The National VA Parkinson

The Parkinson Alliance attended The National VA Parkinson's Disease Consortium in San Francisco, California, September 9 & 10, 2010.  The National VA Parkinson's Disease Consortium was established in 2003 as a means to broaden the impact of the Parkinson's Disease Research, Education and Clinical Centers (PADRECCs) and encourage the delivery of modern Parkinson's disease management across the collective VA Healthcare System. While the PADRECCs serve as Centers of Excellence, the Consortium aims to revolutionize clinical care at unique VA Medical Centers through professional education, collaboration, and support.  
 
Dr. Robert Ruff, the National Director of Neurology, addressed the importance of specialized care for individuals with Parkinson’s disease (PD). He stated that primary care providers are often not comfortable with managing the complex nature of PD, and disease specific networks optimize care by providing resources for primary care providers, and enhancing care and cross communication. Moreover, care networks provide “specialty access” to highly technical care (e.g. such as disease modifying agents; Deep Brain Stimulation), research opportunities (tracking outcomes), and education and support to patients, families, and treatment providers. The networks of care for Veterans with PD provide ways to maximize existing healthcare resources within the VA health system and extending specialty care to all Veterans. They do so with potential cost savings and reduction in outsourced (fee-basis) care. These networks strongly support the concept of “veteran centered” care.

The Keynote Address:  Parkinson’s Disease: An Overview of the Current Concepts Regarding Etiology
Bill Langston, MD.

Dr. Langston provided an excellent overview of the history of PD, and the current issues.  Dr. Langston is well known for his vast contributions to research for PD and clinical contributions in addressing patient needs. He spent time reviewing his findings pertaining to the neurotoxin MPTP (a neurotoxin that causes symptoms of PD by destroying dopaminergic neurons in the substantia nigra of the brain). The symptoms and brain structures of MPTP-induced PD are fairly indistinguishable to the point that MPTP is often used to simulate the disease in order to study PD physiology and possible treatments within the laboratory. Dr. Langston’s work has inspired many scientists striving to improve treatment for and to identify a cure for PD.

Dr. Langston discussed the influence of genetic factors and environmental factors in the development of PD. He indicated that since the 1990s, over 20 case-control studies (where people with a disease are compared to those who do not have the disease) have shown an association of PD and pesticides.  PD risk is about twice as high in pesticide-exposed patients.

With regard to genetic factors, he pointed out that there has been a renaissance of interest in genetics of PD since the 1990s with discovery of mono-genetic forms of PD.  That being said, most cases of PD are classified as “sporadic” and occur in people with no apparent history of the disorder in their family. Although the cause of these cases remains unclear, sporadic cases probably result from a complex interaction of environmental and genetic factors, with genetics making an individual vulnerable and environmental factors being the trigger for disease onset.

Dr. Langston went on to discuss how PD is a wide spread disease in various parts of the brain and spinal cord. Dr. Langston posed the questions: Where does PD actually begin? Does PD begin outside of the brain? Some research has demonstrated that certain abnormalities, such as “lewy bodies” (abnormal protein that develop inside nerve cells), have been found in the olfactory bulb (a structure involved in the perception of smell) that is officially located outside of the brain; these abnormalities can predict pathology (abnormalities) in parts of the brain.  Additionally, lewy bodies found in parts of the brain stem and even in parts of the gastrointestinal tract have been found to also increase the risk of abnormalities/disease in other parts of the body.

Agent Orange, Pesticides and PD:
Webster Ross, MD,
Jeff Bronstein, M.D., Ph.D.

There has been a surge of interest in studying the effects of pesticides on the brain.  In recent review,  several research articles have shown an association between PD and pesticides. One manuscript indicated that PD risk was 1.6 to 7 times higher in pesticide exposed groups, and the higher the exposure the greater the risk- dose effect (Brown et al, 2006).  There has been indication that individuals who live in rural areas may be more vulnerable to developing PD, as it is common for individuals in rural areas to work in agricultural occupations and drink well water. The question remains as to whether these factors function as surrogates for exposure to pesticides.

In other studies, it has been found that the longer one is exposed to environments where pesticides are prevalent (plantations), the incidence of PD increased.   Also, there is a dose effect, where the more pesticides to which one is exposed, there is a greater risk of developing symptoms of PD.

The relationship between Agent Orange and PD is currently being studied. Agent Orange is a defoliant (chemical sprayed or dusted on plants to cause its leaves to fall off ) that was used during the Vietnam war.  There has been some evidence identifying a relationship between Agent Orange and PD.  The Veteran Affairs is providing support to veterans with PD who were exposed to Agent Orange.

Further studies are needed to better understand the relationship between pesticides and PD.

Neuroprotection and PD
John Duda, M.D.
Alec Glass, M.D.

Dr. John Duda  began his talk with a quote from James Parkinson (1817) “There appears to be sufficient reason for hoping that some remedial process may ere long be discovered, by which at least the progress of the disease may be stopped.”

