The Role of Brain Frailty in Stroke Outcomes: A Systematic Review

Cerebrovascular strokes and transient ischemic attacks (TIAs) remain leading causes of global mortality and long-term disability. Emerging evidence suggests that pre-existing structural brain frailty-driven by chronic cerebral small vessel disease (CSVD)-critically limits neuroplastic compensation and determines overall recovery potential. This systematic review aims to synthesize current evidence evaluating brain frailty as an independent determinant of functional and cognitive outcomes.

Following PRISMA and Cochrane SWiM guidelines, a comprehensive literature search was conducted across PubMed, Web of Science, Embase, and Scopus. Methodological quality was evaluated using the Newcastle-Ottawa Scale (NOS). Due to anticipated clinical and methodological heterogeneity, data were synthesized via a structured narrative approach. A total of 15 studies comprising more than 18,000 participants met the inclusion criteria, including prospective cohorts, retrospective cohorts, registry analyses, pooled cohort studies, and post hoc analyses of randomized controlled trials.

Structural disconnection burden emerged as one of the strongest predictors of post-stroke cognitive impairment, demonstrating remarkably large effect sizes at both 6 months (OR 9.96, 95% CI 2.21-52.40) and 36 months (OR 12.27, 95% CI 2.80-63.40). Additionally, blood-brain barrier (BBB) leakage was significantly associated with longitudinal cognitive decline (β -3.62 to -0.16, p < 0.001). Pre-existing brain frailty was also consistently associated with poorer functional recovery following acute ischemic stroke, even among patients undergoing advanced reperfusion strategies such as endovascular thrombectomy or intravenous thrombolysis.

Brain frailty should be integrated into clinical prognostic frameworks as a key marker for predicting long-term cognitive function and functional independence in stroke patients. However, the substantial methodological and clinical heterogeneity observed across the included literature must be acknowledged as a key limitation of the current evidence base. Large-scale, prospective, multicenter longitudinal studies are required to better standardize brain frailty metrics and validate their utility in clinical practice.