Where Your Money Goes > Grants Archive

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

 
Project Title:  Levodopa Restoration of Normal Behavior in Parkinson’s  Disease: Development of a Model of Parkinson’s Disease Combining Fast Scan Cyclic Voltammetry and Tetrode Ensemble Recording

Investigators: Ann M. Graybiel, Ph.D

Organization: Massachusetts Institute of Technology McGovern Institute for Brain Research

Objectives:

1) To inform new therapy development by improving understanding of the mechanisms by which levodopa therapy helps people with Parkinson’s disease (PD) and its side effects.

2) To determine how levodopa therapy affects neural activity, from therapeutic benefits to changes in gross neural firing patterns.

Background:  Prof. Ann Graybiel developed a model of PD in the rat where dopamine production was restricted on one side of the brain but not the other.  In addition, from 2006-2008, the National Parkinson Foundation funded Dr. Graybiel to develop a new method for identifying neural activity using an array of implanted electrodes.  As a result of this work, Professor Graybiel made a significant breakthrough finding:  she explained previously unknown characteristics of the brain, most significantly how the brain tracks time. This NPF-funded work was recognized by the Movement Disorders Society for its seminal importance. Now, we are providing follow-up funding to apply this work directly to Parkinson’s disease. For the first time, Dr. Graybiel will be combining her neural signal array with her PD model of a one-sided dopamine deficit and looking at the impact of a specific therapy on neural activity.

Potential Impact: Although we now know many things about how dopamine is involved in PD, we still do not why, for example, a severely affected PD patient given levodopa can find it so much easier to start to walk, walk reasonably normally, and stop at will.  While the function of the neurotransmitter dopamine at a synapse is well understood, the effect on the whole brain of improved synaptic function is not.  By recording the activity across the brain, and tracking signals in time and space (i.e., which cells fire when), new insight can be obtained into how levodopa affects not just cells but thinking more generally.  These experiments will track, with cell-level granularity, the changes that levodopa generates in the brain.  In addition to understanding the therapeutic effects, Professor Graybiel will be looking at side effects such as dyskinesias:   beyond cellular chemistry, what changes in thinking result in dyskinesias?  The answers to these questions should offer insight to guide therapy development to prolong the positive effects of levodopa and reduce the long-term side effects.

Relevance to Diagnosis/Treatment of Parkinson’s disease:  With this project investigators hope to understand how Levo-dopa (L-DOPA) helps Parkinson’s disease patients so that they can help in the development of even better therapeutic interventions without the side effects of L-DOPA.

Results:  This is a two-year grant and results are not anticipated until the end, but the grant requires an interim report after one year.

September 2011 Project Update:

Methods/Design: Although we now know many things about how dopamine is involved in PD, we still do not why, for example, a severely affected PD patient given levodopa can find it so much easier to start to walk, walk reasonably normally, and stop at will.  While the function of the neurotransmitter dopamine at a synapse is well understood, the effect on the whole brain of improved synaptic function is not.  By recording the activity across the brain, and tracking signals in time and space (i.e., which cells fire when), new insight can be obtained into how levodopa affects not just cells but thinking more generally.  These experiments will track, with cell-level granularity, the changes that levodopa generates in the brain.  In addition to understanding the therapeutic effects, Professor Graybiel will be looking at side effects such as dyskinesias:   beyond cellular chemistry, what changes in thinking result in dyskinesias?  The answers to these questions should offer insight to guide therapy development to prolong the positive effects of levodopa and reduce the long-term side effects.

Results:  After the first year of this two-year grant, the analysis of striatal unit activity is nearly completed. Investigators are preparing a manuscript reporting the results for publication and plan to submit it during the next funding year. Investigators are currently analyzing oscillations in local field potentials recorded simultaneously with neuronal spike activity in the striatum with or without dopamine depletion. Investigators are also trying to identify how dopamine depletion and L-DOPA administration affect task-related oscillatory activity in the striatum. Investigators are now prepared to carry out experiments to measure phasic dopamine release in the striatum of rats with unilateral dopamine depletion, using fast-scan cyclic voltammetry. They will determine whether striatal dopamine levels increase with administration of L-DOPA and will correlate changes in dopamine release with activity patterns of striatal neurons. The finding of these next actions may be important for future therapies related to the performance of sequential behaviors or previously learned tasks that have been shown impaired in PD patients.

September 2012 Project Update: 

Results:  Investigators recorded single-unit and local field potential (LFP) activity in the striatum in normal and dopamine-depleted hemispheres simultaneously as hemi-parkinsonian rats learned and performed a procedural T-maze task with and without L-DOPA treatment. They also measured the release of dopamine onto these striatal neurons, before and after the L-DOPA therapy. They found that the effects of dopamine depletion, and of L-DOPA therapy, are remarkably dependent on the exact task context in which the animals are performing, and are also dependent on the state of learning that the animals have reached as they perform. This context and plasticity dependence suggests clues to the long-standing puzzle of how the effects of dopamine depletion can be so different from time to time and form person to person. The study may help understand the benefits of L-DOPA therapy to improve the ability to start and stop behavioral movements in PD patients.

 

Project Title: Comparative Efficacy of Aquatic-Based Physical Therapy vs. Land-Based Physical Therapy for Parkinson's Disease

Investigators: David J. Houghton, MD, MPH

Name of Organization: University of Louisville, Division of Movements Disorders

Objective: This clinical study will evaluate and compare aquatic-based physical therapy (PT) and land-based PT in PD patients with gait and balance for short-term and long-term benefits.

