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in category neurology

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1: Brain imaging before and after COVID-19 in UK Biobank
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Posted 15 Jun 2021

Brain imaging before and after COVID-19 in UK Biobank
172,544 downloads medRxiv neurology

Gwenaëlle Douaud, Soojin Lee, Fidel Alfaro-Almagro, Christoph Arthofer, Chaoyue Wang, Paul McCarthy, Frederik J Lange, Jesper L.R. Andersson, Ludovica Griffanti, Eugene Duff, Saad Jbabdi, Bernd Taschler, Anderson M. Winkler, Thomas E. Nichols, Rory Collins, Paul M Matthews, Naomi Allen, Karla L Miller, Stephen Mark Smith

There is strong evidence for brain-related pathologies in COVID-19, some of which could be a consequence of viral neurotropism, or of neuroinflammation following viral infection. Most brain imaging studies have focused on qualitative, gross pathology in moderate to severe cases, most typically carried out on hospitalised patients. It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, in a quantitative and automated manner, and whether this can reveal possible mechanisms for the spread of the disease. UK Biobank scanned over 40,000 participants before the start of the COVID-19 pandemic, making it possible in 2021 to invite back hundreds of previously-imaged participants for a second imaging visit. Here, we studied the possible brain changes associated with the coronavirus infection using multimodal MRI data from 785 adult participants (aged 51-81) from the UK Biobank COVID-19 re-imaging study, including 401 adult participants who tested positive for SARS-CoV-2 infection between their two scans. We used structural, diffusion and functional brain scans from before and after infection, to compare longitudinal changes between these 401 SARS-CoV-2 cases and 384 controls who had either tested negative to rapid antibody testing or had no COVID-19 medical and public health record, and who were matched to the cases for age, sex, ethnicity and interval between scans. The controls and cases did not differ in blood pressure, body mass index, diabetes diagnosis, smoking, alcohol consumption, or socio-economic status. Using both hypothesis-driven and exploratory approaches, with false discovery rate multiple comparison correction, we identified respectively 68 and 67 significant longitudinal effects associated with SARS-CoV-2 infection in the brain, including, on average: (i) a more pronounced reduction in grey matter thickness and contrast in the lateral orbitofrontal cortex (min P=1.7x10-4, r=-0.14) and parahippocampal gyrus (min P=2.7x10-4, r=-0.13), (ii) a relative increase of diffusion indices, a marker of tissue damage, in the regions of the brain functionally-connected to the piriform cortex, anterior olfactory nucleus and olfactory tubercle (min P=2.2x10-5, r=0.16), and (iii) greater reduction in global measures of brain size and increase in cerebrospinal fluid volume suggesting an additional diffuse atrophy in the infected participants (min P=4.0x10-6, r=-0.17). When looking over the entire cortical surface, these grey matter thickness results covered the parahippocampal gyrus and the lateral orbitofrontal cortex, and extended to the anterior insula and anterior cingulate cortex, supramarginal gyrus and temporal pole. The increase of a diffusion index (mean diffusivity) meanwhile could be seen voxel-wise mainly in the medial and lateral orbitofrontal cortex, the anterior insula, the anterior cingulate cortex and the amygdala. These results were not altered after excluding cases who had been hospitalised. We further compared hospitalised (n=15) and non-hospitalised (n=386) infected participants, resulting in similar findings to the larger cases vs control group comparison, with, in addition, a marked reduction of grey matter thickness in fronto-parietal and temporal regions (all FDR-significant, min P=4.0x10-6). The 401 SARS-CoV-2 infected participants also showed larger cognitive decline between the two timepoints in the Trail Making Test compared with the controls (both FDR-significant, min P=1.0x10-4, r=0.17; and still FDR-significant after excluding the hospitalised patients: min P=1.0x10-4, r=0.17), with the duration taken to complete the alphanumeric trail correlating post hoc with the cognitive and olfactory-related crus II of the cerebellum (FDR-significant, P=2.0x10-3, r=-0.19), which was also found significantly atrophic in the SARS-CoV-2 participants (FDR-significant, P=6.1x10-5, r=-0.14). Our findings thus relate to longitudinal abnormalities in limbic cortical areas with direct neuronal connectivity to the primary olfactory system. Unlike in post hoc cross-sectional studies, the availability of pre-infection imaging data mitigates to some extent the issue of pre-existing risk factors or clinical conditions being misinterpreted as disease effects. We were therefore able to demonstrate that the regions of the brain that showed longitudinal differences post-infection did not already show any difference between (future) cases and controls in their initial, pre-infection scans. These brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease -- or of the virus itself -- via olfactory pathways (a possible entry point of the virus to the central nervous system being via the olfactory mucosa), or of neuroinflammatory events due to the infection, or of the loss of sensory input due to anosmia. Whether this deleterious impact can be partially reversed, for instance after improvement of the hyposmic symptoms, or whether these are effects that will persist in the long term, remains to be investigated with additional follow up.

2: Six-month Neurological and Psychiatric Outcomes in 236,379 Survivors of COVID-19
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Posted 24 Jan 2021

Six-month Neurological and Psychiatric Outcomes in 236,379 Survivors of COVID-19
26,343 downloads medRxiv neurology

