1. American Parkinson Disease Association is using its distribution to fund:

Project Title: Parkin, DJ-1, and Glutathione Peroxidase-Deficient Mouse Models of PD

Investigator: Matthew S. Goldberg, PhD

Objective: To test whether Parkin-DJ-1 dKO mice on a Gpx1-/- background results in a progressive PD animal model.

Background: One of the greatest obstacles to testing more effective treatments for Parkinson’s disease (PD) is the lack of adequate animal models with age-dependent specific nigral cell loss that mirrors the progressive neurodegeneration in PD.

Methods/Design: To obtain these vitally needed animal models, the investigator proposes to analyze mice bearing mutations in Parkin and DJ-1 combined with mice deficient for the major antioxidant protein, glutathione peroxidase. The rationale is that cumulative oxidative damage is a likely cause of idiopathic PD and oxidative damage to Parkin and DJ-1 proteins are observed in idiopathic PD brains.

Revelance to Parkinson’s disease: Development of a reliable laboratory animal model for the
evaluation of effective treatments for Parkinson’s disease.

Project Title: Bilateral Clinical and Neurophysiological Effects of Unilateral STN DBS in PD

Investigator: Harrison Walker, MD

Objectives: (1.) Measure bilateral changes in cortical neuronal activity in response to unilateral STN DBS with magnetoencephalography (MEG) at rest. (2.) Evaluate the intraoperative effects of unilateral STN DBS on contralateral subthalamic activity, and correlate with clinical outcomes and MEG recordings from Aim 1.

Background: Bilateral improvement in the cardinal symptoms of Parkinson Disease (PD) following unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been observed, yet the mechanism of this effect has not been established.

Methods/Design: Subjects in this study will arrive in the laboratory in the “practically defined off” medication state. Baseline MEG recordings of cortical activity at rest will be obtained for 10 minutes with the stimulator deactivated, during 10 minutes of stimulation, and immediately following deactivation of unilateral STN DBS, not informing the subjects regarding whether the stimulator is on or off.

Revelance to Parkinson’s disease: Patients with progressive symptoms of PD who return for
contralateral STN DBS offer a unique opportunity to examine the mechanism of bilateral clinical
benefit following unilateral brain stimulation.

Project Title: Redox Regulation of NMDA Currents in Midbrain Dopamine Neurons

Investigator: Steven W. Johnson, MD, PhD

Objective: To characterize physiological mechanisms and identify second messenger systems that underlie potentiation of NMDA currents by MPP+ in substantia nigra dopamine neurons.

Backgound: Classic symptoms of Parkinson’s disease are caused by progressive loss of dopamine containing neurons in the substantia nigra pars compacta. Many studies suggest that dopamine neurons are injured by increased amounts of reactive oxygen species (ROS) that are generated by defective complex I activity in mitochondria.

Methods/Design: Preliminary data show that perfusing rat brain slices with the dopamine neurotoxin 1-methyl-4-phenylpyridinium significantly increases currents generated by NMDA receptor stimulation in dopamine cells. Moreover, this ability to potentiate NMDA currents is mimicked by hydrogen peroxide.

Revelance to Parkison’s disease: The proposed research may help define oxidative mechanisms that increase the risk of Parkinson’s disease.

Project Title: Identification of PINK1 Substrates Using Conditional PINK1 Knockout Cells and Quantitative Phosphoproteomics

Investigator: H. Bueler, PhD

Objective: Mutations in the PARK6 (PINK1) gene cause early-onset recessive Parkinson’s disease (PD). PINK1 is a mitochondrial serine/threonine kinase, whose deficiency leads to mitochondrial abnormalities and dopamine neuron and muscle degeneration in flies. PINK1 is believed to phosphorylate specific proteins (substrates) that are necessary to maintain mitochondrial homeostasis and to protect cells against endogenous and exogenous stress.

Background: The investigator hypothesizes that abolishing cellular PINK1 kinase activity will result in decreased or absent phosphorylation of PINK1 substrates.

Experimental Design: To test the hypothesis that abolishing PINK1 kinase activity will result in altered or absent phosphorylation of PINK1 substrates, the scientist will compare the levels of mitochondrial and cytoplasmic phosphoproteins using quantitative mass spectrometry before and after Cre recombinase-mediated PINK1 gene inactivation in mouse ES cells harboring a homozygous conditionally targeted PINK1 gene.

Revelance to Parkinson’s disease: Uncovering new PINK1 substrates will increase our understanding of the molecular mechanisms underlying dopamine neuron death and may reveal new targets for PD therapy.

