PET imaging of hyperphosphorylated tau differentiates PSP and CBD from PD

描述(申请人提供)：帕金森氏症表现的多种神经退行性脑疾病，包括特发性帕金森病、进行性核上性麻痹(PSP)和皮质基底膜变性(CBD)。生活中这些疾病的诊断和鉴别是困难的，特别是在他们病程的早期。在神经病理学上，它们的区别在于沉积蛋白的化学成分和区域分布，其中α-突触核蛋白是与帕金森病相关的蛋白，成对螺旋细丝(PHF)tau位于神经纤维缠结(NFT)和与PSP和CBD相关的神经胶质束(因此而被称为“tauopathies”)。未来的治疗方法可能会根据每种疾病的潜在分子病理而量身定做。在生命中对这些疾病进行安全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基于分子的治疗直接相关。最近开发的一种名为[F18]T807的放射性药物可以结合活人的大脑PHF tau，可能是建立临终前分子诊断的有价值的工具。在这个项目中，我们将评估用[F18]T807测量的PHF tau沉积是否将PSP和CBD与PD和健康对照组(HCS)区分开来；并探索在这些疾病中PHF tau沉积与临床损害指数、皮质变薄和淀粉样蛋白负荷的关系。患有PSP、CBD和PD的受试者将接受标准化的神经学检查、详细的神经心理测试、[F18]T807PET、[C11]PIB PET和结构脑MRI，并将其与先前获得的年龄匹配的HCS队列的临床和PET数据进行比较，以检验以下假设：(1)[F18]T807PET将区分由PSP和CBD引起的疑似共核病受试者与因特发性PD和HCS引起的疑似合核症受试者，PSP和CBD中的PHF tau负荷与这些疾病的已知NFT拓扑相关。(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)地区性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]T807PET成像作为帕金森氏症的生物标记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.