MECHANISMS OF CENTRAL NERVOUS SYSTEM DAMAGE IN COVID-19

The issues of diagnosis and treatment of nervous system damage in the new coronavirus infection (COVID-19) remain relevant, regardless of information and experience in treating such patients, accumulated nowadays. The review contains updated data on the ways of SARS-CoV-2 invasion, examines mechanisms of central nervous system damage: direct virus-induced damage, immune dysfunction, excessive thrombo-inflammation, coagulation disorder, cytokine and metabolic imbalance, hypoxia, etc.;it presents clinical examples with one variant of damage — the development of Guillain-Barre syndrome that, to some extent, allows to confirm the virus neurotropism. Doctors' knowledge about this infection is constantly expanding, new information appears on its various neuropsychiatric effects during an acute period and post-COVID syndrome, on symptoms, treatment and prevention strategy. These data enables to understand better the reasons for developing the main clinical manifestations, from a headache or myalgia to more severe symptoms, such as a stroke, psychosis and anosmia, severity and reversibility of their course. Although several hypothesis of CNS damage pathogenesis in COVID-19 are being discussed, the unified pathophysiological mechanism of many dysfunctions remains unclear, and, probably, additional factors, such as social isolation during a pandemic, presence and treatment in the intensive care unit, premorbid somatic status of a patient, contribute to the development of some registered nervous system disorders. © 2023, HIV Infection and Immunosuppressive Disorders.All Rights Reserved.

SARS-CoV-2 Infection Increases the Gene Expression Profile for Alzheimer's Disease Risk

The COVID-19 pandemic is a global outbreak of coronavirus, an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One in five adults who have had COVID-19 in the past was still experiencing any one of the symptoms of long COVID like headache, brain fog, fatigue, and shortness of breath. Up to 30% of individuals with mild to severe infection show diverse neurological symptoms, including dementias. Hence, it is very much important to characterize the neurotropism and neurovirulence of the SARS-CoV-2 virus. This helps us understand the mechanisms involved in initiating inflammation in the brain, further leading to the development of earlyonset Alzheimer's disease and related dementias (ADRDs). In our brain gene expression analysis, we found that severe COVID-19 patients showed increased expression of innate immune response genes and genes that are implicated in AD pathogenesis. To study the infection-induced ADRDs, we used a mouse-adapted strain of the SARS-CoV-2 (MA10) virus to infect mice of different age groups (3, 6, and 20 Months). In this study, we found that aged mice showed evidence of viral neurotropism, prolonged viral infection, increased expression of tau aggregator FKBP51, interferoninducible gene Ifi204, and complement genes like C4 and C5AR1. Brain histopathology also showed the AD signature including tau-phosphorylation, tau-oligomerization, and alpha-synuclein expression in aged MA10-infected mice. The results from gene expression profiling of SARS-CoV-2 infected and AD brains and studies with MA10 aged mice show that COVID-19 infection increases the risk of AD in the aged population. Furthermore, this study helps us to understand the crucial molecular markers that are regulated during COVID infection that could act as major players in developing ADRDs. Future studies will be involved in understanding the molecular mechanisms of ADRD in response to COVID infection and developing novel therapies targeting AD.

Neuronal progenitors of the dentate gyrus express the SARS-CoV-2 cell receptor during migration in the developing human hippocampus.

The COVID-19 pandemic spread around the world is due to the enormous capacity of the SARS-CoV-2 coronavirus to be transmitted between humans, causing a threat to global public health. It has been shown that the entry of this virus into cells is highly facilitated by the presence of angiotensin-converting enzyme 2 (ACE2) in the cell membrane. Currently, we have no precise knowledge of how this receptor expresses in the brain of human fetus and, as a consequence, we do not know how susceptible the neural cells in the developing brain are to being infected through the vertical transmission of this virus, from mother to fetus. In this work, we describe the expression of ACE2 in the human brain at 20 weeks of gestation. This stage corresponds to the period of neuronal generation, migration, and differentiation in the cerebral cortex. We describe the specific expression of ACE2 in neuronal precursors and migratory neuroblasts of the dentate gyrus in the hippocampus. This finding implies that SARS-CoV-2 infection during the fetal period may affect neuronal progenitor cells and alter the normal development of the brain region where memory engrams are generated. Thus, although vertical transmission of SARS-CoV-2 infection was reported in few cases, the massive infection rate of young people in terms of the new variants leads to the possibility of increasing the ratio of congenital infections and originating cognitive alterations, as well as neuronal circuit anomalies that may represent vulnerability to mental problems throughout life.

