Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Publisher Copyright: © 2021 The Authors, some rights reserved.Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-alpha and/or IFN-omega are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-alpha and/or IFN-omega (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-beta. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-alpha and/or IFN-omega are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-beta do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases.Peer reviewe

Sex-specific depressive symptoms as markers of pre-Alzheimer dementia: findings from the Three-City cohort study

International audienceLate-life depression, as a potential marker of pre-dementia, has seldom been explored by symptom dimension and sex, despite sexual dimorphic differences. This study aimed to examine whether specific depressive dimensions were associated with pre-Alzheimer's disease dementia (pre-AD), separately for women and men. Data were drawn from 5617 (58% women) community-dwellers aged 65+ recruited in 1999-2000 and followed at 2-year intervals for 12 years. We used Cox proportional hazard models to study associations between time-dependent Centre for Epidemiologic Studies-Depression Scale (CES-D) symptom dimensions (namely somatic, depressed, positive affect, and interpersonal challenge) and pre-AD, defined retrospectively from validated diagnoses established 3.5 (IQR: 3.2-4.0) years onwards. Analyses were performed according to overall depressive symptomatology (DS+: CES-D score ≥ 16) and antidepressant/anxiolytic medication use (AA). Results indicated that in DS+ women only, all four dimensions were significantly associated with pre-AD in the AA-group, in particular somatic item 'Mind' and depressed affect items 'Depressed' and 'Blues'. The most depression-specific dimension, depressed affect, was also significantly associated with pre-AD in the DS-AA-women (HR:1.28, 95%CI: 1.12;1.47). In both sexes, in the DS-groups somatic affect was the most robust pre-AD marker, irrespective of treatment (women: HR = 1.22, 95%CI: 1.08;1.38; men: HR = 1.30, 95%CI: 1.14;1.48). Our findings highlight sex-specific associations between depressive symptom dimensions and pre-AD, modulated by depressive symptomatology and treatment. Assessment of specific symptom dimensions taking into account overall symptomatology and treatment could help identify and target high-risk AD-dementia profiles for interventions

