title: Preexisting Serum Autoantibodies Against the NMDAR Subunit NR1 Modulate Evolution of Lesion Size in Acute Ischemic Stroke.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.).
authors.forename: Maria
authors.initials: M
authors.lastname: Zerche
authors.affiliation: 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.).
authors.forename: Karin
authors.initials: K
authors.lastname: Weissenborn
authors.affiliation: 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.).
authors.forename: Christoph
authors.initials: C
authors.lastname: Ott
authors.affiliation: 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.).
authors.forename: Ekrem
authors.initials: E
authors.lastname: Dere
authors.affiliation: 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.).
authors.forename: Abdul R
authors.initials: AR
authors.lastname: Asif
authors.affiliation: 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.).
authors.forename: Hans
authors.initials: H
authors.lastname: Worthmann
authors.affiliation: 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.).
authors.forename: Imam
authors.initials: I
authors.lastname: Hassouna
authors.affiliation: 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.).
authors.forename: Kristin
authors.initials: K
authors.lastname: Rentzsch
authors.affiliation: 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.).
authors.forename: Anita B
authors.initials: AB
authors.lastname: Tryc
authors.affiliation: 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.).
authors.forename: Liane
authors.initials: L
authors.lastname: Dahm
authors.affiliation: 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.).
authors.forename: Johann
authors.initials: J
authors.lastname: Steiner
authors.affiliation: 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.).
authors.forename: Lutz
authors.initials: L
authors.lastname: Binder
authors.affiliation: 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.).
authors.forename: Jens
authors.initials: J
authors.lastname: Wiltfang
authors.affiliation: 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.).
authors.forename: Anna-Leena
authors.initials: AL
authors.lastname: Sirén
authors.affiliation: 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.).
authors.forename: Winfried
authors.initials: W
authors.lastname: Stöcker
authors.affiliation: 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.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D053327:Apolipoprotein E4 / Q000235:genetics; D001323:Autoantibodies / Q000032:analysis*; D001812:Blood-Brain Barrier / Q000276:immunology / Q000473:pathology; D002545:Brain Ischemia / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006579:Heterozygote; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D020300:Intracranial Hemorrhages / Q000209:etiology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology*; D016036:Seroepidemiologic Studies; D020521:Stroke / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D053327:Apolipoprotein E4; D001323:Autoantibodies; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate
keywords: apolipoprotein E4; blood–brain barrier; immunoglobulin class