2006 Grants

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Funding from The Parkinson Alliance helped to finance the following Parkinson's research. Grantees were selected by scientific review committees of participating organizations. Updates will be posted, when available.


 

Does Deep Brain Stimulation (DBS) prevent progression of Parkinson’s Disease (PD) or it only masks some of the symptoms of PD?

Long term biochemical changes in the Parkinsonian brain with and without deep brain stimulation using Magnetic Resonance Spectroscopy (MRS).

Sub-title: Non-invasive Neurochemical Monitoring of Parkinson’s Patients undergoing DBS is being performed at St. John’s Hospital, Oxnard, California and Huntington Medical Research Institutes, Pasadena, California, in a bid to discover whether DBS goes further than controlling symptoms (tremor and rigidity are significantly improved by this neurosurgical approach) by preventing cognitive deficits.

A proportion of PD patients develop cognitive deficits as they age (so called Lewy Body Dementia (LBD). Using a revolutionary brain imaging method, magnetic resonance spectroscopy (MRS) we observed neurochemical changes of LBD in four of 19 PD patients (20%) on medical treatment alone. With the hypothesis that DBS may prevent progression of PD, we are now examining these patients again after treatment, in anticipation that DBS may prevent the development of these troubling cognitive defects.

During the last decade deep brain stimulation (DBS) has become a widely accepted method for the treatment of advanced Parkinson’s disease (PD).

However, little is known about the mechanisms of DBS for the subthalamic nucleus (DBS-STN) action. Protection of brain cells (neuroprotection) has been theorized to occur by eliminating STN-mediated excitotoxicity in animal models of PD. What that means is that PD makes the STN hyperactive. This hyperactivity results in production of excessive amount of glutamate – a chemical that normally excites the brain cells – neurons. Too much of glutamate overexcites (overworks) the cells. If this condition lasts, eventually the overworked cells die – the phenomenon known as glutamate toxicity.

It is quite logical to assume that if DBS turns off the STN, the glutamate toxicity also disappears, that is the neurons are not been killed anymore. It has been shown in animals already that destruction of the STN in animals with a model of PD prevents death of neurons in yet another structure of the brain called striatum.

The important question is whether protective role of DBS-STN takes place when we perform it in the patients with PD? It is very well known that a lot of things we are finding in animal models are not relevant to human diseases.

Magnetic Resonance Spectroscopy (MRS) can help us to answer this question. MRS looks and feels exactly as a routine Magnetic Resonance Image (MRI), but a different software transforms MRI into MRS – a highly sensitive, totally noninvasive (no injections at all), and quantitative tool that will contribute to studying mechanisms of PD and DBS. MRS can assist in diagnosis of Alzheimer’s disease (even when there are no clinical symptoms yet) and PD and differentiate between them. MRS will help to better understand the progressive nature of PD and, thereby, to fight it at the earlier stages. It will help to reconsider the timing of DBS: should it be performed only at a very advanced stage of PD as the last line of defense, or somewhat earlier?

Using the enormous investigational potential of MRS, The California Neuroscience Institute in collaboration with Huntington Research Institutes, has launched a longitudinal study ‘Does DBS-STN retard progression of PD?

The project will involve 24 patients with DBS and 24 patients without DBS. The latter group will help us to better understand the natural progression of PD, determine which areas of the Parkinsonian brain undergo progressive degeneration, and serve as the control for the patients with DBS.

Possible outcomes:

1) Using MRS we prove that DBS protects brain from progressive degeneration.

2) DBS-STN only masks the PD symptoms and does not address the disease itself.

3) Better understanding of the progressive nature of PD.

Our open label pilot 2 year long MRS study has shown in two PD patients that DBS-STN has mitigated or reversed neuronal loss in the basal ganglia of the brain.

Results:

1. We have established the first PD MRS data repository to transfer MRI and MRS data acquired in PD patients to a central database where raw data is analyzed and quantified. This ensures that data processing routines are normalized and quality control is maintained, both of which are critical to the success of MRS in the presence of deep brain stimulators. Over 100 spectra from patients and control subjects have now been acquired in this ongoing clinical trial, using non-invasive MRI and MRS monitoring, supervised by Alexander Lin and Thao Tran at HMRI.

