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(searched for: doi:10.1002/alz.12255)
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Anushree Tripathi, Krishna Misra
Homocysteine Metabolism in Health and Disease pp 241-256; https://doi.org/10.1007/978-981-16-6867-8_13

The publisher has not yet granted permission to display this abstract.
Zakir Ullah, Prasad M. Sonawane, Y. Sheena Mary, C. Yohannan Panicker,
Journal of Biomolecular Structure and Dynamics pp 1-17; https://doi.org/10.1080/07391102.2022.2053742

Abstract:
This combined Al12E12 (E = N, P) surface adsorption and docking study describes the new possibility of prospective potential probing(photophysical/optical) and therapy(medicinal/biochemical) with these adsorbent conjugates. DFT investigations were undertaken herein to help generate geometrical models and better understand the possible favorable adsorption energetics. We attempt to explain their adsorption behaviors and docking involving SARS–CoV–2 viruses (PDB)to assess their possible pharmaceutical potential against the pandemic virus (COVID–19). The adsorption behavior of 8–hydroxy–2–methylquinoline (MQ) and its halogenated derivatives, 5,7–diiodo–8–hydroxy–2–methylquinoline (MQI), 5,7–dichloro–8–hydroxy–2–methylquinoline (MQCl), and 5,7–dibromo–8–hydroxy–2–methylquinoline (MQBr), with aluminum–nitrogen (AlN), and aluminum–phosphorous (AlP) fullerene–like nanocages is reported. A decrease in the hardness of the nanoclusters when adsorbed with drug molecules resulted in an incrementally improved chemical softness (see e.g., Hard–Soft Acid Base theory) indicating that reactivity of the drug molecule in the resulting complex increases upon cluster chemical adsorption. The energy gap is found to be maximized for AlN–MQ and minimized for AlP–MQI; the reduced density gradient (RDG) iso–surfaces and AIM studies also corroborated this. Therefore, these two were found, respectively, to be the least and most electrically conductive of the species under study. We selected a simple medicinal building block (chelator)in addition to selecting the cluster based on previous literature reports. Important parameters such as gap energies and global indices were determined. We assessed NLO properties. The SARS–CoV–2 virus PDB docking data for 6VW1, 6VYO, 6WKQ, 7AD1, 7AOL, 7B3C, were enlisted as ligand targets for studies of docking (PatchDock Server) using the requisite PDB geometries (For the structure of 6VW1, kindly see reference, 2020 For the structure of 6VW1, kindly see reference, Shang, J. , Ye, G. , Shi, K. , Wan, Y. , Luo, C. , Aihara, H. , Geng, Q. , Auerbach, A. , & Li, F. (2020). Structural basis of receptor recognition by SARS-CoV-2. Nature22, 221–224. https://doi.org/10.1038/s41586-020-2179-y [Google Scholar] ; For the structure of 6VYO kindly see reference, 2020 For the structure of 6VYO kindly see reference, Chang, C. , Michalska, K. , Jedrzejczak, R. , Maltseva, N. , Endres, M. , Godzik, A. , Kim, Y. , & Joachimiak, A. (2020). Crystal structure of RNA binding domain of nucleocapsid phosphoprotein from SARS coronavirus 2, RCSB PDB. https://doi.org/10.2210/pdb6VYO/pdb. [Google Scholar] ; For the structure of 6WKQ kindly see reference, 2020 For the structure of 6WKQ kindly see reference, Rosas-lemus, M. , Minasov, G. , Shuvalova, L. , Inniss, N. L. , Kiryukhina, O. , Brunzelle, J. , & Satchell, K. J. F. (2020). High resolution structures of the SARS-CoV-2 2’-O-methyltransferase reveal strategies for structure based inhibitor design. Science Signaling, 13(651), eabe1202. https://doi.org/10.1126/scisignal.abe1202. [Web of Science ®] , [Google Scholar] ; For the structure of 7AD1 kindly see reference, 2021 For the structure of 7AD1 kindly see reference, Juraszek, J. , Rutten L. , Blokland, S. , Bouchier, P. , Voorzaat, R. , Ritschel, T. , Bakkers, M. J. G. , Renault, L. L. R. , & Langedijk, J. P. M. (2021). Stabilizing the closed SARS-CoV-2 spike trimer. Nature Communications, 12, 244. https://doi.org/10.1038/s41467-020-20321-x. [Crossref], [PubMed], [Web of Science ®] , [Google Scholar] ; For the structure of 7AOL kindly see reference, 2021 For the structure of 7AOL kindly see reference, Guenther, S. , Reinke, P. , & Oberthuer, D. (2021). X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease. Science372, 642–646. https://doi.org/10.1126/science.abf7945. [Crossref], [PubMed], [Web of Science ®] , [Google Scholar] ; For the structure of 7B3C kindly see reference, 2021 For the structure of 7B3C kindly see reference, Kokic, G. , Hillen, H. S. , Tegunov, D. , Dienemann, C. , Seitz, F. , Schmitzova, J. , Farnung, L. , Siewert, A. , Hobartner, C. , & Cramer, P. (2021). Mechanism of SARS-CoV-2 polymerase stalling by remdesivir, Nature Communications, 12, 279. https://doi.org/10.1093/bib/bbaa378 [Crossref], [PubMed], [Web of Science ®] , [Google Scholar] ). Such findings indicate that the AlN–drug conjugation have inhibitory effect against these selected receptors. Graphical Abstract Communicated by Ramaswamy H. Sarma
International Journal of Sexual Health pp 1-15; https://doi.org/10.1080/19317611.2022.2053921

Abstract:
Objective: This review sought to describe the main trends and findings on the SARS-CoV-2 and the pandemic’s effect on reproduction (i.e., effects on fertility, reproductive tissue, pregnancy, vertical and sexual transmission) and sexual function and behaviors. Methods: A review was conducted on studies assessing these variables through the Scopus and PubMed databases between the years 2019–2021. Results: Results showed SARS-CoV-2 pandemic and social distancing measures have affected—and in some cases not—different aspects of people’s reproductive function, sexual function and behaviors. Conclusions: Suggestions are offered for researchers and professionals focused on future research and clinical practice.
, Florine Ruthmann, Fanny Vuotto, Louise Carton, Patrick Gelé, Karine Faure, Dominique Deplanque, Régis Bordet
Published: 24 March 2022
Journal of Neurology pp 1-8; https://doi.org/10.1007/s00415-022-11077-z

The publisher has not yet granted permission to display this abstract.
Alfonsina Tirozzi, Federica Santonastaso, Giovanni de Gaetano, , Alessandro Gialluisi
World Journal of Psychiatry, Volume 12, pp 536-540; https://doi.org/10.5498/wjp.v12.i3.536

