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Aims: This study aimed to analyze the potential association between cognition reserve (CR) components, including education, working activity, and leisure time activity, and cognitive function in subjects with white matter hyperintensities (WMH). The study also explored the role of the frontoparietal control network (FPCN) in such association., Methods: White matter hyperintensities subjects with and without cognitive impairment (CI) were evaluated with multimodal magnetic resonance imaging, neuropsychological testing, and CR survey. FPCN patterns were assessed with dorsolateral prefrontal cortex seed-based functional connectivity analysis., Results: Education was positively associated with cognitive function in WMH subjects with or without CI, whereas working activity and leisure time activity were positively associated with cognitive function only in those without CI. Similarly, education was associated with bilateral FPCN in both WMH groups, whereas working activity and leisure time activity were associated with bilateral FPCN mainly in the group without CI. Furthermore, FPCN partially mediated the association between education and cognitive function in both WMH groups., Conclusion: Education showed a positive impact on cognitive function in WMH subjects regardless of their cognitive status, whereas working activity and leisure time activity exhibited beneficial effects only in those without CI. The FPCN mediated the beneficial effect of education on cognitive function., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

High cognitive reserve (CR) protects against cognitive decline in individuals with white matter hyperintensities (WMH). However, the functional mechanisms remain relatively unknown. This work aimed to explore the effects of CR on the frontoparietal control network (FPCN) and cognitive function in subjects with WMH. One hundred and thirty-seven subjects with WMH and 95 control subjects without WMH underwent neuropsychological testing, CR assessments, and multimodal magnetic resonance imaging (MRI) scanning. A mixed analysis of covariance with CR level (high CR vs. low CR) and WMH status (with WMH vs. without WMH) as fixed factors was performed on the FPCN. WMH volume was negatively correlated with global cognitive function in subjects with low CR not in those with high CR, suggesting a buffering effect of high CR. An interaction between CR and WMH was detected on the right FPCN in frontal regions. Specifically, control subjects with high CR had significantly higher functional connectivity (FC) in frontal regions than control subjects with low CR, whereas this relation was inverted in WMH subjects. Correlative analyses showed positive associations of the FC with cognitive performance in both WMH subjects and control subjects, although the associations were not significant after correction for multiple comparisons. In conclusion, CR differentially regulated the FPCN in frontal regions between subjects with WMH and those without WMH. This regulation supports the flexibility of CR in regulating brain function and may underlie the effects of CR on cognitive function in WMH subjects., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)