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Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis

Research output: Contribution to journalArticlepeer-review

EUGEI High-Risk Study, Stefania Tognin, Gemma Modinos

Original languageEnglish
Pages (from-to)1-15
Number of pages15
JournalMolecular Psychiatry
Volume26
Issue number6
Early online date19 Oct 2020
DOIs
Accepted/In press21 Sep 2020
E-pub ahead of print19 Oct 2020

Bibliographical note

Funding Information: Conflict of interest Dr. Pollak was supported by a clinical research training fellowship grant from the Wellcome Trust (no 105758/Z/14/ Z). The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) Project is funded by grant agreement HEALTH-F2–2010–241909 (Project EU-GEI) from the European Community’s Seventh Framework Programme. Additional support was provided by a Medical Research Council Fellowship to M Kempton (grant MR/J008915/1). Dr. Irani is supported by a Wellcome Trust Intermediate Fellowship (104079/Z/14/Z), the British Medical Association Research Grants: Vera Down (2013) and Margaret Temple (2017). Dr. Nelson was supported by a NHMRC Senior Research Fellowship. Dr. Glenthøj is the leader of a Lundbeck Foundation Centre of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), which is partially financed by an independent grant from the Lundbeck Foundation based on international review and partially financed by the Mental Health Services in the Capital Region of Denmark, the University of Copenhagen, and other foundations. Her group has also received a research grant from Lundbeck A/S for another independent investigator-initiated study. All grants are the property of the Mental Health Services in the Capital Region of Denmark and administrated by them. She has no other conflicts to disclose. Dr. De Haan has no conflicts to disclose. Dr. Ruhrmann is a project consultant of Boehringer Ingelheim. Bart PF Rutten is funded by a VIDI award number 91718336 from the Netherlands Scientific Organisation. Barnaby Nelson was supported by an NHMRC Senior Research Fellowship (1137687). ASD is supported by the NIHR University College London Hospital (UCLH) Biomedical Research Centre. Dr. Barrantes-Vidal was supported by the Ministerio de Ciencia, Innovación e Uni-versidades (PSI2017-87512-C2-1-R), Generalitat de Catalunya (2017SGR1612 and ICREA Academia Award). Dr Bressan has received research grants from Janssen and the governmental funding research agencies: CAPES, CNPq and FAPESP (2016/022465 and 2011/50740-5) and has participated in speaker bureaus for Janssen and Sanofi-Aventis, all outside the submitted work. The authors acknowledge financial support from the National Institute for Health Research (NIHR) Biomedical Research Centres at the South London and Maudsley NHS Foundation Trust, University College London Hospital and the John Radcliffe Hospital NHS Foundation Trust, Oxford. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Additional support was provided by the Maudsley Charity (Grant Ref. 980) and Guy’s and St. Thomas’s Charity (Grant Ref. STR130505). These funders had no involvement in study design, data collection, analysis or the decision to submit for publication. The study received financial support by French Government’s Agence Nationale pour la Recherche (ANR, 08-MNP-007) and by the French Health Ministry’s Programme Hospitalier de Recherche Clinique (PHRC, AOM-07-118, ‘Influence of cannabis psychopathological outcome in At risk mental state’ (ICAAR study)). The Sainte-Anne hospital center promoted the study. Additional financial support was obtained from the Institut National de la Santé et de la Recherche Médicale (INSERM, recurrent funding and fellowships) and by Fon-dation Pierre Deniker. AV and SRI are coapplicants and receive royalties on patent application WO/2010/046716 (U.K. patent no., PCT/ GB2009/051441) entitled ‘Neurological Autoimmune Disorders’. The patent has been licensed to Euroimmun AG for the development of assays for LGI1 and other VGKC-complex antibodies. MOK participated on boards (Roche, Janssen) and received financial support from Janssen, Otsuka Lundbeck alliance, EIsai for conference or dissemination initiatives. Publisher Copyright: © 2020, The Author(s).

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Abstract

Serum neuronal autoantibodies, such as those to the NMDA receptor (NMDAR), are detectable in a subgroup of patients with psychotic disorders. It is not known if they are present before the onset of psychosis or whether they are associated with particular clinical features or outcomes. In a case–control study, sera from 254 subjects at clinical high risk (CHR) for psychosis and 116 healthy volunteers were tested for antibodies against multiple neuronal antigens implicated in CNS autoimmune disorders, using fixed and live cell-based assays (CBAs). Within the CHR group, the relationship between NMDAR antibodies and symptoms, cognitive function and clinical outcomes over 24 month follow-up was examined. CHR subjects were not more frequently seropositive for neuronal autoantibodies than controls (8.3% vs. 5.2%; OR = 1.50; 95% CI: 0.58–3.90). The NMDAR was the most common target antigen and NMDAR IgGs were more sensitively detected with live versus fixed CBAs (p < 0.001). Preliminary phenotypic analyses revealed that within the CHR sample, the NMDAR antibody seropositive subjects had higher levels of current depression, performed worse on the Rey Auditory Verbal Learning Task (p < 0.05), and had a markedly lower IQ (p < 0.01). NMDAR IgGs were not more frequent in subjects who later became psychotic than those who did not. NMDAR antibody serostatus and titre was associated with poorer levels of functioning at follow-up (p < 0.05) and the presence of a neuronal autoantibody was associated with larger amygdala volumes (p < 0.05). Altogether, these findings demonstrate that NMDAR autoantibodies are detectable in a subgroup of CHR subjects at equal rates to controls. In the CHR group, they are associated with affective psychopathology, impairments in verbal memory, and overall cognitive function: these findings are qualitatively and individually similar to core features of autoimmune encephalitis and/or animal models of NMDAR antibody-mediated CNS disease. Overall the current work supports further evaluation of NMDAR autoantibodies as a possible prognostic biomarker and aetiological factor in a subset of people already meeting CHR criteria.

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