2007 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.


We are supporting 3 projects from the University of California (USC). These items will become part of shared resources between a number of labs investigating PD here at USC including those labs of Drs. Giselle Petzinger, Michael Jakowec, Brett Lund, Jon Walsh, Wendy Gilmore, Daniel Holschneider, and Ruth Wood. These investigators reflect the inter-departmental and multi-disciplinary approach we have here at USC in finding new treatment modalities for PD.


Project 1:

Inflammation has long been recognized as a component of PD but little is known about which immune cell types are found in the affected CNS, if they change over the course of the disease and if they play a solely destructive role in cell death, a beneficial role in neural repair and disease resolution, or a combination of both. By understanding the role that peripheral leukocytes play in the pathology that occurs following MPTP lesioning, we may be able to more accurately define the role of the immune system in PD. This project will address a fundamental question: Are peripheral leukocytes recruited to the CNS following injury? To accomplish this goal we will acquire a specialized strain of mice in which all the peripheral blood cells of the mouse will express either i) green fluorescent protein (GFP) which will cause the cells to be bright green. Mice will be administered the neurotoxin MPTP, to initiate PD-like features and the migration pattern of these cells monitored in tissues using immuno-histochemistry, advanced fluorescent imaging (in the live animal), and cell-sorting. Migrating cells will be analyzed for their molecular features to tell us their origin and function. These studies will allow us to determine the molecular link between the immune system, the peripheral system, and the progression of PD-like injury within the brain. This data is essential to support an application to the NIH on this important topic.

Dollars will be used to purchase mice, per diem, immunohistochemical reagents, fluorescent sorting, microscope supplies, technical support

Project 2:

A fundamental question in the analysis of changes (termed neuroplasticity) that take place in the brain in patients with PD and in animal models is the identity of cells within the basal ganglia and their phenotype. For example, within the basal ganglia there are 2 major types of projection neurons making contacts to other regions of the brain termed indirect and direct. Our ongoing studies have shown dramatic changes in the ability of cells in the injured brain (in which we use the neurotoxicant MPTP to replicate features of PD) to use dopamine differently if the animal is subjected to intensive treadmill exercise. These results are reported in a manuscript published in the Journal of Neuroscience and highlighted as a feature by the editor. To pursue fundamental questions of the molecular and physiological features of these cells we have to opportunity to obtain 3 important transgenic mouse strains that expression a unique molecular in our cells of interest such that they fluoresce green allowing us to monitor them and target them in our studies. These mice termed BAC-eGFP D1, D2, and TH are available from NIH supported services.

This will include purchase of breeding pairs from frozen embryonic stocks, breeding cost in our facility, and per diem costs.

Project 3:

In USC’s lab the MPTP-lesioned mouse model of basal ganglia injury serves as an important link to PD in the human condition. We are interested in the effects of intensive treadmill exercise in promoting motor improvement in this model with the intention that what we learn in the mouse will allow us to better understand how exercise and physical therapy altered the brain and can lead to improved symptoms in patients. One important question is the effects of exercise on the other motor features in the mouse. We have examined learning, memory and mood in our mode and show that some of these features are influenced by exercise in the injured brain. We need to know more about the normal movement of the mouse using an objective measure. For this purpose an activity monitor interfaced with computer imaging will allow analysis of movement of mice in their home environment. We can than monitor improvement of movement with our exercise intervention and identify important factors necessary for this benefit.


 

Project Title:
Long-term Lack of Motor Symptom Progression in Parkinson's Disease Patients with Bilateral STN Deep Brain Stimulation

Caitlin Martin, Ron L Alterman and Michele Tagliati
Mount Sinai School of Medicine, New York, NY

Objective: To evaluate the long-term progression of motor symptoms in Parkinson s disease (PD) patients treated with subthalamic nucleus (STN) deep brain stimulation (DBS).

Background: STN DBS improves motor function in PD, but the duration of benefits is still poorly defined. In particular, the effects of STN DBS over the natural progression of PD and its possible neuroprotective function are debated.

Design/Methods: We retrospectively analyzed data from 48 PD patients implanted with bilateral STN DBS. Clinical records at baseline and at several yearly intervals after the implant were reviewed. Preoperative UPDRS scales were performed after withholding medications for at least 12 hours (Off state) and after taking the usual dose of levodopa (On state). Postoperative evaluations were completed at yearly intervals in four clinical states: 1) Off medications - stimulators Off (Off/Off); 2) Off medications - stimulators On; 3) On medications - stimulators Off; and 4) On medications - stimulators On. UPDRS-III scores obtained at baseline Off state were compared with those obtained Off/Off after surgery.

Results: The average percent change of UPDRS-III Off/Off scores was virtually unmodi�ed up to 5 years follow-up. At one year (n=19) the average percentage change from baseline was 0.0 37. The average changes recorded for the following years were 0.0 23 percent at two years (n=18); 0.9 30 percent at three years (n=13); 1.0 27 percent at four years (n=13); and 3.2 19 at �ve years (n=5).

Conclusions/Relevance: Our data show that untreated PD motor scores do not worsen over time in patients undergoing STN DBS, suggesting that there is no progression of disease severity. These results could be explained either by a ‘natural’ stabilization of PD progression after many years or neuroprotective properties of STN DBS. However, possible study design artifacts, including insufficient stimulation washout times, could have affected these data.

Study supported by a grant of The Parkinson Alliance.


Project Title:

Development of an animal model for alpha-synuclein

The lack of animal models of Parkinson’s disease is a significant hurdle in the development of Parkinson’s disease therapeutics. A model that mirrors the constellation of symptoms and pathology observed in Parkinson’s disease would be invaluable to understanding the mechanism of the disease and also as a tool in which new therapies could be tested. One animal model that shows particular promise is a rodent model that utilizes a virus to deliver a gene associated with hereditary Parkinson’s disease called alpha-synuclein to the brains of rodents. This reproduces the brain cell loss and protein clumping that is observed in PD. Research groups encountered several challenges in reproducing this animal model of Parkinson’s disease consistently. Laboratories who are working on this model are combining forces in a collaboration to leverage their collective experiences in using this model with the objective of fine-tuning an acceptable and consistent animal model for the entire PD research community.

