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1.
Neurology ; 99(14): e1486-e1498, 2022 Oct 04.
Article in English | MEDLINE | ID: covidwho-2109249

ABSTRACT

BACKGROUND AND OBJECTIVES: Increased anxious-depressive symptomatology is observed in the preclinical stage of Alzheimer disease (AD), which may accelerate disease progression. We investigated whether ß-amyloid, cortical thickness in medial temporal lobe structures, neuroinflammation, and sociodemographic factors were associated with greater anxious-depressive symptoms during the COVID-19 confinement. METHODS: This retrospective observational study included cognitively unimpaired older adults from the Alzheimer's and Families cohort, the majority with a family history of sporadic AD. Participants performed the Hospital Anxiety and Depression Scale (HADS) during the COVID-19 confinement. A subset had available retrospective (on average: 2.4 years before) HADS assessment, amyloid [18F] flutemetamol PET and structural MRI scans, and CSF markers of neuroinflammation (interleukin-6 [IL-6], triggering receptor expressed on myeloid cells 2, and glial fibrillary acidic protein levels). We performed multivariable linear regression models to investigate the associations of prepandemic AD-related biomarkers and sociodemographic factors with HADS scores during the confinement. We further performed an analysis of covariance to adjust by participants' prepandemic anxiety-depression levels. Finally, we explored the role of stress and lifestyle changes (sleep patterns, eating, drinking, smoking habits, and medication use) on the tested associations and performed sex-stratified analyses. RESULTS: We included 921 (254 with AD biomarkers) participants. ß-amyloid positivity (B = 3.73; 95% CI = 1.1 to 6.36; p = 0.006), caregiving (B = 1.37; 95% CI 0.24-2.5; p = 0.018), sex (women: B = 1.95; 95% CI 1.1-2.79; p < 0.001), younger age (B = -0.12; 95% CI -0.18 to -0.052; p < 0.001), and lower education (B = -0.16; 95% CI -0.28 to -0.042; p = 0.008) were associated with greater anxious-depressive symptoms during the confinement. Considering prepandemic anxiety-depression levels, we further observed an association between lower levels of CSF IL-6 (B = -5.11; 95% CI -10.1 to -0.13; p = 0.044) and greater HADS scores. The results were independent of stress-related variables and lifestyle changes. Stratified analysis revealed that the associations were mainly driven by women. DISCUSSION: Our results link AD-related pathophysiology and neuroinflammation with greater anxious-depressive symptomatology during the COVID-19-related confinement, notably in women. AD pathophysiology may increase neuropsychiatric symptomatology in response to stressors. This association may imply a worse clinical prognosis in people at risk for AD after the pandemic and thus deserves to be considered by clinicians. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier NCT02485730.


Subject(s)
Alzheimer Disease , COVID-19 , Aged , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Anxiety , Biomarkers , Depression , Female , Glial Fibrillary Acidic Protein , Humans , Interleukin-6 , Male , Positron-Emission Tomography , Retrospective Studies , tau Proteins/metabolism
2.
de Erausquin, Gabriel A.; Snyder, Heather, Brugha, Traolach S.; Seshadri, Sudha, Carrillo, Maria, Sagar, Rajesh, Huang, Yueqin, Newton, Charles, Tartaglia, Carmela, Teunissen, Charlotte, Håkanson, Krister, Akinyemi, Rufus, Prasad, Kameshwar, D'Avossa, Giovanni, Gonzalez‐Aleman, Gabriela, Hosseini, Akram, Vavougios, George D.; Sachdev, Perminder, Bankart, John, Mors, Niels Peter Ole, Lipton, Richard, Katz, Mindy, Fox, Peter T.; Katshu, Mohammad Zia, Iyengar, M. Sriram, Weinstein, Galit, Sohrabi, Hamid R.; Jenkins, Rachel, Stein, Dan J.; Hugon, Jacques, Mavreas, Venetsanos, Blangero, John, Cruchaga, Carlos, Krishna, Murali, Wadoo, Ovais, Becerra, Rodrigo, Zwir, Igor, Longstreth, William T.; Kroenenberg, Golo, Edison, Paul, Mukaetova‐Ladinska, Elizabeta, Staufenberg, Ekkehart, Figueredo‐Aguiar, Mariana, Yécora, Agustín, Vaca, Fabiana, Zamponi, Hernan P.; Re, Vincenzina Lo, Majid, Abdul, Sundarakumar, Jonas, Gonzalez, Hector M.; Geerlings, Mirjam I.; Skoog, Ingmar, Salmoiraghi, Alberto, Boneschi, Filippo Martinelli, Patel, Vibuthi N.; Santos, Juan M.; Arroyo, Guillermo Rivera, Moreno, Antonio Caballero, Felix, Pascal, Gallo, Carla, Arai, Hidenori, Yamada, Masahito, Iwatsubo, Takeshi, Sharma, Malveeka, Chakraborty, Nandini, Ferreccio, Catterina, Akena, Dickens, Brayne, Carol, Maestre, Gladys, Blangero, Sarah Williams, Brusco, Luis I.; Siddarth, Prabha, Hughes, Timothy M.; Zuñiga, Alfredo Ramírez, Kambeitz, Joseph, Laza, Agustin Ruiz, Allen, Norrina, Panos, Stella, Merrill, David, Ibáñez, Agustín, Tsuang, Debby, Valishvili, Nino, Shrestha, Srishti, Wang, Sophia, Padma, Vasantha, Anstey, Kaarin J.; Ravindrdanath, Vijayalakshmi, Blennow, Kaj, Mullins, Paul, Łojek, Emilia, Pria, Anand, Mosley, Thomas H.; Gowland, Penny, Girard, Timothy D.; Bowtell, Richard, Vahidy, Farhaan S..
Alzheimer's & dementia (New York, N. Y.) ; 8(1), 2022.
Article in English | EuropePMC | ID: covidwho-2045308

