Experimental Parkinson's Treatment Rewires the Brain

Thursday, 29 November 2018 

An experimental gene therapy for Parkinson's disease seems to work by rewiring key areas of the brain, a new study finds.

The researchers focused on 15 Parkinson's patients who, in an earlier trial, had received so-called GAD gene therapy. GAD is an enzyme that spurs the production of a brain chemical involved in movement control.

In the previous trial, patients had shown improvements in their movement problems after receiving infusions of the GAD gene into the brain.

What hadn't been clear was precisely why, said researcher Dr. David Eidelberg, who directs the Center for Neurosciences at the Feinstein Institute for Medical Research, in Manhasset, N.Y.

So for the new study, Eidelberg's team examined specialized brain scans from 15 of the trial patients. The investigators found an unexpected answer: The gene therapy did not change the abnormal brain circuitry that marks Parkinson's disease.

Instead, it essentially rewired a small area of the brain, to partially compensate for the faulty circuitry.

"It created its own set of circuits," Eidelberg explained. "The disease circuitry continues — so this is not a cure."

Still, he said, the gene therapy seems to spur new brain connections that can benefit people with Parkinson's.

The study findings were published online Nov. 28 in Science Translational Medicine.

Parkinson's disease affects nearly 1 million people in the United States alone, according to the Parkinson's Foundation.

The root cause is unclear, but as the disease progresses, the brain loses cells that produce dopamine — a chemical that regulates movement. As a result, people suffer symptoms like tremors, stiff limbs, and balance and coordination problems that gradually worsen over time.

There are treatments to lessen those symptoms, including medications that boost dopamine levels or mimic the actions of dopamine. Another option for some patients is deep brain stimulation (DBS), where electrodes are implanted in a specific brain area to deliver continuous electrical pulses. It's thought to help by suppressing abnormal electrical activity.

GAD gene therapy is done by inserting the gene into an inactivated cold virus. That viral "vector" is infused into a specific brain area called the subthalamic nucleus — which is one of the brain regions targeted in DBS treatment.

Originally, Eidelberg added, researchers thought the gene therapy would work in a "DBS-like" way.

But based on the new findings, that's not the case.

Dr. Michael Okun is medical director of the Parkinson's Foundation. He called the study "fascinating." "It showed that GAD gene therapy, unlike subthalamic nucleus DBS, did not change the expected Parkinson's disease brain network," Okun said. "Instead, it co-opted adjacent non-motor pathways."

Why does that matter? One reason, according to Okun, is that it offers an "important lesson" for the gene therapy field going forward. Researchers cannot make assumptions about a therapy's "mechanism of action," he said, based on the brain area it targets.

Eidelberg made another point: In future studies, researchers could use brain imaging to be sure that patients' symptom improvements are due to a true effect of the gene therapy — rather than a "placebo effect."

In the original trial, which involved a few dozen Parkinson's patients, some were randomly assigned to receive GAD gene infusions. The rest underwent a "sham" procedure for comparison.

Over six months, both groups showed improvements in movement symptoms like stiffness and tremor. But the gene therapy group saw greater gains.

"It wasn't a slam dunk," Eidelberg stressed. "But they were doing better. And that persisted to the one-year mark."

With any such therapy, there is a theoretical concern that the infused gene will have unintended effects.

"What we've seen is that this gene stays put," Eidelberg said. "It doesn't percolate all over the brain."

In the original trial, there were no red flags, according to the researchers. The most common side effects were temporary headaches and nausea.

Various research teams are looking at different approaches to gene therapy for Parkinson's. The hope, Eidelberg said, is to develop additional options that work for at least some patients — possibly freeing them from taking daily medications.

At this point, he noted, there is "a lot of interest" in doing a larger, later-stage trial of the GAD therapy. But none has begun yet.

The current study was funded by Neurologix Inc., the company that developed the gene therapy.

The Parkinson's Foundation has more on Parkinson's treatment.