2. We have reached the first goal of establishing a non-invasive neurochemical test using MRS to screen patients for evidence of Lewy Body dementia. Using NAA/Cr and mI/Cr measurements from normal controls in conjunction with previously acquired data in patients with known dementia, a neurochemical screen can be established using the two measurements as shown in Figure 1. Patients with dementia (open square) show decreased NAA (loss of healthy neurons) and increased mI (increased glial activity) when compared to normal controls (filled square) which can be used to establish a receiver operator characteristic (ROC) as shown by the dotted line. The PD patients (indicated by X) can therefore be screened using this ROC. Our results demonstrate that four of the 15 PD patients show evidence of dementia.

Conclusion:

We have successfully established much of the groundwork for this research project:

1) electronic data transfer of the MRS data acquired at St. John’s not only allows for quantitative measurements and databasing of all data but also provides quality control.

2) A significant amount of control data has been obtained in both normal healthy age-matched subjects as well as those with Parkinson’s disease but without DBS treatment. These datasets are important for establishing statistical validity. The results demonstrate excellent reproducibility and sensitivity of MRS for treatment monitoring.

Authors:

Oleg Kopyov MD PhD Principal Investigator (St John’s Oxnard)
Brian Ross MD PhD Principal Investigator (HMRI)
Alexander Lin MS Neuroscientist (HMRI and RSRI)
Thao T. Tran BS MR spectroscopist (HMRI and RSRI)
William Theurer MD Neuroradiologist (St John’s Oxnard)
Jeffrey XXX RT MR Technologist (St John’s Oxnard)

Progress Report: (2008)

Deep brain stimulation (DBS) effectively controls motor symptoms of Parkinson’s disease.  The mechanisms of this control are unknown.  There is animal data that indicates that DBS of the subthalamic nucleus can prevent progression of Parkinson’s disease.  To test this result in humans, we use a non-invasive method called magnetic resonance spectroscopy (MRS) that allows us to study the chemical composition of the brain without biopsies.  We have reached the first goal of demonstrating the feasibility of this approach with and without DBS.  In this study we examine the neurodegenerative processes in the brains of patients without DBS and to determine if neurodegeneration is halted in patients with DBS.  Our preliminary analysis shows significant changes in white matter in patients without DBS.  However, these changes are not apparent in patients with DBS.  Furthermore, concentrations of glutamate in the basal ganglia do not appear to be significantly different in patients with DBS but decline over a period of two years in patients without DBS.  This demonstrates that MRS is sensitive to subtle biochemical changes that reflect the neuroprotective effects of DBS.  Detailed analysis of this data is in progress.


Project Title: Unilateral pedunculopontine deep brain stimulation in patients with advanced Parkinson's disease

Investigators: Dr. Andres Lozano PhD, FRCSC, BMedSci, MD, BSc, Dr. Elena Moro MD, PhD, Dr. Anthony Lang MD, FRCPC, Department of Neurology, Toronto Western Hospital

Dr. Andres Lozano, Dr. Elena Moro, Dr. Anthony Lang and their colleagues at the University of Toronto and Toronto Western Hospital are conducting a pilot study in unilateral pedunculopontine (PPN) deep brain stimulation (DBS) in patients with advanced Parkinson's disease (PD). The PPN is a structure involved in locomotion, muscular tone, cognition and REM sleep generation. The PPN is supposed to be hypoactive in PD and be involved in the pathogenesis of postural and gait dysfunction and akinesia. Preliminary European published data in a few PD patients with bilateral PPN DBS seem to be encouraging. Our study is specifically focused on effectiveness and safety of unilateral PPN DBS, clinical effects of different electrical parameters of stimulation, clinical effects on gait and sleep, neuroimaging study for understanding mechanism of action.

To date, two patients with advanced Parkinson's disease have received left pedunculopontine deep brain stimulation at Toronto Western Hospital. Preliminary data in double-blinded fashion have shown a 20% improvement of the motor score with DBS when compared to “stimulation off” and “off medication” conditions. The improvement was related to gait, contralateral tremor and bradykinesia, and freezing was markedly reduced in both PD patients. Both patients have also reported improved sleep after surgery. While gait data are under analysis, the sleep study in one patient has shown a significant increase of REM sleep.

Our preliminary data confirm that pedunculopontine deep brain stimulation seems to be effective in patients with advanced Parkinson's disease, especially for bradykinesia and axial signs. Pedunculopontine deep brain stimulation seems also to improve sleep and gait in patients with advanced Parkinson's disease. We would like to thank the Parkinson Alliance for their support, which will help to further the study currently in progress, including monitoring the multiple visits by each patient in the study to supervise their treatment to accurately determine the best electrical parameters of stimulation.