ABSTRACT

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

3.
Brain ; 2022 Sep 09.
Article in English | MEDLINE | ID: covidwho-2017744

ABSTRACT

The advancing validation and exploitation of cerebrospinal fluid and blood neurofilament light chain protein as a biomarker of neuroaxonal damage has deeply changed the current diagnostic and prognostic approach to neurological diseases. Further, recent studies have provided evidence of potential new applications of this biomarker also in non-primary neurological diseases. In the present review we summarise the current evidence, future perspectives, but also limitations, of neurofilament light chain protein as a cerebrospinal fluid and blood biomarker in several medical fields, including intensive care, surgery, internal medicine and psychiatry. In particular, neurofilament light chain protein is associated with the degree of neurologic impairment and outcome in patients admitted to intensive care units or in the perioperative phase and it seems to be highly interconnected with cardiovascular risk factors. Beyond that, interesting diagnostic and prognostic insights have been provided by the investigation of neurofilament light chain protein in psychiatric disorders as well as in the current coronavirus disease 19 (COVID-19) pandemic and in normal aging. Altogether, current data outline a multifaceted applicability of cerebrospinal fluid and blood neurofilament light chain protein ranging from the critical clinical setting to the development of precision medicine models suggesting a strict interplay between the nervous system pathophysiology and the health-illness continuum.

4.
Front Neurol ; 13: 915712, 2022.
Article in English | MEDLINE | ID: covidwho-1933730

ABSTRACT

Introduction: Coronavirus disease 2019 (COVID-19) is prevalent among young people, and neurological involvement has been reported. We investigated neurological symptoms, cognitive test results, and biomarkers of brain injury, as well as associations between these variables in non-hospitalized adolescents and young adults with COVID-19. Methods: This study reports baseline findings from an ongoing observational cohort study of COVID-19 cases and non-COVID controls aged 12-25 years (Clinical Trials ID: NCT04686734). Symptoms were charted using a standardized questionnaire. Cognitive performance was evaluated by applying tests of working memory, verbal learning, delayed recall, and recognition. The brain injury biomarkers, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAp), were assayed in serum samples using ultrasensitive immunoassays. Results: A total of 405 COVID-19 cases and 111 non-COVID cases were prospectively included. Serum Nfl and GFAp concentrations were significantly elevated in COVID-19 cases as compared with non-COVID controls (p = 0.050 and p = 0.014, respectively). The COVID-19 cases reported more fatigue (p < 0.001) and post-exertional malaise (PEM) (p = 0.001) compared to non-COVID-19 controls. Cognitive test performance and clinical neurological examination did not differ across the two groups. Within the COVID-19 group, there were no associations between symptoms, cognitive test results, and NfL or GFAp levels. However, fatigue and PEM were strongly associated with older age and female sex. Conclusions: Non-hospitalized adolescents and young adults with COVID-19 reported more fatigue and PEM and had slightly elevated levels of brain injury markers, but showed normal cognitive performance. No associations were found between symptoms, brain injury markers, and cognitive test results, but fatigue and PEM were strongly related to female sex and older age.