Abstract:
Observational studies based on electronic health records (EHR) report an increased risk of neurological/neuropsychiatric sequelae for patients who have had coronavirus disease 2019 (COVID-19). However, these studies may suffer from biases such as unmeasured confounding, residual reverse causality, or lack of precision in EHR-based diagnoses. To rule out these biases, we tested causal links between COVID-19 and different potential neurological/neuropsychiatric sequelae through a two-sample Mendelian randomization analysis of summary statistics from large Genome-Wide Association Scans of susceptibility to COVID-19 and different neurological and neuropsychiatric disorders, including major depression, anxiety, schizophrenia, stroke, Parkinson’s and Alzheimer’s diseases. We found robust evidence suggesting that COVID-19 – notably the hospitalized and most severe forms – carries an increased risk of neuropsychiatric sequelae, particularly Alzheimer’s disease, and to a lesser extent anxiety disorder. In line with a large longitudinal EHR-based study, this evidence was stronger for more severe COVID-19 forms. These results call for a targeted screening strategy to tackle the post-COVID neuropsychiatric pandemic.
Panyuan Guo, Alvaro Benito Ballesteros, Sabine P. Yeung, Ruby Liu, Arka Saha, Lyn Curtis, Muzaffer Kaser, Mark P. Haggard, Lucy G. Cheke
Frontiers in Aging Neuroscience, Volume 14; https://doi.org/10.3389/fnagi.2022.804937

Abstract:
COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been often characterized as a respiratory disease. However, it is increasingly being understood as an infection that impacts multiple systems, and many patients report neurological symptoms. Indeed, there is accumulating evidence for neural damage in some individuals, with recent studies suggesting loss of gray matter in multiple regions, particularly in the left hemisphere. There are several mechanisms by which the COVID-19 infection may lead to neurological symptoms and structural and functional changes in the brain, and cognitive problems are one of the most commonly reported symptoms in those experiencing Long COVID – the chronic illness following the COVID-19 infection that affects between 10 and 25% of patients. However, there is yet little research testing cognition in Long COVID. The COVID and Cognition Study is a cross-sectional/longitudinal study aiming to understand cognitive problems in Long COVID. The first paper from the study explored the characteristics of our sample of 181 individuals who had experienced the COVID-19 infection, and 185 who had not, and the factors that predicted ongoing symptoms and self-reported cognitive deficits. In this second paper from the study, we assess this sample on tests of memory, language, and executive function. We hypothesize that performance on “objective” cognitive tests will reflect self-reported cognitive symptoms. We further hypothesize that some symptom profiles may be more predictive of cognitive performance than others, perhaps giving some information about the mechanism. We found a consistent pattern of memory deficits in those that had experienced the COVID-19 infection, with deficits increasing with the severity of self-reported ongoing symptoms. Fatigue/Mixed symptoms during the initial illness and ongoing neurological symptoms were predictive of cognitive performance.
, Soojin Lee, Fidel Alfaro-Almagro, Christoph Arthofer, , Paul McCarthy, , Jesper L. R. Andersson, Ludovica Griffanti, Eugene Duff, et al.
Published: 7 March 2022
Nature, Volume 604, pp 697-707; https://doi.org/10.1038/s41586-022-04569-5

Abstract:
There is strong evidence of brain-related abnormalities in COVID-191–13. However, it remains unknown whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here we investigated brain changes in 785 participants of UK Biobank (aged 51–81 years) who were imaged twice using magnetic resonance imaging, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans—with 141 days on average separating their diagnosis and the second scan—as well as 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including (1) a greater reduction in grey matter thickness and tissue contrast in the orbitofrontal cortex and parahippocampal gyrus; (2) greater changes in markers of tissue damage in regions that are functionally connected to the primary olfactory cortex; and (3) a greater reduction in global brain size in the SARS-CoV-2 cases. The participants who were infected with SARS-CoV-2 also showed on average a greater cognitive decline between the two time points. Importantly, these imaging and cognitive longitudinal effects were still observed after excluding the 15 patients who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease through olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious effect can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow-up.
Steve Reiken, Leah Sittenfeld, Haikel Dridi, Yang Liu, Xiaoping Liu,
Published: 3 February 2022
Alzheimer's & Dementia, Volume 18, pp 955-965; https://doi.org/10.1002/alz.12558

The publisher has not yet granted permission to display this abstract.
Wei-Bin Shen, James Logue, Penghua Yang, Lauren Baracco, Montasir Elahi, E. Albert Reece, Bingbing Wang, Ling Li, Thomas G Blanchard, , et al.
Published: 1 February 2022
Abstract:
Major cell entry factors of SARS-CoV-2 are present in neurons; however, the neurotropism of SARS-CoV-2 and the phenotypes of infected neurons are still unclear. Acute neurological disorders occur in many patients, and one-third of COVID-19 survivors suffer from “brain diseases”. Here, we show that SARS-CoV-2 invades the brains of five patients with COVID-19 and Alzheimer’s, autism, frontotemporal dementia or no underlying condition by infecting neurons and other cells in the cortex. SARS-CoV-2 induces or enhances Alzheimer’s-like neuropathology with manifestations of β-amyloid aggregation and plaque formation, tauopathy, neuroinflammation and cell death. SARS-CoV-2 infects mature but not immature neurons derived from inducible pluripotent stem cells from healthy and Alzheimer’s individuals through its receptor ACE2 and facilitator neuropilin-1. SARS-CoV-2 triggers Alzheimer’s-like gene programs in healthy neurons and exacerbates Alzheimer’s neuropathology. A gene signature defined as an Alzheimer’s infectious etiology is identified through SARS-CoV-2 infection, and silencing the top three downregulated genes in human primary neurons recapitulates the neurodegenerative phenotypes of SARS-CoV-2. Thus, SARS-CoV-2 invades the brain and activates an Alzheimer’s-like program.
Dror Shir,
Current Opinion in Neurology, Volume 35, pp 212-219; https://doi.org/10.1097/wco.0000000000001033

Abstract:
Purpose of review Does neuroinflammation promote neurodegeneration? Does neurodegeneration promote neuroinflammation? Or, is the answer to both questions, yes? These questions have proven challenging to answer in patients with typical age-related neurodegenerative diseases in whom the onset of neuroinflammation and neurodegeneration are largely unknown. Patients recovering from diseases associated with abrupt-onset neuroinflammation, including rare forms of antibody-mediated encephalitis (AME) and common complications of novel coronavirus disease 2019 (COVID-19), provide a unique opportunity to untangle the relationship between neuroinflammation and neurodegeneration. This review explores the lessons learned from patients with AME and COVID-19. Recent findings Persistent cognitive impairment is increasingly recognized in patients recovering from AME or COVID-19, yet the drivers of impairment remain largely unknown. Clinical observations, neuroimaging and biofluid biomarkers, and pathological studies imply a link between the severity of acute neuroinflammation, subsequent neurodegeneration, and disease-associated morbidity. Summary Data from patients with AME and COVID-19 inform key hypotheses that may be evaluated through future studies incorporating longitudinal biomarkers of neuroinflammation and neurodegeneration in larger numbers of recovering patients. The results of these studies may inform the contributors to cognitive impairment in patients with AME and COVID-19, with potential diagnostic and therapeutic applications in patients with age-related neurodegenerative diseases.
, Maria Julia Guimarães Caruso, Alissom Vitti Cincoto, Cristiana Castanho De Almeida Rocca, Antonio De Pádua Serafim, Pedro Bacchi, Bruno F. Guedes, André R. Brunoni, Pedro Mario Pan, Ricardo Nitrini, et al.
Published: 6 January 2022
General Hospital Psychiatry, Volume 75, pp 38-45; https://doi.org/10.1016/j.genhosppsych.2022.01.002

