PET imaging of hyperphosphorylated tau differentiates PSP and CBD from PD

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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.