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.

抗 IgLON5 疾病是一种连接自身免疫和神经退行性变的独特疾病。自 10 年前首次描述以来，越来越多的尸检导致观察到更广泛的神经病理学，这些神经病理学是一组特定的临床症状的基础。在这项研究中，我们描述了来自 22 个不同欧洲中心的 9 名抗 IgLON5 疾病患者的神经病理学发现。在 15 名患者 （68%） 中，我们观察到不同严重程度的下丘脑和脑干为主的 tau 蛋白病，其中原始研究神经病理学标准很容易适用。这种病理在较早的病程较长 （中位病程 9） 的年轻患者 （中位发病年龄 61 岁） 中观察到。相比之下，在 7 名 （32%） 患者中，尽管具有轻度至中度神经退行性特征、一致的临床症状以及 CSF 和血清中存在抗 IgLON5 抗体，但最初描述的脑干 tau 蛋白病几乎不存在或仅以细线的形式出现。这些患者发病年龄较大 （中位 79 岁） 且病程较短 （中位 < 1 年）。总体而言，约三分之一的患者在受 tau 病理和/或神经退行性变影响的区域内表现出伴随的 TDP-43 病理。基于这些观察结果，并鉴于疾病涉及的核心区域的 tau 负荷范围，我们提出了一个简单的分期系统：1 期轻度神经变性，没有明显或只有轻微的 tau 病理，2 期中度神经变性和轻度/中度 tau 病和 3 期突出的神经变性和 tau 病理。 这种分期旨在反映 tau 病理学的潜在 （年龄和时间依赖性） 进展，支持当前的观点，即 tau 积累是与 CNS 中存在抗 IgLON5 抗体相关的继发现象。最后，我们调整了抗 IgLON5 疾病相关 tau 病的原始研究标准，以包括在这个更大的尸检系列中观察到的病理范围。