SOURCES: David Eidelberg, M.D., director, Center for Neurosciences, Feinstein Institute for Medical Research, Manhasset, N.Y.; Michael Okun, M.D., medical director, Parkinson's Foundation, Miami; Nov. 28, 2018, Science Translational Medicine, online

© HealthDay

https://www.newsmax.com/health/health-news/parkinsons-treatment-experimental-gene-therapy/2018/11/29/id/892414/

Too many dementia patients prescribed potentially inappropriate drugs, study finds

November 29, 2018, University of Otago

Older adults diagnosed with dementia are frequently being prescribed potentially inappropriate medications, which leaves them at risk of delirium, worsening cognitive impairment, and increased mortality, a University of Otago study has found.

Lead author Dr. Sharmin Bala, of the Department of Preventive and Social Medicine, is calling for improvements to prescriptions and regular reviews to ensure safe prescribing.

The study, co-authored by Dr. Hamish Jamieson, of the University of Otago, Christchurch, and Dr. Prasad Nishtala, of the University of Bath, was published in the International Journal of Geriatric Psychiatry.

It consisted of more than 16,500 individuals who underwent an International Resident Assessment-Home Care assessment in 2015.

About 13 per cent were diagnosed with dementia and, of those, 67 per cent were found to be prescribed potentially inappropriate medications.

Potentially inappropriate medications are the prescribing of drugs where the risk outweighs the benefit, and could also represent under-prescribing of beneficial treatments, Dr. Bala says.

The study also found that 40 per cent of those diagnosed with dementia were prescribed anticholinergic medications, which could be potentially inappropriate to prescribe to such a cohort.

Anticholinergics are prescribed for a variety of medical conditions, such as, for the treatment of overactive bladder, allergies, depression, and the management of symptoms in Parkinson's disease. It is well established that these drugs can cause impairment in cognition and exacerbate cognitive decline.

"The prescription of anticholinergic medications is associated with a higher risk of negative outcomes including risk of falls, delirium, worsening cognitive function, and increased mortality.

"The findings of the study indicate that the quality of prescribing needs to be improved. It is also imperative that medications prescribed to older adults with dementia, especially medications that have anticholinergic side effects, are reviewed regularly by medical professionals to ensure safe prescribing."

Dementia is one of the principal syndromes linked with disability and dependence among older adults and is a major challenge to individuals, communities, and societies globally. 

The estimated prevalence of dementia in New Zealand was more than 62,000 in 2016. By 2050 the number is predicted to increase to nearly 170,000.

Prescribing medications for older adults with dementia is challenging because of the risks associated with cognitive decline, behavioural and psychological disturbances, multiple medications, and their associated costs.

Dr. Bala says a radical component of optimal therapy for older adults with dementia is identifying and de-prescribing potentially inappropriate medications.

"Safe prescribing in individuals with dementia has the potential to mitigate critical adverse effects associated with the prescription of these medications and improve the quality of life in this vulnerable population."

More information: Sharmin S. Bala et al. Determinants of prescribing potentially inappropriate medications in a nationwide cohort of community dwellers with dementia receiving a comprehensive geriatric assessment, International Journal of Geriatric Psychiatry (2018). DOI: 10.1002/gps.5004

Provided by: University of Otago

https://medicalxpress.com/news/2018-11-dementia-patients-potentially-inappropriate-drugs.html

Gene therapy eases Parkinson’s symptoms by rewiring parts of the brain

November 28, 2018   By Alice Klein

A treatment for Parkinson’s rewires parts of the brain   ALFRED PASIEKA/SCIENCE PHOTO LIBRARY

A gene therapy treatment for Parkinson’s disease appears to relieve symptoms by rewiring the brain circuits involved in movement.

People with Parkinson’s disease have tremors and muscle stiffness that are caused by overstimulation of a brain area called the subthalamic nucleus, which is responsible for coordinating the brain’s motor regions.

In a trial published in 2011, researchers at the Feinstein Institute for Medical Research in New York found that a gene therapy designed to turn down the activity of the subthalamic nucleus improved motor control for people with Parkinson’s.

Though the treatment reduced Parkinson’s symptoms for at least a year, it was unclear how. To find out, the researchers have since used PET scans to compare the brains of 15 people who received the gene therapy with 20 who received a placebo.

Reshaping the brain

One year after treatment, the people in the gene therapy group were found to have new brain connections that weren’t seen in the placebo group. Shutting down the disease-causing pathways between the subthalamic nucleus and the brain’s motor regions appeared to encourage alternative pathways to develop instead, says David Eidelberg at the Feinstein Institute, who led the study.

