Relationship between BOLD effects on DA degeneration

描述(申请人提供)：帕金森氏病(PD)的特征是黑质多巴胺神经元的丢失。然而，帕金森病的临床症状直到多巴胺神经元的丢失超过临界阈值时才会显现。因此，为了早期发现帕金森病，人们特别感兴趣的是使用客观、非侵入性、灵敏和经济有效的成像方法来补充现有的临床措施和对治疗的反应。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PD的成像生物标志物。最近，我们已经证明，用药物磁共振成像(PhMRI)测量的对多巴胺能刺激的血氧水平依赖(BOLD)反应与帕金森状态的特定组织学和行为特征有关。例如，d-苯丙胺诱发的激活与存活的多巴胺神经元的数量相关，而阿朴吗啡诱导的激活在运动损伤更严重的帕金森恒河猴中被观察到(见初步研究)。此外，阿朴吗啡诱导的多巴胺去神经支配的壳核的激活可通过神经恢复治疗(壳核内慢性注射GDNF)来减弱。因此，通过使用我们小组几年来开发的成像方案，我们现在提议在恒河猴群体中进行一项大规模的研究，这些群体是：1)正常动物，2)MPTP损害但无症状，3)MPTP损害但轻微的单侧症状，以及4)MPTP损害伴严重的单侧症状，以解决以下具体目的：1)BOLD-phMRI是否可用于监测疾病的进展，即确定BOLD效应是否与PD的严重程度相关，并与疾病的病理分期相关；2)BOLD-phMRI是否可用于评估L-多巴治疗等治疗的疗效。如果被证实可以预测多巴胺功能的变化，BOLD-phMRI未来可以被用作成像生物标记物，以补充现有的临床措施，并提供关于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、高重复性和高性价比的特点，这项技术可以用于普通人群的筛查，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.