Innov Clin Neurosci. 2025;22(10–12):14–23.

by Samaneh Ghorbani Shirkouhi, MSc; Seyed Sepehr Khatami, MD; Zohair Niroomand, MD;
Saeed Sadigh-Eteghad, PhD; Shahrokh Yousefzadeh-Chabok, MD; and Sasan Andalib, PhD

Ms. Ghorbani Shirkouhi is with the School of Medicine at Shahroud University of Medical Sciences in Shahroud, Iran. Dr. Khatami is with the Department of Neurology at the University of California, Irvine in Irvine, California. Dr. Niroomand is with the Department of Neuroradiology at University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University in Mannheim, Germany. Dr. Sadigh-Eteghad is with Neurosciences Research Center (NSRC) at the Tabriz University of Medical Sciences in Tabriz, Iran. 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. 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.

FUNDING: No funding was provided for this article.

DISCLOSURES: The authors have no conflicts of interest to report regarding the content of this manuscript.

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, neurological manifestations, neuropsychological manifestations, molecular mechanisms, cellular mechanisms

Introduction

At the end of 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused coronavirus disease 2019 (COVID-19),¹ which turned into a pandemic in March 2020.² The crown-like structure of the viral spike glycoproteins is the basis for naming coronaviruses. At least 27 proteins including 15 nonstructural, four structural, and eight auxiliary proteins are produced by SARS-CoV-2.³ The four structural proteins include E (envelope), M (membrane), N (nucleocapsid), and S (spike) proteins. The SARS-CoV-2 envelope is formed by the E, M, and S proteins, while the viral ribonucleic acid (RNA) genome is held by the N protein. These proteins exert important roles in the virus’s structure and function, helping the virus to infect host cells and replicate.

The S glycoprotein in SARS-CoV-2 has two subunits, which are critical for endocytosis, including an attachment subunit (S1) and a fusion subunit (S2). The S1 subunit consists of an N-terminal domain (NTD), involved in sugar bindings, and a C-terminal domain (CTD), recognizing angiotensin-converting enzyme 2 (ACE2).⁴ The S glycoprotein of SARS-CoV-2 binds to ACE2 receptors on host cells. This leads to endocytosis of the SARS-CoV-2 to the host cells. The S protein is initially primed by transmembrane protease serine 2 (TMPRSS2) of the host cell. Using ACE2, the protein neuropilin-1 (NRP1)⁵ and basigin⁶ of the host cell might also help with the endocytosis of the virion. TMPRSS2 cleaves the S glycoprotein, exposing the fusion peptide in the S2 subunit, which then interacts with ACE2.⁷ ACE2 recognizes S1 and aids viral binding, and S2 causes membrane fusion and internalization. The S glycoprotein might also be primed by endosomal serine proteases, cathepsin B and L (CatB/L), and furin (Figure 1). Following endocytosis, SARS-CoV-2 RNA is amplified in the cell.⁸

The high presence of ACE2 in the respiratory system, namely, Type I and Type II alveolar epithelial, bronchiolar epithelial, arterial smooth muscle, and endothelial cells of the lung, can justify the respiratory involvement of COVID-19. ACE2 is also expressed in the oral mucosa, especially the tongue’s epithelial cells.⁹ ACE2 is also present in the gastrointestinal tract and endothelial cells, as well as in the neurons and glial cells of the nervous system. On the other hand, the fact that ACE2 receptors have a low affinity to its natural ligand provides an advantage for the virus.¹⁰ The affinity of ACE2 receptors to the viral S glycoprotein suggests that ACE2 receptors in the endothelial cells and myocytes increase risk and mortality during the SARS-CoV-2 systemic transmission to vital organs, such as the heart and kidneys.^11,12

SARS-CoV-2 primarily targets respiratory and gastrointestinal tracts; however, its influence is not limited to these organs, and others can also be involved. COVID-19 has neurological and neuropsychological manifestations. Whereas there is a flurry of publications detailing these clinical manifestations of COVID-19, the pathophysiology of the effect of SARS-CoV-2 on the nervous system is a less well-understood topic. The present narrative review discusses the molecular and cellular mechanisms underlying the neurological and neuropsychological manifestations of COVID-19.

