VALIDATION OF NEUROIMAGING BIOMARKERS FOR NIGROSTRIATAL NEURONS

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DESCRIPTION (provided by applicant): Parkinson disease (PD) affects more than one million people in North America, and no treatment has been proven to slow progression. We must have a validated biomarker of PD progression to permit testing and development of any disease modifying therapy. Without this, we may not be able to reach our ultimate goal of retarding the progression or reversing the inexorable decline of PD. Currently, clinically-based measures and other biomarkers PD progression have major confounds that limit their utility. Neuroimaging biomarkers have potential to provide unbiased measurements of PD progression. However, multiple issues complicate interpretation of currently available SPECT or PET markers and have led to conflicting findings between neuroimaging-based and clincally-based measures of disease severity in several large studies of PD. One key issue is whether any of the currently-available PET markers truly reflects the reduction of the number of nigrostriatal neurons. We propose to compare two different PET tracers in MPTP-treated monkeys: [11C]DTBZ (a vesicular monoamine transporter type 2 [VMAT2] marker) and [11C]CFT (a dopamine transport [DAT] marker), and determine which one provides the most faithful reflection of the decrease in the number of nigrostriatal neurons. PET measurements will be compared to stereological counts of cell bodies of tyrosine hydroxylase (TH) immunostaining neurons in nigra; TH-staining fibers of these neurons in striatum, quantitative in vitro autoradiography of VMAT2 and DAT in striatum, striatal dopamine content measured with high performance liquid chromotography and behavioral ratings of parkinsonism that have been validated for monkeys. Prior to MPTP, each animal will have 3 behavioral measures collected and 2 PET measures with each radiotracer. We previously demonstrated that animals will have stable clinical parkinsonism 2 months after intracarotid MPTP. We will do repeated behavioral measures and then PET with the 2 tracers just prior to euthanasia. In vitro measures will be done on fixed tissue from midbrain and fresh frozen tissue from striatum. We then will determine which PET radiotracer provides the best correlation with the change dopaminergic neurons or behavioral changes determined by ratings scales. This study will provide a critical step in validation of a neuroimaging biomarker of PD progression. We need such a validated biomarker to permit testing of any disease modifying intervention. PUBLIC HEALTH RELEVANCE: Parkinson disease (PD) affects more than one million people in North America, and no treatment has been proven to slow progression. To develop such a treatment, it is necessary to have an objective measure of disease progression. This application proposes to develop and validate a neuroimaging biomarker to measure PD progression; a critical step needed to determine the efficacy of any newly proposed intervention.