These alternative pathways are not found in healthy people. This suggests that gene therapy lets people with Parkinson’s form novel, compensatory brain circuits for controlling movement, says Eidelberg. “We call it adaptive rewiring.”

Another treatment for Parkinson’s disease – called deep brain stimulation – involves sticking electrodes into the subthalamic nucleus and suppressing its activity using electrical pulses. However, Eidelberg and his colleagues found that this did not lead to the same adaptive rewiring.

The team is now planning a larger trial of gene therapy for Parkinson’s disease that is due to start at the end of 2019.

Journal reference: Science Translational Medicine, DOI: 10.1126/scitranslmed.aau0713

https://www.newscientist.com/article/2186723-gene-therapy-eases-parkinsons-symptoms-by-rewiring-parts-of-the-brain/

Staying Active Versus Exercise

 NOVEMBER 28, 2018     BY "SHERRI WOODBRIDGE"

Whether you ask a group of people with Parkinson’s disease (PD) or your neurologist about the best thing you can do to keep PD at bay or slow down its symptoms, the most common response will likely be “exercise.” Some may say, “Stay active.” But do you realize that staying active and exercising are two different things?

Just about anyone can exercise — jumping jacks, touch your toes, jog around your living room, lift a couple of cans of green beans — but it takes sheer determination to stay active when you are battling a little monster like Parkinson’s disease.

Being active involves more than movement on your part. It includes a state of mind to persevere, to keep putting one foot in front of the other, and to not give up even when you feel like quitting. Being active involves a positive outlook.

It is easy to fall into a state of apathy or depression when fighting a chronic illness, but to try to pull yourself out of one can be downright hard. The gray cloud of despair can last days, weeks, months, even years. Staying active can help sidestep those dark times.

Sitting and watching television can sound relaxing, but when flopping on the couch is your go-to place when you’re feeling down, it may take an act of God to get you back up. Depression feeds depression. Apathy feeds depression. At times you will have to force yourself up off that couch and do something. But force you must. You must stay active. You must not allow yourself to succumb to dark days. Fight and fight hard. Get your friends to join you by coming alongside them. Show them you need them because they do want to be needed at this time in your life.

Exercise is essential for a Parkinson’s patient. Walking, boxing, bicycling, tai chi — these are all terrific forms of exercise as you strive to live healthily with PD. However, to determinedly exercise with PD, you have to “master” staying active. Keep your mind on an even and positive keel. You must tell yourself that you can do this thing; you can battle this little monster. You must say to yourself that as this disease strives to master you, you will fight tooth and nail to push forward and stay active.

Following are some techniques I use in my battle to master PD:

• Keep your mind active. Do word puzzles, jigsaw puzzles, sudoku games, and more to keep your mind alert.
• Don’t give in to fear. 
• Make positive thinking a habit. Carry scripture verses or positive thinking quotes in your pants pocket and read them throughout the day.
• Don’t give up and don’t give in: mentally, physically, relationally, emotionally, or spiritually.
• Avoid temptations like empty couches and TV remote controls.
• Fight the dark days. Don’t let them get the upper hand.
• Don’t go it alone. Get connected via a support group.

I am in no way an expert in “staying active” but I do make a valiant effort to do so. I have found the above practices to be helpful in dealing with Parkinson’s and hope they are useful to you too.

***

Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

https://parkinsonsnewstoday.com/2018/11/28/parkinsons-staying-active-exercise-depression-walking-boxing-tai-chi-positive-thinking-puzzles/

Study Links Smoking, Reduced Parkinson’s Risk, But Comes with Caveat

 NOVEMBER 28, 2018 BY JOSE MARQUES LOPES, PHD 

Smoking more cigarettes or for a longer time is associated with a decreased risk of developing Parkinson’s, according to a population-based study.

A reduced risk was also seen in people exposed to passive smoking compared with those who had never smoked.

However, the scientists cautioned that rather than encouraging people to smoke, the findings warrant further research into which compound in tobacco confers this effect.

The study, “Exploring causality of the association between smoking and Parkinson’s disease,” was published in the International Journal of Epidemiology.