Tropism of SARS-COV-2 to the nervous system

Viral transcellular migration occurs when the virus invades the host cells or macrophages to overcome the blood-brain barrier (BBB). This process allows the virus to spread within the central nervous system (CNS). Axonal transport, on the other hand, is achieved when the virus is adhered to proteins of peripheral or cranial nerves, allowing retrograde neuronal transport. This enables the virus to travel along the nerve fibers back to the CNS and facilitates the virus’s spread within the brain.

Axonal transport of SARS-CoV-2 can occur via the cribriform plate, located adjacent to the olfactory bulb, into the brain. The loss of smell (anosmia) can be an early symptom of COVID-19¹³ and supports this route of transmission.

SARS-CoV-2 can also infect the brain by migrating from the general circulation to the cerebral microcirculation via endothelial cells, which express ACE2.¹⁴

Brain renin-angiotensin system

The renin-angiotensin system (RAS) is a critical component of the CNS and plays an important role in various physiological processes. RAS can regulate blood pressure by balancing fluid and electrolyte levels and vascular resistance and tone. RAS includes angiotensinogen, renin, angiotensin I (Ang I), angiotensin II (Ang II), ACE, ACE2, angiotensin type-1 receptor (AT₁R), angiotensin type-2 receptor (AT₂R), and Mas receptor (MAS). Ang II’s interaction with its receptors explains Ang II physiological effect. The brain is very responsive to Ang II, a vasoconstrictive molecule that increases blood pressure. Endocrine Ang II targets the brain regions outside the BBB, such as the circumventricular organs. Ang II receptors are present in the organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO), and supraoptic nucleus, among circumventricular organs.¹⁵ Not only are most of these regions involved in the regulation of fluid and electrolyte homeostasis, but they also have connections with higher brain centers and nuclei regulating blood pressure.¹⁶

In addition to the well-known systemic RAS, local or tissue RAS has been demonstrated in many tissues, such as nervous tissues. The brain RAS operates independently of the systemic RAS. Brain RAS has a special feature because the BBB prevents diffusion of Ang II from the blood into the brain. Ang II receptors are present in the paraventricular nucleus (PVN), rostral ventrolateral medulla (RVLM), amygdala, and nucleus tractus solitarius (NTS), indicating involvement of Ang II in the baroreflex and sympathetic outflow.¹⁶ The role of brain RAS in the regulation of resting metabolism and energy expenditure is shown by the localization of the AT₁R receptors on a subset of arcuate nucleus (ARC) neurons positive for agouti-related peptide.¹⁷ In the brain, the physiological output of Ang II pertains to the type of Ang II receptor and the cell expressing the receptor.¹⁶ Angiotensinogen and renin are simultaneously expressed in many brain areas.¹⁸ Angiotensinogen is mainly expressed in astrocytes.^19,20 ACE2 is expressed in neurons, astrocytes, and oligodendrocytes.²¹ ACE2 is also present in the olfactory bulb, substantia nigra, ventricles, the posterior cingulate cortex, and the middle temporal gyrus.²¹ While 1 to 4 percent of neurons can express AT₁R and AT₂R, different populations of neurons can express either of them.¹⁶ AT₁R is present in the SFO, PVN, OVLT, NTS, median preoptic nucleus (MnPO), and area postrema (AP), which contribute to cardiovascular function, fluid balance, and metabolism.¹⁶ In the OVLT, SFO, PVN, and ARC, the relative content of AT₁R-positive neurons predominates; nevertheless, in the AP and NTS, AT₂R-positive neurons are more prevalent.¹⁶

RAS includes classical (ACE-Ang II-AT₁R) and alternative [ACE2-Ang (1-7)-Mas] axes. Renin cleaves angiotensinogen to Ang I in the classical axis. After hydrolyzation by ACE, Ang I is converted to Ang II, which can simulate AT₁R and AT₂R. Ang II shows a higher affinity to AT₁R with which Ang II²² mediates oxidative stress, vasoconstriction, neuroinflammation, apoptosis, and cellular proliferation.²³ In the alternative axis, however, ACE2 cleaves Ang II to angiotensin (1–7), which binds to the Mas. This can lead to antioxidant, angiogenesis, vasodilation, anti-inflammatory, and anti-apoptotic responses.²³