Dr. Patrick Aebischer (Lausanne, Switzerland) is sharing and distributing his virus and protocol to three other research groups around the world. These groups will all independently test various protocols in order to optimize the model and develop the most consistent protocol. These groups will be sharing data and collaborating in a real time manner so information can be used to guide future optimization steps.

The Parkinson Alliance is pleased to support this research and help to fund animal testing in three different laboratories: Dr. J. William Langston at the Parkinson’s Institute in Sunnyvale, California; Dr. Jeffrey H. Kordower at Rush University Medical Center in Chicago; and Anders Bjorkland at Lund University in Sweden.

Impact on the field

The availability of a standard protocol for producing and consistently reproducing a model of alpha-synuclein induced toxicity would be extremely valuable to the PD research field as a model to test therapeutics. This would also move the field further by preventing other groups from spending time and resources optimizing their own model.


Project Update:
The consortium has made significant progress in establishing a consistent and reproducible model of Parkinson's disease that may be used to test novel interventions. Experiments are still ongoing to optimize and determine the best and most appropriate methodology.


 

Project Title:
Speech Treatment for individuals with Parkinson disease (PD)
Post-Deep Brain Surgery of the Subthalamic Nucleus (DBS-STN):
Systematic Development of a New Approach to Intervention

Lorraine Ramig, Ph.D., CCC-SLP
Jennifer Spielman, M.A., CCC-SLP
Angela Halpern, M.A., CCC-SLP
Leslie Mahler, Ph.D., CCC-SLP
National Center for Voice and Speech, Denver, Colorado
University of Colorado-Boulder

The need: Nearly 90% of individuals with PD have a speech or voice problem that can diminish quality of life. While surgical advances to treat PD, such as STN-DBS offer significant improvements in many body functions in individuals with PD, speech does not typically improve in these patients. In fact, there are reports that up to 30% of patients experience worsening of speech post-STN-DBS.

Today, LSVT is the only speech treatment for PD with level one evidence. Reports of application of LSVT to individuals post-STN-DBS have been mixed. While some reports suggest improvements, others suggest that some speech problems remain after LSVT. Most common complaints are that while patients do improve their volume and speech intelligibility following LSVT, labored articulation (motor problem), lack of carryover (internal cueing and learning problem) and resistance (sensory problem) remain. As a result, some patients do not have optimum communication outcomes. What is needed is an approach to address the specific speech problems in individuals post STN-DBS. Our years of experience developing LSVT position us well to take on this task.

Goal: The goal for this project is to begin to develop a systematic approach to speech treatment planning in individuals with PD post STN-DBS. We propose to develop a speech assessment protocol that will allow speech clinicians to optimize treatment outcomes with these individuals.

Plan: Our first step is to evaluate LSVT outcomes in three individuals with PD post STN-DBS compared with age, gender and severity matched individuals with PD (who had not been surgically managed) and an untreated PD control group. These data will be compared in order to identify post-treatment differences in these groups. A key element in our assessments will be the addition of detailed analysis of the most common communication breakdowns post-STN-DBS and their impact on speech treatment outcomes.

Based upon these findings, our next step will be a Phase 1 pilot study using multiple single subject designs. Eight individuals post STN-DBS will be studied across two months: pre-treatment (one week), LSVT (one month of treatment), post treatment 1 (one week), LSVT-DBS (one to two weeks) and post assessment 2 (1 week). Experimental speech data will be collected on these well-defined (stage of disease, medication, site of leads, stimulator settings) individuals.

A unique element of this work is that treatment related changes will be studied as they emerge during the course of treatment (not simply pre-post) in order to define the key breakdowns in individuals post STN-DBS. These key breakdowns will be used to systematically determine additions to be made to LSVT. Following standard LSVT, these individuals will participate in an LSVT-DBS “module” designed to specifically target the remaining challenges to their communication (e.g., motor, internal cueing, sensory). Post-treatment data will be collected after that LSVT-DBS module.

Outcome: These data will be used to inform an intake protocol tailored for planning speech treatment LSVT-DBS and outcome data following LSVT-DBS modules. These outcome data will be used to guide our further enhancement of DBS specific treatment modules.

Project Update:

Part 1: Treatment effects on subjects with and without STN-DBS. Four subjects with bilateral STN-DBS who received LSVT have been compared to 8 matched PD subjects without STN-DBS - 4 treated and 4 untreated. Analysis of voice intensity, vowel articulation, and self/other rating scales of voice and speech disability indicate that the subjects with STN-DBS were able to make clinically significant improvements in vocal loudness and articulation through treatment, and maintain some of these gains through follow up.

Acoustic data and ratings from subjects and significant others also revealed pre-treatment differences between DBS vs. non-DBS subjects. Specifically, subjects with STN-DBS were rated (by themselves and others) with higher levels of speech and voice disability, and were considered softer, more slurred, and less effective at communicating. Three out of four DBS subjects also fell below the median intensity level for speech tasks before treatment
(69.8 dB SPL).These findings are consistent with literature suggesting that STN-DBS has a negative effect on speech production in some individuals.

see: Mahler, L.A., Ramig, L.O., Spielman, J., & Halpern, A. (2008). Effects of LSVTR on four participants with PD who received deep brain stimulation. Movement Disorders, 23 (1), S286. (Abstract)

Part 2: Treatment of additional subjects with bilateral STN-DBS. One subject has completed evaluation and six weeks of LSVT, with data collected at pre, post week 4, and post week 6 intervals. Initial results indicate a positive treatment effect for vocal intensity, and a benefit to extending treatment from 4 to 6 weeks. Four additional subjects are in line for receiving therapy, and recruitment is ongoing. The project is expected to be completed by July 2009.

2nd Project Update:

PI: Lorraine Ramig Ph.D., CCC-SLP
Professor, University of Colorado-Boulder
Senior Scientist, National Center for Voice and Speech-Denver
Adjunct Professor, Columbia University, NY

Grant period: July 2007 – July 2009
Requesting extension of funding past July 2009 to complete data analysis (see below)

Goal: The goal for this project is to begin to develop a systematic approach to speech treatment planning in individuals with PD post STN-DBS, with a focus on optimizing treatment outcomes for this population.

