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.

神经原纤维tau病理学是典型的炎症阿尔茨海默氏病（AAD）的标志。 Braak首先描述 AD中Tau病理学的分期，在涉及中间颞叶（MTL）的早期经典显而易见 情节记忆受损，然后传播到对语言，视觉空间和 执行功能和运动功能的基底神经节。但是，AD病理变化也可以存在 在临床上是没有健忘症的局灶性新皮质综合征，称为非疾病的轻度认知障碍 （NAMCI）。这包括语言障碍（徽标变体主要渐进式失语症，lvppa）， 视觉空间（后皮质萎缩，PCA），高管（额叶变体MCI，FVMCI）和运动 由于AD，CBS-AD）功能而引起的综合征。罕见的临床，成像和尸检研究表明TAU病理学 在NAMCI中，新皮层大于MTL，对MTL起源的基本假设具有挑战性 AD中的大脑Tau病理学。但是，尚未研究NAMCI尸检时的Tau病理学 和纵向在体内成像以验证NAMCI中疾病的扩散疾病非常罕见，涉及小组 使用单个成像方式的临床病例。这些代表了我们所知的主要差距。在AIM 1中，我们 NAMCI尸检和AAD的研究阶段，具有新颖的，经过验证的数字方法。 我们假设累积tau病理学的阶段与新皮质的起源一致，并在 NAMCI，后来才传播到MTL，与AAD中Tau病理的MTL起源不同。病理分期 取决于尸检时横截面研究的推论，因此AIM 2提出了验证阶段 使用新型的纵向MRI和NAMCI和AMCI/ AAD中的新型纵向MRI和TAU-PET成像在体内扩散疾病 独特的成像和图理论方法。我们假设tau在namci中的皮质起源和传播 随后在MTL中积累了Tau，逆转了AMCI/ AAD中疾病的MTL起源。这些发现会 关于AD中Tau病理学的MTL起源的挑战假设。我们检验了遗传的新假设 FTLD-TAU偏置的因素tau病理学的解剖学分布有助于tau在 Namci。在AIM 1中，我们期望NAMCI中Tau病理学的阶段类似于原发性tauopathies中 由于ftld-tau，包括非氟/农业变体PPA，行为变体额颞痴呆， 和皮质性肥大变性/进行性核上麻痹。在AIM 2中，我们期望纵向的模式 NAMCI中的体内成像类似于FTLD-TAU中看到的。最后，AIM 3提出了针对FTLD的目标研究 NAMCI中与TAU相关的单核苷酸多态性（SNP）风险等位基因。根据我们的初步发现，我们 假设FTLD-TAU相关的风险等位基因在NAMCI中比AMCI/ AAD更为常见。这些发现 将挑战有关AD病理学的病理生理基础的长期假设，开发经过验证的 NAMCI的诊断标准支持纳入疾病改良的AD治疗试验，导致经过验证 这些试验的终点，并为服务不足的人群提供所需的预后信息。