The Epidemiological and Mechanistic Understanding of the Neurological Manifestations of COVID-19: A Comprehensive Meta-Analysis and a Network Medicine Observation

Abstract

The clinical characteristics and biological effects on the nervous system of infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain poorly understood. The aim of this study is to advance epidemiological and mechanistic understanding of the neurological manifestations of coronavirus disease 2019 (COVID-19) using stroke as a case study. In this study, we performed a meta-analysis of clinical studies reporting stroke history, intensive inflammatory response, and procoagulant state C-reactive protein (CRP), Procalcitonin (PCT), and coagulation indicator (D-dimer) in patients with COVID-19. Via network-based analysis of SARS-CoV-2 host genes and stroke-associated genes in the human protein-protein interactome, we inspected the underlying inflammatory mechanisms between COVID-19 and stroke. Finally, we further verified the network-based findings using three RNA-sequencing datasets generated from SARS-CoV-2 infected populations. We found that the overall pooled prevalence of stroke history was 2.98% (95% CI, 1.89–4.68; I2=69.2%) in the COVID-19 population. Notably, the severe group had a higher prevalence of stroke (6.06%; 95% CI 3.80–9.52; I2 = 42.6%) compare to the non-severe group (1.1%, 95% CI 0.72–1.71; I2 = 0.0%). There were increased levels of CRP, PCT, and D-dimer in severe illness, and the pooled mean difference was 40.7 mg/L (95% CI, 24.3–57.1), 0.07 μg/L (95% CI, 0.04–0.10) and 0.63 mg/L (95% CI, 0.28–0.97), respectively. Vascular cell adhesion molecule 1 (VCAM-1), one of the leukocyte adhesion molecules, is suspected to play a vital role of SARS-CoV-2 mediated inflammatory responses. RNA-sequencing data analyses of the SARS-CoV-2 infected patients further revealed the relative importance of inflammatory responses in COVID-19-associated neurological manifestations. In summary, we identified an elevated vulnerability of those with a history of stroke to severe COVID-19 underlying inflammatory responses (i.e., VCAM-1) and procoagulant pathways, suggesting monotonic relationships, thus implicating causality.

Coronavirus disease 2019 and acute cerebrovascular events: a comprehensive overview

“…Individuals with a prior history of ischemic stroke, diabetes, high D-dimer levels, and other conventional risk factors for stroke are seemingly at an increased susceptibility to ischemic stroke in the context of SARS-CoV-2 infection (68)(69)(70). In comparison to uninfected controls, patients diagnosed with COVID-19 exhibited a 3.6-fold augmented susceptibility to ischemic stroke (57), which is consistent with the findings of other meta-analyses (71).…”

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment

“…Serum VCAM1 levels were also significantly elevated in severe COVID-19 patients compared to mild patients and controls, and significantly decreased in the convalescence phase compared to severe patients [ 86 ]. Notably, VCAM1 also plays an important role in COVID-19-induced vasculitis [ 87 ]. RAB7A is a direct target of non-structural protein 7 (nsp7) of SARS-CoV-2 [ 29 ], and also one of the top host factors in CRISPR-Cas9-based SARS-CoV-2 datasets.…”

Cerebrovascular Complications of COVID-19 and COVID-19 Vaccination

“… 4 , 5 , 11 , 25 Compared with patients with influenza requiring hospitalization, COVID-19 patients have a 7- to 8-fold greater risk of stroke, although the CIs of these estimates are wide and overlap significantly with the risk estimates when compared with historical controls. 5 Patients with COVID-19 at the highest risk of ischemic stroke appear to be those with a history of ischemic stroke, 26 possibly a history of diabetes 4 and other traditional stroke risk factors, 27 and higher serum d -dimer levels. 28 , 29 …”

“…4,5,11,25 Compared with patients with influenza requiring hospitalization, COVID-19 patients have a 7-to 8-fold greater risk of stroke, although the CIs of these estimates are wide and overlap significantly with the risk estimates when compared with historical controls. 5 Patients with COVID-19 at the highest risk of ischemic stroke appear to be those with a history of ischemic stroke, 26 possibly a history of diabetes 4 and other traditional stroke risk factors, 27 and higher serum d-dimer levels. 28,29 Outcomes in strokes occurring in patients with COVID-19 also appear worse, in terms of initial stroke severity (compared with historical controls), 30 functional outcome at discharge (compared with contemporary and historical controls), 30,31 discharge destination (compared with historical controls), 32 and inpatient mortality (compared with both contemporary and historical controls).…”