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

Background: Sex 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. Methods: We 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. Results: Among 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. Conclusion: PBV 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.