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1.
Music and Science ; 6, 2023.
Article in English | Scopus | ID: covidwho-2195669

ABSTRACT

COVID-19 continues to strain healthcare systems around the globe. Research has shown a relationship between COVID-19 and an inflammatory response, including neuropathological outcomes. Additionally, studies have shown positive effects of engagement with music on inflammatory responses;music may have potential, as a method, to reduce inflammation triggered by COVID-19. This review compiles exhaustive research from multiple disciplines to account for this possibility. The authors utilized a meta-narrative approach to complete this review. The search was conducted using PubMed, Embase, OneSearch, Primo, Google Scholar, Clinicaltrials.gov, and the bibliographies of relevant articles. In total, 84 articles were included for full-text review, discussion, and analysis. Articles pertaining to music and acoustics encompassed a date range from 1964–2020. Articles referencing COVID-19 spanned the years 2019–2021. This work focused on associations between engagement with music, stress response, blood-brain barrier integrity, inflammation, COVID-19, and neuropathology in preclinical and clinical models. Detailed analysis revealed that engagement with music has the potential to reduce the harmful effects of COVID-19, particularly in the inflammation and blood clotting pathways associated with a range of pathophysiological and neuropathological issues. Further work is warranted to standardize and validate existing methods associating positive effects of engagement with music on the negative effects of COVID-19. © The Author(s) 2023.

2.
Alzheimer's and Dementia ; 18(S4) (no pagination), 2022.
Article in English | EMBASE | ID: covidwho-2172414

ABSTRACT

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may impact neurological function acutely or chronically, even in the absence of severe respiratory illness. Developing clinically relevant laboratory models to understand the neuropathogenesis of SARS-CoV-2 infection is an important step towards unravelling this neurologic consequence. We hypothesize that mouse adapted SARS-CoV-2 viral infection will induce neuroinflammation in immuno-competent C57BL/6J (10 weeks old male) as well as immunodeficient RAG2-/- (10 weeks old male) and BALB/c (1 year old female) mice. Method(s): All three mouse strains were inoculated intranasally with a dose of 1x103 PFU/mouse (50 microL) of either mock or the mouse-adapted (MA)10 strain of SARS-CoV-2 (BEI resource, NR-55329). Mice were euthanized on day 2, 3, 7, 15 or 30 post infection and brain samples processed for qRT-PCR, immunofluorescence, and H&E analysis. Result(s): SARS-CoV-2 MA10 resulted in a significantly higher (p < 0.05) mRNA expression for chemokine ligand 2 (CCL2) and lower (p < 0.05) mRNA expression for the blood-brain barrier component Claudin-5 in RAG2-/- and WT mice when compared to mock infection. Also, SARS-CoV-2 MA10 infection increased microglial expression in 1 year old female BALB/c mice after 2 days of infection, compared to mock infected group. At 30 days post infection, MA10 infected BALB/c mice had a higher perivascular lymphocyte cuffing in the brain. Conclusion(s): This study demonstrates that the mouse-adapted MA10 strain of SARS-CoV-2 can induce a neuroinflammatory state in the brain and more so in immunodeficient and aging mouse models. These mouse models will enable the investigation of the long-term neurological effects of SARS-CoV-2 infection. Copyright © 2022 the Alzheimer's Association.

3.
Alzheimers Dement ; 18(4): 790-809, 2022 04.
Article in English | MEDLINE | ID: covidwho-2172367

ABSTRACT

In tandem with the ever-increasing aging population in low and middle-income countries, the burden of dementia is rising on the African continent. Dementia prevalence varies from 2.3% to 20.0% and incidence rates are 13.3 per 1000 person-years with increasing mortality in parts of rapidly transforming Africa. Differences in nutrition, cardiovascular factors, comorbidities, infections, mortality, and detection likely contribute to lower incidence. Alzheimer's disease, vascular dementia, and human immunodeficiency virus/acquired immunodeficiency syndrome-associated neurocognitive disorders are the most common dementia subtypes. Comprehensive longitudinal studies with robust methodology and regional coverage would provide more reliable information. The apolipoprotein E (APOE) ε4 allele is most studied but has shown differential effects within African ancestry compared to Caucasian. More candidate gene and genome-wide association studies are needed to relate to dementia phenotypes. Validated culture-sensitive cognitive tools not influenced by education and language differences are critically needed for implementation across multidisciplinary groupings such as the proposed African Dementia Consortium.