Project Update:

Balance and falls are a major source of disability in patients with advanced Parkinson’s disease (PD) patients and are often issues that are difficult to manage. Both medications and subthalamic nucleus (STN) deep brain stimulation (DBS) surgery can be ineffective. A number of important scientific observations suggest that the pedunculopontine nucleus (PPN) and surrounding areas in the brainstem play an important role in gait and balance control. We conducted a pilot study aimed at investigating the clinical effects of unilateral PPN DBS surgery in 6 patients with advanced PD and severe gait and balance issues. The surgical procedure was well tolerated and there were no adverse events. Double blinded evaluations were performed looking at changes in PD symptoms at 3 and 12 months after surgery. The motor assessments were made using the Unified Parkinson’s Disease Rating Scale (UPDRS) part III after one week of randomized stimulation on and off and with and without anti-PD medications. Although there were no significant differences in the motor scores with stimulation on versus stimulation off condition, all patients presented with a significant reduction in falls both at 3 and 12 months after PPN DBS. These results were captured using the UPDRS part II scores.

Our study suggests that unilateral PPN DBS may be effective in preventing falls in patients with advanced PD. We feel that PPN DBS merits further evaluation in a larger group of PD patients with gait and postural disturbances who are disabled by falls.

 

Project Title: Effects of Levodopa and Deep Brain Stimulation on Parkinsonian Locomotion

Award Granted to: Catherine Cho, PhD and Michele Tagliati, MD

Locomotion is a poorly understood and neglected aspect of Parkinson's disease (PD). Previous studies have been qualitative and have not led to understanding of the deficits in processing that underlie the gait problems. Deep brain stimulation (DBS) offers the possibility of improving gait, but how DBS works together with medication is not known. The Mount Sinai Movement Disorders Division has a highly active DBS program and a locomotion laboratory equipped with sophisticated software and a state-of-the-art video-based motion-detection system (OPTOTRAK 3020, Northern Digital, Inc.) which allow for the measurement of foot, ankle, knee, thigh, and hip movements in three dimensions with unprecedented levels of accuracy.

The purpose of this study is to discover how the legs and feet move while walking in subjects with varying degrees of PD. We have developed a model of leg and foot movements based on completed experiments of healthy subjects walking on a treadmill. Movements of the foot and leg during the swing (when the foot is moving forward) and stance (when the foot is supporting the body) will be recorded, and the gait patterns recorded will be compared to those of normal subjects. The degree of deficiency of walking will be correlated with the disability due to disease.

We will also study how medications and DBS affect the motion of the foot and leg during the stance and swing phases of gait. Preliminary data, point towards specific abnormalities in toe clearance and foot rotation in parkinsonian subjects that may play a pivotal role in gait impairment. When DBS or medications are helpful, these abnormalities are improved. Unfortunately, the deficits identified are not always rectified by current treatment. We will try to take advantage of DBS programming to help identify "gait pathways" in the brain and further characterize how DBS affects gait. Further investigations are needed to identify other potential targets of rehabilitative therapy.

When the study is completed, we should have a better understanding of how foot and leg movements are altered in PD gait and how medication and DBS change these abnormalities. This should help identify dosages, stimulation settings, and rehabilitative procedures that would improve disability due to impairment in locomotion.

Project Title: The Study of molecular mechanisms responsible for the role in overcoming many of the motor deficits seen in injuries to the basal ganglia

Investigator: The Laboratories of Michael Jakowec, PhD, and Giselle Petzinger, MD., Department of Neurology, University of Southern California

The adult brain possesses a tremendous capacity to change in response to environmental cues including learning, memory, and injury. This phenomenon is termed neuroplasticity. One of the key areas of focus of research in our laboratories is to find ways by which we can guide neuroplasticity in the adult brain in order to overcome injuries to the basal ganglia, an area of the brain affected in Parkinson's disease. Our recent studies in an animal model of Parkinson's disease have shown that intensive treadmill exercise plays a critical role in overcoming many of the motor deficits seen in this model. In collaboration with a number of investigators at USC, we are studying the molecular mechanisms responsible for this observation. At this point we know that there are significant changes in how the brain handles dopamine including alterations in the pattern of expression of receptors that normally bind this important neurotransmitter. In addition, we have found that despite a severe depletion of dopamine, similar to that which may exist in Parkinson's disease, exercise is to change how the brain releases dopamine from remaining nigrostriatal terminals. This new way to handle dopamine may be one mechanism by which the brain is able to compensate for injury leading to improvement in motor function. We have also found significant alterations in other neurotransmitter systems in the injured brain with exercise, including changes in the expression of pathways that use both glutamate and serotonin, two systems that may lead to altered dopamine function in recovery.

