New Target for Treating Symptoms of Parkinson's Disease

ScienceDaily (Sep. 11, 2011) — A scientist at the Gladstone Institutes has identified how the lack of a brain chemical known as dopamine can rewire the interaction between two groups of brain cells and lead to symptoms of Parkinson's disease. This discovery offers new hope for treating those suffering from this devastating neurodegenerative disease.

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In a paper being published online September 8 in Neuron, Gladstone Investigator Anatol Kreitzer, PhD, identifies how the loss of dopamine alters the wiring of a small group of brain cells, kicking off a chain of events that eventually leads to difficulties controlling movement -- a hallmark of Parkinson's disease. More than a half-million people suffer from Parkinson's in the United States, including the boxer Muhammad Ali and the actor Michael J. Fox.

"The development of truly effective and well-tolerated therapies for Parkinson's has proven difficult," said Lennart Mucke, MD, who directs neurological disease research at the Gladstone Institutes, a leading and independent biomedical-research organization. Dr. Mucke is also a professor of neurology and neuroscience at the University of California, San Francisco (UCSF), with which Gladstone is affiliated. "Dr. Kreitzer's discovery sheds new light on the intricate processes that underlie motor problems in this disabling condition and will hopefully lead to the development of more effective medicines."

Normally, two types of brain cells called medium spiny neurons, or MSNs, work together to coordinate body movements, with one type acting like a gas pedal and the other as a brake. It has been thought that a reduction in dopamine, an important chemical in the brain, throws off the balance between the two opposing MSN forces, leading to problems with movement. But Dr. Kreitzer wondered if another factor might also be involved. To better understand the relationship between dopamine and MSNs in people with Parkinson's, Dr. Kreitzer artificially removed dopamine from the brains of laboratory mice and monitored the specific changes in the brain that followed.

Just as happens in humans, the mice without dopamine began to experience the motor symptoms of Parkinson's, including tremors, problems with balance and slowed movement. But Dr. Kreitzer found that decreased dopamine levels didn't just throw off the balance between the two types of MSNs, as was already known, but they also changed the interaction between MSNs and another group of neurons called fast-spiking neurons, or FSNs.

Dr. Kreitzer's experiments showed that under normal circumstances, FSNs connect to both types of MSNs in a similar way. But without dopamine, the signaling between the FSN circuits gets rewired and the neurons begin to target one type of MSN over the other. Dr. Kreitzer used computer simulations to show that this small shift disrupts the timing of MSN activity, which is key to normal movement. Ultimately, this rewiring may be an important factor in the development of Parkinson's motor problems.

"Our research has uncovered how an entirely different group of neurons can play a role in the development of Parkinson's disease symptoms," said Dr. Kreitzer, who is also an assistant professor of physiology and neurology at UCSF. "We hope to target the changes among these neurons directly with drug therapies, in order to help relieve some of Parkinson's most debilitating symptoms."

Other scientists who participated in the research at Gladstone include Aryn Gittis, Giao Hang, Eva LaDow and Steven Finkbeiner. Funding for the research came from a wide variety of organizations, including the Tourette Syndrome Association, the National Institutes of Health, the Pew Biomedical Scholars Program, the W.M. Keck Foundation and the McKnight Foundation.

Dr. Kreitzer is an Assistant Investigator at the Gladstone Institute of Neurological Disease and an Assistant Professor of Physiology and Neurology at UCSF. The Kreitzer lab focuses on understanding the neural mechanisms that control motor planning, learning and movement. Their long-term goal is to understand how circuitry and activity in the brain shapes motor behavior and how disorders such as Parkinson's disease and Huntington's disease affect circuits in the brain.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Gladstone Institutes.

