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

Sarah Doss; Klaus Peter Wandinger; Bradley T. Hyman; Jessica A. Panzer; Matthis Synofzik; Bradford Dickerson; Brit Mollenhauer; Clemens R. Scherzer; Adrian J. Ivinson; Carsten Finke; Ludger Schöls; Jennifer Müller vom Hagen; Claudia Trenkwalder; Holger Jahn; Markus Höltje; Bharat B. Biswal; Lutz Harms; Klemens Ruprecht; Ralph Buchert; Günther U. Höglinger; Wolfgang H. Oertel; Marcus M. Unger; Peter Körtvélyessy; Daniel Bittner; Josef Priller; Eike J. Spruth; Friedemann Paul; Andreas Meisel; David R. Lynch; Ulrich Dirnagl; Matthias Endres; Bianca Teegen; Christian Probst; Lars Komorowski; Winfried Stöcker; Josep Dalmau; Harald Prüss

doi:10.1002/acn3.120

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

Sarah Doss, Klaus Peter Wandinger, Bradley T. Hyman, Jessica A. Panzer, Matthis Synofzik, Bradford Dickerson, Brit Mollenhauer, Clemens R. Scherzer, Adrian J. Ivinson, Carsten Finke, Ludger Schöls, Jennifer Müller vom Hagen, Claudia Trenkwalder, Holger Jahn, Markus Höltje, Bharat B. Biswal, Lutz Harms, Klemens Ruprecht, Ralph Buchert, Günther U. HöglingerWolfgang H. Oertel, Marcus M. Unger, Peter Körtvélyessy, Daniel Bittner, Josef Priller, Eike J. Spruth, Friedemann Paul, Andreas Meisel, David R. Lynch, Ulrich Dirnagl, Matthias Endres, Bianca Teegen, Christian Probst, Lars Komorowski, Winfried Stöcker, Josep Dalmau, Harald Prüss^*

^*Corresponding author for this work

Institute of Clinical Chemistry

105 Citations (Scopus)

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.

Original language	English
Journal	Annals of Clinical and Translational Neurology
Volume	1
Issue number	10
Pages (from-to)	822-832
Number of pages	11
DOIs	https://doi.org/10.1002/acn3.120
Publication status	Published - 01.10.2014

Funding

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 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. 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.

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Doss, S., Wandinger, K. P., Hyman, B. T., Panzer, J. A., Synofzik, M., Dickerson, B., Mollenhauer, B., Scherzer, C. R., Ivinson, A. J., Finke, C., Schöls, L., Müller vom Hagen, J., Trenkwalder, C., Jahn, H., Höltje, M., Biswal, B. B., Harms, L., Ruprecht, K., Buchert, R., ... Prüss, H. (2014). High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types. Annals of Clinical and Translational Neurology, 1(10), 822-832. https://doi.org/10.1002/acn3.120

@article{106bab00846048f0ac01316535024288,

title = "High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types",

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.",

author = "Sarah Doss and Wandinger, \{Klaus Peter\} and Hyman, \{Bradley T.\} and Panzer, \{Jessica A.\} and Matthis Synofzik and Bradford Dickerson and Brit Mollenhauer and Scherzer, \{Clemens R.\} and Ivinson, \{Adrian J.\} and Carsten Finke and Ludger Sch{\"o}ls and \{M{\"u}ller vom Hagen\}, Jennifer and Claudia Trenkwalder and Holger Jahn and Markus H{\"o}ltje and Biswal, \{Bharat B.\} and Lutz Harms and Klemens Ruprecht and Ralph Buchert and H{\"o}glinger, \{G{\"u}nther U.\} and Oertel, \{Wolfgang H.\} and Unger, \{Marcus M.\} and Peter K{\"o}rtv{\'e}lyessy and Daniel Bittner and Josef Priller and Spruth, \{Eike J.\} and Friedemann Paul and Andreas Meisel and Lynch, \{David R.\} and Ulrich Dirnagl and Matthias Endres and Bianca Teegen and Christian Probst and Lars Komorowski and Winfried St{\"o}cker and Josep Dalmau and Harald Pr{\"u}ss",

year = "2014",

month = oct,

day = "1",

doi = "10.1002/acn3.120",

language = "English",

volume = "1",

pages = "822--832",

journal = "Annals of Clinical and Translational Neurology",

issn = "2328-9503",

publisher = "John Wiley \& Sons Inc.",

number = "10",

}

Doss, S, Wandinger, KP, Hyman, BT, Panzer, JA, Synofzik, M, Dickerson, B, Mollenhauer, B, Scherzer, CR, Ivinson, AJ, Finke, C, Schöls, L, Müller vom Hagen, J, Trenkwalder, C, Jahn, H, Höltje, M, Biswal, BB, Harms, L, Ruprecht, K, Buchert, R, Höglinger, GU, Oertel, WH, Unger, MM, Körtvélyessy, P, Bittner, D, Priller, J, Spruth, EJ, Paul, F, Meisel, A, Lynch, DR, Dirnagl, U, Endres, M, Teegen, B, Probst, C, Komorowski, L, Stöcker, W, Dalmau, J & Prüss, H 2014, 'High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types', Annals of Clinical and Translational Neurology, vol. 1, no. 10, pp. 822-832. https://doi.org/10.1002/acn3.120

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

PY - 2014/10/1

Y1 - 2014/10/1

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.

UR - https://www.scopus.com/pages/publications/84938978398

U2 - 10.1002/acn3.120

DO - 10.1002/acn3.120

M3 - Journal articles

AN - SCOPUS:84938978398

SN - 2328-9503

VL - 1

SP - 822

EP - 832

JO - Annals of Clinical and Translational Neurology

JF - Annals of Clinical and Translational Neurology

IS - 10

ER -

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

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