New Alzheimer Disease Drugs, Long COVID and the Central Nervous System, and a Nasal Spray for Migraines-Highlights From the 2023 American Academy of Neurology Conference.

This Medical News article discusses research presented at the recent American Academy of Neurology Conference.

Progressive Worsening of Neurological Manifestations in HIV-Associated Opportunistic Central Nervous System (CNS) Infection Patients After COVID-19 Vaccinations: A Possible Co-Incidence Causality.

BACKGROUND The iceberg phenomenon (in which the most of a problem is invisible) of people living with HIV/AIDS, particularly those with unknown HIV status, has been epidemiologically challenging. Central nervous system (CNS) opportunistic infections in patients with HIV/AIDS are one of the leading causes of morbidity and mortality in people living with HIV/AIDS. There are currently limited data on the immunogenicity, safety, and efficacy of COVID-19 vaccines in people living with HIV/AIDS with its associated opportunistic CNS infections as well as those without antiretroviral treatment. CASE REPORT Two young men with previously unknown HIV status and its related opportunistic infections received their first doses of COVID-19 vaccine (Vero Cell), inactivated. Both patients had the risk factor of having sex with men (men who have sex with men). Fever and first neurological symptoms occurred within the first few days after vaccination. Both patients were hospitalized and were tested positive for HIV for the first time. Both were further diagnosed from brain imaging as having CNS opportunistic infections. A presumptive diagnosis of cerebral toxoplasmosis was established as the working diagnosis according to the laboratory and epidemiological factors. Despite the treatment, neurological and clinical deficits worsened and eventually led to death in both patients. CONCLUSIONS The causality analyses showed that both adverse events had a possible inconsistent causal relationship to COVID-19 vaccination. Our cases may reflect the need for further studies on the safety of COVID-19 vaccines in people with HIV/AIDS-associated CNS opportunistic infection as well as people with HIV/AIDS who never receive antiretroviral treatment (ART).

Neuroinvasion and Neurotropism by SARS-CoV-2 Variants in the K18-hACE2 Mouse.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) not only affects the respiratory tract but also causes neurological symptoms such as loss of smell and taste, headache, fatigue or severe cerebrovascular complications. Using transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2), we investigated the spatiotemporal distribution and pathomorphological features in the CNS following intranasal infection with SARS-CoV-2 variants, as well as after prior influenza A virus infection. Apart from Omicron, we found all variants to frequently spread to and within the CNS. Infection was restricted to neurons and appeared to spread from the olfactory bulb mainly in basally oriented regions in the brain and into the spinal cord, independent of ACE2 expression and without evidence of neuronal cell death, axonal damage or demyelination. However, microglial activation, microgliosis and a mild macrophage and T cell dominated inflammatory response was consistently observed, accompanied by apoptotic death of endothelial, microglial and immune cells, without their apparent infection. Microgliosis and immune cell apoptosis indicate a potential role of microglia for pathogenesis and viral effect in COVID-19 and the possible impairment of neurological functions, especially in long COVID. These data may also be informative for the selection of therapeutic candidates and broadly support the investigation of agents with adequate penetration into relevant regions of the CNS.

SARS-CoV-2 Psychiatric Sequelae: A Review of Neuroendocrine Mechanisms and Therapeutic Strategies.

From the earliest days of the coronavirus disease 2019 (COVID-19) pandemic, there have been reports of significant neurological and psychological symptoms following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. This narrative review is designed to examine the potential psychoneuroendocrine pathogenic mechanisms by which SARS-CoV-2 elicits psychiatric sequelae as well as to posit potential pharmacologic strategies to address and reverse these pathologies. Following a brief overview of neurological and psychological sequelae from previous viral pandemics, we address mechanisms by which SARS-CoV-2 could enter or otherwise elicit changes in the CNS. We then examine the hypothesis that COVID-19-induced psychiatric disorders result from challenges to the neuroendocrine system, in particular the hypothalamic-pituitary-adrenal stress axis and monoamine synthesis, physiological mechanisms that are only further enhanced by the pandemic-induced social environment of fear, isolation, and socioeconomic pressure. Finally, we evaluate several FDA-approved therapeutics in the context of COVID-19-induced psychoneuroendocrine disorders.

