Disentangling the contribution of tau to aging and AD

描述(申请人提供)：阿尔茨海默病(AD)的定义神经病理损害是淀粉样蛋白-b斑块和tau神经原纤维缠结，两者都在认知障碍症状出现前多年出现。这项提案的首要目标是评估一种被称为[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可能潜在的三个特定环境 通过确定T807保留的阶段，提供在临床AD研究中有用的关键信息 根据已建立的Braak分期方案，反映PHF tau的水平和程度：1)识别与年龄相关的内侧颞叶PHF-tau，与Braak I/II期一致，这是一种开始于生命第三个十年的缓慢积累的形式，但在晚年可能与更微妙的认知能力相关，或者可能与AB沉积的生物标志物证据相结合，对最终的损害具有预测价值；2)识别新皮质PHF-tau的阳性临界点，表明认知和临床功能受损的阶段，当作为连续变量评估时，它与疾病的表型特征密切相关；3)确定tau的沉积与AD的其他生物标志物之间的联系，包括淀粉样蛋白-b，神经变性的其他指标，如体积MRI，脑脊液tau，以及用fcMRI测量的大规模网络破坏的指标。这项建议建立在我们以前的工作和现有的多学科合作的基础上，以开发具有临床意义、高度敏感的方法来追踪：1)可能与早期损害有关的早期tau沉积；ii)假说与痴呆有关的新皮质tau沉积(目标1)，以阐明更恶性、解剖学上更具特异性的tau沉积与局部和全身性容量损失及网络连通性崩溃之间的关系(目标2)，以及首次在体内直接与脑tau和淀粉样蛋白b沉积在整个卧床跨度内的联合进化相关(目标3)。

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).