Subject(s)
Alzheimer Disease , Dementia, Vascular , Dementia , Aged , Alzheimer Disease/genetics , Apolipoprotein E4/genetics , Dementia/epidemiology , Dementia/genetics , Dementia, Vascular/complications , Genome-Wide Association Study , Genotype , Humans
4.
Cells ; 11(21)2022 Oct 28.
Article in English | MEDLINE | ID: covidwho-2090008

ABSTRACT

Several reports have shown that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential to also be neurotropic. However, the mechanisms by which SARS-CoV-2 induces neurologic injury, including neurological and/or psychological symptoms, remain unclear. In this review, the available knowledge on the neurobiological mechanisms underlying COVID-19 was organized using the AOP framework. Four AOPs leading to neurological adverse outcomes (AO), anosmia, encephalitis, stroke, and seizure, were developed. Biological key events (KEs) identified to induce these AOs included binding to ACE2, blood-brain barrier (BBB) disruption, hypoxia, neuroinflammation, and oxidative stress. The modularity of AOPs allows the construction of AOP networks to visualize core pathways and recognize neuroinflammation and BBB disruption as shared mechanisms. Furthermore, the impact on the neurological AOPs of COVID-19 by modulating and multiscale factors such as age, psychological stress, nutrition, poverty, and food insecurity was discussed. Organizing the existing knowledge along an AOP framework can represent a valuable tool to understand disease mechanisms and identify data gaps and potentially contribute to treatment, and prevention. This AOP-aligned approach also facilitates synergy between experts from different backgrounds, while the fast-evolving and disruptive nature of COVID-19 emphasizes the need for interdisciplinarity and cross-community research.


Subject(s)
Adverse Outcome Pathways , COVID-19 , Stroke , Humans , SARS-CoV-2 , Blood-Brain Barrier
5.
Cells ; 11(19)2022 10 04.
Article in English | MEDLINE | ID: covidwho-2065731

ABSTRACT

Here, we aim to describe COVID-19 pathology across different tissues to clarify the disease's pathophysiology. Lungs, kidneys, hearts, and brains from nine COVID-19 autopsies were compared by using antibodies against SARS-CoV-2, macrophages-microglia, T-lymphocytes, B-lymphocytes, and activated platelets. Alzheimer's Disease pathology was also assessed. PCR techniques were used to verify the presence of viral RNA. COVID-19 cases had a short clinical course (0-32 days) and their mean age was 77.4 y/o. Hypoxic changes and inflammatory infiltrates were present across all tissues. The lymphocytic component in the lungs and kidneys was predominant over that of other tissues (p < 0.001), with a significantly greater presence of T-lymphocytes in the lungs (p = 0.020), which showed the greatest presence of viral antigens. The heart showed scant SARS-CoV-2 traces in the endothelium-endocardium, foci of activated macrophages, and rare lymphocytes. The brain showed scarce SARS-CoV-2 traces, prominent microglial activation, and rare lymphocytes. The pons exhibited the highest microglial activation (p = 0.017). Microthrombosis was significantly higher in COVID-19 lungs (p = 0.023) compared with controls. The most characteristic pathological features of COVID-19 were an abundance of T-lymphocytes and microthrombosis in the lung and relevant microglial hyperactivation in the brainstem. This study suggests that the long-term sequelae of COVID-19 derive from persistent inflammation, rather than persistent viral replication.