SARS-CoV-2’s Effect on Brain RAS

SARS-CoV-2 binds to ACE2 with the facilitation of TMPRSS2 and CatB/L and enters the cell. TMPRSS2 helps in priming the spike protein of the virus, enabling it to fuse with the host cell membrane, and CatB/L helps in the endosomal entry. Cathepsins are a class of acid-activated cysteine proteases located within endosomes and lysosomes.²⁴ ACE2 is co-expressed with TMPRSS2 and CatB/L in specific organs, including the brain.^24,25 The olfactory epithelium expresses ACE2 and CatL.²⁵ CatL cleaves the SARS-CoV-2 S protein onto S1 and S2 subunits by proteolysis and strengthens viral entry via activation of cell-cell fusion.^26,27 The virion’s ability to enter the cell is approximately 10 to 20 times as high as that of SARS-COV-1.²⁸ There are antigenic drift variations in the S glycoprotein of the virus that likely heighten S glycoprotein’s affinity to ACE2.²⁹ Variants of SARS-CoV-2 with the 614G mutation are correlated with infectivity and fatality rates,^30,31 regardless of declined affinity for ACE2 owing to faster dissociation rates.³² The higher affinity of the S1 subunit for ACE2 in SARS-CoV-2 can justify the greater virulence of SARS-COV-2, compared to SARS-COV-1.²⁸ SARS-CoV-2 downregulates ACE2³³ and underactivates the RAS alternative pathway in the nervous system.³⁴ This can also overactivate the classical RAS pathway. Such imbalance of RAS classic and alternative pathways can cause oxidative stress, neuroinflammation, vasodilation, and thrombotic events.³⁴ Figure 1 shows the process of SARS-CoV-2’s endocytosis and its effect on the RAS.

Furin Cleavage site in the spike protein, a reason for high infectivity of SARS-CoV-2

Furin, a member of the proprotein convertases family, is a highly expressed calcium-dependent serine protease in the lungs.³⁵ Proprotein convertases activate various precursor proteins, such as hormones, receptors, growth factors, adhesion molecules, and viral surface glycoproteins.³⁶ Moreover, furin is involved in the brain-derived neurotrophic factor (BDNF) formation by cleaving proBDNF³⁷ and in the upregulation of BDNF in reactive astrocytes that are exposed to oxygen-glucose deprivation.³⁸ Recently, the furin-like cleavage site of coronavirus has been implicated as an important determinant of its neurotropism.³⁹ A specific furin cleavage sites basic residues motif, namely RRAR, can be carried by the SARS‐CoV‐2 S protein,⁴⁰ which is efficiently cleaved by various proteases, including furin, compared to the other coronaviruses.^41,42 The RRAR motif is located at the junction between the S1 and S2 subunits^42,43 and is involved in high contagiousness and increased infectivity of SARS-CoV‐2 compared to other coronaviruses.⁴⁴

CD147 as a different route for SARS-CoV-2 infection

Cluster of differentiation 147 (CD147), also called basigin, is a transmembrane glycoprotein of the immunoglobulin superfamily.⁴⁵ CD147 is expressed in the amygdala, hypothalamus, mitral cells in the olfactory bulb, Purkinje cells in the cerebellum, thalamus, and retina.⁴⁶ CD147 has been proposed as a possible route by which SARS-CoV-2 invades certain host cells.⁶ The CD147 C-terminal domain can interact with the external subdomain of the SARS-CoV-2 spike.⁴⁷ Wang et al⁶ showed that SARS-CoV-2 amplification could be inhibited by blocking CD147 in the Vero E6 and BEAS-2B cell lines with an anti-CD147 antibody called meplazumab. Furthermore, immunofluorescence does not show colocalization of CD147 and ACE2 in the lung tissue of patients with COVID-19.⁶ The expression of CD147 and ACE2 is completely independent in lung cells, suggesting they might be two complementary receptors in mediating the viral infection.⁶

