TY - JOUR
T1 - High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types
AU - Doss, Sarah
AU - Wandinger, Klaus Peter
AU - Hyman, Bradley T.
AU - Panzer, Jessica A.
AU - Synofzik, Matthis
AU - Dickerson, Bradford
AU - Mollenhauer, Brit
AU - Scherzer, Clemens R.
AU - Ivinson, Adrian J.
AU - Finke, Carsten
AU - Schöls, Ludger
AU - Müller vom Hagen, Jennifer
AU - Trenkwalder, Claudia
AU - Jahn, Holger
AU - Höltje, Markus
AU - Biswal, Bharat B.
AU - Harms, Lutz
AU - Ruprecht, Klemens
AU - Buchert, Ralph
AU - Höglinger, Günther U.
AU - Oertel, Wolfgang H.
AU - Unger, Marcus M.
AU - Körtvélyessy, Peter
AU - Bittner, Daniel
AU - Priller, Josef
AU - Spruth, Eike J.
AU - Paul, Friedemann
AU - Meisel, Andreas
AU - Lynch, David R.
AU - Dirnagl, Ulrich
AU - Endres, Matthias
AU - Teegen, Bianca
AU - Probst, Christian
AU - Komorowski, Lars
AU - Stöcker, Winfried
AU - Dalmau, Josep
AU - Prüss, Harald
N1 - Funding Information:
NeuroCure; SFB TR 43, KFO 247, KFO 213), A. M. (NeuroCure Cluster of Excellence, Exc 257, Collaborative Research Centres SFB TR 43 and SFB TR 84), J. P. (NeuroCure, SFB TR 43 und FOR1336), and G. H. (DFG, HO2402/ 6-1), the German Ministry for Education and Research (BMBF) to F. P. and K. R. (Competence Network Multiple Sclerosis), A. M. (Center for Stroke Research Berlin, 01 EO 08 01) and M. E. (Centre for Stroke Research Berlin), the Berlin Institute of Health (BIH) to J. P., the National Institute of Health RO1NS077851 to J. D., the National Institute of Neurological Disorders and Stroke T32NS007413 to J. A. P., and Fondo de Investigaciones Sanitarias/Instituto Carlos III (FIS PI11/01780) to J. D. Biospecimens were provided by the Harvard Biomarker Study. The Harvard Biomarker Study is supported by the Harvard NeuroDiscovery Center (HNDC), the Parkinson’s Disease Biomarkers Program (PDBP) grant U01 NS082157 of the NINDS, and the Massachusetts Alzheimer’s Disease Research Center (ADRC) P50 AG005134 grant of the National Institute on Aging.
Funding Information:
This study has been supported by grants from the German Academic Exchange Service (DAAD, D/10/43923) and German Research Foundation (DFG, PR 1274/2-1) to H. P., from the German Research Foundation to F. P. (DFG Exc 257), M. E. (Excellence cluster
Funding Information:
S. D. received financial support for a research project, travel, and speakers’ honoraria from Actelion, and financial support for a research project from teva. B. M. has received grants from TEVA-Pharma, Desitin, Boehringer Ingelheim, GE Healthcare and honoraria for consultancy from Bayer Schering Pharma AG, AbbVie, TEVA-Pharma, for presentations from GlaxoSmithKline, Orion Pharma, TEVA-Pharma. B. M. is a member of the executive steering committee of the Parkinson Progression Marker Initiative of the Michael J. Fox Foundation for Parkinson’s Research and has received grants from the BMBF, EU, Deutsche Parkinson Vereinigung, Michael J. Fox Foundation for Parkinson’s Research, Stifterverband fu€r die deutsche Wissenschaft, and has scientific collaborations with Roche, Ely Lilly, Covance. F. P. has received research support and speaker honoraria from Biogen, Bayer, MerckSerono, Teva, Sanofi and Novartis. K. R. received research support from Novartis as well as speaking fees and travel grants from Bayer Healthcare, Biogen Idec, Merck Serono, Sanofi/Genzyme, Teva, and Novartis. J. P. is an advisor to Actelion and Neuroim-mune. C. P., B. T., and L. K. are employees of EU-ROIMMUN AG. C. P. and W. S. are shareholders of EUROIMMUN AG. W. S. is member of the Board of EUROIMMUN AG. J. D. and D. R. L. hold a patent for the use of NMDAR as antibody test and have a research grant from Euroimmun. The other authors report no disclosures.
Publisher Copyright:
© 2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
PY - 2014/10
Y1 - 2014/10
N2 - 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.
AB - 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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U2 - 10.1002/acn3.120
DO - 10.1002/acn3.120
M3 - Article
AN - SCOPUS:84938978398
VL - 1
SP - 822
EP - 832
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
SN - 2328-9503
IS - 10
ER -