PET imaging of hyperphosphorylated tau differentiates PSP and CBD from PD

描述（由申请人提供）：多发性神经退行性脑疾病，包括特发性帕金森病，进行性核上性麻痹（PSP）和皮质基底变性（CBD）。诊断和鉴别这些疾病在生活中是困难的，特别是在病程的早期。它们在神经病理学上通过沉积蛋白的化学成分和区域分布来区分，与PD相关的蛋白为α -突触核蛋白，神经原纤维缠结（NFT）中的成对螺旋丝（PHF） tau和与PSP和CBD相关的胶质簇（因此它们被称为“tau病”）。未来的治疗方法可能会根据每种疾病的潜在分子病理学进行调整。在生命中对这些疾病进行可靠的分子诊断的能力将是一个重大的进步，与临床试验以及未来的分子治疗直接相关。最近开发的一种名为[F18] T807的放射性药物可以结合活人大脑中的PHF tau，可能是建立死亡分子诊断的有价值的工具。在本项目中，我们将评估用[F18] T807测量的PHF tau沉积是否能区分PSP和CBD与PD和健康对照组（HCS）；并探讨PHF tau沉积与这些疾病的临床损伤、皮质变薄和淀粉样蛋白负荷指标的关系。患有PSP、CBD和PD的受试者将接受标准化的神经学检查、详细的神经心理学测试、[F18] T807 PET、[C11] PiB PET和脑结构MRI，并将与先前获得的年龄匹配HCS队列的临床和PET数据进行比较，以检验以下假设：(1) [F18] T807 PET将区分疑似PSP和CBD所致的tau病变与疑似特发性PD和HCS所致的突触核蛋白病变，PSP和CBD中PHF tau负荷与已知的这些疾病的NFT拓扑结构相关；(2)PHF tau负荷的分布与PSP和CBD的特定运动和认知特征相关；(3)区域性PHF tau负荷与皮质变薄有关。我们将使用淀粉样蛋白PET成像来排除伪装成PSP或CBD的AD。总之，这些努力将为开发[F18] T807 PET成像作为帕金森病的生物标志物和诊断工具奠定基础。

DESCRIPTION (provided by applicant): Multiple neurodegenerative brain disorders present with parkinsonism, including idiopathic Parkinson disease, Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). Diagnosis and differentiation of these disorders in life is difficult, especially early in their course. They are distinguished neuropathologically by he chemical composition and regional distribution of deposited proteins, with alpha-synuclein the protein associated with PD, and paired helical filament (PHF) tau in neurofibrillary tangles (NFT) and glial tufts associated with PSP and CBD (for which they are known as 'tauopathies'). Future therapeutics will likely be tailored to the underlying molecular pathology of each disease. The capacity to make a secure molecular diagnosis of these illnesses in life would be a significant advance, with immediate relevance for clinical trials as well as for future molecularly-based therapies. A recently developed radiopharmaceutical known as [F18] T807 binds brain PHF tau in living humans, and may be a valuable tool for establishing a molecular diagnosis antemortem. In this project, we will evaluate whether PHF tau deposition measured with [F18] T807 differentiates PSP and CBD from PD and healthy control subjects (HCS); and explore the relation of PHF tau deposition to indices of clinical impairment, cortical thinning, and amyloid burden in these disorders. Subjects with PSP, CBD, and PD will undergo standardized neurological examination, detailed neuropsychological testing, [F18] T807 PET, [C11] PiB PET, and structural brain MRI, and will be compared to previously acquired clinical and PET data of an aged-matched HCS cohort to test the following hypotheses: (1) [F18] T807 PET will differentiate subjects with suspected tauopathy due to PSP and CBD from subjects with suspected synucleinopathy due to idiopathic PD and from HCS, with PHF tau burden in PSP and CBD correlating with the known NFT topology of those diseases, (2) the distribution of PHF tau burden will correlate with specific motor and cognitive features of PSP and CBD; and (3) regional PHF tau burden will be associated with cortical thinning. We will use amyloid PET imaging to exclude AD masquerading as PSP or CBD. Together, these efforts will establish the potential for developing [F18] T807 PET imaging as a biomarker and diagnostic tool for the parkinsonian tauopathies.