Central nervous system outcomes of COVID-19.

The worldwide pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected an estimated 200 million people with over 4 million deaths. Although COVID-19, the disease caused by the SARS-CoV-2 virus, is primarily a respiratory disease, an increasing number of neurologic symptoms have been reported. Some of these symptoms, such as loss of smell or taste, are mild and non-life threatening, while others, such as stroke or seizure, are more critical. Many of these symptoms remain long after the acute illness has passed, a phenomenon known as "long COVID" or postacute sequelae of SARS-CoV-2 infection (PASC). Neurological symptoms can be difficult to study due to the complexity of the central and peripheral nervous system. These neurologic symptoms can be difficult to identify and quantitate. This narrative review will describe approaches for assessing neurologic manifestations of COVID-19, with examples of the data they provide, as well as some directions for future research to aid in understanding the pathophysiology of COVID-19-related neurological implications.

Can Covid-19 attack our nervous system?

Nowadays, Covid-19 is considered a serious health problem worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human coronavirus that has sparked a global pandemic of the coronavirus disease of 2019 (COVID-19). It is well known that the Corona Virus attacks mainly the respiratory system. Meanwhile, it has been established that coronavirus infection can extend beyond the respiratory system and unfortunately, can also affect our nervous system. Multiple neurological symptoms and signs had been documented during and post covid conditions. This virus gets access to the central nervous system (CNS) via the bloodstream leading to infect the endothelial lining cells. Also, it was reported that the virus can enter the peripheral nervous system via retrograde neuronal routes. The virus could be internalized in nerve synapses through endocytosis, transported retrogradely, and spread trans-synoptically to other brain regions. This minireview highlights the possible routes by which SARS-CoV-2 can invade the central nervous system (CNS) and its pathophysiology and manifestation.

Consensus for prevention and management of coronavirus disease 2019 (COVID-19) for neurologists.

Coronavirus disease 2019 (COVID-19) has become a pandemic disease globally. Although COVID-19 directly invades lungs, it also involves the nervous system. Therefore, patients with nervous system involvement as the presenting symptoms in the early stage of infection may easily be misdiagnosed and their treatment delayed. They become silent contagious sources or 'virus spreaders'. In order to help neurologists to better understand the occurrence, development and prognosis, we have developed this consensus of prevention and management of COVID-19. It can also assist other healthcare providers to be familiar with and recognise COVID-19 in their evaluation of patients in the clinic and hospital environment.

SARS-CoV-2 Spike Targets USP33-IRF9 Axis via Exosomal miR-148a to Activate Human Microglia.

SARS-CoV-2, the novel coronavirus infection has consistently shown an association with neurological anomalies in patients, in addition to its usual respiratory distress syndrome. Multi-organ dysfunctions including neurological sequelae during COVID-19 persist even after declining viral load. We propose that SARS-CoV-2 gene product, Spike, is able to modify the host exosomal cargo, which gets transported to distant uninfected tissues and organs and can initiate a catastrophic immune cascade within Central Nervous System (CNS). SARS-CoV-2 Spike transfected cells release a significant amount of exosomes loaded with microRNAs such as miR-148a and miR-590. microRNAs gets internalized by human microglia and suppress target gene expression of USP33 (Ubiquitin Specific peptidase 33) and downstream IRF9 levels. Cellular levels of USP33 regulate the turnover time of IRF9 via deubiquitylation. Our results also demonstrate that absorption of modified exosomes effectively regulate the major pro-inflammatory gene expression profile of TNFα, NF-κB and IFN-ß. These results uncover a bystander pathway of SARS-CoV-2 mediated CNS damage through hyperactivation of human microglia. Our results also attempt to explain the extra-pulmonary dysfunctions observed in COVID-19 cases when active replication of virus is not supported. Since Spike gene and mRNAs have been extensively picked up for vaccine development; the knowledge of host immune response against spike gene and protein holds a great significance. Our study therefore provides novel and relevant insights regarding the impact of Spike gene on shuttling of host microRNAs via exosomes to trigger the neuroinflammation.