5.
Alzheimers Dement (Amst) ; 13(1): e12145, 2021.
Article in English | MEDLINE | ID: covidwho-1680307

ABSTRACT

INTRODUCTION: This study investigated alternative pre-analytical handling of blood for neurofilament light (NfL) analysis where resources are limited. METHOD: Plasma NfL was measured with single molecule array after alternative blood processing procedures: dried plasma spots (DPS), dried blood spots (DBS), and delayed 48-hour centrifugation. These were compared to standardized plasma processing (reference standard [RS]). In a discovery cohort (n = 10) and a confirmatory cohort (n = 21), whole blood was obtained from individuals with unknown clinical etiology. In the confirmatory cohort, delayed centrifugation protocol was paired with either 37°C incubation or sample shaking to test the effect of these parameters. RESULTS: Delayed centrifugation (R2 = 0.991) and DPS (discovery cohort, R2 = 0.954; confirmatory cohort, DPS: R2 = 0.961) methods were strongly associated with the RS. Delayed centrifugation with higher temperatures (R2 = 0.995) and shaking (R2 = 0.975) did not affect this association. DPS (P < 0.001) returned concentrations considerably lower than the RS. DISCUSSION: DPS or delayed centrifugation are viable pre-analytical procedures for the accurate quantification of plasma NfL.

6.
J Neurochem ; 161(2): 146-157, 2022 04.
Article in English | MEDLINE | ID: covidwho-1673193

ABSTRACT

SARS-CoV-2 infection can damage the nervous system with multiple neurological manifestations described. However, there is limited understanding of the mechanisms underlying COVID-19 neurological injury. This is a cross-sectional exploratory prospective biomarker cohort study of 21 patients with COVID-19 neurological syndromes (Guillain-Barre Syndrome [GBS], encephalitis, encephalopathy, acute disseminated encephalomyelitis [ADEM], intracranial hypertension, and central pain syndrome) and 23 healthy COVID-19 negative controls. We measured cerebrospinal fluid (CSF) and serum biomarkers of amyloid processing, neuronal injury (neurofilament light), astrocyte activation (GFAp), and neuroinflammation (tissue necrosis factor [TNF] ɑ, interleukin [IL]-6, IL-1ß, IL-8). Patients with COVID-19 neurological syndromes had significantly reduced CSF soluble amyloid precursor protein (sAPP)-ɑ (p = 0.004) and sAPPß (p = 0.03) as well as amyloid ß (Aß) 40 (p = 5.2 × 10-8 ), Aß42 (p = 3.5 × 10-7 ), and Aß42/Aß40 ratio (p = 0.005) compared to controls. Patients with COVID-19 neurological syndromes showed significantly increased neurofilament light (NfL, p = 0.001) and this negatively correlated with sAPPɑ and sAPPß. Conversely, GFAp was significantly reduced in COVID-19 neurological syndromes (p = 0.0001) and this positively correlated with sAPPɑ and sAPPß. COVID-19 neurological patients also displayed significantly increased CSF proinflammatory cytokines and these negatively correlated with sAPPɑ and sAPPß. A sensitivity analysis of COVID-19-associated GBS revealed a non-significant trend toward greater impairment of amyloid processing in COVID-19 central than peripheral neurological syndromes. This pilot study raises the possibility that patients with COVID-19-associated neurological syndromes exhibit impaired amyloid processing. Altered amyloid processing was linked to neuronal injury and neuroinflammation but reduced astrocyte activation.


Subject(s)
Alzheimer Disease , Amyloidosis , COVID-19 , Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , COVID-19/complications , Cohort Studies , Cross-Sectional Studies , Humans , Pilot Projects , Prospective Studies , SARS-CoV-2
7.
Alzheimer's & Dementia ; 17(S5):e057889, 2021.
Article in English | Wiley | ID: covidwho-1589188

ABSTRACT

Background Neurologic manifestations are well-recognized features of coronavirus disease 2019 (COVID-19). However, the longitudinal association of biomarkers reflecting CNS impact and neurological symptoms is not known. We wished to determine whether plasma biomarkers of CNS injury were associated with neurologic sequelae after COVID-19. Method Patients with confirmed acute COVID-19 were studied prospectively. Neurological symptoms were recorded during the acute phase of the disease and at six months follow-up, and blood samples were collected longitudinally. Healthy age-matched individuals were included as controls. We analyzed plasma concentrations of neurofilament light-chain (NfL), glial fibrillary acidic protein (GFAp), and growth differentiation factor 15 (GDF-15). Result We recruited 100 patients with mild (n = 24), moderate (n = 28), and severe (n = 48) COVID-19 who were followed for a median of (IQR) 225 (187?262) days. In the acute phase, patients with severe COVID-19 had higher concentrations of NfL than all other groups (all p < 0.001) and higher GFAp than controls (p < 0.001). GFAp was also significantly increased in moderate disease (p < 0.05) compared with controls. NfL (r = 0.53, p < 0.001) and GFAp (r = 0.39, p < 0.001) correlated with GDF-15 during the acute phase. After six months, NfL and GFAp concentrations had normalized, with no persisting group differences. Despite this, 50 patients reported persistent neurological symptoms, most commonly included fatigue (n = 40), ?brain-fog? (n = 29), and changes in cognition (n = 25). We found no relation between persistent neurological symptoms and CNS injury biomarkers in the acute phase. Conclusion The normalization of CNS injury biomarkers in all individuals, regardless of previous disease severity or persisting neurological symptoms, indicate that post-acute COVID-19 neurological sequelae are not accompanied by ongoing CNS injury. Although injury biomarkers commonly increase in severe acute COVID-19, further investigations into the causes of post-infectious sequelae are needed.

