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      Cognitive impairment in long-COVID and its association with persistent dysregulation in inflammatory markers

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          Abstract

          Objective

          To analyze the potential impact of sociodemographic, clinical and biological factors on the long-term cognitive outcome of patients who survived moderate and severe forms of COVID-19.

          Methods

          We assessed 710 adult participants (Mean age = 55 ± 14; 48.3% were female) 6 to 11 months after hospital discharge with a complete cognitive battery, as well as a psychiatric, clinical and laboratory evaluation. A large set of inferential statistical methods was used to predict potential variables associated with any long-term cognitive impairment, with a focus on a panel of 28 cytokines and other blood inflammatory and disease severity markers.

          Results

          Concerning the subjective assessment of cognitive performance, 36.1% reported a slightly poorer overall cognitive performance, and 14.6% reported being severely impacted, compared to their pre-COVID-19 status. Multivariate analysis found sex, age, ethnicity, education, comorbidity, frailty and physical activity associated with general cognition. A bivariate analysis found that G-CSF, IFN-alfa2, IL13, IL15, IL1.RA, EL1.alfa, IL45, IL5, IL6, IL7, TNF-Beta, VEGF, Follow-up C-Reactive Protein, and Follow-up D-Dimer were significantly (p<.05) associated with general cognition. However, a LASSO regression that included all follow-up variables, inflammatory markers and cytokines did not support these findings.

          Conclusion

          Though we identified several sociodemographic characteristics that might protect against cognitive impairment following SARS-CoV-2 infection, our data do not support a prominent role for clinical status (both during acute and long-stage of COVID-19) or inflammatory background (also during acute and long-stage of COVID-19) to explain the cognitive deficits that can follow COVID-19 infection.

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          Most cited references55

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          The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.

          Much biomedical research is observational. The reporting of such research is often inadequate, which hampers the assessment of its strengths and weaknesses and of a study's generalisability. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative developed recommendations on what should be included in an accurate and complete report of an observational study. We defined the scope of the recommendations to cover three main study designs: cohort, case-control, and cross-sectional studies. We convened a 2-day workshop in September, 2004, with methodologists, researchers, and journal editors to draft a checklist of items. This list was subsequently revised during several meetings of the coordinating group and in e-mail discussions with the larger group of STROBE contributors, taking into account empirical evidence and methodological considerations. The workshop and the subsequent iterative process of consultation and revision resulted in a checklist of 22 items (the STROBE statement) that relate to the title, abstract, introduction, methods, results, and discussion sections of articles.18 items are common to all three study designs and four are specific for cohort, case-control, or cross-sectional studies.A detailed explanation and elaboration document is published separately and is freely available on the websites of PLoS Medicine, Annals of Internal Medicine, and Epidemiology. We hope that the STROBE statement will contribute to improving the quality of reporting of observational studies
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            Extrapulmonary manifestations of COVID-19

            Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.
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              Neuroinflammation in Alzheimer's disease.

              Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease. Copyright © 2015 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/1220893
                URI : https://loop.frontiersin.org/people/740716
                URI : https://loop.frontiersin.org/people/102843
                URI : https://loop.frontiersin.org/people/191506
                URI : https://loop.frontiersin.org/people/469271
                URI : https://loop.frontiersin.org/people/83315
                URI : https://loop.frontiersin.org/people/1280204
                URI : https://loop.frontiersin.org/people/185691
                URI : https://loop.frontiersin.org/people/2281394
                URI : https://loop.frontiersin.org/people/956111
                URI : https://loop.frontiersin.org/people/110149
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                23 May 2023
                2023
                23 May 2023
                : 14
                : 1174020
                Affiliations
                [1] 1 Departamento e Instituto de Psiquiatria, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP) , São Paulo, SP, Brazil
                [2] 2 Instituto de Psicologia, Universidade de São Paulo , São Paulo, SP, Brazil
                [3] 3 Research & Development Service, VA Portland Health Care System , Portland, OR, United States
                [4] 4 Departments of Psychiatry and Behavioral Neuroscience, Oregon Health and Science University , Portland, OR, United States
                [5] 5 Departamento de Psiquiatria, Universidade Federal de São Paulo , São Paulo, SP, Brazil
                [6] 6 Departamento de Cínica Médica, Universidade de São Paulo FMUSP , São Paulo, SP, Brazil
                [7] 7 Institute for Investigation in Immunology/National Institutes for Science and Technology (iii/INCT) , São Paulo, Brazil
                [8] 8 Cancer Metabolism Research Group, Department of Surgery and LIM 26, Hospital das Clínicas, University of São Paulo , São Paulo, SP, Brazil
                [9] 9 Departamento de Neurologia, Universidade de São Paulo FMUSP , São Paulo, Brazil
                [10] 10 Departamento de Emergências Médicas, Universidade de São Paulo FMUSP , São Paulo, SP, Brazil
                Author notes

                Edited by: Diana Boraschi, Chinese Academy of Science (CAS), China

                Reviewed by: Arantzazu Alfranca, Servicio de Inmunología, Hospital de la Princesa, Spain; Piergiuseppe De Berardinis, Consiglio Nazionale delle Ricerche (Napoli), Istituto di Biochimica e Biologia Cellulare, Italy

                *Correspondence: Rodolfo Furlan Damiano, damianorf@ 123456gmail.com
                Article
                10.3389/fimmu.2023.1174020
                10242059
                37287969
                01c5f19c-05e2-4724-856a-12ac323e80e4
                Copyright © 2023 Damiano, Rocca, Serafim, Loftis, Talib, Pan, Cunha-Neto, Kalil, de Castro, Seelaender, Guedes, Nagahashi Marie, de Souza, Nitrini, Miguel, Busatto, Forlenza and HCFMUSP COVID-19 Study Group

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 25 February 2023
                : 10 May 2023
                Page count
                Figures: 0, Tables: 5, Equations: 0, References: 55, Pages: 13, Words: 6807
                Funding
                Funded by: Fundação de Amparo á Pesquisa do Estado de São Paulo , doi 10.13039/501100001807;
                Award ID: 2021/14379-8, 2020/02988-7, 2022/01769-5
                This work was partially supported by donations from the general public under the HC-COMVIDA crowdfunding scheme ( https://viralcure.org/c/hc), the Fundação Faculdade de Medicina (ALA) and Fundação de Amparo a Pesquisa do Estado de São Paulo - FAPESP (process nos. 2020/02988-7 and 2022/01769-5). RFD received grant from FAPESP (process number #2021/14379-8). This material is the result of work supported, in part, by the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Merit Review Program (JML under grant #I01BX002061); United States Department of Veterans Affairs Clinical Sciences Research and Development Merit Review Program (JML under grant #COVID19-8900-14).
                Categories
                Immunology
                Original Research
                Custom metadata
                Cytokines and Soluble Mediators in Immunity

                Immunology
                covid-19,sars- cov-2,cognition,inflammation,cohort study (or longitudinal study)
                Immunology
                covid-19, sars- cov-2, cognition, inflammation, cohort study (or longitudinal study)

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