Maxime Taquet, John R Geddes, Masud Husain, Sierra Luciano, Paul Harrison

Background. Neurological and psychiatric sequelae of COVID-19 have been reported, but there are limited data on incidence rates and relative risks. Methods. Using retrospective cohort studies and time-to-event analysis, we estimated the incidence of ICD-10 diagnoses in the 6 months after a confirmed diagnosis of COVID-19: intracranial haemorrhage; ischaemic stroke; Parkinsonism; Guillain-Barre syndrome; nerve/nerve root/plexus disorders; myoneural/muscle disease; encephalitis; dementia; mood, anxiety, and psychotic disorders; substance misuse; and insomnia. Data were obtained from the TriNetX electronic health records network (over 81 million patients). We compared incidences with those in propensity score-matched cohorts of patients with influenza or other respiratory infections using a Cox model. We investigated the effect on incidence estimates of COVID-19 severity, as proxied by hospitalization and encephalopathy (including delirium and related disorders). Findings. 236,379 patients survived a confirmed diagnosis of COVID-19. Among them, the estimated incidence of neurological or psychiatric sequelae at 6 months was 33.6%, with 12.8% receiving their first such diagnosis. Most diagnostic categories were commoner after COVID-19 than after influenza or other respiratory infections (hazard ratios from 1.21 to 5.28), including stroke, intracranial haemorrhage, dementia, and psychotic disorders. Findings were equivocal for Parkinsonism and Guillain-Barre syndrome. Amongst COVID-19 cases, incidences and hazard ratios for most disorders were higher in patients who had been hospitalized, and markedly so in those who had experienced encephalopathy. Results were robust to sensitivity analyses, including comparisons against an additional four index health events. Interpretation. The study provides evidence for substantial neurological and psychiatric morbidity following COVID-19 infection. Risks were greatest in, but not limited to, those who had severe COVID-19. The information can help in service planning and identification of research priorities.

3: Morphological, cellular and molecular basis of brain infection in COVID-19 patients
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Posted 13 Oct 2020

Morphological, cellular and molecular basis of brain infection in COVID-19 patients
15,680 downloads medRxiv neurology

Fernanda Crunfli, Victor Corasolla Carregari, Flavio Protasio Veras, Pedro Henrique Vendramini, Aline Gazzola Fragnani Valenca, Andre Saraiva Leao Marcelo Antunes, Carolina Brandao-Teles, Giuliana da Silva Zuccoli, Guilherme Reis-de-Oliveira, Licia C. Silva-Costa, Verônica Monteiro Saia-Cereda, Bradley Joseph Smith, Ana Campos Codo, Gabriela Fabiano de Souza, Stéfanie Primon Muraro, Pierina Lorencini Parise, Daniel A. Toledo-Teixeira, Icaro Maia Santos de Castro, Bruno Marcel Silva Melo, Glaucia M. Almeida, Egidi Mayara Silva Firmino, Isadora Marques Paiva, Bruna Manuella Souza Silva, Rafaela Mano Guimaraes, Niele D. Mendes, Raíssa Guimarães Ludwig, Gabriel Palermo Ruiz, Thiago Leite Knittel, Gustavo Gastão Davanzo, Jaqueline Aline Gerhardt, Patrícia Brito Rodrigues, Julia Forato, Mariene Ribeiro Amorim, Natália Brunetti Silva, Matheus Cavalheiro Martini, Maíra Nilson Benatti, Sabrina Batah, Li Siyuan, Rafael Batista João, Lucas Scardua Silva, Mateus Henrique Nogueira, ítalo Karmann Aventurato, Mariana Rabelo de Brito, Marina Koutsodontis Machado Alvim, José Roberto da Silva Junior, Lívia Liviane Damião, Maria Ercilia de Paula Castilho Stefano, Iêda Maria Pereira de Sousa, Elessandra Dias da Rocha, Solange Maria Gonçalves, Luiz Henrique Lopes da Silva, Vanessa Bettini, Brunno Machado de Campos, Guilherme Ludwig, Lucas Alves Tavares, Marjorie Cornejo Pontelli, Rosa Maria Mendes Viana, Ronaldo Martins, Andre S. Vieira, José Carlos Alves-Filho, Eurico Arruda, Guilherme Podolski-Gondim, Marcelo Volpon Santos, Luciano Neder, Fernando Cendes, Paulo Louzada-Junior, Rene Donizeti Oliveira, Fernando Q Cunha, André Damásio, Marco Aurélio Ramirez Vinolo, Carolina Demarchi Munhoz, Stevens K Rehen, Helder I Nakaya, Thais Mauad, Amaro Nunes Duarte-Neto, Luiz Fernando Ferraz da Silva, Marisa Dolhnikoff, Paulo Saldiva, Alessandro S Farias, Pedro Manoel M. Moraes-Vieira, Alexandre T Fabro, Adriano Sebollela, José Luiz Proença Módena, Clarissa Lin Yasuda, Marcelo A. Mori, Thiago M Cunha, Daniel Martins-de-Souza

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, the long-term neuropsychiatric dysfunction has been frequently observed after mild infection. Here we show the spectrum of the cerebral impact of SARS-CoV-2 infection ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal trans-ethmoidal approach) from individuals who died of COVID-19. We used surface-based analyses of 3T MRI and identified orbitofrontal cortical atrophy in a group of 81 mildly infected patients (77% referred anosmia or dysgeusia during acute stage) compared to 145 healthy volunteers; this atrophy correlated with symptoms of anxiety and cognitive dysfunction. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection, and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these 5 patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a non-canonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes and consequently leads to neuronal death or dysfunction. These deregulated processes are also likely to contribute to the structural and functional alterations seen in the brains of COVID-19 patients.

4: Acute myelitis after SARS-CoV-2 infection: a case report.
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Posted 18 Mar 2020

Acute myelitis after SARS-CoV-2 infection: a case report.
8,904 downloads medRxiv neurology

Kang Zhao, Jucun Huang, Dan Dai, Yuwei Feng, Liming Liu, Shuke Nie

We report a case of acute myelitis in a patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A 66-year-old man with coronavirus disease 2019 was admitted with acute flaccid paralysis of the bilateral lower limbs and urinary and bowel incontinence. All serum microbiological test results were negative, except for SARS-CoV-2 nucleic acid testing. Clinical findings indicated post-infectious acute myelitis. He received treatment containing ganciclovir, lopinavir/ritonavir, moxifloxacin, dexamethasone, human immunoglobulin, and mecobalamin. With a diagnosis of post-infectious acute myelitis and comprehensive treatment, paralysis of the bilateral lower extremities ameliorated. After two negative novel coronavirus RNA nasopharyngeal swab tests, he was discharged and transferred to a designated hospital for isolation and rehabilitation therapy.

