POSTMORTEM VALIDATION OF BIOMARKERS FOR IMAGING PARKINSON DISEASE

帕金森病成像生物标志物的死后验证

• 批准号: 9105072
• 负责人: Jinbin Xu
• 金额: $ 33.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9105072
• 关键词: Affect; Affinity; Amyloid beta-Protein; Astrocytes; Autopsy; Autoradiography; Behavioral; Benzodiazepine Receptor; Biological Markers; Brain; Brain region; Carboxy-Lyases; Cells; Cerebrum; Cessation of life; Chronic; Clinic; Confocal Microscopy; Corpus striatum structure; Cytoplasm; Dementia; Deposition; Disease; Disease Progression; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Down-Regulation; Female; Frozen Sections; Functional disorder; Gene Expression; Globus Pallidus; Goals; Grant; High Pressure Liquid Chromatography; Human; In Vitro; Inflammation; Injury; Interneurons; Lead; Lewy Bodies; Measurement; Measures; Messenger RNA; Microglia; Midbrain structure; Monitor; Monkeys; Motor; Motor Manifestations; Nerve Degeneration; Neurites; Neurons; North America; Nucleus Accumbens; Output; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Play; Population; Positioning Attribute; Positron-Emission Tomography; Procedures; Process; Proteins; Quantitative Autoradiography; Regulation; Reporting; Research; Role; Severities; Severity of illness; Staining method; Stains; Substantia nigra structure; Synapses; System; Thalamic structure; Time; Tracer; Treatment Efficacy; Tyrosine 3-Monooxygenase; Up-Regulation; Validation; Ventral Tegmental Area; Women' s Group; acetylcholine transporter; alpha synuclein; beta amyloid pathology; brain tissue; case control; cholinergic; density; dopamine D3 receptor; dopamine transporter; dopaminergic neuron; illness length; imaging biomarker; mRNA Expression; male; men' s group; microscopic imaging; mind control; neuroimaging; neuroinflammation; neuron loss; new therapeutic target; nigrostriatal pathway; novel; patient stratification; postsynaptic; postsynaptic neurons; presynaptic; presynaptic neurons; public health relevance; putamen; radioligand; radiotracer; receptor; synaptotagmin; synuclein; synucleinopathy; tau Proteins; therapeutic target; therapy development; transmission process; uptake; vesicular monoamine transporter

 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. A reliable imaging biomarker is urgently needed to monitor disease progression and therapy efficacy. Neuroimaging biomarkers have potential to provide unbiased measurements of PD progression, as indicated by loss of nigrostriatal dopaminergic neurons. We previously evaluated three different PET tracers for presynaptic markers of nigrostriatal neurons in MPTP-treated monkeys: [11C]DTBZ (a vesicular monoamine transporter type 2 [VMAT2] marker), [11C]CFT (a dopamine transport [DAT] marker) and [18F]FD (primarily reflects cerebral decarboxylase activity and storage) and demonstrated that striatal uptake of each of these linearly correlates with the number of nigrostriatal neurons but only when the loss of nigrostriatal neurons does not exceed 50%. In contrast, each of these tracers does linearly correlate with striatal dopamine as measured with high performance liquid chromatography. We recently found that direct PET measures of midbrain uptake of DTBZ or CFT does correlate with nigral cell loss. Yet, the relationship of changes in presynaptic neurons with other measures that affect function of this pathway remains unclear. We also recently reported that PD patients with amyloid-beta pathology in addition to cortical synucleinopathy have faster progression to death from either time of PD motor onset or time of dementia onset. This raises questions about whether those with amyloid-beta have different pathologic changes underlying this faster progression. In this R01, we will leverage human brain tissues collected previously, to determine the relationship between postsynaptic dopaminergic markers and related transmitter systems and the loss of nigrostriatal neurons. We propose to conduct quantitative autoradiography measures of the VMAT2, DAT, dopamine receptors (D1, D2, D3 and D4), cholinergic marker vesicular acetylcholine transporter (VAChT) and the peripheral benzodiazepine receptor (PBR) using pathologically well characterized control and PD brains (n=120, 15 each group for 8 groups, male and female cognitively healthy controls without or with amyloid-beta (tau negative), PD with only synuclein pathology and PD with synuclein plus amyloid-beta). Striatal (caudate, putamen and nucleus accumbens) and extra-striatal (substantia nigra, globus pallidus, thalamus and cortex) distribution of these biomarkers will be analyzed systematically to correlate with the PD disease duration and severity for both male and female groups. We then will determine which receptor and radioligand will have the best correlation with the dopaminergic neuron loss, dopamine loss or motor ratings. This study will provide a critical step for further validation of a neuroimaging biomarker of PD progression in clinic. The studies proposed in this grant have great potential on extending our understanding of the functional roles of dopamine receptor subtypes on dopamine transmission and PBR regulation in the PD. This will be the first comprehensive study using a large and pathologically well characterized population of PD and healthy control cases. We are in a unique position to conduct quantitative autoradiography of D2 and D2 receptors, neuroinflammation and evaluate the pre- and postsynaptic dopamine D2 and D3 receptors. This will be the first cross validation and valid comparisons with systematic measures of these biomarkers in the same subjects.