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged 4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute; The Rockefeller University; the St. Giles Foundation; the NIH (Grants R01AI088364 and R01AI163029); the National Center for Advancing Translational Sciences; NIH Clinical and Translational Science Awards program (Grant UL1 TR001866); a Fast Grant from Emergent Ventures; Mercatus Center at George Mason University; the Yale Center for Mendelian Genomics and the Genome Sequencing Program Coordinating Center funded by the National Human Genome Research Institute (Grants UM1HG006504 and U24HG008956); the Yale High Performance Computing Center (Grant S10OD018521); the Fisher Center for Alzheimer’s Research Foundation; the Meyer Foundation; the JPB Foundation; the French National Research Agency (ANR) under the “Investments for the Future” program (Grant ANR-10-IAHU-01); the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (Grant ANR-10-LABX-62-IBEID); the French Foundation for Medical Research (FRM) (Grant EQU201903007798); the French Agency for Research on AIDS and Viral hepatitis (ANRS) Nord-Sud (Grant ANRS-COV05); the ANR GENVIR (Grant ANR-20-CE93-003), AABIFNCOV (Grant ANR-20-CO11-0001), CNSVIRGEN (Grant ANR-19-CE15-0009-01), and GenMIS-C (Grant ANR-21-COVR-0039) projects; the Square Foundation; Grandir–Fonds de solidarité pour l’Enfance; the Fondation du Souffle; the SCOR Corporate Foundation for Science; The French Ministry of Higher Education, Research, and Innovation (Grant MESRI-COVID-19); Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM; and the University Paris Cité. P. Bastard was supported by the FRM (Award EA20170638020). P. Bastard., J.R., and T.L.V. were supported by the MD-PhD program of the Imagine Institute (with the support of Fondation Bettencourt Schueller). Work at the Neurometabolic Disease lab received funding from Centre for Biomedical Research on Rare Diseases (CIBERER) (Grant ACCI20-767) and the European Union's Horizon 2020 research and innovation program under grant agreement 824110 (EASI Genomics). Work in the Laboratory of Virology and Infectious Disease was supported by the NIH (Grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1), a George Mason University Fast Grant, and the G. Harold and Leila Y. Mathers Charitable Foundation. The Infanta Leonor University Hospital supported the research of the Department of Internal Medicine and Allergology. The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (Grant PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (Grant RECOVER WP 6). This work was also partly supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research, NIH (Grants ZIA AI001270 to L.D.N. and 1ZIAAI001265 to H.C.S.). This program is supported by the Agence Nationale de la Recherche (Grant ANR-10-LABX-69-01). K.K.’s group was supported by the Estonian Research Council, through Grants PRG117 and PRG377. R.H. was supported by an Al Jalila Foundation Seed Grant (Grant AJF202019), Dubai, United Arab Emirates, and a COVID-19 research grant (Grant CoV19-0307) from the University of Sharjah, United Arab Emirates. S.G.T. is supported by Investigator and Program Grants awarded by the National Health and Medical Research Council of Australia and a University of New South Wales COVID Rapid Response Initiative Grant. L.I. reports funding from Regione Lombardia, Italy (project “Risposta immune in pazienti con COVID-19 e co-morbidità”). This research was partially supported by the Instituto de Salud Carlos III (Grant COV20/0968). J.R.H. reports funding from Biomedical Advanced Research and Development Authority (Grant HHSO10201600031C). S.O. reports funding from Research Program on Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and Development (Grant JP20fk0108531). G.G. was supported by the ANR Flash COVID-19 program and SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University iCOVID programs. The 3C Study was conducted under a partnership agreement between INSERM, Victor Segalen Bordeaux 2 University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also supported by the Caisse Nationale d’Assurance Maladie des Travailleurs Salariés, Direction générale de la Santé, Mutuelle Générale de l’Education Nationale, Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Program “Cohortes et collections de données biologiques.” S. Debette was supported by the University of Bordeaux Initiative of Excellence. P.K.G. reports funding from the National Cancer Institute, NIH, under Contract 75N91019D00024, Task Order 75N91021F00001. J.W. is supported by a Research Foundation - Flanders (FWO) Fundamental Clinical Mandate (Grant 1833317N). Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. Work at Vall d’Hebron was also partly supported by research funding from Instituto de Salud Carlos III Grant PI17/00660 cofinanced by the European Regional Development Fund (ERDF/FEDER). C.R.-G. and colleagues from the Canarian Health System Sequencing Hub were supported by the Instituto de Salud Carlos III (Grants COV20_01333 and COV20_01334), the Spanish Ministry for Science and Innovation (RTC-2017-6471-1; AEI/FEDER, European Union), Fundación DISA (Grants OA18/017 and OA20/024), and Cabildo Insular de Tenerife (Grants CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”). T.H.M. was supported by grants from the Novo Nordisk Foundation (Grants NNF20OC0064890 and NNF21OC0067157). C.M.B. is supported by a Michael Smith Foundation for Health Research Health Professional-Investigator Award. P.Q.H. and L. Hammarström were funded by the European Union’s Horizon 2020 research and innovation program (Antibody Therapy Against Coronavirus consortium, Grant 101003650). Work at Y.-L.L.’s laboratory in the University of Hong Kong (HKU) was supported by the Society for the Relief of Disabled Children. MBBS/PhD study of D.L. in HKU was supported by the Croucher Foundation. J.L.F. was supported in part by the Evaluation-Orientation de la Coopération Scientifique (ECOS) Nord - Coopération Scientifique France-Colombie (ECOS-Nord/Columbian Administrative department of Science, Technology and Innovation [COLCIENCIAS]/Colombian Ministry of National Education [MEN]/Colombian Institute of Educational Credit and Technical Studies Abroad [ICETEX, Grant 806-2018] and Colciencias Contract 713-2016 [Code 111574455633]). A. Klocperk was, in part, supported by Grants NU20-05-00282 and NV18-05-00162 issued by the Czech Health Research Council and Ministry of Health, Czech Republic. L.P. was funded by Program Project COVID-19 OSR-UniSR and Ministero della Salute (Grant COVID-2020-12371617). I.M. is a Senior Clinical Investigator at the Research Foundation–Flanders and is supported by the CSL Behring Chair of Primary Immunodeficiencies (PID); by the Katholieke Universiteit Leuven C1 Grant C16/18/007; by a Flanders Institute for Biotechnology-Grand Challenges - PID grant; by the FWO Grants G0C8517N, G0B5120N, and G0E8420N; and by the Jeffrey Modell Foundation. I.M. has received funding under the European Union’s Horizon 2020 research and innovation program (Grant Agreement 948959). E.A. received funding from the Hellenic Foundation for Research and Innovation (Grant INTERFLU 1574). M. Vidigal received funding from the São Paulo Research Foundation (Grant 2020/09702-1) and JBS SA (Grant 69004). The NH-COVAIR study group consortium was supported by a grant from the Meath Foundation.Peer reviewe

