Distinct Patterns of Hippocampal Pathology in Alzheimer's Disease with Transactive Response DNA-binding Protein 43

IF 8.1 1区医学 Q1 CLINICAL NEUROLOGY

Annals of Neurology Pub Date : 2023-08-18 DOI:10.1002/ana.26762

Grace Minogue BA, Allegra Kawles BA, Antonia Zouridakis BS, Rachel Keszycki MS, Alyssa Macomber BS, Vivienne Lubbat, Nathan Gill PhD, Qinwen Mao MD, Margaret E. Flanagan MD, Hui Zhang PhD, Rudolph Castellani MD, Eileen H. Bigio MD, M.-Marsel Mesulam MD, Changiz Geula PhD, Tamar Gefen PhD

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引用次数: 0

Abstract

Objective

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).

Methods

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.

Results

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.

Interpretation

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

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反式反应DNA结合蛋白在阿尔茨海默病海马病理学中的独特模式 43

目的：与年龄相关的痴呆综合征通常与单一的病理生理过程无关，导致尸检中发现多种神经病理学。遗忘性痴呆综合征可能与阿尔茨海默病（AD）和共病反式反应DNA结合蛋白有关 43（TDP-43）病理学（AD/TDP）。在这里，我们研究了由AD/TDP引起的遗忘性痴呆、由单独AD引起的遗忘型痴呆或由与额颞叶变性相关的TDP-43蛋白病引起的非遗忘型痴呆（FTLD-TDP）的参与者的神经元完整性和TDP-43和tau的病理负荷，以及绘制良好的三突触海马回路（齿状回[DG]、CA3和CA1）。方法：共48例具有广泛特征的病例（14例广告，16 AD/TDP，18FTLD-TDP），以量化病理负荷和神经元损失。结果：在AD/TDP和FTLD-TDP中，TDP-43在DG中的免疫反应性最强。与纯AD相比，AD/TDP中DG和CA3的Tau免疫反应性显著增强。所有临床组的DG神经元数量最多，其次是CA3，然后是CA1。与FTLD-TDP组相比，AD和AD/TDP组在所有海马亚区的神经元计数均较低，这与遗忘表型的显著性一致。解释：根据海马tau和TDP-43的不同区域分布，我们得出结论，AD/TDP可以与AD和FTLD-TDP区分开来。研究结果表明，TDP-43可能增强AD/TDP中的tau聚集。ANN NEUROL 2023。

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来源期刊

Annals of Neurology 医学-临床神经学

CiteScore

18.00

自引率

1.80%

发文量

270

审稿时长

3-8 weeks

期刊介绍： Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.