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Preexisting Serum Autoantibodies Against the NMDAR Subunit NR1 Modulate Evolution of Lesion Size in Acute Ischemic
Maria Zerche1, Karin Weissenborn1, Christoph Ott1
1From 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.).
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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