Relationship between BOLD Effects and DA Degeneration

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-Iesioned but asymptomatic, 3) MPTP-Iesioned but mild, unilateral symptoms and 4) MPTP-Iesioned 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.