The link between smoking and a reduced risk for Parkinson’s is supported by substantial evidence in men and women, and has included cigarette, pipe, and cigar smoking, as well as using smokeless tobacco. Also, children of smokers have shown a lower risk for developing the disease.

However, researchers have recommended considerable caution in interpreting this association as protective. They have been studying a potential effect of personality, in particular whether a low-risk-taking personality would be a confounder, especially if induced by dopamine shortage — a Parkinson’s hallmark — which may make it easier to quit smoking. In this regard, a link between passive smoking and protection from Parkinson’s — which is not susceptible to different personalities — could not be determined.

To better understand this correlation, researchers from Queen Mary University of London, Imperial College London and University of Campania Luigi Vanvitelli, in Italy, analyzed the link between Parkinson’s risk and smoking duration, amount and time since quitting smoking. They looked at a potential delaying effect, smoking patterns among current and former smokers, the association with passive smoking, and the consistency across clinical subtypes.

The study included 220,494 people participating in NeuroEPIC4PD, a prospective European population-based study in 13 centers from eight countries. A total of 715 cases of Parkinson’s (mean age at recruitment 61.4 years, age at onset 67.5) were analyzed.

Data on smoking habits were collected at recruitment, including whether participants were never, former or current smokers, their age when they started smoking and when they quit, and number of cigarettes per day at different ages.

The results showed that, compared with people who had never smoked, former smokers had a 20% lower risk and current smokers a halved risk for developing Parkinson’s during follow-up (12.8 years).

Smoking more cigarettes and for a longer period of time were also associated with a lower risk of developing the disease, as the risk in people smoking 12 or more cigarettes a day or for longer than 30 years was about 55% lower compared to those who had never smoked.

Smoking correlated with reduced disease risk in both mid-age and late-onset Parkinson’s, as well as in tremor-dominant and akinetic-rigid (slowed movement, muscle stiffness, postural instability, gait impairment) Parkinson’s. Also, the risk did not vary over the follow-up period, which argues against a delaying effect of smoking on Parkinson’s onset, the team observed.

Exposure to passive smoking at home or work was also linked to lower risk, as passive smokers were 30% less likely to develop the disease than non-exposed individuals.

“In conclusion, the present findings are consistent with a protective effect of smoking on the risk of [Parkinson’s],” scientists stated.

“Our discovery is incredibly important from a scientific point of view and should prompt basic science research aimed at identifying the agent responsible for this effect found in tobacco,” Valentina Gallo, MD, PhD. the study’s first author, said in a press release. “Hopefully this will give insight for preventive treatment options.”

“However, no one would ever be advised to use smoking as a preventive treatment for Parkinson’s based on this research, because of the disastrous effects we know smoking has on people’s general health,” Gallo added.

https://parkinsonsnewstoday.com/2018/11/28/smoking-linked-reduced-parkinsons-risk-but-carries-caveat/

PF-06412562 Safe, Eases Motor Impairments in Parkinson’s Patients, Phase 1 Trial Finds

NOVEMBER 28, 2018 BY JOSE MARQUES LOPES, PHD 

A compound that targets two specific dopamine receptors in the brain is safe and can ease motor deficits in Parkinson’s patents, recent clinical data reveals.

The study, “Evaluation of D1/D5 Partial Agonist PF-06412562 in Parkinson’s Disease following Oral Administration,” was published in Neurodegenerative Diseases.

Pharmacological treatment of Parkinson’s patients mostly has used the dopamine precursor levodopa and agonists (activators) of dopamine D2 receptors.

Dopamine receptors can be divided into two classes (D1-like and D2-like) on the basis of their biochemical and physiological effects and are a target of action for different therapeutic compounds. Dopaminergic neurons can regulate movement via the activation of these receptors.

Long-term administration of levodopa, however, may lead to the development of motor complications, including dyskinesia (involuntary, jerky movements).

The potential benefit of selective D1 agonists is not as well-characterized. Although early studies have suggested little anti-parkinsonian potential in primates or humans, later research with different compounds indicated comparable effectiveness to levodopa in Parkinson’s patients with dyskinesia.

However, D1 agonists’ blood pressure-lowering (hypotensive) effects, low oral bioavailability (the proportion that reaches systemic circulation) and short half-life (the time required for the agonist’s amount in the body to be reduced by half) have limited their development.

