Anticipated Long-Term Neurobehavioral Outcomes Following COVID-19

First identified in December 2021, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)-the virus causing COVID-19, is responsible for significant morbidity and mortality rates. Given the worldwide impact of COVID-19, there is much interest in the anticipated long-term effects for those with history of SARS-CoV-2 infection. While initially presumed as a respiratory infection, there is now evidence of a broader array of pathophysiological mechanisms which result in a wide spectrum of reported acute and chronic symptoms in patients with confirmed COVID-19. These include including memory and other neurocognitive changes as well as psychiatric and behavioral symptoms. These nonspecific, but often debilitating, sequalaeare complex and difficult to disentangle from more common causes of neurobehavioral change. The goal of this chapter is to discuss anticipated chronic neurocognitive and psychiatric outcomes of COVID-19 survivors based on emerging peer-reviewed literature, data from prior pandemics, and outcome studies from well-characterized, clinically similar syndromes. This unpacking of long-term complications from COVID-19 will seek to set expectations and provide guidance for clinicians who will undoubtably encounter increased volumes of patients with residual post-COVID-19 neurobehavioral changes. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

Neurodegenerative and Neurodevelopmental Diseases and the Gut-Brain Axis: The Potential of Therapeutic Targeting of the Microbiome.

The human gut microbiome contains the largest number of bacteria in the body and has the potential to greatly influence metabolism, not only locally but also systemically. There is an established link between a healthy, balanced, and diverse microbiome and overall health. When the gut microbiome becomes unbalanced (dysbiosis) through dietary changes, medication use, lifestyle choices, environmental factors, and ageing, this has a profound effect on our health and is linked to many diseases, including lifestyle diseases, metabolic diseases, inflammatory diseases, and neurological diseases. While this link in humans is largely an association of dysbiosis with disease, in animal models, a causative link can be demonstrated. The link between the gut and the brain is particularly important in maintaining brain health, with a strong association between dysbiosis in the gut and neurodegenerative and neurodevelopmental diseases. This link suggests not only that the gut microbiota composition can be used to make an early diagnosis of neurodegenerative and neurodevelopmental diseases but also that modifying the gut microbiome to influence the microbiome-gut-brain axis might present a therapeutic target for diseases that have proved intractable, with the aim of altering the trajectory of neurodegenerative and neurodevelopmental diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorder, and attention-deficit hyperactivity disorder, among others. There is also a microbiome-gut-brain link to other potentially reversible neurological diseases, such as migraine, post-operative cognitive dysfunction, and long COVID, which might be considered models of therapy for neurodegenerative disease. The role of traditional methods in altering the microbiome, as well as newer, more novel treatments such as faecal microbiome transplants and photobiomodulation, are discussed.

Adipose tissue, systematic inflammation, and neurodegenerative diseases

Obesity is associated with several diseases, including mental health. Adipose tissue is distributed around the internal organs, acting in the regulation of metabolism by storing and releasing fatty acids and adipokine in the tissues. Excessive nutritional intake results in hypertrophy and proliferation of adipocytes, leading to local hypoxia in adipose tissue and changes in these adipokine releases. This leads to the recruitment of immune cells to adipose tissue and the release of pro-inflammatory cytokines. The presence of high levels of free fatty acids and inflammatory molecules interfere with intracellular insulin signaling, which can generate a neuroinflammatory process. In this review, we provide an up-to-date discussion of how excessive obesity can lead to possible cognitive dysfunction. We also address the idea that obesity-associated systemic inflammation leads to neuroinflammation in the brain, particularly the hypothalamus and hippocampus, and that this is partially responsible for these negative cognitive outcomes. In addition, we discuss some clinical models and animal studies for obesity and clarify the mechanism of action of anti-obesity drugs in the central nervous system.Copyright © 2023 Wolters Kluwer Medknow Publications. All rights reserved.

Interplay of cGAS with micronuclei: Regulation and diseases.

