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Logo of the University of PittsburghMorris K. Udall Parkinson's Disease Research Center of Excellence
at the University of Pittsburgh
in Collaboration with Wake Forest School of Medicine, and University of Texas Austin

Our research regarding the behavioral and neurobiological effects of loss of central dopamine (DA) neurons has been ongoing since 1971. At present, our Center's research focuses on four sets of issues: (1) How can we detect PD in its earliest stages, (2) what are the biological bases for the extended preclinical period of Parkinson's disease (PD), (3) what is the mechanism by which forced exercise produces neuroprotective effects, and do the effects continue with age, and (4) can trophic factor expression be increased by pharmacological and/or hormonal manipulations? We also have an ongoing postdoctoral training program in neurodegenerative disease (Program Director, Michael J. Zigmond), and are part of both the National Parkinson Foundation Center of Excellence in Parkinson's disease at the University of Pittsburgh (Co-directors, Michael J. Zigmond and Robert Y. Moore) and the Pittsburgh Institute for Neurodegenerative Disease (Director, J. Timothy Greenamyre).

Project 1: Exercise and neuroprotection in models of PD (PI: Michael J. Zigmond; Co-PIs, Amanda D. Smith Timothy Schallert, Karoly Mirnics)

This project focuses on strategies for inducing endogenous neuroprotective mechanisms in animal models of PD. The work derives from recent evidence from our labs indicating that the contralateral motor neglect normally following unilateral damage to the nigrostriatal DA projection can be prevented by forced use of the contralateral limb. Moreover, we find that this behavioral sparing is accompanied by a significant reduction in the loss of DA. We hypothesize that forced execution of a motor act that is otherwise compromised by injury is neuroprotective, and that this results from an interaction between the motor act, injury, and concomitant increase in the availability of one or more trophic factors (e.g., GDNF) and hormones (e.g., estrogen). Our project utilizes 6-hydroxydopamine (6-OHDA)-treated rodent models of PD. At present we are focusing on several objectives: (1) We are determining the impact of forced use/disuse on the state of DA neurons, including the use of microPET, microdialysis, and immunohistochemistry. Our results to date suggest that prior use of a limb reduces the vulnerability of DA neurons to 6-OHDA. (2) We are establishing a mouse model of exercise-induced neuroprotection against ROS. At the same time we are establishing colonies of mice deficient in the genes for GDNF or GFRα1 to examine the impact of these abnormalities on the response to 6-OHDA, exercise, and GDNF. We also will use the mouse models to continue our microarray studies. (3) As an additional strategy to determine the relationship between use-dependent neuroprotection and increased GDNF factor expression, we are using blocking antibodies to GDNF. Other strategies will follow. (4) We are expanding our examination of trophic factors to determine exercise-induced changes in other factors, including BDNF, FGF, and IGF. (5) We also are expanding our examination of neuroprotection by looking at the effects of exercise on the response of the DA projections to the nucleus accumbens and frontal cortex. And with support from the Department of Defense, we are looking at other forms of exercise, including the use of treadmill, running wheels, and a rotorod. (5) Finally, we are examining the signaling cascades that underlie the neuroprotective effects of exercise using both in vivo and in vitro models. The in vivo studies are supported by a grant from the Michael J. Fox Foundation to Amanda D. Smith.

Project 2: Neural correlates of exercise therapy in a model of PD (PI: Donald J. Woodward, Co-PIs, Kristin A. Anstrom, Jing-Yu Chang)

The goal of this project is to characterize the neurophysiological changes induced by 6-OHDA during the recovery of function in awake behaving rat. Preliminary studies have shown that depletion of DA results in an elevation of resting firing rates of neurons in the neostriatum. This effect is seen on both the depleted and the "normal" sides of the striatum after a unilateral lesion. Activation of rotation activates reciprocal changes in neighboring neurons on both sides with no net changes in mean rates, thus indicating the presence of an effective synaptic input to both intact and DA depleted striatum. An interpretation is that absence of DA induces a motor dysfunction directly on the affected side. This in turn activates a widespread motor recovery adaptive mechanism that engages both sides of the cortical striatal nigral thalamic system. As noted above, forced use of a limb results in neuroprotection against 6-OHDA, and this raises the possibility that the widespread bilateral elevation of activity may play a neuroprotective as well as a compensatory role. An aim of this project is to record activity of populations of neurons recorded simultaneously from 64 microwires implanted bilaterally in striatum, substantia nigra reticulata/compacta, and forelimb sensorimotor cortex. These advanced recording procedures developed in this laboratory will determine activity of populations over the two weeks after 6-OHDA administration. Casting to restrict limb use will be done on both the DA depleted and intact side to compare effects of restriction of movement and to determine the neural signals during movements during tests of motor impairment. Casting will be done prior to 6-OHDA to test whether elevation of activity appears during the early period of motor reorganization and may serve to activate neuroprotection. Recordings made from dopamine neurons will test the emerging concept of a role in motor learning and reorganization. A prediction is that the novel movement patterns during forced use will produce many signals in striatum and cortex correlated with movement that are not present in over-trained circuits.

