Department of Neurology, University of California, Irvine, Office 364, Med Surge II Building, Irvine, CA, 92697, USA.
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA.
Acta Neuropathol. 2024 Jun 19;147(1):103. doi: 10.1007/s00401-024-02728-8.
TDP-43 proteinopathy is a salient neuropathologic feature in a subset of frontotemporal lobar degeneration (FTLD-TDP), in amyotrophic lateral sclerosis (ALS-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and is associated with hippocampal sclerosis of aging (HS-A). We examined TDP-43-related pathology data in the National Alzheimer's Coordinating Center (NACC) in two parts: (I) availability of assessments, and (II) associations with clinical diagnoses and other neuropathologies in those with all TDP-43 measures available. Part I: Of 4326 participants with neuropathology data collected using forms that included TDP-43 assessments, data availability was highest for HS-A (97%) and ALS (94%), followed by FTLD-TDP (83%). Regional TDP-43 pathologic assessment was available for 77% of participants, with hippocampus the most common region. Availability for the TDP-43-related measures increased over time, and was higher in centers with high proportions of participants with clinical FTLD. Part II: In 2142 participants with all TDP-43-related assessments available, 27% of participants had LATE-NC, whereas ALS-TDP or FTLD-TDP (ALS/FTLD-TDP) was present in 9% of participants, and 2% of participants had TDP-43 related to other pathologies ("Other TDP-43"). HS-A was present in 14% of participants, of whom 55% had LATE-NC, 20% ASL/FTLD-TDP, 3% Other TDP-43, and 23% no TDP-43. LATE-NC, ALS/FTLD-TDP, and Other TDP-43, were each associated with higher odds of dementia, HS-A, and hippocampal atrophy, compared to those without TDP-43 pathology. LATE-NC was associated with higher odds for Alzheimer's disease (AD) clinical diagnosis, AD neuropathologic change (ADNC), Lewy bodies, arteriolosclerosis, and cortical atrophy. ALS/FTLD-TDP was associated with higher odds of clinical diagnoses of primary progressive aphasia and behavioral-variant frontotemporal dementia, and cortical/frontotemporal lobar atrophy. When using NACC data for TDP-43-related analyses, researchers should carefully consider the incomplete availability of the different regional TDP-43 assessments, the high frequency of participants with ALS/FTLD-TDP, and the presence of other forms of TDP-43 pathology.
TDP-43 蛋白病是额颞叶变性（FTLD-TDP）、肌萎缩侧索硬化症（ALS-TDP）和边缘为主的与年龄相关的 TDP-43 脑病神经病理改变（LATE-NC）的显著神经病理学特征，与衰老相关的海马硬化（HS-A）有关。我们在国家阿尔茨海默病协调中心（NACC）的两个部分检查了与 TDP-43 相关的病理学数据：（I）评估的可用性，以及（II）在所有 TDP-43 测量结果可用的情况下，与临床诊断和其他神经病理学的相关性。第 I 部分：在使用包含 TDP-43 评估的表格收集神经病理学数据的 4326 名参与者中，HS-A（97%）和 ALS（94%）的可用性最高，其次是 FTLD-TDP（83%）。77%的参与者进行了 TDP-43 区域病理评估，其中最常见的是海马。随着时间的推移，与 TDP-43 相关的测量值的可用性增加，并且在临床 FTLD 参与者比例较高的中心更高。第 II 部分：在 2142 名有所有 TDP-43 相关评估的参与者中，27%的参与者有 LATE-NC，而 ALS-TDP 或 FTLD-TDP（ALS/FTLD-TDP）在 9%的参与者中存在，2%的参与者有 TDP-43 与其他病理学有关（“其他 TDP-43”）。HS-A 存在于 14%的参与者中，其中 55%的人有 LATE-NC，20%的人有 ALS/FTLD-TDP，3%的人有其他 TDP-43，23%的人没有 TDP-43。与没有 TDP-43 病理学的参与者相比，LATE-NC、ALS/FTLD-TDP 和其他 TDP-43 与痴呆、HS-A 和海马萎缩的几率更高相关。与其他 TDP-43 相比，LATE-NC 与阿尔茨海默病（AD）临床诊断、AD 神经病理学改变（ADNC）、路易体、小动脉硬化和皮质萎缩的几率更高相关。ALS/FTLD-TDP 与原发性进行性失语症和行为变异额颞叶痴呆的临床诊断、皮质/额颞叶萎缩的几率更高相关。当使用 NACC 数据进行 TDP-43 相关分析时，研究人员应仔细考虑不同区域 TDP-43 评估的不完全可用性、ALS/FTLD-TDP 参与者的高频率以及其他形式的 TDP-43 病理学的存在。
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