2. National Parkinson Foundation is using its distribution to fund the following:

Project Title: Behavioral and Neural Deficits of Reversal Learning as a Model for Impulse Control Disorders in Patients with Parkinson’s Disease

Grant awarded to: Tanya Simuni, MD, Northwestern Parkinson’s Disease and Movement Disorders Center, Chicago, IL

Project Description: Parkinson’s disease (PD) is associated with a high prevalence of impulse control disorders (ICDs). Recent data suggest that PD patients are impaired on tasks of reversal learning, in which they need to inhibit (“reverse”) learned response tendencies. We have hypothesized that PD patients with ICD have further functional disruptions and subtle structural changes in meso-cortico-limbic brain circuits associated with reversal learning mechanisms.

Extensive behavioral, physiologic and functional MRI data on PD patients with and without an ICD performing a reversal learning task were obtained in year 1 of this grant. Year 2 of the grant will focus on completing subject recruitment and analyzing the extensive dataset as detailed in the initial grant application. In addition, we propose new high-dimensional anatomic analyses of the structural MRI data. The anatomical analyses will allow us to evaluate for subtle structural changes in meso-cortico-limbic brain circuits. Results from the proposed studies will lead to a better understanding of the functional and structural neural underpinnings of ICDs in PD.


Project Title: Calcium Channel Blockers, Anti-Inflammatories, Statins and the Risk of PD Progression

Grant awarded to: Andrew Siderowf, MD, MSCE, University of Pennsylvania Parkinson's Disease and Movement Disorders Center, Philadelphia, PA

Project Description: Do widely available medications have the potential to be neuroprotective treatments for Parkinson’s disease (PD) Calcium channel antagonists, anti-inflammatory medications, and HMG-CoA reductase inhibitors (statins) all have properties which address mechanisms of cell injury in PD. The over-arching hypothesis of this proposal is that these commonly prescribed medications do have the potential to be protective treatments for PD. To address this important question, we will conduct a patient-level meta-analysis using data from 5 existing Parkinson Study Group (PSG) clinical trials databases: PRECEPT, TEMPO, CALM-PD, QE-2 and ELLDOPA. Teva Pharmaceuticals has also permitted access to long-term extension data from the TEMPO study. Collectively, these trial databases contain 1952 individual patients and over 4,000 person-years of observation. There is detailed information on concomitant medication use and careful measurements of symptom severity assessed over multiple time-points. Using a combined dataset constructed from these trials, we will examine the relationship between current exposure to 4 classes of commonly prescribed medications: 1) calcium channel blockers; 2) non-steroidal anti-inflammatory medications; 3) cyclo-oxygenase type-2 (COX-2) inhibitors and 4) HMG-CoA reductase inhibitors (statins) and progression of a range of motor and non-motor features of PD. The advantages of the proposed study are: 1) that it provides adequate power to detect differences in disease progression even if the proportion of subjects using a given medication is relatively low, 2) includes only well-characterized patients who are likely to be correctly diagnosed in the vast majority of cases, 3) makes use of detailed and quantified information on medication use and high-quality assessments of disease progression within each trial. This study will provide clinically relevant information about these commonly prescribed medications as disease-modifying agents for PD, and could lead to subsequent randomized clinical trials.


Project Title: Inflammation and Parkinson’s Disease: The Honolulu-Asia Aging Study (HAAS)

Grant awarded to: Beatrice Rodriguez, MD, PhD Hawaii Parkinson Disease Center of Excellence at Kuakini Medical Center, Honolulu, HI

Project Description: This is a study of factors which lead to increased risk of Parkinson disease in the Honolulu Heart program (HHP) cohort. The Honolulu Heart Program was established as a long-term prospective cohort study in 1965 with enrollment of 8,006 Japanese-American men born in 1900-1919. The original focus of the HHP was research on heart disease and stroke. In 1991 with the establishment of the HAAS, the focus of research shifted to aging and neurodegenerative diseases. Utilization of the same cohort has allowed for continued use of prospectively obtained data since 1965. The study is now one of a very limited number of population-based longitudinal studies of neurodegenerative disease of aging.

Parkinson's research began in 1991 and has continued to present. Risk factor information is available from interviews and examinations since 1965. Collected information includes: education, occupation, occupational exposures, dietary nutritients, neurologic exam, physical activity information, cognitive function, and olfactory testing. Research suggests that inflammation may play an important role in the neurodegenerative processes leading to Parkinson's disease. We are in the process of analyzing available data from this study on non-steroidal anti-inflammatory drug use, plasma fibrinogen, white blood cell counts and CRP measured in 1991 as predictors of incident Parkinson disease.