The publisher has not yet granted permission to display this abstract.
Published: 2 January 2022
by MDPI
Journal of Personalized Medicine, Volume 12; https://doi.org/10.3390/jpm12010029

Abstract:
The current coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, is affecting every aspect of global society, including public healthcare systems, medical care access, and the economy. Although the respiratory tract is primarily affected by SARS-CoV-2, emerging evidence suggests that the virus may also reach the central nervous system (CNS), leading to several neurological issues. In particular, people with a diagnosis of Alzheimer’s disease (AD) are a vulnerable group at high risk of contracting COVID-19, and develop more severe forms and worse outcomes, including death. Therefore, understanding shared links between COVID-19 and AD could aid the development of therapeutic strategies against both. Herein, we reviewed common risk factors and potential pathogenetic mechanisms that might contribute to the acceleration of neurodegenerative processes in AD patients infected by SARS-CoV-2.
Risna K. Radhakrishnan,
American Journal of Alzheimer's Disease & Other Dementias®, Volume 37; https://doi.org/10.1177/15333175221078418

Abstract:
A significant portion of COVID-19 patients and survivors display marked clinical signs of neurocognitive impairments. SARS-CoV-2-mediated peripheral cytokine storm and its neurotropism appear to elicit the activation of glial cells in the brain proceeding to neuroinflammation. While adult neurogenesis has been identified as a key cellular basis of cognitive functions, neuroinflammation-induced aberrant neuroregenerative plasticity in the hippocampus has been implicated in progressive memory loss in ageing and brain disorders. Notably, recent histological studies of post-mortem human and experimental animal brains indicate that SARS-CoV-2 infection impairs neurogenic process in the hippocampus of the brain due to neuroinflammation. Considering the facts, this article describes the prominent neuropathogenic characteristics and neurocognitive impairments in COVID-19 and emphasizes a viewpoint that neuroinflammation-mediated deterioration of hippocampal neurogenesis could contribute to the onset and progression of dementia in COVID-19. Thus, it necessitates the unmet need for regenerative medicine for the effective management of neurocognitive deficits in COVID-19.
, Daniel R. George, Brigid K. McVaugh
Handbook of Evidence-Based Prevention of Behavioral Disorders in Integrated Care pp 415-438; https://doi.org/10.1007/978-3-030-83469-2_18

The publisher has not yet granted permission to display this abstract.
Xiaoru Sun, Hui Zhang, Dongdong Yao, Yaru Xu, Qi Jing, Silu Cao, Li Tian, Cheng Li
Published: 11 December 2021
Journal of Alzheimer's Disease, pp 1-9; https://doi.org/10.3233/jad-215232

Abstract:
Background: Alzheimer’s disease (AD) is a fatal neurodegenerative disease, the etiology of which is unclear. Previous studies have suggested that some viruses are neurotropic and associated with AD. Objective: By using bioinformatics analysis, we investigated the potential association between viral infection and AD. Methods: A total of 5,066 differentially expressed genes (DEGs) in the temporal cortex between AD and control samples were identified. These DEGs were then examined via weighted gene co-expression network analysis (WGCNA) and clustered into modules of genes with similar expression patterns. Of identified modules, module turquoise had the highest correlation with AD. The module turquoise was further characterized using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis. Results: Our results showed that the KEGG pathways of the module turquoise were mainly associated with viral infection signaling, specifically Herpes simplex virus, Human papillomavirus, and Epstein-Barr virus infections. A total of 126 genes were enriched in viral infection signaling pathways. In addition, based on values of module membership and gene significance, a total of 508 genes within the module were selected for further analysis. By intersecting these 508 genes with those 126 genes enriched in viral infection pathways, we identified 4 hub genes that were associated with both viral infection and AD: TLR2, COL1A2, NOTCH3, and ZNF132. Conclusion: Through bioinformatics analysis, we demonstrated a potential link between viral infection and AD. These findings may provide a platform to further our understanding of AD pathogenesis.
Published: 8 December 2021
Fighting the COVID-19 Pandemic; https://doi.org/10.5772/intechopen.99414

Abstract:
When SARS-CoV-2 began to spread, older adults experienced disproportionately greater adverse effects from the pandemic, including exacerbation of pre-existing physical and cognitive frailty conditions. More severe complications, higher mortality, and concerns about disruptions to their daily routines and access to care. Knowledge about the impact of COVID-19 on the brain is rapidly accumulating and this is reflected in the increasing use of the term “neurocovid”. Co-involvement of the central and peripheral nervous system had already been observed in SARS patients, but COVID-19 seems to invade it with greater affinity than other coronaviruses. This chapter provides an overview of the expanding understanding of the multiple ways in which COVID-19 affects the human brain, discuss the likelihood of long-term sequelae of neurocovid, and their implications for cognitive functions and behaviors in the elderly.
Tiffany J. Petrisko, Angela Gomez-Arboledas,
Published: 18 November 2021
Advances in Immunology, Volume 152, pp 157-222; https://doi.org/10.1016/bs.ai.2021.09.003

The publisher has not yet granted permission to display this abstract.
Published: 30 October 2021
by MDPI
Viruses, Volume 13; https://doi.org/10.3390/v13112193

Abstract:
SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is primarily responsible for coronavirus disease (COVID-19) and it is characterized by respiratory illness with fever and dyspnea. Severe vascular problems and several other manifestations, including neurological ones, have also been frequently reported, particularly in the great majority of “long hauler” patients. SARS-CoV-2 infects and replicates in lung epithelial cells, while dysfunction of endothelial and neuronal brain cells has been observed in the absence of productive infection. It has been shown that the Spike protein can interact with specific cellular receptors, supporting both viral entry and cellular dysfunction. It is thus clear that understanding how and when these receptors are regulated, as well as how much they are expressed would help in unveiling the multifaceted aspects of this disease. Here, we show that SH-SY5Y neuroblastoma cells express three important cellular surface molecules that interact with the Spike protein, namely ACE2, TMPRSS2, and NRP1. Their levels increase when cells are treated with retinoic acid (RA), a commonly used agent known to promote differentiation. This increase matched the higher levels of receptors observed on HUVEC (primary human umbilical vein endothelial cells). We also show by confocal imaging that replication-defective pseudoviruses carrying the SARS-CoV-2 Spike protein can infect differentiated and undifferentiated SH-SY5Y, and HUVEC cells, although with different efficiencies. Neuronal cells and endothelial cells are potential targets for SARS-CoV-2 infection and the interaction of the Spike viral protein with these cells may cause their dysregulation. Characterizing RNA and protein expression tempo, mode, and levels of different SARS-CoV-2 receptors on both cell subpopulations may have clinical relevance for the diagnosis and treatment of COVID-19-infected subjects, including long hauler patients with neurological manifestations.
, Betty Raman, Fidel Alfaro-Almagro, Nicola Filippini, Mark Philip Cassar, Fintan Sheerin, Thomas W. Okell, Flora A. Kennedy McConnell, Michael A. Chappell, Chaoyue Wang, et al.
Published: 29 October 2021
Frontiers in Neurology, Volume 12; https://doi.org/10.3389/fneur.2021.753284