An important need in our Parkinson's Disease Research Program is to improve our capacity to carryout critical electrophysiological studies of individual neurons within the injured basal ganglia of our models of Parkinson's disease. In close collaboration with Dr. John Walsh in the Andrus Center for Gerontology here at USC, we are carrying out such investigations. By studying single cells we are able to dissect their molecular profile and directly compare those whose recovery has been enhanced by exercise with those that have not. The addition of a new state-of-the-art camera to our existing equipment will allow us to improve the precision and impact of our studies. Under high magnification the new camera will assist us to probe deep within the basal ganglia, target individual neurons, gather their electrophysiological characteristics, and remove their sub-cellular contents for the molecular analysis of genes and proteins responsible for their altered function. Such information will reveal to us the important mechanisms responsible for exercise enhanced recovery of motor behavior within the injured brain and may help identify new therapeutic targets for the treatment of Parkinson's disease.

We would like to thank Team Parkinson for their support and the important role they play in making critical research studies in our laboratories at USC possible.

Project Title: FDDNP-PET as a Surrogate marker in Parkinson’s disease

Investigator: Yvette M. Bordelon, MD, PhD, Department of Neurology, UCLA

I was recruited to the UCLA Department of Neurology as an Assistant Professor in November of 2004 after completing my fellowship in Movement Disorders with Dr. Stanley Fahn at Columbia University. I divide my time between clinical work in the Movement Disorders clinic and translational research (bringing the information gained from basic science laboratory investigation into the clinical practice and treatment of Parkinson disease and other neurologic disorders). I believe that we will see dramatic progress in clinical research in the next several years if we are allowed to pursue translational research projects now that will identify promising studies and techniques to expedite and refine the many impending clinical trials in the study of Parkinson disease. This translational research needs to keep pace with the basic science work in order to provide the scientific community and our patients with the meaningful results necessary to further identify the underlying causes of disease and guide disease-modifying treatments for disorders such as PD for which there are no known cures.

Surrogate markers are test results that can be used to measure a certain characteristic of a disease. Surrogate markers can be used to test effectiveness of particular treatments quickly and efficiently in clinical trials. Currently, there are no known surrogate markers for PD but the need to identify them cannot be overemphasized. Brain imaging holds the highest promise in this capacity as it is safe and non-invasive. A powerful imaging technique in the study of neurologic diseases is positron emission tomography (PET). UCLA has a long history in the field of PET imaging and is home to many researchers responsible for the development of novel imaging compounds and techniques. Recently, Dr. Jorge Barrio developed a new PET compound (FDDNP) that labels abnormal protein aggregates in brains of patients with Alzheimer disease. Altered protein processing and accumulation of protein aggregates is emerging as a common process in many neurologic diseases including Parkinson disease. Alpha-synuclein and other proteins aggregate into Lewy bodies in neurons in PD. A surrogate marker for this hallmark of PD would revolutionize the study of the disorder and expedite the identification of potentially curative therapies. We are now planning to conduct a pilot study using FDDNP-PET in patients with PD. If FDDNP-PET is able to identify abnormal protein accumulation in PD patients, the effects on the world of PD clinical trials would be far-reaching. We plan to use the funds contributed by Team Parkinson to obtain these FDDNP-PET scans in PD patients for the pilot study examining it as a possible surrogate marker in Parkinson disease. The data collected from this pilot study will then be used to apply for a federal grant to support a large project examining this technique further. The support from Team Parkinson is greatly appreciated and will have a significant impact on the conduction of this important line of research.

Project Title: Motor control studies at UCLA

Investigator: Dr. Allan Wu

The UCLA Motor Control Laboratory, under the direction of Dr. Allan Wu, within the Division of Movement Disorders, Department of Neurology, will research transcranial magnetic stimulation (TMS) studies in Parkinson’s disease (PD) patients.

The goal of the UCLA Motor Control Laboratory is to apply motor control principles toward the assessment of movement problems in PD patients. Such principles have the potential to be objective markers of parkinsonian impairment which can then be used to characterize different stages of PD or to assess responses to therapy. The laboratory studies motor control by analyzing goal-directed actions (reaching, grasping, pointing) using a 3-dimensional motion capture system. Transcranial magnetic stimulation (TMS) now adds the ability to investigate the neural basis for these motor control principles.

