Neurology · Medical Literature
Clinical and preclinical evidence of meningeal immunity and glymphatic pathways in stroke: a systematic review.
Abstract
Glymphatic transport, meningeal lymphatic drainage, and meningeal immunity have been implicated in metabolic waste clearance, cerebral edema formation, and the regulation of neuroinflammation after stroke. However, the available evidence remains fragmented and has not been systematically integrated. This review was conducted in accordance with PRISMA guidelines. PubMed, Embase, Scopus, the Cochrane Library, and Web of Science were searched from database inception to April 3, 2026, for studies investigating glymphatic pathways, the meningeal lymphatic system, meningeal immune responses, and related imaging biomarkers in patients with clinical stroke or in experimental stroke models. Two investigators independently screened studies, extracted data, and assessed study quality. Because of substantial heterogeneity in study design, imaging methodology, experimental models, and outcome measures, findings were synthesized narratively. A total of 64 studies were included, comprising 17 clinical studies and 47 preclinical studies. Clinical studies, which were largely based on MRI-derived glymphatic imaging biomarkers, suggest that glymphatic dysfunction is associated with stroke severity, cognitive impairment, and clinical outcomes. Preclinical evidence indicates that AQP4 dysregulation, impaired meningeal lymphatic drainage, and border-associated immune activation may influence waste clearance, cerebral edema, inflammation, and tissue repair after stroke. Future studies should establish standardized imaging frameworks, conduct prospective longitudinal validation, define mechanistic differences across stroke subtypes, and facilitate the translation of targeted interventions. https://www.crd.york.ac.uk/PROSPERO/home, identifier CRD420261359988.
Clinical relevance
This systematic review addresses a critical gap in stroke neurology by synthesizing fragmented clinical and preclinical evidence on glymphatic transport, meningeal lymphatic drainage, and meningeal immunity — three interconnected systems increasingly recognized as modulators of post-stroke pathophysiology. The findings are relevant to a broad stroke population, encompassing patients at risk for cerebral edema, neuroinflammation, and post-stroke cognitive impairment. Clinicians should attend to this evidence now as glymphatic imaging biomarkers are emerging as potentially actionable tools for stroke severity stratification and outcome prediction.
Key findings
1. A total of 64 studies were included in this PRISMA-compliant systematic review: 17 clinical studies and 47 preclinical studies, reflecting a predominantly experimental evidence base with limited prospective human data to date. 2. Clinical studies, largely reliant on MRI-derived glymphatic imaging biomarkers, demonstrated an association between glymphatic dysfunction and stroke severity, cognitive impairment, and overall clinical outcomes — though specific effect sizes and p-values were not reported in the abstract. 3. Preclinical evidence identified AQP4 (aquaporin-4) dysregulation as a key mechanistic driver of impaired glymphatic waste clearance, cerebral edema formation, and neuroinflammatory cascades following stroke. 4. Impaired meningeal lymphatic drainage was implicated preclinically in disrupted metabolic waste clearance and aberrant neuroinflammatory regulation after stroke, suggesting it is a distinct and targetable pathophysiological mechanism. 5. Border-associated immune cell activation was identified as a contributor to post-stroke inflammation and tissue repair processes, highlighting the meningeal immune compartment as a modulator of stroke recovery. 6. Substantial heterogeneity across study designs, imaging methodologies, experimental stroke models, and outcome measures precluded meta-analysis, limiting the ability to derive pooled quantitative estimates and underscoring the need for standardized frameworks.
Practice implications
At present, glymphatic imaging biomarkers (MRI-derived) should be interpreted as investigational tools for stroke severity and cognitive outcome stratification rather than established clinical standards, given the absence of prospective longitudinal validation and standardized acquisition protocols. Clinicians involved in translational research or advanced neuroimaging programs should prioritize study designs that harmonize imaging methodology and distinguish mechanistic differences across ischemic stroke subtypes, hemorrhagic stroke, and small vessel disease to accelerate the validation of AQP4 and meningeal lymphatic targets. Future therapeutic strategies targeting AQP4 modulation or meningeal lymphatic augmentation hold promise for reducing cerebral edema and neuroinflammation post-stroke, but require prospective human trials with clearly defined patient selection criteria before clinical adoption.