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Journal Reference:

1.     Aryn H. Gittis, Giao B. Hang, Eva S. LaDow, Liza R. Shoenfeld, Bassam V. Atallah, Steven Finkbeiner, Anatol C. Kreitzer. Rapid Target-Specific Remodeling of Fast-Spiking Inhibitory Circuits after Loss of Dopamine. Neuron, September 8, 2011 DOI: 10.1016/j.neuron.2011.06.035

Gladstone Institutes (2011, September 11). New target for treating symptoms of Parkinson's disease. ScienceDaily. Retrieved September 12, 2011, from http://www.sciencedaily.com­ /releases/2011/09/110908081242.htm

Dr. Kreitzer found that as the supply of dopamine decreased, the brain's fast-spiking neurons grew new branches and rewired their connections, disrupting precisely timed activity patterns in a part of a brain that controls movement. (Credit: Image courtesy of Gladstone Institutes)

Generic vs. Branded Drugs for Parkinson’s Disease

Currently, there are multiple pharmaceutical companies that manufacture a generic formulation of carbidopa/levodopa, dopamine agonists, monoamine oxidase inhibitors and anticholinergics. If you have Parkinson’s, are taking brand name medication and then are offered a generic substitution for one of your Parkinson’s medications, you should know that the FDA requires that generic drugs must show an “essential similarity” to the branded drug prior to market approval, but that in some cases, this standard is not high enough. A review supported by NPF chronicles compelling evidence that if you are in more advanced stages of the disease, switching from branded drugs to generic, or from one generic to another, may have adverse effects. The authors, including NPF National Medical Director Dr. Michael S. Okun, believe that the standards for approving generic drugs for Parkinson's may not be strict enough to demonstrate that the generic alternatives are equally effective.
Work with your physician to develop a tailored treatment plan. Using generic drugs may provide a cost savings, but they may not be appropriate for you, especially if you already tolerate the branded drug.
If you make the switch, be sure to follow these tips:

• Report to your physician how effective the drug is
• Carefully keep a diary of any side effects
• Record dose adjustments that your physicians make (higher or lower)
• In general, try to stay with a single drug manufacturer for your generic medications (You may need to ask your pharmacist to special order for you)

When attempts to tailor drug therapy with a generic drug have been unsuccessful, have your doctor appeal to the insurance company for a branded drug. It is important to include meticulous details of the various adverse side effects with the generic medication in your appeal letter.
If you have questions about this information, please call NPF’s Helpline at
1-800-4PD-INFO (473-4636).
Ask the Pharmacist about your medications in NPF’s online forum.

Medication timing critical in Parkinson’s disease

Marjie Zacks
Hospital News - A one-week disruption of his Parkinson’s medication schedule resulted in nearly three months of distress for Lorne Collis after he returned home from a brief hospital stay for a kidney ailment in December 2009. “My tremors were uncontrollable,” says Collis.

“My restless legs syndrome was extremely uncomfortable. It took about three months of getting back on my medication routine and exercising before my body felt normal again.”

It’s a common experience. People with Parkinson’s enter hospital for reasons that may or may not be related to Parkinson’s and find that the hospital’s drug rounds do not coincide with their own medication regimen. However, in Parkinson’s, a minor change in medication timing can have major negative effects on symptom management and general recovery.

The uneven release of dopamine can result in a person suddenly not being able to move, get out of bed or walk down a corridor. It can also lead to serious complications such as aspiration pneumonia and bowel obstruction.

“When Parkinson’s symptoms get out of control, it tends to exacerbate the reason why the person is in hospital.” says Barbara Snelgrove, director of education and support services for Parkinson Society Canada. “It also makes care of the person more difficult for health-care professionals.”

To address these issues, Parkinson Society Canada is the first Parkinson’s organization in North America to introduce Get it on time, an innovative education and awareness program designed to ensure that people with Parkinson’s receive their medication on time, every time, whether they are in emergency rooms, hospital wards, or long-term care facilities.

Get it on time was developed and implemented successfully by Parkinson’s United Kingdom. Parkinson Society Canada has adapted it to the Canadian health-care environment, with financial support from the Canadian Institutes of Health Research and the Canadian Patient Safety Institute.

Launched in January 2011, the program uses the voices of people with Parkinson’s and their care partners to target the “Get it on time” message to nursing staff and front line health professionals through in-service training and communication tools such as information kits, posters and Get it on time stickers to attach to patients’ charts or care plans.

The program also has a self-advocacy component, encouraging people with Parkinson’s to bring their own medication to the hospital or care facility and inform staff about their precise medication needs.