TMS uses a brief magnetic field to noninvasively and painlessly stimulate the human brain. When TMS is applied over a given brain region during the planning or execution of a goal-oriented action, the resulting effects on that action provide information about the role that brain region plays in generating that particular movement. When applied over the motor cortex, TMS can evoke a muscle twitch. By monitoring this muscle twitch, we can obtain direct information about the activity of the motor output circuit when planning or executing movements. By examining differences in TMS effects between PD patients and normal subjects, we increase our understanding of the neural basis of normal motor control of voluntary movements and how this neural system is altered in Parkinson's disease.

Project Update 2009:

The Wu Laboratory studies the how noninvasive brain stimulation using repetitive magnetic stimulation (rTMS) can modulate and improve symptoms of Parkinson's disease (PD).  This field is advancing rapidly as shown by the recent Food and Drug Administration approval of rTMS as a treatment for patients with severe depression.  With support from Team Parkinson and the Parkinson Alliance, the Wu Laboratory developed a TMS infrastructure to study effects of rTMS in patients with PD.  In the last few years, the laboratory was awarded pilot funding to study short-term effects of rTMS in patients with atypical Parkinsonism (PSP and CBD).  In November 2009, the Michael J. Fox Foundation announced funding for a 3 year clinical trial of rTMS for the treatment of PD symptoms.  The $1.5 million project consists of a consortium of TMS investigators led by Dr. Pascual-Leone in Boston (Beth Israel Deaconess Medical Center-Harvard Medical School) and includes Dr Allan Wu (UCLA), Dr Hubert Fernandez (University of Florida in Gainesville), and Dr. Robert Chen (Toronto Western Research Institute).  This project is the first multicenter, sham-controlled clinical trial of rTMS in North America to determine the efficacy and duration of benefit of rTMS in improving motor and mood symptoms in PD.  Seed funding from Team Parkinson was instrumental in leveraging a relatively new TMS laboratory and investigator at UCLA to the forefront of current TMS research in PD.

Project Update:

The Wu Laboratory studies how noninvasive brain stimulation using repetitive magnetic stimulation (rTMS) can modulate and improve symptoms of Parkinson's disease (PD).  This field is advancing rapidly as shown by the recent Food and Drug Administration approval of rTMS as a treatment for patients with severe depression.  With local support from The Parkinson Alliance and Team Parkinson, the Wu Laboratory has developed a TMS infrastructure to study effects of rTMS in patients with PD.  In the last few years, the laboratory has been awarded pilot funding to study short-term effects of rTMS in patients with atypical Parkinsonism (PSP and CBD).  Dr. Wu has also collaborated with colleagues in Boston (Massachusetts), Gainesville (Florida) and Toronto (Canada) in  designing the first multicenter, sham-controlled clinical trial of  rTMS in the US and Canada to determine the efficacy and duration of  benefit of rTMS in improving motor and mood symptoms in PD.  The resulting clinical trial proposal is currently being reviewed for funding at both NIH and the Michael J Fox Foundation.

 



Project Title: Neuropsychiatric behaviors/compulsive behaviors in Parkinson’s disease and the neuroimaging component of a large trial evaluating the effects of exercise in PD.

Principal Investigator: Dr. Jennifer S. Hui, MD with the division of Movement Disorders at the University of Southern California:

Non-motor symptoms of Parkinson’s disease: Mood, Cognition, and Behavioral Changes:

Although non-motor symptoms are often not well-recognized in Parkinson’s disease (PD), they can be even more disruptive and disabling than the motor manifestations of the disease in up to 30% of patients. These non-motor symptoms include changes in mood, memory, cognition, and behavioral changes such as obsessions and compulsions.

Recent increased awareness of certain compulsive behaviors in PD has highlighted the potential role of medication in the manifestation of these behavioral changes. In particular, dopamine agonists have been implicated in compulsive gambling, shopping, eating and hypersexuality. These behaviors have not been studied in detail, and the risk factors for developing these behaviors are unknown.

Dr. Hui has been studying these behaviors in PD, and is developing an easily administered confidential questionnaire for the screening and detection of compulsive behaviors in PD. It is important to recognize these behaviors early on, because they can be alleviated by simple medication changes. A questionnaire will allow for earlier and confidential reporting of these symptoms, on topics which may be of a personally sensitive nature to patients. Additionally, identifying risk factors for these behaviors will lead to more appropriate, therapeutic choices.