DPP4 (CD26), an important route for astrocyte infection

Serine exopeptidases such as dipeptidyl peptidase 4 (DPP4), also called CD26, are expressed in various tissues.⁴⁸ A strong tropism of the SARS-CoV-2 to astrocytes mediating by DPP4 has been observed.⁴⁹ Astrocytes have various important functions in both the developing brain and adult brain; they regulate the concentration of neurotransmitters and mediate the function of the BBB. Moreover, astrocytes regulate neural metabolism and inflammation.⁵⁰ Human brain cortical cells, including astrocytes, which can be infected by SARS-CoV-2, contain high levels of DPP4.⁴⁹ Human DPP4 might interact with the S1 domain of SARS-CoV-2.⁵¹ Inhibition of DPP4 leads to a reduction in SARS-CoV-2 infection, suggesting that DPP4 plays a role in the entry of the virus into cortical astrocytes.⁴⁹

The Role of Neuropilin-1 in the pathogenesis of SARS-CoV-2

Neuropilins are transmembrane glycoproteins that influence the nervous system development.⁵² The neuropilin family consists of two members, NRP1 and NRP2. NRP1 is highly expressed in the respiratory and olfactory epithelium⁵ and throughout the brain, particularly in the hippocampal formation.⁵³ NRP1 is expressed in endothelial cells, macrophages, neurons, fetal astrocytes, and oligodendrocytes, with the highest level in mature astrocytes.⁵³ NRP1 is involved in the pathogenesis of COVID-19 and increases the entry of SARS-CoV-2 into the CNS.⁵ The attachment of NRP1 and the subsequent conformational change of the S protein initiates SARS-CoV-2 entrance into the host cells. The S1 subunit conforms to the C-end-rule (CendR) and binds to an NRP1 or NRP2 in the target cell.⁵⁴

Possible Role of SAMHD1 in Neurological manifestations associated with COVID-19

Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) acts as an immunomodulator for various viral infections, which is speculated to be associated with cerebral vasculopathy and early onset stroke.⁵⁵ SAMHD1 interacts with the nuclear factor kappa-light-chain-enhancer of activated B cells 1/2 (NF-κB1/2) and decreases phosphorylation of the NF-κB inhibitory protein nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα). This process leads to the inhibition of NF-κB activation.⁵⁶ The association between SAMHD1 and NF-κB signaling pathways in the pathogenesis and neurological complications of COVID-19 has been eluciated.⁵⁷ SAMHD1 controls the innate immune response and is upregulated in response to viral infection and might be involved in the mediating of tumor necrosis factor-alpha (TNF-α) proinflammatory responses⁵⁷ which are involved in neurological symptoms of COVID-19.⁵⁸

The Role of Inflammation in Neurological and Neuropsychological Manifestations associated with COVID-19

Cytokines such as interleukin 1 beta (IL1β), interferon-gamma (IFNγ), IFNγ-induced protein 10 (IP10), and monocyte chemoattractant protein-1 (MCP-1) are considerably elevated in COVID-19.⁵⁹ COVID-19 can promote a cytokine storm,⁶⁰ which is an excessive immune response characterized by releasing inflammatory factors, including interferons, interleukins, tumor necrosis factors, chemokines, and several other mediators.⁶¹

The Role of Thrombosis in neurological manifestations associated with COVID-19

Thromboembolic complications have been observed in patients with COVID-19.^62,63 The brain can be affected by COVID-19-associated coagulopathy.⁶⁴ The thrombotic events that occur in patients with COVID-19 include pulmonary embolism, deep vein thrombosis, and bleeding.^65,66 COVID-19-associated coagulopathy might be an outcome of the host’s inflammatory response to SARS-CoV-2 and activation of innate immune system.⁶⁷ In addition, an association between increased IL-6 and elevated fibrinogen at the time of intensive care unit admission of patients with COVID-19 has been demonstrated.^68,69

Neurological and Neuropsychological manifestations associated with COVID-19 and their possible mechanisms

