Einfluss von Anti-NMDA-Rezeptor-NR1-Autoantikörpern bei ApoE4-bedingter chronischer Beeinträchtigung der Blut-Hirn-Schranke
Role of anti-NMDA-receptor NR1 autoantibodies depending on ApoE4 related chronic impairment of the blood brain barrier
Maria Zerche
Doctoral thesis
Date of Examination:
2018-07-19
Date of issue:
2018-07-18
Advisor:
Ehrenreich, Hannelore Prof. Dr. Dr.
Referee:
Ehrenreich, Hannelore Prof. Dr. Dr.
Referee:
Liman, Jan Dr.
Referee:
Meyer, Thomas Prof. Dr.
Persistent Address: http://hdl.handle.net/11858/00-1735-0000-002E-E454-5
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Einfluss von Anti-NMDA-Rezeptor-NR1-Autoantikörpern bei ApoE4-bedingter chronischer Beeinträchtigung der Blut-Hirn-Schranke_Web.pdf
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Dissertation
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Abstract
English
Anti-N-methyl-D-aspartate-receptor subunit 1 autoantibodies (NMDAR-NR1-AB) have mainly been described in context of central nervous system (CNS) pathologies. In contrast, recent studies reported high seroprevalence of NMDAR-NR1-AB in both healthy and neuropsychiatrically ill subjects. It was hypothesized that this might be due to the significance of the blood-brain barrier (BBB) for both development and potential effects of CNS-reactive AB. Apolipoprotein E4 (ApoE4) represents a genetic risk factor for a chronically impaired BBB. Therefore, the present study investigates the role of NMDAR-NR1-AB depending on ApoE4-related chronic impairment of the BBB. ApoE genotype and NMDAR-NR1-AB seropositivity were determined in a cohort of 2492 neuropsychiatric patients and healthy control subjects as well as a second cohort of 464 patients with acute ischemic stroke of the middle cerebral artery. A high seroprevalence of NMDAR-NR1-AB independent of disease status could be replicated and extended to older age groups. The interaction of APOE4 carrier status and NMDAR-NR1-AB seropositivity was found to be significantly associated with the diagnosis of schizoaffective disorder. In patients with acute ischemic stroke, pre-existing NMDAR-NR1-AB were found to modulate the evolution of lesion size in diffusion-weighted magnetic resonance imaging (DW-MRI). The present results demonstrate the importance of BBB integrity for the influence of NMDA-NR1-AB. Both projects provide evidence of ApoE4-related chronic BBB disruption mediating pathological NMDAR-NR1-AB effects not occurring in patients with an intact BBB. Furthermore, first data for beneficial effects of circulating CNS-reactive AB is provided supporting the concept of physiological autoimmunity.
Keywords: Anti-NMDA-receptor subunit 1 autoantibodies; ApoE4; blood brain barrier; schizoaffective disorder; ischemic stroke
Schlagwörter: Anti-NMDA-Rezeptor-NR1-Autoantikörper; ApoE4; Blut-Hirn-Schranke; Schizoaffektive Störung; Ischämischer Schlaganfall
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Human- und Zahnmedizin [2120]