Alzheimer's disease clinical variants show distinct regional patterns of neurofibrillary tangle accumulation
Alzheimer's disease clinical variants show distinct regional patterns of neurofibrillary tangle accumulation
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DOI：
10.1007/s00401-019-02036-6
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发表时间：
2019-10-01
影响因子：
12.7
通讯作者：
Grinberg, Lea Tenenholz
中科院分区：
文献类型：
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作者：
Petersen, Cathrine;Nolan, Amber L.;Grinberg, Lea Tenenholz
阿尔茨海默病 (AD) 的临床谱远远超出了经典的遗忘为主的综合征。先前的研究表明，AD 的遗忘性和语言减少性原发性进行性失语症表现之间的神经原纤维缠结（NFT）负担存在差异。在这项研究中，我们探讨了 NFT 病理学的区域分布及其与五种不同临床综合征的 AD 表现的关系。我们使用硫黄素-S 荧光显微镜在一组经过充分表征的纯 AD 病例（富含非典型临床表现）的临床病理学队列中评估了六个选定的新皮质和海马区域的 NFT 密度。受试者接受了载脂蛋白 E 基因分型和神经心理学测试。使用既定的综合 z 分数评估主要认知领域（执行、视觉空间、语言和记忆功能）。我们的结果表明，NFT 区域负担与临床表现和区域特定认知评分一致。与遗忘综合征相关的非典型临床变异中，皮质而非海马的 NFT 负担较高。在对特定临床变异的分析中，与遗忘综合征相比，语言减少的原发性进行性失语症在颞上回显示出更高的 NFT 密度 (p = 0.0091)，而皮质基底综合征在初级运动皮层中显示出更高的 NFT 密度 (p = 0.0205)。海马角回和 CA1 区较高的 NFT 负担与视觉空间功能障碍恶化独立相关。此外，基于区域 NFT 密度的无偏层次聚类确定了三个组，其特征分别是总体 NFT 负担低、总体负担高和皮质主导负担，这些组在性别比例、年龄、疾病持续时间和临床表现方面存在差异。相比之下，源自先前提出的算法的典型亚型、海马保留亚型和边缘主导亚型在该样本中并未重现相同程度的临床相关性。总体而言，我们的结果表明区域 NFT 积累的特定领域功能后果。绘制这些后果为加深对非典型临床表现背后的神经病理学框架的理解提供了机会。
The clinical spectrum of Alzheimer's disease (AD) extends well beyond the classic amnestic-predominant syndrome. The previous studies have suggested differential neurofibrillary tangle (NFT) burden between amnestic and logopenic primary progressive aphasia presentations of AD. In this study, we explored the regional distribution of NFT pathology and its relationship to AD presentation across five different clinical syndromes. We assessed NFT density throughout six selected neocortical and hippocampal regions using thioflavin-S fluorescent microscopy in a well-characterized clinicopathological cohort of pure AD cases enriched for atypical clinical presentations. Subjects underwent apolipoprotein E genotyping and neuropsychological testing. Main cognitive domains (executive, visuospatial, language, and memory function) were assessed using an established composite z score. Our results showed that NFT regional burden aligns with the clinical presentation and region-specific cognitive scores. Cortical, but not hippocampal, NFT burden was higher among atypical clinical variants relative to the amnestic syndrome. In analyses of specific clinical variants, logopenic primary progressive aphasia showed higher NFT density in the superior temporal gyrus (p = 0.0091), and corticobasal syndrome showed higher NFT density in the primary motor cortex (p = 0.0205) relative to the amnestic syndrome. Higher NFT burden in the angular gyrus and CA1 sector of the hippocampus were independently associated with worsening visuospatial dysfunction. In addition, unbiased hierarchical clustering based on regional NFT densities identified three groups characterized by a low overall NFT burden, high overall burden, and cortical-predominant burden, respectively, which were found to differ in sex ratio, age, disease duration, and clinical presentation. In comparison, the typical, hippocampal sparing, and limbic-predominant subtypes derived from a previously proposed algorithm did not reproduce the same degree of clinical relevance in this sample. Overall, our results suggest domain-specific functional consequences of regional NFT accumulation. Mapping these consequences presents an opportunity to increase understanding of the neuropathological framework underlying atypical clinical manifestations.