Spreading Tau Pathology in Non-Amnestic Alzheimer's Disease

典型的遗忘性阿尔茨海默病(AAD)的一个特征是神经原纤维tau病理。布拉克首先描述了 阿尔茨海默病的tau病理分期，典型的早期出现在内侧颞叶(MTL)。 情节记忆受损，然后扩散到对语言、视觉空间和大脑皮质重要的新皮质区域 执行功能和基底节的运动功能。然而，AD的病理改变也可以出现 临床表现为无遗忘的局灶性新皮质综合征，称为非遗忘性轻度认知障碍 (NAMCI)。这包括语言障碍(对数变异型原发性进行性失语，LvPPA)， 视觉空间(后皮质萎缩，PCA)、执行(额叶变异MCI，fvMCI)和运动(皮质-基底 阿尔茨海默病综合征，CBS-AD)功能。罕见的临床、影像和尸检研究表明tau病理 在NAMCI中，新皮质比MTL更大，挑战了关于MTL起源的基本假设 阿尔茨海默病的脑tau病理。然而，在NAMCI中尸检时tau病理分期尚未被研究， 而用纵向活体成像来验证NAMCI中的传播疾病是非常罕见的，涉及到小群体 使用单一成像模式的临床病例的比例。这些代表了我们知识上的重大差距。在目标1中，我们 用一种新的、有效的数字方法研究NAMCI和AAD尸检时tau病理的传播阶段。 我们假设tau病变的累积阶段与新皮质起源和扩散相一致。 NAMCI，后来才扩散到MTL，不同于AAD中tau病理的MTL起源。病理分期 取决于尸检横断面研究的推论，因此目标2建议验证 应用新的纵向MRI和tau-PET成像在nMCI和aMCI/AAD中的体内传播疾病 独特的成像和图论方法。我们假设tau在NAMCI中的皮质起源和扩散， 随着tau在MTL中的随后积累，逆转了aMCI/AAD中MTL的疾病起源。这些发现将 挑战有关AD中tau病理的MTL起源的假设。我们测试了新的假设，即基因 影响FTLD-tau偏倚的因素tau病变的解剖分布导致了tau的不典型扩散。 NaMCI。在目标1中，我们预计在NAMCI中tau病理分期与在原发tauopathy中看到的类似 由于FTLD-tau，包括非流利/无语法变异型PPA，行为变异型额颞痴呆， 皮质基底性变性/进行性核上性麻痹。在目标2中，我们预计纵向模式 NAMCI的活体成像与FTLD-tau相似。最后，目标3提出了一项有针对性的FTLD研究-- NAMCI的tau相关单核苷酸多态(SNP)风险等位基因。根据我们的初步调查结果，我们 假设与FTLD-tau相关的风险等位基因在NAMCI中比aMCI/AAD中更常见。这些发现 将挑战关于AD病理的病理生理学基础的长期假设，开发经过验证的 NAMCI的诊断标准支持纳入疾病修改AD治疗试验，导致验证 这些试验的终点，并为这一服务不足的人群提供所需的预后信息。

A hallmark of typical amnestic Alzheimer's disease (aAD) is neurofibrillary tau pathology. Braak first described staging of tau pathology in AD, classically evident early in the medial temporal lobe (MTL) implicated in impaired episodic memory, and then spreading to neocortical regions important for language, visuospatial and executive function and to basal ganglia for motor function. However, AD pathological change can also present clinically as a focal neocortical syndrome without amnesia, known as non-amnestic Mild Cognitive Impairment (naMCI). This includes disorders of language (logopenic variant primary progressive aphasia, lvPPA), visuospatial (posterior cortical atrophy, PCA), executive (frontal variant MCI, fvMCI), and motor (corticobasal syndrome due to AD, CBS-AD) function. Rare clinical, imaging, and autopsy studies suggest that tau pathology in naMCI is greater in neocortex than MTL, challenging fundamental assumptions about the MTL origin of cerebral tau pathology in AD. However, staging tau pathology at autopsy in naMCI has not been investigated, and longitudinal in vivo imaging to validate spreading disease in naMCI is very rare and involves small groups of clinical cases using a single imaging modality. These represent major gaps in our knowledge. In Aim 1, we study stages of spreading tau pathology at autopsy in naMCI and aAD with a novel, validated, digital method. We hypothesize that stages of accumulating tau pathology are consistent with neocortical origin and spread in naMCI, and only later spread to MTL, differing from the MTL origin of tau pathology in aAD. Pathologic staging depends on inferences from cross-sectional studies at autopsy, so Aim 2 proposes to validate stages of spreading disease in vivo with novel longitudinal MRI and tau-PET imaging in naMCI and aMCI/ aAD using unique imaging and graph theory approaches. We hypothesize a cortical origin and spread of tau in naMCI, with later accumulation of tau in MTL, reversing the MTL origin of disease in aMCI/ aAD. These findings would challenge assumptions about the MTL origin of tau pathology in AD. We test the novel hypothesis that genetic factors in FTLD-tau bias the anatomic distribution of tau pathology contributing to the atypical spread of tau in naMCI. In Aim 1, we expect that stages of tau pathology in naMCI resemble that seen in primary tauopathies due to FTLD-tau, including non-fluent/agrammatic variant PPA, behavioral variant frontotemporal dementia, and corticobasal degeneration/progressive supranuclear palsy. In Aim 2, we expect that patterns of longitudinal in vivo imaging in naMCI resemble that seen in FTLD-tau. Finally, Aim 3 proposes a targeted study of FTLD- tau-related single nucleotide polymorphism (SNP) risk alleles in naMCI. Based on our preliminary findings, we hypothesize that FTLD-tau-related risk alleles are more common in naMCI than aMCI/ aAD. These findings would challenge long-held assumptions about the pathophysiologic basis for AD pathology, develop validated diagnostic criteria for naMCI to support inclusion in disease-modifying AD treatment trials, lead to validated endpoints for these trials, and provide needed prognostic information for this underserved population.