Neurological diseases caused by coronavirus infection of the respiratory airways

Infections of the central nervous system (CNS) infections are critical problems for public health. They are caused by several different organisms, including the respiratory coronaviruses (CoVs). CoVs usually infect the upper respiratory tract causing the common cold. However, in infants, and in elderly and immunocompromised persons, they can also affect the lower respiratory tract causing pneumonia and various syndromes of respiratory distress. CoVs also have neuroinvasive capabilities because they can spread from the respiratory tract to the CNS. Once infection begins in the CNS cells, it can cause various CNS problems such as status epilepticus, encephalitis, and long‐term neurological disease. This neuroinvasive properties of CoVs may damage the CNS as a result of misdirected host immune response, which could be associated with autoimmunity in susceptible individuals (virus‐induced neuro‐immunopathology) or associated with viral replication directly causing damage to the CNS cells (virus‐induced neuropathology). In December 2019, a new disease named COVID‐19 emerged which is caused by CoVs. The significant clinical symptoms of COVID‐19 are related to the respiratory system, but they can also affect the CNS, causing acute cerebrovascular and intracranial infections. We describe the possible invasion routes of coronavirus in this review article, and look for the most recent findings associated with the neurological complications in the recently published literature.

Aged brain and neuroimmune responses to COVID-19: post-acute sequelae and modulatory effects of behavioral and nutritional interventions.

Advanced age is one of the significant risk determinants for coronavirus disease 2019 (COVID-19)-related mortality and for long COVID complications. The contributing factors may include the age-related dynamical remodeling of the immune system, known as immunosenescence and chronic low-grade systemic inflammation. Both of these factors may induce an inflammatory milieu in the aged brain and drive the changes in the microenvironment of neurons and microglia, which are characterized by a general condition of chronic inflammation, so-called neuroinflammation. Emerging evidence reveals that the immune privilege in the aging brain may be compromised. Resident brain cells, such as astrocytes, neurons, oligodendrocytes and microglia, but also infiltrating immune cells, such as monocytes, T cells and macrophages participate in the complex intercellular networks and multiple reciprocal interactions. Especially changes in microglia playing a regulatory role in inflammation, contribute to disturbing of the brain homeostasis and to impairments of the neuroimmune responses. Neuroinflammation may trigger structural damage, diminish regeneration, induce neuronal cell death, modulate synaptic remodeling and in this manner negatively interfere with the brain functions.In this review article, we give insights into neuroimmune interactions in the aged brain and highlight the impact of COVID-19 on the functional systems already modulated by immunosenescence and neuroinflammation. We discuss the potential ways of these interactions with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and review proposed neuroimmune mechanisms and biological factors that may contribute to the development of persisting long COVID conditions. We summarize the potential mechanisms responsible for long COVID, including inflammation, autoimmunity, direct virus-mediated cytotoxicity, hypercoagulation, mitochondrial failure, dysbiosis, and the reactivation of other persisting viruses, such as the Cytomegalovirus (CMV). Finally, we discuss the effects of various interventional options that can decrease the propagation of biological, physiological, and psychosocial stressors that are responsible for neuroimmune activation and which may inhibit the triggering of unbalanced inflammatory responses. We highlight the modulatory effects of bioactive nutritional compounds along with the multimodal benefits of behavioral interventions and moderate exercise, which can be applied as postinfectious interventions in order to improve brain health.

Correlation of covid-19 and Guillain-Barré syndrome: A Mechanistic Perspective.

Aims: Coronaviruses, SARS-CoV-2 particles are spherical and have proteins called spikes that stick out on the surface. COVID-19 most commonly affects the respiratory system, but various clinical manifestations on coronavirus have revealed their potential neurotropism. The neuroinvasive affinity of Coronavirus infections has been reported nearly for all the ß Coronavirus infections, including MERS-CoV, SARS-CoV, HCoV-OC43 and HEV. Coronavirus invasion occurs through hypoxia injury, immune injury, ACE2, and direct infection. The pathophysiology of SARS-CoV-2 and other human Coronaviruses reveals the possible mechanisms of neurodegeneration. Methods: A systematic literature review carried out from various search engines like Scopus, PubMed, Medline, and Elsevier for investigating the therapeutic perspective of association between Covid-19 and Guillain-Barré syndrome. Results: SARS-CoV-2 uses angiotensin-converting enzyme 2 as its entry receptor and enters the central nervous system through a Blood-brain barrier constituted of inflammatory mediators, direct infection of the endothelial cells, or endothelial injury. Guillain-Barré syndrome is an autoimmune disease that injures and attacks the nerves in the peripheral nervous system. Studies suggest that the virus can infect peripheral neurons to cause direct damage through various mechanisms, including direct damage by cytokine-related injury, ACE2 receptors, and the sequelae of hypoxia. Conclusion: we have discussed the possible mechanisms between neuroinvasion of SARs-cov2 and Guillain-barre syndrome.