Dr. Duda stated that some of the medications for PD may indeed be slowing the disease progression, extending the lifespan for those with PD.  Dr. Duda pointed out that there are several challenges to developing neuroprotective therapies, however. For example, animal models do not reliably or fully replicate the clinical disease. Clinical trials (with humans) require large numbers of patients and take a long time. And, we have minimal or non-validated biomarkers of impact on disease progression. 

Dr. Duda’s take home message was that there is not sufficient evidence for neuroprotective therapies for PD, and we need to improve:

1.  The understanding of the pathophysiology of PD
2.  Animal models
3.  The understanding of the biomarkers of progression
4.  Research designs

Dr. Alec Glass underscored the point that we need to rethink research design and conduct “true translational research.” For example, he stated that many of our research designs require trials that are too large and costly and/or are inefficient and often result in questionable outcomes.   Dr. Glass proposed a new research design that is complex in nature, but will possibly prove to be more favorable in answering several of the many questions that still exist about the effectiveness of some of the treatments for PD.

Update on Emerging Therapies Co-op Study update:
Fran Weaver, Ph.D.

Dr. Fran Weaver provided an overview of the results from the VA/NINDS Cooperative Study, a study attempting to differentiate the pros and cons of the two most common targets for the PD patient, the subthalamic nucleus (STN) and the globus pallidus interna (GPi). This study is a well-designed research endeavor incorporating a large group of individuals with PD, with enrollment for the study occurring from May 2002 through October 2006.  The participants in the study were evaluated at several time points (6, 12, 18, and 24 months, with a subgroup being evaluated again at 36 months). Data continues to be collected to assess the effectiveness of DBS overtime.

Both the STN and the GPi were found to be effective for treating motor symptoms and have favorable outcomes for many of the patients who are good candidates for the for DBS therapy.

The following concluding statements were provided:

1. Research has confirmed that DBS is useful in smoothing out motor fluctuations, and DBS has been found to be better than the best medical therapy (medications alone) on some of the outcome measures, such as quality of life and UPDRS III motor scores in the “off” state.  There was no difference between DBS and the best medical therapy on the UPDRS motor “on” state and measures of cognition (thinking skills) and emotional well-being.

2. There was not a significant difference in motor improvements between the subthalamic nucleus (STN) DBS and the globus pallidus interna (GPi) DBS at baseline, 6 months, and 24 months.  In other words, one target was not superior to another target; both targets appear to be effective in treating motor symptoms for PD.

3. The benefits of DBS (e.g., whether it was minimal improvement or major improvement) that was seen at the 6 month mark was steady and found again at the 24 month mark. 

4. Motor diaries (where patients documented their perspective of their PD symptoms) revealed that patients with DBS of the STN and GPi had less “off” time after DBS, and “on” time without dyskinesia improved for both STN and GPi DBS.

5. There needs to be more detailed analyses for specific motor features.

6. Quality of life measures revealed improved quality of life for both groups.

7. Although emotional well-being remained in the minimally depressed range for the GPi and STN groups, mood was slightly improved for the GPi group, whereas mood was not improved for the STN group.

8. There were a greater number of falls with STN over the GPi target with otherwise no significant event differences between groups.

9. With regard to medication reduction, more individuals in the STN group experienced medication reduction than those in the GPi group. Thus, the need or desire for medication reduction may influence choice of target.

Advances in DBS Targeting:
Phil Starr, MD

Dr. Phil Starr presented his approach to DBS implantation. He stated that he uses intra-operative imaging using a CT scan during DBS implantation surgery. He indicated that he has found significant success in identifying the appropriate lead placement when using the intra-operative CT brain scan, resulting in the implication that a post-operative MRI may not be needed in the future.  He stated that correction of placement errors intraoperatively is now possible.

Dr. Starr stated that the placement of DBS leads using high-field interventional MRI is also on the horizon. Dr. Starr stated that the goal is to develop methods for instruments that will improve speed and simplicity, as well as safety and patient comfort. For example, patients can be under general anesthesia.  He stated that the patient would then go through the procedure of DBS implantation. The diagnostic MRI is performed during surgery and can provide real time confirmation of accurate placement prior to completing the procedure.

Dr. Starr indicated that the placement of the DBS leads are done through using high-field intraoperative MRI. The method he was describing eliminates the frame (a different head-holder device is used), the “Operating Room” (the patient’s procedure can be done in a radiology suite), and the need for the patient to be awake. He indicated that accuracy and safety are provided by real time, high resolution images.  The outcomes at his institution appear favorable, but more research is needed.

Impulse Control Disorders in PD
Dan Weintraub, MD

Psychiatric symptoms are commonly experienced in PD. A subset of these symptoms can be categorized as Impulse Control Disorders (ICDs), which include symptoms such as excessive gambling, spending, eating, and sexual behaviors.  The essential feature is the failure to resist an impulse, drive, or other temptation to perform an act that is harmful to the person  who has the symptom or to another person. Younger age and dopamine agonists were the most common variables accounting for ICDs.  Dr. Weintraub stated that 17% as compared to 7 % of those taking dopamine agonists and non-dopamine agonists, respectively, showed ICD.  