Researchers now hypothesized whether selective D1 partial agonists, which are less effective than full agonists, may be an alternative or add-on treatment to manage Parkinson’s symptoms.

Researchers at Pfizer designed a double-blind, Phase 1 study (NCT02006290) that assessed PF-06412562 — a partial agonist of  the D1 receptor — for motor benefit in Parkinson’s patients. Safety, tolerability and pharmacokinetics (how the body affects a medicine) of PF-06412562 also were evaluated. Of note, this partial agonist also binds to D5, another dopamine receptor that is very similar to D1.

Selective partial D1/D5 stimulation was predicted to ease several motor symptoms, including dyskinesia.

The safety and effectiveness of a single, oral dose of PF-06412562 was tested at four U.S. sites in 19 Parkinson’s patients — 42% men, all white, mean age 63.8 years, and mean disease duration 6.7 years.

Maximum percent improvement in finger-tapping speed — assessed with the Kinesiatechnology — was the study’s primary goal. Because  this measure still requires validation, change from baseline in Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale – Part 3 (MDS-UPDRS-III) also was analyzed to assess change in motor symptoms.

Patients received Merck’s Sinemet (25 mg of carbidopa and 100 or 250 mg of levodopa), PF-06412562 in 5 mg tablets, or placebo in the morning following an overnight fast and no Parkinson’s medications after 8 p.m. the previous night.

Thirteen patients received a second 30 mg dose of PF06412562 (plus 20 mg four hours later), or placebo four hours after the first dose. Each patient served as his/her own control.

With this split-dosing scheme, researchers intended to increase the length of time patients spent at projected efficacious levels without going over the exposure limit.

The maximum dose of PF-06412562 was 30 mg, which was well-tolerated by healthy volunteers in a previous study and led to maximum plasma levels shown to induce motor benefits in primates.

Treatment with PF-06412562 did not improve finger-tapping speed (a measure of slowness of movement, or bradykinesia), which scientists attributed to inconsistencies in the task that led to large fluctuations of baseline values.

In contrast, patients receiving PF-06412562 showed statistically significant lessening of motor symptom severity as assessed via change from baseline in MDS-UPDRS-III score at 1.5-2.5 hours post-dose, compared to placebo. This clinically meaningful improvement gradually decreased over 12 hours.

Median peak concentration of PF06412562 and its by-product — PF-06663872 — in plasma was reached at approximately one hour post-treatment and 5.1 hours post-split doses, respectively. In turn, levodopa reached peak concentration at approximately 30 minutes after a single oral dose.

“The observed PK indicate that PF-06412562 is suitable for once-daily or twice-daily oral administration,” researchers wrote.

All adverse events (AEs, or side effects) were mild-to-moderate and did not lead to any treatment discontinuation or dose reduction. Five participants receiving PF-06412562 30 + 20 mg experienced seven treatment-emergent AEs. Nausea and fatigue were the most common.

“This study demonstrates the potential for further studies to explore the efficacy and safety of an orally available D1/D5 agonist in the improvement of motor deficits in patients with [Parkinson’s] in an acute-treatment setting,” researchers concluded.

Of note, three of the study’s authors are employees of Pfizer. Two others are former employees.

https://parkinsonsnewstoday.com/2018/11/28/phase-1-trial-pf-06412562-safe-eases-parkinsons-motor-deficits/

Discovery of New Brain Region Could Have Implications for Neurodegenerative Disorders

NOVEMBER 27, 2018 BY JONATHAN GRINSTEIN 

The recent discovery of a previously unknown region of the human brain could have significant implications for neurodegenerative disorders affecting motor skills, such as Parkinson’s disease and motor neuron diseases including amyotrophic lateral sclerosis and spinal muscular atrophy

Neuroscientist George Paxinos’ discovery of the endorestiform nucleus, which functions to control fine motor skills, is detailed in his new book, “Human Brainstem: Cytoarchitecture, Chemoarchitecture, Myeloarchitecture,” and published in Elsevier.

An increasingly detailed map of the brain and spinal cord has been essential to most major discoveries in neuroscience in the past century. In the book, Paxinos and colleagues from Neuroscience Research Australia (NeuRA) present the first detailed atlas of the human brainstem — the back section of the brain that is continuous with the spinal cord — in over twenty years.