Abstract:
SARS-CoV-2 infection has been shown to damage multiple organs, including the brain. Multiorgan MRI can provide further insight on the repercussions of COVID-19 on organ health but requires a balance between richness and quality of data acquisition and total scan duration. We adapted the UK Biobank brain MRI protocol to produce high-quality images while being suitable as part of a post-COVID-19 multiorgan MRI exam. The analysis pipeline, also adapted from UK Biobank, includes new imaging-derived phenotypes (IDPs) designed to assess the possible effects of COVID-19. A first application of the protocol and pipeline was performed in 51 COVID-19 patients post-hospital discharge and 25 controls participating in the Oxford C-MORE study. The protocol acquires high resolution T1, T2-FLAIR, diffusion weighted images, susceptibility weighted images, and arterial spin labelling data in 17 min. The automated imaging pipeline derives 1,575 IDPs, assessing brain anatomy (including olfactory bulb volume and intensity) and tissue perfusion, hyperintensities, diffusivity, and susceptibility. In the C-MORE data, IDPs related to atrophy, small vessel disease and olfactory bulbs were consistent with clinical radiology reports. Our exploratory analysis tentatively revealed some group differences between recovered COVID-19 patients and controls, across severity groups, but not across anosmia groups. Follow-up imaging in the C-MORE study is currently ongoing, and this protocol is now being used in other large-scale studies. The protocol, pipeline code and data are openly available and will further contribute to the understanding of the medium to long-term effects of COVID-19.
Panyuan Guo, Alvaro Benito Ballesteros, Sabine P Yeung, Ruby Liu, Arka Saha, Lyn Curtis, Muzaffer Kaser, Mark P Haggard,
Published: 28 October 2021
Abstract:
Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been often characterized as a respiratory disease. However, it is increasingly being understood as an infection that impacts multiple systems, and many patients report neurological symptoms. Indeed, there is accumulating evidence for neural damage in some individuals, with recent studies suggesting loss of gray matter in multiple regions particularly in the left hemisphere. There are a number of mechanisms by which COVID-19 infection may lead to neurological symptoms and structural and functional changes in the brain, and cognitive problems are one of the most commonly reported symptoms in those suffering from Long COVID—the chronic illness following COVID-19 infection that affects between 10–25% of sufferers. However, there is as yet little research testing cognition in Long COVID. The COVID and Cognition Study is a cross-sectional/longitudinal study aiming to understand cognitive problems in Long COVID. The first paper from the study explored the characteristics of our sample of 181 individuals who had suffered COVID-19 infection, and 185 who had not, and the factors that predicted ongoing symptoms and self-reported cognitive deficits. In this second paper from the study, we assess this sample on tests of memory, language and executive function. We hypothesize that performance on “objective” cognitive tests will reflect self-reported cognitive symptoms. We further hypothesize that some symptom profiles may be more predictive of cognitive performance than others, perhaps giving some information as to mechanism. We found a consistent pattern of memory deficits in those that had suffered COVID-19 infection, with deficit increasing with severity of self-reported ongoing symptoms. Fatigue/Systemic symptoms during the initial illness and ongoing neurological symptoms were predictive of cognitive performance.
Arvind Vyas, Vasim Raja Panwar, , Parth Patel, Surabhi Mathur, Arvind Sharma, Raja Babu Panwar, Rajeev Gupta
International Journal of Mental Health pp 1-10; https://doi.org/10.1080/00207411.2021.1988402

Abstract:
The coronavirus disease 2019 (COVID-19) pandemic has been impacting individuals throughout the world. Millions have been affected, and while many have recovered, a growing number of recovered COVID-19 patients are reportedly facing neurological symptoms, described as “slow thinking,” “difficulty in focusing,” “confusion,” “lack of concentration,” “forgetfulness,” or “haziness in thought process.” These experiences of mental fatigue, associated with and related to mild cognitive impairments, may be conceptually defined as “brain fog.” To study the prevalence and severity of these brain fog symptoms in COVID-19 recovered patients, and examining their association with age, gender, and COVID-19 symptom severity. A total of 300 patients who tested positive for Real-Time Reverse Transcriptase–Polymerase Chain Reaction (RT-PCR) for SARSCoV-2 during April–August 2020 were included in our study after complete recovery from their acute illness. They were assessed for brain fog symptoms using the 9-item validated Wood’s mental fatigue inventory. The overall cumulative prevalence of any components of brain fog was 34%, with a mean score of 6.11 ± 1.7 in those who experienced it. Males were more affected than females (42.3% vs. 29.1%) with males scoring higher than females. The mean score was higher in severe ill and Intensive Care Unit (ICU) patients and those who required oxygen or were on a ventilator.
Cynthia Putri, Jessie Arisa, Joshua Edward Hananto, Timotius Ivan Hariyanto,
World Journal of Psychiatry, Volume 11, pp 821-829; https://doi.org/10.5498/wjp.v11.i10.821

Abstract:
In December 2019, a novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was initially reported in Wuhan, China. Previous epidemics including SARS and middle east respiratory syndrome raises concern that COVID-19 infection may pose a significant threat to the mental health of affected individuals. Studies and reviews have shown the acute psychiatric manifestations in COVID-19 patients, although long term psychiatric sequelae are predicted, there are only few review studies about the long term psychiatry outcome in COVID-19 survivors. Clinically significant post-traumatic stress disorder, anxiety, and/or depression among COVID-19 survivors during 14-90 d were observed following the diagnosis. Risk of anxiety or depression were higher in patients with more severe illness at 6 mo follow-up, early convalescence, and at 1 mo follow-up. Diagnosis of COVID-19 Led to more first diagnoses and relapses of psychiatric illness during the first 14-90 d after COVID-19 diagnosis. The possible underlying mechanisms of psychiatric sequelae in COVID-19 infection are neurotropism, immune response to SARS-CoV-2, hypothalamo-pituitary-adrenal axis hyperactivity, disrupted neuronal circuits in several brain regions, increased stress levels, neuroinflammation, and neuronal death. This study will review the psychiatric sequelae in previous coronavirus pandemics, current studies, risk factors, and thorough explanation on pathophysiology of the psychiatric sequalae in COVID-19 survivors.
, Philippe Amouyel, Diane E. Bovenkamp, Maria C. Carrillo, Geraldine Drexel De Buchy, Magali Dumont, Howard Fillit, Lauren Friedman, Gregor Henderson‐Begg, Jakub Hort, et al.
Published: 1 October 2021
Alzheimer's & Dementia, Volume 18, pp 1067-1070; https://doi.org/10.1002/alz.12472

