Evidence map›Paper›PMID 34108016›Full record

ArticleAlzheimer's research & therapy2021

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

Yadi Zhou, Jielin Xu, Yuan Hou, James B Leverenz, Asha Kallianpur, Reena Mehra, Yunlong Liu, Haiyuan Yu, Andrew A Pieper, Lara Jehi and 1 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Alzheimer's research & therapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 95 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
95citing papers in PubMed, 3 pooled it
14.9field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

95 citing papers in PubMed, 3 syntheses or guidelines pooled it, 160 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Pooled it
  4. Review
  5. Review
  6. Observational
  7. Article
  8. Article
  9. Review
  10. Article
  11. Article
  12. Review
  13. Article
  14. Article
  15. Article
  16. Review
  17. Review
  18. Article
  19. Article
  20. Article

35 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

11 authors at 4 institutions in 1 country.

Yadi Zhou *Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
Jielin Xu *Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
Yuan Hou *Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
James B LeverenzDepartment of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA.
Asha KallianpurGenomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
Reena MehraDepartment of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA.
Yunlong LiuDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Haiyuan YuWeill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, 14850, USA.
Andrew A PieperHarrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA.
Lara JehiDepartment of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA.
Feixiong ChengGenomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. chengf@ccf.org.ORCID 0000-0002-1736-2847
Cleveland Clinic Lerner College of Medicine · USCleveland Clinic · USCornell University · USIndiana University School of Medicine

Funding

Endophenotype Network-based Approaches to Prediction and Population-based Validation of In Silico Drug Repurposing for Alzheimer's DiseaseR01AG066707 · NIA · CLEVELAND CLINIC LERNER COM-CWRU · PI Feixiong Cheng · 2020 to 2026
$4.9M
An individualized network medicine infrastructure for precision cardio-oncologyR00HL138272 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI CHENG, FEIXIONG · 2018 to 2020
$747k
Foundation for the National Institutes of Health 3R01NS097719-04S1Foundation for the National Institutes of Health R00HL138272NHLBI NIH HHS R00 HL138272NIA NIH HHS 3R01AG066707-01S1NIA NIH HHS R01 AG066707NIA NIH HHS R01AG066707
6 · The paper itself

Abstract

backgroundDementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive and therapeutic interventions.

methodsIn this study, we conducted a network-based, multimodal omics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9-based genetic assay results and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer's disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2.

resultsWe found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Overall, individuals with the AD risk allele APOE E4/E4 displayed reduced expression of antiviral defense genes compared to APOE E3/E3 individuals.

conclusionOur results suggest significant mechanistic overlap between AD and COVID-19, centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions, although causal relationship and mechanistic pathways between COVID-19 and AD need future investigations.

Indexed as

Alzheimer DiseaseCognitive DysfunctionCOVID-19BrainEndothelial CellsHumansMembrane ProteinsRNA-Binding ProteinsSARS-CoV-2IFITM2 protein, humanIFITM3 protein, humanMembrane ProteinsRNA-Binding ProteinsAlzheimer’s diseaseBrain microvasculatureCognitive impairmentCOVID-19DementiaNetwork medicineNeuroinflammationSARS-CoV-2Single-cell/nucleus

Identifiers

PMID34108016
PMCPMC8189279
OpenAlexW3167321976

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.