COVID-19 and neurocognitive disorders.

PURPOSE OF REVIEW: The COVID-19 infection results in various viral-related physical and mental health problems, joined with the long-term psychological impact of the pandemic in general. However, the accompanying neurocognitive changes remain poorly understood. RECENT FINDINGS: We synthetize the current knowledge of viral (SARS-CoV-2) induced inflammation, mechanisms to viral entry into the central nervous system and altered neurotransmitter systems to provide an informed neurobiological explanation for the rise of neurocognitive disorders (defined as per the DSM-5 criteria). SUMMARY: The mild and major neurocognitive disorder symptoms due to the COVID-19 pandemic provide a unique opportunity to address the early changes underlying neurocognitive impairment at both clinical and molecular level. We discuss the utilization of the available evidence for their management and future novel therapeutic opportunities.

Using 7T MRI to Evaluate COVID‐19 and Brain

Background SARS‐CoV‐2 causes neurological, psychiatric and neurocognitive deficits in a large proportion of patients via direct or indirect viral invasion, systemic or intracranial inflammation, micro‐ or macrovascular pathologies, and hypoxic or systemic metabolic complications. The insult to brain function during the acute phase of COVID‐19 may accelerate neurodegenerative process and potentially increase the risk of Alzheimer's Disease or Related Dementias. Ultrahigh Field (7T) MRI has an enhanced sensitivity and spatial resolution over and above clinical 3T MRI, allowing detection of small changes in brain sub‐structures and integrity. Methods The 7T COVID Consortium is an international collaboration across 5 sites which aims to study Ultrahigh Field neuroimaging correlates of clinical phenotypes, neuroimmunology, viral and host genetics, and neurodegenerative markers in a diverse, multi‐ethnic cohort of adults following SARS‐CoV2 infection. Multiple population cohorts include matched individuals following a clinically similar non‐COVID19 illness, and healthy controls including Framingham cohort and further comparative data from an independently‐funded genetically inherited Alzheimer's disease. Synergized imaging sequences across the sites with Ultrahigh Field (7T) facilities, standardized bio‐sampling protocols, and adaptation of centralised REDCAP with WHO protocols and other studies within the COVID consortia1permit harmonised data analyses. Results Pilot data from the UK site, in Nottingham, included individuals who presented with neurological disorders associated with SARS‐CoV2 Alpha variant of concern (B.1.1.7). Clinical phenotypes and biochemical measures of patients during the acute phase of COVID‐19 were documented2and a prospective follow up for neurocognitive assessments and 7T MRI were arranged. Compared with healthy controls, hospitalised patients showed neuroimaging features of cerebral white matter hyperintensities suggestive of neurovascular ischaemia or neuroinflammation. These radiological cerebral white matter hyperintensities could progress 7 months after the acute illness despite clinical silence. Long COVID appeared to have increased susceptibility, that is suggestive of iron accumulation or inflammation, within the basal ganglia structures. Conclusion Pilot data suggest persistent or emergent neuroimaging abnormalities within a year after SARS‐CoV2 infection. Serial follow up may clarify long‐term impact of COVID‐19. Funding: NIH/NIA, USA (R56AG074467), Nottingham Biomedical Research Centre (NIHR), Medical Research Council, UK (MR/T005580/1). References: 1.de Erausquin, et al. http://doi.org/10.1002/alz.12255 2.Dhillon, et al. https://doi.org/10.3389/fneur.2021.640017

European Working Group on SARS-CoV-2: Current Understanding, Unknowns, and Recommendations on the Neurological Complications of COVID-19.