Other research highlighted the relationship between dopamine agonists and the experience of ICDs.  In one study looking at the effect of DBS on pathological gambling, the gambling behavior resolved postoperatively (over a mean of 18 months) in the 7 patients who participated in the study. It was noted that there was a 74% medication reduction in these patients; the reduction of gambling behavior paralleled the time course and degree of reduction in dopaminergic treatment. Furthermore, it has become evident that individuals with ICDs have greater functional difficulties than individuals without ICDs. For example, in a study where there were 282 patients with ICDs and 282 patients without ICDs, individuals with ICDs were more functionally impaired on the Unified Parkinson’s Disease Rating Scale (UPDRS) and more depressed and anxious. 

Dr. Weintraub indicated that there  is a need for medications to reduce the ICDs while not having to reduce the medications that assist in the management of PD symptoms.  Research to better understand ICDs and various treatments for these symptoms is underway.

Advances in Gene Therapy
Bill Marks, MD

Gene therapy may provide an effective approach to delivering biological treatment to the brain. Data thus far has not demonstrated robust superiority of any biological treatment, however.  Evidence has emerged to at least make gene therapy a hopeful intervention.   For example, in one study using primates to investigate the effectiveness of gene therapy’, the gene therapy called AAV2-NTN (CERE-120) was injected into brain structures of monkeys. The data demonstrated that CERE-120 can preserve function and anatomy in degenerating neurons, supporting the need for ongoing clinical tests in PD patients.

CERE-120  has been used in a study to determine the tolerance and safety in humans. The initial phase of the study found support for the safety, tolerability, and potential effectiveness of CERE-120 as a possible treatment for PD; however, these results must be viewed as preliminary.  Continued research with CERE-120 is currently underway, and the study is looking at the long-term effectiveness of this therapy.

Driving and PD
Uc  EY, MD

In Dr. EY’s research, the drivers with PD generally had poorer road safety compared to healthy controls. He noted, however, there was considerable variability among the drivers with PD, and some individuals performed normally. Familiarity with the driving environment was a mitigating factor against unsafe driving in PD. In other words, the more familiar the PD patients were with the environment in which they were driving, the better their performance; conversely, the more unfamiliar the PD patients were with their environment, the worse their driving performance was.

Some variables were clearly influential in the outcomes of driving performance. Cognitive difficulties, including slowed processing speed, visual perception difficulties, and visual inattention, for example, adversely impacted driving performance.  These cognitive impairments and visual perception difficulties were associated with road safety errors in drivers with PD. Notably, tremor by itself did not effect driving performance, but stress while driving can induce tremors.

Parkinson’s Action Network
Jennifer Sheridan

The Parkinson’s Action Network (PAN) is the unified voice of the Parkinson’s community advocating for better treatments and a cure.  PAN continues to be the leading voice for patient advocacy in Washington, D.C., working to bring much-needed awareness to the public and lawmakers about the affects of Parkinson's disease.

As it relates to some of the aforementioned highlights at this Consortium, the PAN has:
1. Secured much-needed funding for Parkinson's disease (PD) research at the Department of Defense--the Neurotoxin Exposure Treatment Research Program (NETRP). 
2. Assured congressional funding for Department of Veterans Affairs Parkinson's Disease Research, Education and Clinical Centers (PADRECCs).
3. Ensured that the PD research portfolio at NIH is focused on better treatments and a cure as well as securing much-needed funding for PD.
4. Pursued support for human embryonic stem cell research (ESCR) funding.

Role of Health Services Research in Neuroscience Research Continuum
Karen Connor, PhD, RN, MBA

Dr. Connor discussed the VA Quality Enhancement Research Initiative (QUERI), which has the following facets:

1.   Indentify high risk and high burden conditions, such as PD
2.   Establish Quality Care Indicators for PD
3.   Improve assessment and management of PD motor and non-motor symptoms
4.   Define practice patterns and identified gaps in care
5.   Develop a new model for “Higher Quality PD Care”
6.   Establish Funding to develop a novel PD care intervention in the VA
7.   Look at care intervention based on a “Chronic Care Model”
8.   Identify the “community component” in the VA Health Systems
9.   Look at self management support and delivery system design
10. Establish clear clinical information systems.

Dr. Connor introduced a model where a nurse care manager can assist in facilitating a program to improve the patient care for PD patients. The model includes improving care protocols, improving collaboration with veterans, establishing care coordination with subspecialists, increase surveillance of unmet needs, improve follow-up monitoring of motor and non-motor symptoms, increase education and counseling for PD patients, and increase the connection to the community and VA resources.

CONCLUDING REMARKS FROM THE CONFERENCE

This conference provided a venue for a comprehensive discussion about identifying the causes of PD, improving the understanding of the symptoms that the individual with PD may experience (e.g., particularly non-motor symptoms), and enhancing the treatments for PD.  Additionally, what continues to emerge at conferences, such as this one, is the importance of continuing to improve education to patients, care providers, and clinicians, as well as to facilitate the accessibility to adequate resources in the PD community.