Relationship between BOLD effects on DA degeneration

描述（由申请人提供）：帕金森病（PD）的标志是黑质中多巴胺神经元的丢失。然而，PD的临床症状直到多巴胺神经元的损失超过临界阈值才表现出来。因此，对于PD的早期检测，特别感兴趣的是使用客观、无创、灵敏且具有成本效益的成像方法来补充现有的临床措施和对治疗的反应。本项目的主要目标是确定BOLD-phMRI是否可以满足上述标准作为PD的成像生物标志物。最近，我们已经证明，通过药理学MRI（phMRI）测量的对多巴胺能刺激的血氧水平依赖性（BOLD）反应与帕金森病状态的特定组织学和行为学特征相关。例如，d-安非他明诱发的激活与存活的多巴胺神经元的数量相关，在运动受损更严重的帕金森病恒河猴中观察到更强的阿扑吗啡诱导的激活（见初步研究）。此外，阿扑吗啡诱导的多巴胺失神经的壳核的激活被神经恢复疗法（GDNF的慢性壳核内输注）减弱。因此，通过使用我们小组几年来开发的成像方案，我们现在提出在恒河猴组中进行大规模研究，这些恒河猴是：1）正常动物，2）MPTP损伤但无症状，3）MPTP损伤但轻度，单侧症状和4）MPTP损伤伴严重单侧症状，以解决以下特定目标：1）BOLD-phMRI是否可用于监测疾病的进展，即确定BOLD效应是否与经口腔评估的PD特征的严重程度以及疾病的病理学阶段相关;以及2）BOLD-phMRI是否可用于评估对治疗（如左旋多巴治疗）的反应。如果证明预测多巴胺功能的变化，BOLD-phMRI可以在未来用作成像生物标志物，以补充现有的临床措施，并提供有关疾病过程或干预的有价值的信息。此外，由于BOLD-phMRI的非侵入性，高灵敏度，高重现性和成本效益的特点，该技术可用于筛选一般人群，以研究疾病的发病机制。

DESCRIPTION (provided by applicant): The hallmark of Parkinson's disease (PD) is the loss of dopamine neurons in the substantia nigra. However, clinical symptoms of PD do not manifest until the loss of dopamine neurons exceeds a critical threshold. Thus, for the early detection of PD, there is particular interest in using an objective, noninvasive, sensitive and cost-effective imaging method to supplement existing clincal measures and response to treatments. The primary goal of this project is to determine whether BOLD-phMRI can meet these aforementioned criteria as an imaging biomarker of PD. Recently, we.have demonstrated that the blood oxygenation level dependent (BOLD) response to dopaminergic stimulation as measured by pharmacological MRI (phMRI) correlated with specific histological and behavioral features of the parkinsonian state. For example, d-amphetamine-evoked activations correlated with the number of surviving dopamine neurons, and stronger apomorphine-induced activations were seen in more severely motor impaired parkinsonian rhesus macaques (see preliminary studies). In addtion, apomorphine-induced activations in the dopamine denervated putamen were attenuated by a neurorestorative therapy (chronic intraputamenal infusion of GDNF). Therefore, by using the imaging proctocol developed by our group over several years, we are now proposing a large scale study in groups of rhesus monkeys that are: 1) normal animals, 2) MPTP-lesioned but asymptomatic, 3) MPTP-lesioned but mild, unilateral symptoms and 4) MPTP-lesioned with severe unilateral symptoms in order to address the following specific aims: 1) whether BOLD-phMRI can be used to monitor the progression of the disease, namely to determine if the BOLD effects will correlate with severity of PD features assessed behaivorally and also with pathological stages of the disease; and 2) whether BOLD-phMRI can be used to assess responses to therapy, such as L-dopa treatment. If proven predictive of changes in dopamine functions, BOLD-phMRI could be used in the future as an imaging biomarker to supplement existing clinical measures and to provide valuable information about the disease process or intervention. In addition, because of the noninvasive, highly sensitive, highly reproducible and cost-effective features of BOLD-phMRI, this technique may be used to screen the general population to investigate pathogenesis of the disease.