Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Comprehensive Center for Clinical Neurosciences & Mental Health Vienna, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Acta Neuropathol. 2024 Oct 14;148(1):53. doi: 10.1007/s00401-024-02805-y.
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 病是一种独特的疾病，它将自身免疫和神经退行性变联系在一起。自 10 年前首次描述以来，越来越多的尸检导致观察到更多潜在的神经病理学，这些神经病理学为特定的临床症状组合提供了基础。在这项研究中，我们描述了来自 9 个不同欧洲中心的 22 例抗 IgLON5 病患者的神经病理学发现。在 15 例患者（68%）中，我们观察到下丘脑和脑干为主的 tau 病，其严重程度不同，最初的研究神经病理学标准很容易适用。这种病理学发生在较年轻的患者（发病中位年龄 61 岁）中，疾病持续时间较长（中位 9 年）。相比之下，在 7 例（32%）患者中，尽管存在轻度至中度神经退行性特征、一致的临床症状和 CSF 和血清中抗 IgLON5 抗体的存在，但最初描述的脑干 tau 病几乎不存在或仅以细微的细丝形式存在。这些患者发病年龄较大（发病中位年龄 79 岁），疾病持续时间较短（中位时间<1 年）。总的来说，大约三分之一的患者在受 tau 病变和/或神经退行性病变影响的区域内同时存在 TDP-43 病理学。基于这些观察结果，并鉴于疾病核心区域 tau 负担的范围，我们提出了一个简单的分期系统：第 1 期轻度神经退行性变，无明显或仅有轻微的 tau 病理学；第 2 期中度神经退行性变和轻度/中度 tau 病；第 3 期明显的神经退行性变和 tau 病理学。这种分期旨在反映 tau 病理学的潜在（年龄和时间依赖）进展，支持 tau 积累是与 CNS 中抗 IgLON5 抗体存在相关的二级现象的当前观点。最后，我们将抗 IgLON5 病相关 tau 病的原始研究标准进行改编，以纳入本较大的尸检系列中观察到的病理谱。
