Kenda Alhadid1, Robert W. Regenhardt1, Natalia S. Rost1, Markus D. Schirmer11- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA,USA. Correspondence:Markus D. Schirmermschirmer1@mgh.harvard.eduKeywords: arterial ischemic stroke, brain volume, brain parenchymal fraction, BPF, modified Rankin Scale, mRSAbstractObjective: To assess if brain volume at the time of ischemic stroke injury is a better biomarker of functional outcome than brain atrophy.Background: Brain parenchymal fraction (BPF) has been used as a surrogate measure of global brain atrophy, and as a neuroimaging biomarker of brain reserve in studies evaluating clinical outcomes after brain injury. Brain volume itself is affected by natural aging, cardiovascular risk factors, and biological sex, amongst other factors. Recent works have shown that brain volume at the time of injury can influence functional outcomes, where larger brain volumes are associated with better outcomes. Methods: Acute ischemic stroke cases at a single center between 2003 and 2011, with MR neuroimaging obtained within 48 hours from presentation were eligible. Functional outcomes UHSUHVHQWHG  E\  WKH  PRGLILHG  5DQNLQ  6FRUH   P56   DW      GD\V  SRVW  DGPLVVLRQ   P56”   GHHPHG  D favorable outcome) were obtained via patient interview or per chart review. Deep learning enabled automated segmentation pipelines were used to calculate brain volume, intracranial volume (ICV), and BPF on the acute neuroimaging data. Patient outcomes were modeled through logistic regressions, and model comparison was conducted using the Bayes Information Criterion (BIC). Results: 467 patients with arterial ischemic stroke were included in the analysis. Median age was 65.8 (interquartile range: 55.3-76.3) years, and 65.3% were male. In both models, age and a larger stroke lesion volume were associated with worse functional outcomes. Higher BPF and a larger brain volume were both associated with favorable functional outcomes, however, comparison of both models suggested that the brain volume model (BIC=501) explains the data better compared to the BPF model (BIC=511).Conclusions: The extent of global brain atrophy (and its surrogate biomarker BPF) has been regarded as an important biomarker of post-stroke functional outcomes and resilience to acute injury. Here, we demonstrate that a higher global brain volume at the time of injury better explains favorable functional outcomes, which can be directly clinically assessed.