ACE2 expression in the brain during development and susceptibility to brain infection by SARS-COV-2.

The COVID-19 pandemic spread around the world due to the enormous transmission of the SARS-CoV-2 among humans. COVID-19 represents a threat to global public health. The entry of this virus into cells is greatly facilitated by the presence of angiotensin-converting enzyme 2 (ACE2) in the cell membrane. Today we do not have a precise understanding of how this receptor expresses in the brain during human development and, as a consequence, we do not know whether neural cells in the developing brain are susceptible to infection. We review the knowledge about ACE2 expression in the developing human brain, with special attention to the fetal stage. This stage corresponds to the period of the cerebral cortex formation. Therefore, SARS-CoV-2 infection during the fetal period may alter the normal development of the cerebral cortex. Although few cases have been published demonstrating vertical transmission of SARS-CoV-2 infection, the large number of infected young people may represent a problem which requires health surveillance, due to the possibility of cognitive alterations and abnormalities in the development of cortical circuits that may represent a predisposition to mental problems later in life.Copyright © 2023, Instituto de Investigaciones Medicas. All rights reserved.

Is There a Rendezvous for SARS-CoV-2 and Agmatine?

The catastrophe of the ongoing COVID-19 pandemic is caused by Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2). The respiratory system appears to be ground zero in the majority of the patients. However, many other organs can get infected by cytokines, chemokines and other mediators released in response to the presence of the virus. The neurotropism by the SARS-CoV-2 is established beyond doubt. In addition to non-specific symptoms, the symptoms specific to central and/or peripheral nervous system diseases as well as neuromuscular diseases have been observed in numerous clinical cases. These observations and the experiences with other coronavirus infections earlier and flu pandemics raise concerns not only about the neurological effects in active disease but also about the long-term effects generated by the infection, immune and inflammatory functions. The knowledge of biological actions of agmatine in the backdrop of physiological events instigated by invading SARS-CoV-2 and host's response, especially in neural events, focuses on the possible overlaps of biomolecular pathways at a number of instances. This is not surprising since the factors stimulated during SARS-CoV-2 infection are the disease-generating neuroinflammatory components altered by agmatine. Hence, we hypothesize the possible beneficial role of agmatine in SARS-CoV-2 infection. Based on a narrative review of the literature, agmatine can be proposed as a plausible beneficial candidate for supporting treatment of SARS-CoV-2 infection and for addressing post-infection neurological complications.Copyright © 2022 Bentham Science Publishers.

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.

Respiratory Distress in SARS-CoV-2 without Lung Damage: Phrenic Paralysis Should Be Considered in COVID-19 Infection.

We describe an overweight COVID-19 patient with respiratory distress preceded by anosmia/dysgeusia with no lung injury shown on CT, angio-CT or ventilation/perfusion scans. Orthopnoea and paradoxical abdominal respiration were identified. Phrenic paralysis, demonstrated by examination of patient breathing, and on x-ray while standing breathing in and out, explained the respiratory distress. This is a rare and previously undescribed neurological complication of COVID-19 infection caused by vagus nerve injury. LEARNING POINTS: Phrenic paralysis must be kept in mind as a rare neurological complication of COVID-19.Vagus nerve palsy is a neurological manifestation as anosmia and dysgeusia, that were already identified in the olfactory system of COVID-19 patients.

Impact of SARS-CoV-2 Infection on Cognitive Function: A Systematic Review.

