Cerebral small vessel disease pathology in COVID-19 patients: A systematic review

Cameron D Owens¹, Camila Bonin Pinto¹, Sam Detwiler¹, Peter Mukli², Anna Peterfi², Zsofia Szarvas², Jordan R Hoffmeister³, Juliette Galindo³, Jila Noori⁴, Angelia C Kirkpatrick⁵, Tarun W Dasari⁶, Judith James⁷, Stefano Tarantini⁸, Anna Csiszar², Zoltan Ungvari⁹, Calin I Prodan¹⁰, Andriy Yabluchanskiy¹¹

Affiliations

¹ Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
² Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, Hungary.
³ Department of Psychiatry and Behavioral Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁴ Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁵ Cardiovascular Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Veterans Affairs Medical Center, Oklahoma City, OK, USA.
⁶ Cardiovascular Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁷ Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁸ Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, Hungary; The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁹ Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, Hungary; Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
¹⁰ Veterans Affairs Medical Center, Oklahoma City, OK, USA; Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
¹¹ Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Electronic address: andriy-yabluchanskiy@ouhsc.edu.

PMID: 37224885
PMCID: PMC10202464
DOI: 10.1016/j.arr.2023.101962

Cerebral small vessel disease pathology in COVID-19 patients: A systematic review

Cameron D Owens et al. Ageing Res Rev. 2023 Jul.

. 2023 Jul:88:101962.

doi: 10.1016/j.arr.2023.101962. Epub 2023 May 22.

Authors

Affiliations

¹ Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
² Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, Hungary.
³ Department of Psychiatry and Behavioral Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁴ Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁵ Cardiovascular Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Veterans Affairs Medical Center, Oklahoma City, OK, USA.
⁶ Cardiovascular Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁷ Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁸ Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, Hungary; The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁹ Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, Hungary; Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
¹⁰ Veterans Affairs Medical Center, Oklahoma City, OK, USA; Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
¹¹ Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Electronic address: andriy-yabluchanskiy@ouhsc.edu.

PMID: 37224885
PMCID: PMC10202464
DOI: 10.1016/j.arr.2023.101962

Abstract

Cerebral small vessel disease (CSVD) is the leading cause of vascular cognitive impairment and is associated with COVID-19. However, contributing factors that often accompany CSVD pathology in COVID-19 patients may influence the incidence of cerebrovascular complications. Thus, a mechanism linking COVID-19 and CSVD has yet to be uncovered and differentiated from age-related comorbidities (i.e., hypertension), and medical interventions during acute infection. We aimed to evaluate CSVD in acute and recovered COVID-19 patients and to differentiate COVID-19-related cerebrovascular pathology from the above-mentioned contributing factors by assessing the localization of microbleeds and ischemic lesions/infarctions in the cerebrum, cerebellum, and brainstem. A systematic search was performed in December 2022 on PubMed, Web of Science, and Embase using a pre-established search criterion related to history of, or active COVID-19 with CSVD pathology in adults. From a pool of 161 studies, 59 met eligibility criteria and were included. Microbleeds and ischemic lesions had a strong predilection for the corpus callosum and subcortical/deep white matter in COVID-19 patients, suggesting a distinct CSVD pathology. These findings have important implications for clinical practice and biomedical research as COVID-19 may independently, and through exacerbation of age-related mechanisms, contribute to increased incidence of CSVD.

Keywords: Aging; COVID-19; Cerebral small vessel disease; Cognitive impairment.

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Conflict of interest statement

Declaration of Competing Interest None.

Figures

**Fig. 1**
*PRISMA flow diagram of study identification and screening.* “Other” reasons for exclusion include neuropathology not related to CSVD, reports of patients without COVID-19 diagnosis, reader response publications, abstract with no imaging for MRI or histopathologic results.

**Fig. 2**
*Neuroanatomical areas of CSVD pathology in COVID patients.* (A) Number of studies that report cerebral, cerebellar, and brainstem locations of small vessel ischemic lesions/infarctions in COVID-19 patients. White bars indicate the three most common areas of insult per study (Subcortical/deep WM, Periventricular WM, Corpus callosum). (B) Number of studies that report cerebral, cerebellar, and brainstem locations of microbleeds in COVID-19 patients. Red bars indicate the three most common areas of insult per study (Corpus callosum, Subcortical/deep WM, Juxtacortical WM). Abbreviations: White matter (WM), Microbleeds (MB).

**Fig. 3**
*COVID-19 exacerbation of age-related mechanisms contributing to cognitive impairment.* The diagram outlines COVID-19 (red arrows) and aging (black arrows) independent effects on cerebromicrovascular function and COVID-19 exacerbation (large red arrows) on age-related cerebromicrovascular dysfunction and cognitive impairment. We hypothesize that the effect of COVID-19 on cognition is through exacerbation of age-related pathophysiological elevations in inflammation and reactive oxygen species, resulting in cerebromicrovascular dysfunction and contributing to CSVD pathology, concluding with impaired NVC and cognitive impairment.

See this image and copyright information in PMC

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Cerebral small vessel disease pathology in COVID-19 patients: A systematic review

Affiliations

Cerebral small vessel disease pathology in COVID-19 patients: A systematic review

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

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