Periodontitis, Cerebral Microbleeds, and Cognitive Decline

/ABSTRACT This project is an investigation of vascular contributions to cognitive impairment and dementia (VCID) due to cerebral microbleeds (the pathologic substrate of which is cerebral microhemorrhage) in the context of periodontitis. The proposed project will utilize a combination of novel animal models of cerebral microhemorrhage to identify mechanisms of the dementia-cerebral microbleeds link specifically related to periodontitis, an emerging risk factor for dementia and stroke, as well as hypertension, the most important treatable risk factor for cerebral microbleeds. The project investigators are a unique group with expertise in stroke neurology, vascular neurobiology, brain aging, bioengineering, brain imaging, and biostatistics, all with capabilities relevant to animal studies. We specifically propose the following aims and hypotheses: Specific Aim 1: To determine effects of periodontitis on cerebral microhemorrhages in a mouse model of hypertension and aging. Hypothesis 1A: Periodontitis enhances cerebral microhemorrhage development. Hypothesis 1B: Periodontitis alters size and number of source vessels of cerebral microhemorrhages. Hypothesis 1C: Periodontitis-enhanced cerebral microhemorrhage formation provokes cognitive decline. Hypothesis 1D: Periodontitis-enhanced cerebral microhemorrhage formation is inhibited by CXCR3 antagonists. Specific Aim 2: To determine the effects of periodontitis on microglial activation in a mouse model of hypertension and aging. Hypothesis 2A: Periodontitis enhances microglial activation. Hypothesis 2B: Microglia mediate periodontitis-induced microhemorrhage formation. This project addresses VCID from the perspective of the highly prevalent hemorrhagic microvascular disease of the brain. Our work and that of others have shown the near-ubiquitous presence of microhemorrhagic changes in the aging human brain. Our multi-disciplinary team is uniquely capable of taking this project to completion with the expectation that robust insights will emerge to assist the management of VCID and microvascular disorders of the brain which, along with Alzheimer’s disease, represent some of the most common causes of neurological morbidity of aging: cognitive decline, vascular cognitive impairment, and dementia. Project Number: 1R21NS140846-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: MARK FISHER (+1 co-PI) | Institution: UNIVERSITY OF CALIFORNIA-IRVINE, IRVINE, CA | Award Amount: $431,750 | Activity Code: R21 | Study Section: Brain Injury and Neurovascular Pathologies Study Section[BINP] View on NIH RePORTER: https://reporter.nih.gov/project-details/11304694