8.
J Neuroradiol ; 2021 Nov 18.
Article in English | MEDLINE | ID: covidwho-1521436

ABSTRACT

BACKGROUND AND PURPOSE: A wide range of neuroradiological findings has been reported in patients with coronavirus disease 2019 (COVID-19), ranging from subcortical white matter changes to infarcts, haemorrhages and focal contrast media enhancement. These have been descriptively but inconsistently reported and correlations with clinical findings and biomarkers have been difficult to extract from the literature. The purpose of this study was to quantify the extents of neuroradiological findings in a cohort of patients with COVID-19 and neurological symptoms, and to investigate correlations with clinical findings, duration of intensive care and biomarkers in blood. MATERIAL AND METHODS: Patients with positive SARS-CoV-2 and at least one new-onset neurological symptom were included from April until July 2020. Nineteen patients were examined regarding clinical symptoms, biomarkers in blood and MRI of the brain. In order to quantify the MRI findings, a semi-quantitative neuroradiological severity scale was constructed a priori, and applied to the MR images by two specialists in neuroradiology. RESULTS AND CONCLUSIONS: The score from the severity scale correlated significantly with blood biomarkers of CNS injury (glial fibrillary acidic protein, total-tau, ubiquitin carboxyl-terminal hydrolase L1) and inflammation (C-reactive protein), Glasgow Coma Scale score, and the number of days spent in intensive care. The underlying radiological assessments had inter-rater agreements of 90.5%/86% (for assessments with 2/3 alternatives). Total intraclass correlation was 0.80. Previously reported neuroradiological findings in COVID-19 have been diverse and heterogenous. In this study, the extent of findings in MRI examination of the brain, quantified using a structured report, shows correlation with relevant biomarkers.

9.
Clin Infect Dis ; 73(9): e3019-e3026, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1501050

ABSTRACT

BACKGROUND: Recent findings indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related neurological manifestations involve cytokine release syndrome along with endothelial activation, blood brain barrier dysfunction, and immune-mediated mechanisms. Very few studies have fully investigated the cerebrospinal fluid (CSF) correlates of SARS-CoV-2 encephalitis. METHODS: Patients with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection and encephalitis (COV-Enc), encephalitis without SARS-CoV-2 infection (ENC), and healthy controls (HC) underwent an extended panel of CSF neuronal (neurofilament light chain [NfL], T-tau), glial (glial fibrillary acidic protein [GFAP], soluble triggering receptor expressed on myeloid cells 2 [sTREM2], chitinase-3-like protein 1 [YKL-40]) and inflammatory biomarkers (interleukin [IL]-1ß, IL-6, Il-8, tumor necrosis factor [TNF] α, CXCL-13, and ß2-microglobulin). RESULTS: Thirteen COV-Enc, 21 ENC, and 18 HC entered the study. In COV-Enc cases, CSF was negative for SARS-CoV-2 real-time PCR but exhibited increased IL-8 levels independently from presence of pleocytosis/hyperproteinorracchia. COV-Enc patients showed increased IL-6, TNF- α, and ß2-microglobulin and glial markers (GFAP, sTREM2, YKL-40) levels similar to ENC but normal CXCL13 levels. Neuronal markers NfL and T-tau were abnormal only in severe cases. CONCLUSIONS: SARS-CoV-2-related encephalitis were associated with prominent glial activation and neuroinflammatory markers, whereas neuronal markers were increased in severe cases only. The pattern of CSF alterations suggested a cytokine-release syndrome as the main inflammatory mechanism of SARS-CoV-2-related encephalitis.