Subject(s)
COVID-19 , Thrombosis , Aged , Antigens, Viral , Brain/pathology , Humans , Kidney , Lung/pathology , Macrophages , RNA, Viral , SARS-CoV-2 , T-Lymphocytes , Thrombosis/pathology
7.
Annals of Neurosciences ; 2022.
Article in English | EMBASE | ID: covidwho-2005563

ABSTRACT

Background and Purpose: About 56% of symptomatic COVID-19 survivors have been found with neuropsychological comorbidities, such as depression, anxiety, posttraumatic stress disorders (PTSD), and impaired quality of life (QoL). Alongside, antimicrobial, anti-inflammatory, neuroprotective, regenerative, immunomodulatory, cardio-pulmonary health promotive, and psychological benefits of yogic and Ayurvedic intervention are well documented. Therefore, this study aimed to assess the effect of online Yoga (OYI) and Yoga cum Ayurveda intervention (OYAI) on COVID-19-induced depression, anxiety, PTSD, and poor QoL. Method: Seventy-two participants (males/females: 33/26) with at least a 3-month back history of symptomatic COVID-19 infection and age (mean ± SD: 32.33 ± 9.9 and 33.04 ± 12.9 for males and females, respectively) were recruited from Patanjali Ayurveda Hospital, Haridwar, India, and All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India, before random allocation into an equal-sized control group (CG), Yoga group (YG) and Yoga cum concoction (YCG) group. Split-plot analysis of variance and Kruskal–Wallis tests with Bonferroni adjusted post hoc comparisons were computed for normal and nonnormal data using IBM SPSS (25th Version, SPSS South Asia Private Limited, Bangalore, India). Results: Both the treatments—the 30-day OYI and OYAI, significantly improved depression (P <.002, ES: -0.99 and P <.001, ES: -2.11), anxiety (P <.001, ES: -1.32 and -1.89), PTSD (P <.001, ES: -1.8 and -1.83) and QoL related constructs (P <.001, ES: 0.63 and 0.76;0.71 and 0.93 for each OYI and OYAI versus general health and physical health;P <.001, ES: 0.65 for OYAI versus psychological health;and P <.003, ES: 0.54 for OYI versus environment) of the participants compared to the controls. Conclusion: OYAI may better ameliorate COVID-19-induced psychological comorbidities than OYI with no adverse effects.

8.
Canadian Journal of Neurological Sciences ; 49, 2022.
Article in English | EMBASE | ID: covidwho-2002963

ABSTRACT

The proceedings contain 174 papers. The topics discussed include: deep learning prediction of response to disease modifying therapy in primary progressive multiple sclerosis;changes in ischemic stroke presentations and associated workflow during the first wave of the COVID-19 pandemic: a population study;a novel recessive TNNT1 congenital core-rod myopathy in French Canadians;identification of predictors of response to Erenumab in episodic and chronic migraine in a cohort of patients: a preliminary analysis;entropy on routine EEG: an interictal marker of seizure frequency?;can quantitative susceptibility mapping help diagnose and predict recovery of concussion in children?;neuropathology of eight cases of the new Brunswick cluster of neurological syndrome of unknown cause (NSUC);does gender equality exist in the surgical management of degenerative lumbar disease?;cerebral venous sinus thrombosis in preterm infants;endovascular treatment of acute ischemic stroke in patients with pre-morbid disability: a meta-analysis;and muscular MRI pattern recognition for muscular dystrophies: the era of artificial intelligence beyond a systematic review.

9.
J Neuropsychiatry Clin Neurosci ; : appineuropsych22010002, 2022 Jul 25.
Article in English | MEDLINE | ID: covidwho-1962561

ABSTRACT

Encephalopathy, a common condition among patients hospitalized with COVID-19, can be a challenge to manage and negatively affect prognosis. While encephalopathy may present clinically as delirium, subsyndromal delirium, or coma and may be a result of systemic causes such as hypoxia, COVID-19 has also been associated with more prolonged encephalopathy due to less common but nevertheless severe complications, such as inflammation of the brain parenchyma (with or without cerebrovascular involvement), demyelination, or seizures, which may be disproportionate to COVID-19 severity and require specific management. Given the large number of patients hospitalized with severe acute respiratory syndrome coronavirus-2 infection, even these relatively unlikely complications are increasingly recognized and are particularly important because they require specific management. Therefore, the aim of this review is to provide pragmatic guidance on the management of COVID-19 encephalopathy through consensus agreement of the Global COVID-19 Neuro Research Coalition. A systematic literature search of MEDLINE, medRxiv, and bioRxiv was conducted between January 1, 2020, and June 21, 2021, with additional review of references cited within the identified bibliographies. A modified Delphi approach was then undertaken to develop recommendations, along with a parallel approach to score the strength of both the recommendations and the supporting evidence. This review presents analysis of contemporaneous evidence for the definition, epidemiology, and pathophysiology of COVID-19 encephalopathy and practical guidance for clinical assessment, investigation, and both acute and long-term management.