5: Autoantibodies against the prion protein in individuals with PRNP mutations
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Posted 08 Oct 2019

Autoantibodies against the prion protein in individuals with PRNP mutations
7,389 downloads medRxiv neurology

Karl Frontzek, Manfredi Carta, Marco Losa, Mirka Epskamp, Georg Meisl, Alice Anane, Jean-Philippe Brandel, Ulrike Camenisch, Joaquín Castilla, Stéphane Haïk, Tuomas Knowles, Ewald Lindner, Andreas Lutterotti, Eric Vallabh Minikel, Ignazio Roiter, Jiri G Safar, Raquel Sanchez-Valle, Dana Žáková, Simone Hornemann, Adriano Aguzzi

Structured abstractO_ST_ABSObjectiveC_ST_ABSTo determine whether naturally occurring autoantibodies against the prion protein are present in individuals with genetic prion disease mutations and controls, and if so, whether they are protective against prion disease. MethodsIn this case-control study, we collected 124 blood samples from individuals with a variety of pathogenic PRNP mutations and 78 control individuals with a positive family history of genetic prion disease but lacking disease-associated PRNP mutations. Antibody reactivity was measured using an indirect ELISA for the detection of human IgG1-4 antibodies against wild-type human prion protein. Multivariate linear regression models were constructed to analyze differences in autoantibody reactivity between a) PRNP mutation carriers versus controls and b) asymptomatic versus symptomatic PRNP mutation carriers. Robustness of results was examined in matched cohorts. ResultsWe found that antibody reactivity was present in a subset of both PRNP mutation carriers and controls. Autoantibody levels were not influenced by PRNP mutation status nor clinical manifestation of prion disease. Post hoc analyses showed anti-PrPC autoantibody titers to be independent of personal history of autoimmune disease and other immunological disorders, as well as PRNP codon 129 polymorphism. ConclusionsPathogenic PRNP variants do not notably stimulate antibody-mediated anti-PrPC immunity. Anti-PrPC IgG autoantibodies are not associated with the onset of prion disease. The presence of anti-PrPC autoantibodies in the general population without any disease-specific association suggests that relatively high titers of naturally occurring antibodies are well tolerated. Clinicaltrials.gov identifier NCT02837705.

6: New insights on the genetic etiology of Alzheimer and related dementia
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Posted 04 Oct 2020

New insights on the genetic etiology of Alzheimer and related dementia
7,193 downloads medRxiv neurology

Celine Bellenguez, Fahri Kucukali, Iris Jansen, Victor Andrade, Sonia Morenau-Grau, Najaf Amin, Adam Naj, Benjamin Grenier-Boley, Rafael Campos Martin, Peter Holsman, Anne Boland, Luca Kleideman, Vincent Damotte, Sven Vander Lee, Pablo Garcia, Yang Qiong, Joshua Bis, Marcos Costa, Julien Chapuis, Vilmentas Giedraitis, Maria J Bullido, Adolfo Lopez de Munain, Jordi Perez-Tur, Pascual Sanchez-Juan, Raquel Sanchez-Valle, Victoria Alvarez, Pau Pastor, Miguel Medina, Jasper Van Dongen, Christine van Broeckhoven, Rik Vandenberghe, Sebastiaan Engelborghs, Gael Nicolas, Florence Pasquier, Olivier Hanon, Carole Dufouil, Claudine Berr, Stephanie Debette, Jean-Francois Dartigues, Gianfranco Spalletta, Benedetta Nacmias, Vincenzo Solfrezzi, Barbara Berroni, Lucio Tremolizzo, Davide Seripa, Paolo Caffara, Antonio Daniele, Daniela Galimberti, Innocenzo Rainero, Luisa Benussi, Alesio Squassina, Patricia Mecoci, Lucilla Parnetti, Carlo Masullo, Beatrice Arosio, John Hardy, Simon H Mead, Kevin Morgan, Clive Holmes, Patrick Kehoe, Bob Woods, EADB consortium, Charge Consortium, ADGC Consortium, Jin Sha, Yi Zhao, Chien-Yueh Lee, Pavel p Kuksa, Kara L Hamilton-Nelson, Brian Kunkle, William S Bush, Eden R. Martin, Li San Wang, Richard Mayeux, Lindsay Farrer, Jonathan L. Haines, Ruiqi Wang, Claudia Satizabal, Bruce Psaty, Oscar Lopez, Florentino Sanchez-Garcia, Borge G Nordestgaard, Anne Tybjaeg-hansen, Jesper Qvist Thomassen, Caroline Graff, Goran Papenberg, Hilkka Soininen, Miia Kivipelto, Annakaisa Haapasalo, Tiia Ngandu, Anne Koivisto, Teemu Kuulasmaa, Laura Molina Porcel, Johannes Kornhuber, Oliver Peters, Anja Schneider, Nikolaos Scarmeas, Martin Dichgans, Lutz Froelich, Dan Rujescu, Janine Diehl-Schmid, Timo Grimmer, Matthias Schmid, Markus M Mothen, Edna Grunblatt, Julius Popp, Norbert Scherbaum, Shima Mehrabian, Deckert Jurgen, dag Aareland, Geir Selbaeck, Ingvild Saltvedt, Srdjan Djurovic, Henne Holstege, Yolande A.L. Pijnenburg, John Van Swieten, Inez Ramakers, Aad Van der Lugt, Jurgen A.H.R. Claassen, Geert Jan Biessels, Philip Scheltens, Carmen Antunez, Pablo Mir, Luis Miguel Real, Jose Maria Garcia-Alberca, Gerard Pinol-Ripoll, Guillermo Garcia-Ribas, Manuel Serrano-Rios, Franck Jessen, Alexandre de Mendoca, Jakub Hort, Margaret A. Pericak-Vance, Magda Tsolaki, Philippe Amouyel, Julie Williams, Ruth Frikke-Schmidt, Jordi Clarimon, Jean-Francois Deleuze, Giacomina Rossi, Sudha Seshadri, Ole Andreassen, Martin Ingelsson, Mikko Hiltunen, Kristel Sleegers, Gerald SChellenberg, Cornelia van Duijn, Rebecca Sims, Wiesje Van der Flier, Agustin Ruiz, Alfredo Ramirez, Jean-Charles Lambert