Subject(s)
COVID-19 , Encephalitis , Cytokine Release Syndrome , Glial Fibrillary Acidic Protein , Humans , SARS-CoV-2
10.
Cardiol Cardiovasc Med ; 5(5): 551-565, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1498306

ABSTRACT

In critically ill COVID-19 patients, the risk of long-term neurological consequences is just beginning to be appreciated. While recent studies have identified that there is an increase in structural injury to the nervous system in critically ill COVID-19 patients, there is little known about the relationship of COVID-19 neurological damage to the systemic inflammatory diseases also observed in COVID-19 patients. The purpose of this pilot observational study was to examine the relationships between serum neurofilament light protein (NfL, a measure of neuronal injury) and co-morbid cardiovascular disease (CVD) and neurological complications in COVID-19 positive patients admitted to the intensive care unit (ICU). In this observational study of one-hundred patients who were admitted to the ICU in Tucson, Arizona between April and August 2020, 89 were positive for COVID-19 (COVID-pos) and 11 was COVID-negative (COVID-neg). A healthy control group (n=8) was examined for comparison. The primary outcomes and measures were subject demographics, serum NfL, presence and extent of CVD, diabetes, sequential organ failure assessment score (SOFA), presence of neurological complications, and blood chemistry panel data. COVID-pos patients in the ICU had significantly higher mean levels of Nfl (229.6 ± 163 pg/ml) compared to COVID-neg ICU patients (19.3 ± 5.6 pg/ml), Welch's t-test, p =.01 and healthy controls (12.3 ± 3.1 pg/ml), Welch's t-test p =.005. Levels of Nfl in COVID-pos ICU patients were significantly higher in patients with concomitant CVD and diabetes (n=35, log Nfl 1.6±.09), and correlated with higher SOFA scores (r=.5, p =.001). These findings suggest that in severe COVID-19 disease, the central neuronal and axonal damage in these patients may be driven, in part, by the level of systemic cardiovascular disease and peripheral inflammation. Understanding the contributions of systemic inflammatory disease to central neurological degeneration in these COVID-19 survivors will be important to the design of interventional therapies to prevent long-term neurological and cognitive dysfunction.

11.
Brain Commun ; 3(3): fcab099, 2021.
Article in English | MEDLINE | ID: covidwho-1358433

ABSTRACT

Preliminary pathological and biomarker data suggest that SARS-CoV-2 infection can damage the nervous system. To understand what, where and how damage occurs, we collected serum and CSF from patients with COVID-19 and characterized neurological syndromes involving the PNS and CNS (n = 34). We measured biomarkers of neuronal damage and neuroinflammation, and compared these with non-neurological control groups, which included patients with (n = 94) and without (n = 24) COVID-19. We detected increased concentrations of neurofilament light, a dynamic biomarker of neuronal damage, in the CSF of those with CNS inflammation (encephalitis and acute disseminated encephalomyelitis) [14 800 pg/ml (400, 32 400)], compared to those with encephalopathy [1410 pg/ml (756, 1446)], peripheral syndromes (Guillain-Barré syndrome) [740 pg/ml (507, 881)] and controls [872 pg/ml (654, 1200)]. Serum neurofilament light levels were elevated across patients hospitalized with COVID-19, irrespective of neurological manifestations. There was not the usual close correlation between CSF and serum neurofilament light, suggesting serum neurofilament light elevation in the non-neurological patients may reflect peripheral nerve damage in response to severe illness. We did not find significantly elevated levels of serum neurofilament light in community cases of COVID-19 arguing against significant neurological damage. Glial fibrillary acidic protein, a marker of astrocytic activation, was not elevated in the CSF or serum of any group, suggesting astrocytic activation is not a major mediator of neuronal damage in COVID-19.

