Neuronal autoantibodies associated with poorer neuropsychological and motor outcomes 6 months after stroke: Results from the PHYS-STROKE trial

Charlotte Pietrock^1,2*Konrad Neumann³Kristin Rentzsch⁴Harald Prüss^1,5Andreas Meisel^1,2,6Matthias Endres^1,2,5,7,8Alexander Heinrich Nave^1,2,7,9

• ¹Department of Neurology with Experimental Neurology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
• ²Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, Berlin, Germany
• ³Institute of Biometry and Clinical Epidemiology, Charité – Universitätsmedizin Berlin, Berlin, Germany
• ⁴Clinical Immunological Laboratory Prof. h.c. (RCH) Dr. med. Winfried Stöcker, Groß Grönau, Germany
• ⁵German Centre for Neurodegenerative Diseases (DZNE), Berlin, Berlin, Germany
• ⁶Neuroscience Clinical Research Center, Charité – Universitätsmedizin Berlin, Berlin, Germany
• ⁷German Center for Cardiovascular Research (DZHK), Partner site Berlin, Berlin, Germany
• ⁸German Center for Mental Health (DZPG), Partner Site Berlin, Berlin, Germany
• ⁹Berlin Institute of Health at Charite, Berlin, Germany

Introduction Emerging evidence suggests a role of neuronal autoantibodies (nAbs) for long-term stroke outcomes. However, data remain limited and many domains unexamined. We present a comprehensive analysis of nAbs and their association with a broad range of outcome measures at multiple timepoints in the six months following moderate stroke. Methods In this explorative analysis of the multicenter, randomized-controlled PHYS-STROKE trial, serum samples from stroke patients were tested for 40 nAbs at baseline (5-45 days post-stroke), post-intervention (4 weeks after baseline), and at three and six months after stroke. Generalized estimating equation (GEE)-models were used to evaluate the dynamics of nAbs over time. Multiple linear regression models were applied to investigate the prognostic role of nAbs on various outcomes at three and six months. Results Two hundred stroke patients (41% female; mean age: 69±12 years, median acute National Institutes of Health Stroke Scale: 8) were enrolled. Cell-based seroreactivity decreased from baseline to six months (39 of 183 patients [21%] vs. 18 of 137 patients [13%]). while tissue-based reactivity increased (4 of 183 patients [2%] vs. 9 of 137 patients [7%]). The GEE applied to the imputed dataset indicated a statistically significant decreased likelihood of seroreactive nAbs in cell-based assays from baseline to six months (95%CI=0.36 to 0.98; p=0.041), while tissue-based analyses showed an inverse effect for the same time period (95%CI=1.11 to 8.51; p=0.032). The most frequently detected antibody was anti-N-Methyl-D-Aspartate receptor GluN1 (NMDAR (IgM, IgA, IgG), 30 patients [15.1%]). Baseline nAB seropositivity was associated with worse depression scores (95%CI=0.03 to 7.82; p=0.048) and poorer subjective mobility (95%CI=0.04 to 0.99; p=0.033) at six months post-stroke. NMDAR-antibodies at baseline were linked to a lower subjective overall health rating (95%CI=-17.96 to -0.16; p=0.046) and lower maximum walking speed (95%CI=-0.57 to -0.03; p=0.027) at six months. No associations were found with outcomes at three months. Conclusions Antibody seropositivity was associated with poorer outcomes in certain neuropsychological and motor outcome measures at six but not three months post-stroke. These findings require confirmation in larger cohorts and emphasize the need for future studies with longer follow-up periods in this patient population. Trial registration clinicaltrials.gov NCT01953549.