The prevalence and etiology of COVID-19's impact on brain health and cognitive function is poorly characterized. With mounting reports of delirium, systemic inflammation, and evidence of neurotropism, a statement on cognitive impairment among COVID-19 cases is needed. A substantial literature has demonstrated that inflammation can severely disrupt brain function, suggesting an immune response, a cytokine storm, as a possible cause of neurocognitive impairments. In this light, the aim of the present study was to summarize the available knowledge of the impact of COVID-19 on cognition (i.e., herein, we broadly define cognition reflecting the reporting on this topic in the literature) during the acute and recovery phases of the disease, in hospitalized patients and outpatients with confirmed COVID-19 status. A systematic review of the literature identified six studies which document the prevalence of cognitive impairment, and one which quantifies deficits after recovery. Pooling the samples of the included studies (total sample n = 644) at three standards of quality produced conservative estimates of cognitive impairment ranging from 43.0 to 66.8% prevalence in hospitalized COVID-19 patients only, as no studies which report on outpatients met criteria for inclusion in the main synthesis. The most common impairment reported was delirium and frequent reports of elevated inflammatory markers suggest etiology. Other studies have demonstrated that the disease involves marked increases in IL-6, TNFα, and IL-1ß; cytokines known to have a profound impact on working memory and attention. Impairment of these cognitive functions is a characteristic aspect of delirium, which suggests these cytokines as key mediators in the etiology of COVID-19 induced cognitive impairments. Researchers are encouraged to assay inflammatory markers to determine the potential role of inflammation in mediating the disturbance of cognitive function in individuals affected by COVID-19.

Post-Vaccination/Post-COVID Immune-Mediated Demyelination of the Brain and Spinal Cord: A Novel Neuroimaging Finding.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which not only produces respiratory symptoms but is known to involve almost every system, and its neuroinvasive properties have been well demonstrated throughout the pandemic. Also, to combat the pandemic, there was rapid development and induction of various vaccination drives, following which many adverse events following immunization (AEFIs) have been reported, which include neurological complications as well. Method: We present a series of three cases, post vaccination, with and without a history of COVID illness that showed remarkably similar findings on magnetic resonance imaging (MRI). Result: A 38-year-old male presented with complaints of weakness of the bilateral lower limbs with sensory loss and bladder disturbance a day after receiving his first dose of ChadOx1 nCoV-19 (COVISHIELD) vaccine. A 50-year-old male with hypothyroidism characterized by autoimmune thyroiditis and impaired glucose tolerance experienced difficulty in walking 11.5 weeks after being administered with COVID vaccine (COVAXIN). A 38-year-old male presented with subacute onset progressive symmetric quadriparesis 2 months after their first dose of a COVID vaccine. The patient also had sensory ataxia, and his vibration sensation was impaired below C7. All three patients had typical pattern of involvement of the brain and spine on MRI with signal changes in bilateral corticospinal tracts, trigeminal tracts in the brain, and both lateral and posterior columns in the spine. Conclusion: This pattern of brain and spine involvement on MRI is a novel finding and is likely a result of post-vaccination/post-COVID immune-mediated demyelination.

SARS-CoV-2 Omicron (B.1.1.529) shows minimal neurotropism in a double-humanized mouse model.

