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Abstract：
We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer\'s-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the \'oldest-old\' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer\'s disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.
摘要：
我们描述了一种最近公认的疾病实体，边缘型年龄相关性TDP-43脑病(晚期)。晚期神经病理学改变（LATE-NC）是由老年人的TDP-43蛋白病，伴有或不伴有海马硬化病理。LATE-NC是一种常见的TDP-43蛋白病，在回顾性尸检研究中与模仿阿尔茨海默型痴呆的遗忘型痴呆综合征相关。根据其流行病学，LATE与具有TDP-43病理的额颞叶变性不同（LATE通常影响老年受试者），TDP-43蛋白病的神经解剖分布相对受限。在基于社区的尸检队列中，25%的大脑有足够的LATE-NC负担，与明显的认知障碍有关。许多患有LATE-NC的受试者都患有脑部疾病，通常包括淀粉样蛋白-β斑块和tau蛋白病变。鉴于“最旧的”是LATE-NC的最大风险，在许多国家，高龄受试者构成了快速增长的人口群体，LATE对公共卫生的影响不断扩大，但认识不足。由于这些原因,召集了一个工作组来制定晚期的诊断标准，旨在刺激研究并提高对痴呆症途径的认识。我们报告了基于共识的建议，包括LATE-NC的诊断和分期指南。对于LATE-NC的常规尸检检查，一个基于解剖学的初步分期方案提出了TDP-43免疫组织化学从三个大脑区域的组织，反映了大脑参与的分层模式：杏仁核，海马体,和中额回.LATE-NC似乎优先影响内侧颞叶结构，但其他领域也受到影响。神经影像学研究表明，患有LATE-NC的受试者在内侧颞叶也有萎缩，额叶皮质,和其他大脑区域。到目前为止，遗传研究表明有五个具有LATE-NC风险等位基因的基因：GRN，TMEM106B,ABCC9、KCNMB2和APOE。这些遗传风险变异的发现表明，LATE与额颞叶变性和阿尔茨海默病具有共同的致病机制，但也提示了疾病特异性的潜在机制。我们对后期的理解仍然存在很大的差距。为了预防方面的进步，诊断,和治疗,迫切需要集中在晚期的研究，包括体外和动物模型。临床进展的一个障碍是缺乏诊断工具，如生物流体或神经成像生物标志物，用于晚期的死前检测。疾病生物标志物的开发将增加旨在进一步定义风险因素的观察性研究。自然史,和晚期的临床特征，以及临床试验中靶向治疗的最终受试者招募。