In higher eukaryotes, sophisticate regulation of genome function requires all chromosomes to be packed into a single nucleus. Micronucleus (MN), the dissociative nucleus-like structure frequently observed in aging and multiple disease settings, has critical, yet under-recognized, pathophysiological functions. Micronuclei (MNi) have recently emerged as major sources of cytosolic DNA that can activate the cGAS-STING axis in a cell-intrinsic manner. However, MNi induced from different genotoxic stressors display great heterogeneity in binding or activating cGAS and the signaling responses downstream of the MN-induced cGAS-STING axis have divergent outcomes including autoimmunity, autoinflammation, metastasis, or cell death. Thus, full characterization of molecular network underpinning the interplay of cGAS and MN is important to elucidate the pathophysiological roles of immunogenic MN and design improved drugs that selectively target cancer via boosting the MN-derived cGAS-STING axis. Here, we summarize our current understanding of the mechanisms for self-DNA discrimination by cGAS. We focus on discussing how MN immunogencity is dictated by multiple mechanisms including integrity of micronuclear envelope, state of nucleosome and DNA, competitive factors, damaged mitochondrial DNA and micronucleophagy. We also describe emerging links between immunogenic MN and human diseases including cancer, neurodegenerative diseases and COVID-19. Particularly, we explore the exciting concept of inducing immunogenic MN as a therapeutic approach in treating cancer. We propose a new theoretical framework to describe immunogenic MN as a biological sensor to modulate cellular processes in response to genotoxic stress and provide perspectives on developing novel experimental approaches to unravel the complexity of MN immunogenicity regulation and immunogenic MN pathophysiology.

Clinical and Functional Evolution in Subjects with Parkinson's Disease during SARS-CoV-2 Pandemic

The COVID-19 pandemic has been a stress test for the population, especially for people with chronic disorders such as Parkinson's disease (PD). In addition to public health restrictions that contrast with PD management recommendations, there were deep changes in health care delivery. This retrospective study evaluates the impact of COVID-19 on the clinical and functional evolution of a cohort of 221 PD patients consecutively referred to the Movement Disorders Center between 2018 and 2021. We analyzed the trend in motor and non-motor symptoms and functional status across years based on the Unified Parkinson's Disease Rating Scale (UPDRS) and Non-Motor Symptom Scale (NMSS). We also compared the number of emerging complications, neurologic visits, and rehabilitation sessions per subject per year. In 2020, all primary endpoint measures worsened compared to 2019, without age, disease duration, or greater neurologic impairment explaining this outcome. Concurrently, the percentage of patients receiving neurologic visits or rehabilitation sessions reduced by 53% and 58%, respectively. The subgroup analysis of 167 subjects revealed that those who received at least one cycle of rehabilitation sessions in 2020 maintained their independence level. These findings lead to emphasizing the importance of regular monitoring and rehabilitation delivery in people with chronic neurological disorders.

The emerging role of furin in neurodegenerative and neuropsychiatric diseases.

Furin is an important mammalian proprotein convertase that catalyzes the proteolytic maturation of a variety of prohormones and proproteins in the secretory pathway. In the brain, the substrates of furin include the proproteins of growth factors, receptors and enzymes. Emerging evidence, such as reduced FURIN mRNA expression in the brains of Alzheimer's disease patients or schizophrenia patients, has implicated a crucial role of furin in the pathophysiology of neurodegenerative and neuropsychiatric diseases. Currently, compared to cancer and infectious diseases, the aberrant expression of furin and its pharmaceutical potentials in neurological diseases remain poorly understood. In this article, we provide an overview on the physiological roles of furin and its substrates in the brain, summarize the deregulation of furin expression and its effects in neurodegenerative and neuropsychiatric disorders, and discuss the implications and current approaches that target furin for therapeutic interventions. This review may expedite future studies to clarify the molecular mechanisms of furin deregulation and involvement in the pathogenesis of neurodegenerative and neuropsychiatric diseases, and to develop new diagnosis and treatment strategies for these diseases.

Impact of COVID-19 lockdown on physical exercise among participants receiving the Promoting Activity, Independence and Stability in Early Dementia (PrAISED) intervention: a repeated measure study.