Background: The emergence of COVID-19 was rapidly followed by infection and the deaths of millions of people across the globe. With much of the research and scientific advancement rightly focused on reducing the burden of severe and critical acute COVID-19 infection, the long-term effects endured by those who survived the acute infection has been previously overlooked. Now, an appreciation for the post-COVID-19 condition, including its neurological manifestations, is growing, although there remain many unknowns regarding the etiology and risk factors of the condition, as well as how to effectively diagnose and treat it. Methods: Here, drawing upon the experiences and expertise of the clinicians and academics of the European working group on COVID-19, we have reviewed the current literature to provide a comprehensive overview of the neurological sequalae of the post-COVID-19 condition. Results: In this review, we provide a summary of the neurological symptoms associated with the post-COVID-19 condition, before discussing the possible mechanisms which may underly and manifest these symptoms. Following this, we explore the risk factors for developing neurological symptoms as a result of COVID-19 and the post-COVID-19 condition, as well as how COVID-19 infection may itself be a risk factor for the development of neurological disease in the future. Lastly, we evaluate how the post-COVID condition could be accurately diagnosed and effectively treated, including examples of the current guidelines, clinical outcomes, and tools that have been developed to aid in this process, as well as addressing the protection provided by COVID-19 vaccines against the post-COVID-19 condition. Conclusions: Overall, this review provides a comprehensive overview of the neurological sequalae of the post-COVID-19 condition. Impact statement With our understanding of the neurological complications of the post-COVID-19 condition currently lacking sufficient depth, this review aimed at highlighting the current knowns and unknowns of the post-COVID-19 condition. In this review, we draw upon the experiences and expertise of the clinicians and academics of the European working group on COVID-19, as well as explore the current published literature, to evaluate a range of topics associated with the neurological complications of the post-COVID-19 condition. As a result, we have provided a comprehensive review of the topic. The European Working Group on SARS-CoV-2 Many essential questions surrounding COVID-19 remain unanswered, including its neurological complications and associated sequalae. In this review, we aim at identifying the current gaps in our understanding of post-COVID-19 neurological sequalae and suggest how future studies should be undertaken to fill these gaps. This review will draw upon the current biological and mechanistic understanding of COVID-19 and post-COVID-19 complications to discuss the clinically relevant aspects associated with the neurological manifestations of post-COVID-19 syndrome. From our discussions, the following questions were considered highly relevant for contemplation.

Chronic neuropsychiatric sequelae of SARS-CoV-2: Protocol and methods from the Alzheimer's Association Global Consortium.

Introduction: Coronavirus disease 2019 (COVID-19) has caused >3.5 million deaths worldwide and affected >160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID-19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID-19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID-19 to neurologic illness, both short and long term. Methods: This article describes what is known so far in terms of links among COVID-19, the brain, neurological symptoms, and Alzheimer's disease (AD) and related dementias. We focus on risk factors and possible molecular, inflammatory, and viral mechanisms underlying neurological injury. We also provide a comprehensive description of the Alzheimer's Association Consortium on Chronic Neuropsychiatric Sequelae of SARS-CoV-2 infection (CNS SC2) harmonized methodology to address these questions using a worldwide network of researchers and institutions. Results: Successful harmonization of designs and methods was achieved through a consensus process initially fragmented by specific interest groups (epidemiology, clinical assessments, cognitive evaluation, biomarkers, and neuroimaging). Conclusions from subcommittees were presented to the whole group and discussed extensively. Presently data collection is ongoing at 19 sites in 12 countries representing Asia, Africa, the Americas, and Europe. Discussion: The Alzheimer's Association Global Consortium harmonized methodology is proposed as a model to study long-term neurocognitive sequelae of SARS-CoV-2 infection. Key Points: The following review describes what is known so far in terms of molecular and epidemiological links among COVID-19, the brain, neurological symptoms, and AD and related dementias (ADRD)The primary objective of this large-scale collaboration is to clarify the pathogenesis of ADRD and to advance our understanding of the impact of a neurotropic virus on the long-term risk of cognitive decline and other CNS sequelae. No available evidence supports the notion that cognitive impairment after SARS-CoV-2 infection is a form of dementia (ADRD or otherwise). The longitudinal methodologies espoused by the consortium are intended to provide data to answer this question as clearly as possible controlling for possible confounders. Our specific hypothesis is that SARS-CoV-2 triggers ADRD-like pathology following the extended olfactory cortical network (EOCN) in older individuals with specific genetic susceptibility.The proposed harmonization strategies and flexible study designs offer the possibility to include large samples of under-represented racial and ethnic groups, creating a rich set of harmonized cohorts for future studies of the pathophysiology, determinants, long-term consequences, and trends in cognitive aging, ADRD, and vascular disease.We provide a framework for current and future studies to be carried out within the Consortium. and offers a "green paper" to the research community with a very broad, global base of support, on tools suitable for low- and middle-income countries aimed to compare and combine future longitudinal data on the topic.The Consortium proposes a combination of design and statistical methods as a means of approaching causal inference of the COVID-19 neuropsychiatric sequelae. We expect that deep phenotyping of neuropsychiatric sequelae may provide a series of candidate syndromes with phenomenological and biological characterization that can be further explored. By generating high-quality harmonized data across sites we aim to capture both descriptive and, where possible, causal associations.