The publisher has not yet granted permission to display this abstract.
, Sunyang Fu, Heidi Lindroth, Sunghwan Sohn, M. Caroline Burton, Maria Lapid
International Psychogeriatrics, Volume 33, pp 1105-1109; https://doi.org/10.1017/s104161022100106x

Abstract:
Delirium is reported to be one of the manifestations of coronavirus infectious disease 2019 (COVID-19) infection. COVID-19 hospitalized patients are at a higher risk of delirium. Pathophysiology behind the association of delirium and COVID-19 is uncertain. We analyzed the association of delirium occurrence with outcomes in hospitalized COVID-19 patients, across all age groups, at Mayo Clinic hospitals.A retrospective study of all hospitalized COVID-19 patients at Mayo Clinic between March 1, 2020 and December 31, 2020 was performed. Occurrence of delirium and outcomes of mortality, length of stay, readmission, and 30-day mortality after hospital discharge were measured. Chi-square test, student t-test, survival analysis, and logistic regression analysis were performed to measure and compare outcomes of delirium group adjusted for age, sex, Charlson comorbidity score, and COVID-19 severity with no-delirium group.A total of 4351 COVID-19 patients were included in the study. Delirium occurrence in the overall study population was noted to be 22.4%. The highest occurrence of delirium was also noted in patients with critical COVID-19 illness severity. A statistically significant OR 4.35 (3.27–5.83) for in-hospital mortality and an OR 4.54 (3.25–6.38) for 30-day mortality after discharge in the delirium group were noted. Increased hospital length of stay, 30-day readmission, and need for skilled nursing facility on discharge were noted in the delirium group. Delirium in hospitalized COVID-19 patients is a marker for increased mortality and morbidity. In this group, outcomes appear to be much worse when patients are older and have a critical severity of COVID-19 illness.
, Oscar Javier Díaz‐Castillo, Angely Carolina Pearson‐Arrieta, Alexandra Galeano‐Buelvas, Luis Rafael Moscote‐Salazar
Published: 5 September 2021
Alzheimer's & Dementia, Volume 18, pp 542-543; https://doi.org/10.1002/alz.12459

Angela Gomez-Arboledas, ,
Published: 1 September 2021
ImmunoTargets and Therapy, pp 373-386; https://doi.org/10.2147/itt.s305420

Abstract:
The complement system, an essential part of the innate immune system, is composed of a group of secreted and membrane proteins that collectively participate in maintaining the function of the healthy and diseased brain. However, an inappropriate activation of the complement system has been related to an inflammatory response in multiple diseases, such as stroke, traumatic brain injury, multiple sclerosis, and Alzheimer’s disease, as well as Zika infection and radiotherapy. In addition, C1q and C3 (initial activation components of the complement cascade) have been shown to play a key beneficial role in the refinement of synaptic circuits during developmental stages and adult plasticity. Nevertheless, excessive synaptic pruning in the adult brain can be detrimental and has been associated with synaptic loss in several pathological conditions. In this brief review, we will discuss the role of the complement system in synaptic pruning as well as its contribution to neurodegeneration and cognitive deficits. We also mention potential therapeutic approaches to target the complement system to treat several neuroinflammatory diseases and unintended consequences of radiotherapy.
Laura M. Hack, Jacob Brawer, Megan Chesnut, Xue Zhang, Max Wintermark, Bin Jiang, Philip Grant, Hector Bonilla, Patrick Stetz, , et al.
Published: 26 August 2021
Abstract:
A significant number of individuals experience physical, cognitive, and mental health symptoms in the months after acute infection with SARS-CoV-2, the virus that causes COVID-19. This study assessed depressive and anxious symptoms, cognition, and brain structure and function in participants with symptomatic COVID-19 confirmed by PCR testing (n=100) approximately three months following infection, leveraging self-report questionnaires, objective neurocognitive testing, and structural and functional neuroimaging data. Preliminary results demonstrated that over 1/5 of our cohort endorsed clinically significant depressive and/or anxious symptoms, and >40% of participants had cognitive impairment on objective testing across multiple domains, consistent with ‘brain-fog’. While depression and one domain of quality of life (physical functioning) were significantly different between hospitalized and non-hospitalized participants, anxiety, cognitive impairment, and most domains of functioning were not, suggesting that the severity of SARS-CoV-2 infection does not necessarily relate to the severity of neuropsychiatric outcomes and impaired functioning in the months after infection. Furthermore, we found that the majority of participants in a subset of our cohort who completed structural and functional neuroimaging (n=15) had smaller olfactory bulbs and sulci in conjunction with anosmia. We also showed that this subset of participants had dysfunction in attention network functional connectivity and ventromedial prefrontal cortex seed-based functional connectivity. These functional imaging dysfunctions have been observed previously in depression and correlated with levels of inflammation. Our results support and extend previous findings in the literature concerning the neuropsychiatric sequelae associated with long COVID. Ongoing data collection and analyses within this cohort will allow for a more comprehensive understanding of the longitudinal relationships between neuropsychiatric symptoms, neurocognitive performance, brain structure and function, and inflammatory and immune profiles.
, Marianthi Breza, Theodore Mavridis, Karen Angeliki Krogfelt
Published: 18 August 2021
Brain Disorders, Volume 3; https://doi.org/10.1016/j.dscb.2021.100022

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Hans Rittmannsberger, Martin Barth, Peter Malik,
Fortschritte der Neurologie · Psychiatrie, Volume 90, pp 108-120; https://doi.org/10.1055/a-1523-3850