COVID-19-Associated Schizophrenia-Like Psychosis

Background: COVID-19-associated psychoses are psychotic disorders that have developed during a new coronavirus infection. Criteria of these psychoses are the manifestation of psychosis simultaneously with infection with the SARS-CoV-2 virus and the presence of documented COVID-19 disease. Information about these diseases appears as brief reports of mental services or with rare clusters. The need to study COVID-19-associated psychoses is due to the relatively high risk of their development, reaching 2.8%. The aim of study was to analyse the identified cases of COVID-19-associated psychosis in comparison with the results presented in the scientific literature. Patients and methods: 50 cases of COVID-19-associated psychosis were analyzed using a clinical method, taking into account the results of physical examination from April 2020 to September 2021. Results: 27 women and 23 men aged 20 to 57 were examined. Common symptoms were revealed: simultaneously or immediately after infection and identification of the virus against the background of growing anxiety and dissomnia, delusional ideas were formed, which quickly turned into fantastic delusion with disturbing agitation and hallucinations and subsequent marked disorganization of behavior with possible confusion of consciousness at the peak of psychosis. Perceptual deceptions were the most common, auditory hallucinations were the most prevalent, and catatonia was relatively common. The cupping therapy led to reduction of psychotic symptoms, and returned patients to a pre-morbid level of functioning. In most cases, there was a critical resolution of the attack, which probably indicates a favorable outcome of the disorder. Such dynamics is consistent with scientific literature data. Conclusion: the question of the primary or secondary nature of COVID-19-associated psychoses remains unresolved. It is necessary to continue the study of COVID-19-associated psychosis with the identification of risk factors for the development of psychosis, manifestation features, psychopathological picture, outcome options to determine the optimal rehabilitation program © Бравве Л.В., Захарова Н.В., 2022

Neurological and Neuropsychiatric Impacts of COVID-19 Pandemic.

BACKGROUND: Albeit primarily a disease of respiratory tract, the 2019 coronavirus infectious disease (COVID-19) has been found to have causal association with a plethora of neurological, neuropsychiatric and psychological effects. This review aims to analyze them with a discussion of evolving therapeutic recommendations. METHODS: PubMed and Google Scholar were searched from 1 January 2020 to 30 May 2020 with the following key terms: "COVID-19", "SARS-CoV-2", "pandemic", "neuro-COVID", "stroke-COVID", "epilepsy-COVID", "COVID-encephalopathy", "SARS-CoV-2-encephalitis", "SARS-CoV-2-rhabdomyolysis", "COVID-demyelinating disease", "neurological manifestations", "psychosocial manifestations", "treatment recommendations", "COVID-19 and therapeutic changes", "psychiatry", "marginalised", "telemedicine", "mental health", "quarantine", "infodemic" and "social media". A few newspaper reports related to COVID-19 and psychosocial impacts have also been added as per context. RESULTS: Neurological and neuropsychiatric manifestations of COVID-19 are abundant. Clinical features of both central and peripheral nervous system involvement are evident. These have been categorically analyzed briefly with literature support. Most of the psychological effects are secondary to pandemic-associated regulatory, socioeconomic and psychosocial changes. CONCLUSION: Neurological and neuropsychiatric manifestations of this disease are only beginning to unravel. This demands a wide index of suspicion for prompt diagnosis of SARS-CoV-2 to prevent further complications and mortality.