BACKGROUND: The potential decrease in daily physical activity associated with the COVID-19 pandemic lockdowns may have a negative impact on people living with dementia. Given the limited literature around the effects of home confinement in people living with dementia, this study investigated changes in physical exercise levels of participants in the intervention arm of the Promoting Activity, Independence and Stability in Early Dementia (PrAISED) Randomised Controlled Trial during the first COVID-19 national lockdown. It hypothesised that participants would maintain physical exercise levels. METHODS: A repeated measure (three time points) study involving 30 participants (mean age = 78.0 years, 15 male and 15 female, 22 (73.0%) living with their primary caregiver), from four regions in England receiving the PrAISED intervention. PrAISED is an individually tailored intervention of physical exercises and functional activities. Trained therapists deliver therapy sessions over a period of 52 weeks. Study participants received therapy sessions via phone or video calling during the COVID-19 lockdown. This study investigated self-reported minutes of physical exercise recorded on study calendars for the months of February (i.e., baseline - pre-lockdown), May (i.e., T1 - during lockdown), and August (i.e., T2-post-lockdown) 2020. RESULTS: Participants reported a statistically significant increase in activity levels between February and May (Wilcoxon Z = -2.013, p = 0.044) and a statistically significant decrease between May and August (Wilcoxon Z = -2.726, p = 0.004). No significant difference was found in the physical activity levels from pre- to post-lockdown (Wilcoxon Z = 0.485, p = 0.620). CONCLUSION: Despite concerns that the restrictions associated with the COVID-19 pandemic might lead to reductions in physical exercise, participants in receipt of the PrAISED intervention increased their amount of physical exercise during lockdown. Our findings support the potential of remote support for people living with dementia to help them maintain physical exercise levels in circumstances where face-to-face service provision is not possible. TRIAL REGISTRATION: The PrAISED trial and process evaluation have received ethical approval number 18/YH/0059 from the Bradford/Leeds Ethics Committee. The Clinical Trial Identifier for PrAISED is: ISRCTN15320670 ( https://doi.org/10.1186/ISRCTN15320670 ). Registration was made on 04/09/2018.

Microgliosis and neuronal proteinopathy in brain persist beyond viral clearance in SARS-CoV-2 hamster model.

BACKGROUND: Neurological symptoms such as cognitive decline and depression contribute substantially to post-COVID-19 syndrome, defined as lasting symptoms several weeks after initial SARS-CoV-2 infection. The pathogenesis is still elusive, which hampers appropriate treatment. Neuroinflammatory responses and neurodegenerative processes may occur in absence of overt neuroinvasion. METHODS: Here we determined whether intranasal SARS-CoV-2 infection in male and female syrian golden hamsters results in persistent brain pathology. Brains 3 (symptomatic) or 14 days (viral clearance) post infection versus mock (n = 10 each) were immunohistochemically analyzed for viral protein, neuroinflammatory response and accumulation of tau, hyperphosphorylated tau and alpha-synuclein protein. FINDINGS: Viral protein in the nasal cavity led to pronounced microglia activation in the olfactory bulb beyond viral clearance. Cortical but not hippocampal neurons accumulated hyperphosphorylated tau and alpha-synuclein, in the absence of overt inflammation and neurodegeneration. Importantly, not all brain regions were affected, which is in line with selective vulnerability. INTERPRETATION: Thus, despite the absence of virus in brain, neurons develop signatures of proteinopathies that may contribute to progressive neuronal dysfunction. Further in depth analysis of this important mechanism is required. FUNDING: Federal Ministry of Health (BMG; ZMV I 1-2520COR501), Federal Ministry of Education and Research (BMBF 01KI1723G), Ministry of Science and Culture of Lower Saxony in Germany (14 - 76103-184 CORONA-15/20), German Research Foundation (DFG; 398066876/GRK 2485/1), Luxemburgish National Research Fund (FNR, Project Reference: 15686728, EU SC1-PHE-CORONAVIRUS-2020 MANCO, no > 101003651).

Genetic Effects of Covid 19 on the Development of Neurodegenerative Diseases

The coronavirus disease (COVID-19) caused by SARS-COV-2, a highly infectious pathogen, genetically similar to SARS-COV is an unprecedented worldwide health crisis. Rapidly accumulating clinical research revealed that COVID-19 is manifested by various neurological symptoms and also affects the brain in many ways including direct infection to systemic inflammation. Which indicates it may substantially increase the incidence of developing neurodegenerative diseases (NDGDs). To discourse this issue we studied the computable frameworks to address the gene expression association of COVID-19 and NDGDs to identify the link among them. We analyzed GEO microarray datasets from COVID-19 and NDGDs including Epilepsy, Stroke, Multiple Sclerosis, Alzheimer's disease, and Parkinson's disease. We constructed disease-gene relationship networks and identified dysregulated pathways, ontological pathways, protein-protein interaction (PPI) network, and protein-drug interaction (PDI) network. We observed that COVID-19 associated genes share 19, 26, 20, 19, 22 differentially expressed genes with Epilepsy, Stroke, Multiple Sclerosis, Alzheimer's disease, and Parkinson's disease respectively. Gene expression dysregulation, PPI and PDI relationship networks, different pathways suggest that COVID-19 may have a significant link to the development of these NDGDs. This analysis may help to develop therapeutic strategies and raise awareness about the influence of COVID-19 on the progression of NDGDs. © 2021 IEEE.

