Grants & Funding Archive

2011 Grants

Team Parkinson is using its distribution to fund the following:

Project Title:  Identifying Neural and Behavioral Risk Factors for Impulsive-Compulsive Disorders in Parkinson’s Disease

Investigator:  Susan Bookheimer, Ph.D., UCLA Medical School

Background:  A significant minority of patients with Parkinson’s Disease (PD) treated with dopamine agonists experience significant behavior changes including gambling, shopping and sexual addictions, and other impulsive-compulsive disorders, (ICDs), that can result in serious consequences to relationships, financial health and quality of life. This study proposes to use functional brain imaging and neurocognitive testing to identify risk factors that predict which individuals are more likely to develop these side effects, and to understand underlying brain mechanisms.

Objective:  While several studies have identified characteristics that co-occur with ICDs none have examined factors that predict response, nor have current studies examined characteristics that differentiate these patients after removal of agonist therapy and return to behavioral baseline. This study proposes collecting pilot data to fill this knowledge gap in preparation for a future, larger scale predictive study.

We propose a pilot study to use functional MRI in patients with Parkinson's disease with a history of ICD’s after taking dopamine agonists whose behavior improved after a medication shift, and in PD patients about to begin agonist therapy. Using paradigms that examine reward responsiveness, avoidance learning, and cognitive control, we will evaluate each individual's unique brain response to reward based decision making. Subjects will also receive neuropsychological evaluations that include measures of cognitive control, decision making, impulsivity, and will evaluate for signs of addiction, gambling risk, and behavioral disorders. The goal is to identify unique patterns of brain and cognitive performance that are associated with ICDs in comparison with those without ICDs, by recruiting  patients with a history of ICDs and  control subjects prior to agonist therapy.

Methods/Design:  We propose to recruit 25 Subjects with Parkinson’s Disease  through the UCLA Dept. Of Neurology Movement Disorders Program. We will target two groups of patients: the ICD group will be 12 patients identified by Dr. Bronstein as having had ICDs in response to agonist therapy, and were subsequently switched to L-dopa therapy with symptom resolution. A second group of patients will be matched for age, disease duration and gender, but will be agonist naïve and ready to initiate agonist therapy. Thus, both groups of patients will be taking the same class of medications at the time of study, and neither group will have current ICDs. This allows us to have a well-matched sample where the primary factor differentiating groups is whether the subjects have a known propensity for developing impulsive-compulsive behaviors. Subjects will participate in 2 sessions; The first session will test for behavioral and cognitive characteristics associated with ICD; in the second patients will undergo functional MRI.

Relevance to Parkinson’s disease:  The data generated will give us a framework for designing a more comprehensive longitudinal study to predict ICD risk in PD patients. Results of this study may help to prevent these problems and suggest alternative treatments in those at risk. In addition, the knowledge we will gain about the neural mechanisms for ICDs to identify at-risk patients, to evaluate prevention strategies and ultimately, to identify avenues for new pharmacological interventions.

Project Title:  Mechanisms of Pesticide Toxicity and their Role in Parkinson’s Disease

Grant Awarded to:  Jeff Bronstein, MD, Ph.D and Marie-Francoise Chesselet, MD, Ph.D

Background:  We have made significant progress in finding the causes of Parkinson’s disease (PD).  Extensive genetic studies has revealed that a small number of patients have a strong genetic risk (approximately 5%) but for the majority of people with PD, genetic influences appear to contribute only a small portion of the risk.   It is likely that environmental toxins and interactions between genes and the environment play the major role in causing PD.

Objective/Methods:  Pesticide exposure has been suspected for several years to increase the risk of developing PD but only recently have we and others confirmed this association using objective measures.  Importantly, we have identified a number of specific pesticides that increase the risk of PD.   Our labs have been determining the mechanisms of pesticide toxicity.  We have found that many pesticides inhibit 2 important processes believed to be involved in the pathogenesis of PD; proteasome and aldehyde dehydrogenase (ALDH) activity.  The assays used to measure these activities require a piece of equipment (a multilabel plate reader) that can measure fluorescence and absorbance in a multiwell format.  The plate reader we had been using to determine pesticide affects on proteasome and ALDH activity is old and recently broke, and we propose to use funds from the Parkinson Alliance/Team Parkinson to purchase a new one.  It will be used by both of our labs to complete our screen for proteasome and ALDH inhibitors and determine their effects in cellular and animal models.