10.
J Neurochem ; 163(2): 113-132, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-1956772

ABSTRACT

COVID-19 causes more than million deaths worldwide. Although much is understood about the immunopathogenesis of the lung disease, a lot remains to be known on the neurological impact of COVID-19. Here, we evaluated immunometabolic changes using astrocytes in vitro and dissected brain areas of SARS-CoV-2 infected Syrian hamsters. We show that SARS-CoV-2 alters proteins of carbon metabolism, glycolysis, and synaptic transmission, many of which are altered in neurological diseases. Real-time respirometry evidenced hyperactivation of glycolysis, further confirmed by metabolomics, with intense consumption of glucose, pyruvate, glutamine, and alpha ketoglutarate. Consistent with glutamine reduction, the blockade of glutaminolysis impaired viral replication and inflammatory response in vitro. SARS-CoV-2 was detected in vivo in hippocampus, cortex, and olfactory bulb of intranasally infected animals. Our data evidence an imbalance in important metabolic molecules and neurotransmitters in infected astrocytes. We suggest this may correlate with the neurological impairment observed during COVID-19, as memory loss, confusion, and cognitive impairment.


Subject(s)
COVID-19 , Animals , Astrocytes , Carbon , Cricetinae , Disease Models, Animal , Glucose , Glutamine , Ketoglutaric Acids , Mesocricetus , Pyruvates , SARS-CoV-2
11.
EPMA J ; 13(2): 261-284, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1930583

ABSTRACT

COVID-19-caused neurological problems are the important post-CoV-2 infection complications, which are recorded in ~ 40% of critically ill COVID-19 patients. Neurodegeneration (ND) is one of the most serious complications. It is necessary to understand its molecular mechanism(s), define research gaps to direct research to, hopefully, design new treatment modalities, for predictive diagnosis, patient stratification, targeted prevention, prognostic assessment, and personalized medical services for this type of complication. Individualized nano-bio-medicine combines nano-medicine (NM) with clinical and molecular biomarkers based on omics data to improve during- and post-illness management or post-infection prognosis, in addition to personalized dosage profiling and drug selection for maximum treatment efficacy, safety with least side-effects. This review will enumerate proteins, receptors, and enzymes involved in CoV-2 entrance into the central nervous system (CNS) via the blood-brain barrier (BBB), and list the repercussions after that entry, ranging from neuroinflammation to neurological symptoms disruption mechanism. Moreover, molecular mechanisms that mediate the host effect or viral detrimental effect on the host are discussed here, including autophagy, non-coding RNAs, inflammasome, and other molecular mechanisms of CoV-2 infection neuro-affection that are defined here as hallmarks of neuropathology related to COVID-19 infection. Thus, a couple of questions are raised; for example, "What are the hallmarks of neurodegeneration during COVID-19 infection?" and "Are epigenetics promising solution against post-COVID-19 neurodegeneration?" In addition, nano-formulas might be a better novel treatment for COVID-19 neurological complications, which raises one more question, "What are the challenges of nano-bio-based nanocarriers pre- or post-COVID-19 infection?" especially in the light of omics-based changes/challenges, research, and clinical practice in the framework of predictive preventive personalized medicine (PPPM / 3P medicine).

