Molecular and Cellular Mechanisms Underlying Neurological and Neuropsychological Manifestations of COVID-19

Samaneh Ghorbani Shirkouhi; Seyed Sepehr Khatami; Zohair Niroomand; Saeed Sadigh-Eteghad; Shahrokh Yousefzadeh-Chabok; Sasan Andalib

Molecular and Cellular Mechanisms Underlying Neurological and Neuropsychological Manifestations of COVID-19

Innov Clin Neurosci. 2025 Dec 1;22(10-12):14-23. eCollection 2025 Oct-Dec.

Authors

Samaneh Ghorbani Shirkouhi¹, Seyed Sepehr Khatami², Zohair Niroomand³, Saeed Sadigh-Eteghad⁴, Shahrokh Yousefzadeh-Chabok⁵, Sasan Andalib⁶

Affiliations

¹ Ms. Ghorbani Shirkouhi is with the School of Medicine at Shahroud University of Medical Sciences in Shahroud, Iran.
² Dr. Khatami is with the Department of Neurology at the University of California, Irvine in Irvine, California.
³ Dr. Niroomand is with the Department of Neuroradiology at University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University in Mannheim, Germany.
⁴ Dr. Sadigh-Eteghad is with Neurosciences Research Center (NSRC) at the Tabriz University of Medical Sciences in Tabriz, Iran.
⁵ Dr. Yousefzadeh-Chabok is with the Neuroscience Research Center and the Guilan Road Trauma Research Center, Trauma institute, Poursina Hospital at the Guilan University of Medical Sciences in Rasht, Iran.
⁶ Dr. Andalib is with the Research Unit of Neurology, Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark in Odense, Denmark; the Department of Neurology at Odense University Hospital in Odense, Denmark; and the Neuroscience Research Center, Trauma Institute, Guilan University of Medical Sciences in Rasht, Iran.

PMID: 41647062
PMCID: PMC12872055

Abstract

Objective: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with a wide range of neurological symptoms and neuropsychiatric conditions. SARS-CoV-2 shows various degrees of neurotropism. SARS-CoV-2 primarily targets respiratory and gastrointestinal tracts; however, it can affect other organs. Neurological and neuropsychological manifestations of COVID-19 have been reported. Several mechanisms are involved in these manifestations in COVID-19. Therefore, the present narrative review will take account of mechanisms underlying the neurological and neuropsychological manifestations in COVID-19.

Methods: A literature search for relevant articles in different databases was made with a focus on recent publications for this narrative review.

Results: Inflammation and thrombosis have been suggested to be mechanisms contributing to these manifestations. Also, renin-angiotensin system (RAS), transmembrane serine protease 2 (TMPRSS2), cathepsin B and L, furin, neuropilin-1 (NRP1), and sterile alpha motif and HD domain-containing protein 1 (SAMHD1) have been proposed to be involved in pathogenesis of SARS-CoV-2. Moreover, cluster of differentiation 147 (CD147) and dipeptidyl peptidase 4 (DPP4) have been suggested to have a role in SARS-CoV-2 entry into the central nervous system (CNS).

Conclusion: Further investigation on the underlying mechanisms leading to SARS-CoV-2-associated neurological and neuropsychological manifestations is pivotal. Insights into these mechanisms will help the treatment strategies for patients with COVID-19 and such manifestations.

Keywords: COVID-19, SARS-CoV-2; cellular mechanisms; molecular mechanisms; neurological manifestations; neuropsychological manifestations.

Publication types

Review