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Brainstem pathology in anti-IgLON5 disease: new insights into early events and tau progression.

Overview

Authors: Raphael Reinecke1,2, Sophie Nitsch1,2, Francisca Faber1,2, Cansu Elmas1,2, Marlene Gaubinger1,2, Anika Simonovska Serra1,2, Verena Endmayr1,2, Inga Koneczny1,2, Evelyn Berger-Sieczkowski2,3, Morten Blaabjerg4, M Elena Erro5, Julia Ferrari6, Markus Glatzel7, Anna Heidbreder8, Birgit Högl9, Casper Jansen10, Jan Lewerenz11, Patrizia Moser12, Liisa Myllykangas13, Jeanette Krogh Petersen14
and 9 other authorsPeter Schnider15, Ambra Stefani9, Maarten J Titulaer16, Deniz Yilmazer-Hanke17, Serge Weis18, Lidia Sabater19, Carles Gaig20, Ellen Gelpi1,2, Romana Höftberger1,2
ORCID iDs: Cansu Elmas, Jan Lewerenz, Liisa Myllykangas, Jeanette Krogh Petersen, Ambra Stefani, Maarten J Titulaer, Deniz Yilmazer-Hanke, Lidia Sabater, Romana Höftberger
20 affiliations
  1. Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna 1090, Austria
  2. Comprehensive Center for Clinical Neurosciences and Mental Health Vienna, Medical University of Vienna, Vienna 1090, Austria
  3. Department of Neurology, Medical University of Vienna, Austria, Vienna 1090, Austria
  4. Department of Neurology, Odense University Hospital, Odense C DK-5000, Denmark
  5. Neurology Department, Hospital Universitario de Navarra, Health Research Institute of Navarra (IdisNA), Pamplona 31008, Spain
  6. Department of Neurology, Hospital Barmherzige Brüder Vienna, Vienna 1020, Austria
  7. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany
  8. Department of Neurology, Kepler University Hospital Linz, Linz 4021, Austria
  9. Department of Neurology, Medical University of Innsbruck, Innsbruck 6020, Austria
  10. Laboratory of Pathology Eastern Netherlands, BB Hengelo 7555, The Netherlands
  11. Department of Neurology, University Hospital Ulm, Ulm 89081, Germany
  12. Department of Neuropathology, University Hospital Innsbruck, Innsbruck 6020, Austria
  13. Department of Pathology, University of Helsinki and HUS Diagnostic Center, Helsinki University Hospital, Helsinki 00014, Finland
  14. Department of Pathology, Odense University Hospital, Odense C DK-5000, Denmark
  15. Clinical Department of Neurology, University Hospital Wiener Neustadt, NÖ Landesgesundheitsagentur – Danube Private University, Wiener Neustadt 2700, Austria
  16. Department of Neurology, Erasmus University Medical Center, Rotterdam 3015 GD, The Netherlands
  17. Clinical Neuroanatomy, Department of Neurology, University Hospital Ulm, Ulm 89081, Germany
  18. Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University Hospital and Clinical Research Institute for Neuroscience, Johannes Kepler University, Linz 4021, Austria
  19. Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona 08036, Spain
  20. Department of Neurology, Hospital Clínic, Barcelona 08036, Spain
Institutions: Medical University of Vienna (Austria); Odense University Hospital (Denmark); Navarre Institute of Health Research (Spain); Hospital of the Brothers of St. John of God (Austria); University Medical Center Hamburg-Eppendorf (Germany); Johannes Kepler University of Linz (Austria); Kepler Universitätsklinikum (Austria); Innsbruck Medical University (Austria); Universität Innsbruck (Austria); University Hospital Ulm (Germany); University Hospital Innsbruck (Austria); University of Helsinki (Finland); Helsinki University Hospital (Finland); Hospital District of Helsinki and Uusimaa (Finland); Universitätsklinikum Wiener Neustadt (Austria); Erasmus MC (Netherlands); Fundació Clínic per a la Recerca Biomèdica (Spain); Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (Spain); Universitat de Barcelona (Spain); Hospital Clínic de Barcelona (Spain)
Journal: Brain : a journal of neurology, volume 149, issue 5, pages 1704-1717
Dates: received 14 July 2025; accepted 11 December 2025; published online 17 January 2026; in print May 2026
Type: Research article · Language: English
License: CC BY-NC
Identifiers: DOI 10.1093/brain/awag015 · PMID 41544664 · PMCID PMC13140532 · OpenAlex W7124556995
Open access: hybrid, a free copy (OpenAlex)
Status: data only
Categories: histology / microscopy (modality), human (organism), rat (organism), other condition (population), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Connectivity, Statistics
Keywords: autoimmune encephalitis, neurodegeneration, tauopathy, secondary tauopathy, nuclear alterations
MeSH: Autoantibodies*, Brain Stem*, Cell Adhesion Molecules, Neuronal*, tau Proteins*, Tauopathies*, Aged, Aged, 80 and over, Animals, Cells, Cultured, Disease Progression, Female, Humans, Male, Middle Aged, Neurons, Rats (* major topic)
Topic: Autoimmune Neurological Disorders and Treatments (Neurology, Medicine), according to OpenAlex
Funding: Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung); FFG; Austrian Society of Neurology (Österreichische Gesellschaft für Neurologie)
Citations: cited by 4 papers (Europe PMC); 42 references in the paper

Abstract

Anti-IgLON5 disease is a rare neurological disease at the intersection of autoimmunity and neurodegeneration. It is characterized by the presence of anti-IgLON5 antibodies and the development of a brainstem-dominant tau pathology. Recent research indicates that the tau pathology may develop in a time-dependent manner. A three-staged neuropathological classification of the disease has been recently suggested, ranging from no or minimal tau (stage 1) to the characteristic brainstem tau pathology (stage 3) as originally described. This study aimed to characterize the evolution of the disease-associated tauopathy more precisely and to further investigate the early neurodegenerative events in anti-IgLON5 disease.