COVID-19 and chronic fatigue syndrome: Is the worst yet to come?

There has been concern about possible long-term sequelae resembling myalgic encephalomyelitis/chronic fatigue syndrome in COVID-19 patients. Clarifying the mechanisms underlying such a "post-COVID-19 fatigue syndrome" is essential for the development of preventive and early treatment methods for this syndrome. In the present paper, by integrating insights pertaining to the glymphatic system and the nasal cerebrospinal fluid outflow pathway with findings in patients with chronic fatigue syndrome, idiopathic intracranial hypertension, and COVID-19, I provide a coherent conceptual framework for understanding the pathophysiology of post-COVID-19 fatigue syndrome. According to this hypothesis, this syndrome may result from damage to olfactory sensory neurons, causing reduced outflow of cerebrospinal fluid through the cribriform plate, and further leading to congestion of the glymphatic system with subsequent toxic build-up within the central nervous system. I further postulate that patients with post-COVID-19 fatigue syndrome may benefit from cerebrospinal fluid drainage by restoring glymphatic transport and waste removal from the brain. Obviously, further research is required to provide further evidence for the presence of this post-viral syndrome, and to provide additional insight regarding the relative contribution of the glymphatic-lymphatic system to it. Other mechanisms may also be involved. If confirmed, the glymphatic-lymphatic system could represent a target in combating post-COVID-19 fatigue syndrome. Moreover, further research in this area could also provide new insights into the understanding of chronic fatigue syndrome.

Neurological Complications Among Native Americans with COVID-19: Our Experience at a Tertiary Care Academic Hospital in the U.S.

OBJECTIVE: To study the central nervous system (CNS) complications in patients with COVID-19 infection especially among Native American population in the current pandemic of severe acute respiratory syndrome virus (COVID-19). METHODS: Patients with confirmed COVID-19 infection at University of New Mexico hospital (UNMH) were screened for development of neurological complications during Feb 01 to April 29, 2020 via retrospective chart review. RESULTS: Total of 90 hospitalized patients were screened. Out of seven patients, majority were Native Americans females, and developed neurological complications including subarachnoid hemorrhage (SAH), Intraparenchymal hemorrhage (IPH), Ischemic stroke (IS) and seizure. All 7 patients required Intensive care unit (ICU) level of care. Patients who developed CNS complications other than seizure were females in the younger age group (4 patients, 38-58 years) with poor outcome. Out of 7, three developed subarachnoid hemorrhage, two developed ischemic infarction, and four developed seizure. Two patients with hemorrhagic complication expired during the course of hospitalization. All three patients with seizure were discharged to home. CONCLUSION: Patients with serious CNS complications secondary to COVID-19 infection were observed to be Native Americans. Patients who developed hemorrhagic or ischemic events were observed to have poor outcomes as compared to patients who developed seizures.

Neuroinvasive potential of a primary respiratory pathogen SARS- CoV2: Summarizing the evidences.

