Office of Research & Development

VA research on

Parkinson's Disease


Introduction

Parkinson's disease (PD) is a disorder of the central nervous system, characterized by the death of dopamine-producing cells in the brain. The disease causes a variety of "motor" symptoms (symptoms related to movement of the muscles), including rigidity, delayed movement, poor balance, and tremors. Non-motor symptoms of PD include sleep disturbances, urinary dysfunction, constipation, swallowing problems, mood disorders and cognitive deficits.

The exact cause of PD is unknown. Most researchers agree that the disease is caused by both genetic and environmental factors, and by interactions among these factors.

NIH estimates that the disease affects at least 500,000 Americans, mostly people over age 50. The average age of onset is about 60. VA estimates that 80,000 Veterans have PD. There is no cure for PD; however, many effective medications and treatment options are available.

In 2010, VA recognized PD as associated with exposure to Agent Orange or other herbicides during military service. Veterans with PD who were exposed to herbicides during their service may be eligible for disability compensation and health care.

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Selected major accomplishments

  • Conducting the first large scale trial of the results of deep brain stimulation (DBS) surgery.
  • Finding that low-intensity workouts, stretching, and resistance exercise improve the mobility of patients with PD.
  • Defining the role of the immune system in the development of PD.
  • Determining that a certain gene variant is more common in people with dementia who have PD.

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Selected Major Accomplishments

  • 2001: Created Parkinson's Disease Research, Education, and Clinical Centers (PADRECCs), at six sites throughout the nation
  • 2003: Initiated a landmark clinical trial to assess the effectiveness of deep brain stimulators (DBS) for PD
  • 2009: Determined that DBS may hold significant benefits for those with PD who no longer respond well to medication alone
  • 2014: Found that walking is a safe and easily accessible way to improve PD symptoms
  • 2015: Developed a procedure to convert skin cells into dopamine neurons

New, Ongoing, and Published Research

In 2001, VA created six specialized centers to provide Veterans with PD with state of-the art clinical care, education, research, and national outreach and advocacy.

Known as the Parkinson's Disease Research, Education, and Clinical Centers (PADRECCs), these centers are located in Philadelphia; Richmond, Va.; Houston; Los Angeles; San Francisco; and the Seattle/Portland area. The centers also provide comprehensive diagnosis and treatment services for other movement disorders, including essential tremor, restless leg syndrome, dystonia, Lewy body disease, progressive supranuclear palsy, multiple system atrophy and corticobasal degeneration.

Researchers at these sites are studying the biochemical pathways involving dopamine, and testing a variety of treatment approaches, including medication, surgery and electrical stimulation. Biomedical and clinical studies on PD are ongoing at many other VA sites as well.

➤ Warning signs of PD

In December 2011, a team of VA researchers led by investigators at the Spark M. Matsunaga VA Medical Center in Honolulu presented a paper to the World Congress on PD and Related Disorders that found impaired sense of smell, constipation, slow reaction time, excessive daytime sleepiness and faulty executive function (the ability to manage life tasks of all types) may all be warning signs of PD. The researchers stated that combinations of these signs could predict up to a tenfold higher risk of the disease.

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➤ Studies of deep brain stimulation (DBS)

DBS is a surgical procedure used to treat a variety of disabling neurological symptoms, especially those related to PD. DBS uses a surgically implanted, battery-operated device called a neurostimulator. The neurostimulator delivers electrical stimulation to targeted areas in the brain that control movement, blocking abnormal nerve signals that cause tremors and other systems.

The first experimental DBS implants took place in 1987, and the Food and Drug Administration approved the use of the procedure in 2002.

In early 2009, VA, along with the National Institutes of Health, completed the first large scale trial of the results of DBS. The six-year cooperative study (CSP #468), conducted at seven VA medical centers and six university hospitals, looked at 255 PD patients aged 37 to 83 and compared symptoms between those who had undergone the surgery and those who had used drug therapy alone.

The researchers found patients who underwent DBS had better control of their limbs and could walk better than those using medication. They found that older patients, who had previously been excluded from brain stimulation research and treatment, benefited from DBS as much as younger patients.

Researchers also found that potential side effects from DBS included a decrease in neurocognitive functioning and increases in the rate of infections, falls, depression, gait and balance problems, and pain—and that these side effects were more likely to occur than side effects from medication.

In addition, DBS did not help other symptoms of PD, including depression; decline in mental ability; and trouble with gastrointestinal, urinary or sexual functions. On the whole, the researchers concluded that while DBS appears to be riskier than drug therapy, it may hold significant benefits for those with PD who no longer respond well to medication alone.