Project 3:PET, posturographic and clinical markers of early PD (PI: Nico I. Bohnen; Co-PI, Robert Y. Moore)

As neuroprotective strategies are developed for PD, it will probably be important to apply the therapies as early as possible and even before the clinical diagnosis of PD. Therefore, proper identification of patients in the earliest stages of the disease is a priority. The key to effective secondary prevention trials is identifying valid and reliable biomarkers that confidently reflect the preclinical trait of PD. Measures of DA nerve terminal integrity with PET have allowed preclinical disease to be detected in relatives of patients with PD. As screening the whole population for preclinical PD using PET is not cost-effective, there is a clear need for screening methods to identify subjects who are at a high risk for this disease. A biomarker, to be useful in screening large populations to identify very early disease, should be inexpensive, easily administered, and sufficiently sensitive and specific to avoid unacceptable false negatives or positives. Since a single test may not have sufficient specificity or sensitivity to detect very early disease, a multitiered approach may be required. In such a scheme, a battery of tests that is easily administered, inexpensive and sensitive (although not highly specific) would represent the first screening tier to select at-risk individuals who then undergo increasingly more sophisticated tests of higher specificity. As a number of motor and non-motor manifestations of the disease emerge months to years before a diagnosis can be made, a battery of clinicometric tests might be able to identify individuals at a subclinical stage of PD. The overarching goal of this project is to propose a multitiered approach to the diagnosis of preclinical or prodromal PD using risk factor-based subject recruitment (family history), postural motor system, and formalized clinicometric PD test battery screening to identify minimally symptomatic subjects. Dopaminergic (11C-b-CFT) brain PET imaging will be used as the gold standard for the diagnosis of very early PD in subjects with abnormal screening results. We will validate the different components of the clinicometric and posturographic test battery as possible biomarkers by defining their in vivo dopaminergic PET correlations in patients with PD (symptom → PET). As normal aging is also associated with dopaminergic neuronal loss (but in a different striatal pattern), we will more clearly define the clinical specificity of abnormal screening results by comparing the clinical profile associated with a PET-based topographic pattern of PD to that of age-associated striatal dopaminergic denervation (PET → symptom).

Training Program in Neurodegenerative Disease. We have had NIH-supported training grants in neuroscience at the University of Pittsburgh since 1984 and a separate NINDS postdoctoral training grant in basic neuroscience as it relates to neurodegenerative disease since 1996. The program is closely integrated with this Program Project as well as with other key research programs related to Parkinson's disease, Alzheimer's disease, ALS, and stroke. Additional programs in psychiatric disorders and in neuro-AIDS further enhance the training environment. A renewal application for the training grant is currently under review. The grant permits us to maintain the critical mass needed to recruit the best possible postdoctoral trainees, including underrepresented minority trainees, and to offer a training program of the highest quality. All trainees participate in three activities that supplement their research experience: (1) Two seminars on the neurobiology of clinical disorders, (2) a monthly research discussion, and (3) a series of professional development workshops. Issues of professional development and responsible conduct are integrated into the entire program with assistance from our university-wide program in Survival Skills and Ethics. Trainees also participate in courses as needed and have opportunities to teach and to observe clinical practice. The 39 members of the training faculty are members of the university-wide program in neuroscience with a particular interest in neurodegenerative disorders and stroke. At present our training faculty supervises more than 90 postdoctoral trainees (in addition to a large number of predoctoral students).

Pittsburgh Institute for Neurodegenerative Diseases. The National Parkinson Foundation has named the University of Pittsburgh a Center of Excellence with Drs. Robert Moore and Michael Zigmond serving as the co-directors. In 1999, the Pittsburgh Institute for Neurodegenerative Diseases (PIND) was developed with funding from private foundations and the University of Pittsburgh Medical Center (UPMC). J. Timothy Greenamyre became the director of PIND in November 2004. In 2005, PIND will occupy 25,000 sq. ft. of new research space in a biomedical science building now under construction. The facility will be physically connected to UPMC facilities that will house the major outpatient clinics for neurodegenerative disease and stroke. It will provide state-of-the art facilities for basic research in a building that will also house a number of other units of relevance to our work, including some of the laboratories of the Center for the Neural Basis of Cognition and the Center for Drug Development, 36,000 sq. ft. of animal space for housing and testing, a transgenic mouse core, and an imaging core with 3T, 7T, and 9.4T magnets. Approximately 15 members of PIND drawn from a variety of departments on campus will be housed in this space. In designing the facilities of PIND, every effort is being made to maximize interactions. For example, most of the individual research space within the PIND facility will be designed as open labs. In 2000, PIND helped to establish a new organization directed to the lay community. Named "Support Programs in Neurodegenerative Diseases and Stroke (SPINS)," this organization serves as a coordinating committee of representatives of voluntary health organizations and health providers serving patients and caregivers. SPINS holds an annual 1-day educational fair for the public that provides information on neurodegenerative disease and stroke. PIND also has close ties to the Greater Pittsburgh Parkinson Chapter.

Contact Information or Udall Center Link:
Director: Michael J. Zigmond, Ph.D.

Last updated February 09, 2005