudinal evolution, and
3) determine whether 11C-CS1P1 PET uptake at baseline predict cSVD progression. The successful completion
of this study will establish 11C-CS1P1 PET as an neuroinflammation imaging biomarker and investigate the role
of neuroinflammation in cSVD pathogenesis and progression. It will lay a foundation for developing future
therapies in modulating neuroinflammation.

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