Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University Feinberg School of Medicine, Chicago, IL.
Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL.
Ann Neurol. 2023 Dec;94(6):1036-1047. doi: 10.1002/ana.26762. Epub 2023 Sep 5.
Age-related dementia syndromes are often not related to a single pathophysiological process, leading to multiple neuropathologies found at autopsy. An amnestic dementia syndrome can be associated with Alzheimer's disease (AD) with comorbid transactive response DNA-binding protein 43 (TDP-43) pathology (AD/TDP). Here, we investigated neuronal integrity and pathological burden of TDP-43 and tau, along the well-charted trisynaptic hippocampal circuit (dentate gyrus [DG], CA3, and CA1) in participants with amnestic dementia due to AD/TDP, amnestic dementia due to AD alone, or non-amnestic dementia due to TDP-43 proteinopathy associated with frontotemporal lobar degeneration (FTLD-TDP).
A total of 48 extensively characterized cases (14 AD, 16 AD/TDP, 18 FTLD-TDP) were analyzed using digital HALO software (Indica Labs, Albuquerque, NM, USA) to quantify pathological burden and neuronal loss.
In AD/TDP and FTLD-TDP, TDP-43 immunoreactivity was greatest in the DG. Tau immunoreactivity was significantly greater in DG and CA3 in AD/TDP compared with pure AD. All clinical groups showed the highest amounts of neurons in DG, followed by CA3, then CA1. The AD and AD/TDP groups showed lower neuronal counts compared with the FTLD-TDP group across all hippocampal subregions consistent with the salience of the amnestic phenotype.
We conclude that AD/TDP can be distinguished from AD and FTLD-TDP based on differential regional distributions of hippocampal tau and TDP-43. Findings suggest that tau aggregation in AD/TDP might be enhanced by TDP-43. ANN NEUROL 2023;94:1036-1047.
与年龄相关的痴呆综合征通常与单一病理生理过程无关，导致尸检时发现多种神经病理学改变。遗忘型痴呆综合征可与阿尔茨海默病（AD）伴共病转导反应 DNA 结合蛋白 43（TDP-43）病理学（AD/TDP）相关。在此，我们研究了伴有 AD/TDP、单纯 AD 所致遗忘型痴呆以及与额颞叶变性（FTLD-TDP）相关的 TDP-43 蛋白病所致非遗忘型痴呆的参与者中，沿著明确的三突触海马回路（齿状回[DG]、CA3 和 CA1）的神经元完整性和 TDP-43 和 tau 的病理负担。
使用数字 HALO 软件（Indica Labs，新墨西哥州阿尔伯克基）对 48 例经过充分特征描述的病例（14 例 AD、16 例 AD/TDP、18 例 FTLD-TDP）进行分析，以量化病理负担和神经元丢失。
在 AD/TDP 和 FTLD-TDP 中，DG 中 TDP-43 免疫反应性最强。与单纯 AD 相比，AD/TDP 中 DG 和 CA3 中的 tau 免疫反应性显著增加。所有临床组的 DG 神经元数量最多，其次是 CA3，然后是 CA1。AD 和 AD/TDP 组在所有海马亚区的神经元计数均低于 FTLD-TDP 组，这与遗忘型表型的重要性一致。
我们得出结论，基于海马 tau 和 TDP-43 的区域性分布差异，AD/TDP 可以与 AD 和 FTLD-TDP 区分开来。研究结果表明，AD/TDP 中的 tau 聚集可能是由 TDP-43 增强的。ANN NEUROL 2023；94：1036-1047。