“We’re approaching this on many layers,” says Debbie Davis, chief executive officer of Parkinson Society Central & Northern Ontario, one of the regions piloting the national program. “We know that it can improve quality of life for people with Parkinson’s while they are in hospital or in a care facility. We also know that the people caring for them will have an easier time if they are educated as to what Parkinson’s is and what they can do to make people’s lives better.”

To date, over 50 Get it on time presentations have been made to long-term care facilities, retirement residences and Parkinson’s support groups in Ontario. The campaign will expand to Ontario hospitals, this fall.

Get it on time is being piloted in communities in Saskatchewan. In Quebec, it is called Le prendre à temps. Parkinson Society Canada is seeking funding to roll out the program nationally.

Lorne Collis has already benefited from Get it on time. In hospital recently for complications relating to Crohn’s disease, he says, “Because of my knowledge of the Get it on time program, I advocated for myself. I said, ‘these are the times I take my pills – 6 a.m., noon, 5 p.m., 9 p.m.’ One nurse had a relative with Parkinson’s, so she understood. She spoke to the charge nurse. They allowed me to take my own pills at my scheduled times. When I left hospital, this time, my Parkinson’s symptoms were fine and totally under control. It made a huge difference.”

For more information about Get it on time, contact general.info@parkinson.ca.                       

Song used as therapy for those afflicted with Parkinsons

Reinisa MacLeod
Herald Tribune - You put your right foot in,
You put your right foot out;
You put your right foot in,
And you shake it all about.
You do the Hokey-Pokey,
You turn yourself around.
That's what it's all about!

Though one might not make an immediate connection between doing the Hokey-Pokey and Parkinson's disease, it's actually become a tool for Grande Prairie's Parkinson's support group.

According to speech pathologist Matthew Brown, the song and dance is one of the best known across every generation, its popularity dating back more than 60 years.

Because of this, he chose it as part of a singing activity for a speech and voice therapy group he often leads every month. The group is a casual event that takes place before the monthly Parkinson's support meetings at Wild Rose Manor.

At first Brown thought the participants would be unenthusiastic about doing the Hokey-Pokey dance that goes with the song.

Instead, it's become a highlight.

"(Everyone) loved that part of it," he said. "It became this really great thing. Those who could stand were standing up, that part was really cool.

"They really dug it, so we kept it."

Parkinson's disease is a degenerative disorder that attacks the nervous system. Those who have it experience difficulty with muscle co-ordination, tremors, or shaking, a difficulty moving and walking. The disease also affects one's throat muscles, and leads to trouble swallowing and speaking loudly.

It most commonly affects people over the age of 50, and can be prevalent on one or both sides of the body and gets increasingly severe over time.

The loss of bodily control often leads to anxiety, depression, dementia and hallucinations.

"Parkinson's is a confusing disease because it fluctuates so much," said Doreen Larsen, a participant in the speech and support group. "One day, or one hour, you can do things really well, maybe speak well, or your balance is really well – you're co-ordinated. A little while later you try to do something similar and it's not as effective."

Brown said the vocal group explores the Lee Silverman Voice Treatment method, which utilizes a variety of techniques to help those who have the disease speak louder.

"The whole gist of it is loudness, not just producing loud voice, but thinking loudly, breath control, posture corrections in order to project a loud voice," he said.

The group is a fun way for local residents who experience the disease to keep their speech in shape for as long as they can, Brown said. The participants all provide input and feedback as to what to explore and work on, and other methods to keep their vocal quality from declining.

Brown said that the primary exercises for the group include casual conversation, vocal warm-ups and, of course the singing.

"It might seem like we're joking around and having fun," he said "(but) there's always an undercurrent of we're actually doing direct therapy."    
                

New treatment may help those with Parkinson's disease

Maureen McFadden
WNDU.com - Parkinson’s disease is one of the most common neurological disorders with as many as 60,000 Americans diagnosed every year.

Patients may have tremors, stiffness, and loss of motor control as the disease progresses.

Now, a new study is showing experimental gene therapy may hold real promise for some patients.

60-year-old Walter Liskiewicz spends most of his time tickling the electronic ivories.

The accomplished new-age jazz musician and singer has a string of hit songs under his stage name, Waldino.

Connie Smith, Walter’s wife, says, "He was very prolific. People couldn't understand how he could write so many songs. It's because he was stuck in a chair."