CNS manifestations. Headache. Headache is one of the most common neurological symptoms in patients with COVID-19.^70,71 The frontotemporal region is the most common location of pain.⁷⁰ One possible mechanism for headache following COVID-19 is a direct invasion of SARS‐CoV‐2 to trigeminal nerve endings in the nasal cavity.⁷² A possible indirect mechanism is that pro-inflammatory mediators and cytokine release might stimulate perivascular trigeminal nerve endings during the SARS‐CoV‐2 infection.⁷²

Impaired consciousness. Impaired consciousness has been reported following COVID-19,⁷³ probably due to hypoxemia, dehydration, inflammatory systematic response, encephalitis with inflammatory parenchymal lesion, and high cerebrospinal fluid (CSF) white blood cell count.^73,74

Agitation and delirium. Agitation and delirium have been reported in patients with COVID-19.^75,76 The mechanism of delirium in patients with COVID-19 include direct CNS invasion, induction of CNS inflammatory mediators, the secondary effect of other organ system failure, the effect of sedative strategies, prolonged mechanical ventilation time, immobilization, and social isolation.⁷⁷

Seizures. Seizures have been reported in association with COVID-19.^78–80 Seizures in patients with COVID-19 can be triggered after strokes, increased oxidative stress, electrolyte imbalance, and mitochondrial dysfunction.⁸¹

Hypogeusia, dysgeusia, hyposmia, and anosmia. Hypogeusia, dysgeusia, hyposmia, and anosmia are common neurological symptoms of COVID-19.⁸² Possible underlying mechanisms include tissue damage, immune cell infiltration or systemic circulation of cytokines causing inflammatory responses, and downregulation of odorant receptor genes in olfactory sensory neurons.⁸³

Myoclonus and ataxia. Myoclonus has been reported in some patients with COVID-19.^84,85 In a case report and systematic review by Chan et al,⁸⁶ 51 cases of myoclonus or ataxia following COVID-19 were identified. The authors concluded that an immune-mediated mechanism might play a role in the occurrence of myoclonus and ataxia in patients with COVID-19.

Stroke. The risk of an ischemic stroke is increased in patients with COVID-19.^87,88 Ischemic stroke can be triggered by cytokine storm after COVID-19.­⁸⁹ The massive release of cytokines also causes damage and breakdown of the BBB and can lead to hemorrhagic posterior reversible encephalopathy syndrome.⁹⁰

Cerebral venous sinus thrombosis (CVST),⁹¹ intracerebral hemorrhage,⁹² and subarachnoid hemorrhage⁹³ have been reported after COVID-19. CVST is a complex venous thromboembolic event with a variety of clinical presentations and multiple potential complications, such as stroke and visual deficits. The risk of CVST has increased during the COVID-19 pandemic.⁹⁴ Baldini et al⁹⁵ described in a systematic review and meta-analysis that CVST can occur within 1 to 8 weeks after the onset of the respiratory or systemic symptoms of COVID-19. A possible mechanism is that COVID-19 promotes a prothrombotic state and thrombotic events, leading to prothrombotic pathophysiology.⁹⁶

Acute transverse myelitis. Several cases of acute transverse myelitis (ATM) have been reported following COVID-19.^97–99 Several potential mechanisms might contribute to ATM following COVID-19, characterized by the presence of neuroinflammation in both gray and white matter in one or more consecutive segments of the spinal cord, in the absence of a compressive injury. This includes direct invasion of the spinal cord, cytokine storms, or immune responses.¹⁰⁰

Encephalitis. Encephalitis is an inflammation of the brain due to infection or autoimmunity.¹⁰¹ Patients commonly present with seizures, fever, new onset of focal neurologic findings, and altered mental status.¹⁰² There are reports of COVID-19 coinciding with encephalitis.^103,104 Recently, it has been suggested that encephalitis after COVID-19 might be due to anti-N-methyl-D-aspartate (NMDA) receptor antibodies, which lead to functional disruption of glutamatergic signaling in the CNS.¹⁰⁵ Immunologic responses in the brain following COVID-19, through an impact on the glial system, can cause neuroinflammation and thus encephalitis.^106,107

