VALIDATION OF NEUROIMAGING BIOMARKERS FOR NIGROSTRIATAL NEURONS

描述（由申请人提供）：帕金森病（PD）在北美影响超过100万人，没有任何治疗方法被证明可以减缓其进展。我们必须有一个有效的PD进展的生物标志物，以允许测试和开发任何疾病修饰疗法。没有这一点，我们可能无法达到我们的最终目标，即延缓帕金森病的发展或扭转其不可阻挡的衰退。目前，基于临床的测量和其他生物标志物PD进展存在主要的混淆，限制了它们的应用。神经成像生物标志物有可能提供PD进展的公正测量。然而，多个问题使目前可用的SPECT或PET标记物的解释复杂化，并导致在几项PD的大型研究中，基于神经影像学和基于临床的疾病严重程度测量之间的结果相互矛盾。一个关键的问题是，目前可用的PET标记物是否真正反映了黑质纹状体神经元数量的减少。我们建议比较两种不同的PET示踪剂：[11C]DTBZ（一种囊泡单胺转运蛋白2型[VMAT2]标记物）和[11C]CFT（一种多巴胺转运[DAT]标记物），并确定哪一种能最准确地反映黑质纹状体神经元数量的减少。PET测量将与黑质中酪氨酸羟化酶（TH）免疫染色神经元细胞体的立体学计数进行比较；纹状体中这些神经元的th染色纤维，纹状体中VMAT2和DAT的体外定量放射自显影，高效液相色谱法测量纹状体多巴胺含量和帕金森病的行为评分，这些都已在猴子身上得到验证。在MPTP之前，每只动物将对每种放射性示踪剂进行3次行为测量和2次PET测量。我们之前证明，动物在颈动脉内MPTP后2个月将出现稳定的临床帕金森病。我们会在安乐死前做重复的行为测试然后用两种示踪剂做PET。将对来自中脑的固定组织和来自纹状体的新鲜冷冻组织进行体外测量。然后，我们将确定哪种PET示踪剂与多巴胺能神经元的变化或由评分量表确定的行为变化提供最佳相关性。这项研究将为PD进展的神经成像生物标志物的验证提供关键的一步。我们需要这样一种有效的生物标志物，以允许对任何疾病修饰干预进行测试。公共卫生相关性：帕金森病（PD）在北美影响超过100万人，没有任何治疗方法被证明可以减缓其进展。为了开发这样的治疗方法，有必要对疾病进展进行客观测量。该申请旨在开发和验证一种神经成像生物标志物来测量PD的进展；这是确定任何新提出的干预措施有效性的关键步骤。

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.