Relevance to Parkinson’s disease:
  Data from these studies will help determine how environmental toxins cause PD, which is an essential step towards risk factor reduction (i.e. disease prevention) and targeting new therapies to stop disease progression.

Project Title: Understanding the role of the Frontal Cortex in Gait and Balance impairment in PD

Investigators/Authors: Beth Fisher PhD, PT; Ya-Yun Lee, MS, PT, Giselle M. Petzinger, MD, University of Southern California

Objective: To determine the role of the frontal cortex as a critical circuit involved in motor and cognitive problems in individuals with Parkinson’s Disease.  

Background: The basal ganglia and the frontal cortex are important brain circuits responsible for key cognitive functions including the learning and maintenance of new motor skills. Evidence now exists that the loss of dopamine in PD leads to changes in frontal cortex circuitry to the basal ganglia resulting in motor difficulties including walking and balance.  As a consequence of this degenerative circuit is that the learned motor skill, such as gait and balance, may only be performed accurately when the same environmental cues are present, but not when new environmental cues are delivered.  For example, an individual with PD might demonstrate skillful ability to walk in the physical therapy clinic where they are practicing walking but then demonstrate difficulty with the same task when performed in an unfamiliar environment or outside of the clinic such as in a crowded shopping center or when their attention is drawn to other aspects of the environment. This dysfunction has been referred to as context-dependent motor learning. Progression of disease can lead to dramatic deficits in this circuitry such that patients experience severe and debilitating freezing of movement. We have observed abnormal over-activation of a region of the frontal cortex, called the dorsolateral prefrontal cortex (DLPFC). If this over-activation of the frontal cortex could be reversed then the consequences of this abnormal circuitry could represent a novel treatment for motor deficits in PD. Therefore, the purpose of this study is to test whether decreasing the activity of the DLPFC using the non-invasive technology of repetitive Transcranial Magnetic Stimulation ( rTMS) in individuals with PD would improve motor learning and function.

Methods/Design: We have developed a computer based task-specific paradigm that enables us to detect context-dependent motor learning in PD. We will use rTMS to temporarily suppress the cortical excitability of the DLPFC in people with PD. rTMS is a non-invasive technique that is able to directly stimulate regions of the brain such that they can be activated or suppressed. MRI is used to accurately locate the DLPFC in our subjects. By applying rTMS in individuals with PD, we will be able to determine whether context-dependent motor learning in PD is due to an over-activation of the DLPFC. We expect that decreasing the excitability of the DLPFC in PD, will results in a decrease in context-dependency learning in PD implicating the importance of this cortical brain region in PD symptomology.

Relevance to Parkinson’s disease: Ongoing studies in our lab examining features of abnormal cortical processing in individuals with PD has shown that there are severe deficits in learning especially in a specific type of learning termed context-dependent learning. This deficit may account for decline in gait, loss of balance, and eventually motor freezing especially when changing directions, starting and stopping, or entering new environments. Surprisingly, we have shown a deficit in this critical feature of motor control in patients at all stages of disease, and importantly, most patients are completely unaware that they have any kind of deficit. Therefore, these studies are critical because they will reveal to us important circuits within the brain that are responsible for some of the most difficult to treat clinical features of PD for which dopamine replacement therapy fails to combat. In addition, our findings will begin to identify critical regions of the brain that should be targeted for therapeutic treatment. We will be able to optimize treatments, both pharmacological and physical therapy based, to re-train the brain such that the learning of motor skills and preservation of motor memory can occur. For optimal treatment of the individual with PD, it is essential for clinicians to find training strategies that will maximize the ability to perform motor activities at a high level of skill regardless of the environment. It is our hope that such treatments will protect circuits within the brain that are lost as disease progresses and may in fact reverse potentially debilitating features of PD.

Project Title: Enhancing Repair in the Parkinsonian Brain

Investigators/Authors: Giselle M. Petzinger, MD; Michael W. Jakowec, PhD; Beth E. Fisher, PT/PhD, University of Southern California

Objective: To determine if combination therapy of intensive exercise and neurotrophic drugs can enhance brain repair in PD.