Background: Persons with Parkinson’s disease (PD) often suffer progressive impairment from impaired balance and posture. Loss of balance is multi-factorial and accentuated by progressive axial rigidity, bradykinesia, loss of spinal flexibility, gait festinations, freezing of gait, and postural instability. These features contribute to falls and loss of independence for the PD patient. Strategies for enhancing balance among persons with moderate-to-severe PD are needed. Recently, speed-based and amplitude-based physical therapy (PT) modules have been developed in PD (LSVT-BIG®) and limited published data have shown promising efficacy. But, benefits to these strategies may diminish as the disease progress. As an adjunct to such speed/amplitude training, the potential benefits of aquatic-based PT for gait and balance are numerous. Decreased joint force, increased buoyancy, reduced muscle tightness, increased proprioceptive input, and lessened postural issues in water may further enhance PT outcomes in PD.

September 2011 Project Update:

Potential Impact:The evaluation and comparison of benefits between two speed and amplitude-based PT protocols will help establish the efficacy of this strategy, and will be important to inform clinical practice.  Further, it is widely believed in the PD community that more advanced PD patients benefit from pool-based exercise, but at present there is insufficient evidence of the relative benefit to justify additional reimbursement to cover the additional costs.  It is hoped that this study will not only further support the speed and amplitude strategy for PD therapy but also provide much-needed evidence for pool-based interventions.  Future larger studies will be designed to address the greater impact, including cost-benefit analysis, of such therapies on public health models of the care of neurodegenerative patients.

Specific Aims:
1) To examine the short-term and long-term benefits of land-based physical therapy (LSVT-BIG®) on balance, gait, fall prevention, and quality-of-life in moderate-to-severe PD patients.

2) To examine the short-term and long-term benefits of aquatic-based physical therapy on balance, gait, fall prevention, and quality-of-life in moderate-to-severe PD patients.
To compare the short-term and long-term benefits of aquatic-based PT versus land-based PT (LSVT-BIG®) on balance, gait, fall prevention, and quality-of-life in moderate-to-severe PD patients.

3) To compare the short-term and long-term benefits of aquatic-based PT versus land-based PT (LSVT-BIG®) on balance, gait, fall prevention, and quality-of-life in moderate-to-severe PD patients.

All outcomes will be evaluated for immediate benefit and durability of benefit at three- and six-months post-intervention.

September 2012 Project Update:

Results:  After solving Institutional Review Board concerns Dr. David Haughton was able to start enrolling patients for the aquatic physical therapy group. Up to August 2012, a total of 19 individuals have been added to the study and are completing protocol. Dr. Houghton is considering adding a second institution finalize recruitment and precede with data analysis. It is expected that the study will be completed by June 2013.

Project Title: The Role of Visual Attention in the Driving Safety of Parkinson’s Disease Patients

Investigators: Sherrilene Classen, PhD, MPH, OTR/L

Organization: University of Florida Movement Disorders Center

Objectives:
1) To determine whether visual attention, measured by Useful Field of View (UFOV®), is an early and persistent impairment in PD

2) To determine how well the UFOV® predicts driving safety risk in PD (among mild, moderate and severely impaired drivers) compared to age-matched control drivers (AC)

3) To determine how well clinicians, caregivers and PD patients themselves predict driving safety, compared to the UFOV®, using the actual on-road test as the gold standard

Background: PD is manifested by motor, cognitive and visual symptoms that may affect safe driving ability and, therefore, mobility and independent community living. Given the dependency on the automobile as the primary source of transportation in Western societies, identifying safe or, more importantly, remediable PD drivers (through driver rehabilitation programs and/or education in transportation options), may provide continued independent mobility for the driver while enhancing safety on the road as well. Unfortunately, clinicians such as neurologists who are often the first to suspect “at risk” PD drivers primarily base their judgment on motor impairment, and neuropsychologists base their judgments of the “at risk” driver on general patterns of cognitive impairment. Sensitive measures of visual inattention are under-represented in routine motor and cognitive assessments of these clinicians.

Potential Impact: This project is the convergence of clinical tests and on-road driving outcomes to characterize visual attention as an early and sensitive marker of PD driving safety risk. The outcome of this project will culminate in identifying a reliable and efficient screening mechanism for safety among Parkinson’s disease (PD) drivers and the eventual development of rehabilitation strategies that can safely prolong driving independence.

Specific Aims:
1) Determine whether the UFOV®, a test of visual attention, shows homogenous impairment among PD drivers, compared to AC drivers.

2) Determine if the UFOV® is a consistent predictor of driving safety risk, especially among PD drivers who are less motorically and cognitively impaired.

3) Determine whether the UFOV® is the efficient and superior singular screening test for at risk PD drivers compared to the battery of standard clinical assessments performed by neurologists, neuropsychologists and driving rehabilitation specialists.

September 2011 Project Update:

Results: After the first year of this two-year grant, investigators have registered 32% of the enrollment targets. The battery of functional tests has been conducted in controls and study patients. A manuscript for publication in the American Journal of Occupational Therapy entitled “The usefulness of screening tools for predicting driving performance in people with Parkinson ’s disease” written by Dr. Classen and colleagues  is in press. This publication provides information on important issues currently being addressed by the investigator in this current project. Results are not anticipated until the end of the second year of this grant.

September 2012 Project Update:

Results:  The investigators have enrolled a total of 91 individuals of the expected 100 participants. Most of the individuals enrolled have completed a battery of neuropsychological tests and assessment of visual attention and perception through comprehensive driving evaluations. It is anticipated that investigators will reach their enrolment goal by September 2012 and that data analysis will be conducted in the following three months. A final report from the investigators providing conclusions from the study is expected by January 2013.

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: PD4PD: Partnered Dance for Parkinson Disease

Investigator: Gammon Earhart, Ph.D., P.T.; Washington University School of Medicine,St. Louis, MO

Objective: This study will investigate both the short and long-term effects of participation in a community based dance program for people with PD.