Although severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) initially infects the respiratory tract, it also directly or indirectly affects other organs, including the brain. However, little is known about the relative neurotropism of SARS-CoV-2 variants of concern (VOCs), including Omicron (B.1.1.529), which emerged in November 2021 and has remained the dominant pathogenic lineage since then. To address this gap, we examined the relative ability of Omicron, Beta (B.1.351), and Delta (B.1.617.2) to infect the brain in the context of a functional human immune system by using human angiotensin-converting enzyme 2 (hACE2) knock-in triple-immunodeficient NGC mice with or without reconstitution with human CD34+ stem cells. Intranasal inoculation of huCD34+-hACE2-NCG mice with Beta and Delta resulted in productive infection of the nasal cavity, lungs, and brain on day 3 post-infection, but Omicron was surprisingly unique in its failure to infect either the nasal tissue or brain. Moreover, the same infection pattern was observed in hACE2-NCG mice, indicating that antiviral immunity was not responsible for the lack of Omicron neurotropism. In independent experiments, we demonstrate that nasal inoculation with Beta or with D614G, an ancestral SARS-CoV-2 with undetectable replication in huCD34+-hACE2-NCG mice, resulted in a robust response by human innate immune cells, T cells, and B cells, confirming that exposure to SARS-CoV-2, even without detectable infection, is sufficient to induce an antiviral immune response. Collectively, these results suggest that modeling of the neurologic and immunologic sequelae of SARS-CoV-2 infection requires careful selection of the appropriate SARS-CoV-2 strain in the context of a specific mouse model.

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.

Acute neurologic emerging flaviviruses.

The COVID-19 pandemic has shed light on the challenges we face as a global society in preventing and containing emerging and re-emerging pathogens. Multiple intersecting factors, including environmental changes, host immunological factors, and pathogen dynamics, are intimately connected to the emergence and re-emergence of communicable diseases. There is a large and expanding list of communicable diseases that can cause neurological damage, either through direct or indirect routes. Novel pathogens of neurotropic potential have been identified through advanced diagnostic techniques, including metagenomic next-generation sequencing, but there are also known pathogens which have expanded their geographic distribution to infect non-immune individuals. Factors including population growth, climate change, the increase in animal and human interface, and an increase in international travel and trade are contributing to the expansion of emerging and re-emerging pathogens. Challenges exist around antimicrobial misuse giving rise to antimicrobial-resistant infectious neurotropic organisms and increased susceptibility to infection related to the expanded use of immunomodulatory treatments. In this article, we will review key concepts around emerging and re-emerging pathogens and discuss factors associated with neurotropism and neuroinvasion. We highlight several neurotropic pathogens of interest, including West Nile virus (WNV), Zika Virus, Japanese Encephalitis Virus (JEV), and Tick-Borne Encephalitis Virus (TBEV). We emphasize neuroinfectious diseases which impact the central nervous system (CNS) and focus on flaviviruses, a group of vector-borne pathogens that have expanded globally in recent years and have proven capable of widespread outbreak.

Unravelling Pathophysiology of Neurological and Psychiatric Complications of COVID-19 Using Brain Organoids.

Neuropsychiatric manifestations of coronavirus disease 2019 (COVID-19) have been increasingly recognized. However, the pathophysiology of COVID-19 in the central nervous system remains unclear. Brain organoid models derived from human pluripotent stem cells are potentially useful for the study of complex physiological and pathological processes associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as they recapitulate cellular heterogeneity and function of individual tissues. We identified brain organoid studies that provided insight into the neurotropic properties of SARS-CoV-2. While SARS-CoV-2 was able to infect neurons, the extent of neurotropism was relatively limited. Conversely, choroidal epithelial cells consistently showed a high susceptibility to SARS-CoV-2 infection. Brain organoid studies also elucidated potential mechanism for cellular entry, demonstrated viral replication, and highlighted downstream cellular effects of SARS-CoV-2 infection. Collectively, they suggest that the neuropsychiatric manifestations of COVID-19 may be contributed by both direct neuronal invasion and indirect consequences of neuroinflammation. The use of high throughput evaluation, patient-derived organoids, and advent of "assembloids" will provide a better understanding and functional characterization of the neuropsychiatric symptoms seen in post-acute COVID-19 syndrome. With advancement of organoid technology, brain organoids offer a promising tool for unravelling pathophysiologic clues and potential therapeutic options for neuropsychiatric complications of COVID-19.

Finding positive SARS-CoV-2 RT-PCR in cerebrospinal fluid of two pediatric patients with severe COVID-19: a brief case report.

