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

BackgroundSex differences in outcomes after acute ischemic stroke (AIS) are well recognized, but mechanisms remain unclear. This study evaluates whether parenchymal brain volume (PBV), age, and final infarct volume (DWI-FIV) explain sex-specific differences in post-stroke disability. MethodsWe analyzed a prospectively collected multicenter registry of AIS patients treated between 2015 and 2024. Automated pipelines quantified PBV from non-contrast CT and DWI-FIV from 24-48-hour MRI. With the primary outcome being 90-day functional independence (mRS 0-2), sex-stratified logistic regression models evaluated its association with PBV. Logistic and linear models examined sex-specific relationships among covariables. ResultsAmong 1,103 patients, 48% were female, median age was 66 [IQR 56-77], median NIHSS was 9 [IQR 4-17], and median DWI-FIV was 7.8 [IQR 0.2-36.3]. Functional independence at 90 days was achieved in 51.7% of males versus 44.9% of females (p = 0.025). In univariable analyses, greater PBV was associated with higher odds of functional independence in both males (OR 1.30; 95% CI: 1.11-1.53) and females (OR 1.35; 95% CI: 1.13-1.61). After ruling out multicollinearity (mean VIF = 1.32), multivariable analyses showed persistent association in males (aOR 1.30 per 100 cm3; 95% CI: 1.10-1.60) but not in females (aOR 1.10; 95% CI: 0.90-1.33). Each decade of age reduced the odds of functional independence by 30% in females (aOR 0.70; 95% CI: 0.62- 0.79) versus 15% in males (aOR 0.85; 95% CI: 0.72-0.97; p interaction = 0.019). Age was also associated with larger infarcts in females (+4.22 cm3/decade; p = 0.033) but not in males. ConclusionPBV was protective in males but less so in females, where stronger age-related effects on infarct size and severity abrogated its benefit. These suggest aging weakens brain reserve in women, emphasizing the importance of sex and brain volume measurements in outcome models.