Background: For people with Parkinson’s exercise is widely recognized as helping to maintain mobility and improve secondary symptoms such as depression.  But most studies have evaluated only the short-term effects of exercise, and have not addressed whether exercise can modify the progression of PD.  This study will investigate both the short and long-term effects of participation in a community based dance program for people with PD.  Dance is a socially engaging and motivating form of exercise that directly addresses needs of people with PD, including cueing, cognitive strategies, balance exercise and aerobic conditioning.  Participants in a control group will receive no intervention.

Conclusion/Relevance to Parkinson’s Disease: We will evaluate how the dance exercise program impacts the symptoms of PD, how performance on standard clinical measures of physical function may change over time with disease progression in the absence of an exercise intervention and whether exercise may modify disease progression.

September 2011 Project Update:

Results: To summarize our results to date, dance participants showed a significant change in UPDRS-III scores that exceeded the minimally important clinical difference, while no change occurred in the no-exercise control group at 3 months. Even larger improvements were noted in UPDRS-III scores at 6 months and these improvements were maintained in the dance group at 12 months. Dance participants also improved on other measures of balance and mobility that were greater at 6 months than at 3 months and were maintained at 12 months. We recently submitted a manuscript to Neurorehabilitation and Neural Repair describing the full study including baseline data as well as results at 3, 6, and 12 months.

September 2012 Project Update:

The manuscript was accepted and published.  Please see citation and abstract below:

Duncan, R. P., & Earhart, G. M. (2012). Randomized controlled trial of community-based dancing to modify disease progression in Parkinson disease. Neurorehabilitation and Neural Repair, 26(2), 132–143. doi:10.1177/1545968311421614

BACKGROUND: Tango dancing has been effective in improving measures of physical function in people with Parkinson disease (PD). However, all previous studies were institution-based, tested participants on medication, and employed short-term interventions.

OBJECTIVE: To determine the effects of a 12-month community-based tango program for individuals with PD on disease severity and physical function.

METHODS: Sixty-two participants were randomly assigned to a twice weekly, community-based Argentine Tango program or a Control group (no intervention). Participants were assessed off anti-Parkinson medication at baseline, 3, 6, and 12 months. The primary outcome measure was the Movement Disorders Society-Unified Parkinson Disease Rating Scale 3 (MDS-UPDRS-3). Secondary outcome measures were the MDS-UPDRS-1, MDS-UPDRS-2, MiniBESTest balance test; Freezing of Gait Questionnaire (FOG_Q); 6-Minute Walk Test (6MWT); gait velocity for comfortable forward, fast as possible forward, dual task, and backward walking; and Nine-Hole Peg Test (9HPT).

RESULTS: Groups were not different at baseline. Overall, the Tango group improved whereas the Control group showed little change on most measures. For the MDS-UPDRS-3, there was no significant change in the Control group from baseline to 12 months, whereas the Tango group had a reduction of 28.7% (12.8 points). There were significant group by time interactions for MDS-UPDRS-3, MiniBESTest, FOG_Q, 6MWT, forward and dual task walking velocities, and 9HPT in favor of the dance group.

CONCLUSIONS: Improvements in the Tango group were apparent off medication, suggesting that long-term participation in tango may modify progression of disability in PD.

Project Title: Creating a South American Genetics Consortium on Parkinson's Disease; VA Puget Sound Health Care System, Seattle Division and University of Washington; Seattle, WA

Investigator: Cyrus Zabetian, M.D., M.S

Objective: This goal of this project is to create a South American Genetics Consortium on PD, which will include institutions in Argentina, Brazil, Peru and Uruguay.

Background: Scientists have recently identified several genes that, when mutated, cause rare inherited forms of Parkinson’s disease.  However, it is becoming increasingly clear that the frequency and distribution of genetic risk factors — specific mutations in genes linked to PD — varies greatly between world populations.  Few large-scale PD genetic studies have been carried out in people from developing nations.  This goal of this project is to create a South American Genetics Consortium on PD, which will include institutions in Argentina, Brazil, Peru and Uruguay.  Dr. Zabetian aims to collect blood specimens for DNA extraction and demographic, clinical, and environmental exposure data from 1,750 people with PD and 1,650 matched controls.

Conclusion/Relevance to Parkinson’s Disease: The samples and data, held in a consortium coordinating center at the Seattle Institute for Biomedical and Clinical Research in Washington state, will provide a unique resource for future genetic research on PD.

September 2011 Project Update:

Results:  Due to difficulties in getting institutional approval, this project was delayed 9 months and has been awarded a non-cost extension by PDF. The goals for subject enrollment are 875 PD patients and 825 controls in both Years 1 and 2, for a total of 1,750 PD patients and 1,650 controls at the conclusion of the funding period.  Recruitment of PD patients is ahead of schedule, but control recruitment is behind schedule, at most sites. Blood specimens are drawn and processed, and DNA is extracted locally. Thus far, all DNA samples received have been of high quality and adequate concentration. In June 2011 the second LARGE-PD investigator meeting was held in Toronto, Canada at the Movement Disorder Society (MDS) meeting. There is a plan to schedule an annual meeting on a recurring basis to coincide with the MDS meeting each year.

