Intracranial arterial compliance, cerebral blood flow, and dementia risk in older adults with type 2 diabetes

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Type 2 diabetes mellitus (T2DM), which is rising in prevalence, increases risk of cognitive impairment and dementia, including Alzheimer’s disease (AD). In our prior work we have shown that T2DM is associated with steeper cognitive decline and reduced cerebral blood flow (CBF) in regions that are predilection sites for AD pathology. Identifying individuals who are likely to decline prior to the occurrence of brain changes is essential so that interventions can be applied before extensive cerebrovascular lesions and cognitive changes develop. Most previous neuroimaging studies of brain changes underlying cognitive dysfunction in T2DM have applied conventional structural magnetic resonance imaging (MRI) to detect end-stage macrostructural changes associated with cerebrovascular disease (CVD) such as white matter lesions (WML). However, recent advances in MRI have allowed for the development of sensitive methods for the non-invasive measurement of CBF and cerebral arterial compliance (AC), or the ability of vessels to distend or increase in volume in response to changes in blood pressure. Such methods may help elucidate mechanisms that precede the development of irreversible parenchymal/structural damage and may yield important markers of risk for cognitive decline. Although T2DM has been associated with peripheral arterial stiffening using carotid-femoral pulse wave velocity, no studies have examined intracranial arterial stiffening (i.e., decreased AC) in T2DM. We propose to assess cognition, AC and CBF, and established MRI markers CVD in a sample of 100 older adults with T2DM and 50 non-diabetic control participants. Participants will undergo laboratory testing to assess blood-based markers related to glycemia and cardiometabolic health and neuroimaging including novel arterial spin labeling (ASL) MRI protocols that estimate cerebral arterial compliance and blood flow at baseline, 12-month follow up, and 24-month follow up. Our goals are to investigate whether early changes in cerebrovascular functioning (i.e., reduced AC and CBF) relate to MRI markers of CVD lesions and cognition. The current proposal for a research supplement to promote diversity in health-related research would provide funding for Dr. Einat Brenner to add one year to her postdoctoral fellowship in my lab. Through this diversity supplement, she is proposing to extend the parent R01 to obtain serum measures of brain-derived neurotrophic factor (BDNF). Her aims examine whether (1) reduced serum BDNF levels relate to lower cerebral blood flow/arterial compliance and BDNF levels moderate associations between cerebral blood flow/arterial compliance and MRI markers of cerebrovascular disease and (2) reduced serum BDNF levels relate to poorer memory and executive functioning and BDNF levels moderate the associations between cerebral blood flow/arterial compliance and cognition. Her primary goals are to develop and submit a K-award and learn longitudinal data analysis. She will also continue to learn new imaging techniques (e.g., arterial spin labeling to measure cerebral blood flow and arterial compliance) and work with new populations (e.g., older adults with T2DM) to prepare her for a career as an independent researcher.