12.
Neurology ; 98(18 SUPPL), 2022.
Article in English | EMBASE | ID: covidwho-1925583

ABSTRACT

Objective: To describe the clinicopathological correlations of 141 confirmed postmortem cases of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome-coronavirus -2 (SARS-CoV-2). Background: Analysis of 50 cases of COVID-19 with available neuropathology revealed three CNS findings. First, hypoxia-ischemia does not account for all relevant neuropathological features. Second, elevated levels of circulating cytokines suggest activation of post-infectious immunity indicative of a cytokine storm, with increased hypercoagulability leading to a risk for thrombotic and hemorrhagic parenchymal tissue infarction. Third, a minority of cases have acute demyelinating encephalomyelitis-(ADEM) like features or indolent brainstem encephalitis. Such cases may present with early altered sensorium and brainstem signs. Fourth, SARS-CoV-2 staining could not be confirmed due to paucity of available tissue specimens. Design/Methods: Ninety-four additional cases with available postmortem CNS neuropathology showed four additional findings. Results: First, positive SARS-CoV-2 genome by PCR testing is present in brain tissues especially in olfactory bulb neurons and glial cells lending support to a route of entry into the CNS and the importance of early anosmia. Second, SARS-CoV-2-positive neurons appear to be TUNEL positive and caspase-positive, displaying reversible pT231 Tau localization in some cell soma that may be highly neurotoxic and a driver of tauopathy. Third, expression of ACE2 in oligodendrocytes is associated with viral entry, while TMPRSS2 and TMPRSS4 staining is implicated in pruning of viral-decorating spikes. Fourth, meningeal and interstitial brainstem inflammation by cytotoxic T-cells coincides with the localization of SARS-CoV-2 viral proteins in cranial nerves and interstitial areas of lower brainstem encephalitis. The detection of brain microglial activation and sparse perivascular and leptomeningeal T-cell infiltrates correlates with critical illness encephalopathy. Conclusions: Genetic diversity, recombination, and viral mutation carries the foreseeable risk of continued fatality due to the direct and indirect effects of SARS-CoV-2 that include inflammatory vasculopathy, encephalitis, silent infarctions, and critical illness encephalopathy.

13.
Neurology ; 98(18 SUPPL), 2022.
Article in English | EMBASE | ID: covidwho-1925236

ABSTRACT

Objective: Neurological manifestations are common with Covid-19 illness. Many unusual neurological manifestations have been described and we herewith report one such case. Background: COVID-19 is predominantly a respiratory pathogen but can cause multi system involvement. Many studies have shown significant neurological manifestations associated with Covid-19 infection. Some of these neurological manifestations are quite specific like GuillainBarre syndrome. But, many uncommon manifestations have been described like the following case. Design/Methods: A 35-year old woman with no prior history of fever or any other illness presented with insidious onset, gradually progressive weakness of bulbar and bilateral facial weakness along with asymmetrical weakness of both upper limbs of one and half months duration. She was evaluated and investigated accordingly. Results: On neurological examination, the patient had dysphonia, dysphagia, bilateral lower motor neuron facial palsy. Along with weakness of neck flexors and grossly asymmetrical weakness of upper limbs. The motor power on right is MRC 2/5 and MRC 4/5 in left upper limb with diffuse hypotonia. Motor power was normal in lower limbs. There was diffuse hyporeflexia in all the four limbs. Nerve conduction studies showed absent SNAPS with decreased motor nerve conduction velocities and increased CMAP latencies in both upper and lower limbs. CSF examination showed albumin-cytological dissociation. MRI Brain and Cervical Spine were normal. Serum ANA and Serum Ganglioside antibodies were negative. She was tested for total Covid-19 antibodies which was significantly positive with 55.25 COI. Patient was treated initially with IV Methylprednisolone with no significant response. So, followed with intravenous immunoglobulins and showed some improvement. Conclusions: Atypical Pharyngo-cervico-brachial variant of GB Syndrome with gross asymmetrical upper limb weakness and progressed over six weeks associated with positive SARS Cov-2 antibodies. During the pandemic, unusual neurological manifestations should be evaluated for possibility of SARS-CoV-2 associated antibodies as neuropathogenesis has shown both vascular and post infectious demyelinating disorders.

