Vascular and Microstructural Markers of Cognitive Impairment and Dementia

Background: Arterial stiffness may play a role in the development of dementia, presumably through its effects on white matter integrity and hyperintensities (WMH). However, the relationships among arterial stiffness, white matter microstructure, and WMH volumes remain poorly understood. Arterial stiffness increases monotonically with age and its increase is accelerated by cardiometabolic disorders, e.g., hypertension​, metabolic syndrome, and diabetes. Further exploration of these relationships is key to the development of targeted therapies, early management, and detection.

Hypothesis: (1) Higher pulse wave velocity (PWV) is associated with higher free water, lower fractional anisotropy, lower white matter and grey matter cerebral blood flow, and higher volume of WMH. (2) Higher PWV is associated with worse cognitive performance.

Methods: Arterial stiffness was measured using carotid-femoral pulse wave velocity (cfPWV) in individuals with baseline systolic blood pressure (SBP) measurements, detailed cognitive testing, cognitive adjudication, and brain MRI. We examined associations of cfPWV and SBP with cognitive function (Montreal Cognitive Assessment (MoCA), Preclinical Alzheimer’s Cognitive Composite (PACC5), and domain measures of memory and executive function) and brain MRI measures of: macrostructure [volume of gray matter and WMH from T1-weighted and FLAIR imaging], white matter microstructure [neurite orientation dispersion and density imaging (NODDI) free water (FW) and diffusion tensor imaging (DTI) fractional anisotropy (FA)], and cerebral blood flow (CBF) in white matter (WM) and gray matter (GM). Age, race, gender, education, and APOE-4 status were included as covariates and in interaction terms in linear regression analyses.

Results: Among 463 participants with a mean age 70±8 years and cognitive adjudication (44 dementia, 159 MCI, 260 normal cognition), higher cfPWV was associated with lower WM microstructure (higher FW and lower FA), higher WMH volume, and worse cognitive performance (MoCA, PACC5, and executive function). While no main effects between cfPWV and CBF were detected, cfPWV had stronger associations with FW, FA, and WMH in men, and with lower WM CBF in people with dementia. Higher SBP was associated with higher FW, higher WMH volume, and lower WM and GM CBF. ​SBP had stronger associations with WMH in older participants​ and GM CBF in participants with impaired fasting glucose. No other interactions were detected.

Conclusions: Arterial stiffness is associated with microstructural changes and poorer global and executive cognitive function. 

Source of mentor’s funding or other support that funded this research: The project described was supported by Grant number P30 AG049638 from the National Institutes of Health.