Alzheimer disease (AD) is a severe and incurable neurodegenerative disease, and the failure to find effective treatments suggests that the underlying pathology remains poorly understood. Due to its strong heritability, deciphering the genetic landscape of AD and related dementia (ADD) is a unique opportunity to advance our knowledge. We completed a meta-analysis of genome-wide association studies (39,106 clinically AD-diagnosed cases, 46,828 proxy-ADD cases and 401,577 controls) with the most promising signals followed-up in 25,392 independent AD cases and 276,086 controls. We report 75 risk loci for ADD, including 42 novel ones. Pathway-enrichment analyses confirm the involvement of amyloid/Tau pathways, highlight the role of microglia and its potential interaction with APP metabolism. Numerous genes exhibited differential expression or splicing in AD-related conditions and gene prioritization implies EGFR signaling and TNFapha pathway through LUBAC complex. We also generated a novel polygenic risk score strongly associated with the risk of future dementia or progression from mild cognitive impairment to dementia. In conclusion, by more than doubling the number of loci associated with ADD risk, our study offers new insights into the pathophysiological processes underlying AD and offers additional therapeutic entry-points and tools for translational genomics

7: COVID-19 vaccine-associated cerebral venous thrombosis in Germany
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Posted 04 May 2021

COVID-19 vaccine-associated cerebral venous thrombosis in Germany
6,851 downloads medRxiv neurology

Jorg B Schulz, Peter Berlit, Hans-Christoph Diener, Christian Gerloff, Andreas Greinacher, Christine Klein, Gabor C. Petzold, Marco Piccininni, Sven Poli, Rainer Roehrig, Helmuth Steinmetz, Thomas Thiele, Tobias Kurth

ObjectiveReports of cerebral venous thrombosis (CVT) after ChAdOx1 vaccination against SARS-CoV-2 have raised safety concerns and an emerging mechanism termed vaccine induced immune thrombotic thrombocytopenia (VITT) was identified. We aimed to estimate the frequency of CVT and other cerebrovascular events after vaccination with BNT162b2, ChAdOx1, and mRNA-1273, 114 German Departments of Neurology participated in a systematic survey. Designdescriptive study. SettingGermany. PopulationPatients with reported cerebrovascular events within the first month after a COVID-19 vaccine administration. MethodsWe designed web-based questionnaire, which was e-mailed to all Departments of Neurology of University and non-university hospitals in Germany on April 6, 2021. Data collection was closed at midnight on April 14, 2021. We asked to report cases of cerebral sinus-venous thrombosis, cerebral venous thrombosis, ischemic stroke and haemorrhage within one month of a COVID-19 vaccination. Incidence rates of cerebral events and CVT within one month from first vaccine shot administration was calculated by using official statistics of 9 German States. ResultsA total of 62 cases were detected, of whom 45 had CVT, 9 primary ischemic stroke, 4 primary intracerebral hemorrhage (ICH), and 4 other events. Eleven patients of 60 (18.3%) had a fatal outcome. Mean age was 46.7 years (48 patients <60 years, 77.4%), 75.8% of patients were female. Fifty-three events were observed after vaccination with ChAdOx1 (85.5%), 9 after BNT162b2 (14.5%). No events were reported after mRNA-1273 vaccination. The overall incidence rate of CVT within one month from first dose administration was 6.5 (95% CI, 4.4 to 9.2) per 100,000 person-years and 8.8 (95% CI, 6.4 to 11.9) for any included cerebrovascular event. The one-month incidence rate of CVT was higher among ChAdOx1 vaccinated persons (17.9, 95% CI, 11.8 to 26.1). The incidence rate ratio was 9.68 (3.46 to 34.98) for ChAdOx1 compared to mRNA-based vaccines and 3.14 (1.22 to 10.65) for women compared to non-women after adjusting for age group. In 26/45 patients with CVT (57.8%), VITT was graded highly probable, in 19/45 patients (42.2%) the association was less likely. A high-grade probability was not confined to CVT but also occurred in 5/9 patients (55.6%) with primary ischemic stroke and 2/4 patients (50%) with ICH following vaccination. ConclusionsGiven an incidence of CVT in the general population of 0.22 - 1.75 per 100,000 person-years, these findings point towards and higher risk for CVT after ChAdOx1 vaccination, especially for women.

8: Precision Medicine Approach to Alzheimer's Disease: Successful Proof-of-Concept Trial
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Posted 11 May 2021

Precision Medicine Approach to Alzheimer's Disease: Successful Proof-of-Concept Trial
6,275 downloads medRxiv neurology

Kat Toups, Ann Hathaway, Deborah Gordon, Henrianna Chung, Cyrus Raji, Alan Boyd, Benjamin D. Hill, Sharon Hausman-Cohen, Mouna Attarha, Won Jong Chwa, Michael Jarrett, Dale E. Bredesen

