Serum BDNF in subacute stroke: effects of a four-week aerobic exercise intervention in the PHYS-STROKE trial

Introduction The early phase after stroke is considered a period of heightened neuroplasticity and may be responsive to rehabilitation interventions targeting biological recovery. Brain-derived neurotrophic factor is one candidate mediator of post-stroke plasticity, but it remains unclear whether clinically feasible aerobic exercise induces sustained increases in circulating brain-derived neurotrophic factor after stroke. Methods We performed a pre-specified secondary biomarker analysis of the multicentre, randomized, endpoint-blinded Physical Fitness Training in Patients with Subacute Stroke trial. Participants were randomized to 4 weeks of moderate-intensity treadmill-based aerobic training or relaxation therapy. Serum brain-derived neurotrophic factor was assessed from baseline to 6 months post-stroke. Models were adjusted for baseline brain-derived neurotrophic factor, age, sex, stroke severity, platelet count, depressive symptoms, smoking status, and study center. Results Among 200 randomized participants, serum brain-derived neurotrophic factor increased modestly from baseline to 3 months and remained stable thereafter. No relevant between-group difference was observed at 6 months after aerobic training compared with relaxation therapy (training: 24.6 ng/mL; 95% CI, 20.2–29.0 vs. relaxation: 24.3 ng/mL; 95% CI, 19.8–28.8; adjusted p = 0.74). Findings were consistent in complete-case and change-score sensitivity analyses. Exploratory analyses showed no robust treatment effect modification by depressive symptoms or intervention dose. A nominal sex-related subgroup finding should be interpreted cautiously. Discussion Moderate-intensity aerobic exercise in early subacute stroke rehabilitation was not associated with sustained serum brain-derived neurotrophic factor increases compared with relaxation therapy. These findings argue against a robust long-term peripheral neurotrophin response, while not excluding acute, higher-intensity, or subgroup-specific effects. Clinical Trial Registration [ clinicaltrials.gov/study/NCT01953549 ], identifier [NCT01953549].