BACKGROUND: There is growing evidence of nervous system involvement and related complaints in children with coronavirus disease 2019 (COVID-19). However, it seems that attempts to track of the virus in the nervous system have so far been unsuccessful. CASE PRESENTATION: Here we describe two pediatric cases of severe COVID-19 who had positive cerebrospinal fluid (CSF) and nasopharyngeal polymerase chain reaction (PCR) tests for severe acute respiratory syndrome coronavirus disease 2019 (SARS-CoV-2). A 36-month-old girl who presented with fever, diarrhea, mild left ventricular dysfunction and bizarre movements, and a five-month-old boy who presented with fever, watery diarrhea, severe dehydration, mottling, and two episodes of seizure. Their CSF analyses and cultures were normal. They admitted in intensive care unit (ICU) for near four days and discharged after ten days without any complaint. CONCLUSION: This is one of the first reports of the presence of coronavirus in the central nervous system in COVID-19 pediatric patients, emphasizing the neurotropism and neuroinvasion characteristics of the virus.

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.

Alzheimer's disease risk after COVID-19: a view from the perspective of the infectious hypothesis of neurodegeneration.

In light of the rising evidence of the association between viral and bacterial infections and neurodegeneration, we aimed at revisiting the infectious hypothesis of Alzheimer's disease and analyzing the possible implications of COVID-19 neurological sequelae in long-term neurodegeneration. We wondered how SARS-CoV-2 could be related to the amyloid-ß cascade and how it could lead to the pathological hallmarks of the disease. We also predict a paradigm change in clinical medicine, which now has a great opportunity to conduct prospective surveillance of cognitive sequelae and progression to dementia in people who suffered severe infections together with other risk factors for Alzheimer's disease.

Prenatal Exposure to SARS-Cov-2 and Schizophrenia Development: What to Expect?

Introduction: Schizophrenia is a complex and multifactorial psychiatric condition characterized by thought, speech, perception and behaviour disorders, and social and occupational impairment. It has been related that viral prenatal infection may contribute to schizophrenia development. As such, there are some hypotheses regarding SARS-Cov-2 prenatal infection and its potential relation with "future" offspring schizophrenia. Objective(s): Literature review of schizophrenia development and relation with viral infections, and data research of COVID-19 neurotropic effects. Method(s): Non-systematic review through literature using databases as Pubmed and UpToDate. Keywords used: schizophrenia, prenatal, viral infection, COVID-19, SARS-Cov-2. Result(s): Several studies had shown a relationship between prenatal viral infections, such as Influenza, and development of schizophrenia in the offspring. It relates with viral neurotropism mechanisms and inflammatory processes in the fetal neurology system. Regarding SARS-Cov-2, it is early to assume a relation between prenatal COVID-19 and offspring schizophrenia development. However, literature describes psychiatric manifestations post COVID, such as psychotic and manic episodes. As such, a SARSCov- 2 neurotropic effect is demonstrated. Conclusion(s): Schizophrenia has a multifactorial etiology. Since prenatal viral infections may interfere and contribute to schizophrenia development, it is logical to assume prenatal SARS-Cov-2 infection may also contribute. It may be relevant to investigate whether these offspring will manifest schizophrenia symptoms.

SARS-CoV-2 infects neurons and induces neuroinflammation in a non-human primate model of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), can induce a plethora of neurological complications in some patients. However, it is still under debate whether SARS-CoV-2 directly infects the brain or whether CNS sequelae result from systemic inflammatory responses triggered in the periphery. By using high-resolution microscopy, we investigated whether SARS-CoV-2 reaches the brain and how viral neurotropism can be modulated by aging in a non-human primate model of COVID-19. Seven days after infection, SARS-CoV-2 was detected in the olfactory cortex and interconnected regions and was accompanied by robust neuroinflammation and neuronal damage exacerbated in aged, diabetic animals. Our study provides an initial framework for identifying the molecular and cellular mechanisms underlying SARS-CoV-2 neurological complications, which will be essential to reducing both the short- and long-term burden of COVID-19.