DBS improves movement-related functioning—Researchers with CSP #468 have continued to publish articles based on their findings on DBS. In one 2012 study, researchers found that DBS produced marked improvements in movement-related functioning. Patients, on average, gained four to five hours a day free of troubling motor symptoms such as shaking, slowed movement or stiffness. The effects were greatest at six months, and leveled off slightly by three years.

Suicide no more likely with DBS than with medication—In another study, published in 2013, researchers looked at two types of DBS procedures, and at patients taking medication. They found that attempted suicide, or suicidal thinking, was no more common among patients who had undergone either form of the procedure than in those taking medication alone. Some previous international studies had raised the question of whether suicide was an important cause of mortality following DBS procedures.

DBS implantation location—Another study of the two forms of DBS procedures was published in 2015 by researchers from the Edward Hines, Jr. VA Hospital in Hines, Ill., the Jesse Brown VA Medical Center in Chicago, and three-Chicago area schools of medicine.

Researchers found that, 6 to 12 months after DBS surgery, patients whose neurostimulator was implanted in their brain's subthalamic nucleus had a significantly greater increase in their use of medication for mental health issues than those whose neurostimulator was implanted in their brains' globus pallidus internus. The study found no significant differences in the two groups' use of outpatient or inpatient health care, however.

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➤ PD and exercise

Research has demonstrated the great benefits of exercise for patients with PD. Not only have exercise programs been shown to improve motor function and reduce the risk of falls, but they also improve overall quality of life and possibly slow the course of the disease.

Walking improves PD symptoms—A 2014 study led by researchers with the Iowa City VA Health Care System and the University of Iowa found that patients who walked briskly for 45 minutes, three times a week, showed improvements in their Parkinson's symptoms. They were also less depressed and less tired.

The study suggests that walking provides a safe and easily accessible way of improving the symptoms of PD. While previous studies had shown that moderately strenuous exercise is helpful, this research showed that even moderate walking can make a significant difference.

Low-intensity workouts improve mobility—Researchers studying 67 patients with PD at the VA Maryland Health Care System learned, in 2013, that low-intensity workouts, stretching, and resistance exercise all improved the mobility of patients with Parkinson's disease. Those who walked on a treadmill at a comfortable pace for nearly an hour showed the most consistent improvement in gait and mobility.

New exercise programs—Currently, a research team at the VA Boston Healthcare System is evaluating the effectiveness of a home-based approach to providing the benefits of a safe exercise program to people with PD. The program will be centered on remote, real-time instruction and supervision. Ideally, it will make the benefits of exercise available to PD patients who cannot travel to exercise locations.

Another current study, taking place at the VA Portland Health Care System, is looking at whether people with PD can significantly improve their mobility and cognition functioning after participating in six weeks of group exercise and another six weeks of education on how to live better with a chronic disease. The study also hopes to determine if already-existing deficits in cognition functions can predict whether or not exercise programs help PD patients.

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➤ PD and mental symptoms

Antipsychotic drugs linked to mortality—According to a 2016 VA study, up to 60 percent of PD patients experience psychosis (a mental disorder characterized by symptoms that indicate impaired contact with reality) at some point during the course of their illness. Physicians commonly prescribe antipsychotic drugs to treat the condition.

The study, led by researchers at the Corporal Michael J. Crescenz VA Medical Center in Philadelphia, the VA Ann Arbor Healthcare System, and the University of Pennsylvania, looked at 15,000 VA PD patients. It found that those who began using antipsychotic drugs were more than twice as likely to die during the following six months, compared to a matched set of PD patients who did not use such drugs.

The relative risk of the drugs varied by the specific drug prescribed: mortality was 2.16 times higher for quetiapine compared with non-treatment; 2.46 for risperidone; 2.79 for olanzapine; and 5.08 for haloperidol. First-generation, or "typical," antipsychotics, which include haloperidol, were collectively associated with about 50 percent greater relative mortality risk compared with more recently developed "atypical" antipsychotics such as risperidone and quetiapine.

The research team did not find any clues that pointed to a specific cause or mechanism for the higher death rate. They are conducting a follow-up study that might shed more light on this issue. In the interim, the first author, Dr. Daniel Weintraub of the Corporal Michael J. Crescenz VA Medical Center's PADRECC, suggested that antipsychotic drugs should not be prescribed to Parkinson's patients without careful consideration.

PD's effect on cognitive impairment—In 2015, researchers from the Crescenz VA Medical Center and the University of Pennsylvania reported on a study in which they followed a cohort of patients with PD and baseline normal cognition skills (the activities of thinking, understanding, learning and remembering) for a minimum of two years and a maximum of six.

After one year, 8.5 percent of the patients had developed mild cognitive impairment, and by the end of six years that increased to 47.4 percent. All of the patients who had had mild cognitive impairment at the end of the first year developed dementia by the end of the study. The research team concluded that the transition from normal cognition in PD patients to cognitive impairment, including dementia, occurs frequently and quickly.