 描述(申请人提供)：帕金森病(PD)在北美影响着100多万人，目前还没有任何治疗方法被证明可以减缓病情的发展。迫切需要一种可靠的成像生物标记物来监测疾病进展和治疗效果。神经成像生物标志物有可能为帕金森病的进展提供无偏见的测量，如黑质纹状体多巴胺能神经元的丢失所表明的那样。我们先前评估了三种不同的PET示踪剂：[11C]DTBZ(泡状单胺转运体2型[VMAT2]标记物)，[11C]CFT(多巴胺转运[DAT]标记物)和[18F]Fd(主要反映大脑脱羧酶活性和储存)，并证明只有当黑质纹状体神经元的损失不超过50%时，纹状体对黑质纹状体神经元的摄取与黑质纹状体神经元的数量呈线性相关。相反，这些示踪剂中的每一种都与纹状体多巴胺呈线性相关，这一点通过高效液相色谱进行了测量。我们最近发现，直接对中脑摄取DTBZ或CFT的PET测量确实与黑质细胞丢失相关。然而，突触前神经元的变化与其他影响这一通路功能的指标之间的关系尚不清楚。我们最近还报道，除了皮质突触核病外，伴有淀粉样β蛋白病理的帕金森病患者无论是在帕金森病运动发作时间还是在痴呆发作时间都有更快的死亡进展。这引发了人们的疑问，即那些患有淀粉样β蛋白的人是否有不同的病理变化来支持这种更快的进展。在R01中，我们将利用之前收集的人脑组织，来确定突触后多巴胺能标记和相关递质系统与黑质纹状体神经元丢失之间的关系。我们建议对VMAT2、DAT、多巴胺受体(D_1、D_2、D_3和D_4)、胆碱能标记物囊泡乙酰胆碱转运体(VAChT)和外周苯二氮卓类受体(PBR)进行定量放射自显影。这些生物标志物的纹状体(尾状核、壳核和伏隔核)和纹状体外(黑质、苍白球、丘脑和皮质)的分布将被系统地分析，以与男性和女性组的帕金森病病程和严重程度相关。然后，我们将确定哪种受体和放射性配基与多巴胺能神经元丢失、多巴胺丢失或运动评级具有最好的相关性。这项研究将为进一步验证 帕金森病临床进展的神经影像生物标志物。这项资助中提出的研究对于扩大我们对多巴胺受体亚型在帕金森病中多巴胺传递和PBR调节中的功能作用的理解具有很大的潜力。这将是第一次使用大量的、病理特征良好的帕金森病患者和健康对照病例进行的全面研究。我们在进行D2和D2受体的定量放射自显影、神经炎症和评估突触前和突触后的多巴胺D2和D3受体方面具有独特的地位。这将是首次在同一受试者中对这些生物标记物进行交叉验证和与系统测量的有效比较。