Within the Sample Comparison of Prediction Performance of Models andSubmodels: Application to Alzheimer's Disease

International audienceThis paper considers the case of two competing, nested, probability predicting models. The nested model contains traditional factors, and thelarger model contains some expensive, or generally hard to obtain, often genetic, relevant markers. The indices used to compare the respectivepredictive ability of the two models are the integrated discrimination improvement (IDI) and the Brier's score improvement (BRI). Estimation of themodels and their relative IDI and BRI are conducted on the same sample, and their respective asymptotic properties are proved. The results areapplied to Alzheimer's disease. The authors conduct two different simulations: one to check the behavior of the estimates of IDI and BRI, and theother parallel to Gu and Pepe's examples. The three city (3C) study is a cohort study conducted in three cities in France (Bordeaux, Dijon andMontpellier), aiming to estimate the risk of dementia and cognitive impairment attributable to vascular factors

Send Orders for Reprints to [email protected] Effectiveness of a Standardized and Specific Follow-Up in Memory Centers in Patients with Alzheimer's Disease

International audienceObjectives: To compare the 4-year survival, institutionalization, cognitive and functional decline of Alzheimer's patients with specific follow-up in memory centers versus usual care. Design: Four year longitudinal follow-up. Settings: The French Network of memory centers in Alzheimer's disease (REAL-FR study) and The French population-based study (3C study). Participants: 728 patients aged ≥ 65, living at home, meeting criteria for probable Alzheimer's disease and having Mini Mental State Examination (MMSE) scores between 10 and 26 at baseline were included. Measurements: Cox proportional hazards models were performed to test the effectiveness of a specific follow-up in memory centers (REAL-FR study) versus usual care (3C study) on the 4-year survival and institutionalization. Linear mixed models were used to assess cognitive and functional decline in both groups. Results: After adjustment for confounding factors, the 4-year survival did not differ significantly between patients followed-up in memory centers and those who had recourse to usual care (usual care: Hazard Ratio adjusted (HRa) = 0.87, 95% confidence interval (CI) 0.53-1.43, p=0.59). Patients with a specific follow-up in memory centers had a higher risk of being institutionalized (usual care: HRa = 0.24, 95% CI 0.12-0.48, p<0.001). They also exhibited a significant greater cognitive and functional decline over time. Conclusion: Our findings failed to demonstrate any potential benefits of a specific follow-up in memory centers on clinically meaningful outcomes in the natural history of Alzheimer's disease. Recourse to care in memory centers may have been the consequence of a faster dementia progression and a greater burden of Alzheimer's disease, all leading to detrimental consequences on various prognostic outcomes

Prevalence and Co-Occurrence of Geriatric Syndromes in People Aged 75 Years and Older in France: Results From the Bordeaux Three-city Study

BACKGROUND: Geriatric syndromes (GSs) are often the result of cumulative insults to multiple organ systems and are considered common in older adults. However, their frequency and co-occurrence are not well known in the elderly population. This study aimed to determine the prevalence of several GSs and to analyze the co-occurrence of these syndromes in a general population of elderly individuals. METHODS: A cross-sectional analysis of 630 adults aged 75 years or older participating in the 10-year follow-up of the Bordeaux sample of the French Three-City Study was conducted. The following 10 GSs were assessed: physical frailty, dementia and cognitive impairment, depressive symptoms, polymedication, social isolation, thinness, falls, dependence, sensory deficit, and incontinence. The prevalence of the 10 GSs was estimated, and multiple correspondence analysis (MCA) models were used to explore the mutual associations between these GSs. RESULTS: The mean age of the participants was 83.3 years; 69% were women, and 80.5% [95% confidence interval (CI) = 76.3–82.7] had at least one GS. The most frequent GSs were polymedication (50.6% 95%CI = 46.7–54.5) and falls (43.1% 95%CI = 38.4–46.1). The MCA models identified two major dimensions of the 10 GSs: “Dementia–Dependence–Incontinence” and “Frailty–Depression–Isolation.” CONCLUSION: GSs were very common in this French elderly population and were grouped into two major dimensions: the “Dementia–Dependence–Incontinence” and “Frailty–Depression–Isolation.