Background: Studies form our labs have shown that exercise in the form of intensive treadmill running leads to marked improvement in the connection and function between neurons of the basal ganglia responsible for normal movement. Specifically we observe an increase in the number of connections within the basal ganglia of parkinsonian (MPTP) mice after exercise and an improvement in the communication and function of these connections. We believe that it is the enhanced connection and function of neurons within the basal ganglia that are important in helping the repair processes needed to improve mobility and quality of life in PD.  We hypothesize that one reason these connections are formed and their communication improves after exercise is through the synthesis of new proteins or building blocks of the brain that (i) help stabilize connections and (ii) help improve the signaling between these connections.  Protein synthesis can often be enhanced through neurotrophic related compounds or drugs that help the cell function better.   We hypothesize that combining exercise with a neurotrophic related compound will enhance brain recovery by facilitating the synthesis of proteins important in making connections and establishing signaling.   

Methods/Design: For these studies, we will use a drug developed here at USC called ICG-001 that activates biochemical pathways that promote cell signaling and connections.  ICG-001 will be delivered by mini-pumps into the brain of mice 5 days after they have been made parkinsonian through exposure to the dopamine-depleting drug MPTP. A group of mice will undergo treadmill running and will be compared with mice that receive drug but are sedentary and other mice that receive neither drug nor exercise. At the completion of the exercise all mice will be examined for the number of brain connections  and the signaling of their connections (using electrophysiological techniques).

Relevance to Parkinson’s disease: Our studies support the role of exercise in promoting repair processes in PD.  These processes include enhancing the connections between neurons within the basal ganglia, that are known to be impaired or lost in PD.  We believe that results gained from this study can be translated into clinical studies in Parkinson’s disease that are focused on combining both exercise and neurotrophic related compounds that can be used to enhance brain function through facilitating the basal ganglia circuitry and its function.

Project Title:  Developing screening procedures for pre-motor Parkinson’s disease

Investigators/Authors:  J. William Langston, Parkinson’s Institute, Sunnyvale, CA

Objective:  There is a major effort in the medical and scientific community to find ways to identify pre-motor PD.  This will be particularly important to allow us to maximize the possibilities for success in clinical trials aimed at disease modification, as it would allow us to initiate such trials much earlier at a time when there is much less damage to the nervous system and there may be a much greater probability of success.  Therefore, the goal of this work is to identify tools that can be used to screen for PD in the general population well before the potentially disabling motor or cognitive changes develop.  If successful, this work could change the paradigm of diagnosis and treatment of PD.

There is now abundance evidence that a substantial number of non-motor symptoms can precede the motor symptoms of PD, sometimes for more than a decade or more.  This is increasingly referred to as pre-motor PD, and includes such symptoms and physical signs as loss of sense of smell, constipation, agitated and even violent dream-enacting behavior during sleep (known as REM-sleep behavior disorder or RBD), anxiety, depression, subtle changes in color vision, and a loss of normal heart rate variability.  We now have very strong preliminary evidence that heart rate variability is decrease in pre-motor PD because the nerve fibers that are responsible normal variation in heart rate are lost in PD.  

Methods/Design:  In this study we will periodically examine individuals with signs of pre-motor PD (e.g. RBD or severe loss of smell) to see if decreased heart rate variability  as measured by a simple EKG can identify individuals (1) with abnormal brain scans that suggest pre-motor PD and/or (2) who go on to actually develop PD.  

Relevance to Parkinson’s disease:
  The short term goal of this research is to develop screening tools to identify pre-motor PD.  If this can be accomplished, then populations of patients with pre-motor PD can participate in clinical trials aimed at disease modification at the earliest possible time in the course of their disease.  Our long term goal is to develop a test battery for pre-motor PD that could be carried out in primary care physician’s office as part of an annual physical examination in all individuals over the age of 50 years – this would allow for annual screening of the general population when they are at increasing risk for PD.  For example, data from a routine annual EKG to determine heart rate variability, and a simple scratch and sniff test for smell, could easily be incorporated into an annual physical examination and provide clues to pre-motor PD.  Once such a screening battery has been developed and validated, patients with high risk can then be referred for more sophisticated imaging procedures and a full neurological evaluation.  If and when current or future trials aimed at disease modification are successful, early intervention could lead to secondary disease prevention.

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