“I am a brain cartographer and the maps I do are of the normal, the canonical brain, and other scientists can compare their pathological tissue if they study Alzheimer’s disease, Parkinson’s, epilepsy tissue obtained from post-mortems against the canonical brain,” Paxinos said.

The researchers took advantage of new imaging technology that allows for the brain to be studied in live, conscious individuals. Although the imaging resolution has room for improvement, researchers still had the advantage of imaging the brain in its natural location as opposed to removing it and processing it for imaging post-mortem, which distorts the results and, ultimately, identification of brain regions. This new, live imaging technology allowed researchers to identify structures and more accurately map them to specific areas in the brain.

When constructing a new map of the human brainstem, the team identified a region formerly unknown to science. They found that the endorestiform nucleus is in a part of the brain called the restiform body or inferior cerebellar peduncle, which connects the cerebellum — the back of the brain — to the underlying brainstem. The restiform body is known to regulate fine motor skills by integrating information about a person’s surroundings and movements.

Previously, the region was not identified as its own nucleus — a group of nerve cells located deep inside the brain and brainstem that have similar connections and functions. The researchers now say it is a different area from its surroundings.

An initial observation of the region was made years ago in patients who underwent a therapeutic anterolateral cordotomy — a surgical procedure that deactivates selected pain-conducting pathways in the spinal cord to alleviate pain. 

This procedure is commonly performed on patients experiencing severe pain because of cancer or other  diseases. It was observed that some of the pathways that were severed in the spinal cord because of the procedure connected to this sub-region in the restiform body in the brainstem.

The brain region has not been found in several monkeys that are very closely related to humans, making it possibly exclusive to humans and possibly holding clues as to what makes us unique.

“One intriguing thing about this endorestiform nucleus is that it seems to be present only in the human; we have not been able to detect it in the rhesus monkey or the marmoset that we have studied,” Paxinos said. “I can only guess about its function but given the part of the brain where it’s found, the highway that connects the spinal cord to the cerebellum, it might be involved in fine motor control that humans are so good at. It would be hard to imagine a chimpanzee playing the guitar dexterously even if it liked to make music.”

Sample images and 3D animations of the brain can be seen at: 

https://drive.google.com/drive/folders/1-XJv_w4LvIMeDNDtLjNPEnpW8vs-CcQA 

Paxinos can be seen explaining his discovery:

https://www.youtube.com/watch?v=M5zsmKZV5-M&amp=&feature=youtu.be

https://parkinsonsnewstoday.com/2018/11/27/brain-region-discovery-could-have-implications-for-parkinsons/

Exercise That Motivates Parkinson’s Patients to Push Limits Can Offer Range of Benefits, Experts Say

 NOVEMBER 27, 2018 BY EMMA YASINSKI IN NEWS.

With a treatment not yet within reach that might slow the progression of Parkinson’s disease, much less offer a cure, many — doctors, patients, and researchers alike — are looking to exercise in hopes of fending off a worsening of symptoms.

Interest in exercise-based interventions has risen so much that “the number of publications on exercise studies has increased by a factor of 10 since 2000,” Tanya Simuni, MD, chief of Movement Disorders in the Department of Neurology at Northwestern University, said in a 2016 interview on the International Parkinson and Movement Disorder Society website.

Many consider it common sense that exercise can help to compensate for the motor symptoms that mark Parkinson’s — and research points to this possibility — yet scientists still have few clues as to how exactly it does so.

Work done through the Parkinson’s Outcome Project, an ongoing study involving more than 12,000 patients in five countries, suggests that patients should exercise at least 2.5 hours each week to slow decline and maintain a better quality of life. A similar study advised that patients should begin regular exercise at diagnosis.

Still, this research stops short of recommending a specific exercise regimen as a best strategy.

This has led several enterprises — both for-profit companies and nonprofit groups —  to offer classes ranging from dancing to Parkinson’s-only boxing, and products such as specialized at-home exercise equipment that promise to reduce, reverse, and delay symptoms.