Abstract Importance: Effective therapeutics for Alzheimer's disease and mild cognitive impairment are needed. Objective: To determine whether a precision medicine approach to Alzheimer's disease and mild cognitive impairment, in which potential contributors to cognitive decline are identified and targeted therapeutically, is effective enough in a proof-of-concept trial to warrant a larger, randomized, controlled clinical trial. Rationale: Previous clinical trials for Alzheimer's disease have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, that may be unrelated to the primary drivers of the neurodegenerative process. Therefore, increasing data set size to include the potential contributors to cognitive decline for each patient, and addressing the identified potential contributors, may represent a more effective therapeutic strategy. Hypothesis: Alzheimer's disease is a multi-factorial network dysfunction that results from a chronic or repeated insufficiency of support for a neuroplasticity network; thus factors that increase demand -- such as infections or toxin exposure -- or reduce support -- such as reduced energetics or trophic support -- may contribute to the neurodegenerative process. Rectifying this hypothesized network dysfunction represents a rational approach to the treatment of the cognitive decline associated with Alzheimer's disease and mild cognitive impairment. Design: Twenty-five patients with Alzheimer's disease or mild cognitive impairment, with Montreal Cognitive Assessment (MoCA) scores of 19 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure (metals, organic toxicants, and biotoxins), genetic predisposition to cognitive decline, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Patients were treated for nine months with a personalized, precision medicine protocol that addressed each patient's identified potentially contributory factors, and cognition was assessed at t = 0, 3, 6, and 9 months. Trial registration and IRB approval: The clinical trial was registered at clinicaltrials.gov (NCT03883633), 1 and approved by the Advarra IRB. Support for the trial: The trial was supported by a grant from the Four Winds Foundation via Evanthea, LLC, and we are grateful to Diana Merriam and Gayle Brown for their interest, discussions, and support. Main Outcome Measures: Trained external raters evaluated the study subjects with the Montreal Cognitive Assessment (MoCA), CNS Vital Signs (a computerized cognitive assessment battery), AQ-21 (a subjective scale completed by the significant other or study partner), and AQ-C change scale (a subjective scale of cognitive improvement or decline, completed by the significant other or study partner). Follow-up brain MRI with volumetrics was carried out at the completion of the trial. Results: All outcome measures revealed improvement: statistically highly significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and AQ-C were documented. No serious adverse events were recorded. Conclusions and Relevance: Based on the cognitive improvements observed in this study of patients with Alzheimer's disease or mild cognitive impairment, a larger, randomized, controlled trial of the precision medicine therapeutic approach described herein is warranted.

9: Havana Syndrome Among Canadian Diplomats: Brain Imaging Reveals Acquired Neurotoxicity
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Posted 29 Sep 2019

Havana Syndrome Among Canadian Diplomats: Brain Imaging Reveals Acquired Neurotoxicity
5,647 downloads medRxiv neurology

Alon Friedman, Cynthia Calkin, Amanda Adams, Guillermo Aristi Suarez, Tim Bardouille, Noa Hacohen, A. Laine Green, R. Rishi Gupta, Javeria Hashmi, Lyna Kamintsky, Jong Sung Kim, Robert Laroche, Diane MacKenzie, Dan Milikovsky, Darren Oystreck, Jillian Newton, Greg Noel, Jonathan Ofer, Maher Quraan, Claire Reardon, Margaux Ross, Derek Rutherford, Matthias Schmidt, Yonatan Serlin, Crystal Sweeney, Janine Verge, Leah Walsh, Chris Bowen

BACKGROUNDIn late 2016, US diplomats stationed in Havana began presenting with a variety of neurological manifestations that proved difficult to diagnose. Though previous studies suggested a likely association with brain injury, the mechanism of injury, brain regions involved, and etiology remained unknown. METHODSWe conducted a multimodal study examining 26 Canadian diplomats and their family members, the majority of whom presented with symptoms similar to their American counterparts while residing in Havana. Assessments included a medical history, self-reported symptom questionnaires, cognitive assessments, blood tests, and brain imaging assessments (magnetic resonance imaging (MRI) and magnetoencephalography (MEG)). Individuals showing signs of brain injury underwent further neurological, visual, and audio-vestibular assessments. Eight participants were tested both before and after living in Havana. RESULTSOur assessment documents multiple functional and structural impairments, including significant spatial memory impairment, abnormal brain-stem evoked potentials, degradation of fibre tracts in the fornix and posterior corpus callosum, blood-brain barrier injury to the right basal forebrain and anterior insula, and abnormal paroxysmal slowing events of cortical activity. Subsequent mass-spectrometry and blood analyses documented reduced serum cholinesterase activity and the presence of organophosphates (Temephos) and pyrethroid metabolites (3-phenoxybenzoic acid or 3-BPA). CONCLUSIONSOur findings confirm brain injury, specify the regions involved, and raise the hypothesis of overexposure to cholinesterase inhibitors as a plausible etiology. If correct, our hypothesis bears public health ramifications (see Discussion) and suggests a course of action for reducing exposure in the future. FUNDINGGlobal Affairs Canada.

10: Neuropathic symptoms with SARS-CoV-2 vaccination
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Posted 17 May 2022

Neuropathic symptoms with SARS-CoV-2 vaccination
5,126 downloads medRxiv neurology

Farinaz Safavi, Lindsey Gustafson, Brian Walitt, Tanya Lehky, Sara Dehbashi, Amanda Wiebold, Yair Mina, Susan Shin, Baohan Pan, Michael Polydefkis, Anne Louise Oaklander, Avindra Nath

Background and Objectives: Various peripheral neuropathies, particularly those with sensory and autonomic dysfunction may occur during or shortly after acute COVID-19 illnesses. These appear most likely to reflect immune dysregulation. If similar manifestations can occur with the vaccination remains unknown. Results: In an observational study, we studied 23 patients (92% female; median age 40years) reporting new neuropathic symptoms beginning within 1 month after SARS-CoV-2 vaccination. 100% reported sensory symptoms comprising severe face and/or limb paresthesias, and 61% had orthostasis, heat intolerance and palpitations. Autonomic testing in 12 identified seven with reduced distal sweat production and six with positional orthostatic tachycardia syndrome. Among 16 with lower-leg skin biopsies, 31% had diagnostic/subthreshold epidermal neurite densities ([&le;]5%), 13% were borderline (5.01-10%) and 19% showed abnormal axonal swelling. Biopsies from randomly selected five patients that were evaluated for immune complexes showed deposition of complement C4d in endothelial cells. Electrodiagnostic test results were normal in 94% (16/17). Together, 52% (12/23) of patients had objective evidence of small-fiber peripheral neuropathy. 58% patients (7/12) treated with oral corticosteroids had complete or near-complete improvement after two weeks as compared to 9% (1/11) of patients who did not receive immunotherapy having full recovery at 12 weeks. At 5-9 months post-symptom onset, 3 non-recovering patients received intravenous immunoglobulin with symptom resolution within two weeks. Conclusions: This observational study suggests that a variety of neuropathic symptoms may manifest after SARS-CoV-2 vaccinations and in some patients might be an immune-mediated process.

