Neurovascular Coupling as Early, High-Sensitive Biomarker for Cognitive Decline and Vascular Pathology: Protocol for Systematic Review and Meta-Analysis

Background: Neurovascular coupling (NVC) reflects the relationship between neuronal activity and cerebral blood flow and underpins the interpretation of functional neuroimaging. Disruption of NVC has been linked to aging, vascular pathology, and cognitive decline, and may precede structural brain changes. However, current evidence remains fragmented due to methodological heterogeneity, diverse NVC metrics, and small sample sizes. This systematic review and meta-analysis aim to synthesise available evidence and evaluate NVC as a potential biomarker of cognitive decline. Methods: This protocol follows PRISMA-P guidelines. A systematic search will be conducted in PubMed/MEDLINE, EMBASE, Scopus, Web of Science, and CINAHL. Eligible studies will include adults across the lifespan or individuals with vascular pathology and will report quantitative NVC measures alongside cognitive outcomes. Data extraction will include study characteristics, NVC metrics, cognitive assessments, and relevant physiological factors. A unified statistical approach will be applied to synthesise effect estimates describing associations between NVC, cognition, age, and vascular pathology. Analyses will be stratified by NVC modality, vascular condition, and cognitive domain. Heterogeneity will be assessed using the I² statistic and explored using meta-regression where appropriate. Longitudinal studies will be used to evaluate the predictive value of baseline NVC measures for future cognitive outcomes. Discussion: This study will provide a structured synthesis of current evidence on the role of NVC in cognitive decline across aging and vascular pathology. By integrating findings across diverse methodological approaches, it aims to clarify the strength and consistency of NVC–cognition associations and evaluate the potential of NVC as a sensitive biomarker. The results may inform future research directions and support the development of clinically relevant NVC-based predictive models. Systematic review registration: PROSPERO Registration number: CRD420261351976