Biomarkers of post-stroke cognitive impairment-a systematic literature review

Post-stroke cognitive impairment (PSCI) severely affects quality of life and prognosis in stroke survivors, yet reliable predictive, diagnostic and prognostic tools remain limited. Recent advances suggest that molecular, genetic, and imaging-based biomarkers may improve prediction and management of PSCI. The purpose of this systematic review was to provide a synthesis of the current evidence on biomarkers related to PSCI, aiming to highlight knowledge gaps and future research directions.

We conducted a systematic review of observational cohort, cross-sectional, case-control and interventional studies investigating biomarkers associated with PSCI and post-stroke dementia. Eligible studies enrolled patients with acute ischemic or hemorrhagic stroke and reported cognitive outcomes with biomarker assessments in blood, or other body fluids, or neuroimaging. Screening followed PRISMA guidelines. Data extraction included study design, population characteristics, biomarkers, and cognitive outcomes. Biomarkers were clustered by type for evidence synthesis.

Of 834 screened studies, 154 were included (99 cohorts, 19 case-control, 35 cross-sectional, 1 interventional; n = 114,474). The most frequently studied biomarkers were imaging biomarkers, such as infarct volume, brain atrophy, and white matter hyperintensities, which showed consistent associations with PSCI, whereas blood-based biomarkers, notably markers of inflammation (e.g., CRP, IL-6), metabolism (e.g., HbA1c, homocysteine), and neuronal damage (e.g., amyloid-β_1-42, plasma neurofilament light chain), yielded more variable results, thereby limiting their applicability in clinical practice. Genetic markers (e.g., related to APOE ε4, MMP-9, microRNAs) showed moderate evidence of association with PSCI. We found substantial heterogeneity in timing of sampling or acquisition, cognitive assessment tools and population characteristics.

Several body-fluid-based, genetic, and imaging biomarkers demonstrate potential for the prediction of PSCI. However, clinical utility remains constrained by study heterogeneity, lack of standardization and residual confounding. Standardized protocols for cognitive assessments and biomarker timing, as well as multi-center longitudinal studies, are essential to validate and translate these biomarkers into routine clinical care.

https://www.crd.york.ac.uk/PROSPERO/view/CRD42025642710, identifier CRD42025642710.