To many PD patients, the non-motor symptoms of their disease are under-recognized, yet significantly impact quality of life. Research in this area is often overlooked and under-funded, making support for these projects more important for the comprehensive treatment of PD.


The Parkinson’s Alliance awards a grant to the University of Florida Movement Disorders Center to aid in Developing a Computerized Screening Tool for Parkinson’s disease patients interested in DBS

Although appropriate patient selection is widely recognized as the first and most important step of successful DBS therapy in Parkinson disease, there is no standardized assessment tool to accomplish this task. As a consequence, there may be confusion about referral criteria for DBS among general neurologists and other healthcare practitioners. These providers provide the majority of routine care to Parkinsonian patients. A recent paper reported that less than 5% of the patients referred for DBS surgery from private practice neurologists and general practitioners were appropriate and immediate candidates for DBS surgery (Okun et al., Neurology 2004; 63: 161-163). Tools are needed to help practitioners screen appropriate candidates for DBS.

We aim to link together in an integrated web-based computerized system a method for screening DBS candidates. The Florida Surgical Questionnaire for Parkinson Disease (FLASQ-PD) has been shown to be a useful triage tool for the workup of Parkinson disease surgical candidates. In addition to this screening tool this new computerized system will take into consideration possible ongoing behavioral and cognitive dysfunction such as depression, anxiety and dementia, which are common in Parkinson disease, and comprise absolute and relative contraindications for DBS surgery. These effects, if not screened for, can impede the success of the DBS procedure.

The purpose of this grant is to test COMPRESS (the comprehensive surgical screener for Parkinson’s disease) as a one-stop, easy-to-use method of quickly but thoroughly assessing a Parkinson patient’s ‘readiness for DBS surgery.

Project Update:

The aim of this study is to compare office based screening for patients interested in deep brain stimulation (DBS) surgery as a treatment option for their Parkinson’s disease (PD) using the COMPRES-PD software (a combination of the Florida Surgical Questionnaire for Parkinson Disease and other cognitive and mood scales) to screening performed at an expert DBS center.  We hypothesize that office based computer screening will be as effective at choosing appropriate DBS candidates as an assessment by an experienced movement disorders specialist. Six referring centers are participating; Neurological Services of Orlando, Bradenton Neurology, Inc, Neurology Institute of Melbourne, Tallahassee Memorial Neuroscience Center, Southeastern Integrated Medical, and Neurology and Neurosurgery Associates.  We aim to enroll up to 50 Parkinson’s patients who have had symptoms for at least five years and who desire to know if they would qualify for DBS.  Each subject undergoes a routine clinical work-up and the COMPRESS-PD battery with their general neurologist.  The subject is then referred to the University of Florida (UF) to be evaluated by a Movement Disorders Specialist and to receive neuropsychological testing.  At study completion, records from the referring clinician’s visit will be compared to those generated during the traditional UF DBS evaluation  to discern if general neurology practices using COMPRESS-PD software can identify good DBS candidates as well as an experienced DBS Center.

The research is prospective, thus there are no results to report at this time. Twenty-five patients have agreed to participate and 17 have completed the study.  Screening and consenting errors on the part of the referring centers as well as insurance issues account for those who have not been seen at our center (ie. completed study).  Multiple strategies to complete the study in 2010 have been implemented including; re-training of sites, addition of new referring sites (pending IRB approval), and an interim analysis after completion of the 25th subject to examine futility. 

Although appropriate patient selection is widely accepted as the first and most important step of successful DBS therapy in PD, there is no standard assessment tool available for the general neurologists to accomplish this task. The knowledge obtained from this study will discern whether COMPRESS-PD could serve as a triage tool for general neurologists and prove as valuable as a visit to an academic center with a movement disorders specialist.

As a scientist and specialist in the field of PD, it is of great benefit to me to contribute meaningful research that has the potential to directly change and improve how patients are selected for DBS surgery by those who provide the majority of their routine care.  The funding provided by the Parkinson Alliance has been a pivotal incentive to those individual and centers we depend upon to recruit the patients for this project.  The money is especially crucial in the current funding environment.