While the literature on exercise in Parkinson’s is “extensive,” Rebecca Gilbert, MD, PhD, chief scientific officer of the American Parkinson’s Disease Association and a practicing neurologist, told Parkinson’s News Today, studies on its effects are typically small. Only recently have they begun to grow in size and in quality — but “translating [their findings] into practical recommendations” is a challenge.

Exercise and the brain

In Parkinson’s, neurons in a brain area called the substantia nigra that are responsible for producing a neurotransmitter called dopamine gradually die off, leading to motor symptoms such as tremor and bradykinesia (slow movement).

Levodopa — which works to increase dopamine levels in the brain but cannot rescue damaged neurons — is currently the front-line treatment for the disease.

Some evidence suggests that, like levodopa, exercise may exert some of its effects by increasing dopamine. A recent study of 17 Parkinson’s patients used positron emission tomography (PET) scans of the brain before and after stationary cycling. Results showedthat habitual exercisers in this group — eight patients who exercised more than three hours a week — had higher dopamine levels in the dorsal striatum (the brain area that receives dopamine input from the substantia nigra to help control movement) after stationary cycling than the nine others who were sedentary.

The eight exercisers also performed better on functional tests assessing motor symptoms, including the Unified Parkinson’s Disease Rating Scale (UPDRS) part 3 — which measures items such as gait and time to stand — and in tests of non-motor symptoms such as apathy and depression.

Exercise might also go a step further than levodopa by increasing brain-derived-neurotrophic-factor (BDNF), which promotes the survival of neurons that make dopamine — the same neurons that degenerate in Parkinson’s patients.

An analysis of 12 studies of BDNF levels in Parkinson’s patients found lower levels of BDNF in patients’ serum than in healthy individuals (mean difference of 2.99 ng/mL).

Two of these studies showed that patients who completed exercise programs lasting four, eight, or 12 weeks increased both serum levels of BDNF and UPDRS motor scores.

A separate review of 32 studies related to exercise’s effects on BDNF suggested that aerobic exercise increased BDNF serum levels in healthy people. This was seen to be both an acute effect of a single exercise session and a result of consistent exercise. Strength training did not impact BDNF.

Another Phase 2 study (NCT01506479) divided 128 recently diagnosed patients into three groups that either continued not exercising, participated in 30 minutes of gentle treadmill walking four times a week, or were assigned to six months of high-intensity treadmill exercises for 30 minutes four times a week. Those who did the high-intensity workout maintained the same UPDRS motor score at the study’s end as they had at its start, while those in group that did not exercise saw their scores drop by three points, and those who exercised minimally had a two-point drop.

Rock Steady Boxing

Rock Steady Boxing, a nonprofit, non-combat boxing program designed exclusively for Parkinson’s patients, aims to help all — regardless of skill level — take advantage of the benefits of exercise, while building a supportive and understanding community of patients.

Parkinson’s News Today columnist Jean Mellano, an athlete who not only boxes with Rock Steady but also does physical therapy, yoga, weight training, and daily walking to help treat her Parkinson’s, said “the camaraderie is off the charts.”

Joyce Johnson, Rock Steady’s executive director echoed that sentiment, noting “the magic of Rock Steady is the camaraderie and the fact that all of our boxers are fighting back against same disease.”

Founded in 2006, Rock Steady Boxing has grown in popularity and now operates out of more than 700 locations worldwide.

“We’ve actually had neurologists write Rock Steady Boxing on their little prescription pad and sent them to a location,” Johnson said.

Rock Steady allows affiliates to operate for a small fee in boxing gyms, YMCAs, hospitals, and churches. Some programs are free to patients thanks to grants, but most require participants to pay fees similar to that of an average exercise program.

A typical 90-minute class begins with a warm-up, followed by varied exercises designed to mitigate Parkinson’s symptoms through balance and flexibility work, jumping rope, weightlifting, and, of course, boxing.

A case study, listed on the group’s website and published in the journal Physical Therapy, of six Rock Steady boxers showed that after 24-36 classes over the course of 12 weeks, all six boxers improved in at least five out of 12 outcome measures, such as the Functional Reach Test, gait speed, cadence, stride length, step width, and other measures of UPDRS part 3, as well as the Parkinson Disease Quality of Life Scale, an assessment of non-motor symptoms. Patients in earlier disease stages did better at 12 weeks, but those with more advanced disease gained benefits with regular classes that ran for 24 and 36 weeks.

