Brain Health Loss Mediates the Effect of Infarct Volume on Functional Outcome in Ischemic Stroke

Structured abstractO_ST_ABSImportanceC_ST_ABSBrain health may facilitate resilience to detrimental consequences from neurological diseases. Infarct volume is associated with poor functional outcome after acute ischemic stroke (AIS), but potential mediating effects through stroke-related brain health loss have not been investigated. ObjectiveTo determine whether stroke-related brain health loss, quantified by change in MRI derived effective Reserve (eR), mediates the effect of acute infarct volume on functional outcome after AIS. DesignObservational multicenter cohort study. SettingWe analyzed data from the GASROS (n=488) and MRI-GENIE (n=560) cohorts, collected 2003-2011. ParticipantsAdult patients consecutively diagnosed with AIS, with available admission MRI. ExposureAt admission, white matter hyperintensity (WMH) and normal-appearing brain volumes were assessed on T2-FLAIR, and acute infarct volume on diffusion weighted imaging. WMH was normalized by brain volume, creating WMH load. We quantified brain health using eR, a latent variable incorporating age, WMH load, and normal-appearing brain volume. {Delta}eR reflected the change in eR when acute infarct volume was included, representing stroke-related brain health decline. Mediation analysis was used to determine if {Delta}eR mediates the effect of infarct volume on functional outcome (modified Rankin Scale [mRS] at 90 days). Main Outcome MeasureProportion of mediating effect. ResultsWe included 1,048 patients (median age 67y, 38% females). At baseline, median NIHSS score was 3 (IQR 1-7), median infarct volume 3.1mL (IQR 0.9-15.5). At 90 days, median mRS score was 1 (IQR 1-3) and 51 (5%) patients had died. In mediation analysis, {Delta}eR significantly mediated 36% (95% CI 16-56%) of the total effect of infarct volume on functional outcome (direct effect ({beta}=0.15 [95% CI 0.09-0.22], p<0.001; indirect effect mediated through {Delta}eR: {beta}=0.09 [95% CI 0.04 to 0.14], p=0.001). In subgroup-analyses, the mediative effect was apparent among female but not male, and among patients aged >67y but not [&le;]67y. Conclusions and RelevanceStroke-related structural brain health loss mediates about one third of the effect of acute infarct volume on functional outcome after ischemic stroke, with important sex and age differences. Brain health significantly influences outcome and recovery potential, and may be considered a key biomarker when modeling outcome after AIS. Key pointsO_ST_ABSQuestionC_ST_ABSDoes brain health loss associated with acute ischemic stroke mediate the relationship between acute infarct volume and functional outcome? FindingsIn this observational multicenter cohort study of 1,048 patients, mediation analysis suggests that reduction of the brain health MRI marker effective Reserve mediates 36% (95% CI 16-56%) of the total effect of acute infarct volume on functional outcome. The proportion of mediative effect was more pronounced among female compared to male and in older compared to younger patients. MeaningBrain health loss mediates one third of the effect of acute infarct volume on functional outcome after ischemic stroke.