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➤ PD and genomics

In 2010, researchers with several institutions, including the VA Puget Sound Health Care System, found that a group of genes that help control the body's immune response may figure in the development of PD. The team examined the genetic makeup and health histories of nearly 4,000 people, half of whom had PD.

They found those with the disease were more likely to have certain variations in a group of immune genes known as the human leukocyte antigen system. The study provided important evidence of a role for the immune system in the development of PD.

In 2013, VA researchers and their colleagues published the results of a study that found that the E4 variant of the apolipoprotein-E (APOE) gene is more common in people with dementia who have either PD, Alzheimer's disease, or Lewy body disease (a neurodegenerative disorder that causes dementia).

In genetic studies of donated brain tissue, APOE was found in 7 percent of people without dementia. It was found far more often in Alzheimer's patients with and without Lewy body disease, people with only Lewy body disease, and patients with PD.

Because PD is characterized by a loss of dopamine-producing cells in the brain, scientists have been trying for decades to find a way to repair faulty dopamine neurons and put them back into patients, where they will start producing dopamine again.

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➤ PD and gene therapy

Creating new dopamine neurons—In 2015, researchers with the VA Western New York Health Care System, the State University of New York at Buffalo, and Harvard University, along with collaborators in China, reported on a method to convert skin cells into neurons that produce dopamine.

Their research was based on the discovery that transcription factor protein p53 acts as a gatekeeper protein. (Transcription factors are proteins that control which genes are turned on or off in the human genome, by binding to DNA and other proteins. Gatekeepers are proteins that directly control the cell cycle.)

By lowering the expression of p53 at the right time of the cell cycles, the team was able to turn patients' skin cells into dopamine neurons. These neurons, generated in a dish, can then be transplanted into the patients' brains to replace their faulty neurons. The neurons can also be used to efficiently screen new treatments for PD.

According to the paper's senior author, Dr. Jian Feng of China, the paper's findings are important for basic cell biology, not only for PD. The ability to lower the expression of p53 is a generic way to change cells from one type to another, thereby changing the way scientists work with all cells. It will also allow researchers to generate tissue similar to those in the body, even brain tissue.

Preventing PD with gene therapy—Researchers with the VA Pittsburgh Healthcare System and the University of Pittsburgh School of Medicine found, in 2015, that gene therapy to reduce the production of a brain protein can successfully prevent the development of PD in rats.

Aggregates or deposits of a protein called alpha-synuclein within neurons are found in people with PD. PD is also linked to a dysfunction of mitochondria, the powerhouses of the cell that produce energy for the body.

According to the research team, their study was the first to show that mitochondria and α-synuclein can interact in a damaging way in vulnerable cells, and that targeting α-synuclein might be an effective way to treat the disease.

In their study, the team blocked the expression of alpha-synuclein in rats' brains by injecting the rats with a harmless virus called AAV2. They then exposed the rats to a naturally occurring pesticide called rotenone, which creates Parkinson-like body chemistry changes in rats exposed to it.

They found that their gene therapy protected the rats from the effects of rotenone, and concluded that gene therapy aimed at reducing alpha-synuclein production has a protective effect and successfully prevented the development of PD in a rat model.

The team is now working to identify the pathways by which alpha-synuclein affects the mitochondrial function and will work to develop potential drug therapies that target this mechanism. They hope to be able to translate their approach into human clinical trials soon.

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More on Our Website

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Selected Scientific Articles by Our Researchers

Bilateral deep brain stimulation vs. best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ Jr., Rothlind J, Sagher O, Reda D, Moy CS, Pahwa R, Burchiel K, Hogarth P, Lal EC, Duda JE, Holloway K, Samil A, Horn S, Bronstein J, Stoner G, Heemskirk J, Huang GD; CSP 468 study group. In a randomized controlled trial of patients with advanced PD, deep brain stimulation was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months, but was associated with an increased risk of serious adverse events. JAMA. 2009 Jan 7:301(1):63-73.

Randomized trial of deep brain stimulation for Parkinson disease: thirty-six-month outcomes. Weaver FM, Follett K, Stern M, Luo P, Harris CL, Hur K, Marks WJ Jr., Rothlind J, Sagher O, Moy CS, Pahwa R, Burchiel K, Hogarth P, Lal EC, Duda JE, Holloway K, Samil A, Horn S, Bronstein J, Stoner G, Starr PA, Simpson R, Baltuch G, De Salles A, Huang GD, Reda DJ; CSP 468 study group. The beneficial effect of DBS on motor function was stable and comparable by target over 36 months. Slight declines in quality of life following initial gains and gradual decline in neurocognitive function likely reflect underlying disease progression and highlight the importance of nonmotor symptoms in determining quality of life. Neurology. 2012 Jul 3;79(1):55-65.