We analysed the medullary region of 14 autopsy cases of anti-IgLON5 disease with different severity grades of tau pathology and varying disease durations, from 6 to 180 months, and compared our findings with five cases with progressive supranuclear palsy and 10 neurologically healthy controls by immunohistochemistry. We applied a broad panel of antibodies targeting different pathological tau post-translational modification sites and the nuclear membrane. In addition, we performed a cell culture of rat hippocampal neurons incubated with purified anti-IgLON5 antibodies to validate the results of the autopsy samples.

Based on the tau burden in relation to the pathology stage and disease duration, we determined the chronological appearance of the different post-translational modifications of tau. Phosphorylation at serine 422 was identified as one of the first alterations at stage 1 and showed an early neuronal nuclear staining with simultaneous anti-IgLON5 IgG4 deposits on the neuronal surface as observed by double immunolabelling. Nuclear membrane alterations were also evident by Lamin B1 staining. These were significantly more frequent at stage 1 as compared with controls and adopted the form of nuclear invaginations and crenellations. Crenellations of the nuclear membrane also developed in neuronal cell culture after 3 weeks of antibody incubation, supporting the autopsy findings in vitro.

The development of cytoplasmic tau pathology occurs at later stages of the disease with a sequence of post-translational modifications, after an initial nuclear pathology. These new findings contribute to a better understanding of the early pathophysiological events in anti-IgLON5 disease and reinforce the concept of a secondary tauopathy related to an immune-mediated mechanism.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Code

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Data

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Data availability

Data supporting the findings of this study that are not included in the article or the supplementary material are available from the corresponding author upon reasonable request. Supplementry material is available at Zenodo (doi.org/10.5281/zenodo.17486565 (https://doi.org/10.5281/zenodo.17486565)).

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Versions

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 29 authors, 5 keywords, 16 MeSH terms, 3 funders, 42 references.

Cite

This paper

Reinecke, R., Nitsch, S., Faber, F., Elmas, C., Gaubinger, M., Simonovska Serra, A., Endmayr, V., Koneczny, I., Berger-Sieczkowski, E., Blaabjerg, M., Erro, M. E., Ferrari, J., Glatzel, M., Heidbreder, A., Högl, B., Jansen, C., Lewerenz, J., Moser, P., Myllykangas, L., . . . Höftberger, R. (2026). Brainstem pathology in anti-IgLON5 disease: new insights into early events and tau progression. Brain : a journal of neurology, 149(5), 1704-1717. https://doi.org/10.1093/brain/awag015

BibTeX

@article{reinecke2026brainstem,
author = {Reinecke, Raphael and Nitsch, Sophie and Faber, Francisca and Elmas, Cansu and Gaubinger, Marlene and Simonovska Serra, Anika and Endmayr, Verena and Koneczny, Inga and Berger-Sieczkowski, Evelyn and Blaabjerg, Morten and Erro, M Elena and Ferrari, Julia and Glatzel, Markus and Heidbreder, Anna and Högl, Birgit and Jansen, Casper and Lewerenz, Jan and Moser, Patrizia and Myllykangas, Liisa and Krogh Petersen, Jeanette and Schnider, Peter and Stefani, Ambra and Titulaer, Maarten J and Yilmazer-Hanke, Deniz and Weis, Serge and Sabater, Lidia and Gaig, Carles and Gelpi, Ellen and Höftberger, Romana},
title = {{Brainstem pathology in anti-IgLON5 disease: new insights into early events and tau progression}},
journal = {Brain : a journal of neurology},
year = {2026},
month = may,
volume = {149},
number = {5},
pages = {1704--1717},
publisher = {Oxford University Press},
issn = {0006-8950},
doi = {10.1093/brain/awag015},
url = {https://doi.org/10.1093/brain/awag015},
pmid = {41544664},
pmcid = {PMC13140532}
}

RIS

TY - JOUR
AU - Reinecke, Raphael
AU - Nitsch, Sophie
AU - Faber, Francisca
AU - Elmas, Cansu
AU - Gaubinger, Marlene
AU - Simonovska Serra, Anika
AU - Endmayr, Verena
AU - Koneczny, Inga
AU - Berger-Sieczkowski, Evelyn
AU - Blaabjerg, Morten
AU - Erro, M Elena
AU - Ferrari, Julia
AU - Glatzel, Markus
AU - Heidbreder, Anna
AU - Högl, Birgit
AU - Jansen, Casper
AU - Lewerenz, Jan
AU - Moser, Patrizia
AU - Myllykangas, Liisa
AU - Krogh Petersen, Jeanette
AU - Schnider, Peter
AU - Stefani, Ambra
AU - Titulaer, Maarten J
AU - Yilmazer-Hanke, Deniz
AU - Weis, Serge
AU - Sabater, Lidia
AU - Gaig, Carles
AU - Gelpi, Ellen
AU - Höftberger, Romana
TI - Brainstem pathology in anti-IgLON5 disease: new insights into early events and tau progression
T2 - Brain : a journal of neurology
J2 - Brain
PY - 2026
DA - 2026/05/01
VL - 149
IS - 5
SP - 1704
EP - 1717
SN - 0006-8950
PB - Oxford University Press
DO - 10.1093/brain/awag015
UR - https://doi.org/10.1093/brain/awag015
LA - en
ER -

CSL-JSON

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