Some preliminary results have recently published on LRRK2 derived from this unique population:
Ignacio F. Mata, et al. Lrrk2 p.Q1111H substitution and Parkinson's disease in Latin America. Parkinsonism & Related Disorders. In Press, Corrected Proof. Available online 31 May 2011. DOI: 10.1016/j.parkreldis.2011.05.003.
(http://www.sciencedirect.com/science/article/pii/S1353802011001301)

September 2012 Project Update:

Because of the success of this project, several other institutions in South America have expressed interest in becoming part of the LARGE-PD consortium. We have chosen to add one new site in Medellin, Colombia, at the Universidad de Antioquia. The investigators at that site have a long track record of successful research in neurogenetics and they have already recruited a substantial PD case-control sample. IRB approval for this collaboration has been acquired from both our institution and the Universidad de Antioquia. As a reminder, LARGE-PD consists of the following sites:
 

• Instituto Nacional de Ciencias Neurolo?gicas; Lima, Peru
• Instituto de Neurologi?a, Universidad de la Repu?blica; Montevideo, Uruguay
• Hospital de Cli?nicas, Facultad de Medicina, UBA; Buenos Aires, Argentina
• Departamento de Neurologia, Universidade Federal de Sa?o Paulo; Sao Paulo, Brazil
• Ribeirao Preto School of Medicine, University of Sa?o Paulo; Ribeirao Preto, Brazil

Goals for subject enrollment are 1,750 PD patients and 1,650 controls at the conclusion of the funding period and have reached 1,563 and 1,479, respectively.  

We have spent several months upgrading and expanding the LARGE-PD database to more efficiently accommodate the large amount of data (including genetic results) that have been collected thus far. Throughout this process we have identified a series of minor discrepancies at some of the sites (e.g. a subject is reported as female but X/Y genotyping of the DNA sample received indicates male) and have worked with each of the collaborators to resolve these problems. To date all of the data discrepancies encountered at all of the sites have been successfully resolved.

Publications/Presentations: Although the sample is not complete, we have begun to perform small-scale genetic analyses on the patients and controls recruited to date. This work has resulted in two published manuscripts. 1, 2 Three additional manuscripts are in preparation. Results from this work have been presented at several National and International meetings, including the American Academy of Neurology (AAN) and the Movement Disorders Society Meeting (MDS). For example, a poster presented at the MDS Meeting was selected for the guided tour in 2011 (“A novel PARK2 mutation in a Peruvian family: Clinical and pathological characteristics”).

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

Project Title:  Linked Efforts to Accelerate Parkinson’s Solutions (LEAPS), A Phase 1/2 Trial Assessing the Safety and Efficacy of Bilateral Intraputaminal and Intranigral Administration of CERE-120 (Adeno-Associated Virus Serotype 2 [AAV2]-Neurturin [NTN]) in Subjects with Idiopathic PD

Investigators/Authors:  Raymond Bartus, PhD, Executive Vice President & Chief Scientific Officer, and Joao Siffert, MD, Vice President, Chief Medical Officer, Ceregene, Inc.

Objective:  The goal of this study is to generate sufficiently rigorous data with a double-blind, sham surgery-controlled design to enable investigators to ascertain the effectiveness and safety of CERE-120 using a modified dose and delivery procedure.  Pending a favorable efficacy and safety outcome, further clinical testing would be initiated.

Background:  The biopharmaceutical company Ceregene, Inc , who has led the development of CERE-120, to date, is conducting a Phase 2 clinical study to further evaluate its efficacy and safety.  CERE-120 is a gene transfer vector that aims to deliver the neurotrophic factor neurturin to dying dopamine neurons in the brain.  This clinical study follows an earlier Phase 2 trial completed in 2008, also supported by MJFF, which failed to show a benefit of CERE-120 over placebo in the primary endpoint (Unified Parkinson’s Disease Rating Scale) at 12 months.  However, the study did show improvement on other key secondary measures at 12 months, as well as statistically significant improvement on the primary endpoint for CERE-120 treated patients who completed blinded beyond 12 months.  Based on these findings, coupled with other data that suggested inadequate transport of CERE-120 to the area of the brain where the cell bodies affected by PD exist (substantia nigra), Ceregene has significantly enhanced the method of delivery and dosage.  Delivery of CERE-120 to both substantia nigra and putamen, with greater than a fourfold increase in dose, has been demonstrated to be safe and well tolerated in additional nonclinical studies and a Phase 1 clinical trial in subjects with advanced PD conducted by Ceregene.
 
CERE-120 is composed of an adeno-associated virus type 2 (AAV2) vector that transports the gene for neurturin, a naturally occurring protein known to repair damaged and dying dopamine-secreting neurons, keeping them alive and restoring normal function.  Neurturin is a member of the same protein family as glial cell-derived neurotrophic factor (GDNF).  The two molecules have similar pharmacological properties, and both have been shown to benefit the midbrain dopamine neurons that degenerate in PD.  Degeneration of these neurons is responsible for the major motor impairments of PD.  In prior studies, CERE-120 was delivered by stereotactic injection to only the terminal fields (the ends of the degenerating neurons) located in an area of the brain called the putamen.  The cell bodies for these same neurons are located in a different area of the brain, called the substantia nigra, and the amended dosing regimen being employed in the new trial calls for administration of CERE-120 to both the substantia nigra and the putamen.  Preclinical studies have demonstrated that once CERE-120 is delivered to the brain, it provides stable, long-lasting expression of neurturin in a highly targeted fashion.

Methods/Design:  This Phase 2 clinical study is the second of two components of a Phase 1/2 study (ceregene.com/parkinsons.asp).  Dosing in Phase 1 is complete and Phase 2 is ongoing at 11 leading medical centers across the United States.  Each center has strong expertise in Parkinson’s disease neurology and neurosurgery.  52 patients will be randomly assigned into one of two groups — one will receive CERE-120 using a stereotactic surgical procedure, and the other will be given a “sham” or mock surgical procedure without treatment.  Except for the surgeons, no one will know who received CERE-120 until after the entire study is completed.  Once patients have recovered from surgery, they will be asked to return to the clinic every three months, for 15 to 24 months, to evaluate possible changes in motor function.  Patients will be allowed to continue their regular PD medicines.  Those subjects who receive the sham surgery will be offered treatment after the conclusion of this trial, provided CERE-120 is shown to be safe and effective.

