Assessment of hyperphosphorylated tau PET binding in primary progressive aphasia

 描述(由申请人提供)：本R21的主要目标是在诊断为原发性进行性失语症(PPA)和三种公认的PPA变体(无语法、语义和逻辑开放的PPA)的受试者中生成关于新型PET扫描tau-PET的行为数据。病理学研究发现，一种名为tau的异常蛋白质在神经退化过程中发挥着重要作用。Tau被认为是神经退行性疾病的主要原因之一。然而，直到最近，人们才有可能确定在生命过程中是否存在tau沉积在大脑中。最近开发了一种成像配体AV-1451(前身为18F-T807)，它能与人脑中的tau特异结合。还没有研究使用神经成像来研究PPA中tau的结合。在R21的2年中，我们将招募具有所有三个PPA变体的受试者，并将PPA和PPA变体中的AV-1451结合与正常对照组受试者中的AV-1451结合进行比较，以估计PPA受试者和PPA变体中具有AV-1451的tau检测呈阳性的比例。我们还将评估是否有任何证据表明tau的结合模式在三种PPA变体中有所不同。在我们的最终目标中，我们将使用无偏见的聚类分析技术来确定是否有任何支持临床解剖定义的PPA变体，基于tau与AV-1451的结合模式，独立于临床定义的PPA变体。考虑到tau-PET是一项新技术，几乎没有现有数据可用于假设检验，这些重要步骤对于推动该领域的发展是必要的。因此，这一R21对于为未来的R01产生假设将是重要的。为了实现我们的目标，我们将进行详细的神经学、言语和语言、神经心理测试，以及新的AV-1451PET扫描和体积头部MRI扫描。这笔赠款的首席研究员Keith Josephs博士是一位世界知名的神经退行性疾病专家，他组建了一支由世界知名的言语和语言专家(Joseph Duffy博士)、神经成像专家(Clifford Jack博士、Val Lowe博士、Jennifer Whitwell博士)和神经心理学专家(Mary Machulda博士)组成的团队，共同致力于实现这些目标。为了做到这一点，该团队将拥有最先进的设施和设备。

 DESCRIPTION (provided by applicant): The primary goal of this R21 is to generate data on the behavior of a new type of PET scan, tau-PET, in subjects diagnosed with primary progressive aphasia (PPA) and the three well recognized variants of PPA: agrammatic, semantic and logopenic PPA. Pathological studies have identified an abnormal protein, tau, as being an important player in the neurodegenerative process. Tau is thought to be one of the leading causes of neurodegenerative diseases. It was not possible however, until recently, to determine whether tau deposition was present in the brain during life. An imaging ligand AV-1451 (formerly 18F-T807) was recently developed, which specifically binds to tau in human brains. No studies have investigated tau binding in PPA using neuroimaging. Over the 2 years of the R21 we will recruit subjects with all three PPA variants and compare AV-1451 binding in PPA and PPA variants, to AV-1451 binding in normal control subjects to get an estimate of what proportion of PPA subjects and PPA variants do test positive for tau with AV-1451. We will also assess whether there is any evidence that binding patterns for tau differs across the three PPA variants. In our final aim we will use the unbiased technique of cluster analysis to determine whether there is any support for clinico-anatomically defined PPA variants based on binding patterns of tau with AV-1451, independent of the clinically defined PPA variants. These are important steps that are necessary to move the field forward given that tau-PET is a new technique with little existing data to draw upon for hypothesis testing. Therefore, this R21 will b important to generate hypotheses for a future R01.The proposal is novel and feasible. To accomplish our aims, we will perform detailed neurological, speech and language, and neuropsychological testing, as well as the new AV-1451 PET scan and volumetric head MRI scanning. The Principal Investigator of this grant, Dr. Keith Josephs is a world renowned neurodegenerative specialist who has assembled a team of world renowned experts in speech and language (Dr. Joseph Duffy), neuroimaging (Drs. Clifford Jack, Val Lowe, Jennifer Whitwell) and neuropsychology (Dr. Mary Machulda) to collectively work to address the aims. The team will have state of the art facilities and equipment in order to do so.