Les impacts neurologiques et neuropsychiatriques d'une infection à la COVID-19. CONTEXTE: Bien qu'il s'agisse principalement d'une maladie des voies respiratoires, la maladie infectieuse à coronavirus apparue en 2019 (COVID-19) s'est avérée avoir un lien de causalité avec une pléthore d'impacts d'ordre neurologique, neuropsychiatrique et psychologique. Cette étude entend donc analyser ces impacts tout en discutant l'évolution des recommandations thérapeutiques se rapportant à cette maladie. MÉTHODES: Les bases de données PubMed et Google Scholar ont été interrogées entre les 1er janvier et 30 mai 2020. Les termes clés suivants ont été utilisés : « COVID-19 ¼, « SRAS ­ CoV-2 ¼, « Pandémie ¼, « Neuro ­ COVID ¼, « AVC ­ COVID ¼, « Épilepsie ­ COVID ¼, « COVID ­ encéphalopathie ¼, « SRAS ­ CoV-2 ­ encéphalite ¼, « SRAS ­ CoV-2 ­ rhabdomyolyse ¼, « COVID ­ maladie démyélinisante ¼, « Manifestations neurologiques ¼, « Manifestations psychosociales ¼, « Recommandations thérapeutiques ¼, « COVID-19 et changement thérapeutiques ¼, « Psychiatrie ¼, « Marginalisés ¼, « Télémédecine ¼, « Santé mentale ¼, « Quarantaine ¼, « Infodémique ¼ et « Médias sociaux ¼. De plus, quelques articles de journaux relatifs à la pandémie de COVID-19 et à ses impacts psychosociaux ont également été ajoutés en fonction du contexte. RÉSULTATS: Il appert que les manifestations neurologiques et neuropsychiatriques des infections à la COVID-19 sont nombreuses. Les caractéristiques cliniques d'une implication des systèmes nerveux central et périphérique sautent désormais aux yeux. Ces caractéristiques ont fait l'objet d'une brève analyse systématique à l'aide de publications scientifiques. En outre, la plupart des impacts d'ordre psychologique de cette pandémie se sont révélés moins apparents que les changements réglementaires, socioéconomiques et psychosociaux. CONCLUSION: Les manifestations neurologiques et neuropsychiatriques de cette maladie ne font que commencer à être élucidées. Cela exige donc une capacité accrue de vigilance en vue d'un diagnostic rapide, et ce, afin de prévenir des complications additionnelles et une mortalité accrue.

Repeated ethanol exposure and withdrawal alters angiotensin-converting enzyme 2 expression in discrete brain regions: Implications for SARS-CoV-2 neuroinvasion.

BACKGROUND: People with alcohol use disorder (AUD) may be at higher risk for COVID-19. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are required for cellular entry by SARS-CoV-2, but information on their expression in specific brain regions after alcohol exposure is limited. We sought to clarify how chronic alcohol exposure affects ACE2 expression in monoaminergic brainstem circuits and other putative SARS-CoV-2 entry points. METHODS: Brains were examined for ACE2 using immunofluorescence after 4 weeks of chronic intermittent ethanol (CIE) vapor inhalation. We also examined TMPRSS2, Cathepsin L, and ADAM17 by Western blot and RAS pathway mediators and pro-inflammatory markers via RT-qPCR. RESULTS: ACE2 was increased in most brain regions following CIE including the olfactory bulb (OB), hypothalamus (HT), raphe magnus (RMG), raphe obscurus (ROB), locus coeruleus (LC), and periaqueductal gray (PAG). We also observed increased colocalization of ACE2 with monoaminergic neurons in brainstem nuclei. Moreover, soluble ACE2 (sACE2) was elevated in OB, HT, and LC. The increase in sACE2 in OB and HT was accompanied by upregulation of ADAM17, an ACE2 sheddase, while TMPRSS2 increased in HT and LC. Cathepsin L, an endosomal receptor involved in viral entry, was also increased in OB. Alcohol can increase Angiotensin II, which triggers a pro-inflammatory response that may upregulate ACE2 via activation of RAS pathway receptors AT1R/AT2R. ACE2 then metabolizes Angiotensin II to Angiotensin (1-7) and provokes an anti-inflammatory response via MAS1. Accordingly, we report that AT1R/AT2R mRNA decreased in OB and increased in the LC, while MAS1 mRNA increased in both OB and LC. Other mRNAs for pro-inflammatory markers were also dysregulated in OB, HT, raphe, and LC. CONCLUSIONS: Our results suggest that alcohol triggers a compensatory upregulation of ACE2 in the brain due to disturbed RAS and may increase the risk or severity of SARS-CoV-2 infection.

Nervous system manifestations related to COVID-19 and their possible mechanisms.