14.
Free Neuropathology ; 3, 2022.
Article in English | Scopus | ID: covidwho-1904016

ABSTRACT

Here, we review a collection of recent manuscripts and research trends on the neuropathology of neurodegen-eration that are considered by the author to be among the potentially most impactful. To the greatest extent possible, we chose to focus on histopathological studies that are most relevant to experimental and diagnostic neuropathology. While there has been an abundance of important recent discoveries and developments in neu-rodegenerative disease research, there was a deliberate effort here to provide balance to prevent disease categories and experimental approaches from overshadowing the others. The result is a diverse series of outstanding studies, together showing the landscape of progress across neurodegenerative disorders. One is a stereological study examining dystrophic microglia in aging. We highlight the first large genetic study of primary age-related tauopathy, showing convergence and divergence from classical Alzheimer’s disease. There were further advances in the neuropathological criteria and staging of chronic traumatic encephalopathy. Links suggesting a causal role for TMEM106B in TDP-43 proteinopathy emerged. Attempts to subtype Alzheimer’s disease on the molecular level were made. Evidence for a role for the VEGF family in cognitive impairment was advanced. Comparison of gene expression profiles from myeloid cells in peripheral blood and brain tissues from Parkinson’s disease patients revealed pathways that may lead to new mechanistic insights and biomarkers. A large autopsy series identified an increased frequency of central nervous system developmental malformations in Huntington’s disease. A robust and reliable system for assessing Lewy body pathology was proposed. Finally, we continue to be plagued by the COVID-19 pandemic, with lingering concerns of a long-term link with neurodegeneration. © 2022 The author(s).

15.
Trends Mol Med ; 28(9): 781-794, 2022 09.
Article in English | MEDLINE | ID: covidwho-1895341

ABSTRACT

Decreased smell function is related to brain health, future mortality, and quality of life. Most people inflicted with the SARS-CoV-2 virus evidence some measurable smell dysfunction during its acute phase, although many are unaware of the loss. Long-term deficits occur in up to 30% of COVID-19 cases, although total anosmia is relatively rare. This review explores what is presently known about the nature and pathophysiology of olfactory dysfunction due to the SARS-CoV-2 virus, including reversible inflammation within the olfactory cleft, downregulation of olfactory receptor proteins, and long-lasting peripheral and central damage to olfactory structures. It also addresses the question as to whether long-term smell loss might increase the likelihood of future development of cognitive and neurological deficits.


Subject(s)
COVID-19 , Olfaction Disorders , Brain , Humans , Quality of Life , SARS-CoV-2 , Smell
16.
Neurol Neurochir Pol ; 56(2): 118-130, 2022.
Article in English | MEDLINE | ID: covidwho-1887304

ABSTRACT

INTRODUCTION: Neuropathological brain and spinal cord post mortem examination is a distinct procedure that still plays an important role in modern medicine. In front of increasing amounts of clinical and genetic data, together with important developments in the field of neuroimaging, the Polish Association of Neuropathologists have updated their recommendations regarding central nervous system (CNS) examination. These guidelines are aimed at neuropathologists, pathologists and clinicians. AIM OF THE STUDY: Presentation of the outlined recommendations as their goal is to improve the quality, informativity, and cost effectiveness of CNS post mortem examinations. A comprehensive study of the literature was conducted to provide a clinical background of neuropathological autopsy. There are numerous open questions in neuroscience, and new strategies are required to foster research in CNS diseases. These include the challenge of organizing brain banks tasked with managing and protecting detailed multidisciplinary information about their resources. Complex neuropathological analyses of post mortem series are also important to assess the effectiveness of diagnostics and therapy, identify environmental impact on the development of neurological disorders, and improve public health policy. The recommendations outline the need for collaboration between multiple specialists to establish the proper diagnosis and to broaden knowledge of neurological disorders.


Subject(s)
Central Nervous System Diseases , Neuropathology , Autopsy/methods , Brain/pathology , Central Nervous System Diseases/pathology , Humans , Neuroimaging
17.
Pathology ; 54(6): 738-745, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-1882427