Summary:

Six individuals with PD and bilateral STN-DBS (1 F, 5 M) were enrolled in the study. Ages ranged from 54-69 years, time since diagnosis ranged from 5-14 years, and time since surgery ranged from 6 months to 3 years. Participants were judged to have voice and speech problems consistent with PD; two participants were also judged to have moderate to severe articulation difficulties not typically seen in PD. All participants received 16 sessions of LSVT/LOUD (4 times a week for 4 weeks), followed by 2 additional weeks of intensive treatment based on how their speech deficits fit into two areas of difficulty believed to be related to STN-DBS: 1) difficulty with carryover of loud voice into conversation (“calibration”) and 2) difficulty with articulation beyond typical PD-related dysarthria. Three participants were assigned to each group.

Data were collected 3 times before treatment (pre), twice after LSVT/LOUD (mid), and twice after the additional 2 weeks of therapy (post), and included audio recordings for analysis of voice intensity (SPL), articulatory acoustics and intelligibility, and perceptual forms from both participants and their friends or family members.

While only a small portion of the analysis has been completed, results so far indicate that all participants benefited from LSVT/LOUD by substantially increasing vocal loudness, both objectively (in terms of SPL) and perceptually as heard by others. Furthermore, the addition of articulation exercises after 4 weeks of LSVT did not necessarily have a negative impact on a speaker’s ability to stay loud, and clearly had a positive impact on the perceived reduction of slurring in the two participants rated most severe prior to treatment. Finally, all 6 participants perceived improvements in their own communicative effectiveness at mid (after LSVT/LOUD), and 1 participant continued to report large additional gains in this area following two more weeks of treatment. Taken together, results suggest that people with PD can benefit from LSVT/LOUD following STN-DBS, and may benefit further from additional therapy focusing on their unique speech deficits. Analysis of collected data is ongoing.
    
Read a PDF of the detailed progress.

 


 

Project Title:
Proposal for Research on Pathological Gambling and Parkinson Disease

Indu Subramanian MD- Neurologist, Movement Disorders Specialist in Parkinson Disease
Timothy Fong MD- Psychiatrist, Gambling and Addiction Research
Russell Poldrack PhD- Psychologist, Behavioral Decision Making Research Group
Craig Fox PhD- Psychologist, Behavioral Decsion Making, Anderson School of Business

Recently, there have been published reports of patients with Parkinson disease who develop a gambling addiction while taking dopamine agonists. This may be statistically rare, (7% of patients on dopamine agonists), but when it does occur it can be devastating to the patient and family. This problem can lead to significant financial loss, marital discord, loss of employment and requires titration off of a dopamine agonist and may preclude deep brain stimulation (DBS). As a result, understanding why certain patients are vulnerable to develop this while others are not is a critical area to research. The premorbid personality of patients who develop Parkinson disease has been described as non-risk taking. Understanding changes in these risk-taking traits as patients develop the disease and with treatment is also a vital area of research.

A multi-disciplinary approach to this problem has been proposed at UCLA using expertise from the areas of neuropsychology, gambling addiction and neurology. We propose to systematically administer a battery of neuropsychological tests to three distinct populations: 1) Patients with Parkinson Disease 2)Patients with pathological gambling and c) Healthy controls. These tests have been shown to involve parts of the brain that control impulsivity and decision-making. This battery has previously been studied in normal healthy young controls at UCLA and the parts of the brain that are used while being tested have been shown with neuroimaging technology (fMRI). Funding is already in place to study the pathologic gamblers and healthy controls.

The neuropsychological testing takes one hour to complete and is computerized. We plan to recruit 60 patients with PD, 60 patients with Pathological Gambling and 60 healthy controls and then test them all with the same battery. The results of this testing will allow for comparisons between the three different groups which will inform us about the similarities and differences between the diseases. Parkinson disease patients who score similarly to pathological gamblers on these tests may represent a group that is at risk to develop gambling problems while on dopamine agonists.

This paradigm will be repeated over the course of the disease in Parkinson patients to see if differences in test results emerge as therapeutic interventions such as dopamine agonists or deep brain stimulation are added. We hope to predict from tests and other variables which patients may be at risk for this impulse control disorder. Additionally, fMRI testing of PD patients with abnormal computerized testing scores from the above study will be performed to further refine anatomical areas of interest and may lead to potential therapeutic strategies. FMRI for the control populations has already been performed and funding is already secured to scan the gambling group.

In order to support the PD portion of this proposal, resources will be needed for administration of the laptop testing on the 60 patients with PD and for scanner time to perform the fMRI scans on the subset of PD patients. Funds would also be needed for PD patient recruitment and reimbursement for patient parking.

 

Project Update:

Objective: To determine differences in personality and decision-making behavior between (1) PD patients with impulse control disorders (ICD), those without ICD, and aged-matched controls and (2) PD patients off meds, those on dopamine agonist medication (DA), and those taking levodopa (LA).

Background: A spectrum of ICD in PD, such as pathological gambling, hypersexuality, or binge eating, has been associated with side-effects of particularly DA. Since ICD pathophysiology in PD is attributed to dysregulation of dopaminergic pathways related to risk and reward, we hypothesize that monetary decision-making tasks will provide quantitative measures of a patient’s decision-making bias that correlates with risk of developing ICD in order to help clinicians predict and monitor ICD in PD patients.

Methods/Design:  Patients: 59 Parkinson’s patients (35 men; 24 women) who displayed symptoms across the entire spectrum of disease severity were enrolled in this study. They were all recruited from the Movement Disorders Clinic at the UCLA Medical Plaza. None of the PD patients were cognitively impaired. Procedure: Clinical assessments were collected through self-report questionnaires (socio-demographic background, medical history, current medication, the new UPDRS’s Non-Motor Aspects of the Mental State subscale). All patients completed a computer-based test battery—i.e., 2 monetary decision-making tasks followed by 8 personality questionnaires. The order of the 2 subparts was randomized. Statistical Analysis: A univariate GLM model was used with DV being the10 tests controlled for age and gender. All significance tests were two-tailed at a confidence interval of <95% using SPSS 11.0. When a significant difference was detected, post hoc paired t-tests were conducted.


