Neuropathological spectrum of anti-IgLON5 disease and stages of brainstem tau pathology: updated neuropathological research criteria of the disease-related tauopathy
Ellen Gelpí, Raphael Reinecke, Carles Gaig, Álex Iranzo, Lídia Sabater, Laura Molina‐Porcel, Ibán Aldecoa, Verena Endmayr, Birgit Högl, Erich Schmutzhard, Werner Poewe, Bettina Pfausler, Mara Popović, Janja Pretnar Oblak, Frank Leypoldt, Jakob Matschke, Markus Glatzel, Elena Erro, Ivonne Jericó, María Cristina Caballero, María Victoria Zelaya, Sara Mariotto, Anna Heidbreder, Ognian Kalev, Serge Weis, Stefan Macher, Evelyn Berger–Sieczkowski, Julia Ferrari, Christoph Reisinger, Nikolaus Klupp, Pentti Tienari, Osma S. Rautila, Marja Niemelä, Deniz Yilmazer‐Hanke, Mar Guasp, Bas R. Bloem, Judith van Gaalen, Benno Küsters, Maarten J. Titulaer, Nina L. Fransen, Joan Santamaría, Timothy Dawson, Janice L. Holton, Helen Ling, Tamás Révész, Liisa Myllykangas, Herbert Budka, Gábor G. Kovács, Jan Lewerenz, Josep Dalmau, Francesc Graus, Inga Koneczny, Romana Höftberger
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.