ABSTRACT

Severe cases of Coronavirus Disease 2019 (COVID-19) can present with multiple neurological symptoms. The available neuropathological studies have described different lesions; the most frequent was the presence of neuroinflammation and vascular-related lesions. The objective of this study was to report the neuropathological studies performed in a medical institution, with abundant long intensive care unit stays, and their associated clinical manifestations. This is a retrospective monocentric case series study based on the neuropathological reports of 13 autopsies with a wide range of illness duration (13-108 days). A neuroinflammatory score was calculated based on the quantification of CD8- and CD68-positive cells in representative areas of the central nervous system. This score was correlated afterwards with illness duration and parameters related to systemic inflammation. Widespread microglial and cytotoxic T-cell activation was found in all patients. There was no correlation between the neuroinflammatory score and the duration of the illness; nor with parameters of systemic inflammation such as the peak of IL-6 or the HScore (a parameter of systemic macrophage activation syndrome). Two patients had global hypoxic ischaemic damage and five patients had subacute infarcts. One patient had many more brain vascular microthrombi compared to the others and multiple subacute pituitary infarcts. SARS-CoV-2 RNA was not detected with qRT-PCR. The proportion of brain lesions in severe COVID-19 patients could be related to illness duration. In our series, with abundant long hospitalisation stays, neuroinflammation was present in all patients and was more prominent between day 34 and day 45 after onset of symptoms. Clinical correlation showed that two patients with the highest neuroinflammatory scores had severe encephalopathies that were not attributable to any other cause. The second most frequent lesions were related to vascular pathology.


Subject(s)
COVID-19 , Nervous System Diseases , COVID-19/complications , Humans , Infarction , Inflammation , Interleukin-6 , Nervous System Diseases/etiology , Nervous System Diseases/pathology , Retrospective Studies , SARS-CoV-2
18.
Topics in Antiviral Medicine ; 30(1 SUPPL):152-153, 2022.
Article in English | EMBASE | ID: covidwho-1880804

ABSTRACT

Background: Neurological manifestations are a major complication of sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and likely contribute to symptoms of "long COVID". Elucidating the mechanisms that underlie neuropathogenesis in infection is critical for identifying or developing viable therapeutic strategies. While neurological injury in infection is varied, cerebrovascular disease is seen at a high frequency among patients over 50 years of age. Additionally, microhemorrhages and hypoxic-ischemic injury are often described in brain autopsy series of human subjects who died from COVID-19. Here, we report neuropathology in aged SARS-CoV-2 infected non-human primates (NHPs) is consistent with that observed in aged human subjects and provide insight into the underlying cause. Methods: Four adult Rhesus macaques and four African green monkeys were inoculated with the 2019-nCoV/USA-WA1/2020strain of SARS-CoV-2 via a multi-route mucosal or aerosol challenge. Two of each species were included as age-matched controls. Frontal, parietal, occipital, and temporal lobes, basal ganglia, cerebellum, and brainstem were interrogated through histopathological and immunohistochemical techniques to identify and characterize the observed pathology. Results: Like humans, pathology was variable but included wide-spread inflammation with nodular lesions, neuronal injury, and microhemorrhages. Neuronal degeneration and apoptosis were confirmed with FluoroJade C and cleaved caspase 3 IHC, which showed foci of positivity, particularly among cerebellar Purkinje cells. This was seen even among infected animals that did not develop severe respiratory disease but was not seen in age-matched controls. Significant upregulation of the alpha subunit of hypoxia inducible factor 1 (HIF1-α), indicative of tissue hypoxia, was observed in brain of all infected animals, regardless of disease severity. Sparse virus was detected in brain endothelial cells but did not associate with the severity of CNS injury. Conclusion: SARS-CoV-2 infected NHPs are a viable animal model for advancing our current understanding of infection-associated neuropathogenesis. Upregulation of HIF1-α in brain of infected animals suggests cerebral hypoxia may underlie or contribute to neuroinflammation and neuronal injury/death and may provide some insight into neurological manifestations observed among asymptomatic patients or those only suffering mild disease.

