Blunted Cerebrovascular Resistance in Response to Isometric Handgrip Exercise is Associated with Greater White Matter Hyperintensities in Middle-aged and Older Adults

Vascular dysfunction may occur prior to declines in cognition and accumulation of Alzheimer’s disease (AD) neuropathology. White matter hyperintensities (WMH) develop due to chronic cerebral ischemia and elevated blood pressure in midlife increases risk of developing WMH. PURPOSE: The purpose of this study was to evaluate associations between hemodynamic and cerebrovascular responses to hypertensive stimuli and WMH burden in middle-aged and older adults at elevated risk of AD. METHODS: Sixty-eight adults (age = 63 ± 4y, males = 20, females = 48) participated in this study. Participants completed an isometric handgrip exercise (IHG) exercise protocol at 40% of maximal voluntary contraction until fatigue followed by a 90s period of post-exercise ischemia (PEI). Mean arterial pressure (MAP), heart rate (HR), middle cerebral artery velocity (MCAv), and end-tidal CO2 were continuously measured throughout the protocol. Cerebrovascular resistance (CVR) was calculated as MAP/MCAv. Intracranial volume (ICV) and WMH lesion volume were measured using a T1 and FLAIR scan on a 3 T MRI scanner. WMH fraction was calculated as (WMH lesion volume/ICV)*100 and cubic root transformed. Multiple linear regressions were used to determine the influence of hemodynamic and cerebrovascular responses to IHG exercise and PEI on WMH fraction. Regressions were adjusted for age, sex, apolipoprotein ε4 status, and total work performed during IHG. RESULTS: During IHG, there were significant increases from baseline in MAP (27 ± 11%), HR (25 ± 12%), MCAv (5 ± 10%), and CVR (22 ± 17%; P < 0.001 for all). During PEI, MAP (22 ± 9%), HR (8 ± 7%), and CVR (23 ± 16%) remained elevated (P < 0.001) while MCAv (0 ± 10%) was not different compared to baseline. In response to IHG, there was a negative association between the percent change in MAP (r = -0.41, P = 0.002), HR (r = -0.42, P = 0.002), and CVR (r = -0.31, P = 0.045), but not MCAv (r = 0.19, P = 0.971), and WMH fraction. In response to PEI, there were no associations between hemodynamic or cerebrovascular responses and WMH fraction. CONCLUSION: Blunted cerebrovascular resistance in response to handgrip exercise is associated with greater WMH burden in middle-aged to older adults. These findings suggest that individuals with greater WMH burden may have impaired cerebral autoregulatory responses to hypertensive stress.