Case Report: Neurodegenerative Diseases After Severe Acute Respiratory Syndrome Coronavirus 2 Infection, a Report of Three Cases: Creutzfeldt-Jakob Disease, Rapidly Progressive Alzheimer's Disease, and Frontotemporal Dementia.

The relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and neurodegenerative diseases is yet to be fully clarified. Rapid worsening and even new-onset cases of those disorders have been reported in association with coronavirus disease 2019 (COVID-19). We describe three cases of neurodegenerative diseases in patients with SARS-CoV-2: a case of Creutzfeldt-Jakob disease during the COVID-19 acute phase, to our knowledge, is the second one described in the literature; a rapidly progressive Alzheimer's Disease; and a patient with frontotemporal dementia, and a quick decline of both cognitive and behavioral domains. This report suggests an association between SARS-CoV-2 infection and a higher probability of developing or accelerating neurodegenerative chronic neurologic conditions. We reinforce the need for a close cognitive follow-up in the aftermath of Sars-Cov2 infection.

Syncytin, envelope protein of human endogenous retrovirus (HERV): no longer 'fossil' in human genome.

Human endogenous retroviruses (HERVs) are 'fossil viruses' that resulted from stable integrations of exogenous retroviruses throughout evolution. HERVs are defective and do not produce infectious viral particles. However, some HERVs retain a limited coding capacity and produce retroviral transcripts and proteins, which function in human developmental process and various pathologies, including many cancers and neurological diseases. Recently, it has been reported that HERVs are differently expressed in COVID-19 disease caused by infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, we discuss the molecular structure and function of HERV ENV proteins, particularly syncytins, and their conventional roles in human development and diseases, and potential involvement in COVID-19 regarding the newly reported mental symptoms. We also address COVID-19 vaccine-related infertility concerns arising from the similarity of syncytin with the spike protein of SARS-CoV-2, which have been proved invalid.

Using Telemedicine to Assess and Manage Psychosis in Neurodegenerative Diseases in Long-Term Care.

The coronavirus disease 2019 (COVID-19) epidemic has forced a sudden global implementation of telemedicine strategies, including in long-term care (LTC) facilities where many people with dementia and Parkinson disease (PD) reside. Telemedicine offers a unique set of advantages for residents in LTC facilities if effectively supported and implemented, including expanded access to specialists in rural or underserved areas or for people with dementia who cannot travel for off-site visits. Many medical and psychiatric organizations have recently issued new or updated guidelines on the use of telemedicine. On October 22, 2020, a multidisciplinary consensus panel was convened to collate a list of best practices for LTC facilities and specialists when conducting telemedicine with residents with dementia-related psychosis or PD-related psychosis (PDP). A collaborative effort between specialists, facility administrators, and facility staff is essential for the success of telemedicine in the LTC setting. Telemedicine in LTC facilities comes with increased administrative and technical challenges that fall heavily on the shoulders of the LTC facility administrators and staff. Specialists can ease this burden by maintaining flexibility and ensuring expression of empathy and thanks to the staff who are facilitating the visits. LTC staff can provide specialists with valuable information about their patients to aid in evaluation and diagnosis. Specialists can facilitate this exchange of information by speaking to staff who work closely with the resident about any signs of hallucinations or delusions they may have observed. Educational efforts can increase staff understanding of dementia and PDP and empower them to engage with, and facilitate the resident's treatment plan. Using these strategies to take advantage of the benefits of telemedicine, specialists and LTC staff can together expand and improve care for LTC facility residents with dementia-related psychosis or PDP.

Olfactory Characterization and Training in Older Adults: Protocol Study.