19.
Topics in Antiviral Medicine ; 30(1 SUPPL):249, 2022.
Article in English | EMBASE | ID: covidwho-1880130

ABSTRACT

Background: COVID-19 infection-associated cognitive and olfaction impairments have an unclear pathogenesis, possibly related to systemic disease severity, hypoxia, or illness-associated anxiety and depression. A biomarker for these neurocognitive changes is lacking. The kynurenine pathway (KP) is an interferon stimulated myeloid cell mediated tryptophan degradation pathway important in immune tolerance, neurotoxicity and vascular injury, that is dysregulated in COVID-19. We hypothesized that neurocognitive impairments were associated with an activated KP. Methods: The current analysis includes COVID-19 patients as part of the ADAPT study, a prospective cohort (St Vincent's Hospital Sydney, Australia). Disease severity was assessed with 18 acute symptoms and hospitalization status. Blood samples were taken 2 months (N=136) and 4 months (N=121) post diagnosis along with cognitive (Cogstate Computerized Battery, CBB;NIH toolbox Odor Identification Test, OIT) and mental health screenings (DMI-10;IESR, SPHERE-34 Psychological subscale grouped into a composite score). KP metabolites (PIC, QUIN, 3HK, 3HAA, AA, KYN, TRP, log for analyses except for TRP) were measured by GC-MS and uHPLC. The CBB and OIT data were demographically-corrected. CBB follow-up data was also corrected for practice effect. Linear mixed effect regression models with time effect (days post diagnosis) tested whether cognition, and olfaction were associated the KP (main and time interaction);while correcting for disease severity, mental health and comorbidities. Results: 136 patients: mean age=46±15;40% females;90% English speaking background;disease severity: 40% mild, 50% moderate, 10% severe/hospitalised;34% treated comorbidities. At 2 months post diagnosis, 16% had cognitive impairment, and 25% had impaired olfaction. Cognitive impairment was more common in those with anosmia (p=.05). At 4 months, 23% had cognition impairment and 20% had impaired olfaction. QUIN (p=.001), 3HAA (p<.0001) increased over the study period, while TRP decreased (p=.02). QUIN level associated with poorer cognitive scores (p=.0007;QUIN (nM) between 800-1000 was most predictive). There was no time∗QUIN interaction. QUIN association to cognition persisted when severe cases were excluded (p<.005). Conclusion: COVID-19 is associated with KP activation, and the latter with cognitive impairment. QUIN was the only biomarker associated with cognitive impairment, and may be useful in monitoring and elucidating COVID-19 neuropathogenesis and treatment.

20.
Modern Pathology ; 35(SUPPL 2):1203-1204, 2022.
Article in English | EMBASE | ID: covidwho-1857870

ABSTRACT

Background: Increasing numbers of COVID-19 patients experience acute and chronic neurologic symptoms and complications. Despite ample clinical evidence of CNS involvement by COVID-19, reported neuropathological findings in the postmortem brain tissues of COVID19 patents include variety of hypoxic/ischemic changes, thrombosis, intracerebral and subarachnoid hemorrhage, nonspecific microglial activation and/or lymphocytic infiltration. But, there is no clear evidence whether these findings are specific to COVID19 infection or not. Design: Autopsy brains specimens from 94 COVID19 patients and 61 controls (COVID 19 negative PCR test at time of autopsy) were examined. Clinical data on the presence of comorbid conditions, such as hypertension, diabetes, hyperlipidemia, chronic cardiac, and renal disorders were collected for both groups. Using routine neuropathology approaches, the extents of vascular pathology;acute, subacute, and remote ischemic hemorrhagic lesions;microvascular thrombosis, cerebral edema, and intraparenchymal and subarachnoid hemorrhage were examined. For histopathologic examination hippocampus, frontal and parietal neocortices and white matter, basal ganglia, midbrain, pons, medulla, and cerebellum were selected. Results: Mean age in the COVID19 group was 63 years and 60 years in the control group. There were more males in both group than females (COVID19 - 2.8:1, Control - 1.5:1). There was no statistically significant difference between groups in the frequencies of systemic comorbid conditions. 93% of COVID19 cases and 87% of control cases had at least one gross and/or microscopic neuropathologic finding. COVID19 cases showed higher rate of combined acute findings, including brain edema, acute and subacute hypoxic/ischemic lesions, thrombosis, and hemorrhage (61% vs 39%, P value - 0.002). When compared these features separately, none of them reached statistical significance. Arteriolosclerosis (66% vs 66%), atherosclerosis (17% vs 26%), and remote infarcts (19% vs 18%) where quite common findings with similar frequencies in both groups. Conclusions: Our data shows higher tendency of acute and subacute events in the patients with COVID19 infection. These finding do not quite explain the clinical symptoms seen in patients with neurologic complications, and likely represent the sequela of COVID19 systemic complications. More comprehensive neuropathologic and molecular approaches are necessary to better understand the mechanisms of neurologic complications of COVID19 infection.

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