For more than 18 years, Liskiewicz has struggled with Parkinson’s disease. Increasing disabilities forced him to retire at age 44 from his first career as an oral surgeon. Medication helped control the disease early on, but eventually, Liskiewicz started losing his ability to speak and sing.

Walter says, "My life was going down the tubes."

Dr. Peter LeWitt heads the Movement Disorders Program at Henry Ford Health System in Michigan. LeWitt is studying gene transfer therapy to treat Parkinson’s patients.

Dr. LeWitt says, "The foot is now in the door, opening, perhaps, a better way to treat people than just medications."

During the transfer procedure, doctors attach a specialized gene onto a harmless virus and infuse it directly into the brain. Researchers believe that gene, known as GAD, regulates a chemical in the brain that can improve Parkinson’s disease symptoms.

Soon after the surgery, Walter and Connie began to notice small, but meaningful, changes.

Connie says, "Just to see him…the eyes sparkling, the smile, the facial expressions. It was really exciting.”

A cutting edge procedure that may help this dentist-turned-performer not miss a beat.

Researchers say despite concerns that the gene therapy could have unforeseen risks, those enrolled in the study had no significant side effects.

They say the therapy could potentially be repeated, and larger trails would need to be conducted before the FDA would approve the treatment as safe and effective.

RESEARCH SUMMARY

BACKGROUND: Parkinson's disease is a progressive disorder of the nervous system that affects movement. It develops gradually, often starting with a barely noticeable tremor in just one hand. While tremor may be the most well-known sign of Parkinson's disease, the disorder also commonly causes a slowing or freezing of movement. There's no cure for Parkinson's disease, but medications can help control some of the symptoms of Parkinson's disease, and in some case, surgery may be helpful. (SOURCE: Mayo Clinic)

CAUSES: A small region deep within the brain is the source for the symptoms of Parkinson's disease. When brain neurons in this part of the brain begin to die, these cells can no longer manufacture the molecule dopamine -- a chemical critical for controlling movement. The exact cause of Parkinson's disease is unknown, but several factors appear to play a role, including genes. Researchers have found specific genetic mutations that likely play a role in Parkinson's disease. In addition, scientists suspect that many more changes in genes -- whether inherited or caused by an environmental exposure -- may be responsible for Parkinson's disease. Exposure to toxins or certain viruses may trigger Parkinson's signs and symptoms. (SOURCE: Mayo Clinic)

NEW GENE THERAPY: For the first time, gene therapy has proven successful in Parkinson's patients. The therapy uses a virus that is stripped of its infectious properties and delivered with a thin tube into the brain's subthalamic nucleus -- a structure "the size of a pine nut" that is involved with movement. Researchers followed 45 patients for six months after the procedure at seven U.S. medical centers. Half the patients showed improvements early on, which they still sustained six months later. Most current therapies and research approaches target dopamine to treat motor symptoms associated with Parkinson's disease. In contrast, the focus of the current gene therapy strategy is on increasing GABA -- a brain neurotransmitter that regulates movement. In Parkinson's disease, GABA is reduced in the area of the brain known as the subthalamic nucleus, causing it to be overactive. Investigators feel this might be a better way to help advanced Parkinson's disease. (SOURCE: Henry Ford Health System)

FOR MORE INFORMATION, PLEASE CONTACT:
Dwight Angell
Director, Media Relations
Henry Ford Hospital
dangell1@hfhs.org
(313) 876-8709                       

DOPAMINE AGONISTS INCREASE THE RISK OF VALVULAR REGURGITATION

25th August 2011 - New research

Movement Disorders [2011] 26 (5) : 801-806 (V.G.Rasmussen, K.Østergaard, E.Dupont, S.H.Poulsen) 

The use of dopamine agonists increases the risk of valvular regurgitation in people with Parkinson's Disease. Valvular regurgitation is when a cardiac valve becomes diseased or damaged, and is no longer able to close properly. Leakage of blood occurs across the valve.  This leakage of blood is referred to as regurgitation.  Valvular regurgitation can lead to abnormal cardiac function. For more information go to Mitral valvular regurgitation.

