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会表现出来。因此，对于PD的早期检测，使用客观、无创、敏感和经济的成像方法来补充现有的临床措施和对治疗的反应是特别有兴趣的。该项目的主要目标是确定BOLD-phMRI是否能够满足上述标准，作为帕金森病的成像生物标志物。最近,我们。通过药理学磁共振成像（phMRI）测量的多巴胺能刺激的血氧水平依赖性（BOLD）反应与帕金森状态的特定组织学和行为特征相关。例如，d-安非他明诱发的激活与存活的多巴胺神经元数量相关，在运动受损更严重的帕金森恒河猴中可以看到更强的阿吗啡诱导的激活（见初步研究）。此外，阿帕吗啡诱导的多巴胺去神经壳核的激活可以通过神经修复疗法（慢性突变内输注GDNF）减弱。因此，通过使用我们小组多年来开发的成像方案，我们现在提议在恒河猴群体中进行大规模研究：1)正常动物，2)mptp损伤但无症状，3)mptp损伤但轻度单侧症状，4)mptp损伤伴严重单侧症状，以解决以下具体目标：1) BOLD- phmri是否可以用于监测疾病的进展，即确定BOLD效果是否与行为评估的PD特征的严重程度以及疾病的病理分期相关；2) BOLD-phMRI是否可以用于评估对治疗的反应，如左旋多巴治疗。如果证实可以预测多巴胺功能的变化，BOLD-phMRI可以在未来作为一种成像生物标志物来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的无创、高灵敏度、高重复性和成本效益的特点，该技术可用于筛查普通人群，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.