Acute and post-acute neurological manifestations of COVID-19: present findings, critical appraisal, and future directions.

Acute and post-acute neurological symptoms, signs and diagnoses have been documented in an increasing number of patients infected by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which causes Coronavirus Disease 2019 (COVID-19). In this review, we aimed to summarize the current literature addressing neurological events following SARS-CoV-2 infection, discuss limitations in the existing literature and suggest future directions that would strengthen our understanding of the neurological sequelae of COVID-19. The presence of neurological manifestations (symptoms, signs or diagnoses) both at the onset or during SARS-CoV-2 infection is associated with a more severe disease, as demonstrated by a longer hospital stay, higher in-hospital death rate or the continued presence of sequelae at discharge. Although biological mechanisms have been postulated for these findings, evidence-based data are still lacking to clearly define the incidence, range of characteristics and outcomes of these manifestations, particularly in non-hospitalized patients. In addition, data from low- and middle-income countries are scarce, leading to uncertainties in the measure of neurological findings of COVID-19, with reference to geography, ethnicity, socio-cultural settings, and health care arrangements. As a consequence, at present a specific phenotype that would specify a post-COVID (or long-COVID) neurological syndrome has not yet been identified.

Hepcidin Increases Cytokines in Alzheimer's Disease and Down's Syndrome Dementia: Implication of Impaired Iron Homeostasis in Neuroinflammation.

The liver-derived hormone hepcidin, a member of the defensin family of antimicrobial peptides, plays an important role in host defense and innate immunity due to its broad antibacterial and antiviral properties. Ferritin, an iron storage protein is often associated with iron deficiency, hypoferritinemia, hypoxia, and immune complications, which are all significant concerns for systemic infection in Alzheimer's disease (AD) and Down's syndrome (DS) dementia. Serum and post-mortem brain samples were collected from AD, DS and age-matched control subjects. Serum samples were analyzed with ELISA for ferritin, hepcidin and IL-6. Additionally, post-mortem brain sections were assessed by immunohistochemistry for iron-related and inflammatory proteins. A significant increase in serum hepcidin levels was found in DS, compared to controls and AD subjects (p < 0.0001). Hepcidin protein was visible in the epithelial cells of choroid plexus, meningeal macrophages and in the astrocytes close to the endothelium of blood vessels. Hepcidin co-localized with IL-6, indicating its anti-inflammatory properties. We found significant correlation between hypoferritinemia and elevated levels of serum hepcidin in AD and DS. Hepcidin can be transported via macrophages and the majority of the vesicular hepcidin enters the brain via a compromised blood brain barrier (BBB). Our findings provide further insight into the molecular implications of the altered iron metabolism in acute inflammation, and can aid towards the development of preventive strategies and novel treatments in the fight against neuroinflammation.

Investigation of CD26, a potential SARS-CoV-2 receptor, as a biomarker of age and pathology.

OBJECTIVE: In some individuals, coronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection leads to a variety of serious inflammatory symptoms, including blood clotting and acute respiratory distress. Death due to COVID-19 shows a steep rise in relation to age. Comorbidities such as type 2 diabetes mellitus (T2DM), hypertension, and cardiovascular disease also increase susceptibility. It has been reported that T-cell regulatory dipeptidyl peptidase 4 (DPP4; cluster of differentiation 26 (CD26)) binds to the external spike (S) glycoprotein of SARS-CoV-2 as a receptor, for the viral entry into the host cell. CD26 is expressed on many cells, including T and natural killer (NK) cells of the immune system, as a membrane-anchored form. A soluble form (sCD26) is also found in the blood plasma and cerebrospinal fluid (CSF). Approach and results: To investigate a possible relationship between sCD26 levels, age and pathology, serum samples were collected from control, T2DM and age-related dementia (ARD) subjects. A significant reduction in serum sCD26 levels was seen in relation to age. ARD and T2DM were also associated with lower levels of sCD26. The analysis of blood smears revealed different cellular morphologies: in controls, CD26 was expressed around the neutrophil membrane, whereas in T2DM, excessive sCD26 was found around the mononucleated cells (MNCs). ARD subjects had abnormal fragmented platelets and haemolysis due to low levels of sCD26. CONCLUSIONS: These findings may help to explain the heterogeneity of SARS-CoV-2 infection. High serum sCD26 levels could protect from viral infection by competively inhibiting the virus binding to cellular CD26, whereas low sCD26 levels could increase the risk of infection. If so measuring serum sCD26 level may help to identify individuals at high risk for the COVID-19 infection.

