Sex Differences in the Protective Effect of Brain Volume: Age Attenuates Protection in Women

BACKGROUND: Sex differences in outcomes after acute ischemic stroke are well recognized, but mechanisms remain unclear. This study evaluates whether parenchymal brain volume (PBV), age, and final infarct volume explain sex-specific differences in poststroke disability. METHODS: We analyzed a prospectively collected multicenter registry of acute ischemic stroke patients treated between 2015 and 2024. Automated pipelines quantified PBV from noncontrast computed tomography and diffusion-weighted imaging–derived final infarct volume from 24- to 48-hour magnetic resonance imaging. With the primary outcome being 90-day functional independence (modified Rankin Scale score 0–2), sex-stratified logistic regression models evaluated its association with PBV. Stratified logistic and linear models examined sex-specific relationships among covariables, and interaction terms were added to assess effect modification by sex. RESULTS: Among 1103 patients, 48% were women, the median age was 66 (interquartile range, 56–77), the median National Institutes of Health Stroke Scale score was 9 (interquartile range, 4–17), and the median diffusion-weighted imaging–derived final infarct volume was 7.8 (interquartile range, 0.2–36.3). Functional independence at 90 days was achieved in 51.7% of men versus 44.9% of women ( P =0.025). In univariable analyses, greater PBV was associated with higher odds of functional independence in both men (odds ratio [OR], 1.30 [95% CI, 1.11–1.53]) and women (OR, 1.35 [95% CI, 1.13–1.61]). After ruling out multicollinearity (mean variance inflation factor, 1.32), multivariable analyses showed a persistent association in men (adjusted odds ratio, 1.30 per 100 cm 3 [95% CI, 1.10–1.60]) but not in women (adjusted odds ratio, 1.10 [95% CI, 0.90–1.33]). Each decade of age reduced the odds of functional independence by 30% in women (adjusted odds ratio, 0.70 [95% CI, 0.62–0.79]) versus 15% in men (adjusted odds ratio, 0.85 [95% CI, 0.72–0.97]; P for interaction=0.019). In stratified analyses, age was associated with larger infarcts in women (+4.22 cm 3 /decade; P =0.033) but not in men ([95% CI, –4.75 to 2.91]; P =0.637). CONCLUSIONS: PBV was independently associated with functional independence in men but not significantly in women, in whom stronger age-related associations with infarct size and severity may attenuate its effect. These findings highlight the relevance of sex and brain volume in outcome modeling.