Phase I/II randomized trial of aerobic exercise in Parkinson disease in a community setting. Uc Ey, Doerschug KC, Magnotta VA, Dawson JD, Thomsen TR, Kline JN, Rizzo M, Newman SR, Mehta S, Grabowski TJ, Bruss J, Blanchette DR, Anderson SW, Voss MW, Kramer AF, Darling WG. In patients with Parkinson's disease, an aerobic exercise program improves aerobic fitness, motor function, fatigue, mood and cognition. Neurology. 2014 Jul 29;83(5):413-25.

Mental health-related healthcare use following bilateral deep brain stimulation for Parkinson's disease. Westbay LC, Cao L, Burnett-Zeigler I, Reizine N, Barton B, Ippolito D, Weaver FM, Stroupe KT. Mental health care use and costs are stable over time and similar between DBS targets. J Parkinsons Dis. 2015;5(3):497-504.

Gestures make memories, but what kind? Patients with impaired procedural memory display disruptions in gesture production and comprehension. Klooster NB, Cook SWW, Uc EY, Duff MC. The procedural memory system, which is impaired in people with PD, supports the ability of gesture to drive new learning. Front Hum Neurosci. 2015 Jan 13;8:1054.

shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson's disease model. Zharikov AD, Cannon JR, Tapias V, Bai Q, Horowitz MP, Shah V, El Ayadi A, Hastings TG, Greenamyre JT, Burton EA. Short hairpin RNA targeting the SNCA transcript should be further evaluated as a possible neuroprotective therapy in Parkinson's disease. J Clin Invest. 2015 Jul 1;125(7):2721-35.

Advances in the treatment of cognitive impairment in Parkinson's disease. Goldman JG, Weintraub D. This review summarizes the design and outcomes of trials for PD cognitive impairment published since 2013 and highlights future therapeutic research opportunities and challenges. Mov Disord. 2015 Sep 15;30(111):1471-89.

Longitudinal study of normal cognition in Parkinson disease. Pigott K, Rick J, Xie SX, Hurtig H, Chen-Plotkin A, Duda JE, Morley JF, Chahine LM, Dahodawala N, Akhtar RS, Siderowf A, Trojanowski JQ, Weintraub D. The transition from normal cognition to cognitive impairment in PD patients, including dementia, occurs frequently and quickly. Neurology. 2015 Oct. 13;85(15):1276-82.

Do cognitive measures and brain circuitry predict outcomes of exercise in Parkinson disease: a randomized clinical trial. King LA, Peterson DS, Mancini M, Carlson-Kuhta P, Fling BW, Smulders K, Nutt JG, Dale M, Carter J, Winters-Stone KM, Horak FB. Description of a study to determine if people with PD can improve mobility or cognition after taking part in a cognitively challenging mobility exercise program and to determine if cognition and brain circuitry deficits predict responsiveness to exercise rehabilitation. BMC Neurol. 2015 Oct. 24;15:218.

Cell cycle and p53 gate the direct conversion of human fibroblasts to dopaminergic neurons. Jiang H, Xu Z, Zhong P, Ren Y, Liang G, Schilling HA, Hu Z, Zhang Y, Wang X, Chen S, Yan Z, Feng J. Transcription factor protein p53 acts as a gatekeeper protein allowing for the conversion of skin cells into neurons that produce dopamine. Nat Commun. 2015 Dec. 7;6:10100.

Cognitive, affective, and behavioral dimensions of the lower urinary tract symptom experience in men with Parkinson's disease. Moriarty HJ, Robinson JP, Bunting-Perry L, Bradway CW. Misconceptions about lower urinary tract symptoms among men with PD may result in underreporting, missed opportunities for professional assistance, and diminished health-related quality of life. J Wound Ostomy Continence Nurs. 2016 Jan-Feb;43(1):80-7.

Association of antipsychotic use with mortality risk in patients with Parkinson disease. Weintraub D, Chiang C, Kim HM, Wilkinson J, Marras C, Stanislawski B, Mamikonyan E, Kales HC. Use of antipsychotics is associated with a significantly increased mortality risk in patients with PD, highlighting the need for cautious use of these drugs in patients with the disease. JAMA Neurol. 2016 Mar 21. (epub ahead of print)

The Penn Parkinson's Daily Activities Questionnaire-15: Psychometric properties of a brief assessment of cognitive instrumental activities of daily living in Parkinson's disease. Brennan L, Siderowf A, Rubright JD, Rick J, Dahodwala N, Duda JE, Hurtig H, Stern M, Xie SX, Rennert L, Karlawish J, Shea JA, Trojanowski JQ, Weintraub D. The questionnaire appears suitable to assess daily cognitive functioning in PD. Parkinsonism Relat Disord. 2016 Apr:25:21-6.

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