In December 2019, the novel coronavirus disease (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection broke. With the gradual deepening understanding of SARS-CoV-2 and COVID-19, researchers and clinicians noticed that this disease is closely related to the nervous system and has complex effects on the central nervous system (CNS) and peripheral nervous system (PNS). In this review, we summarize the effects and mechanisms of SARS-CoV-2 on the nervous system, including the pathways of invasion, direct and indirect effects, and associated neuropsychiatric diseases, to deepen our knowledge and understanding of the relationship between COVID-19 and the nervous system.

Superantigens and SARS-CoV-2.

It has been posited SARS-CoV-2 contains at least one unique superantigen-like motif not found in any other SARS or endemic coronaviruses. Superantigens are potent antigens that can send the immune system into overdrive. SARS-CoV-2 causes many of the biological and clinical consequences of a superantigen, and, in the context of reinfection and waning immunity, it is important to better understand the impact of a widely circulating, airborne pathogen that may be a superantigen, superantigen-like or trigger a superantigenic host response. Urgent research is needed to better understand the long-term risks being taken by governments whose policies enable widespread transmission of a potential superantigenic pathogen, and to more clearly define the vaccination and public health policies needed to protect against the consequences of repeat exposure to the pathogen.

COVID-19: Brain Effects.

Severe acute respiratory syndrome coronavirus 2, the novel coronavirus responsible for the coronavirus disease (COVID-19), affects the brain. Neurologic and neuropsychiatric symptoms may manifest in the acute and post-acute phases of illness. The vulnerability of the brain with aging further increases the burden of disease in the elderly, who are at the highest risk of complications and death from COVID-19. The mechanisms underlying the effects of COVID-19 on the brain are not fully known. Emerging evidence vis-à-vis pathogenesis and etiologies of COVID-19 brain effects is promising and may pave the way for future research and development of interventions.

Patterns of COVID-19-related headache: A cross-sectional study.

BACKGROUND: Headache is the most common COVID-19-related neurological symptom. We investigated the characteristics of COVID-19-related headache and their relationship with clinical severity in Kirsehir Province, Turkey. METHODS: This cross-sectional study prospectively enrolled 226 COVID-19-positive patients who developed headache during acute infection. Demographic data, headache characteristics, and infection symptoms were recorded. The clinical severity of COVID-19 was documented in each participant. RESULT: New-onset COVID-19-related headaches lasting 4 days were reported in 164 patients (72.5 %); these were mostly bilaterally or localized to the forehead (58.4 %), pulsating (42.5 %), moderate to severe intensity (30.1 %), with a partial response to paracetamol (23.5 %). The other 62 patients (27.4 %) reported headaches before COVID-19. Their COVID-related headaches were fiery type (p = 0.025), of very severe intensity (p = 0.008), had a holocranial distribution (p = 0.004), and were less response to paracetamol (p = 0.003); the headaches were significantly more frequent after COVID-19 than before COVID-19. Older age, high body mass index, and low education level were significantly higher in the severe group (all p < 0.001). Female sex (p = 0.019) and being a healthcare worker (p < 0.001) were significantly more frequent in mild cases. CONCLUSIONS: Bilateral, prolonged, moderate to severe headaches that were analgesic resistant are more frequent in patients with COVID-19 infection. Further study should examine whether the headache characteristics distinguish COVID-19-related headaches from other types, particularly in asymptomatic subjects.

Human brain organoids to explore SARS-CoV-2-induced effects on the central nervous system.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). In less than three years, an estimated 600 million infections with SARS-CoV-2 occurred worldwide, resulting in a pandemic with tremendous impact especially on economic and health sectors. Initially considered a respiratory disease, COVID-19, along with its long-term sequelae (long-COVID) rather is a systemic disease. Neurological symptoms like dementia or encephalopathy were reported early during the pandemic as concomitants of the acute phase and as characteristics of long-COVID. An excessive inflammatory immune response is hypothesized to play a major role in this context. However, direct infection of neural cells may also contribute to the neurological aspects of (long)-COVID-19. To mainly explore such direct effects of SARS-CoV-2 on the central nervous system, human brain organoids provide a useful platform. Infecting these three-dimensional tissue cultures allows the study of viral neurotropism as well as of virus-induced effects on single cells or even the complex cellular network within the organoid. In this review, we summarize the experimental studies that used SARS-CoV-2-infected human brain organoids to unravel the complex nature of (long)-COVID-19-related neurological manifestations.

Clinical Aspects of Manic Episodes After SARS-CoV-2 Contagion or COVID-19.