Results: (1) The Loss Aversion monetary decision-making task revealed that PD patients with ICD were more loss-aversive relative to PD patients without ICD and age-matched controls. (2) PD patients with ICD scored significantly higher on the Attentional Impulsivity scale of the BIS relative to those without ICD and age-matched controls. (3) Age-matched controls were significantly more extroverted than PD patients without ICD, who in turn, were significantly more extroverted than PD patients with ICD. As a whole group, PD patients were less extroverted than age-matched controls. The recreational and ethical domains of the DOSPERT revealed that age-matched controls took significantly more risks relative to PD patients in general. The social domain of the DOSPERT showed that patients with ICD took significantly more risks compared with those without ICD.

Conclusion / Relevance to Parkinson’s disease: (1) Patients with ICD took more risks relative to age-matched controls and PD patients without ICD. Further, PD patients as a group vs. age-matched controls showed no significant differences. However, significant differences emerged when age-matched controls were compared with the ICD and no ICD groups, separately, suggesting that within the PD population, the ICD group may be a separate entity within PD. (2) It is unclear why PD patients with ICD in this study were less extroverted relative to the PD patients without ICD. It is plausible that extroversion may be unrelated, and thus be an unreliable measurement of impulsivity in PD patients. (3) Contrary to our hypothesis, the Loss Aversion task revealed that PD patients take fewer risks relative to PD patients without ICD and age-matched controls. Interestingly, Brañas-Garza et al. found that pathological gamblers took fewer risks compared with controls in a lottery-choice task. (5) Lastly, there is an overall trend of patients on DA taking more risks than those on LD,  regardless of ICD (n.s). However, similar to (4), patients on DA were slightly more loss-aversive than those on LD. To our knowledge, no quantitative neuroimaging study has reported biomarkers for ICD in PD, and future neuroimaging studies may fill the gap.


Project Title:

Pathological Evaluation of Alpha-Synuclein and Lewy Bodies in Parkinson’s disease and Related Disorders

Emad Farag MD

Parkinson’s disease (PD) is usually diagnosed clinically based on a patients symptoms, physical examine, laboratory tests, and response to medications. The only way to actually be certain that someone had PD is by looking at brain tissue and determining if there are Lewy Bodies (LB) in certain brain regions. LB are basically an abnormal clump of proteins (inclusions) that have certain characteristics by various staining techniques and contain a high concentration of a protein called alpha-synuclein. It turns out that LB can be found in other disorders that resemble PD such as Diffuse Lewy Body disease (DLBD) and clumps of alpha-synuclein are found in another related disorder called Multiple System Atrophy (MSA). It is not known whether LB and inclusions are formed by the same processes or whether they reflect completely different diseases. This is an extremely important question because if they are the same thing only in different cells, information about the causes of each disorder will be useful in understanding the others. More importantly, therapies that are being developed for one disease could be used for the others. If the formation of LB and inclusions differ, we can learn a lot about how similar structures can be caused by different processes thus, possibly providing new insights into how people get these disorders.

Dr. Farag and UCLA are perfectly suited to perform these studies. Dr. Farag is a Board Certified Neurologist with specialty training in Movement Disorders (PD), Neurobehavior (DLB, PSP, and Alzheimer’s disease), and Neuropathology (the study of brain tissue). He was recently recruited to our Movement Disorders group and is an Assistant Professor. UCLA has several donated brains from patients with all of these disorders and has all of the equipment and scientific expertise to perform the studies. The results of this project will be used to apply for NIH funds.

Project Update:

Dr. Farag has reviewed autopsy data from all brains autopsied at UCLA from 1986 to 2006 (410 autopsies), and created a searchable database of diagnostic data.  The database has been queried to identify cases of Parkinson’s disease and Lewy body disease.  The histologic, immunohistochemical, and morphometric counting methods to be employed have been tested on tissue from a patient with Parkinson’s disease who had undergone an experimental cell implantation treatment during life.  These results will be published in a peer reviewed scientific journal (accepted, in press).  The precise antigenic targets are being selected to apply the methods to all cases identified.


 

Project Title:
Impact of Subthalamic Nucleus Deep Brain Stimulation On Speech And Swallowing In Patients With Parkinson’s Disease

Principal Investigator:
Tanya Simuni, MD. Parkinson’s disease and Movement Disorders Center, Department of NeurologyFeinberg School of Medicine, Northwestern University
710 North Lake Shore drive, Chicago, IL 60611

Co-Principal Investigator:
Jeri Logemann, PhD. Professor, Department of Communication Sciences and Speech Disorders.
Northwestern University

Parkinson's disease (PD) is the second most common neurodegenerative disease that affects 1% of the population above the age 65 [Kessler, 1972 #189]. The cardinal manifestations of PD include bradykinesia, rigidity, tremor, and frequently postural instability. However, PD related disability is not limited to pure motor symptoms, and often includes swallowing, speech and voice dysfunction. At least 75% of PD patients have a speech disorder, and up to 50% have symptomatic swallowing dysfunction [Logemann, 1978 #190]. The mainstream of treatment of PD is pharmacological management in the form of either dopamine precursor, levodopa, or dopamine agonists. The degree of response of speech and swallowing to dopaminergic therapy is variable and does not parallel the degree of motor benefit [Hunter, 1997 #69]. Overall success of pharmacological treatment is suboptimal. Fifty % of patients develop treatment related complications (motor fluctuations and dyskinesias) within five years of initiation of therapy.

