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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050242-03
Application #
7560359
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Sieber, Beth-Anne
Project Start
2007-02-16
Project End
2012-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
3
Fiscal Year
2009
Total Cost
$320,469
Indirect Cost
Name
University of Kentucky
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Zhang, Rui; Andersen, Anders H; Hardy, Peter A et al. (2018) Objectively measuring effects of electro-acupuncture in parkinsonian rhesus monkeys. Brain Res 1678:12-19
Andersen, Anders H; Hardy, Peter A; Forman, Eric et al. (2015) Pharmacologic MRI (phMRI) as a tool to differentiate Parkinson's disease-related from age-related changes in basal ganglia function. Neurobiol Aging 36:1174-82
Fan, X T; Zhao, F; Ai, Y et al. (2014) Cortical glutamate levels decrease in a non-human primate model of dopamine deficiency. Brain Res 1552:34-40
Zhao, Feng; Fan, Xiaotong; Grondin, Richard et al. (2010) Improved methods for electroacupuncture and electromyographic recordings in normal and parkinsonian rhesus monkeys. J Neurosci Methods 192:199-206
Stephens, Michelle L; Pomerleau, Francois; Huettl, Peter et al. (2010) Real-time glutamate measurements in the putamen of awake rhesus monkeys using an enzyme-based human microelectrode array prototype. J Neurosci Methods 185:264-72
Ding, Feng; Luan, Liming; Ai, Yi et al. (2008) Development of a stable, early stage unilateral model of Parkinson's disease in middle-aged rhesus monkeys. Exp Neurol 212:431-9
Xin, Tao; Ai, Yi; Gerhardt, Greg et al. (2008) Globus pallidus plays a critical role in neurotrophic factor induced functional improvements in hemiparkinsonian monkeys. Biochem Biophys Res Commun 370:434-9
Luan, Liming; Ding, Feng; Ai, Yi et al. (2008) Pharmacological MRI (phMRI) monitoring of treatment in hemiparkinsonian rhesus monkeys. Cell Transplant 17:417-25