BACKROUND AND AIMS: After the emergence of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in the last two decades, the world is facing its new challenge in SARS-CoV-2 pandemic with unfathomable global responses. The characteristic clinical symptoms for Coronavirus (COVID-19) affected patients are high fever, dry-cough, dyspnoea, lethal pneumonia whereas some patients also show additional neurological signs such as headache, nausea, vomiting etc. The accumulative evidences suggest that SARS-CoV-2 is not only confined within the respiratory tract but may also invade the central nervous system (CNS) and peripheral nervous system (PNS) inducing some fatal neurological diseases. Here, we analyze the phylogenetic perspective of SARS-CoV-2 with other strains of ß-Coronaviridae from a standpoint of neurological spectrum disorders. METHODOLOGY: A Pubmed/Medline, NIH Lit Covid, Cochrane library and some open data bases (BioRxiv, MedRxiv,preprint.org and others) search were carried out by using keywords relevant to our topic of discussion. The extracted literatures are scrutinized by the authors. RESULTS: 58 literatures including original articles, case reports and case series were selected by the authors to analyze the differential distribution of neurological impairments in COVID-19 positive patients along with angiotensin-converting enzyme-2 (ACE2) expression dynamics in neuronal and non-neuronal tissue in CNS and PNS with neuroinvasive potential of SARS-CoV2. CONCLUSION: We discuss the need for modulations in clinical approach from a neurological point of view, as a measure towards reducing disease transmission, morbidity and mortality in SARS-CoV2 positive patients.

Clinical time course of COVID-19, its neurological manifestation and some thoughts on its management.

Coronavirus disease-2019 (COVID-19) has become a global pandemic. COVID-19 runs its course in two phases, the initial incubation phase and later clinical symptomatic phase. Patients in the initial incubation phase often have insidious clinical symptoms, but they are still highly contagious. At the later clinical symptomatic phase, the immune system is fully activated and the disease may enter the severe infection stage in this phase. Although many patients are known for their respiratory symptoms, they had neurological symptoms in their first 1-2 days of clinical symptomatic phase, and ischaemic stroke occurred 2 weeks after the onset of the clinical symptomatic phase. The key is to prevent a patient from progressing to this severe infection from mild infection. We are sharing our experience on prevention and management of COVID-19.

The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients.

Following the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), another highly pathogenic coronavirus named SARS-CoV-2 (previously known as 2019-nCoV) emerged in December 2019 in Wuhan, China, and rapidly spreads around the world. This virus shares highly homological sequence with SARS-CoV, and causes acute, highly lethal pneumonia coronavirus disease 2019 (COVID-19) with clinical symptoms similar to those reported for SARS-CoV and MERS-CoV. The most characteristic symptom of patients with COVID-19 is respiratory distress, and most of the patients admitted to the intensive care could not breathe spontaneously. Additionally, some patients with COVID-19 also showed neurologic signs, such as headache, nausea, and vomiting. Increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases. The infection of SARS-CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Furthermore, some coronaviruses have been demonstrated able to spread via a synapse-connected route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lung and lower respiratory airways. Considering the high similarity between SARS-CoV and SARS-CoV2, it remains to make clear whether the potential invasion of SARS-CoV2 is partially responsible for the acute respiratory failure of patients with COVID-19. Awareness of this may have a guiding significance for the prevention and treatment of the SARS-CoV-2-induced respiratory failure.

Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms.

The recent outbreak of coronavirus infectious disease 2019 (COVID-19) has gripped the world with apprehension and has evoked a scare of epic proportion regarding its potential to spread and infect humans worldwide. As we are in the midst of an ongoing pandemic of COVID-19, scientists are struggling to understand how it resembles and differs from the severe acute respiratory syndrome coronavirus (SARS-CoV) at the genomic and transcriptomic level. In a short time following the outbreak, it has been shown that, similar to SARS-CoV, COVID-19 virus exploits the angiotensin-converting enzyme 2 (ACE2) receptor to gain entry inside the cells. This finding raises the curiosity of investigating the expression of ACE2 in neurological tissue and determining the possible contribution of neurological tissue damage to the morbidity and mortality caused by COIVD-19. Here, we investigate the density of the expression levels of ACE2 in the CNS, the host-virus interaction and relate it to the pathogenesis and complications seen in the recent cases resulting from the COVID-19 outbreak. Also, we debate the need for a model for staging COVID-19 based on neurological tissue involvement.