Surgical intervention in the form of deep brain stimulation usually targeting subthalamic nucleus (STN DBS) is widely used for patients who exhausted pharmacological options. Approximately 10% of PD patients are considered to be surgical candidates. The benefits of surgery for improvement of PD motor symptoms are well documented in literature, and averages 60% improvement in PD motor scores in medications off state. However the impact of STN DBS on speech and swallowing is less defined. This is especially important in view of the known negative impact of ablative procedures (pallidotomy and thalamotomy) on speech. Studies based on the objective acoustic voice analysis and oral force control in patients with STN DBS have been inconsistent: some demonstrated improvement in all domains of speech with STN DBS on versus off postoperatively (Gentil 1999, 2003) while Dromey at al (2000) documented no change in speech with stimulation alone. The difference in the outcomes could be attributed to the small sample sizes. The clinical outcome studies demonstrated improvement in speech with DBS short term (1 year) but subsequent decline of speech by five years of follow up (Krack, Batir et al. 2003). The deterioration was attributed to the natural progression of the disease. Two studies implicated a negative effect of stimulation on speech and related it to the laterality of STN DBS implantation: in both studies left STN DBS resulted in speech deterioration which interestingly was compensated for when both stimulators were turned on (Santens 2003). These
results implicate potential stimulation-induced disruption of left hemispheric networks involved with speech production. However, the sample size in both studies was small and additional data are necessary. There are no objective data on the short or long term impact or STN DBS on swallowing as determined by standard quantitative swallowing studies. In conclusion, additional data are necessary to characterize the impact of STN DBS on speech and swallowing and to “tease” out the effects of surgery, medication and stimulation.

Specific aims:

To study the impact of STN DBS on speech so that we can:
1. Characterize the effect(s) of the surgical procedure on speech based on selected measures from standard speech recordings completed pre and 1-3 month postoperatively in the medications off/stimulation off state

2. Establish the effect of STN stimulation on speech based on the selected measures from the speech recordings in the stimulation off versus on state at 1 month after the surgery and to compare the stimulation effect versus medications effect.

3. Characterize the impact of laterality of stimulation on speech based on speech recordings with unilateral and bilateral stimulation.

To study the impact of STN DBS on swallowing so that we can:

1. Establish the impact of the surgical procedure on swallowing based on analysis of the videofluoroscopic study of the oropharyngeal swallow performed pre and at 1month postoperatively.

2. Establish the impact of STN DBS on swallowing based on the videofluoroscopic oropharyngeal swallow study performed in the stimulation off and on state and to compare the stimulation versus medications effect.

Preliminary work
We have completed some preliminary work. Provided data on potential negative impact of STN-DBS on speech, we now perform speech/swallow evaluation on all patients planned to undergo surgery as part of the preoperative assessment. In the past 2 years we have performed testing on 6 patients scheduled to be implanted and 10 patients who already had surgery and were complaining of new onset dysphagia. They had no difficulty with the duration or complexity of the clinical testing. They had
repeated radiographic studies separated by at least one hour during which they received other testing for both speech and voice. They also tolerated a period off medication with no difficulty. The patients had no complaints with the protocol, were not over fatigued, and did not mind the prolonged testing. The data are all complete and data reduction has revealed that the quality of the data are excellent. Thus, the protocol and the available patients appear ready to complete the study. The protocol has been approved by the Institutional Review Board for accrual. We have presented preliminary data at the Parkinson World Congress as abstracts but need funding for further data accrual and analysis.

Research Design and Methods
1. Subjects: Twelve study patients will be recruited from the Northwestern University Movement Disorders program. There are 900 active PD patients in the database.

2. Study Design: Speech and swallowing evaluation is part of the standard preoperative assessment of all patients scheduled to undergo STN DBS. All patients will be asked to participate in the study. Provided that subjects agree, informed consent will be signed. Subjects will undergo initial study related procedures during the preoperative evaluation performed within 1 month prior to surgery. Postoperative evaluations will be performed 1-3 month after surgery provided that stimulation
settings were optimized by that time.

Each evaluation will consist of motor PD assessment and speech/swallow assessment as outlined below. The same personnel will perform the evaluations for the duration of the study. The speech therapy personnel will be blinded to the stimulation and medications status of the patients during the assessment. The speech and swallow tasks in each evaluation will be randomized for each visit.

Significance: Swallowing and speech disorders occur in a large proportion of patients with PD. They interfere with the patient’s nutritional status, as in the case of swallowing, and ability to communicate effectively, as in the case of speech. Both of these functions are critical to independent living and psychosocial interaction and health. Inefficient swallow can result in aspiration and pneumonia. Pilot data from this study will enable us to apply for a larger research grant from NIH, to look at immediate and long-term effects of DBS-STN stimulation.

Project Update:

Speech:

Results: All patients had a significant improvement in motor disability with DBS STN. The mean reduction of UPDRS motor score in the medications off state was 54%. The mean reduction of the dose of medications was 46%. Majority of patients were programmed in the monopolar setting (7/10). The average voltage was 2.8. pulse width 85 , and rate 185 Hz. 3/10 subjects reported mild swallowing dysfunction rated 1/4 on UPDRS II scale. On objective swallowing measures, OTT averaged .53 sec with stim off, .5 sec with stim on. Average PDT was .13 sec with stim off, .17 sec with stim on. Average duration of CPO was .49 seconds with stim off, .51 seconds with stim on.

Conclusions: In this cohort of patients DBS stimulation did not have an impact on swallowing parameters. This is the first report analyzing effects of DBS surgery on swallowing. Larger sample size and comparison between pre and postoperative objective swallowing assessment measures are necessary to establish the effect of surgery versus stimulation on swallow function.

Swallowing:

Results: All patients had a significant improvement with DBS STN. The mean reduction of UPDRS motor score in the medications off state was 54%. The mean reduction of the dose of medications was 46%. Majority of patients were programmed in the monopolar setting (7/10). The average voltage was 2.8 pulse width 85, and rate 185 Hz. At the time of the speech evaluation the patients speech impairment ranged between 0-3, mean 1.7 based on items 5 and 18 UPDRS scale in the medications off, stimulation on state. Patient’s assessment of speech impairment correlated with the physician’s assessment in all cases. 2 subjects reported worsening of speech with stimulation. On objective speech assessment, average change in max sustained phonation was +0.9 seconds, range -5 to +9 seconds. This subject with a gain of 9 sec with stim off also had the most articulation errors in the stim on condition (8 errors), which was reduced to 0 errors in the stim off condition. The remaining subjects had 0-1 articulation errors. The average change in loudness was +2.7dB, range from -2dB to +8dB. Qualitative changes in speech rate and degree of vocal breathiness were also observed.