Relevance to Parkinson’s disease:  LEAPS 2010 was launched to address specific challenges for neurotrophic factors.  Neurotrophic factors are specialized proteins that protect and nourish neurons in the brain, including the dopamine neurons that are lost in Parkinson’s disease.  Preclinical studies and several early-phase clinical trials of neurotrophic factors have shown potential to slow or stop the progression of Parkinson’s disease — a significant end goal for the entire patient community.  However, the results from Phase 2 clinical trials have yet to demonstrate the efficacy of neurotrophic factor therapies.  One complication in developing trophic-based therapies is the inability for these large proteins to cross directly into the brain and therefore calls for innovative methods for drug delivery.

August 2011 Project Update:

Progress Update: Ceregene’s Phase 2 study (CERE-120-09) is currently enrolling people with moderately advanced Parkinson’s across 11 centers in the United States (www.ceregene.com).  Enrollment is expected to be completed in early Fall, 2011. This portion of the study is double blind and participants are randomized (like the flip of a coin) to either receive CERE-120 or undergo a placebo (sham) surgery. If CERE-120 remains safe and is found efficacious, those in the placebo group will be offered CERE-120 treatment in 2013. Dosing in an earlier part of the study (Phase 1, open-label) was completed in June, 2010 without any complications. All study participants continue to be followed according to the study protocol.  An independent committee reviews study safety regularly and remains supportive of the study continuation.

September 2012 Project Update:

Progress Update:  Ceregene’s Phase 2 study is progressing as expected. All of the Phase 2 patients have undergone the surgery and are being evaluated at routine intervals to continue to assess safety as well as to determine whether CERE-120 might be providing any benefit to relieve the symptoms of Parkinson’s disease. Results of the study are expected to be out by mid-year 2013.

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

Project Title:  Neuroimaging Repetitive Transcranial Magnetic Stimulation Effects in Patients with Parkinson’s Disease

Grant Awarded to:  Principal investigator: Allan D. Wu, MD, Co-investigator:  Janice Lin, PT, PhD, TMS Fellow / Study Coordinator:  Choi Deblieck, PhD

Objective:  Our objective is to determine the effects of daily repetitive transcranial magnetic stimulation (rTMS) on task-related brain activity in Parkinson’s disease (PD) patients.
 
More specifically, we want to know how rTMS stimulation of the motor cortex (which is related to making voluntary movements) will change the brain activity of tasks that require the motor cortex.  We also want to know how rTMS stimulation of the prefrontal cortex (part of the brain related to mood and cognition) will change brain activity in tasks that require cognitive effort. 

Background:  The UCLA Transcranial Magnetic Stimulation (TMS) Laboratory is in the 2nd year of a multi-center clinical trial testing repetitive TMS (rTMS) for the treatment of mood and motor symptoms in Parkinson’s disease (PD) patients, the MASTER-PD trial.

Repetitive TMS is a non-invasive and relatively painless way of stimulating the brain.  This is the first multicenter clinical trial of rTMS in PD patients in North America and the first one which will test to see if rTMS can help both movement problems and mood problems (like depression).  This is a growing and exciting concept, particularly since rTMS is now an FDA approved therapy for certain types of major depression.  In depression, rTMS is applied for 4-6 weeks over a part of the brain within an area called the prefrontal cortex.  After 2 weeks, patients who receive rTMS show an significant improvement in depression compared to patients who receive a placebo (sham-rTMS).

In our MASTER-PD trial, we study the effects of 2 weeks of rTMS on motor and non-motor symptoms of Parkinson’s disease.  The motor symptoms we aim to improve include walking, freezing of gait, imbalance, rigidity, loss of dexterity, and slowness of movement.  The non-motor symptoms we aim to improve are those related to depression (lack of motivation).
 
In our study, we are seeing if rTMS of the motor cortex will help the motor symptoms and if rTMS of the prefrontal cortex will help the depression symptoms.  The study is a blinded, sham-controlled study with 4 conditions.  Patients who are eligible for the study will have both depression symptoms and movement symptoms in spite of medical treatment.  Each patient will then be randomized to receive real or sham-(placebo)-rTMS over the motor cortex (part of the brain controlling movement symptoms) and real or sham-rTMS over the prefrontal cortex (part of the brain responsible for depressed mood) for 10 sessions over 2 weeks. Patients will be followed up to 6 months after rTMS to see how long effects of rTMS may last.

The study involves 5 academic centers across North America (Beth Israel Deaconess Medical Center, Boston; Cleveland Clinic; University of Florida, Gainesville; Toronto Western University; and UCLA) with the goal of 120 patients over 4 years.  When the study is complete in another 2 years, we feel that the results will tell us whether rTMS will help PD patients with their symptoms.  However, this clinical trial will not tell us how rTMS works on the brain.  Understanding how rTMS might work (or not work) will be important in figuring out how to best use rTMS treatment for PD symptoms and how to make rTMS a better or more specific treatment for PD.
    
Methods/Design:  To address this issue of how rTMS works, at UCLA, we used pilot funds from Team Parkinson to add a functional imaging component to our MASTER-PD trial.  We offer every MASTER-PD patient the opportunity to have a functional MRI (fMRI) scan done at the beginning and at the end of their 10 sessions of rTMS.  Functional MRI scans allow us to see which parts of the brain are active when we ask patients to perform movement and cognitive (thinking) tasks while they are being scanned.  We will obtain fMRI scans before and after the 2 weeks of rTMS treatment for each patient in the MASTER-PD clinical trial.  When we compare the brain activity before and after rTMS treatment, we can find out what nearly 2 weeks of daily rTMS does to modulate (change) the activity of brain networks needed to perform the movement and cognitive (thinking) tasks.
 