The first manuscript on fibrinogen and PD has been finalized and has been submitted to the Journal of Neurology and is currently under review. Dr. Rodriguez has traveled to Miami to attend the National Parkinson Foundation’s Center of Excellence leadership conference last October and presented a poster with the findings on Fibriogen-PD association.

The next paper will be focused on fibrinogen disease and Lewy bodies at autopsy given the positive findings we observed. To date, over 600 autopsies have been conducted in members of the Honolulu Heart program/Honolulu-Asia Aging Study.


Project Title: Depression in Parkinson's Disease: A Cognitive-Behavioral Based Resiliency Training (CBT) Program

Grant awarded to: Julie Carter, RN, MS, ANP

Project Description: Depression is the most common nonmotor problem in Parkinson’s disease and is associated with increased disability, decreased quality of life (QOL), and increased caregiver strain independent from motor symptoms. In spite of this, it is under recognized and under treated. Antidepressant therapy has not been overwhelmingly beneficial in PD. Nonpharmacological interventions designed specifically for PD are limited. This project proposes to test the feasibility of a group CBT intervention for people with depression and PD. CBT is based on the concept that a person can be taught to change their attitude and thereby reduce the perceived distress related to their disease and situation.

The first phase of the project will be to develop curricula for PD patients that will focus on building resiliency using the principles of CBT. This curriculum will be first tested in an 8 week series for patients. Using refinements from the evaluation of the first 8-week session we will offer a second 8-week session and add a caregiver companion program that will meet separately but at the same time as the patient group. Overall, the program will be evaluated for the feasibility of group intervention, subjective benefits to participants, and practicality of dissemination to a larger population of PD patients and caregivers.

3. Parkinson's Action Network (PAN), founded in 1991, is the unified education and advocacy voice of the Parkinson's community, fighting for a cure. Through education and interaction with the Parkinson's community, scientists, lawmakers, opinion leaders, and the public at large, PAN works to increase awareness about Parkinson's disease and advocates for increased federal support for Parkinson's research.

PAN also provides the information and resources necessary to empower people with Parkinson's disease to act on their own behalf and gain a greater sense of control over their health and their future. For more information on PAN, please see its website at www.parkinsonsaction.org.

4. Parkinson’s Disease Foundation is using its distribution to fund the following:

Project Title: Combining fast scan cyclic voltammetry and tetrode ensemble recording in a rat model of Parkinson's Disease

Investigators/Authors: Ledia F. Hernandez, PhD, Massachusetts Institute of Technology

Objective: This project will examine the nature of dopamine release in the striatum, the effects of L-Dopa treatment in the striatum, and the potential detrimental effects of L-Dopa on parts of the striatum that already have enough dopamine.

Background: Tremors and other motor symptoms of Parkinson’s disease develop when nerve cells in a
brain area called the striatum do not receive enough dopamine, a chemical messenger. Very little is known about how the release of dopamine in the striatum is controlled, either in normal individuals or in people with PD. And, although the drug L-Dopa increases dopamine levels in the striatum, little is known about how it affects cells.

Methods/Design: Studying a rat model of PD in which the number of dopamine-producing cells has been
reduced on one side of the brain.

Results: Conclusion/Relevance to Parkinson’s Disease: The results of these experiments will provide key information about physiological dysfunctions underlying PD and could lead to new targets for the treatment and cure of PD and L-DOPA induced dyskinesias.

Project Title: Properties and adaptations of the subthalamopallidal synapse in mouse models of Parkinson’s Disease

Investigators/Authors: C. Savio Chan, PhD, Northwestern University

Objective: This project investigates how the abnormal activity is generated in the external segment of the globus pallidus (GPe) in the forebrain in PD.

Background: Certain nerve cells in the brain control movement of the body’s muscles. Normally these cells produce a chemical messenger called dopamine, which transmits signals to a brain area called the striatum. Tremors and other motor symptoms of Parkinson’s disease develop when these dopamine neurons die. The death of dopamine neurons also affects other brain areas. In particular, nerve cells in an area next to the striatum called the globus pallidus begin sending abnormal signals that contribute to the motor symptoms of PD.

Methods/Design: In studies with mice, important signaling molecules will be identified and studied. In addition, since nerve cell communication involves electrical signals as well as chemical messengers, we are using techniques to measure the electrical current component of nerve cell communication in individual cells.