Alzheimer’s Association International Cohort Study of Chronic Neuropsychiatric Sequeale of SARS-CoV-2 (CNS-SARS-CoV-2)

Abstract Background The pandemic of SARS-CoV-2 is focusing all energies on the impact on survival of affected individuals, treatment and prevention, but increasingly attention is focusing on its enduring consequences. We established a global consortium to study a longitudinal representative cohort of individuals, to characterize neurological and neuropsychiatric sequalae from direct viral, immune-, vascular- or accelerated neurodegenerative injury to the central nervous system (CNS). Method We propose to characterize the neurobehavioral phenomenology associated with SARS-CoV-2 in a large, multinational, longitudinal cohort of post COVID-19 infection patients following three sampling strategies: 1) Opportunity sample of patients discharged after hospital admission for COVID-19 related symptoms. 2) A stratified random sample from COVID-19 testing registries (including asymptomatic and negative participants). 3) Ascertaining COVID-19 exposure (antibody) status in ongoing longitudinal, community-based cohort studies that are already collecting biosamples, cognitive, behavioral and neuroimaging data. We will obtain core data within 6 months of discharge or testing. Core characterization will include interviews with the Schedules of Clinical Assessment in Neuropsychiatry (SCAN), neurological exams, emotional reactivity scales and a neurocognitive assessment. Wherever feasible, we will also collect neuroimaging, biosamples and genetic data. Longitudinal follow up will be conducted at 9 and 18 months of the initial evaluation. An mHealth keeping-in-touch process will be set up to minimize attrition rates. The population cohorts provide a large, unbiased, normative and validation sample, albeit with more heterogenous outcome ascertainment. They also permit examination of pre- and post-COVID trends in symptoms and biomarkers. Since some ethnic groups, as well as in individuals with blood type A, are at higher risk of COVID-19 infection and death, a role of genetics in determining susceptibility to infection and poor outcomes seems well supported. We will collect genome-wide genotypes from our cohort individuals to address the role of ancestry and genetic variation on susceptibility to neuropsychiatric sequelae. High rates of mutation in COVID-19 strongly suggest that viral infectivity, including neurotropism, may not be uniform across countries affected by the pandemic. Results Pending. Conclusion Our consortium is in a unique position to address the interaction between genetics (including ancestral DNA), and viral strain variation on CNS sequelae of SARS-CoV-2.

The Early Impact of the COVID-19 Pandemic on Acute Care Mental Health Services.

OBJECTIVE: This study aimed to explore the effects of COVID-19 and the lockdown measures adopted in England on patients with acute mental illness. METHODS: The authors analyzed referrals to the crisis resolution and home treatment (CRHT) team and inpatient admissions to acute adult wards, at Leicestershire Partnership National Health Service Trust, an integrated community and mental health trust in the United Kingdom. Number of CRHT referrals and inpatient admissions during a 4-week period starting March 16, 2020 ("COVID-19 period"), was studied and compared with the same period in 2018 and 2019 ("control periods"). Demographic and clinical characteristics of patients admitted during the COVID-19 period were compared with those admitted during the 2019 control period. RESULTS: The number of CRHT referrals and inpatient admissions were lower during the COVID-19 period, compared with the control periods, by approximately 12% and 20%, respectively. Patients admitted during the COVID-19 period were significantly more often detained under the Mental Health Act and were considered to pose a risk of aggression. The pattern of diagnoses differed significantly between 2020 and 2019. A higher percentage of patients admitted during the COVID-19 period were diagnosed as having nonaffective psychotic disorders (52% versus 35%) or bipolar disorder (25% versus 15%), and fewer received a diagnosis of depression (8% versus 16%), anxiety disorder (0% versus 3%), adjustment disorder (0% versus 8%), emotionally unstable personality disorder (6% versus 15%), or any other personality disorder (0% versus 5%) (p=0.01). CONCLUSIONS: These findings suggest that the pandemic has profoundly affected care by acute mental health services.