As COVID-19 pandemic spread all over the world, it brought serious health consequences in every medical field, including mental health. Not only healthcare professionals were more prone to develop anxiety, depression, and stress, but the general population suffered as well. Some of those who had no prior history of a psychiatric disease developed peculiar symptoms following infection with SARS-CoV-2, mostly because of psychological and social issues triggered by the pandemic. People developed traumatic memories, and hypochondria, probably triggered by social isolation and stress. Infection with SARS-CoV-2 has influenced the mental health of psychiatric patients as well, exacerbating prior psychiatric conditions. In this review, we focus on analyzing those cases of mania in the context of bipolar disorder (BD) reported after COVID-19 disease, both in people with no prior psychiatric history and in psychiatric patients who suffered an exacerbation of the disease. Results have shown that COVID-19 may trigger a pre-existing BD or unmask an unknown BD, due to social and psychological influences (decreased social interaction, change in sleep patterns) and through biological pathways both (neuroinflammation and neuroinvasion through ACE-2 receptors expressed in the peripheral and central nervous systems (PNS and CNS respectively). No direct correlation was found between the severity of COVID-19 disease and manic symptoms. All cases presenting severe symptoms of both diseases needed specific medical treatment, meaning that they concur but are separate in the treatment strategy needed. This review highlights the importance of a now widespread viral disease as a potential agent unmasking and exacerbating bipolar mood disorder, and it can hopefully help physicians in establishing a rapid diagnosis and treatment, and pave the road for future research on neuroinflammation triggered by SARS-CoV-2.

Do SARS-CoV-2 Variants Differ in Their Neuropathogenicity?

Neurological complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are a huge societal problem. Although the neuropathogenicity of SARS-CoV-2 is not yet fully understood, there is evidence that SARS-CoV-2 can invade and infect cells of the central nervous system. Kong et al. (https://doi.org/10.1128/mbio.02308-22) shows that the mechanism of virus entry into astrocytes in brain organoids and primary astrocytes differs from entry into respiratory epithelial cells. However, how SARS-CoV-2 enters susceptible CNS cells and whether there are differences among SARS-CoV-2 variants is still unclear. In vivo and in vitro models are useful to study these important questions and may reveal important differences among SARS-CoV-2 variants in their neuroinvasive, neurotropic, and neurovirulent potential. In this commentary we address how this study contributes to the understanding of the neuropathology of SARS-CoV-2 and its variants.

Spatial Mapping of Genes Implicated in SARS-CoV-2 Neuroinvasion to Dorsolateral Prefrontal Cortex Gray Matter.

Introduction: SARS-CoV-2 is the newest beta coronavirus family member to demonstrate neuroinvasive capability in severe cases of infection. Despite much research activity in the SARS-CoV-2/COVID-19 space, the gene-level biology of this phenomenon remains poorly understood. In the present analysis, we leveraged spatial transcriptomics methodologies to examine relevant gene heterogeneity in tissue retrieved from the human prefrontal cortex. Methods: Expression profiles of genes with established relations to the SARS-CoV-2 neuroinvasion process were spatially resolved in dorsolateral prefrontal cortex tissue (N = 4). Spotplots were generated with mapping to six (6) previously defined gray matter layers. Results: Docking gene BSG, processing gene CTSB, and viral defense gene LY6E demonstrated similar spatial enrichment. Docking gene ACE2 and transmembrane series proteases involved in spike protein processing were lowly expressed across DLPFC samples. Numerous other findings were obtained. Conclusion: Efforts to spatially represent expression levels of key SARS-CoV-2 brain infiltration genes remain paltry to date. Understanding the sobering history of beta coronavirus neuroinvasion represents a weak point in viral research. Here we provide the first efforts to characterize a motley of such genes in the dorsolateral prefrontal cortex.

COVID-19 and Dementia; Hard to Forget Yet Haunting Forgetfulness!

The current pandemic has affected almost everyone worldwide. Although the majority of people survive the illness, bad cognitive repercussions might last a long time, resulting in a lower quality of life and disability, particularly in severe cases. We tried to understand and bring together the various possible mechanisms leading to dementia in COVID-19. The link between COVID-19 and dementia will help public health workers plan and allocate resources to provide better care for a community suffering from sickness and improve quality of life. A conceptual framework for care of infected people in the older age group and care of dementia people is proposed.

Anatomical barriers against SARS-CoV-2 neuroinvasion at vulnerable interfaces visualized in deceased COVID-19 patients.

