Disentangling the contribution of tau to aging and AD

解开 tau 蛋白对衰老和 AD 的影响

• 批准号: 8852524
• 负责人: Keith A. Johnson
• 金额: $ 69.08万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852524
• 关键词: Address; Age; Aging; Alzheimer' s Disease; Amyloid; Anatomy; Area; Atrophic; Autopsy; Binding; Biological Markers; Brain; Cerebrospinal Fluid; Clinical; Cognition; Cognitive; Cognitive aging; Complement; Data; Dementia; Deposition; Development; Disease; Elderly; Enrollment; Event; Evolution; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Health; Hippocampus (Brain); Human; Impaired cognition; Impairment; Individual; Interdisciplinary Study; Joints; Lesion; Life; Ligands; Link; Magnetic Resonance Imaging; Malignant - descriptor; Massachusetts; Measures; Medial; Memory impairment; Methods; Monitor; Neocortex; Nerve Degeneration; Neurofibrillary Tangles; Observational Study; Participant; Pathology; Patients; Pittsburgh Compound-B; Positron-Emission Tomography; Predictive Value; Proteins; Public Health; Recruitment Activity; Research; Role; Sampling; Scheme; Senile Plaques; Severities; Staging; Structure; Symptoms; Synapses; Temporal Lobe; Testing; Time; Tracer; Work; age related; aging brain; base; brain volume; cerebral atrophy; clinically relevant; cognitive capacity; cognitive performance; cognitive testing; cohort; disease diagnosis; drug development; entorhinal cortex; follow-up; improved; in vivo; indexing; mild cognitive impairment; neocortical; neuron loss; normal aging; novel; tau Proteins; tau aggregation

DESCRIPTION (provided by applicant): The defining neuropathologic lesions of Alzheimer's disease (AD) are amyloid-b plaques and tau neurofibrillary tangles, both of which appear many years before the onset of symptoms of cognitive impairment. The overarching goal of this proposal is to evaluate a novel PET tracer, known as [F18] T807, that detects the tau neurofibrillary tangles. We will address three specific contexts in which tau PET could potentially provide critical information useful in clinical AD research by identifying stages of T807 retention that reflect the levels and extent of PHF tau according to the established Braak staging scheme: 1) The identification of age- associated medial temporal lobe PHF-tau that is consistent with Braak Stage I/II, the slowly accumulating form that begins in the third decade of life, but in late years may possibly correlate with more subtle cognitive capacities or have predictive value for eventual development of impairment, perhaps when combined with biomarker evidence of Ab deposition; 2) The identification of a neocortical PHF-tau cut point of positivity that indicates a impaired stage of cognitive and clinical function, which when evaluated as a continuous variable is closely correlated with phenotypic features of the illness; 3) A determination of the links between deposition of tau and other biomarkers of AD, including amyloid-b, additional measures of neurodegeneration such as volumetric MRI, CSF tau, and measures of large-scale network disruption measured with fcMRI. This proposal builds on our previous work and existing multidisciplinary collaborations to develop clinically relevant, highly sensitive methods for tracking i) early tau deposition that may be linked to early impairment and ii) neocortical tau deposition that is hypothetically linked to dementia (Aim 1), to illuminate the relationship between more malignant, anatomically specific tau deposition that relates to local and generalized volume loss and network connectivity breakdown (Aim 2), and to relate directly in vivo for the first time the joint evolution of brain tau and amyloid-b deposition throughout the lie span (Aim 3).

描述（由申请人提供）：阿尔茨海默氏病（AD）的定义性神经病理学病变是淀粉样蛋白-b 斑块和 tau 神经原纤维缠结，两者均在认知障碍症状出现前许多年出现。该提案的总体目标是评估一种新型 PET 示踪剂，称为 [F18] T807，可检测 tau 神经原纤维缠结。我们将讨论 tau PET 可能发挥作用的三种具体情况 通过识别 T807 保留阶段，提供对临床 AD 研究有用的关键信息 根据已建立的 Braak 分期方案，反映 PHF tau 的水平和范围： 1) 识别与年龄相关的内侧颞叶 PHF-tau，与 Braak I/II 期（从第三期开始缓慢积累的形式）一致十年后，但在晚年可能与更微妙的认知能力相关，或者对最终的损伤发展具有预测价值，或许与抗体沉积的生物标志物证据相结合； 2) 确定新皮质 PHF-tau 阳性切点，表明认知和临床功能受损阶段，当作为连续变量进行评估时，其与疾病的表型特征密切相关； 3) 确定 tau 沉积与 AD 的其他生物标志物之间的联系，包括淀粉样蛋白-b、神经变性的其他测量（例如体积 MRI、脑脊液 tau）以及使用 fcMRI 测量的大规模网络破坏的测量。该提案建立在我们之前的工作和现有的多学科合作的基础上，开发临床相关的、高度敏感的方法来跟踪 i) 可能与早期损伤有关的早期 tau 沉积，以及 ii) 假设与痴呆有关的新皮质 tau 沉积（目标 1），阐明更恶性、解剖学上特定的 tau 沉积与局部和全身体积损失以及网络连接破坏相关的关系（目标 2），并首次在体内直接将关节进化联系起来整个谎言期间脑 tau 蛋白和淀粉样蛋白 B 沉积的情况（目标 3）。