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 now 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 synthesizes global evidence to (1) elucidate the pathophysiological mechanisms underlying post-acute neurological sequelae of COVID-19, (2) evaluate the prevalence and clinical spectrum of neuroimmune, cerebrovascular, and cognitive disturbances, and (3) propose actionable strategies for clinical management and future research. Methods A comprehensive search of PubMed, EMBASE, and 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 performed, supported by tabulated summaries and descriptive visualizations of key findings. Results From 2,178 screened records, 15 studies (n = 73,435 participants) met inclusion criteria. Three interrelated pathological domains were identified: (1) Neuroimmune Dysregulation: Persistent elevation of pro-inflammatory cytokines (e.g., IL-6, TNF-α), microglial activation, and neuronal autoantibodies were reported in 42% of patients, implicating chronic neuroinflammation. (2) Cerebrovascular Complications: A 3.7-fold increased stroke risk and microvascular injury (22% prevalence) were linked to SARS-CoV-2-induced endothelial dysfunction, blood-brain barrier disruption, and thromboinflammatory pathways. (3) Cognitive Dysfunction: Deficits in memory, executive function, and processing speed (58% prevalence) correlated with neuroimaging evidence of grey matter atrophy and functional connectivity loss. Conclusions Post-acute COVID-19 manifests as a triad of neuroimmune, vascular, and cognitive pathologies, driven by synergistic mechanisms such as endothelial injury and chronic inflammation. Early detection via multimodal screening (e.g., neuroimaging, cytokine profiling) and multidisciplinary care models are essential to mitigate long-term disability. Future research must prioritize standardized diagnostic criteria, mechanistic studies elucidating viral neurotropism, and clinical trials evaluating therapies targeting endothelial stabilization and immunomodulation. Addressing these priorities will inform evidence-based interventions to improve outcomes for the growing population of survivors grappling with neurological sequelae.