VALIDATION OF NEUROIMAGING BIOMARKERS FOR NIGROSTRIATAL NEURONS

描述（由申请人提供）：帕金森病（PD）影响北美超过100万人，并且没有治疗被证明可以减缓进展。我们必须有一个经过验证的PD进展生物标志物，以允许测试和开发任何疾病修饰疗法。如果没有这一点，我们可能无法达到我们的最终目标，即延缓PD的进展或逆转PD的不可阻挡的下降。目前，基于临床的测量和其他生物标志物PD进展具有限制其效用的主要混淆。神经影像学生物标志物有可能提供PD进展的无偏倚测量。然而，多个问题使目前可用的SPECT或PET标记物的解释复杂化，并导致在几项大型PD研究中基于神经成像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。我们建议在MPTP处理的猴子中比较两种不同的PET示踪剂：[11 C]DTBZ（囊泡单胺转运体2型[VMAT 2]标记物）和[11 C]CFT（多巴胺转运[DAT]标记物），并确定哪一种提供了黑质纹状体神经元数量减少的最忠实反映。将PET测量结果与黑质中酪氨酸羟化酶（TH）免疫染色神经元的细胞体的体视学计数、纹状体中这些神经元的TH染色纤维、纹状体中VMAT 2和DAT的定量体外放射自显影、用高效液相色谱法测量的纹状体多巴胺含量和已在猴中验证的帕金森病行为评级进行比较。在MPTP之前，每只动物将采集3次行为测量值，并使用每种放射性示踪剂进行2次PET测量。我们以前证明，动物将有稳定的临床帕金森病2个月后，颈动脉MPTP。我们将进行重复的行为测量，然后在安乐死前使用2种示踪剂进行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放射性示踪剂提供与多巴胺能神经元变化或由评级量表确定的行为变化的最佳相关性。本研究将为PD进展的神经影像学生物标志物的验证提供关键步骤。我们需要这样一种经过验证的生物标志物，以允许测试任何疾病修饰干预。公共卫生相关性：帕金森病（PD）在北美影响着100多万人，没有任何治疗方法被证明可以减缓病情进展。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。该申请提出开发和验证神经影像学生物标志物以测量PD进展;这是确定任何新提出的干预措施的有效性所需的关键步骤。

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.