Enlarged Perivascular Spaces as Markers of Vascular and Alzheimer pathology: predictors, pathophysiology and clinical consequences

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Dementia is a major public health problem affecting 4.7 million individuals with estimated annual costs of $200 billion. There is a pressing need to understand its pathophysiology, identify treatment targets and develop preventive strategies. Enlarged perivascular spaces (ePVS) are an emerging MRI marker thought to reflect dysfunction of the newly discovered glymphatic system crucial to removal of beta-amyloid (Aβ) load in individuals at risk for Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA). ePVS also appear to reflect small vessel vascular brain injury that may be synergistic with the Alzheimer neurodegenerative process. In the Framingham Heart Study (FHS), we are uniquely positioned to study ePVS as a measure of glymphatic dysfunction, as well as a marker of CSVD and risk of stroke and dementia in healthy adults. Similarly, we are uniquely situated to explore novel aspects in their pathophysiology that may identify preventive and treatment strategies for stroke and dementia. We will create a new dataset of ePVS on over 7,000 brain MRI scans already available in the FHS Cohorts. FHS participants represent the entire life span (ages 19 – 101 years), have been thoroughly characterized and followed over decades for incident AD, all dementia, and stroke. We propose to study ePVS to determine their age and sex-specific prevalence and relation to vascular risk factors; novel predictors focused on the relation to circulating biomarkers of systemic and vascular inflammation that may reveal insight into potential treatment targets. We will study the ePVS role as mediator in the novel association between sleep dysfunction and brain amyloid burden (assessed in PET imaging and neuropathology) that may also represent a treatment target for prevention of dementia. Finally, in the last of our primary aims we will evaluate the adverse clinical consequences of high burden of ePVS in healthy community dwelling individuals. In an exploratory aim we propose to assess the brain MRI correlates, traditional and novel measures of brain integrity and aging (DTI, including probabilistic tractography, gray matter volumes, and functional connectivity). Our hypotheses are: (1) the prevalence of ePVS will increase with age, will differ in women and men, and increase with exposure to traditional vascular risk factors; (2) higher levels of circulating biomarkers of inflammation will relate to ePVS severity; (3) ePVS mediate at least in part the association between sleep dysfunction and amyloid burden; (4) higher burden of ePVS will relate to higher risk of AD, all dementia, stroke, impaired cognition, physical function and depression symptomatology. Epidemiological characterization of ePVS may help identify individuals at high risk for targeted preventive strategies, identify novel mechanisms leading to AD and may lead to identification of novel treatment targets for AD, other dementias and stroke.