The movement task that patients perform is a sequential finger movement task where patients push sequences of 4 buttons each, guided by visual cues in the scanner.  There are several sequences of 4 buttons which repeat in random order.  This task is designed to test the brain activation patterns used by PD patients to make these complex sequential movements.  Even though PD patients have difficulty in making complex sequential movements, this task was designed to be easy to perform while lying in the MRI scanner.

The cognitive task is based on the difficulty PD patients have in controlling movements.  The prefrontal cortex is associated with control of movement by inhibiting (preventing) inappropriate actions. In this task, patients are asked to respond with a button press to every letter shown on the screen except for a given target letter.  When the target letter is shown, patients are asked to not respond (to inhibit or prevent the default action of pressing the button). This task tests the brain activity required to monitor the letters shown and to inhibit (prevent) the inappropriate action.  This task is called the “go-nogo” task and is known to activate a network of brain regions related to the prefrontal cortex and was designed to also be easy to perform in the MRI scanner.

September 2011 Project Update:

Results:  At UCLA, we enrolled 5 patients in the MASTER-PD study in the last year. Four patients underwent MRI scanning at the beginning and end of their rTMS.  One was claustrophobic and elected not to undergo MRI scanning.  All 4 patients who performed two sets of MRI scan sessions were able to successfully complete both motor and cognitive tasks.  One patient had too much head motion from dyskinesia.  With data from 3 patients and being still early in the study recruitment process (we have not unblinded Dr Lin as to what type of rTMS each of these patients received), no conclusions as to rTMS effects at this point can be drawn.

For our motor task, we found that the sequential key pressing task activated a consistent set of brain regions associated with a motor execution network including bilateral motor cortex, premotor cortex, supplementary motor area, and parietal regions.  The overall pattern remains visible after 6-9 days of daily rTMS but an analysis of real or sham-rTMS associated change cannot be made. This confirms the robust nature of this task in activating a motor network and provides a good basis for later comparison after rTMS.

In the cognitive “go-nogo” task, we found more variability in the inhibitory control network than in the motor task among our 3 patients.  In general, when patients are monitoring for and stopping inappropriate responses, we see more brain activity in inferior frontal, inferior parietal, and prefrontal brain regions.  However, 1 patient showed this pattern on the left side of the brain and the other two showed this on the right side of the brain.  Overall, the patterns confirm an expected dependence of this task on the prefrontal cortex in all patients, but not all patients showed the same pattern.  Differences in the individual pattern are apparent after rTMS, but at this point cannot be interpreted because we have not unblinded the type of rTMS each patient received.
     
Relevance to Parkinson's disease:  It remains too early to say anything definitive about the results from this project.  The main results are practical issues that are being solved with how to obtain and collect data from PD patients in a rTMS study.  We have tested two tasks for use in the MRI scanner on normal control subjects without PD and have successfully run the MRI scans before and after daily rTMS on 4 PD patients who were able to complete and tolerate the tasks.

The motor task appears highly promising as its pre-rTMS results are consistent across patients.  The cognitive (go-nogo) task is consistent with activation of the prefrontal network, but since results are more variable, we are considering further testing of other prefrontal fMRI tasks in non-PD patients.  We have also collected additional MRI data in all our PD patients to date (not task-related) in our routine scan protocol.  These MRI data permit additional analysis of resting-state brain activity, functional connectivity, and brain structure before and after rTMS.  These analyses require more data from additional patients and are anticipated to yield additional information about effects of rTMS on different aspects of brain structure and function in PD patients. 

We have been pursuing this pilot project with the knowledge of the other sites involved in the multicenter clinical trial.  In fall 2011, the protocol we used has attracted attention from Beth Israel Deaconess Medical Center (BIDMC), the coordinating site for the MASTER-PD study, who has expressed in collaborating on adding functional MRI imaging to their patients as well.  As such, we will be sharing our scanning protocol and data with BIDMC.  This will likely double the number of patients we can image with our MRI protocols and improve our ability to draw pilot conclusions on the effects of rTMS within the rigor of a randomized sham-controlled clinical trial.  We anticipate that the pilot data from these imaging studies by the 4th year of this project will be sufficient to be used as pilot data in larger grant applications aimed at understanding the rationale of how daily application of rTMS achieves its hopefully beneficial clinical effects.  It is also noteworthy that this is an example of how pilot ideas and projects that were supported and started at UCLA can spread to other sites in larger clinical trials.

December 2012 Project Update:

We continue to study the effects of repetitive transcranial magnetic stimulation (rTMS) on motor (movement) control problems and depression symptoms in Parkinson’s disease (PD) patients.     

In the last year, UCLA recruited 5 more PD patients into the MASTER-PD study with no significant adverse events and excellent tolerance of 2 weeks of rTMS.  Three of these 5 patients were scanned in the MRI scanner during their rTMS sessions without incident.  In total, we have scanned 7 out of 10 PD patients recruited at UCLA.  One patient showed too much dyskinesia (head movement) to make scans interpretable.  The remaining 6 patients completed two sets of MRI scan sessions.  

These functional MRI (fMRI) scans allow us to see which parts of the brain are active when we ask patients to perform movement and cognitive (thinking) tasks while they are being scanned.  We obtain fMRI scans before and after the 2 weeks of rTMS treatment for each patient in the MASTER-PD clinical trial.

We also have been obtaining scans of the brain at “rest,” when patients just lay quietly in the scanner.  This allows us to do “resting-state” analysis, a measure of how different parts of the brain are connected to each other.  It is thought that different PD symptoms (such as movement or mood symptoms) are due to different functional connections between movement or mood brain networks. Since the MASTER-PD protocol applies rTMS to either movement networks or mood networks, this resting-state analysis provides another potential means to understand how rTMS may be working. This resting-state fMRI protocol has been shared with a second MASTER-PD site (Beth Israel Deaconess Medical Center, Bosoton) and both sites are now pursuing data collection for resting-state fMRI before and after rTMS jointly.