Conclusions: In this cohort of patients DBS stimulation did not overall have an impact on speech parameters. However, 2/10 subjects demonstrated worsening of speech with stim on. These two subjects with stimulation induced worsening of speech also presented with the greatest degree of speech impairment at baseline. The UPDRS assessment of speech is not sensitive enough to demonstrate these changes. Objective speech assessment is warranted. Larger sample size and comparison between pre and postoperative objective speech assessment measures are necessary to establish the effect of surgery versus stimulation on speech. We also are in the process of analyzing the effect of the laterality of stimulation on speech.


Project Title: A Neurochemical Link Between Motor And Autonomic Deficits In Parkinson's Disease

Principal Investigator: Dr. Gay Holstein
Co-Investigators: Drs. Giorgio Martinelli And Victor Friedrich
Departments Of Neurology And Neuroscience
Mount Sinai School Of Medicine, New York

Difficulties with blood pressure regulation are common in Parkinson’s Disease patients, and may occur years before the emergence of the motor symptoms of the disease. The basis for this relationship between the neural control of blood pressure and the dopaminergic nigrostriatal pathway is not known. We hypothesize that a newly recognized neuromodulator involved in blood pressure regulation (IAA-RP) provides one basis for this association. The aim of the research is to identify the anatomical relationship between cells containing IAA-RP and those of the nigrostriatal projection, which utilize the classic neurotransmitters dopamine and GABA. We will test three hypotheses: (1) that IAA-RP is co-localized in dopaminergic neurons in substantia nigra, (2) that IAA-RP is present in GABAergic neurons in the striatum, and (3) that IAA-RP is present in dopaminergic and GABAergic terminals contacting GABAergic neurons in the striatum. The results of these experiments will provide the first evidence for a neurochemical link between autonomic and motor symptoms of Parkinson’s Disease. Since the blood pressure alterations typically precede the classic motor deficits, the results of this study are likely to contribute to our understanding of the earliest cellular changes that occur in the disease. They may provide a new approach for early diagnosis of the disease, as well as a new avenue for pharmacologic treatment.

Project Update:

GOAL
The long-term objectives of this research program are to identify the physiological, anatomical and chemo-anatomical bases underlying the specific relationship between central autonomic and dopaminergic cellular vulnerabilities in Parkinson’s Disease. The specific aim of the research supported by the Parkinson Alliance was to identify the chemoanatomic relationship between the putative neuromodulator imidazole-4-acetic acid-ribotide (IAA-RP) and the classic neurotransmitters of the substantia nigra (SN), dopamine (DA) and GABA. Two hypotheses were tested in these experiments: (1) that IAA-RP is co-localized in dopaminergic - but not GABAergic - neurons in substantia nigra, and (2) that IAA-RP immunolabeling is significantly reduced after 6-OHDA lesions in SN.
    
EXPERIMENTAL APPROACH
Single-, double- and triple-label immunofluorescence staining was conducted on 50 µm thick Vibratome sections through the rat SN. In addition to experiments on normal rat tissue, we labeled and examined tissue sections obtained from rats that had been injected unilaterally with 6-hydroxydopamine (6-OHDA), a neurotoxin that specifically targets and lesions dopaminergic cells of the SN. In order to localize IAA-RP in relation to dopaminergic and GABAergic cells, we used polyclonal anti-IAA-RP and monoclonal anti-GABA and anti-catecholamine antisera produced in our laboratory, as well as monoclonal and polyclonal anti-tyrosine hydroxylase (TH) antisera (from Sigma and Imgenex, respectively) as primary antibodies. All secondary antibodies were AlexaFluor conjugates (Invitrogen) and anti-mouse secondary reagents were IgG subtype-specific. Light microscopy was performed and image sets were collected using a Zeiss Axioplan 2 microscope with an Apotome slider.

RESULTS
Immunostaining in the SN contralateral to the 6-OHDA lesion is indistinguishable from the staining in normal (non-injected) SN. In these sections, two tiers of TH+ cells are present in SN, dorsal and ventral, as well as a cell cluster in the ventral tegmental area. GABAergic cells are present in pars reticulata, and an extremely dense GABAergic fiber plexus extends throughout the region as well. There is a substantial population of IAA-RP-immunolabeled neurons, which are located primarily in the vicinity of the upper tier of pars compacta cells. The IAA-RP+ cells are fusiform and multipolar in shape, and approximately 15 - 25 µm in cross-sectional diameter. Both cytological cell types, and their proximal dendrites, are encapsulated by, and embedded in, the GABAergic fiber plexus. No co-localization of GABA and IAA-RP is apparent in somata or processes. In contrast, a small but consistent subpopulation of dopaminergic cells, identified in separate experiments by immunostaining for TH or for catecholamines in general, co-localizes IAA-RP.
    
    The presence and density of the GABAergic fiber plexus in the SN appears to be unaffected by the 6-OHDA lesion, as does the density of GABA-immunolabeled somata. In addition, the substantial population of IAA-RP-positive neurons with long radiating dendritic processes survived intact and, as observed in the normal tissue, is surrounded by GABAergic processes. As a result of the 6-OHDA lesion, there is a marked reduction in the TH and catecholamine immunostaining in SN, although a high density of such cells persists in the ventral tegmental area. Many of the surviving dopaminergic neurons appear to co-localize IAA-RP.

CONCLUSIONS
The major findings of this study are (1) that IAA-RP is present in a subpopulation of dopaminergic neurons in the rat substantia nigra, (2) that IAA-RP is not present in GABAergic nigral neurons, (3) that IAA-RP immunostaining is not eliminated by 6-OHDA lesioning of dopaminergic cells in SN, but (4) that this lesion destroys most dopaminergic/IAA-RP-positive SN cells. The observed co-localization of IAA-RP in dopaminergic SN neurons supports our overall hypothesis that IAA-RP plays a role in the nigrostriatal pathway. In addition, since our previous studies have shown that IAA-RP is a putative CNS neurotransmitter/modulator and an endogenous regulator of systemic blood pressure, the present results provide support for our hypothesis that the autonomic deficits experienced by many Parkinson’s Disease patients are related to the loss of neuronal IAA-RP in dopaminergic SN neurons.
    