Stephanie Combs-Miller, PhD, the case series’ lead author and an associate professor at the Krannert School of Physical Therapy at the University of Indianapolis, published a slightly larger study in 2013 comparing Rock Steady Boxing with a community-based exercise program that included stretching, resistance, aerobic, and balance-based exercises in 31 patients.

Patients again took part in 24-36 sessions of either workout over the course of 12 weeks. The researchers expected that both programs would lead to improvements, but that the boxers’ improvements would be more dramatic than those of patients in the traditional exercise program.

However, Combs-Miller and her team concluded that “both groups demonstrated significant improvements with the balance, mobility, and quality of life,” supporting the idea that any group-based exercise can help Parkinson’s patients, provided they do it consistently.

Still, as Johnson put it: “How much more fun is that for a grandpa to tell his grandkids that he’s going to boxing instead of saying he’s going to therapy?” 

Theracycle and forced exercise

Rock Steady boxers are encouraged by coaches and peers to attempt moves and workout intensities that seem to push the limits of their abilities.

The Theracycle takes this idea a step further, using a motor that forces patients to pedal the stationary bike faster than they could on their own, theoretically maximizing workout effects.

Jay Alberts, PhD, a biomedical engineer at the Cleveland Clinic and an avid cyclist, went on a 200-mile trip in 2003 on a tandem bike with a friend, who also happened to be a Parkinson’s patient. The friend was forced to pedal at Alberts’ pace, which was about 30 revolutions per minute faster than she would have been able to pedal on her own.  According to Alberts, her tremors disappeared during the ride and for a period of time afterward. 

Alberts brought another patient on his tandem bike and noticed similarly striking results. 

But requiring a strong cyclist to take patients out on tandem bike rides regularly is not a practical treatment plan for 10 million patients worldwide.

The Theracycle, a motorized stationary bicycle based on the exercycle invented in 1932, gives patients a safe way to engage in forced exercise — exercise where, in this case, a motor helps them pedal at a speed they wouldn’t be able to reach on their own — at home without a tandem bike or partner.

Alberts conducted a small study in 2009 at the Cleveland Clinic, which appears on the Theracycle website and was published in the journal Neurorehabilitation and Neural Repair, comparing the effects of forced exercise and voluntary exercise (in which patients choose the intensity at which they exercise) on Parkinson’s symptoms.

Ten patients were randomly assigned to complete three one-hour sessions per week of either voluntary cycling or forced exercise using a motorized cycle. After eight weeks, both groups showed improved aerobic capacity, but only the forced exercise group showed improvements (an average of 35%) on the UPDRS part 3.

Mike Studer, president and co-owner of Northwest Rehabilitation Associates, has been using the Theracycle in his Oregon physical therapy clinic since the company reached out to him more than eight years ago, shortly after the Cleveland Clinic study was published. He said he “remained skeptical” of the new research at first, but that the Theracycle “meets and exceeds” expectations.

His clinic also offers the Rock Steady Boxing program, yoga, treadmills, underwater exercises, and more. Studer says “a repetition is not equal to every other repetition.” With the Theracycle, he can control the intensity of a patient’s workout, a crucial factor in its effectiveness.

The main drawback of the machine is its price. It’s not covered by Medicare, and Rich Blumenthal, chief operating officer of Theracycle, admits that the $3,700-$5,900 price tag (depending on the model) can make the equipment difficult to sell. But patients’ lives “are just better when they start using this,” he says.

Both regimens have one thing in common — pushing patients to do more than they may think they are capable of doing.

“There is nothing wrong with people’s bodies. What’s wrong is that neurologically they quit producing dopamine,” Johnson said.

Whether they are encouraged by coaches or by motors, patients often end up doing more than they ever thought they could.

We may never know which exercise regimen is the most effective for preventing Parkinson’s decline, or which is better for any given patients.

“It’s virtually impossible to imagine testing every single modality versus every other modality,” Gilbert said, but “the answer is it’s probably a little of everything.”

https://parkinsonsnewstoday.com/2018/11/27/exercise-pushes-parkinsons-patients-limits-offers-benefits-experts/