The aim of this article is to present the research protocol for a prospective cohort study that will assess the olfactory function and the effect of an intervention based on olfactory training in healthy very old adults (≥75 years old). A convenience sample of 180 older people (50% female) will be recruited in three different environments: hospitalized control group (CH) with stable acute illness (n = 60); ambulatory control group (CA) of community-based living (n = 60); and an experimental odor training group (EOT) from nursing homes (n = 60). The odor training (OT) intervention will last 12 weeks. All the volunteers will be assessed at baseline; CA and EOT groups will also be assessed after 12 weeks. The primary end point will be change in olfactory capacity from baseline to 12 weeks period of intervention or control. The intervention effects will be assessed with the overall score achieved in Sniffin Sticks Test (SST) - Threshold, Discrimination, and Identification (TDI) extended version. Secondary end points will be changes in cognitive tasks, quality of life, mood, immune status, and functional capacity. All these measurements will be complemented with an immune fitness characterization and a deep proteome profiling of the olfactory epithelium (OE) cultured ex vivo. The current study will provide additional evidence to support the implementation of olfactory precision medicine and the development of immunomodulatory nasal therapies based on non-invasive procedures. The proposed intervention will also intend to increase the knowledge about the olfactory function in very elderly people, improve function and quality of life, and promote the recovery of the health.

Residual olfactory dysfunction in coronavirus disease 2019 patients after long term recovery.

INTRODUCTION: Hyposmia is among the most common symptoms of COVID-19 patients. Previous research has mainly described this issue at the disease's early stages. Because olfactory impairment can indicate neurological degeneration, we investigated the possibility of permanent olfactory damage by assessing hyposmia during the late recovery stage of COVID-19 patients. METHODS: Ninety-five patients were assessed with the Brief Smell Identification Test for Chinese (B-SITC) and Hyposmia Rating Scale (HRS) after 16 weeks from disease onset. Five weeks later, 41 patients were retested with B-SITC. RESULTS: At the first visit, hyposmia was identified in 26/82 (31.7%) and 22/95 (23.2%) of participants by HRS (HRS score ≤22) and B-SITC (B-SITC score <8), respectively. The rates of hyposmia in patients who performed B-SITC after 14-15 weeks, 16-17 weeks, and ≥18 weeks from disease onset were 7/25 (28%), 8/35 (23%) and 7/35 (20%), respectively, which demonstrated a trend of olfaction improvement as recovery time prolonging. Hyposmia percentages decreased from the first visit (34.1%) to the second visit (24.4%) for the 41 patients who completed 2 visits. B-SITC scores of the first-visit hyposmia participants increased significantly at the second visit (5.29 ± 2.02 to 8.29 ± 2.40; n = 14, P = 0.001). Severe cases tended to recover less than common cases. CONCLUSIONS: Hyposmia was present in up to one-third of COVID-19 patients after about 3 months from disease onset. Notable recovery of olfactory function was observed at a next 5-weeks follow-up. Clinical severity had little influence on olfactory impairment and recovery.

Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates.

Liquid-liquid phase separation (LLPS) is a rapidly growing research focus due to numerous demonstrations that many cellular proteins phase-separate to form biomolecular condensates (BMCs) that nucleate membraneless organelles (MLOs). A growing repertoire of mechanisms supporting BMC formation, composition, dynamics, and functions are becoming elucidated. BMCs are now appreciated as required for several steps of gene regulation, while their deregulation promotes pathological aggregates, such as stress granules (SGs) and insoluble irreversible plaques that are hallmarks of neurodegenerative diseases. Treatment of BMC-related diseases will greatly benefit from identification of therapeutics preventing pathological aggregates while sparing BMCs required for cellular functions. Numerous viruses that block SG assembly also utilize or engineer BMCs for their replication. While BMC formation first depends on prion-like disordered protein domains (PrLDs), metal ion-controlled RNA-binding domains (RBDs) also orchestrate their formation. Virus replication and viral genomic RNA (vRNA) packaging dynamics involving nucleocapsid (NC) proteins and their orthologs rely on Zinc (Zn) availability, while virus morphology and infectivity are negatively influenced by excess Copper (Cu). While virus infections modify physiological metal homeostasis towards an increased copper to zinc ratio (Cu/Zn), how and why they do this remains elusive. Following our recent finding that pan-retroviruses employ Zn for NC-mediated LLPS for virus assembly, we present a pan-virus bioinformatics and literature meta-analysis study identifying metal-based mechanisms linking virus-induced BMCs to neurodegenerative disease processes. We discover that conserved degree and placement of PrLDs juxtaposing metal-regulated RBDs are associated with disease-causing prion-like proteins and are common features of viral proteins responsible for virus capsid assembly and structure. Virus infections both modulate gene expression of metalloproteins and interfere with metal homeostasis, representing an additional virus strategy impeding physiological and cellular antiviral responses. Our analyses reveal that metal-coordinated virus NC protein PrLDs initiate LLPS that nucleate pan-virus assembly and contribute to their persistence as cell-free infectious aerosol droplets. Virus aerosol droplets and insoluble neurological disease aggregates should be eliminated by physiological or environmental metals that outcompete PrLD-bound metals. While environmental metals can control virus spreading via aerosol droplets, therapeutic interference with metals or metalloproteins represent additional attractive avenues against pan-virus infection and virus-exacerbated neurological diseases.