12.
EClinicalMedicine ; 39: 101070, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1351631

ABSTRACT

BACKGROUND: A high prevalence of antiphospholipid antibodies has been reported in case series of patients with neurological manifestations and COVID-19; however, the pathogenicity of antiphospholipid antibodies in COVID-19 neurology remains unclear. METHODS: This single-centre cross-sectional study included 106 adult patients: 30 hospitalised COVID-neurological cases, 47 non-neurological COVID-hospitalised controls, and 29 COVID-non-hospitalised controls, recruited between March and July 2020. We evaluated nine antiphospholipid antibodies: anticardiolipin antibodies [aCL] IgA, IgM, IgG; anti-beta-2 glycoprotein-1 [aß2GPI] IgA, IgM, IgG; anti-phosphatidylserine/prothrombin [aPS/PT] IgM, IgG; and anti-domain I ß2GPI (aD1ß2GPI) IgG. FINDINGS: There was a high prevalence of antiphospholipid antibodies in the COVID-neurological (73.3%) and non-neurological COVID-hospitalised controls (76.6%) in contrast to the COVID-non-hospitalised controls (48.2%). aPS/PT IgG titres were significantly higher in the COVID-neurological group compared to both control groups (p < 0.001). Moderate-high titre of aPS/PT IgG was found in 2 out of 3 (67%) patients with acute disseminated encephalomyelitis [ADEM]. aPS/PT IgG titres negatively correlated with oxygen requirement (FiO2 R=-0.15 p = 0.040) and was associated with venous thromboembolism (p = 0.043). In contrast, aCL IgA (p < 0.001) and IgG (p < 0.001) was associated with non-neurological COVID-hospitalised controls compared to the other groups and correlated positively with d-dimer and creatinine but negatively with FiO2. INTERPRETATION: Our findings show that aPS/PT IgG is associated with COVID-19-associated ADEM. In contrast, aCL IgA and IgG are seen much more frequently in non-neurological hospitalised patients with COVID-19. Characterisation of antiphospholipid antibody persistence and potential longitudinal clinical impact are required to guide appropriate management. FUNDING: This work is supported by UCL Queen Square Biomedical Research Centre (BRC) and Moorfields BRC grants (#560441 and #557595). LB is supported by a Wellcome Trust Fellowship (222102/Z/20/Z). RWP is supported by an Alzheimer's Association Clinician Scientist Fellowship (AACSF-20-685780) and the UK Dementia Research Institute. KB is supported by the Swedish Research Council (#2017-00915) and the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and theUK Dementia Research Institute at UCL. BDM is supported by grants from the MRC/UKRI (MR/V007181/1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). MSZ, MH and RS are supported by the UCL/UCLH NIHR Biomedical Research Centre and MSZ is supported by Queen Square National Brain Appeal.

13.
EBioMedicine ; 70: 103512, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1330766

ABSTRACT

BACKGROUND: Neurologic manifestations are well-recognized features of coronavirus disease 2019 (COVID-19). However, the longitudinal association of biomarkers reflecting CNS impact and neurological symptoms is not known. We sought to determine whether plasma biomarkers of CNS injury were associated with neurologic sequelae after COVID-19. METHODS: Patients with confirmed acute COVID-19 were studied prospectively. Neurological symptoms were recorded during the acute phase of the disease and at six months follow-up, and blood samples were collected longitudinally. Healthy age-matched individuals were included as controls. We analysed plasma concentrations of neurofilament light-chain (NfL), glial fibrillary acidic protein (GFAp), and growth differentiation factor 15 (GDF-15). FINDINGS: One hundred patients with mild (n = 24), moderate (n = 28), and severe (n = 48) COVID-19 were followed for a median (IQR) of 225 (187-262) days. In the acute phase, patients with severe COVID-19 had higher concentrations of NfL than all other groups (all p < 0·001), and higher GFAp than controls (p < 0·001). GFAp was also significantly increased in moderate disease (p < 0·05) compared with controls. NfL (r = 0·53, p < 0·001) and GFAp (r = 0·39, p < 0·001) correlated with GDF-15 during the acute phase. After six months, NfL and GFAp concentrations had normalized, with no persisting group differences. Despite this, 50 patients reported persistent neurological symptoms, most commonly fatigue (n = 40), "brain-fog" (n = 29), and changes in cognition (n = 25). We found no correlation between persistent neurological symptoms and CNS injury biomarkers in the acute phase. INTERPRETATION: The normalization of CNS injury biomarkers in all individuals, regardless of previous disease severity or persisting neurological symptoms, indicates that post COVID-19 neurological sequelae are not accompanied by ongoing CNS injury. FUNDING: The Swedish State Support for Clinical Research, SciLifeLab Sweden, and the Knut and Alice Wallenberg Foundation have provided funding for this project.


Subject(s)
Astrocytes/pathology , Astrocytes/virology , COVID-19/pathology , COVID-19/virology , SARS-CoV-2/pathogenicity , Aged , Astrocytes/metabolism , Biomarkers/blood , Biomarkers/metabolism , COVID-19/blood , COVID-19/metabolism , Disease Progression , Female , Follow-Up Studies , Glial Fibrillary Acidic Protein/metabolism , Humans , Longitudinal Studies , Male , Middle Aged , Neurofilament Proteins/metabolism , Neurons/metabolism , Neurons/pathology , Neurons/virology , Sweden
15.
Clin Neurophysiol ; 132(7): 1733-1740, 2021 07.
Article in English | MEDLINE | ID: covidwho-1163547