The MASTER-PD project is a multicenter one involving 5 academic centers across North America (Beth Israel Deaconess Medical Center, Boston; Cleveland Clinic; University of Florida, Gainesville; Toronto Western University; and UCLA).  Recruitment of eligible patients for this project has been challenging and we have recently added a 6th site in Oregon.  Eligible patients must show both signficant depression and motor symptoms, both of which had been adequately treated medically with insufficient benefit, – and be willing to travel to UCLA for treatments daily for 2 weeks.  This issue is not been unique to UCLA and all sites have increased our support group and recruitment efforts. UCLA continues to be the second highest recruiting site among the group.  Nevertheless, all sites are committed to bringing this rTMS project to a successful close.

The MASTER-PD study will close later this year.  Then, work will begin to consolidate the data across 6 sites to see if rTMS can help PD patients with their motor (movement) or mood (depression) symptoms.  When the study closes, we will have completed pilot fMRI scanning in PD patients here at UCLA and jointly at BIDMC in Boston.  These functional imaging data are anticipated to yield some novel insights into how rTMS may work on the brain and generate new hypothesis for the design of more effective brain stimulation therapies for PD.

Project Title:  Cortical Mapping of Pathology in Early versus Later Stage Parkinson Disease

Grant Awarded to:  Yvette M. Bordelon, MD, PhD, Liana Apostolova, MD, Kristy Hwang, Hans Bogg, UCLA

Objective:  This proposal seeks to define the cortical distribution of pathology in later stages of Parkinson disease as a marker or correlate of the Braak PD pathologic stages 5 and6 using FDDNP-PET imaging.

Background:  The Braak staging system describes the progression of Lewy body pathology from brainstem (stages 1 and 2)  to subcortical structures (stages 3 and 4) to cortical areas (stages 5 and 6). We have investigated the utility of a positron emission tomography (PET) molecular imaging probe, 2-(1-{6-[(2-[F18]fluoroethyl) (methyl) amino]-2-naphthyl}ethylidene) malononitrile or [18F]FDDNP, as a biomarker of Lewy body pathology in living subjects with Parkinson disease.  FDDNP binds misfolded proteins in the brain that assumes an amyloid conformation.  This probe has been shown to label Lewy bodies in tissue sections from PD brains

Methods/Design:  FDDNP binding in the brains of subjects with varying  PD duration will be compared.  This proposal began a detailed analysis of cortical  [18F]FDDNP uptake in these patients to better define the load and distribution of pathology in early versus later stage PD using state-of-the-art quantification techniques.

September 2011 Project Update:

Results:  During the study period data continued to be collected with enrollment goal (total subjects=20) being met in mid-2011.  Dr. Apostolova’s lab began the proposed analysis as the data collection continued through late 2010 and 2011.

The first and more complicated phase of analysis involved preparation and processing of the structural MRI data.  The interim analysis of the structural data were on a total of 12 PD subjects.

Conclusion/Relevance to Parkinson's disease:  The extent of gray matter atrophy in the PD patients imaged in this study parallels the duration of their pathology, agreeing with a common sense hypothesis that atrophy will increase over the course of disease progression.  Our results show decreased grey matter density in the occipital cortices.  Considering that visuospatial difficulties arise in Parkinson’s, manifested in difficulty recognizing faces or the orientation of lines, it is entirely possible that the cortical atrophy witnessed in the occipital cortices is to blame for the loss of function.

The next phase of this study will use these structural images to map FDDNP signal onto them to determine whether the Lewy body pathology also has more cortical signal with advancing disease with earliest signal in the occipital lobe (initial analysis shows this trend).

October 2012 Project Update:

A total of 20 subjects were enrolled with 10 classified as early PD and 10 determined to be later PD according to these critieria. All subjects completed neurologic, imaging and neuropsychologic assessments which included UPDRS, brain MRI, [18F] FDDNP-PET, FDG-PET, UPDRS, MMSE and cognitive measures.  However, 2 subjects were eventually excluded from analysis as they met criteria for dementia upon review of their detailed testing.  Thus, a total of 18 subjects were included in the final analysis: 9 subjects with early PD and 9 subjects with later PD. One subject from each category did not have a full motor UPDRS at the time of the scan and one early PD subject did not have an MMSE performed at the time of scanning.

Image analysis included motion correction for [18F] FDDNP-PET scans and generation of the parametric images using a modified Logan plot approach with cerebellum as the reference region.  Region of interest (ROI) analysis of [18F] FDDNP parametric images was performed by manually selecting regions on axial sections to include: midbrain, right and left striata, right and left frontal cortices, right and left temporal cortices and right and left occipital cortices.  

Higher [18F] FDDNP binding levels were appreciated in almost all brain areas in subjects with later stage PD as compared to early PD with the right occipital lobe being the only region reaching statistical significance.  

Conclusions: Our PET imaging results have revealed that [18F] FDDNP uptake is present in PD subjects and is greater in the cortex of patients with later stage PD compared to early PD, particularly the occipital cortex.  This correlates with known progression of Lewy body pathology to involve the cortex through later PD stages according to Braak and colleagues.  We continue to work to refine the cortical mapping techniques of FDDNP binding.  We feel that FDDNP-PET may serve as a useful marker of progression of the cortical pathology in PD and hence as a potential therapeutic biomarker for interventions in early PD aimed at slowing or preventing PD progression.

