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: 8612866
• 负责人: Keith A. Johnson
• 金额: $ 71.21万
• 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/8612866
• 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; 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; Performance; 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; cohort; disease diagnosis; drug development; entorhinal cortex; follow-up; improved; in vivo; indexing; mild cognitive impairment; neocortical; neuron loss; normal aging; novel; public health relevance; tau Proteins; tau aggregation

ABSTRACT 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 later 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 an 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 life span (Aim 3).

摘要 阿尔茨海默病（AD）的定义性神经病理学病变是淀粉样蛋白-b斑块和tau蛋白神经胶质瘤。 缠结，这两种情况都出现在认知障碍症状出现的许多年前。的 该提案的首要目标是评估一种新的PET示踪剂，称为[F18] T807，其检测tau蛋白， 神经系统缠结我们将讨论tau PET可能提供的三种特定背景 通过识别反映T807水平的T807保留阶段，在临床AD研究中有用的关键信息 根据已建立的Braak分期方案，PHF tau的范围：1）年龄的确定- 相关的内侧颞叶PHF-tau与Braak I/II期一致，缓慢积累的形式 这开始于生命的第三个十年，但在以后的几年可能与更微妙的认知有关， 能力或对损害的最终发展具有预测价值，也许当与 Ab沉积的生物标志物证据; 2）鉴定新皮质PHF-tau阳性切割点， 表示认知和临床功能的受损阶段，当作为连续变量进行评估时， 与疾病的表型特征密切相关; 3）确定沉积之间的联系， tau和AD的其他生物标志物，包括淀粉样蛋白-b，神经变性的其他指标， 体积MRI、CSF tau和用fcMRI测量的大规模网络中断的测量。这项建议 建立在我们以前的工作和现有的多学科合作，以开发临床相关的，高度 用于追踪i）可能与早期损伤相关的早期tau沉积和ii）新皮质的敏感方法 假设tau蛋白沉积与痴呆症有关（目的1），以阐明更多 与局部和全身体积损失和网络相关的恶性、解剖学特异性tau沉积 连接性破坏（目的2），并首次在体内直接涉及脑tau蛋白和 淀粉样蛋白-b在整个生命周期中的沉积（Aim 3）。