ABSTRACT

OBJECTIVE: The aim was to characterize the electrophysiological features and plasma biomarkers of critical illness polyneuropathy (CIN) and myopathy (CIM) in coronavirus disease 2019 (COVID-19) patients with intensive care unit acquired weakness (ICUAW). METHODS: An observational ICU cohort study including adult patients admitted to the ICU at Uppsala University Hospital, Uppsala, Sweden, from March 13th to June 8th 2020. We compared the clinical, electrophysiological and plasma biomarker data between COVID-19 patients who developed CIN/CIM and those who did not. Electrophysiological characteristics were also compared between COVID-19 and non-COVID-19 ICU patients. RESULTS: 111 COVID-19 patients were included, 11 of whom developed CIN/CIM. Patients with CIN/CIM had more severe illness; longer ICU stay, more thromboembolic events and were more frequently treated with invasive ventilation for longer than 2 weeks. In particular CIN was more frequent among COVID-19 patients with ICUAW (50%) compared with a non-COVID-19 cohort (0%, p = 0.008). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAp) levels were higher in the CIN/CIM group compared with those that did not develop CIN/CIM (both p = 0.001) and correlated with nerve amplitudes. CONCLUSIONS: CIN/CIM was more prevalent among COVID-19 ICU patients with severe illness. SIGNIFICANCE: COVID-19 patients who later developed CIN/CIM had significantly higher NfL and GFAp in the early phase of ICU care, suggesting their potential as predictive biomarkers for CIN/CIM.


Subject(s)
COVID-19/complications , Muscular Diseases/etiology , Polyneuropathies/etiology , Aged , Biomarkers/blood , COVID-19/physiopathology , Critical Illness , Female , Humans , Intensive Care Units , Length of Stay/statistics & numerical data , Male , Middle Aged , Muscle Weakness/etiology , Muscular Diseases/blood , Muscular Diseases/physiopathology , Polyneuropathies/blood , Polyneuropathies/physiopathology , Prospective Studies , Respiration, Artificial/statistics & numerical data , Thromboembolism/etiology
16.
Sci Rep ; 11(1): 6357, 2021 03 18.
Article in English | MEDLINE | ID: covidwho-1142469

ABSTRACT

The recent SARS-CoV-2 pandemic manifests itself as a mild respiratory tract infection in most individuals, leading to COVID-19 disease. However, in some infected individuals, this can progress to severe pneumonia and acute respiratory distress syndrome (ARDS), leading to multi-organ failure and death. This study explores the proteomic differences between mild, severe, and critical COVID-19 positive patients to further understand the disease progression, identify proteins associated with disease severity, and identify potential therapeutic targets. Blood protein profiling was performed on 59 COVID-19 mild (n = 26), severe (n = 9) or critical (n = 24) cases and 28 controls using the OLINK inflammation, autoimmune, cardiovascular and neurology panels. Differential expression analysis was performed within and between disease groups to generate nine different analyses. From the 368 proteins measured per individual, more than 75% were observed to be significantly perturbed in COVID-19 cases. Six proteins (IL6, CKAP4, Gal-9, IL-1ra, LILRB4 and PD-L1) were identified to be associated with disease severity. The results have been made readily available through an interactive web-based application for instant data exploration and visualization, and can be accessed at https://phidatalab-shiny.rosalind.kcl.ac.uk/COVID19/ . Our results demonstrate that dynamic changes in blood proteins associated with disease severity can potentially be used as early biomarkers to monitor disease severity in COVID-19 and serve as potential therapeutic targets.


Subject(s)
Biomarkers/blood , COVID-19/blood , Central Nervous System Diseases/virology , Proteome , Aged , COVID-19/complications , Case-Control Studies , Cohort Studies , Female , Gene Expression Profiling , Gliosis/virology , Humans , Male , Middle Aged , Nerve Tissue Proteins/blood
17.
J Neurol ; 268(10): 3574-3583, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1141418

ABSTRACT

OBJECTIVE: To test the hypotheses that blood biomarkers for nervous system injury, serum concentrations of neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAp) can serve as biomarkers for disease severity in COVID-19 patients. METHODS: Forty-seven inpatients with confirmed COVID-19 had blood samples drawn on admission for assessing serum biomarkers of CNS injury by Single molecule array (Simoa), NfL and GFAp. Concentrations of NfL and GFAp were analyzed in relation to symptoms, clinical signs, inflammatory biomarkers and clinical outcomes. We used multivariate linear models to test for differences in biomarker concentrations in the subgroups, accounting for confounding effects. RESULTS: In total, 21% (n = 10) of the patients were admitted to an intensive care unit, and the overall mortality rate was 13% (n = 6). Non-survivors had higher serum concentrations of NfL (p < 0.001) upon admission than patients who were discharged alive both in adjusted analyses (p = 2.6 × 10-7) and unadjusted analyses (p = 0.001). The concentrations of NfL in non-survivors increased over repeated measurements; whereas, the concentrations in survivors were stable. The GFAp concentration was also significantly higher in non-survivors than survivors (p = 0.02). CONCLUSION: Increased concentrations of NfL and GFAp in COVID-19 patients on admission may indicate increased mortality risk. Measurement of blood biomarkers for nervous system injury can be useful to detect and monitor CNS injury in COVID-19.


