Investigating the Neuroimmune, Cerebrovascular, and Cognitive Disturbances Associated with SARS‑CoV‑2 Infection: A Systematic Review of Post‑Acute Outcomes

Background SARS-CoV-2, initially identified as a respiratory pathogen, has emerged as a significant driver of neurological morbidity in the post-acute phase of infection. A substantial body of evidence underscores persistent neuroimmune dysregulation, cerebrovascular injury, and cognitive impairment as critical contributors to long-term disability among COVID-19 survivors. However, the mechanistic interplay between these processes and their clinical implications remains incompletely characterized. Objectives This systematic review and meta-analysis aim to (1) elucidate the pathophysiological mechanisms underlying post-acute neurological outcomes of COVID-19, (2) evaluate the prevalence and clinical spectrum of neuroimmune, cerebrovascular, and cognitive disturbances using both qualitative and quantitative data, and (3) propose strategies for early detection and clinical management based on rigorous, evidence-based findings. Methods A comprehensive search of PubMed, EMBASE, and the Cochrane Library was conducted for studies published between January 1, 2020, and January 31, 2025. Included studies reported on neuroinflammatory biomarkers, cerebrovascular events, or cognitive dysfunction assessed ≥ 4 weeks after acute SARS-CoV-2 infection. Two independent reviewers screened records, extracted data, and appraised study quality using PRISMA 2020 guidelines. A narrative synthesis was supplemented by a quantitative meta-analysis of key outcomes, with pooled effect estimates calculated using random-effects models to address heterogeneity. Results From 2,178 screened records, 10 studies (n ≈ 77,300) met the inclusion criteria. Three interrelated pathological domains were identified: (1) Neuroimmune Dysregulation: Persistent cytokine elevations (e.g., IL-6, TNF-α), microglial activation, and neuronal autoantibodies (detected in ~ 18% of patients) indicate a state of chronic neuroinflammation. (2) Cerebrovascular Complications: A 3.7-fold increased risk of stroke, along with evidence of blood–brain barrier (BBB) disruption and microvascular injury, underscores the role of endothelial dysfunction and thromboinflammatory pathways. (3) Cognitive Dysfunction: Deficits in memory, executive function, and processing speed, reported in up to 58% of patients, correlated with neuroimaging findings of grey matter atrophy and altered functional connectivity. The meta-analysis yielded a pooled standardized mean difference for IL-6 elevation of 0.78 (95% CI: 0.55–1.01; p < 0.001) and a pooled odds ratio for stroke risk of 3.7 (95% CI: 2.1–6.4; p < 0.001). Moderate-to-high heterogeneity (I² between 50% and 70%) was addressed using random-effects models and sensitivity analyses, which confirmed the robustness of these associations. Conclusions Post-acute COVID-19 manifests as a triad of neuroimmune, vascular, and cognitive disturbances, supported by both narrative and quantitative analyses. Early identification through multimodal screening including advanced neuroimaging, comprehensive inflammatory biomarker profiling, and validated cognitive assessments are essential. Targeted therapeutic strategies focusing on endothelial stabilization and immunomodulation may prove pivotal in mitigating long-term disability. Future research should prioritize standardized outcome measures and mechanistic studies to further refine interventional approaches and inform clinical policy.