Meningoencephalitis. Meningoencephalitis is the inflammation of the meninges and the brain.¹⁰⁸ Symptoms include neck stiffness, fever, a change in mental status, and headache, presumably due to inflammation of the meninges.¹⁰⁹ Moriguchi et al¹¹⁰ reported the first case of meningoencephalitis associated with SARS-CoV-2. In this study, the virus was detected in the CSF of the patient with COVID-19 and meningoencephalitis. There are several possible reasons to explain this phenomenon in patients with COVID-19, including increased levels of pro-inflammatory cytokine IL-6, ferritin, and high protein levels in CSF without pleocytosis.¹¹¹

Hypoxic-ischemic encephalopathy. Hypoxic-ischemic encephalopathy (HIE) is a severe complication of the CNS. The disease results from acute respiratory distress syndrome, which can occur during SARS-CoV-2 infection.¹¹² Some cases of HIE have been reported following COVID-19.¹¹³ The inflammatory response to the virus, which leads to hypoxic and metabolic disturbances, can trigger a cytokine storm and develop acute respiratory distress syndrome and subsequently HIE.¹¹²

Acute necrotizing encephalopathy. Acute necrotizing encephalopathy (ANE) is a neurological deterioration that occurs following a viral infection, including SARS-CoV-2.¹¹⁴ ANE has been reported in association with COVID-19.¹¹⁵ Potential underlying mechanisms include direct viral invasion and autoimmune response.¹¹⁶

Posterior reversible encephalopathy syndrome. Posterior reversible encephalopathy syndrome (PRES) is a disorder of brain edema. It leads to severe neurological symptoms including seizures, encephalopathy, headache, and visual disturbances.¹¹⁷ Some of the risk factors for PRES include renal failure, blood pressure fluctuations, cytotoxic drugs, autoimmune disorders, and pre-eclampsia or eclampsia.¹¹⁷ The occurrence of PRES in patients with COVID-19 has been reported.¹¹⁸ The potential mechanism includes COVID-19-mediated cytokine storm syndrome, which might lead to endothelial damage and elevated permeability of the cerebral vessels, thereby causing edema of PRES.¹¹⁹

Acute disseminated encephalomyelitis. Acute disseminated encephalomyelitis or acute demyelinating encephalomyelitis (ADEM) is an acute inflammatory autoimmune disorder that affects the CNS.¹²⁰ Several studies have reported ADEM following COVID-19.^121,122 One of the potential mechanisms of ADEM following COVID-19 is cytokine storm syndrome.¹²³ Another possible mechanism is the molecular mimicry of SARS-CoV-2. The virus and human proteins have analogous peptide sequences. This similarity directs the immune response toward human proteins¹²⁴ that might lead to autoimmune and inflammatory conditions, including ADEM.¹²⁵

Parkinson’s disease. COVID-19 might influence several chronic neurological conditions, including Parkinson’s disease (PD).¹²⁶ As the brainstem is a target of SARS-CoV-2, patients with PD who develop COVID-19 might be vulnerable to developing respiratory failure.¹²⁶ Some cases of parkinsonism have been reported after COVID-19.^127,128 Cohen et al¹²⁷ reported a 45-year-old male patient with probable PD who was diagnosed after developing COVID-19. Moreover, Faber et al¹²⁸ reported a 35-year-old female patient who developed symptoms of PD 10 days after recovering from COVID-19. An assumption is that the virus triggers inflammation by microglial activation, leading to protein aggregation and neurodegeneration.¹²⁹ PD is often accompanied by anosmia, which is a common feature of COVID-19. Immune system activation in the olfactory system following COVID-19 might ultimately lead to misfolding of alpha-synuclein and the development of PD.^130,131 Additionally, cytokine storm in COVID-19 might exacerbate PD symptoms.¹³²