Abstract:
Zusammenfassung: Das Virus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus Type 2) und die von ihm ausgelöste Erkrankung COVID-19 (Coronavirus Disease 2019) können zahlreiche Organsysteme betreffen. In vorliegender Arbeit bieten wir einen Überblick bezüglich des aktuellen Wissensstands über die psychiatrischen Aspekte der SARS-CoV-2 Infektion.Die Datenbanken Medline, Embase und LIVIVO wurden nach relevanter Literatur untersucht, die letzte Abfrage erfolgte am 02.03.2021. Unterschiedliche Stressfaktoren im Rahmen der Epidemie können zu manifesten psychischen Erkrankungen führen. Zusätzlich besteht das Risiko psychischer Veränderungen durch die biologischen Effekte des Virus selbst.Beschrieben werden in unserer Arbeit psychische Symptome von an COVID-19 Erkrankten selbst sowie die psychischen Auswirkungen der Epidemie und der damit einhergehenden sozioökonomischen und psychosozialen Stressfaktoren auch auf nicht Erkrankte.Bei an COVID-19 Erkrankten zeigen sich als häufigste psychiatrische Komplikation das Auftreten von Delirien, bei hospitalisierten Patienten scheint es zu gehäuftem Auftreten von Symptomen von Angst, Depression und posttraumatischen Belastungsstörungen zu kommen. Es liegen auch zahlreiche Kasuistiken über psychotische Störungen vor. Allgemein steigert eine vorliegende psychiatrische Erkrankung (besonders eine psychotische oder dementielle Störung) auch das Risiko einer Infektion und eines schweren Verlaufes. Nach Ablauf einer COVID-19-Infektion ist ebenfalls eine höhere Inzidenz von psychischen Erkrankungen zu finden, hier ist das „Chronic Post-SARS Syndrome“ mit seinen Ausprägungen wie Fatigue, Angst, Depression und PTSD zu nennen. Außerdem scheint der Verlauf einer dementiellen Erkrankung durch eine Infektion mit SARS-CoV-2 negativ beeinflusst zu werden.Ferner wird auf die Auswirkungen eingegangen, die das Bedrohungsszenario der Epidemie und die etablierten gesellschaftlichen Schutzmaßnahmen auf die psychische Gesundheit von Menschen mit und ohne psychische Vorerkrankungen haben. Es zeigen sich hier in der derzeit vorliegenden Literatur hohe Symptomwerte betreffend Angst- und depressiven Störungen sowie posttraumatischen Belastungsstörungen, Stress, Suizidalität, Schlafstörungen, etc. Risikofaktoren scheinen unter anderem weibliches Geschlecht, jüngeres Alter und geringere Ressourcen sowie psychische oder körperliche Vorerkrankungen darzustellen. Extrinsische Faktoren wie z-B. hohes Infektionsgeschehen, große Anzahl von Todesfällen, lange Ausgangssperren/Lockdowns, geringes Vertrauen in die Regierung und ineffektive Maßnahmen gegen wirtschaftliche und soziale Folgen steigern die Belastung.
Chun Shen, Barbara J. Sahakian, Wei Cheng, Jujiao Kang, Guiying Dong, Chao Xie, Xing-Ming Zhao,
Published: 6 July 2021
Abstract:
INTRODUCTION Current findings of the relative influence of social isolation and loneliness on dementia are contradictory, and the potential neurobiological mechanisms are unclear. METHODS We utilized the UK Biobank to investigate the relationships of social isolation and loneliness with dementia (n = 462,619). Neuroanatomical correlates were identified in a subset of participants (n = 32,263). The transcriptomic signatures of related brain changes were characterized by gene enrichment analysis. RESULTS After full adjustment, social isolation but not loneliness was associated with dementia (hazard ratio: 1.28, 95% confidence interval: 1.17-1.39). Isolated individuals had reduced gray matter volumes in temporal, frontal, occipital and subcortical regions (e.g., hippocampus and amygdala). Relevant brain changes were spatially correlated with genes involved in mitochondrial dysfunction and oxidative phosphorylation, and down-regulated Alzheimer’s disease-related genes. DISCUSSION Social isolation is an independent risk factor for dementia, which could be partly explained by related structural changes coupling with altered molecular functions.
, Bruno F. Guedes, Cristiana Castanho de Rocca, Antonio De Pádua Serafim, Luiz Henrique Martins Castro, Carolina Demarchi Munhoz, Ricardo Nitrini, Geraldo Busatto Filho, Eurípedes Constantino Miguel, Giancarlo Lucchetti, et al.
European Archives of Psychiatry and Clinical Neuroscience, Volume 272, pp 139-154; https://doi.org/10.1007/s00406-021-01286-4

Abstract:
Recently, much attention has been drawn to the importance of the impact of infectious disease on human cognition. Several theories have been proposed, to explain the cognitive decline following an infection as well as to understand better the pathogenesis of human dementia, especially Alzheimer’s disease. This article aims to review the state of the art regarding the knowledge about the impact of acute viral infections on human cognition, laying a foundation to explore the possible cognitive decline followed coronavirus disease 2019 (COVID-19). To reach this goal, we conducted a narrative review systematizing six acute viral infections as well as the current knowledge about COVID-19 and its impact on human cognition. Recent findings suggest probable short- and long-term COVID-19 impacts in cognition, even in asymptomatic individuals, which could be accounted for by direct and indirect pathways to brain dysfunction. Understanding this scenario might help clinicians and health leaders to deal better with a wave of neuropsychiatric issues that may arise following COVID-19 pandemic as well as with other acute viral infections, to alleviate the cognitive sequelae of these infections around the world.
Saniya Khullar,
Published: 22 June 2021
Abstract:
Background Genome-wide association studies have found many genetic risk variants associated with Alzheimer’s disease (AD). However, how these risk variants affect deeper phenotypes such as disease progression and immune response remains elusive. Also, our understanding of cellular and molecular mechanisms from disease risk variants to various phenotypes is still limited. To address these problems, we performed an integrative multi-omics analysis of genotype, transcriptomics, and epigenomics for revealing gene regulatory mechanisms from disease variants to AD phenotypes. Method First, given the population gene expression data of a cohort, we construct and cluster its gene co-expression network to identify gene co-expression modules for various AD phenotypes. Next, we predict transcription factors (TFs) regulating co-expressed genes and AD risk SNPs that interrupt TF binding sites on regulatory elements. Finally, we construct a gene regulatory network (GRN) linking SNPs, interrupted TFs, and regulatory elements to target genes and gene modules for each phenotype in the cohort. This network thus provides systematic insights into gene regulatory mechanisms from risk variants to AD phenotypes. Results Our analysis predicted GRNs in three major AD-relevant regions: Hippocampus, Dorsolateral Prefrontal Cortex (DLPFC), Lateral Temporal Lobe (LTL). Comparative analyses revealed cross-region-conserved and region-specific GRNs, in which many immunological genes are present. For instance, SNPs rs13404184 and rs61068452 disrupt SPI1 binding and regulation of AD gene INPP5D in the Hippocampus and LTL. However, SNP rs117863556 interrupts bindings of REST to regulate GAB2 in DLPFC only. Driven by emerging neuroinflammation in AD, we used Covid-19 as a proxy to identify possible regulatory mechanisms for neuroimmunology in AD. To this end, we looked at the GRN subnetworks relating to genes from shared AD-Covid pathways. From those subnetworks, our machine learning analysis prioritized the AD-Covid genes for predicting Covid-19 severity. Decision Curve Analysis also validated our AD-Covid genes outperform known Covid-19 genes for classifying severe Covid-19 patients. This suggests AD-Covid genes along with linked SNPs can be potential novel biomarkers for neuroimmunology in AD. Finally, our results are open-source available as a comprehensive functional genomic map for AD, providing a deeper mechanistic understanding of the interplay among multi-omics, brain regions, gene functions like neuroimmunology, and phenotypes.
, Soojin Lee, Fidel Alfaro-Almagro, Christoph Arthofer, , Paul McCarthy, , Jesper L.R. Andersson, , Eugene Duff, et al.
Published: 15 June 2021
Abstract:
There is strong evidence for brain-related abnormalities in COVID-191–13. It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here, we investigated brain changes in 785 UK Biobank participants (aged 51–81) imaged twice, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans, with 141 days on average separating their diagnosis and second scan, and 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including: (i) greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus, (ii) greater changes in markers of tissue damage in regions functionally-connected to the primary olfactory cortex, and (iii) greater reduction in global brain size. The infected participants also showed on average larger cognitive decline between the two timepoints. Importantly, these imaging and cognitive longitudinal effects were still seen after excluding the 15 cases who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease via olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious impact can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow up.
Hannah A.B. Whitmore,
The American Journal of Pathology, Volume 191, pp 1946-1954; https://doi.org/10.1016/j.ajpath.2021.04.017

