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 (Bangen et al., 2018; Bangen et al., in prep). Identifying individuals who are most likely to decline prior to the occurrence of significant brain changes is essential so that interventions can be applied before extensive cerebrovascular lesions and cognitive changes develop. Studies investigating incipient cognitive and brain changes prior to the development of dementia are critical to optimize brain health and improve outcomes. 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 therefore propose to advance the field by longitudinally assessing neuropsychological functioning, AC and CBF, and established MRI markers CVD in a sample of 150 older adults (aged 65-85) including 100 with T2DM and 50 non-diabetic control participants. Participants will undergo comprehensive neuropsychological assessment; laboratory testing to assess blood-based markers related to glycemia and cardiometabolic health; and neuroimaging exams including high resolution structural imaging and 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 in T2DM. We will also investigate whether diabetes related factors (e.g., duration, glycemic control) and comorbid cardiometabolic conditions (e.g., hypertension) moderate associations between AC, CBF, CVD markers, and cognition. Findings will help address an important public health need by identifying markers of cognitive decline in T2DM and elucidating potentially modifiable mechanisms underlying these changes. Results may also assist in facilitating targeted interventions given that presence of cognitive dysfunction may affect both dosing and broader management of individuals with T2DM.