Alzheimer’s disease. Alzheimer’s disease (AD) is one of the most common comorbidities with COVID-19.¹³³ Lim et al¹³⁴ stated that elevated ACE2 expression in patients with AD could be a risk factor for COVID-19 transmission. The overproduction of ACE2 in the brains of patients with AD might support SARS-CoV-2 invasion into the CNS and viral transmission.¹³⁵ In AD neuroinflammation, microglial-derived cytokines such as TNF-α, IL-1, and IL-6 are elevated.¹³⁶ Neuroinflammation in patients with AD might accelerate the accumulation of pro-inflammatory cytokines after COVID-19, worsen the immune response, and increase COVID-19 mortality.¹³⁵ Moreover, the relationship between COVID-19 and brain microvascular injury and neuroinflammation pathways implicated in AD has been demonstrated.¹³⁷

Amyotrophic lateral sclerosis. COVID-19 can result in the development of amyotrophic lateral sclerosis (ALS),¹³⁸ a neurodegenerative disorder in which the peripheral nervous system (PNS) and CNS are affected in different ways. ACE2, which is essential for SARS-CoV-2 invasion into the CNS, can be expressed in the motor cortex and influenced by SARS-CoV-2 in the cytoplasm of neurons in cerebral regions implicated in ALS pathogenesis. In addition, protein misfolding caused by SARS-CoV-2-induced oxidative stress and binding of the S protein of SARS-CoV-2 to heparin-binding proteins can lead to transactive response DNA binding protein of 43kDa (TDP-43) aggregation, a hallmark of ALS and neural damage.^139,140

Multiple sclerosis. The occurrence of multiple sclerosis (MS) has been reported following COVID-19.¹⁴¹ IL-17 receptor A (IL17RA) physically interacts with SARS-CoV-2 Orf8 protein,¹⁴² which is one of the nine accessory proteins encoded by SARS-CoV-2 that interferes with host immune response.¹⁴³ Possible mechanisms of MS associated with COVID-19 are molecular mimicry between SARS-CoV-2 proteins and autoantigens and delayed activation autoimmunity after the viral infection.^144,145

Depression. In patients with COVID-19, most symptoms of depression are visible during the disease and after a partial recovery.¹⁴⁶ Elevated and abnormal levels of blood cortisol in the hypothalamic-pituitary axis have a role in depression after COVID-19.¹⁴⁷ Uncontrolled activation of microglia releases inflammatory cytokines (TNF-α, IL-6, IL-1B), nitric oxide (NO), prostaglandin E2, and free radicals in the brain after entry of SARS-CoV-2 into the CNS.¹⁴⁷ It has been suggested that depression is mediated by inflammatory responses and cytokines.¹⁴⁷ Furthermore, mitochondrial dysfunction can be a possible mechanism of COVID-19-induced depression.¹⁴⁸ COVID-19 damages the mitochondria either directly by hijacking the organelle for transcription of the virus genome¹⁴⁹ or indirectly by increasing pro-inflammatory cytokines and reactive oxygen species (ROS) production.^150,151

Obsessive-compulsive disorder. Obsessive-compulsive disorder (OCD) has been reported in patients with COVID-19.^{152, 153} Increased pro-inflammatory conditions might be associated with the development of OCD symptoms in COVID-19 patients.¹⁵³

Schizophrenia. Patients with schizophrenia have been found to have low levels of vitamin D.¹⁵⁴ Moreover, the association between vitamin D deficiency and the risk of COVID-19 has been demonstrated.¹⁵⁵ Patients with schizophrenia and vitamin D deficiency are more vulnerable to COVID-19 because vitamin D plays a critical role in the immune system and therefore its deficiency leads to a pro-inflammatory state.¹⁵⁴ Baranova et al¹⁵⁶ showed that severe COVID-19 is associated with an 11-percent increased risk for schizophrenia using a two-sample Mendelian randomization analysis. Also, the authors showed COVID-19 might not increase the risk for schizophrenia.