11: The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis
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Posted 13 Jan 2020

The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis
4,874 downloads medRxiv neurology

David Baker, Gareth Pryce, Louisa K James, Monica Marta, Klaus Schmierer

ObjectiveOcrelizumab inhibits relapsing multiple sclerosis when administered every six months. Based on potential similar memory B cell depletion mechanisms with cladribine and alemtuzumab, we hypothesised that CD20-depletion of B cells by ocrelizumab may exhibit a duration of response exceeding the current licenced treatment interval. MethodsInternet-located information from regulatory submissions and meeting reports relating to the unpublished open-label, phase II ocrelizumab extension trial (NCT00676715) were reviewed. This followed people (54-55/arm) with MS, who switched from placebo or interferon-beta to ocrelizumab for three 600mg treatment cycles (week 24, 48, 72) or people treated with ocrelizumab for four 600mg treatment cycles (week 0-72), followed by an 18 month treatment-free period. ResultsCD19+ B cells were rapidly depleted within 2 weeks and slow CD19+ B cell repopulation began about 6 months after the last infusion with median-repletion of over 15 months. The reduced annualized relapse rate during the published efficacy study appeared to be maintained in the extension study and there were no new T1 gadolinium-enhancing or T2 lesions detected in the treatment-free period. Importantly, within these extension cohorts, there appeared to be fewer adverse events and infections events. ConclusionsOcrelizumab appears to induce durable relapsing disease inhibition, within 3 treatment cycles Therefore, it may be possible to reduce the frequency of dosing to maintain efficacy, whilst limiting infection and other risks associated with continuous immunosuppression. Further studies are now clearly required to determine whether this data is robust, as few people seemed to complete the study.

12: COVID-19-Associated Acute Disseminated Encephalomyelitis: A Case Report
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Posted 21 Apr 2020

COVID-19-Associated Acute Disseminated Encephalomyelitis: A Case Report
4,717 downloads medRxiv neurology

Tianshu Zhang, Michael B. Rodricks, Ellen Hirsh

We present the first described case of Acute disseminated encephalomyelitis (ADEM) in a COVID-19 patient. The clinical features with head CT and brain MRI changes were described. Our described case is an atypical presentation of the novel coronavirus in a young patient and is illustrative of the possible approaches to explore the treatable differential etiologies.

13: High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms
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Posted 06 Jul 2020

High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms
4,673 downloads medRxiv neurology

Christiana Franke, Caroline Ferse, Jakob Kreye, S. Momsen Reincke, Elisa Sanchez-Sendin, Andrea Rocco, Mirja Steinbrenner, Stefan Angermair, Sascha Treskatsch, Daniel Zickler, Kai-Uwe Eckardt, Rick Dersch, Jonas Hosp, Heinrich J. Audebert, Matthias Endres, Christoph J Ploner, Harald Pruess

COVID-19 intensive care patients occasionally develop neurological symptoms. The absence of SARS-CoV-2 in most cerebrospinal fluid (CSF) samples suggests the involvement of further mechanisms including autoimmunity. We therefore determined whether anti-neuronal or anti-glial autoantibodies are present in eleven consecutive severely ill COVID-19 patients presenting with unexplained neurological symptoms. These included myoclonus, cranial nerve involvement, oculomotor disturbance, delirium, dystonia and epileptic seizures. Most patients showed signs of CSF inflammation and increased levels of neurofilament light chain. All patients had anti-neuronal autoantibodies in serum or CSF when assessing a large panel of autoantibodies against intracellular and surface antigens relevant for central nervous system diseases using cell-based assays and indirect immunofluorescence on murine brain sections. Antigens included proteins well-established in clinical routine, such as Yo or NMDA receptor, but also a variety of specific undetermined epitopes on brain sections. These included vessel endothelium, astrocytic proteins and neuropil of basal ganglia, hippocampus or olfactory bulb. The high frequency of autoantibodies targeting the brain in the absence of other explanations suggests a causal relationship to clinical symptoms, in particular to hyperexcitability (myoclonus, seizures). While several underlying autoantigens still await identification in future studies, presence of autoantibodies may explain some aspects of multi-organ disease in COVID-19 and can guide immunotherapy in selected cases.

14: The clinical spectrum of encephalitis in COVID-19 disease: the ENCOVID multicentre study
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Posted 20 Jun 2020

The clinical spectrum of encephalitis in COVID-19 disease: the ENCOVID multicentre study
4,552 downloads medRxiv neurology

Andrea Pilotto, Stefano Masciocchi, Irene Volonghi, Elisabetta del Zotto, Eugenio Magni, Valeria De Giuli, Francesca Caprioli, Nicola Rifino, Maria Sessa, Michele Gennuso, Maria Sofia Cotelli, Marinella Turla, Ubaldo Balducci, Sara Mariotto, Sergio Ferrari, Alfonso Ciccone, Fabrizio Fiacco, Alberto Imarisio, Barbara Risi, Alberto Benussi, Emanuele Foca', Francesca Caccuri, Matilde Leonardi, Roberto Gasparotti, Francesco Castelli, Gianluigi Zanusso, Alessandro Pezzini, Alessandro Padovani