FUTURE DIRECTIONS
These findings lead to several new hypotheses about the role of IAA-RP in the nigrostriatal pathway. They are:
    (1) Relevant to this project, there are four populations of SN neurons: GABAergic, IAA-RP-immunopositive, dopaminergic, and cells that co-localize IAA-RP and DA. Since only the latter two cell groups are affected by 6-OHDA lesions, we can hypothesize that the neurons specifically responsible for mediating autonomic functions in basal ganglia pathways are those that co-localize DA and IAA-RP.
    (2) Since autonomic dysfunction in Parkinson’s Disease often precedes the emergence of motor symptoms, we hypothesize that nigrostriatal cells containing both DA and IAA-RP lose IAA-RP content prior to cell death and the attendant loss of striatal dopaminergic innervation. This in turn suggests the hypothesis
    (3) That IAA-RP is neuroprotective in cells that co-localize DA and IAA-RP.
We hope to evaluate these hypotheses in a series of future studies that will utilize quantitative assays to measure IAA-RP levels ipsilateral and contralateral to 6-OHDA lesions at different time points post-injection as well as physiologic assessment of autonomic function in the lesioned animals and further immunofluorescence studies of SN and the caudo-putamen.

2nd Project Update:

Results: We have found that IAA-RP is co-localized in striatal cells that contain the calcium binding protein calbindin. While all calbindin-positive neurons co-localized IAA-RP, not all IAA-RP-containing cells co-localized calbindin. This suggested that calbindin-containing neurons in the rat caudo-putamen are a subset of all IAA-RP-positive striatal cells. Moreover, some of the IAA-RP-immunofluorescent neurons did not appear to be confined to the striatal matrix, but instead were present in the calbindin-poor patch compartment. This is important because the patch and matrix compartments have different afferent and efferent connectivity, and are associated with different functional loops of the basal ganglia. To pursue this, tissue sections were immunostained for IAA-RP and parvalbumin, a calcium binding protein that is present in fast-spiking GABAergic striatal interneurons. We found no evidence for co-localization of IAA-RP and parvalbumin in individual striatal neurons, leading to the conclusion that IAA-RP is not present in this interneuron subtype.

Conclusion/Relevance to Parkinson’s disease
: The major conclusion of our studies in the striatum thus far is that IAA-RP is not present in all striatal cell types. Our current research continues to pursue this, in order to identify the chemoanatomic phenotype of all IAA-RP-containing striatal neurons. Our subsequent research will then address the selective vulnerability of these IAA-RP-positive striatal neurons, and the possibility that such cells are responsible for the autonomic dysfunction associated with PD.


Project Title: Pre-surgical Screening and Prospective Assessment of Balance and Gait in PD Patients Undergoing STN DBS

Principal Investigators: Michele Tagliati, MD Catherine Cho, MD Joan Miravite, FNP Ron Alterman, MD DBS Program
Mount Sinai School of Medicine

Specific Aims
The goal of this study is to carry out a clinical screening and prospective evaluation of postural balance and gait in patients with advanced Parkinson’s disease (PD) undergoing subthalamic nucleus (STN) deep brain stimulation (DBS). STN DBS improves most motor symptoms of advanced PD, but its effect on postural balance and gait are controversial. One of the problems in evaluating the effects of STN DBS on balance and gait is that these features are not routinely addressed in pre-surgical assessment. The Tinetti balance scale is a simple clinical instrument that assesses both balance and gait (Tinetti, 1986). In this study, 25 consecutive patients with advanced PD and STN DBS candidates will be systematically evaluated with a validated yet simple, relatively fast clinical protocol including UPDRS, Hoehn and Yahr, Schwab and England and Tinetti balance scale. Each patient will also undergo clinical evaluations at selected intervals post-surgery using the same clinical scales and quality of life measures in order to evaluate the effect of DBS on gait, balance and general PD symptoms.
Specific aims of this study will be:
1. To describe the clinical effects of STN DBS on balance and gait in PD patients.
2. To define possible presurgical outcome predictors for development of balance and gait abnormalities in PD patients after STN DBS.

Background
Parkinson's disease (PD) is a chronic neurodegenerative disorder of unknown cause due to the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Over 1 million people suffer from PD in the United States and every year approximately 50-60,000 new cases of PD are diagnosed. Rigidity, akinesia and resting tremor represent the main motor symptoms of PD. Early in the course of the disease, dopaminergic therapies such as levodopa and dopamine-agonists provide excellent clinical benefit. However, the progressive features of the disease lead to severe disability as drug treatment becomes refractory. In addition, disabling levodopa-related dyskinesias may further complicate the clinical picture. In these advanced stages of PD, surgical approaches often represent the only hope for achieving relief from the debilitating disorder.

Historically a variety of surgical approaches have been tried for the treatment of PD. With the recent development of DBS techniques, bilateral surgery can now be performed without the high incidence of side effects associated with ablative surgery. An additional advantage to DBS is that side effects associated with stimulation are reversible and stimulation parameters can be adjusted allowing one to tailor the stimulation to each individual’s needs. A large body of evidence supports the use of DBS for patients with advanced, medication refractory PD (Walter and Vitek, 2004) In addition, clinical improvement from DBS and reduction of the dopaminergic drugs appear to be long-lasting and patients often recover a satisfactory autonomy for activities of daily living.

A potential, though controversial, drawback of STN DBS for PD is the apparent lack of beneficial effects or possibly detrimental outcome on balance and gait. Typically, parkinsonian gait is slow and shuffling, stride length is shortened and velocity reduced despite the presence of a normal cadence. In the advanced phase of the disease, patients have difficulty in the initiation of walking or can experience sudden immobility during walking (freezing of gait). In addition, reduced postural control is one of the most disabling symptoms in patients suffering from advanced PD and is responsible for significant mortality and morbidity. The nature of postural instability in PD is debated and seems to possibly result from an alteration at the central information processing level, where peripheral inputs could be misinterpreted or misintegrated (Horak et al., 1992). The influence of treatment for PD on balance control is controversial. While treatment with levodopa should improve postural adjustments (Bejjani et al., 2000), some studies have reported that balance control is poorly improved (Burn, 2002) and may even be impaired by dopaminergic medications (O’Suilleabhain et al., 2001; Rocchi et al., 2002). Similarly, experience with DBS therapy has yielded controversial results. Postural instability is widely considered a poor outcome predictor for STN DBS and some authors considered it an exclusion criterion (Welter et al., 2002). However, few systematic posturographic studies have been performed after DBS and their results have been controversial (Rocchi et al. 2002; Maurer et al, 2003)

Although an individual's risk of falling is probably multifactorial, a standardized and valid screening instrument to identify people at risk of falling after STN DBS has never been used to our knowledge. The Tinetti balance scale (Tinetti, 1986) is a simple clinical instrument measuring characteristics associated with falls. This test assesses balance with 14 items (score out of 24) and gait with ten items (score out of 16) for a total score out of 40, where the higher the score, the better the performance. It is easy to administer in a clinic. The Tinetti balance scale has shown good performance on interrater reliability and concurrent validity (Cipriani et al. 1997) and potential cut-off scores identifying those at risk of falling have been proposed (Raiche et al, 2000).

