Stroke Connectome MRI biomarkers for VCID risk assessment

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PROJECT SUMMARY Vascular Contributions to Cognitive Impairments and Dementia (VCID) is one of the four Alzheimer’s Disease and Related Dementias (ADRDs). VCID research investigates the effects of a range of vascular disease and vascular risk factors on cognition. Every year 610,000 people in the US have first-time strokes and three-quarters of strokes occur in people aged 65 and older. Post-stroke cognitive impairment and dementia is highly prevalent (~30%) and is a major cause of adult disability in the US, with economic burden in the billions. Post-stroke dementia is defined as an immediate and or delayed cognitive decline that begins within 6 months after a stroke. Therefore, post-stroke cognitive impairments and dementia is recognized as a major VCID. However, the underlying disease biology linked to stroke is not fully understood. There is robust evidence that AD pathology often coexists with cerebrovascular disorders such as stroke, with many risk factors being shared, resulting in additive or synergistic effects on cognitive decline. However, there is also a distinction made between ‘early- onset post-stroke dementia’ which depends on the complex interplay between stroke and brain resilience, versus ‘late-onset post-stroke dementia’ which depends on severe small vessel disease, rather than by recurrent stroke or concurrent AD pathology. However no biological biomarkers have yet been reported to reliably differentiate between neurodegenerative and cerebrovascular disease. Understanding the relationships between the two diseases therefore remains a high priority to enable targeting of underlying mechanisms and reducing the overall burden of VCID. The specific goal of this project is to investigate the utility of blood-plasma based phosphorylated-tau (p-tau) and apolipoprotein 𝜖𝜖-4 gene (APOE4) in predicting progression to post-stroke VCID. p-tau represents the extent of amyloid burden in the brain and APOE4 is linked to risk for developing AD. Our central hypothesis is that interactions between amyloid burden, APOE4 genetic risk, and stroke would better explain the underlying pathology of why a subset of stroke patients go on to develop VCID. Specific Aim: Characterize specific relationships between VCID risk factors, cognitive reserve, blood plasma biomarkers (p- tau, APOE4), brain health and cognitive function at 6 and 12-months after stroke. Successful completion of the project will provide currently lacking scientific understanding of the intricate biological relationships among VCID risk factors, blood, and stroke MRI biomarkers, which underlie the biology of cognitive decline after a stroke. Blood-based biomarker testing is more accessible, and less complex compared to PET scan or lumbar puncture for assessing amyloid burden in the brain. Therefore, the proposed project is expected to exert a significant influence on the field of molecular and genetic biomarkers of post stroke VCID. The results will lay a strong foundation for building accurate diagnosis, prognosis, and future clinical studies that can aid in positively altering disease progression and reducing the burden of illness on patients due to post stroke VCID.