Background: Several preclinical and clinical investigations have argued for nervous system involvement in SARS-CoV-2 infection. Some sparse case reports have described various forms of encephalitis in COVID-19 disease, but very few data have focused on clinical presentations, clinical course, response to treatment and outcomes yet. Objective: to describe the clinical phenotype, laboratory and neuroimaging findings of encephalitis associated with SARS-CoV-2 infection, their relationship with respiratory function and inflammatory parameters and their clinical course and response to treatment. Design: The ENCOVID multicentre study was carried out in 13 centres in northern Italy between February 20th and May 31st, 2020. Only patients with altered mental status and at least two supportive criteria for encephalitis with full infectious screening, CSF, EEG, MRI data and a confirmed diagnosis of SARS-CoV-2 infection were included. Clinical presentation and laboratory markers, severity of COVID-19 disease, response to treatment and outcomes were recorded. Results: Out of 45 cases screened, twenty-five cases of encephalitis positive for SARS-CoV-2 infection with full available data were included. The most common symptoms at onset were delirium (68%), aphasia/dysarthria (24%) and seizures (24%). CSF showed hyperproteinorrachia and/or pleocytosis in 68% of cases whereas SARS-CoV-2 RNA by RT-PCR resulted negative. Based on MRI, cases were classified as ADEM (n=3), limbic encephalitis (LE, n=2), encephalitis with normal imaging (n=13) and encephalitis with MRI alterations (n=7). ADEM and LE cases showed a delayed onset compared to the other encephalitis (p=0.001) and were associated with previous more severe COVID-19 respiratory involvement. Patients with MRI alterations exhibited worse response to treatment and final outcomes compared to other encephalitis. Conclusions and relevance: We found a wide clinical spectrum of encephalitis associated with COVID19 infection, underlying different pathophysiological mechanisms. Response to treatment and final outcome strongly depended on specific CNS-manifestations.

15: Cerebral venous thrombosis and portal vein thrombosis: a retrospective cohort study of 537,913 COVID-19 cases
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Posted 11 May 2021

Cerebral venous thrombosis and portal vein thrombosis: a retrospective cohort study of 537,913 COVID-19 cases
4,244 downloads medRxiv neurology

Maxime Taquet, Masud Husain, John R Geddes, Sierra Luciano, Paul Harrison

Objectives: To estimate the absolute risk of cerebral venous thrombosis (CVT) and portal vein thrombosis (PVT) in the two weeks following a diagnosis of COVID-19, and to assess the relative risks (RR) compared to influenza or the administration of an mRNA vaccine against COVID-19. Design: Retrospective cohort study based on an electronic health records network Setting: Linked records between primary and secondary care centres within 59 healthcare organisations, primarily in the USA Participants: All patients with a confirmed diagnosis of COVID-19 between January 20, 2020 and March 25, 2021 were included (N=537,913, mean [SD] age: 46.2 [21.4] years; 54.9% females). Cohorts (matched for age, sex, and race) of participants diagnosed with influenza (N=392,424) or receiving the BNT162b2 or mRNA-1273 vaccine (N=366,869) were used for comparison. Main outcome measures: Diagnosis of CVT (ICD-10 code I67.6) or PVT (ICD-10 code I81) within 2 weeks after a diagnosis of COVID-19. Results: The incidence of CVT after COVID-19 diagnosis was 42.8 per million people (95% CI 28.5-64.2) including 35.3 per million (95% CI 22.6-55.2) first diagnoses. This was significantly higher than the CVT incidence in a matched cohort of patients with influenza (RR=3.83, 95% CI 1.56-9.41, P<0.001) and people who received an mRNA vaccine (RR=6.67, 95% CI 1.98-22.43, P<0.001). The incidence of PVT after COVID-19 diagnosis was 392.3 per million people (95% CI 342.8-448.9) including 175.0 per million (95% CI 143.0-214.1) first diagnoses. This was significantly higher than the PVT incidence in a matched cohort of patients with influenza (RR=1.39, 95% CI 1.06-1.83, P=0.02) and people who received an mRNA vaccine (RR=7.40, 95% CI 4.87-11.24, P<0.001). Mortality after CVT and PVT was 17.4% and 19.9% respectively. Conclusions: The incidence of CVT and PVT is significantly increased after COVID-19. The data highlight the risk of serious thrombotic events in COVID-19 and can help contextualize the risks and benefits of vaccination in this regard.

16: Gamma Frequency Sensory Stimulation in Probable Mild Alzheimer's Dementia Patients: Results of a Preliminary Clinical Trial
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Posted 03 Mar 2021

Gamma Frequency Sensory Stimulation in Probable Mild Alzheimer's Dementia Patients: Results of a Preliminary Clinical Trial
3,955 downloads medRxiv neurology

Diane Chan, Ho-Jun Suk, Brennan L Jackson, Noah P Milman, Danielle Stark, Elizabeth B Klerman, Erin Kitchener, Vanesa S. Fernandez Avalos, Arit Banerjee, Sara D. Beach, Joel Blanchard, Colton Stearns, Aaron D Boes, Brandt Uitermarkt, Phillip Gander, Matthew Howard, Eliezer J. Sternberg, Alfonso Nieto-Castanon, Sheeba Anteraper, Susan Whitfield-Gabrieli, Emery N Brown, Edward S Boyden, Bradford C Dickerson, Li-Huei Tsai

Non-invasive Gamma ENtrainment Using Sensory stimuli (GENUS) at 40Hz reduced Alzheimers disease (AD) pathology, prevented cerebral atrophy and improved performance during behavioral testing in mouse models of AD. We report data from a safety study (NCT04042922) and a randomized, placebo-controlled trial in participants with probable mild AD dementia after 3 months of one-hour daily 40Hz light and sound GENUS (NCT04055376) to assess safety, compliance, entrainment and possible effects on brain structure, function, sleep and cognitive function. GENUS was well-tolerated and compliance was high in both groups. Electroencephalography recordings show that our GENUS device safely and effectively induced 40Hz entrainment in cognitively normal subjects and participants with mild AD. After 3 months of daily stimulation, participants with mild AD in the 40Hz GENUS group showed less ventricular enlargement and stabilization of the hippocampal size compared to the control group. Functional connectivity increased in both the default mode network and the medial visual network after 3 months of stimulation. Circadian rhythmicity also improved with GENUS. Compared to controls, the active group performed better on the face-name association delayed recall test. These results suggest that 40Hz GENUS can be used safely at home daily and shows favorable outcomes on cognitive function, daily rhythms, and structural and functional MRI biomarkers of AD-related degeneration. These results support further evaluation of GENUS in larger and longer clinical trials to evaluate its potential as a disease modifying therapeutic for Alzheimers disease.