Subject(s)
COVID-19 , Biomarkers , Glial Fibrillary Acidic Protein , Humans , Intermediate Filaments , Neurofilament Proteins , Prognosis , SARS-CoV-2
18.
Eur J Neurol ; 28(10): 3324-3331, 2021 10.
Article in English | MEDLINE | ID: covidwho-1035403

ABSTRACT

BACKGROUND AND PURPOSE: Neurological symptoms have been frequently reported in hospitalized patients with coronavirus disease 2019 (COVID-19), and biomarkers of central nervous system (CNS) injury are reported to be increased in plasma but not extensively studied in cerebrospinal fluid (CSF). This study examined CSF for biomarkers of CNS injury and other pathology in relation to neurological symptoms and disease severity in patients with neurological manifestations of COVID-19. METHODS: Nineteen patients with neurological symptoms and mild to critical COVID-19 were prospectively included. Extensive analysis of CSF, including measurement of biomarkers of CNS injury (neurofilament light chain [NfL] protein, glial fibrillary acidic protein [GFAp], and total tau), was performed and compared to neurological features and disease severity. RESULTS: Neurological symptoms included altered mental status (42%), headache (42%), and central (21%) and peripheral weakness (32%). Two patients demonstrated minor pleocytosis, and four patients had increased immunoglobulin G levels in CSF. Neuronal autoantibody testing using commercial tests was negative in all patients. Increased CSF levels of NfL protein, total tau, and GFAp were seen in 63%, 37%, and 16% of patients, respectively. Increased NfL protein correlated with disease severity, time in intensive care, and level of consciousness. NfL protein in CSF was higher in patients with central neurological symptoms. CONCLUSIONS: Although limited by the small sample size, our data suggest that levels of NfL protein, GFAp, and total tau in CSF are commonly elevated in patients with COVID-19 with neurological symptoms. This is in contrast to the standard CSF workup where pathological findings are scarce. NfL protein, in particular, is associated with central neurological symptoms and disease severity.


Subject(s)
COVID-19 , Neurofilament Proteins , Biomarkers , Central Nervous System , Glial Fibrillary Acidic Protein , Humans , SARS-CoV-2 , Severity of Illness Index
19.
J Alzheimers Dis ; 76(1): 27-31, 2020.
Article in English | MEDLINE | ID: covidwho-637281

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic led to an abrupt halt of many Alzheimer's disease (AD) research studies at sites spanning the world. This is especially true for studies requiring in-person contact, such as studies collecting biofluids. Since COVID-19 is likely to remain a threat for an extended period, the resumption of fluid biomarker studies requires the development and implementation of procedures that minimize the risk of in-person visits to participants, staff, and individuals handling the biofluid samples. Some issues to consider include structuring the visit workflow to minimize contacts and promote social distancing; screening and/or testing participants and staff for COVID-19; wearing masks and performing hand hygiene; and precautions for handling, storing, and analyzing biofluids. AD fluid biomarker research remains a vitally important public health priority and resuming studies requires appropriate safety procedures to protect research participants and staff.


Subject(s)
Alzheimer Disease/metabolism , Betacoronavirus , Coronavirus Infections/metabolism , Health Personnel/trends , Patient Safety , Personal Protective Equipment , Pneumonia, Viral/metabolism , Alzheimer Disease/diagnosis , Biomarkers/metabolism , Body Fluids/metabolism , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/transmission , Humans , Pandemics , Personal Protective Equipment/trends , Pneumonia, Viral/diagnosis , Pneumonia, Viral/transmission , SARS-CoV-2
20.
Annals of Neurology ; n/a(n/a), 2020.
Article | WHO COVID | ID: covidwho-600958

ABSTRACT

Coronavirus disease 2019 (COVID-19) infection has the potential for targeting the central nervous system, and several neurological symptoms have been described in patients with severe respiratory distress. Here, we described the case of a 60-year-old patient with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but only mild respiratory abnormalities who developed an akinetic mutism attributable to encephalitis. Magnetic resonance imaging was negative, whereas electroencephalography showed generalized theta slowing. Cerebrospinal fluid analyses during the acute stage were negative for SARS-CoV-2, positive for pleocytosis and hyperproteinorrachia, and showed increased interleukin-8 and tumor necrosis factor-α concentrations. Other infectious or autoimmune disorders were excluded. A progressive clinical improvement along with a reduction of cerebrospinal fluid parameters was observed after high-dose steroid treatment, thus arguing for an inflammatory-mediated brain involvement related to COVID-19. ANN NEUROL 2020

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