Abstract:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was originally identified as an outbreak in Wuhan, China, toward the end of 2019 and quickly became a global pandemic, with a large death toll. Originally identified as a respiratory disease, similar to previously discovered SARS and Middle East respiratory syndrome (MERS), concern has since been raised about the effects of SARS-CoV-2 infection on the vasculature. This viral-vascular involvement is of particular concern with regards to the small vessels present in the brain, with mounting evidence demonstrating that SARS-CoV-2 is capable of crossing the blood-brain barrier. Severe symptoms, termed coronavirus disease 2019 (COVID-19), often result in neurologic complications, regardless of patient age. These neurologic complications range from mild to severe across all demographics; however, the long-term repercussions of neurologic involvement on patient health are still unknown.
Yadi Zhou, Jielin Xu, Yuan Hou, James B. Leverenz, Asha Kallianpur, Reena Mehra, Yunlong Liu, Haiyuan Yu, Andrew A. Pieper, Lara Jehi, et al.
Alzheimer's Research & Therapy, Volume 13, pp 1-19; https://doi.org/10.1186/s13195-021-00850-3

Abstract:
Background Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive and therapeutic interventions. Methods In this study, we conducted a network-based, multimodal omics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9-based genetic assay results and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer’s disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2. Results We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Overall, individuals with the AD risk allele APOE E4/E4 displayed reduced expression of antiviral defense genes compared to APOE E3/E3 individuals. Conclusion Our results suggest significant mechanistic overlap between AD and COVID-19, centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions, although causal relationship and mechanistic pathways between COVID-19 and AD need future investigations.
Sonali Kumar, Ozasvi R Shanker, Neeraj Kumari, Manjari Tripathi, P Sarat Chandra, ,
Expert Opinion on Therapeutic Targets, Volume 25, pp 509-519; https://doi.org/10.1080/14728222.2021.1953475

Abstract:
Although SARS-CoV-2 primarily manifests in the form of respiratory symptoms, emerging evidence suggests that the disease is associated with numerous neurological complications, such as stroke and Guillain–Barre syndrome. Hence, further research is necessary to seek possible therapeutic targets in the CNS for effective management of these complications. This review examines the neurological complications associated with SARS-CoV-2 infections and the possible routes of infection. It progresses to illuminate the possible therapeutic targets for effective management of these neuromodulatory effects and the repurposing of drugs that could serve this purpose. To this end, literature from the year 1998–2021 was derived from PubMed. The neurological manifestations associated with COVID-19 may be related to poor prognosis and higher comorbidity. Identification of the key molecular targets in the brain that are potential indicators of the observed neuropathology, such as inflammatory mediators and chromatin modifiers, is key. The repurposing of existing drugs to target potential candidates could reduce the mortality attributed to these associated neurological complications.
, Raphael Stuber, Martin Müller, Annette Mettler, Hansjakob Furrer, Rashida A Ferrand, Aristomenis K Exadaktylos, Wolf E Hautz, Thomas C Sauter
Journal of Global Health Reports, Volume 5; https://doi.org/10.29392/001c.21403

Abstract:
# Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) high infectivity and perceived substantial fatality rates are causing negative psychosocial effects, including the increased psychiatric and economic burden. Research has demonstrated that a severe diagnosis triggers various responses in a person, including depression, sense of hopelessness, shame, and self-destructive behaviours. This manuscript explores the reasons why people did not follow the recommendations to be tested for SARS-CoV-2. # Methods A mixed study design, sequential explanatory study was carried out from March-Dec 2020, based on an online COVID-19 symptom checker. Quantitative and qualitative data were collected. Video interviews were held with Key Informants (n=19), who were selected purposefully from the online tool users’ group that consented to the study. # Results Among 176 users of the online triage tool, 150 (85%) followed the recommendations and 26 (15%) did not. The reasons people did not test for SARS-CoV-2 emerged as fivefold: i) improved symptoms, ii) the cost of test, iii) fear of a painful test procedure, iv) test kit shortages, and v) fear of a positive SARS-CoV-2 test result. # Conclusions Of the reasons why people did not test, fear of a positive SARS-CoV-2 result remains unaddressed in our view. Integrating pre- and post-test counselling into SARS-CoV-2 testing strategies, similarly as done for HIV-testing, seems warranted to address this problem.
Yadi Zhou, Jielin Xu, Yuan Hou, James B. Leverenz, Asha Kallianpur, Reena Mehra, Yunlong Liu, , Andrew A. Pieper, Lara Jehi, et al.
Published: 22 March 2021
Abstract:
Background: Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive interventions.Methods: In this study, we conducted a network-based, multimodal genomics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9 based genetic assay results, and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer’s disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2.Results: We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was significantly elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Notably, individuals with the AD risk allele APOE E4/E4 displayed reduced levels of antiviral defense genes compared to APOE E3/E3 individuals.Conclusion: Our results suggest significant mechanistic overlap between AD and COVID-19, strongly centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions.
International Journal of Molecular Sciences, Volume 22; https://doi.org/10.3390/ijms22052681

Abstract:
Emerging data indicate that neurological complications occur as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The blood–brain barrier (BBB) is a critical interface that regulates entry of circulating molecules into the CNS, and is regulated by signals that arise from the brain and blood compartments. In this review, we discuss mechanisms by which SARS-CoV-2 interactions with the BBB may contribute to neurological dysfunction associated with coronavirus disease of 2019 (COVID-19), which is caused by SARS-CoV-2. We consider aspects of peripheral disease, such as hypoxia and systemic inflammatory response syndrome/cytokine storm, as well as CNS infection and mechanisms of viral entry into the brain. We also discuss the contribution of risk factors for developing severe COVID-19 to BBB dysfunction that could increase viral entry or otherwise damage the brain.
Published: 27 February 2021
by MDPI
Brain Sciences, Volume 11; https://doi.org/10.3390/brainsci11030305