Parkinson's Disease and Movement Disorders Center Northwestern University

Co-Principal Investigator's
Colum MacKinnon, Ph.D
Tanya Simuni, MD

Impact of STN DBS on fine finger dexterity
Project Background and Significance

Impairment of the size and speed of movements, specifically, fine finger dexterity is a significant part of PD-related disability. Currently, the mechanisms for the deterioration of these types of movements remain poorly understood. STN DBS significantly improves the overall degree of PD-related bradykinesia (slowness), but has a variable affect on fine finger dexterity (writing, repetitive finger movements) and does not improve these types of movements to the same extent as levodopa. We have recently discovered that patients with PD show two distinct abnormalities in the performance of paced repetitive finger movements: (1) a marked impairment in the performance of syncopated movements (movements initiated between beats of a metronome) and (2) a movement rate “barrier” characterized by the inability to maintain paced movements above about 2.25 Hz. We have also found that the impairment in syncopated movement can be reversed with anti-parkinsonian medications, but the high frequency movement impairment is unaffected by medication.

Why are these findings important?

These findings demonstrate that some aspects of movement performance in PD benefit from levodopa replacement therapy and others do not. The restoration of syncopated movement with levodopa suggests that these types of tasks are dependent upon dopamine, whereas the impairment in high frequency movements is due to dysfunction of other pathways. This means that a combination of therapies is likely required to restore movement towards normal. We will explore the possibility that a combination of levodopa and STN-DBS can be used to optimize performance.

We will compare and contrast the effects of levodopa and STN-DBS on syncopated and high frequency movements. We hypothesize that STN-DBS, as it is currently used, will not improve syncopated movements, but can be programmed to restore the ability of patients to make high-speed movements up to 3 Hz.

Update: March 22, 2007
Progress Report to the Parkinson Alliance
Project Title: Impact of STN DBS on fine finger dexterity
Investigators: Tanya Simuni, Colum D. MacKinnon, Elizabeth Stegemöller

Performance of repetitive movements of the fingers, hands and feet is an important test used by movement disorders clinicians to assess the severity of bradykinesia in Parkinson's disease (PD). Currently, the mechanism contributing to the deterioration of these types of movements is unknown. For the past year we have been studying the effects of movement frequency and timing on the performance of repetitive finger movements and how levodopa and deep brain stimulation of the subthalamic nucleus (STN-DBS) affects these movements. We have found that, when patients are off anti-parkinsonian medications, there are two distinct abnormalities in repetitive movements: (1) there is a frequency limit at which movements can be performed, which we have termed the “2 Hz barrier”; (2) patients have a marked impairment in movement timing when they attempt to initiate movements between external cues (syncopated movements), even for movements at low frequencies (less than 2 Hz). Optimal medication was associated with improvement in the amplitude of movements above 2 Hz, but low frequency movements (< 2 Hz) were only moderately improved and movement timing was still impaired. In contrast to optimal medication, our preliminary findings have shown that STN-DBS at optimal clinical settings (130-185 Hz, pulse width 90 ºs, voltage 1-3 V) produces a significant improvement in movement regularity and amplitude for movements performed at rates of less than 2 Hz. However, STN-DBS did not improve movements performed at frequencies of 2 Hz or above (i.e. the 2 Hz barrier remained). We are currently conducting experiments to explore the possibility that STN-DBS at mean frequencies near 40 Hz or 70 Hz may improve repetitive movements to a greater extent than at frequencies above 100 Hz. If these medium frequency stimulation patterns improve repetitive movements more than conventional high frequency DBS, these findings will suggest that the next generation of DBS stimulators will need to deliver stimulation simultaneously across multiple frequency bands, since other symptoms of PD respond best at frequencies above 100 Hz (e.g. tremor).

The Parkinson Alliance grant was instrumental in supporting the initial studies examing the effects of medication, external cueing, movement frequency and the effects of optimized DBS on the performance of repetitive finger movements. This data was used as pilot data for a grant submitted to the National Institutes of Health/National Institute of Neurological Disorders and Stroke (RO1 NS054199; Principal Investigator Dr. CD MacKinnon). This grant application was successful and will be funded for four years. The NIH-funded grant will delve in much greater detail into the mechanisms contributing to impaired repetitive movements by recording brain activity during movments using both scalp surface electroencephalography (EEG) and local field potential from implanted macroelectrodes in patients who have undergone STN-DBS. These studies will provide important insight into the cause of movement impairment in PD.

 

American Parkinson Disease Association, Inc.
Research Grant Awardees 2005-2006

Principal Investigator: Mel B. Feany, MD, PhD, Brigham and Women’s Hospital, Boston, MA

Title: Identification of Tyrosine-Phosphorylation Specific a-synuclein Binding Proteins.

