1 Department of Physical Therapy, University of British Columbia, Vancouver, British Columbia, Canada.
2 The Centre for Aging SMART at Vancouver Coastal Health, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada.
3 Djavad Mowafaghian Centre for Brain Health, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada.
4 Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong, China.
5 Department of Health, Kinesiology, and Applied Physiology, Faculty of Arts and Science, Concordia University, Montréal, Québec, Canada.
6 School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.
7 Department of Medicine, Division of Geriatric Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
8 Department of Medicine, King Saud University, Riyadh, Saudi Arabia.
9 Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.

Background: Subcortical ischemic vascular cognitive impairment (SIVCI) is characterized by white matter hyperintensities (WMH) that contribute to executive dysfunction and increased risk of Alzheimer's disease. Cognitive reserve (CR) is the brain's ability to maintain cognitive performance despite pathology. Resting-state functional connectivity (FC) of default mode network (DMN), fronto-executive network (FEN), and fronto-parietal network (FPN) may support CR. Whether WMH and FC interact on executive functions in SIVCI remains unknown.

Objective: To examine whether WMH volume interacts with resting-state FC within DMN, FEN, or FPN on executive functions in SIVCI.

Methods: A cross-sectional analysis of 38 community-dwelling older adults with SIVCI enrolled in a 12-month randomized controlled trial. Three executive processes were assessed: set-shifting by Trail Making Test (B-A), working memory by Digit Span Forward and Backward, and response inhibition by Stroop Colour-Word Test. WMH volume was quantified via T2-weighted and proton-density-weighted MRI and log-transformed. Resting-state FC was computed from resting-state functional MRI using region-of-interest masks. We assessed bivariate associations between WMH volume and each executive process; for significant bivariate associations, we then assessed interactions of WMH × FC on executive functions.

Results: Log-transformed WMH volume was significantly associated with set-shifting (p = 0.006). There were significant WMH × FC interactions for set-shifting. Specifically, higher within-network FC of DMN (b = -2914.10, p < 0.001), lower within-network FC of FEN (b = 1706.23, p = 0.019), and lower within-network FC of FPN (b = 1806.43, p = 0.003) were associated with better set-shifting at high WMH volume.

Conclusions: Within-network FC of DMN, FEN, and FPN interacts with WMH on set-shifting, suggesting a potential neural basis for CR in SIVCI.Trial registry name: Reshaping the Path of Vascular Cognitive Impairment (VCI)Registration ID: ClinicalTrials.gov NCT02669394 URL: https://clinicaltrials.gov/study/NCT02669394.