Associations of Brain Volume with Post-Stroke Outcomes in Acute Ischemic Stroke

Introduction Global brain volume, a surrogate marker of brain reserve, may predict functional recovery after acute ischemic stroke (AIS). Previous studies have showed that greater PBV may predict better outcomes, greater FIV predicts a worse prognosis, and AIS outcomes differ between sex. However, whether PBV's beneficial effect varies by infarct size or differs between women and men remains uncertain. Our aim is to examine differential PBV–AIS outcome associations across sex and infarct‐size strata (FIV <5 vs ≥5 mL). Methods We analyzed data from a prospectively collected, multicenter stroke registry, including patients with AIS treated between February 2015‐March 2024. Patients were excluded if they lacked 90‐day mRS scores, FIV, PBV, NIHSS at baseline, PBV<1,000 cc, or FIV/PBV >100. PBV data were binned in 100‐cc increments, and FIV was categorized in small vs. large with <5 vs ≥5 cc as the cut‐off. The primary outcome was poor functional outcome (90‐day mRS 3‐6). Univariable and multivariable logistic regression were performed adjusting for age, NIHSS, and FIV. Analyses were stratified by FIV and, separately, by sex, enabling evaluation of both infarct‐size–dependent and sex‐specific PBV effects. Results Among 1,103 AIS patients, median age was 66 years (IQR:56‐77), median NIHSS 9 (IQR:4‐17), median PBV was 1,698 mL (IQR:1,611‐1,759), and 48% were female. Large FIV was identified in 611 patients (235[48.0%] female) and small FIV in 492 patients (293[48.0%] female). Females were older than males in both FIV groups. In the small FIV stratum, males had larger FIV, whereas in large FIV stratum, females had higher NIHSS. In multivariable analysis without FIV stratification, each +100cc PBV was associated with lower odds of poor outcome (aOR:0.998; 95% CI:0.996,0.999). Stratified by FIV, this association persisted in patients with small FIV (aOR:0.998; 95% CI:0.996‐0.999) but not in those with large FIV (aOR:1.000; 95% CI:0.996,1.000). In sex‐stratified multivariable models, higher PBV was associated with lower odds of poor outcome in males (small and large FIV strata: aOR 0.997; 95% CI:0.994,0.9997), but not in females (small FIV: aOR 0.998; 95% CI:0.995,1.005; large FIV: aOR 1.000; 95% CI, 0.997‐1.003). Conclusion The protective effect of larger parenchymal brain volume is pronounced in patients with small infarct volumes, and in men regardless of infarct size. In contrast, the effect of large brain volume was not evident in women nor in patients with larger infarcts. These findings suggest that sex and infarct size should be considered when using brain volumes as a brain‐reserve marker.