Maria Zerche1, Karin Weissenborn1, Christoph Ott1, Ekrem Dere1, Abdul R Asif1, Hans Worthmann1, Imam Hassouna1, Kristin Rentzsch1, Anita B Tryc1, Liane Dahm1, Johann Steiner1, Lutz Binder1, Jens Wiltfang1, Anna-Leena Sirén1, Winfried Stöcker1, Hannelore Ehrenreich2. 1. From the Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany (M.Z., C.O., E.D., I.H., L.D., H.E.); Department of Neurology, Hannover Medical School, Hannover, Germany (K.W., H.W., A.B.T.); DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany (J.W.); Institute of Clinical Chemistry, University Medical Center, Göttingen, Germany (A.R.A., L.B.); Institute for Experimental Immunology, affiliated to Euroimmun, Lübeck, Germany (K.R., W.S.); Department of Psychiatry, University of Magdeburg, Magdeburg, Germany (J.S.); Department of Psychiatry and Psychotherapy, University of Göttingen, Germany (J.W.); and Department of Neurosurgery, University of Würzburg, Germany (A.-L.S.). 2. From the Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany (M.Z., C.O., E.D., I.H., L.D., H.E.); Department of Neurology, Hannover Medical School, Hannover, Germany (K.W., H.W., A.B.T.); DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany (J.W.); Institute of Clinical Chemistry, University Medical Center, Göttingen, Germany (A.R.A., L.B.); Institute for Experimental Immunology, affiliated to Euroimmun, Lübeck, Germany (K.R., W.S.); Department of Psychiatry, University of Magdeburg, Magdeburg, Germany (J.S.); Department of Psychiatry and Psychotherapy, University of Göttingen, Germany (J.W.); and Department of Neurosurgery, University of Würzburg, Germany (A.-L.S.). ehrenreich@em.mpg.de.
Abstract
BACKGROUND AND PURPOSE: Recently, we reported high seroprevalence (age-dependent up to >19%) of N-methyl-d-aspartate-receptor subunit NR1 (NMDAR1) autoantibodies in both healthy and neuropsychiatrically ill subjects (N=4236). Neuropsychiatric syndrome relevance was restricted to individuals with compromised blood-brain barrier, for example, apolipoprotein E4 (APOE4) carrier status, both clinically and experimentally. We now hypothesized that these autoantibodies may upon stroke be protective in individuals with hitherto intact blood-brain barrier, but harmful for subjects with chronically compromised blood-brain barrier. METHODS: Of 464 patients admitted with acute ischemic stroke in the middle cerebral artery territory, blood for NMDAR1 autoantibody measurements and APOE4 carrier status as indicator of a preexisting leaky blood-brain barrier was collected within 3 to 5 hours after stroke. Evolution of lesion size (delta day 7-1) in diffusion-weighted magnetic resonance imaging was primary outcome parameter. In subgroups, NMDAR1 autoantibody measurements were repeated on days 2 and 7. RESULTS: Of all 464 patients, 21.6% were NMDAR1 autoantibody-positive (immunoglobulin M, A, or G) and 21% were APOE4 carriers. Patients with magnetic resonance imaging data available on days 1 and 7 (N=384) were divided into 4 groups according to NMDAR1 autoantibody and APOE4 status. Groups were comparable in all stroke-relevant presenting characteristics. The autoantibody+/APOE4- group had a smaller mean delta lesion size compared with the autoantibody-/APOE4- group, suggesting a protective effect of circulating NMDAR1 autoantibodies. In contrast, the autoantibody+/APOE4+ group had the largest mean delta lesion area. NMDAR1 autoantibody serum titers dropped on day 2 and remounted by day 7. CONCLUSIONS: Dependent on blood-brain barrier integrity before an acute ischemic brain injury, preexisting NMDAR1 autoantibodies seem to be beneficial or detrimental.
BACKGROUND AND PURPOSE: Recently, we reported high seroprevalence (age-dependent up to >19%) of N-methyl-d-aspartate-receptor subunit NR1 (NMDAR1) autoantibodies in both healthy and neuropsychiatrically ill subjects (N=4236). Neuropsychiatric syndrome relevance was restricted to individuals with compromised blood-brain barrier, for example, apolipoprotein E4 (APOE4) carrier status, both clinically and experimentally. We now hypothesized that these autoantibodies may upon stroke be protective in individuals with hitherto intact blood-brain barrier, but harmful for subjects with chronically compromised blood-brain barrier. METHODS: Of 464 patients admitted with acute ischemic stroke in the middle cerebral artery territory, blood for NMDAR1 autoantibody measurements and APOE4 carrier status as indicator of a preexisting leaky blood-brain barrier was collected within 3 to 5 hours after stroke. Evolution of lesion size (delta day 7-1) in diffusion-weighted magnetic resonance imaging was primary outcome parameter. In subgroups, NMDAR1 autoantibody measurements were repeated on days 2 and 7. RESULTS: Of all 464 patients, 21.6% were NMDAR1 autoantibody-positive (immunoglobulin M, A, or G) and 21% were APOE4 carriers. Patients with magnetic resonance imaging data available on days 1 and 7 (N=384) were divided into 4 groups according to NMDAR1 autoantibody and APOE4 status. Groups were comparable in all stroke-relevant presenting characteristics. The autoantibody+/APOE4- group had a smaller mean delta lesion size compared with the autoantibody-/APOE4- group, suggesting a protective effect of circulating NMDAR1 autoantibodies. In contrast, the autoantibody+/APOE4+ group had the largest mean delta lesion area. NMDAR1 autoantibody serum titers dropped on day 2 and remounted by day 7. CONCLUSIONS: Dependent on blood-brain barrier integrity before an acute ischemic brain injury, preexisting NMDAR1 autoantibodies seem to be beneficial or detrimental.
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