Cabergoline, which is also known by the brand names Dostinex and Cabaser, was the worst of those dopamine agonists assessed. The likelihood of valvular regurgitation in people with Parkinson's Disease taking Cabergoline was more than six times greater than would otherwise be expected.. The dopamine agonist Pergolide, which is also known as Permax, makes valvular regurgitation in people with Parkinson's Disease more than three times more likely. The likelihood of Permax causing valvular regurgitation led to its withdrawal in the U.S. in 2007, but it is still used elsewhere. Other dopamine agonists were not assessed. So it is not known to what extent they are harmful in this respect or if they are harmful at all.

What is Deep Brain Stimulation for Parkinson's Disease?

 

Deep brain stimulation (DBS) is a surgical procedure used to treat a variety of disabling neurological symptoms—most commonly the debilitating symptoms of Parkinson’s disease (PD), such as tremor, rigidity, stiffness, slowed movement, and walking problems.  The procedure is also used to treat essential tremor, a common neurological movement disorder.  At present, the procedure is used only for patients whose symptoms cannot be adequately controlled with medications.

DBS uses a surgically implanted, battery-operated medical device called a neurostimulator—similar to a heart pacemaker and approximately the size of a stopwatch—to deliver electrical stimulation to targeted areas in the brain that control movement, blocking the abnormal nerve signals that cause tremor and PD symptoms. 

Before the procedure, a neurosurgeon uses magnetic resonance imaging (MRI) or computed tomography (CT) scanning to identify and locate the exact target within the brain where electrical nerve signals generate the PD symptoms.  Some surgeons may use microelectrode recording—which involves a small wire that monitors the activity of nerve cells in the target area—to more specifically identify the precise brain target that will be stimulated.  Generally, these targets are the thalamus, subthalamic nucleus, and globus pallidus.

The DBS system consists of three components:  the lead, the extension, and the neurostimulator.  The lead (also called an electrode)—a thin, insulated wire—is inserted through a small opening in the skull and implanted in the brain.  The tip of the electrode is positioned within the targeted brain area.

The extension is an insulated wire that is passed under the skin of the head, neck, and shoulder, connectng the lead to the neurostimulator.  The neurostimulator (the "battery pack") is the third component and is usually implanted under the skin near the collarbone.  In some cases it may be implanted lower in the chest or under the skin over the abdomen.

Once the system is in place, electrical impulses are sent from the neurostimulator up along the extension wire and the lead and into the brain.  These impulses interfere with and block the electrical signals that cause PD symptoms.

Is there any treatment?

What is the prognosis?

What research is being done?

The NINDS supports research on DBS to determine its safety, reliability, and effectiveness as a treatment for PD.  Currently, NINDS-supported scientists are trying to determine the site(s) in the brain where DBS surgery will be most effective in reducing PD symptoms.  These researchers are also comparing DBS to other PD therapies to find out which is more effective.

Although most patients still need to take medication after undergoing DBS, many patients experience considerable reduction of their PD symptoms and are able to greatly reduce their medications.  The amount of reduction varies from patient to patient but can be considerably reduced in most patients.  The reduction in dose of medication leads to a significant improvement in side effects such as dyskinesias (involuntary movements caused by long-term use of levodopa).  In some cases, the stimulation itself can suppress dyskinesias without a reduction in medication.

Unlike previous surgeries for PD, DBS does not damage healthy brain tissue by destroying nerve cells.  Instead the procedure blocks electrical signals from targeted areas in the brain.  Thus, if newer, more promising treatments develop in the future, the DBS procedure can be reversed.  Also, stimulation from the neurostimulator is easily adjustable—without further surgery—if the patient’s condition changes.  Some people describe the stimulator adjustments as "programming."

