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

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.

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.

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 cm³ [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 cm³/decade; P=0.033) but not in men ([95% CI, -4.75 to 2.91]; P=0.637).

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.