Protecting the Brain From Post-Stroke Cognitive Impairment and Dementia With Multimodal Exercise Training

Rationale: Stroke triggers acute vascular and inflammatory mechanisms that predispose the brain to rapid neurodegeneration. Up to 52% of stroke survivors develop cognitive impairment within 6 months and 20% receive a clinical diagnosis of dementia within 5 years. The subacute phase (\<6 months) represents a critical window in which the brain may be most responsive to neuroprotective interventions. Multimodal aerobic and resistance training improves cognition in chronic stroke, but whether it improves cognition, neuroimaging markers, and blood biomarkers of dementia risk when delivered during this early window remains unknown.

Aims: To compare the effects of 12 weeks of multimodal exercise (moderate-to-high-intensity resistance and aerobic training) versus a low-intensity community-based stroke exercise comparator on cognition, neuroimaging outcomes, blood biomarkers of cognitive decline and dementia risk in people with subacute stroke.

Sample size estimates: Sample size was estimated via 20,000 Monte Carlo simulations using an Alzheimer's Disease Assessment Scale-Cognitive assessment (ADAS-Cog) effect size of Cohen's d = 0.63 from a previous exercise RCT. The target was ≥80% power to detect this treatment effect at a one-sided Type I error rate of 2.5%, using a weakly informative prior centered at zero with a variance of 100. The minimum required was 45 completers per arm (N = 90) and accounting for 25% attrition, up to 120 participants (60 per arm) will be enrolled.

Methods and design: PROTECT is a 12-week, Phase 3, assessor-blinded, multisite Bayesian adaptive RCT following a two-arm parallel group sequential design with 6- and 12-month follow-up (NCT07445841). Participants will be randomized to multimodal training or the comparator using concealed allocation with permuted blocks of varying sizes. Pre-planned adaptive features include: (1) two interim analyses at 50% and 75% of completers; (2) early stopping for efficacy and futility; and (3) sample size re-estimation.

Study outcomes: The primary outcome is cognition, measured using the 13-item ADAS-Cog. Secondary outcomes include ADAS-Cog-Plus, structural and perfusion neuroimaging, and blood biomarkers of inflammation and neurodegeneration. Tertiary outcomes will include cardiorespiratory fitness, functional mobility, muscle strength, body composition, neuropsychological battery, patient-reported cognition, quality of life, fatigue, and healthcare utilization. Outcomes will be assessed at baseline, post-intervention (primary endpoint) and at 6- and 12-month follow-up.

Expertise: Our team includes a diverse group of physical therapists, kinesiologists, neurologists, neuroscientists, neuroimmunologists, physicists, biostatisticians and clinicians at different career stages. We have expertise in exercise RCTs post-stroke and the development of novel imaging and blood predictive biomarkers of dementia risk.

Expected outcomes: We expect that multimodal training will be more effective at improving cognition and that differences between groups will persist 12 months after training, indicating a long-lasting protective effect of multimodal training when introduced in early stages of stroke recovery. We also expect that, compared with the control condition, multimodal training will increase more significantly cerebral blood flow and reduce blood brain barrier permeability as well as the concentration of blood biomarkers of inflammation, neurodegeneration, and axonal injury. We anticipate that the identification of associations between changes in biomarkers and cognition will provide important insights about the mechanisms by which exercise can protect the brain against early neurodegeneration post-stroke.

Significance: Patients with stroke have identified the development of interventions to reduce cognitive dysfunction as the most important problem that research must address. However, cognitive post- stroke impairment is commonly neglected and there is a lack of interventions specifically designed to mitigate this problem. This project will determine if exercise implemented in early stages of recovery can reduce the burden of accelerated cognitive decline and dementia risk in these patients.

• Cognition [Time frame: Baseline (T0), 12-week post-intervention (T1), follow-up at 6 months (T2) and 12 months (T3)]
• Cerebral Blood Flow [Time frame: Baseline (T0), 12-week post-intervention (T1), and follow-up at 12 months (T3)]
• Blood Brain Barrier Permeability [Time frame: Baseline (T0), 12-week post-intervention (T1), and follow-up at 12 months (T3)]
• White Matter Structure and Integrity [Time frame: Baseline (T0), 12-week post-intervention (T1), and follow-up at 12 months (T3)]
• Cerebral Blood Velocity (Middle Cerebral Artery Velocity) [Time frame: Baseline (T0), 12-week post-intervention (T1), follow-up at 6 months (T2) and follow-up at 12 months (T3)]
• Inflammation [Time frame: Baseline (T0), 12-week post-intervention (T1), and follow-up at 6 (T2), and 12 months (T3)]
• Neurodegeneration [Time frame: Baseline (T0), 12-week post-intervention (T1), and follow-up at 6 (T2), and 12 months (T3)]
• Axonal Injury [Time frame: Baseline (T0), 12-week post-intervention (T1), follow-up at 6 (T2) and 12 months (T3)]