COVID-19 as a Trigger of Brain Autoimmunity.

Entry of SARS-CoV-2 into the central nervous system (CNS) activates microglia, triggering chronic neuroinflammation and possibly neurodegeneration. The complex transcriptome of SARS-CoV-2 shares molecular similarities with diverse human CNS protein epitopes, leading to a cytokine storm and various autoantibodies, potentially culminating in an autoimmune state. A COVID-19 initiated CNS autoimmune cascade may occur via multiple pathways including molecular mimicry, bystander activation, epitope spreading, production of autoantibodies, and immortalization of effector B-cells.

COVID-19, Neuropathology, and Aging: SARS-CoV-2 Neurological Infection, Mechanism, and Associated Complications.

The spectrum of health complications instigated by coronavirus disease 2019 (COVID-19, caused by the novel severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2) pandemic has been diverse and complex. Besides the evident pulmonary and cardiovascular threats, accumulating clinical data points to several neurological complications, which are more common in elderly COVID-19 patients. Recent pieces of evidence have marked events of neuro infection and neuroinvasion, producing several neurological complications in COVID-19 patients; however, a systematic understanding of neuro-pathophysiology and manifested neurological complications, more specifically in elderly COVID-19 patients is largely elusive. Since the elderly population gradually develops neurological disorders with aging, COVID-19 inevitably poses a higher risk of neurological manifestations to the aged patients. In this report, we reviewed SARS-CoV-2 infection and its role in neurological manifestations with an emphasis on the elderly population. We reviewed neuropathological events including neuroinfection, neuroinvasion, and their underlying mechanisms affecting neuromuscular, central- and peripheral- nervous systems. We further assessed the imminent neurological challenges in the COVID-19 exposed population, post-SARS-CoV-2-infection. Given the present state of clinical preparedness, the emerging role of AI and machine learning was also discussed concerning COVID-19 diagnostics and its management. Taken together, the present review summarizes neurological outcomes of SARS-CoV-2 infection and associated complications, specifically in elderly patients, and underlines the need for their clinical management in advance.

NOX2 Activation in COVID-19: Possible Implications for Neurodegenerative Diseases.

Coronavirus disease 2019 (COVID-19) is a rapidly spreading contagious infectious disease caused by the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that primarily affects the respiratory tract as well as the central nervous system (CNS). SARS-CoV-2 infection occurs through the interaction of the viral protein Spike with the angiotensin II receptor (ACE 2), leading to an increase of angiotensin II and activation of nicotinamide adenine dinucleotide phosphate oxidase2 (NOX2), resulting in the release of both reactive oxygen species (ROS) and inflammatory molecules. The purpose of the review is to explain that SARS-CoV-2 infection can determine neuroinflammation that induces NOX2 activation in microglia. To better understand the role of NOX2 in inflammation, an overview of its involvement in neurodegenerative diseases (NDs) such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) is provided. To write this manuscript, we performed a PubMed search to evaluate the possible relationship of SARS-CoV-2 infection in NOX2 activation in microglia, as well as the role of NOX2 in NDs. Several studies highlighted that NOX2 activation in microglia amplifies neuroinflammation. To date, there is no clinical treatment capable of counteracting its activation, however, NOX2 could be a promising pharmaceutical target useful for both the treatment and prevention of NDs and COVID-19 treatment.