17: Similarities between the neurological symptoms of COVID-19 and Functional Neurological Disorder: A systematic overview of systematic reviews and implications for future neurological healthcare services
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Posted 25 Jul 2020

Similarities between the neurological symptoms of COVID-19 and Functional Neurological Disorder: A systematic overview of systematic reviews and implications for future neurological healthcare services
3,749 downloads medRxiv neurology

Tamar Wildwing, Nicole Holt

Objective: In response to the rapid spread of COVID-19, this paper provides health professionals with better accessibility to available evidence, summarising findings from a systematic overview of systematic reviews of the neurological symptoms seen in patients with COVID-19. Implications of so-called Long Covid on neurological services and primary care and similarities with other neurological disorders are discussed. Methods: Firstly, a systematic overview of current reviews of neurological symptoms of COVID-19 was conducted. Secondly the implications of these findings are discussed in relation to the potential effect on neurological services and the similarities in the experience of patients with COVID-19 and those with other neurological disorders. Results: Twenty-nine systematic reviews were identified within seven databases, published between 11th April 2020 and 27th August 2020. The results indicated (so far), that COVID-19 exhibits two types of neurological symptoms; life threatening symptoms such as Guillain Barre Syndrome and encephalitis, and less devastating symptoms such as fatigue and myalgia. These so-called lesser symptoms appear to be emerging as longer-term for some sufferers and have been recently labelled Long Covid. When compared, these Long Covid symptoms are very similar to other neurological conditions such as Chronic Fatigue Syndrome (CFS) and Functional Neurological Disorder (FND). Conclusions: Implications for neurological healthcare services in the UK may include longer waiting times and a need for more resources (including more qualified health professionals). There is also a possible change-effect on perceptions of other neurological conditions such as CFS and FND, particularly for health professionals. Future research is recommended to explore changes in perceptions of neurological symptoms because of COVID-19, particularly for health professionals.

18: Steroid-responsive severe encephalopathy in SARS-CoV-2 infection
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Posted 17 Apr 2020

Steroid-responsive severe encephalopathy in SARS-CoV-2 infection
2,819 downloads medRxiv neurology

Andrea Pilotto, SIlvia Odolini, Stefano Masciocchi, Agnese Comelli, Irene Volonghi, Stefano Gazzina, Sara Nocivelli, Alessandro Pezzini, Emanuele Focà, Arnaldo Caruso, Matilde Leonardi, Maria Pia Pasolini, Roberto Gasparotti, Francesco Castelli, Nicholas J Ashton, Kaj Blennow, Henrik Zetterberg, Alessandro Padovani

SARS-CoV-2 infection has the potential for targeting central nervous system and several neurological symptoms have been described in patients with severe respiratory distress. Here we described the case of an otherwise healthy 60-year old subject with SARS-CoV-2 infection but only mild respiratory abnormalities who developed severe progressive encephalopathy associated with mild pleocytosis and hyperproteinorrachia. MRI was negative whereas EEG showed theta waves on the anterior brain regions. Serum and CSF analyses excluded other known infectious or autoimmune disorders. The patient dramatically improved after high-doses steroid treatment suggesting an inflammatory-mediated brain involvement related to SARS-CoV-2 infection

19: Long-term neurological manifestations of COVID-19: prevalence and predictive factors
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Posted 02 Jan 2021

Long-term neurological manifestations of COVID-19: prevalence and predictive factors
2,772 downloads medRxiv neurology

Andrea Pilotto, viviana cristillo, stefano cotti Piccinelli, Nicola Zoppi, Giulio Bonzi, Davide Sattin, Silvia Schiavolin, Alberto Raggi, Antonio Canale, Stefano Gipponi, Ilenia Libri, martina frigerio, Michela Bezzi, Matilde leonardi, alessandro padovani

Background: Clinical investigations have argued for long-term neurological manifestations in both hospitalized and non-hospitalized COVID-19 patients. It is unclear whether long-term neurological symptoms and features depend on COVID-19 severity. Methods: from a sample of 208 consecutive non-neurological patients hospitalized for COVID-19 disease, 165 survivors were re-assessed at 6 months according to a structured standardized clinical protocol. Prevalence and predictors of long-term neurological manifestations were evaluated using multivariate logistic regression analyses. Results At 6-month follow-up after hospitalisation due to COVID-19 disease, patients displayed a wide array of symptoms; fatigue (34%), memory/attention (31%), and sleep disorders (30%) were the most frequent. At neurological examination, 40% of patients exhibited neurological abnormalities, such as hyposmia (18.0%), cognitive deficits (17.5%), postural tremor (13.8%) and subtle motor/sensory deficits (7.6%). Older age, premorbid comorbidities and severity of COVID-19 were independent predictors of neurological manifestations in logistic regression analyses. Conclusions: premorbid vulnerability and severity of SARS-CoV-2 infection impact on prevalence and severity of long-term neurological manifestations.

20: Long COVID neuropsychological deficits after severe, moderate or mild infection
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Posted 26 Feb 2021

Long COVID neuropsychological deficits after severe, moderate or mild infection
2,690 downloads medRxiv neurology

P. Voruz, G. Allali, L. Benzakour, A. Nuber-Champier, M. Thomasson, I. Jacot, J. Pierce, P. Lalive, K-O. Lövblad, O. Braillard, M. Coen, J. Serratrice, J. Pugin, R. Ptak, I. Guessous, B.N. Landis, F. Assal, J.A. Péron

BackgroundThere is growing awareness that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can include long-term neuropsychological deficits, even in its mild or moderate respiratory forms. MethodsStandardized neuropsychological, psychiatric, neurological and olfactory tests were administered to 45 patients (categorized according to the severity of their respiratory symptoms during the acute phase) 236.51 {+/-} 22.54 days post-discharge following SARS-CoV-2 infection. ResultsDeficits were found in all the domains of cognition and the prevalence of psychiatric symptoms was also high in the three groups. The severe performed more poorly on long-term episodic memory and exhibited greater anosognosia. The moderate had poorer emotion recognition, which was positively correlated with persistent olfactory dysfunction. The mild were more stressed, anxious and depressed. ConclusionThe data support the hypothesis that the virus targets the central nervous system (and notably the limbic system), and support the notion of different neuropsychological phenotypes.

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