Project Title:  The Role of Context-Specific Learning in Motor Skill Acquisition in Individuals with Parkinson’s Disease

Name of Organization: University of Southern California

Investigators/Authors: Principal Investigators: Beth E. Fisher, PhD, PT & Giselle M. Petzinger, MD

Investigators: Ya-Yun Lee, MS, PT; Michael Jakowec, PhD; Carolee Winstein, PhD, PT.

Objective:  To determine the affected brain areas associated with the set-shifting deficits seen in individuals with Parkinson’s disease (PD) and to determine whether set-shifting deficits leads to context-specific learning in PD.

September 2011 Project Update:

Results: During the past year, the main focus of this study was to develop a paradigm that enables us to test context-dependent learning in both people with and without Parkinson’s disease (PD). The most robust results were observed utilizing a paradigm that involved key press learning of 3 numerical sequences with both hands under a random practice schedule.

The participants were given a total of 324 trials (36 blocks of 9 trials) to practice the three sequences. Twenty-four hours after practice, the participants are asked to return to the lab and complete a retention test under two conditions: SAME and SWITCH conditions. The SAME condition is when the number sequence and the associated contexts are the same as what was practiced, while the SWITCH condition is when the original sequence-context associations are changed from those in the practice condition.

To date, 9 participants with PD and 8 healthy age and gender matched participants have completed the final version of the task.  An additional 52 subjects have been tested with various other forms of the paradigm. Our preliminary results show that while both PD and healthy participants are slower in executing the sequences during the SWITCH condition compared to the SAME condition, people with PD are much slower and made more errors than healthy individuals. This indicates that people with PD may have greater difficulty generalizing what they learned across different contexts when compared to healthy individuals. Using a correlation analysis to investigate the relationship between set-shifting ability (using a Trail Making Task, frontal lobe function) and the amount of context-dependency, we found a positive (r = 0. 67) relationship between set-shifting and context-dependency  in individuals with PD.  In the next year we plan to finish our recruitment for the study and prepare a manuscript for publication

Relevance to Parkinson’s disease: Our study indicates that individuals with PD may have a greater dependency on context related cues for motor learning than individuals without PD.   This dependency may be related to frontal lobe changes observed in PD and emphasize its role in basal ganglia circuitry and motor function.   This study suggests that individuals with PD have difficulty “carrying over” or “translating” physical therapy practice in the gym to walking at home or outside because of PD related changes in the frontal lobe that are necessary for generalizing the benefits of their gait practice to different environments/surroundings.    These findings support the utility of compounds that facilitate frontal lobe function in combination with physical therapy that would train individuals with PD under a variety of contexts to restore motor function and quality of life.

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

Project Title:  Synthesizing new small molecule inhibitors of alpha-synuclein aggregation as potential disease modifying therapies for Parkinson’s disease

Investigators/Authors:  Ian Irwin/ J W Langston

Objective: The goal of this research is to identify small molecules that inhibit the potentially “toxic” aggregation of the protein alpha-synuclein with the specific goal of identifying disease modifying drugs that can be used to slow or halt the progression of Parkinson’s disease (PD).
 
Background: There is a wide consensus that abnormal aggregation of alpha-synuclein (AS) is involved in the process of neurodegeneration that underlies Parkinson’s disease.  Aggregated AS is a cardinal pathological feature of PD and AS gene mutations that favor aggregation lead to inherited forms of PD that replicate virtually all of its clinical and pathologic features.

Methods/Design:  In this proposal we target the process of AS aggregation/ fibrillation directly. We have now identified 80 promising lead chemical structures several of which are active in an in vitro screen for AS aggregation.  The purpose of this study is to optimize one or more of the best lead compounds by altering the basic chemical structure to produce one or more compounds with ideal pharmaceutical properties to advance into preclinical testing.  This will involve the synthesis of new chemical entities based on our existing data. We hope to emerge from these studies with a list of 3-5 new lead compounds to advance to clinical trials.

September 2011 Project Update:

Results:  The funding from the Unity walk allowed us to advance this drug discovery/ development program toward our ultimate goal of identifying “drug like” molecules that inhibit the aggregation of alpha synuclein.  We believe that inhibitors of AS have the potential to become disease modifying neuroprotective treatment for PD.  Our initial screen of 3000 compounds identified 80 leads.  With this funding from Unity walk we further tested these compounds to identify the most potent among them.  What is especially exciting is the finding that 2-3 compounds that are active at concentrations that would “achievable” in the human brain.  Many of these compounds appear to have limited potential to penetrate the brain.  Under this funding we focused on one of these compounds and were able to synthesize several new derivatives that are likely to be (1) active orally and that would (2) capable of sustaining effective brain levels over time.

Conclusion/Relevance to Parkinson’s disease:  We believe that targeting AS aggregation/fibrillation currently represents the most promising avenue for the discovery of disease modifying treatments that can slow the progress of the disease.   Identifying lead molecules that have potent activity and synthesizing agents that have drug like properties –e.g. oral bioavailability, sustained concentrations over time are critical to making this a reality.   Our next steps are to test these compounds in living animals to measure their concentrations in blood and brain and to determine how long they persist in these tissues.  It is hard to overestimate the impact of finding one more drugs capable of slowing, halting or reversing the progression of PD and we believe that targetting AS aggregation/fibrillation currently represents the most promising avenue for the discovery of such treatments.  While there are symptomatic therapies currently available for PD, virtually all are limited by side-effects, and none slow the inexorable disease progress.

September 2012 Project Update:

Results: The work, facilitated by this Unity Walk Grant in 2010 allowed us to  identify 3 lead molecules and also funded the synthesis of new novel small molecules which are “pro-drug” derivatives of our lead compound that have the improved bioavailability and brain penetration necessary for further drug development.  We are grateful to the Unity Walk funding that allowed the completion of this phase of this project.  These new chemical entities will provide promising candidates for future drug development studies.