The rationale of this study is that a careful yet simple definition of the pre-surgical postural balance and gait function in PD patients will greatly help the interpretation of their outcome after STN-DBS and potentially contribute a screening tool to predict those patients at risk. The CAPSIT, the most used, validated pre-surgical screening tools for PD, does not include evaluation of postural balance, while gait is only briefly assessed (Defer et al., 1999). Therefore, when patients complain post-surgically of problems with gait and balance, it is difficult to attribute these difficulties to specific DBS effects (or lack of). As such, there is a pressing need for a simple clinical tool to evaluate balance and gait before and after DBS surgery, in order to establish factors that may help either selecting appropriate patients or predicting outcome and therefore establish a more accurate risk/benefit profile for DBS surgery candidates.

Methods
Every PD patient selected for DBS surgery over the next 12 months will be invited to participate to the study until 25 consecutive patients will be recruited. After signing informed consent, demographic data will be collected for each subject, including age, gender, duration of disease and presence of any major orthopedic or neurologic diagnoses (other than PD) potentially affecting balance and gait.

1) At baseline (i.e. < 2 weeks prior to their surgery), patients will be evaluated in the mid-morning, after withholding their dopaminergic medications for at least 12 hours (‘OFF state’) and then again approximately one hour after taking their usual dose of levodopa/carbidopa (‘ON state’). Besides standard UPDRS, Hoehn and Yahr and Schwab and England scales, patients will be evaluated using the Tinetti balance scale, both in the OFF and ON conditions. Evaluation in each clinical state will be videotaped for later review and documentation. In addition, patients will be instructed to keep a diary of falls in the 2 weeks preceding DBS surgery. Levodopa equivalent dosages will be recorded.

2) Follow-up examinations including the same clinical scales and standardized videotaping will be conducted at three and twelve months after initial DBS programming. Postoperative evaluations will be performed in four clinical states: Off medications - stimulators Off (OFF/OFF); Off medications - stimulators On (OFF/ON); On medications - stimulators Off (ON/OFF); and On medications - stimulators On (ON/ON). Evaluation in each clinical state will be videotaped for later review and documentation. In addition, patients will be instructed to keep a diary of falls in the 2 weeks preceding each evaluation. Levodopa equivalent dosages will be recorded.

Baseline test scores of each scale will be compared to post STN DBS scores in the different clinical states in order to evaluate the relative effects of DBS and medications on balance, gait and the other parkinsonian features. In addition, scores obtained in the Tinetti balance scale before surgery will be correlated to overall UPDRS results and frequency of falls in order to define potential cutoff/screening value of testing balance before surgery. Finally, diary of falls before and after surgery will be compared.

Statistical analysis
Each data set will be tested for normality employing the Kolmogorov-Smirnov test. When both comparative data sets are normally distributed, the paired student’s t-test will be employed to test for statistically significant differences. If either data set will not be normally distributed, the Mann-Whitney Rank Sums Test will be employed. The relationship between each subject's Tinetti balance and gait score before surgery and his or her reported frequency of falls after DBS will be analyzed by a chi-square test. p values < 0.05 will be considered to be statistically significant.

References
Bejjani BP, Gervais D, Arnulf I, et al. Axial parkinsonian symptoms can be improved: the role of levodopa and bilateral subthalamic stimulation. J Neurol Neurosurg Psychiatry 2000;68:595–600.

Burn DJ. The effect of deep brain stimulation and levodopa on postural sway in subjects with Parkinson’s disease. J Neurol Neurosurg Psychiatry 2002;73:240

Cipriany.Dacko LM, Innerst D, Johannsen J and Rude V. Interrater reliability of the Tinetti balance scores in novice and experienced physical therapy clinicians, Arch Phys Med Rehabil 78 (1997), pp. 1160–1164

Defer GL, Widner H, Marie RM, Remy P, Levivier M. Core assessment program for surgical interventional therapies in Parkinson's disease (CAPSIT-PD). Mov Disord. 1999 Jul;14:572-84.

Horak FB, Nutt JG, Nashner LM. Postural inflexibility in parkinsonian subjects. J Neurol Sci 1992;111:46–58

Maurer C, Mergner T, Xie J, et al. Effect of chronic bilateral subthalamic nucleus (STN) stimulation on postural control in Parkinson’s disease. Brain 2003;126:1146–63.

O’Suilleabhain P, Bullard J, Dewey RB. Proprioception in Parkinson’s disease is acutely depressed by dopaminergic medications. J Neurol Neurosurg Psychiatry 2001;71:607–10;

Raiche M, Hebert R, Prince F, Corriveau H. Screening older adults at risk of falling with the Tinetti balance scale. Lancet. 2000 Sep 16;356(9234):1001-2.

Rocchi L, Chiari L, Horak FB. Effects of deep brain stimulation and levodopa on postural sway in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2002;73:267–74.

Tinetti ME, Performance-oriented assessment of mobility problems in elderly patients, J Am Geriatr Soc 34 (1986), pp. 119–126.

Walter BL, Vitek JL. Surgical treatment for Parkinson's disease.Lancet Neurol. 2004;3:719-28.

Welter ML, Houeto JL, Tezenas du Montel S, et al. Clinical predictive factors of subthalamic stimulation in Parkinson’s disease. Brain 2002;125:575–83.

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