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: 9210662
• 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/9210662
• 关键词: Affect; Affinity; Amyloid beta-Protein; Astrocytes; Autopsy; Autoradiography; Behavioral; Benzodiazepine Receptor; Biological Markers; Brain; Brain Diseases; Brain region; Carboxy-Lyases; Cells; Cerebrum; Cessation of life; Chronic; Clinic; Cognitive; Confocal Microscopy; Corpus striatum structure; Cytoplasm; Dementia; Deposition; Development; 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; motor disorder; neuroimaging marker; 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; 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（由申请人提供）：帕金森病 (PD) 影响着北美超过一百万人，目前迫切需要一种可靠的影像学生物标志物来监测疾病进展和治疗效果。正如黑质纹状体多巴胺能神经元的丧失所表明的，我们之前评估了三种不同的 PET 示踪剂，以检测黑质纹状体神经元的突触前标记。 MPTP 处理的猴子：[11C]DTBZ（2 型囊泡单胺转运蛋白 [VMAT2] 标记）、[11C]CFT（多巴胺转运 [DAT] 标记）和 [18F]FD（主要反映脑脱羧酶活性和储存）和研究表明，纹状体对这些物质的摄取与黑质纹状体神经元的数量呈线性相关，但前提是黑质纹状体神经元的损失与黑质纹状体神经元的数量无关。相比之下，通过高效液相色谱法测量，这些示踪剂中的每一种都与纹状体多巴胺呈线性相关，我们最近发现中脑摄取 DTBZ 或 CFT 的直接 PET 测量确实与黑质细胞损失相关。我们最近还报道，除了皮质突触核蛋白病外，患有淀粉样β蛋白病理的帕金森病患者的进展速度更快。从帕金森病运动发作时间或痴呆发作时间到死亡，这提出了一个问题：β-淀粉样蛋白是否具有导致这种更快进展的不同病理变化。我们建议对 VMAT2、DAT、多巴胺受体（D1、D2、D3 和）进行定量放射自显影测量。 D4)、胆碱能标记物囊泡乙酰胆碱转运蛋白 (VAChT) 和外周苯二氮卓受体 (PBR)，使用病理学上明确表征的对照和 PD 大脑（n=120，每组 15 个，共 8 组，男性和女性认知健康对照，无或有淀粉样蛋白- β（tau 阴性）、仅具有突触核蛋白病理学的 PD 和具有突触核蛋白加淀粉样蛋白-β 的 PD）。我们将系统地分析这些生物标志物（尾核、壳核和伏隔核）和纹状体外（黑质、苍白球、丘脑和皮质）的分布，以与男性和女性群体的 PD 疾病持续时间和严重程度相关。确定哪种受体和放射性配体与多巴胺能神经元损失、多巴胺损失或运动评级具有最佳相关性这项研究将为进一步验证提供关键的一步。 该资助中提出的研究对于扩展我们对多巴胺受体亚型对 PD 中多巴胺传递和 PBR 调节的功能作用的理解具有巨大的潜力。我们具有独特的优势，可以对 D2 和定量 D2 受体、神经炎症进行放射自显影，并评估突触前和突触后多巴胺 D2 和 D3。这将是对同一受试者中这些生物标志物的系统测量的首次交叉验证和有效比较。