PNS manifestations. Guillain-Barré syndrome. Guillain-Barré syndrome (GBS) is an autoimmune disorder of the PNS that often occurs after respiratory or gastrointestinal infections from viruses or bacteria.¹⁵⁷ The two most common types of GBS are acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN), in which immunological processes target the myelin or the axons, respectively.¹⁵⁸ GBS has been reported following COVID-19.^159,160 Given that many cytokines are involved in typical GBS pathogenesis, the cytokine storm in COVID-19 could play a critical role in the progression of GBS.¹⁶¹ The occurrence of GBS could be related to the disruption of microvascular function during SARS‐CoV‐2 infection.¹⁶¹ The findings of Lucchese et al¹⁶² showed that there is a molecular mimicry between SARS‐CoV‐2 and human heat shock proteins 90 and 60, which are associated
with GBS.

Miller-Fisher syndrome. Miller-Fisher syndrome (MFS) is a rare variant of GBS that usually presents with ataxia, areflexia, and ophthalmoplegia.¹⁶³ MFS has been reported in patients with COVID-19.^164,165 The pathogenesis of MFS following SARS-CoV-2 infection might be mediated by neurotropism or autoimmune process.¹⁶⁵ Neurotropism is a phenomenon where a specific infection, such as a viral infection, naturally prefers brain tissues.¹⁶⁶

Myasthenia gravis. Myasthenia gravis (MG) has been reported after SARS-CoV-2 infection.¹⁶⁷ A cross-reaction between antibodies targeted at SARS-CoV-2 proteins and nicotinic acetylcholine receptors (AchR) at the neuromuscular junction can result in MG.¹⁶⁷ Virus epitopes resemble components within neuromuscular junctions, which explains this characteristic.¹⁶⁷ In addition, about five to eight percent of MG cases are associated with antibodies against muscle-specific kinase (MuSK).¹⁶⁸ MuSK antibody MG (MuSK-MG) is characterized by different mechanisms from AChR antibody MG (AChR-MG). MuSK-associated MG caused by SARS-CoV-2 is more likely a result of a breakdown in self-tolerance mechanisms than from cross-reactivation.¹⁶⁹

Bell’s palsy. Bell’s palsy following COVID-19 has been reported.¹⁷⁰ It might be a consequence of ACE2 receptor activation in the nervous system.¹⁷¹ SARS-CoV-2 binding to ACE2 receptors in the CNS results in the release of cytokines. SARS-CoV-2 entry into the CNS via mucosa or viremia can cause peripheral neuropathies in the facial nerve and olfactory nerve, which might lead to Bell’s palsy.^171,172 The other potential mechanisms include an inflammatory process that can induce ischemia of vasa nervorum¹⁷³ and demyelination.¹⁷⁴

Other neurological manifestations associated with COVID-19. Other neurological manifestations following SARS-CoV-2 infection include dizziness,¹⁷⁵ diplopia,¹⁷⁶ delayed post-hypoxic leukoencephalopathy,¹⁷⁷ Kawasaki-like disease,¹⁷⁸ neuroleptic malignant syndrome,¹⁷⁹ vision impairment, neuropathic pain, skeletal muscle injury,⁷⁴ myalgia,⁵⁹ myopathy,¹⁸⁰ myositis,¹⁸¹ multiple cranial neuropathies,¹⁸² sensorineural hearing loss,¹⁸³ cranial nerve palsies,^184,185 and neuro-ophthalmic complications, such as optic neuritis¹⁸⁶ and ophthalmoplegia.¹⁸⁷

Conclusion

Several neurological and neuropsychiatric conditions have been reported in patients with COVID-19. It is assumed that SARS-CoV-2 might induce neurological and neuropsychological symptoms directly or indirectly. Several mechanisms have been proposed for neurological and neuropsychological manifestations of COVID-19. Inflammation and thrombosis contribute to these manifestations. The roles of RAS, TMPRSS2, CatB/L, Furin, NRP1, and SAMHD1 in the pathogenesis of SARS-CoV-2 have been underscored. Additionally, evidence suggests potential routes for SARS-CoV-2 entry into the CNS, such as CD147 and DPP4. Therefore, it is crucial to further investigate underlying mechanisms leading to SARS-CoV-2-associated neurological and neuropsychological manifestations. Understanding these mechanisms will guide the treatment strategies of patients with COVID-19 with such manifestations.

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