Depressive symptoms and anti-N-methyl-D-aspartate-receptor GluN1 antibody seropositivity in the PROSpective cohort with incident stroke

Pia S Sperber; Pimrapat Gebert; Leonie H A Broersen; Anna Kufner; Shufan Huo; Sophie K Piper; Bianca Teegen; Peter U Heuschmann; Harald Prüss; Matthias Endres; Thomas G Liman; Bob Siegerink

doi:10.1016/j.bbih.2023.100705

Depressive symptoms and anti-N-methyl-D-aspartate-receptor GluN1 antibody seropositivity in the PROSpective cohort with incident stroke

Brain Behav Immun Health. 2023 Nov 9:34:100705. doi: 10.1016/j.bbih.2023.100705. eCollection 2023 Dec.

Authors

Pia S Sperber^{1

2

3

4}, Pimrapat Gebert^{5

6}, Leonie H A Broersen¹, Anna Kufner^{1

3}, Shufan Huo^{1

2

3

4}, Sophie K Piper^{5

6

7}, Bianca Teegen⁸, Peter U Heuschmann^{9

10}, Harald Prüss^{3

11}, Matthias Endres^{1

2

3

4

11}, Thomas G Liman^{1

2

3

12}, Bob Siegerink^{1

13}

Affiliations

¹ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, And Berlin Institute of Health, Center for Stroke Research Berlin (CSB), Berlin, Germany.
² German Centre for Cardiovascular Research DZHK, Partner Site, Berlin, Germany.
³ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, And Berlin Institute of Health, Department of Neurology with Experimental Neurology, Berlin, Germany.
⁴ Charité - Universitätsmedizin Berlin & Max Delbrück Center for Molecular Medicine, Experimental and Clinical Research Center (ECRC), Berlin, Germany.
⁵ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, And Berlin Institute of Health, Institute of Biometry and Clinical Epidemiology, Berlin, Germany.
⁶ Berlin Institute of Health (BIH), Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
⁷ Charité - Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, And Berlin Institute of Health, Institute of Medical Informatics, Germany.
⁸ Institute of Experimental Immunology, EUROIMMUN AG, Luebeck, Germany.
⁹ University of Würzburg, Institute of Clinical Epidemiology and Biometry, Würzburg, Germany.
¹⁰ University Hospital Würzburg, Clinical Trial Center Würzburg, Würzburg, Germany.
¹¹ German Center for Neurodegenerative Disease DZNE, Partner Site, Berlin, Germany.
¹² Carl von Ossietzky-University, Evangelisches Krankenhaus Oldenburg, Department of Neurology, Oldenburg, Germany.
¹³ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden University, Leiden, the Netherlands.

Abstract

Background: Anti-NMDA-receptor GluN1 antibodies (NMDAR1-abs) are present in an autoimmune encephalitis with severe neuropsychiatric symptoms. We aimed to estimate the impact of serum NMDAR1-abs on depressive symptoms years after first-ever ischemic stroke (IS).

Methods: Data were used from the PROSpective Cohort with Incident Stroke-Berlin (PROSCIS-B; NCT01363856). Serum NMDAR1-abs (IgM/IgA/IgG) were measured within 7 days after IS using cell-based assays. We defined seropositivity as titers ≥1:10, thereof low titers as ≤1:100 and high titers as >1:100. We used the Center for Epidemiological Studies-Depression (CES-D) scale to measure depressive symptoms at year one, two and three following IS. We calculated crude and confounder adjusted weighted generalized linear models to quantify the impact of NMDAR1-abs on CES-D assessed at three annual time-points.

Results: NMDAR1-abs were measured in 583 PROSCIS-B IS patients (mean age = 67 [SD = 13]; 42%female; median NIHSS = 2 [IQR = 1-4]) of whom 76 (13%; IgM: n = 49/IgA: n = 43/IgG: n = 2) were seropositive, 55 (9%) with low and 21 (4%) with high titers. CES-D regarded over all follow-up time-points was higher in seropositive patients (β_crude = 2.56 [95%CI = -0.34 to 5.45]; β_adjusted = 2.26 [95%CI = -0.68 to 5.20]) and effects were highest in patients with high titer (low titers: β_crude = 1.42 [95%CI = -1.79 to 4.62], β_adjusted = 0.53 [95%CI = -2.47 to 3.54]; high titers: β_crude = 5.85 [95%CI = 0.20 to 11.50]; β_adjusted = 7.20 [95%CI = 0.98 to 13.43]).

Conclusion: Patients with serum NMDAR1-abs (predominantly IgM&IgA) suffer more severe depressive symptoms after mild-to-moderate IS compared to NMDAR1-abs seronegative patients.

Keywords: Antibodies; Depression; Humans; Ischemia; N-Methyl-D-Aspartate; Prospective studies; Receptors; Stroke.