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Cerebral small vessel disease (CSVD) is a common cause of stroke and cognitive impairment in older adults. White matter hyperintensities (WMH) observed on magnetic resonance imaging (MRI) images are the most common feature of cerebral small vessel disease. However, the magnitude of WMH’s relationship to cognition and to the rate of cognitive decline varies considerably across individuals. Sex may be an important moderator in how risk factors for development and progression of WMH are related to WMH incidence and severity.

To improve our understanding of sex differences in WMH burden and subsequent effects on cognition, investigators including Noah Schweitzer (Department of Bioengineering), and Sang Joon Son, MD, PhD (Department of Psychiatry, Ajou University), along with Rebecca Thurston, PhD (Pittsburgh Foundation Chair in Women's Health and Dementia and Professor of Psychiatry, Clinical and Translational Science, Epidemiology and Psychology); Howard Aizenstein, MD, PhD (Charles F. Reynolds III and Ellen G. Detlefsen Endowed Chair in Geriatric Psychiatry and Professor of Bioengineering and Clinical and Translational Science); Shaolin Yang, PhD (Assistant Professor of Psychiatry and Bioengineering); and Minjie Wu, PhD (Assistant Professor of Psychiatry), from Pitt Psychiatry, conducted a study to  identify sex-specific modifiable risk factors for WMH and explore whether there were sex-specific associations of WMH to longitudinal clinical dementia outcomes.

Participants comprising a large cohort of predominantly cognitively impaired individuals (ages 49-89) from South Korea underwent MRI scans to measure WMH volume. At follow-up visits scheduled one to two years apart, participants’ clinical dementia scores were assessed. The investigators first explored which known modifiable risk factors for WMH were significant when tested for a sex-interaction effect. They additionally tested which risk factors were significant when stratified by sex, and tested to see whether WMH is longitudinally associated with clinical dementia that is sex-specific.

Findings from the study, recently published in Alzheimer's Research & Therapy, showed that older females have an accelerated increase in WMH cerebrovascular burden compared to males; type 2 diabetes status was associated with greater WMH burden in females but not males; and WMH volume was associated with worse clinical dementia outcomes longitudinally in females only.

“These findings emphasize the importance of considering sex when examining the risk factors for and cognitive sequelae of CSVD,” said Dr. Wu, the study’s senior and corresponding author.

Sex-specific risk factors and clinical dementia outcomes for white matter hyperintensities in a large South Korean cohort
Schweitzer N, Son SJ, Thurston RC, Li J, Chen C, Aizenstein H, Yang S, Iordanova B, Hong CH, Roh HW, Cho YH, Hong S, Nam YJ, Lee DY, Park B, Kim N, Choi WJ, Cheong J, Seo SW, An Y, Moon SY, Han SJ, Wu M.
Alzheimer's Research & Therapy 16, 243 (2024). https://doi.org/10.1186/s13195-024-01598-2