Results: Conclusion/Relevance to Parkinson’s Disease: Ultimately, this research may lead to new therapies to
help restore normal brain signaling activity in late-stage PD.

Project Title: Identification of a novel gene for Parkinson’s Disease

Investigators/Authors: Carles Vilariño-Güell, PhD, Mayo Clinic; Jacksonville, FL

Objective: To identify a new gene for PD, focusing on two large families from North America, both with strong histories of PD as well as other, related, neurological disorders.

Background: Most people with PD do not have a relative with the disease. But in a very few families, several people are affected by PD, and the disease is inherited. Affected family members often have a specific mutation in a gene called LRRK2, which is linked to PD--but are diagnosed with a different disease. This suggests a mutation in a different, unknown, gene is causing PD.

Methods/Design: To identify this gene, DNA samples from all family members willing to participate will be analyzed to discover a unique region inherited by those with a neurological disease but not by healthy individuals. Further refining the analysis will lead to identification of the PD gene and its mutation.

Results: Conclusion/Relevance to Parkinson’s Disease: Identification of a novel gene will result in a greater understanding of the causes of the disease, improve diagnosis, and may ultimately lead to more effective treatments.

5. The Michael J. Fox Foundation for Parkinson's Research is using its distribution to fund the following:

Target Validation Initiative and the Clinical Intervention Awards.

The Target Validation Initiative is designed to accelerate the rate at which new Parkinson's therapies are brought to market. Target Validation provides awards of up to $250,000 to validate the therapeutic potential of scientific discoveries and push them one step closer to the clinic. While research continues to identify new genetic, cellular and biological targets for therapeutic intervention to benefit PD patients, the translation of these discoveries into practical treatments requires additional applied work. Target Validation funds this work with the ultimate goal of ‘de-risking’ potential investment in the most promising targets by biotech and pharmaceutical companies, who are generally best-suited to carry promising therapies forward into the clinic.

The Clinical Intervention Awards drive clinical intervention trials of promising therapeutic approaches with potential to significantly improve the treatment of PD. Ideal proposals will focus on tests of novel treatments that can slow or halt disease progression, or that can greatly reduce PD motor and non-motor symptoms beyond (and without the complications of) current standards of care. There is no pre-set budget limitation for applications under this initiative.

For a complete list of projects that were awarded grants under the Target Validation Initiative and Clinical Intervention Awards, please visit the website of The Michael J. Fox Foundation for Parkinson’s Research.

6. The Parkinson Alliance is using its distribution to fund the following:

Project Title: Effects of Deep Brain Stimulation (DBS) on Balance Control

Investigators: Fay B. Horak, PhD; Patricia Carlson-Kuhta, PhD; Penny Hogarth, MD
Name of Organization: Oregon Health and Science University, Dept. of Neurology, Movement Disorders

Objective: To compare the effects of DBS in the Subthalamic Nucleus (STN) and the Globus Pallidus, internus (GPi) for Parkinson’s Disease on balance control. We will determine which aspects of balance and gait initiation are improved, and which are worsened, by DBS and whether one site has better outcome for balance.

Background: Although DBS ameliorates many symptoms of PD, how much these clinical benefits extend to the disabling problem of poor balance is still controversial. The few studies of DBS on axial motor function have been limited to STN stimulation and suggest improvement in some tasks such as walking and quiet stance but with worsening in other tasks, such as balance responses and gait initiation. No previous studies have directly compared the effects of DBS in STN and GPi on balance control.

We hypothesize that stimulation in STN and in GPi will affect different types of balance control. Specifically, we predict that the STN is involved in anticipatory postural adjustments prior to step initiation, whereas the GPi may be more involved in balance responses to slips and trips. If this is true, then patients with start-hesitation freezing should target STN, whereas patients with falls due to poor balance responses should target GPi for their DBS surgery. We also predict that some types of balance control will be improved, but other aspects will be worsened by DBS.

Methods/Design: Thirty subjects with PD have been randomized into DBS surgery either in the STN or GPi. They will be tested a few days before DBS surgery, while on levodopa and off levodopa, as well as 6-months after surgery under 4 conditions: off both DBS and levodopa, on levodopa alone, on DBS alone, and on both levodopa and DBS. Two control groups will also be tested at baseline and 6 months later: 1) subjects with PD who choose not to get DBS surgery and 2) age-matched controls without PD. Step initiation and balance strategies in response to computerized surface perturbations will be quantified with forces under the feet, body motion and muscle activation patterns. We will determine if changes in gait and balance after surgery, compared to before surgery, differ compared to gait and balance changes across 6 months in subjects with PD who have not had surgery and compare effects of DBS in the two sites.

