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. 2022 Oct;269(10):5521-5530.
doi: 10.1007/s00415-022-11203-x. Epub 2022 Jun 19.

Serum anti-NMDA-receptor antibodies and cognitive function after ischemic stroke (PROSCIS-B)

Pia S Sperber  1   2   3   4 , Pimrapat Gebert  5   6 , Leonie H A Broersen  1 , Shufan Huo  1   3   7 , Sophie K Piper  5   6   8 , Bianca Teegen  9 , Peter U Heuschmann  10   11 , Harald Prüss  3   7 , Matthias Endres  1   2   3   4   7 , Thomas G Liman #  12   13 , Bob Siegerink #  1   14
Affiliations

Serum anti-NMDA-receptor antibodies and cognitive function after ischemic stroke (PROSCIS-B)

Pia S Sperber et al. J Neurol. 2022 Oct.

Abstract

Objective: We aimed to investigate whether serum anti-N-methyl-D-aspartate-receptor GluN1 (previously NR1) antibody (NMDAR1-abs) seropositivity impacts cognitive function (CF) in the long term following ischemic stroke.

Methods: Data were used from the PROSpective Cohort with Incident Stroke-Berlin. NMDAR1-abs (IgM/IgA/IgG) were measured with cell-based assays from serum obtained within 7 days after the first-ever stroke. Seropositivity was defined as titers ≥ 1:10, low titers as ≤ 1:100 and high titers as > 1:100. We assessed CF at 1, 2 and 3 years after stroke with the Telephone Interview for Cognitive Status-modified (TICS-m) and used crude and propensity score adjusted inverse probability weighted generalized linear models to estimate the impact of NMDAR1-abs serostatus on TICS-m.

Results: Data on NMDAR1-abs (median day of sampling = 4[IQR = 2-5]) were available in 583/621 PROSCIS-B patients (39% female; median NIHSS = 2[IQR = 1-4]; median MMSE = 28[IQR:26-30]), of whom 76(13%) were seropositive (IgM: n = 48/IgA: n = 43/IgG: n = 2). Any NMDAR1-abs seropositivity had no impact on TICS-m compared to seronegative patients (βcrude = 0.69[95%CI = - 0.84 to 2.23]; βadjusted = 0.65[95%CI = - 1.00 to 2.30]). Patients with low titers scored better on TICS-m compared to seronegative patients (βcrude = 2.33[95%CI = 0.76 to 3.91]; βadjusted = 2.47[95%CI = 0.75 to 4.19]); in contrast, patients with high titers scored lower on TICS-m (βcrude = -2.82[95%CI = - 4.90 to - 0.74], βadjusted = - 2.96[95%CI = - 5.13 to - 0.80]), compared to seronegative patients.

Conclusion: In our study, NMDAR1-abs seropositivity did not affect CF over 3 years after a first mild to moderate ischemic stroke. CF differed according to NMDAR1-abs serum titer, with patients with high NMDAR1-abs titers having a less favorable cognitive outcome compared to seronegative patients.

Keywords: Antibodies; Cognitive dysfunction; Epidemiology; Ischemia; Stroke.

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Conflict of interest statement

The PROSCIS-B study received funding from the Federal Ministry of Education and Research via the grant Center for Stroke Research Berlin (01 EO 0801). NMDAR1-abs were measured by the EUROIMMUN/W.Stöcker, Lübeck (Germany) free of cost. EUROIMMUN had neither insight nor influence on data collection other than the antibody measurements. PG, LHAB, SH, SKP, HP, TGL and BS report no disclosures related to this work. PSS reports funding from FAZIT-STIFTUNG between March 2018 and March 2020. BT works at the EUROIMMUN laboratory. PUH reports research grants from the German Ministry of Research and Education, German Research Foundation, European Union, Charité, Berlin Chamber of Physicians, German Parkinson Society, University Hospital Würzburg, Robert-Koch-Institute, German Heart Foundation, Federal Joint Committee (G-BA) within the Innovationsfond, Charité–Universitätsmedizin Berlin (within MonDAFIS; supported by an unrestricted research grant to the Charité from Bayer), University Göttingen (within FIND-AF-randomized; supported by an unrestricted research grant to the University Göttingen from Boehringer-Ingelheim), and University Hospital Heidelberg (within RASUNOA-prime; supported by an unrestricted research grant to the University Hospital Heidelberg from Bayer, BMS, Boehringer-Ingelheim, Daiichi Sankyo), all outside of the submitted work. ME reports grant support from Bayer, the German Research Foundation (DFG), the German Federal Ministry of Education and Research (BMBF), the German Center for Neurodegenerative Diseases (DZNE), the German Centre for Cardiovascular Research (DZHK), the European Union, Corona Foundation, and Fondation Leducq; fees paid to the Charité from Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Amgen, GlaxoSmithKline, Sanofi, Covidien, Ever, Novartis, all outside of the submitted work.

Figures

Fig. 1
Fig. 1
Flowchart of PROSCIS-B inclusion and exclusion and overview on follow-up data on cognitive function
Fig. 2
Fig. 2
Anti-NMDA-receptor GluN1 antibody seropositive and seronegative patients and cognitive function (TICS-m Scores) after the first stroke. Cognitive function sum scores assessed with the Telephone Interview for Cognitive Status-modified (TICS-m) for A, anti-NMDA-receptor GluN1 antibody (NMDAR1-abs) seropositive and NMDAR1-abs seronegative patients and B, for NMDAR1-abs seropositive patients with low serum titers (titers of 1:10–1:100) and high serum titers (titers of 1:320 and 1:1000). Gray dots represent observed values, combined by respective subject. Red lines represent fitted lines over time from weighted linear mixed models
See this image and copyright information in PMC

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