Abstract:
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a neurotropic virus with a high neuroinvasive potential. Indeed, more than one-third of patients develop neurological symptoms, including confusion, headache, and hypogeusia/ageusia. However, long-term neurological consequences have received little interest compared to respiratory, cardiovascular, and renal manifestations. Several mechanisms have been proposed to explain the potential SARS-CoV-2 neurological injury that could lead to the development of neurodegenerative diseases, including Alzheimer’s Disease (AD). A mutualistic relationship between AD and COVID-19 seems to exist. On the one hand, COVID-19 patients seem to be more prone to developing AD. On the other hand, AD patients could be more susceptible to severe COVID-19. In this review, we sought to provide an overview on the relationship between AD and COVID-19, focusing on the potential role of biomarkers, which could represent precious tool for early identification of COVID-19 patients at high risk of developing AD.
Е.а. Хаустова, О.с. Чабан
Психиатрия, психотерапия и клиническая психология pp 85-105; https://doi.org/10.34883/pi.2021.12.1.008

Abstract:
Нарушениям психического здоровья, тесно связанным с COVID-19 на биологическом, психологическом и социальном уровнях, в настоящее время уделяется все больше и больше внимания. Психические и поведенческие расстройства могут быть проявлениями или осложнениями острого COVID-19, такими как острые психотические расстройства, чаще в виде гиперактивного делирия, или нарушения когнитивного функционирования, тревожные расстройства, нарушения сна, депрессия, суицидные попытки. Период постковида также представлен большим спектром психических расстройств, когда на первый план выступают когнитивные нарушения, тревожно-депрессивные расстройства и ПТСР.Проблема ранней диагностики и комплексной терапии психических расстройств, ассоциированных с COVID-19 на всех этапах течения этого заболевания, может быть успешно решена с использованием холистического психосоматического подхода. Медико-психологическое сопровождение и консультативная психиатрическая помощь осуществляются преимущественно в режиме телемедицины. Назначение психотропных препаратов обязательно должно учитывать риск лекарственных взаимодействий: лопинавир/ритонавир, хлорохин/гидрохлорохин и антибиотики часто дают потенциально опасные комбинации с психотропными препаратами в терапии острого COVID-19. В то же время ремдесивир, фавипиравир, тоцилизумаб, барицитиниб и анакинра могут использоваться одновременно с психотропными средствами без значимого риска лекарственного взаимодействия (за исключением гематологического риска при применении клозапина и барицитиниба).В статье представлены международные и национальные рекомендации по выбору наиболее эффективной терапии психических расстройств (антипсихотиков, антидепрессантов, тимостабилизаторов и анксиолитиков) в период острого COVID-19 с указанием доз и режима приема. Также даны рекомендации по менеджменту последствий COVID-19 с позиций доказательной медицины. Mental health disorders are closely related to COVID-19 at the biological, psychological, and social levels, and they are receiving more and more attention now. Mental and behavioral disorders may be the manifestations or complications of acute COVID-19, such as acute psychotic disorders, more often in the form of hyperactive delirium, cognitive impairment, anxiety disorders, sleep disorders, depression, and suicide attempts. The post-Covid period is also represented by a wide range of mental disorders, when cognitive impairment, anxiety, depression, and PTSD come to the fore.The problem of early diagnosis and complex therapy of mental disorders associated with COVID-19 at all stages of the disease can be successfully solved using a holistic psychosomatic approach. Medical and psychological support and counseling psychiatric care are provided mainly in the mode of telemedicine. When prescribing psychotropic drugs, the doctor should take into account the risk of drug interactions: lopinavir/ritonavir, chloroquine/hydroxychloroquine, and antibiotics often give potentially dangerous combinations with psychotropic drugs in the treatment of acute COVID-19. At the same time, remdesivir, favipiravir, tocilizumab, baricitinib, and anakinra can be used concomitantly with psychotropic drugs without significant risk of drug interaction (except for the hematological risk with clozapine and baricitinib).The article presents international and national recommendations for the selection of the most effective therapy for mental disorders (antipsychotics, antidepressants, thymostabilizers, and anxiolytics) during acute COVID-19, indicating the doses and mode of administration. The recommendations for the management of the consequences of COVID-19 from the standpoint of evidence-based medicine are also given.
Paul Sanberg, Donna C Morrison,
Published: 1 January 2021
Cell Transplantation, Volume 30; https://doi.org/10.1177/09636897211053872

Abstract:
The 28th American Society for Neural Therapy and Repair (ASNTR) returned to the Sheraton Sand Key in Clearwater Beach, Florida after an 18 month hiatus. Like nearly all conferences during the pandemic, the ASNTR conference was held in person while offering a virtual option to the event. These formats are advantageous for those under travel restrictions or personal constraints, but they lack the spontaneity of in-person connections. Highlights from the meeting included the return of the Bernard Sanberg Memorial Award and the Roy Bakay Memorial lecture. The presidential lecture was given by Gabriel de Erausquin, who discussed the possibility of long-term CNS effects resulting from SARS-CoV2 infection. With both virtual and in-person events, including oral and poster presentations, the ASNTR managed to maintain the unique essence of this small important meeting.
A.J. Nikitina, A.Sh. Chimagomedova, O.S. Levin
Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova, Volume 121; https://doi.org/10.17116/jnevro20211211025

Published: 7 December 2020
Abstract:
Background Definitive diagnosis of COVID-19 requires resources frequently restricted to the severely ill. Cohort studies must rely on surrogate indicators to define cases of COVID-19 in the community. We describe the prevalence and overlap of potential indicators including self-reported symptoms, suspicion, and routine test results, plus home antibody testing. Methods An occupational cohort of 2807 staff and postgraduate students at a large London university. Repeated surveys covering March to June 2020. Antibody test results from ‘lateral flow’ IgG/IgM cassettes in June 2020. Results 1882 participants had valid antibody test results, and 124 (7%) were positive. Core symptoms of COVID-19 were common (770 participants positive, 41%), although fewer met criteria on a symptom algorithm (n=297, 16%). Suspicion of COVID-19 (n=509, 27%) was much higher than positive external tests (n=39, 2%). Positive antibody tests were rare in people who had no suspicion (n=4, 1%) or no core symptoms (n=10, 2%). In those who reported external antibody tests, 15% were positive on the study antibody test, compared with 24% on earlier external antibody tests. Discussion Our results demonstrate the agreement between different COVID indicators. Antibody testing using lateral flow devices at home can detect asymptomatic cases and provide greater certainty to self-report; but due to weak and waning antibody responses to mild infection, may under-ascertain. Multiple indicators used in combination can provide a more complete story than one used alone. Cohort studies need to consider how they deal with different, sometimes conflicting, indicators of COVID-19 illness to understand its long-term outcomes. THUMBNAIL What is already known on this subject? Research into the effects of COVID-19 in the community is needed to respond to the pandemic, and guidance is needed as to how cohort studies measure COVID-19 infection status retrospectively, particularly given that objective testing for infection was not widely available in the first wave of COVID-19 in many countries. Retrospective testing might be possible using antibodies as a proxy for previous COVID-19 infection. What this study adds? Antibody testing is feasible in community cohorts but sensitivity may be poor. Self-report of suspected infection, recall of symptoms and results of tests received elsewhere add different aspects to the ascertainment of COVID-19 exposure. Combining self-report and objectively measured indicators may enable tailored algorithms for COVID-19 case definition that suits the aims of different research studies.
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