Relevance to Parkinson’s Disease: This study will help clinicians and patients better understand the effects of DBS on balance and gait initiation so they can make informed decisions about treatment options.

This award from The Parkinson Alliance will help support work in the creation of animal models and in the production of novel viral vectors.

Lay Description Of The Burke Laboratory

The Laboratory is under the direction of Dr. Robert Burke. He is the Alfred and Minnie Bressler Professor of Neurology and Pathology at Columbia.  He has served as the Director of Laboratory Research in Parkinson’s Disease and Related Disorders in the Department of Neurology at Columbia since 1997, and as the Director of the Morris K. Udall Center of Excellence for Parkinson’s Disease Research at Columbia University since 2003.

Parkinson’s disease (PD) is the most common neurodegenerative disorder of the basal ganglia. Although  many effective treatments for the motor symptoms of PD exist, their benefits are limited in degree and duration.   The greatest challenge posed by this disease is to develop therapies that address the underlying degenerative process.  The goal of the Burke Laboratory is to address this challenge. Our efforts have two guiding principles. The first is that development of such therapies ultimately depends on a better understanding of mechanisms of disease. The second is that patients cannot wait for a full understanding of this disease to be in hand before efforts are made to translate new knowledge into treatments.

While there are many good approaches to developing neuroprotective therapies, we focus on targeting the pathways of programmed cell death (PCD), also known as apoptosis. There is a growing consensus that the degeneration of neurons in PD is not a passive event, but rather it is due to the activation of genes which destroy the cell. These genes are the mediators of PCD, and we believe that It may be possible to prevent neuron death by blocking these pathways.

We utilize information about the basic mechanisms of PCD to attempt to develop translational approaches that may ultimately prove useful in the treatment of patients.  Most recently, we have focused our efforts on the development of gene therapy as a way of blocking PCD in dopamine neurons in the living brain.  For example, in one of our recent publications, we show that it is possible to use a viral vector to block important death-mediator molecules in the dopamine neurons and thereby prevent their death in a neurotoxin model (Journal of Neuroscience, 2008).

7. The Parkinson’s Institute and Clinical Center is using its distribution to fund the following:

Project Title: Epidemiologic Studies of PD Etiology

Investigators/Authors: Tanner CM, Goldman S, Langston JW

Objective: The goal of this study is to investigate the hypothesis that Parkinson’s disease is a complex disorder with both genetic and environmental determinants.

Background: The cause of Parkinson’s disease is not known. Our work indicates that Parkinson’s disease is likely a complex disorder, that is, no single factor causes Parkinson’s disease. Instead, it is likely that combinations of risk factors, protective factors and genetic makeup determine whether an individual develops Parkinson’s disease or not. Because so many factors are involved, and the pattern likely differs among people, investigations in different populations are essential. The goal of this research project is to understand the causes of Parkinson’s disease, focusing on the interplay between inherited (genetic) and acquired (environmental) factors.

Methods/Design: This study will take advantage of extensive genetic and risk factor information collected as part of several large epidemiologic investigations. We will conduct secondary analyses investigating complex models of disease, focusing on the combined effects of genes and environment. We will focus our work in a well-characterised population of more than 500 men and women with Parkinson’s disease and more than 500 “controls” (men and women of the same age as the people with Parkinson’s disease) have been identified by movement disorders experts across the United States and Canada for a study of occupational risk factors. Detailed lifelong information on environmental risk factors and DNA have been collected . We will take advantage of this population to investigate the following hypotheses: 1. The risk of Parkinson’s disease is lower in association with exposure to tobacco, caffeine or nonsteroidal anti-inflammatory agents. 2. In individuals with genetic variants of genes encoding proteins involved in the processing of nicotine, caffeine and nonsteroidal anti-inflammatory drugs, the effect of these exposures will be increased or decreased, in accordance with the metabolic effect of the specific variant.

Relevance to Parkinson’s disease: This project will take advantage of a rich resource of environmental and genetic information in a clinically well-characterised population of Parkinson’s disease cases and controls. The existing data in this population provides the opportunity to investigate the complex effects of genetic predisposition and environmental exposures on the cause of Parkinson’s disease, focusing on common exposures that could be easily translated into strategies for primary disease prevention, which is a major focus of research at the Parkinson’s Institute.