Neuropathological spectrum of anti-IgLON5 disease and stages of brainstem tau pathology: updated neuropathological research criteria of the disease-related tauopathy

Anti-IgLON5 disease is a unique condition that bridges autoimmunity and neurodegeneration. Since its initial description 10 years ago, an increasing number of autopsies has led to the observation of a broader spectrum of neuropathologies underlying a particular constellation of clinical symptoms. In this study, we describe the neuropathological findings in 22 patients with anti-IgLON5 disease from 9 different European centers. In 15 patients (68%), we observed a hypothalamic and brainstem-predominant tauopathy of varying severity in which the original research neuropathological criteria were readily applicable. This pathology was observed in younger patients (median age at onset 61 years) with a long disease duration (median 9 years). In contrast, in 7 (32%) patients, the originally described brainstem tauopathy was nearly absent or only minimal in the form of delicate threads, despite mild-to-moderate neurodegenerative features, consistent clinical symptoms and the presence of anti-IgLON5 antibodies in CSF and serum. These patients were older at onset (median 79 years) and had shorter disease duration (median < 1 year). Overall, about one-third of the patients showed concomitant TDP-43 pathology within the regions affected by tau pathology and/or neurodegeneration. Based on these observations and in view of the spectrum of the tau burden in the core regions involved in the disease, we propose a simple staging system: stage 1 mild neurodegeneration without overt or only minimal tau pathology, stage 2 moderate neurodegeneration and mild/ moderate tauopathy and stage 3 prominent neurodegeneration and tau pathology. This staging intends to reflect a potential (age- and time-dependent) progression of tau pathology, supporting the current notion that tau accumulation is a secondary phenomenon related to the presence of anti-IgLON5 antibodies in the CNS. Finally, we adapt the original research criteria of the anti-IgLON5 disease-related tauopathy to include the spectrum of pathologies observed in this larger postmortem series.

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Journal
Acta Neuropathologica
Published
2024-10-14
DOI
https://doi.org/10.1007/s00401-024-02805-y
Citations
27
Primary Topic
Alzheimer's disease research and treatments
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article
Field-Weighted Citation Impact
8.82

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article

Neuropathological spectrum of anti-IgLON5 disease and stages of brainstem tau pathology: updated neuropathological research criteria of the disease-related tauopathy

Helen Ling, Jan Lewerenz, Laura Molina‐Porcel, Julia Ferrari et al.
27 citations
Acta Neuropathologica
Alzheimer's disease research and treatments
8.82
article

Neuropathological spectrum of anti-IgLON5 disease and stages of brainstem tau pathology: updated neuropathological research criteria of the disease-related tauopathy

Helen Ling, Jan Lewerenz, Laura Molina‐Porcel, Julia Ferrari, Timothy Dawson, María Victoria Zelaya, Tamás Révész, Gábor G. Kovács, Elena Erro, Francesc Graus, Verena Endmayr, Jakob Matschke, Benno Küsters, Frank Leypoldt, Lídia Sabater, Herbert Budka, Inga Koneczny, Ivonne Jericó, Anna Heidbreder, Deniz Yilmazer‐Hanke, Serge Weis, Nikolaus Klupp, Joan Santamaría, Birgit Högl, Pentti Tienari, Ellen Gelpí, Raphael Reinecke, Werner Poewe, Ognian Kalev, Maarten J. Titulaer, Mar Guasp, Evelyn Berger–Sieczkowski, Josep Dalmau, Judith Van Gaalen, Liisa Myllykangas, Janice L. Holton, María Cristina Caballero, Erich Schmutzhard, Markus Glatzel, Romana Höftberger, Janja Pretnar Oblak, Sara Mariotto, Ibán Aldecoa, Mara Popović, Stefan Macher, Nina L. Fransen, Bettina Pfausler, Carles Gaig, Miska Aleksanteri Niemelä, Osma S. Rautila, Christoph Reisinger, Bas R. Bloem, Álex Iranzo
article en
27 citations

Abstract

Anti-IgLON5 disease is a unique condition that bridges autoimmunity and neurodegeneration. Since its initial description 10 years ago, an increasing number of autopsies has led to the observation of a broader spectrum of neuropathologies underlying a particular constellation of clinical symptoms. In this study, we describe the neuropathological findings in 22 patients with anti-IgLON5 disease from 9 different European centers. In 15 patients (68%), we observed a hypothalamic and brainstem-predominant tauopathy of varying severity in which the original research neuropathological criteria were readily applicable. This pathology was observed in younger patients (median age at onset 61 years) with a long disease duration (median 9 years). In contrast, in 7 (32%) patients, the originally described brainstem tauopathy was nearly absent or only minimal in the form of delicate threads, despite mild-to-moderate neurodegenerative features, consistent clinical symptoms and the presence of anti-IgLON5 antibodies in CSF and serum. These patients were older at onset (median 79 years) and had shorter disease duration (median < 1 year). Overall, about one-third of the patients showed concomitant TDP-43 pathology within the regions affected by tau pathology and/or neurodegeneration. Based on these observations and in view of the spectrum of the tau burden in the core regions involved in the disease, we propose a simple staging system: stage 1 mild neurodegeneration without overt or only minimal tau pathology, stage 2 moderate neurodegeneration and mild/ moderate tauopathy and stage 3 prominent neurodegeneration and tau pathology. This staging intends to reflect a potential (age- and time-dependent) progression of tau pathology, supporting the current notion that tau accumulation is a secondary phenomenon related to the presence of anti-IgLON5 antibodies in the CNS. Finally, we adapt the original research criteria of the anti-IgLON5 disease-related tauopathy to include the spectrum of pathologies observed in this larger postmortem series.

Acta NeuropathologicaVol. 148(1)
Institució Catalana de Recerca i Estudis Avançats (ES), University of Verona (IT), Johannes Kepler University of Linz (AT), Lancashire Teaching Hospitals NHS Foundation Trust (GB), University Health Network (CA), University of Helsinki (FI), Innsbruck Medical University (AT), Radboud University Nijmegen (NL), University of Ljubljana (SI), Universität Hamburg (DE), University of Toronto (CA), Universität Innsbruck (AT), Helsinki University Hospital (FI), Ljubljana University Medical Centre (SI), Erasmus MC (NL), Radboud University Medical Center (NL), University Medical Center Utrecht (NL), Christian-Albrechts-Universität zu Kiel (DE), Comprehensive Cancer Center Vienna (AT), University Medical Center Hamburg-Eppendorf (DE), Hospital Clínic de Barcelona (ES), Navarrabiomed (ES), Kepler Universitätsklinikum (AT), Hospital of the Brothers of St. John of God (AT), National Hospital for Neurology and Neurosurgery (GB), Banc de Sang i Teixits (ES), Amsterdam University Medical Centers (NL), Rijnstate Hospital (NL), University Hospital Ulm (DE), Ontario Brain Institute (CA), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), University College London (GB), Medical University of Vienna (AT), University of Pennsylvania (US), Universidad de Navarra (ES)
Helsingin Yliopisto, Bundesministerium für Bildung und Forschung, Austrian Science Fund, Universität Wien, Medizinische Universität Wien, Tekniikan Akatemia, Horizon 2020 Framework Programme, Instituto de Salud Carlos III
Good health and well-being
Openalex Percentile: Top 2%
Alzheimer's disease research and treatments
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