9th August 2011; THE LONG TERM EFFECTS OF DBS ON PARKINSON'S DISEASE

Archives of Neurology [2011] Published online August 8 (A.Castrioto, A.M.Lozano, Yu-Yan Poon, A.E.Lang, M.Fallis, E.Moro) 

Researchers assessed the outcome of Deep Brain Stimulation of the subthalamic nucleus (STN-DBS) in people with Parkinson's Disease over a period of 10 years. Deep Brain Stimulation (DBS) involves the use of electrodes that are implanted into the brain and connected to a small electrical device called a pulse generator that can be externally programmed. DBS requires careful programming of the stimulator device in order to work correctly. DBS improved the Parkinson's Disease symptom score by 25% in comparison to no treatment, including resting and action tremor by over 85%, and bradykinesia by 23%. It did not stop deterioration in speech, walking, and postural instability, including falling and freezing. L-dopa dosages reduced to about 63% of what they were initially. Daily living activity also improved. Dyskinesia and motor fluctuation scores also remained significantly lower. Potential adverse events included : a trend to weight loss, visual hallucinations, impulse control disorders possibly related to dopamine agonists, progressive cognitive decline culminating in dementia,  device related infections.

Nicotine Protects Against Parkinson’s?

Northwest Parkinson's Foundation:

The addictive component of cigarettes saves dopamine neurons from a Parkinson’s-like decline, providing a new avenue for potential treatment.Jef Akst

The Scientist - Nicotine protects the brain against the loss of dopamine neurons, a characteristic sign of Parkinson’s disease, according to a study published this week in The FASEB Journal.

By activating the alpha-7 nicotinic receptor, nicotine—which increases dopamine levels in the brain—appears to be able to rescue mouse dopaminergic neurons cultured under conditions that favor their loss. Genetically engineered mouse cells that lacked a specific nicotine receptor (the alpha-7 subtype), however, were unaffected by nicotine treatment.

The findings suggest that new Parkinson’s therapies may be developed to target nicotine receptors, FierceBiotech reports. “This study raises the hope for a possible neuroprotective treatment,” said co-author Patrick P. Michel of the Institut du Cerveau et de la Moelle Épinière, Hôpital de la Salpêtrière, in Paris, France, in a statement.

But this is not an endorsement for cigarettes, FASEB noted. “If you’re a smoker, don’t get too excited,” Gerald Weissmann, editor-in-chief of The FASEB Journal, said in a statement. “Even if smoking protects you from Parkinson’s, you might not live long enough to develop the disease because smoking greatly increases the risk for deadly cancers and cardiovascular diseases.”

Sleep Disorder is Risk Factor for Parkinson’s

From the Northwest Parkinson's Foundation: Rick Nauert PhD

Psych Central - A new European study suggests individuals suffering from REM sleep behavior disorders have an increased risk of developing Parkinson’s disease (PD).

REM sleep behavior disorders are characterized by dream nightmares in which a person is attacked and pursued leading an individual to scream, cry, punch and kick while sleeping.

The current study is the third work on the topic within the last five years to be published by Lancet Neurology.

The first work showed in 2006 that 45 percent of patients who suffer this sleep disorder develop Parkinson’s disease and other neurodegenerative diseases caused by a lack of dopamine in the brain.

The second article discovered that neuroimaging tests that measure dopamine in the brain, such as the brain SPECT scan (single-photon emission computed tomography), are useful to identify patients with REM sleep disorders with increased risk of developing a neurodegenerative diseases such as Parkinson’s disease.

In the current study, researchers used SPECT to conclude that the levels of dopamine in the brain are quickly lowering over the years in patients with REM sleep behavior disorder.

SPECT is the first neuroimaging technique to detect the disease progression at an early stage. The study involved comparing for three years the evolution of brain SPECT in 20 patients with REM disorder and 20 healthy controls.

The neuroimaging technique measures the presence of dopamine in the substantia nigra, a part of the brain associated with learning and harmony of body movements. In Parkinson’s disease, a deficiency of dopamine in the substantia nigra causes tremor, stiffness and movement slowness in patients.

Results showed that after three years of monitoring the production of dopamine in the control group was reduced by 8 percent due to age, while the group of REM sleep disorder patients experienced a reduction of 20 percent.

Once the three-year follow-up ended, three of 20 patients in the REM sleep disorder group had developed Parkinson’s disease and their dopamine reduction was around 30 percent.

Researchers conclude that more efforts are needed to create neuroprotective drugs that prevent the progression from REM sleep behavior disorders to Parkinson’s disease.

Authors of the study suggest that, to be considered effective, a neuroprotective drug should significantly prevent the dopamine concentration from dropping in these patients.