PET imaging of hyperphosphorylated tau differentiates PSP and CBD from PD

过度磷酸化 tau 蛋白的 PET 成像可区分 PSP 和 CBD 与 PD

• 批准号: 8808816
• 负责人: Stephen N. Gomperts
• 金额: $ 26.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8808816
• 关键词: Address; Alzheimer' s Disease; Amyloid; Autopsy; Basal Ganglia; Binding; Biological Markers; Biometry; Brain; Brain Diseases; Brain Stem; Brain scan; Chemicals; Classification; Clinical; Clinical Trials; Cognitive; Data; Deposition; Diagnosis; Diagnostic; Diagnostics Research; Disease; Enrollment; Environment; Executive Dysfunction; Functional disorder; Future; Globus Pallidus; Goals; Human; Impaired cognition; Impairment; Interdisciplinary Study; Label; Lesion; Levodopa; Lewy Bodies; Life; Magnetic Resonance Imaging; Measures; Medial; Molecular; Molecular Diagnosis; Motor; Movement Disorders; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic Examination; Neuropsychological Tests; Neuropsychology; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathology; Patients; Positron-Emission Tomography; Progressive Supranuclear Palsy; Proteins; Radiopharmaceuticals; Recruitment Activity; Research; Research Personnel; Research Project Grants; Resources; Secure; Severities; Study Subject; Syndrome; TNFRSF5 gene; Tauopathies; Testing; Thalamic structure; Therapeutic; Work; aged; alpha synuclein; base; cohort; corticobasal degeneration; data management; experience; hyperphosphorylated tau; in vivo; indexing; molecular pathology; motor impairment; neuroimaging; patient population; protein aggregate; public health relevance; synuclein; synucleinopathy; tau Proteins; tau aggregation; tool

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.

描述（由申请人提供）：伴有帕金森症的多种神经退行性脑部疾病，包括特发性帕金森病、进行性核上性麻痹（PSP）和皮质基底节变性（CBD）。生活中这些疾病的诊断和鉴别诊断很困难，尤其是在病程早期。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，α-突触核蛋白是与 PD 相关的蛋白，神经原纤维缠结 (NFT) 中的配对螺旋丝 (PHF) tau 蛋白以及与 PSP 和 CBD 相关的神经胶质簇（其中它们被称为“tau蛋白病”）。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定制。对生活中的这些疾病进行安全的分子诊断的能力将是一个重大进步，与临床试验以及未来的分子疗法具有直接相关性。最近开发的一种名为 [F18] T807 的放射性药物可与活人的大脑 PHF tau 蛋白结合，并且可能是建立生前分子诊断的宝贵工具。在这个项目中，我们将评估使用 [F18] T807 测量的 PHF tau 沉积是否能够将 PSP 和 CBD 与 PD 和健康对照受试者 (HCS) 区分开来；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神经学检查、详细的神经心理学测试、[F18] T807 PET、[C11] PiB PET 和结构性脑 MRI，并将与先前获得的老年患者的临床和 PET 数据进行比较。匹配的 HCS 队列来测试以下假设：(1) [F18] T807 PET 将区分疑似由 PSP 和 CBD 引起的 tau 蛋白病的受试者与疑似由 PSP 和 CBD 引起的 tau 蛋白病的受试者由特发性 PD 和 HCS 引起的突触核蛋白病，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 负荷的分布将与 PSP 和 CBD 的特定运动和认知特征相关； (3) 局部 PHF tau 负担与皮质变薄有关。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，这些努力将确立开发 [F18] T807 PET 成像作为帕金森 tau 病生物标志物和诊断工具的潜力。