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Ann Clin Transl Neurol. 2014 Oct;1(10):822-32. doi: 10.1002/acn3.120. Epub 2014 Oct 18.

High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types.

Author information

1
Department of Neurology, Charité - Universitätsmedizin Berlin Berlin, Germany ; Cluster of Excellence NeuroCure, Charité - Universitätsmedizin Berlin Berlin, Germany ; Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medicine Berlin, Germany.
2
University Hospital Schleswig-Holstein Lübeck Lübeck, Germany.
3
Massachusetts Alzheimer Disease Research Center Boston, Massachusetts.
4
Division of Neurology, The Children's Hospital of Philadelphia Philadelphia, Pennsylvania.
5
Centre for Neurology and Hertie-Institute for Clinical Brain Research Tübingen, Germany ; German Center for Neurodegenerative Diseases (DZNE) Tübingen Tübingen, Germany.
6
Paracelsus Elena Klinik Kassel, Germany ; Departments of Neurosurgery and Neuropathology, University Medical Center Goettingen Goettingen, Germany.
7
Harvard NeuroDiscovery Center Boston, Massachusetts.
8
Department of Neurology, Charité - Universitätsmedizin Berlin Berlin, Germany.
9
Klinik für Psychiatrie und Psychotherapie, Universitätsklinikum Hamburg-Eppendorf Hamburg, Germany.
10
Institute for Integrative Neuroanatomy, Charité - Universitätsmedizin Berlin Berlin, Germany.
11
Department of Biomedical Engineering, New Jersey Institute of Technology Newark, New Jersey.
12
Department of Nuclear Medicine, Charité - Universitätsmedizin Berlin Berlin, Germany.
13
Department of Neurology, Technische Universität München Munich, Germany ; German Center for Neurodegenerative Diseases (DZNE) Munich Munich, Germany ; Department of Neurology, Philipps-University Marburg, Germany.
14
Department of Neurology, Philipps-University Marburg, Germany.
15
Department of Neurology, Philipps-University Marburg, Germany ; Department of Neurology, Saarland University Homburg/Saar, Germany.
16
Department of Neurology, Universitätsklinikum Magdeburg Magdeburg, Germany.
17
Department of Neurology, Universitätsklinikum Magdeburg Magdeburg, Germany ; German Center for Neurodegenerative Diseases (DZNE) Magdeburg Magdeburg, Germany.
18
Department of Neuropsychiatry, Charité - Universitätsmedizin Berlin Berlin, Germany ; Cluster of Excellence NeuroCure, Charité - Universitätsmedizin Berlin Berlin, Germany ; German Center for Neurodegenerative Diseases (DZNE) Berlin Berlin, Germany.
19
Department of Neuropsychiatry, Charité - Universitätsmedizin Berlin Berlin, Germany.
20
Department of Neurology, Charité - Universitätsmedizin Berlin Berlin, Germany ; Cluster of Excellence NeuroCure, Charité - Universitätsmedizin Berlin Berlin, Germany.
21
Department of Neurology, Charité - Universitätsmedizin Berlin Berlin, Germany ; German Center for Neurodegenerative Diseases (DZNE) Berlin Berlin, Germany ; Center of Stroke Research Berlin, Germany.
22
Department of Neurology, Charité - Universitätsmedizin Berlin Berlin, Germany ; Cluster of Excellence NeuroCure, Charité - Universitätsmedizin Berlin Berlin, Germany ; German Center for Neurodegenerative Diseases (DZNE) Berlin Berlin, Germany ; Center of Stroke Research Berlin, Germany.
23
Institute for Experimental Immunology, Affiliated to Euroimmun AG Lübeck, Germany.
24
Service of Neurology, Hospital Clinic, University of Barcelona Barcelona, Spain.
25
Department of Neurology, Charité - Universitätsmedizin Berlin Berlin, Germany ; German Center for Neurodegenerative Diseases (DZNE) Berlin Berlin, Germany.

Abstract

OBJECTIVE:

To retrospectively determine the frequency of N-Methyl-D-Aspartate (NMDA) receptor (NMDAR) autoantibodies in patients with different forms of dementia.

METHODS:

Clinical characterization of 660 patients with dementia, neurodegenerative disease without dementia, other neurological disorders and age-matched healthy controls combined with retrospective analysis of serum or cerebrospinal fluid (CSF) for the presence of NMDAR antibodies. Antibody binding to receptor mutants and the effect of immunotherapy were determined in a subgroup of patients.

RESULTS:

Serum NMDAR antibodies of IgM, IgA, or IgG subtypes were detected in 16.1% of 286 dementia patients (9.5% IgM, 4.9% IgA, and 1.7% IgG) and in 2.8% of 217 cognitively healthy controls (1.9% IgM and 0.9% IgA). Antibodies were rarely found in CSF. The highest prevalence of serum antibodies was detected in patients with "unclassified dementia" followed by progressive supranuclear palsy, corticobasal syndrome, Parkinson's disease-related dementia, and primary progressive aphasia. Among the unclassified dementia group, 60% of 20 patients had NMDAR antibodies, accompanied by higher frequency of CSF abnormalities, and subacute or fluctuating disease progression. Immunotherapy in selected prospective cases resulted in clinical stabilization, loss of antibodies, and improvement of functional imaging parameters. Epitope mapping showed varied determinants in patients with NMDAR IgA-associated cognitive decline.

INTERPRETATION:

Serum IgA/IgM NMDAR antibodies occur in a significant number of patients with dementia. Whether these antibodies result from or contribute to the neurodegenerative disorder remains unknown, but our findings reveal a subgroup of patients with high antibody levels who can potentially benefit from immunotherapy.

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