Spreading Tau Pathology in Non-Amnestic Alzheimer's Disease

在非遗忘性阿尔茨海默病中传播 Tau 病理学

• 批准号: 10380572
• 负责人: Jeffrey S Phillips
• 金额: $ 74.72万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380572
• 关键词: Alzheimer' s Disease; Alzheimer' s disease pathology; Amnesia; Anatomy; Area; Autopsy; Basal Ganglia; Biological Markers; Cerebrum; Clinical; Cognitive; Comparative Pathology; Cross-Sectional Studies; Diagnosis; Dimensions; Disease; Eligibility Determination; Family; Foundations; Frequencies; Frontotemporal Lobar Degenerations; Functional disorder; Genetic; Genetic Risk; Hippocampus (Brain); Histopathology; Image; Imaging Techniques; Knowledge; Language; Language Disorders; Lead; Life; Link; Magnetic Resonance Imaging; Measures; Medial; Methods; Molecular; Motor; Neocortex; Neurobiology; Pathologic; Pathological Staging; Pathology; Patients; Pattern; Phenotype; Positron-Emission Tomography; Primary Progressive Aphasia; Prognosis; Progressive Supranuclear Palsy; Reporting; Single Nucleotide Polymorphism; Staging; Syndrome; Tauopathies; Temporal Lobe; Testing; Underserved Population; Validation; Variant; Visuospatial; Work; amnestic mild cognitive impairment; apolipoprotein E-4; base; behavioral variant frontotemporal dementia; burden of illness; cerebral atrophy; clinical care; clinical diagnosis; clinical phenotype; cohort; comparative; corticobasal degeneration; corticobasal syndrome; diagnostic criteria; digital; digital imaging; digital pathology; episodic memory impairment; executive function; graph theory; human model; imaging modality; imaging study; improved; in vivo; in vivo imaging; multimodality; neocortical; neuroimaging; novel; pathology imaging; prognostic; risk variant; serial imaging; tau Proteins; tau aggregation; trait; treatment trial

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.

典型的遗忘型阿尔茨海默病（aAD）的标志是神经元tau病理学。Braak首先描述了 AD中tau病理学的分期，在内侧颞叶（MTL）早期典型地明显， 情节记忆受损，然后扩散到对语言，视觉空间和 执行功能和运动功能的基底神经节。然而，AD的病理改变也可表现为 临床上表现为局灶性新皮质综合征，无遗忘，称为非遗忘性轻度认知障碍 （naMCI）。这包括语言障碍（逻辑缺失变异型原发性进行性失语症，lvPPA）， 视觉空间（后皮质萎缩，PCA）、执行（额叶变异MCI，fvMCI）和运动（皮质基底节 综合征由于AD，CBS-AD）功能。罕见的临床、成像和尸检研究表明，tau蛋白病理学 在naMCI中，新皮层中的NAMCI比MTL更大，挑战了关于MTL起源的基本假设。 AD的大脑tau病理学。然而，尚未研究naMCI尸检时的tau病理分期， 和纵向体内成像来验证naMCI中的疾病扩散是非常罕见的， 使用单一成像模式的临床病例。这些是我们知识中的重大空白。目标1： 用一种新的、经验证的数字方法研究naMCI和aAD尸检时tau病理学的传播阶段。 我们假设tau蛋白病理学的积累阶段与新皮质起源和扩散相一致， naMCI，并且仅在后来传播至MTL，不同于aAD中tau病理学的MTL起源。病理分期 取决于尸检中的横断面研究的推断，因此目标2提出验证 在naMCI和aMCI/ aAD中使用新的纵向MRI和tau-PET成像在体内传播疾病， 独特的成像和图论方法。我们假设在naMCI中tau蛋白的皮质起源和扩散， 随后tau在MTL中积累，逆转aMCI/ aAD中疾病的MTL起源。这些发现 挑战关于AD中tau病理学的MTL起源的假设。我们测试了遗传的新假设 FTLD-tau中的因素使tau病理学的解剖学分布偏向，从而导致tau的非典型扩散， naMCI。在目标1中，我们预期naMCI中tau病理学的阶段类似于原发性tau病变中所见的阶段。 由于FTLD-tau，包括非流利/语法缺失变体PPA，行为变体额颞痴呆， 和皮质基底节变性/进行性核上性麻痹。在目标2中，我们期望纵向模式 在naMCI中的体内成像类似于在FTLD-tau中所见。最后，目标3提出了一个有针对性的研究FTLD- ta-related single nucleotide polymorphism（SNP）risk alleles in naMCI.根据初步调查结果，我们 假设FTLD-tau相关风险等位基因在naMCI中比在aMCI/ aAD中更常见。这些发现 将挑战关于AD病理学的病理生理学基础的长期假设， naMCI的诊断标准，以支持纳入改善疾病的AD治疗试验， 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。