Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis
Authors: Pollak Thomas A. , Kempton Matthew J. , Iyegbe Conrad , Vincent Angela , Irani Sarosh R. , Coutinho Ester , Menassa David A. , Jacobson Leslie , de Haan Lieuwe , Ruhrmann Stephan , Sachs Gabriele , Riecher-Rössler Anita , Krebs Marie-Odile , Amminger Paul , Glenthøj Birte , Barrantes-Vidal Neus , van Os Jim , Rutten Bart P. F. , Bressan Rodrigo A. , van der Gaag Mark , Yolken Robert , Hotopf Matthew , Valmaggia Lucia , Stone James , David Anthony S. ,   The EUGEI High-Risk Study, Calem Maria , Tognin Stefania , Modinos Gemma , de Haan Lieuwe , van der Gaag Mark , Velthorst Eva , Kraan Tamar C. , van Dam Daniella S. , Burger Nadine , Nelson Barnaby , McGorry Patrick , Pantelis Christos , Politis Athena , Goodall Joanne , Borgwardt Stefan , Ittig Sarah , Studerus Erich , Smieskova Renata , Gadelha Ary , Brietzke Elisa , Asevedo Graccielle , Asevedo Elson , Zugman Andre , Rosa Araceli , Racioppi Anna , Monsonet Manel , Hinojosa-Marqués Lídia , Kwapil Thomas R. , Kazes Mathilde , Daban Claire , Bourgin Julie , Gay Olivier , Mam-Lam-Fook Célia , Nordholm Dorte , Randers Lasse , Krakauer Kristine , Glenthøj Louise , Nordentoft Merete , Gebhard Dominika , Arnhold Julia , Klosterkötter Joachim , Lasser Iris , Winklbaur Bernadette , Delespaul Philippe A. , van Os Jim , McGuire Philip 
Published: October 2020

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.