Disentangling the contribution of tau to aging and AD

摘要 阿尔茨海默病(AD)的典型神经病理损害是淀粉样蛋白b斑块和tau神经原纤维。 这两种症状都出现在认知障碍症状出现的很多年前。这个 这项提案的首要目标是评估一种名为[F18]T807的新型PET示踪剂，它可以检测tau 神经原纤维缠结。我们将讨论tau PET可能提供的三种特定环境 通过确定反映水平的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- 伴发内侧颞叶PHF-tau，符合Braak分期I/II，为缓慢堆积形式 这开始于生命的第三个十年，但在以后的岁月中，可能与更微妙的认知相关 能力或对最终发展的损害有预测价值，也许当与 抗体沉积的生物标志物证据；2)新皮质PHF-tau阳性临界点的鉴定 表示认知和临床功能受损的阶段，当评估为连续变量时，该阶段为 与疾病的表型特征密切相关；3)确定沉积与 Tau和AD的其他生物标记物，包括淀粉样蛋白-b，神经退行性变的其他指标，如 容量磁共振、脑脊液tau和fcMRI测量的大规模网络破坏的测量。这项建议 在我们以前的工作和现有的多学科合作的基础上，开发出与临床相关的、高度相关的 1)早期tau沉积可能与早期损害有关的敏感方法；ii)新皮质 Tau沉积假设与痴呆有关(目标1)，以阐明更多 恶性的、解剖学上特异的tau沉积与局部和全身性体积丢失和网络有关 连接性崩溃(目标2)，并首次在体内直接与脑tau和tau的联合进化有关 淀粉样蛋白b在整个生命周期中的沉积(目标3)。

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).