Can SARS-CoV-2 hitchhike on the olfactory projection and take a direct and short route from the nose into the brain? We reasoned that the neurotropic or neuroinvasive capacity of the virus, if it exists, should be most easily detectable in individuals who died in an acute phase of the infection. Here, we applied a postmortem bedside surgical procedure for the rapid procurement of tissue, blood, and cerebrospinal fluid samples from deceased COVID-19 patients infected with the Delta, Omicron BA.1, or Omicron BA.2 variants. Confocal imaging of sections stained with fluorescence RNAscope and immunohistochemistry afforded the light-microscopic visualization of extracellular SARS-CoV-2 virions in tissues. We failed to find evidence for viral invasion of the parenchyma of the olfactory bulb and the frontal lobe of the brain. Instead, we identified anatomical barriers at vulnerable interfaces, exemplified by perineurial olfactory nerve fibroblasts enwrapping olfactory axon fascicles in the lamina propria of the olfactory mucosa.

From common colds to COVID-19: potential neurological consequences of a coronavirus infection / Des rhumes à la Covid-19 : conséquences neurologiques potentielles d'une infection par les coronavirus

For a large proportion of mankind, the word coronavirus only became a reality in the year 2020, as it was the cause of one of the worst pandemics of the last two centuries. Nevertheless, well before this ominous moment, human coronaviruses (HCoV) were well characterized respiratory pathogens since the 1960s. The most recent discovery of SARS-CoV and MERS-CoV showed that coronaviruses have a pandemic potential with important consequences. With the COVID-19 pandemic caused by SARS-CoV-2, this potential is now certain. Moreover, accumulating evidence support an association between coronaviruses and extra-respiratory pathologies, in particular of the central and peripheral nervous system. Linked or not with a neuro-invasive and neurotropic potential, it is now clear that coronaviruses can be associated with the development of neurological disorders.

Pour une grande partie de l'humanité, le terme coronavirus n'est devenu réalité qu'au début de l'année 2020, associé à une des plus importantes pandémies des deux derniers siècles. Pourtant, bien avant ce moment fatidique, les coronavirus humains (HCoV) étaient bien caractérisés en tant que pathogènes respiratoires depuis la fin des années 1960. Depuis le début du XXIe siècle, deux autres coronavirus pouvant infecter l'humain (SARS-CoV et MERS-CoV), ont montré que ces virus avaient un potentiel pandémique pouvant entraîner des conséquences importantes. Avec la survenue de la pandémie de Covid-19 créée par le SARS-CoV-2, ce potentiel ne fait aujourd'hui plus aucun doute. De plus, un nombre grandissant d'études supporte l'idée d'une association entre les coronavirus et diverses pathologies extra-respiratoires, en particulier au niveau des systèmes nerveux central et périphérique. Liés ou non à un véritable potentiel neuro-invasif et neurotrope, il apparaît maintenant de façon claire que les coronavirus peuvent être associés au développement de divers désordres neurologiques.

In vitro and in vivo differences in neurovirulence between D614G, Delta And Omicron BA.1 SARS-CoV-2 variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with various neurological complications. Although the mechanism is not fully understood, several studies have shown that neuroinflammation occurs in the acute and post-acute phase. As these studies have predominantly been performed with isolates from 2020, it is unknown if there are differences among SARS-CoV-2 variants in their ability to cause neuroinflammation. Here, we compared the neuroinvasiveness, neurotropism and neurovirulence of the SARS-CoV-2 ancestral strain D614G, the Delta (B.1.617.2) and Omicron BA.1 (B.1.1.529) variants using in vitro and in vivo models. The Omicron BA.1 variant showed reduced neurotropism and neurovirulence compared to Delta and D614G in human induced pluripotent stem cell (hiPSC)-derived cortical neurons co-cultured with astrocytes. Similar differences were obtained in Syrian hamsters inoculated with D614G, Delta and the Omicron BA.1 variant 5 days post infection. Replication in the olfactory mucosa was observed in all hamsters, but most prominently in D614G inoculated hamsters. Furthermore, neuroinvasion into the CNS via the olfactory nerve was observed in D614G, but not Delta or Omicron BA.1 inoculated hamsters. Furthermore, neuroinvasion was associated with neuroinflammation in the olfactory bulb of hamsters inoculated with D614G. Altogether, our findings suggest differences in the neuroinvasive, neurotropic and neurovirulent potential between SARS-CoV-2 variants using in vitro hiPSC-derived neural cultures and in vivo in hamsters during the acute phase of the infection.