Abstract: a-synuclein is a soluble, natively unfolded protein that is highly enriched in the presynaptic terminals of neurons in the central nervous system. It has a central role in the pathogenesis of Parkinson’s disease. The molecular mechanisms underlying the protective effect of tyrosine phoshorylation on a-synuclein toxity to dopaminergic neurons are unclear. We propose that tyrosine phoshorylation-specfic binding partners modulate the downstream toxic effectors of a-synuclien. To test the hypothesis, we will identify proteins that bind to tyrosine phosphorylated or deposphorylated a-synuclein and examine the role of these proteins in controlling a-synuclein toxicity. The specific aims are to identify proteins that interact with a-synuclein in a tyrosine phosphorylation dependent fashion and to validate genetically the role of interacting proteins in controlling a-synuclein toxicity.

Principal Investigator: Su Guo, Ph.D., University of California San Francisco, CA

Title: Toxicogenomic Analysis of Neurotoxin-induced Parkinson’s Disease in the Zebrafish Danio rerio.

Abstract: The behavioral symptoms associated with PD, such as tremor, rigidity and bradykinsia, are a result of selective degeneration of dopaminergic neurons in the substantia nigra. The proposal is to understand the molecular mechanism by which exogenous neurotoxins interact with endogenous genetic factors to cause degeneration.

The vertebrate model organism for genetics, zebrafish Danio rerio, will be employed.

The specific aims proposed are to carry out a detailed pathophysiological and behavioral analysis of a-synuclein transgenic zebrafish, to determine whether treatment with neurotoxins will enhance the neurodegeneration phenotype of a-synuclein transgenic zebrafish and lastly to identify genes and pathways that are altered upon exposure to these endogenous and exogenous neurotoxins..

Principal Investigator: Eunsung Junn, Ph.D., UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ

Title: Effects of DJ-1and DAXX Interaction on Cell Death.

Abstract: Investigations into cellular and molecular biology of genes that cause inherited Parkinson’s disease (PD), as well as, the downstream pathways that they trigger shed considerable light on the understanding fundamental determinants of life and death in dopaminergic neurons. Genetic data highlight the heterogeneity of the disease; the identification of particular therapeutic opportunities involving specific gene products could have implications for the wider PD population, since such molecular pathways likely coexist in complex harmony within nigral dopaminergic neurons. The proposal plans to investigate an unexplored cell death pathway in PD, which is modulated DJ-1 and links this pathway with a well-known dopaminergic neuronal stress. We hypothesize that DJ-1 can act as a molecular switch by binding to Daxx and inhibiting its interaction with ASK1, thus, preventing stress-induced ASK1 activation and subsequent apoptosis. The specific aims are to determine the role of DJ1 in the Daxx/ASK1-mediated cell death and to determine the role of Daxx/ASK1 pathway in MPP-induced cell death.

Principal Investigator: Weidong Le, MD, PhD, Baylor College of Medicine, Houston, TX

Title: Essential role of Iron in Proteasome Inhibitor-Induced Nigral Cell Degeneration.

Abstract: The cause of the neurodegenerative process in PD remains unclear, but evidence suggests that the failure of the ubiquitin-proteasome system (UPS) may play a major role in the pathogenesis of the disease. Iron is believed to be a key contributor to PD pathology by inducing aggregation of a-synclein and generating oxidant stress. We hypothesize that iron plays a key role in proteasome inhibitor-induced nigral pathology and that reducing iron overload may prevent dopaminergic degeneration and abnormal protein aggregation.

Principal Investigator: Felix Schweizer, Ph.D., University of California Los Angeles, CA

Title: A Role of Parkin in Synaptic Transmission.

Abstract: The proposal is to determine whether dysfunction of synaptic vesicle trafficking could contribute especially to early stages of Parkinson’s disease (PD). In particular we are interested in testing whether ubiquitin-modification of proteins by ubiquitin-ligases such as parkin can influence membrane trafficking directly by initiating or indirectly by regulating protein degradation by proteasome. We propose to test whether proteasome inhibition and parkin dysfunction interact on a molecular level or whether they represent alternate pathways of dysfunction relevant to Parkinson disease. The hypothesis being tested will determine if parkin regulates the trafficking of synaptic vesicles at the presynaptic nerve terminal and if it will increase synaptic vesicle trafficking in a parkin-null background and whether this effect is restricted to hippocampal neurons or can be reproduced in dopaminergic neurons.


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