Mindful Movement Can Help Motor Hesitation

mindful movement

At my last presentation to a support group for Parkinson’s disease (PD), one attendee said, “My husband wobbles a lot when getting up from the sofa. I’m afraid he will fall. What can we do about that?”

I asked her husband to stand, which he did with grace. A slight hesitation accompanied motor initiation, but no severe wobbling was present. I explained how PD movement fluidity can improve in formal settings.

This information was new to the audience, but not to me. I have been told by people with PD that motor symptoms are less disabling in formal settings, such as entertaining company or presenting to a group, than in informal settings, such as sitting at home on the sofa watching TV with a partner.

Unfortunately, patients often view the doctor’s office as a formal setting. When doctors ask me to stand or sit, I perform excellently — occasionally with a little hesitation, but no serious wobbling.

Motor hesitation commonly accompanies motor initiation in formal and informal settings. Wobbling, instability, and stumbling when transitioning from sitting to walking can follow motor hesitation, particularly in everyday settings. We can use this knowledge to explore possibilities with PD, especially in the early stages of the disease.

Why does motor hesitation occur?

I have previously talked about autopilot and scenario looping. We don’t have to think about walking. Walking is an overlearned motor sequence, stored in our memory, accessed via autopilot, and tied into the scenario looping process.

People with PD experience scenario looping breakdowns and a broken autopilot. We cannot rely on our bodies to automatically and smoothly transition from sitting to walking. Broken autopilots will likely result in wobbling, instability, and stumbling — particularly in informal settings, because our minds tend to focus on other things.

We assume our body will automatically get off the sofa and walk into the kitchen without requiring anything special of us. But that is no longer the case for people with PD. Formal settings show us that our movements become less problematic when we pay extra attention to them.

Mindful movements

We need to do anything and everything we can to decrease the possibility of falling, which is a serious concern. It may seem strange, but I’ve started to “perform” my daily movements. It’s similar to practicing tai chi or dancing every time I get out of a chair, walk from the bathroom to the living room, or even leave the bed.

We can incorporate mindful movements into our lives in formal and informal situations. Mindful movements start with a pause. Before I transition to a new position, I pause, focusing on the movement of my arms, legs, and feet. My movements are slower, slightly exaggerated, and — at least in my mind — graceful.

The LVST BIG program touches on mindful movement. The incorporation of mindful movement needs to be personal, intentional, and eventually, common practice. It took me about six months of daily practice before mindful movement became a regular part of how I move in the world. However, we can tailor mindful movements to fit our lifestyles.

Mindful movement turns informal to formal. Remember that improved quality of life, not perfection, is the goal. It takes time for mindful movement to become a regular part of your routine and impact your quality of life, but it is well worth the effort.

Do you practice mindful movement? Do you notice a difference in your movements in formal situations versus informal ones? Please share in the comments below.

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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.

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Parkinson’s Foundation, Zelira Crafting Survey on Cannabis Use and Possible Benefits

medical cannabis

Zelira Therapeutics, an Australia-based medical cannabis company, has partnered with the Parkinson’s Foundation to learn more about patients’ usage and understanding of medical cannabis and hemp-derived treatments.

Zelira and the organization are developing a survey looking at current use and perceived benefits of medical cannabis among those with Parkinson’s (PD).

The partnership marries the nonprofit’s scientific understanding of this disease with Zelira’s experience in pharmaceutical and condition-specific medical cannabis product development. The company participated in the foundation’s first conference  focused on medical marijuana and PD last year.

“The challenge for people with Parkinson’s is clear, as there is a lack of definitive studies informing clinicians and patients with Parkinson’s about the safety and efficacy of medical cannabis,” said Tom Borger, Zelira’s chief business officer, in a press release.

“One of the objectives of the survey and this collaboration is to provide guidance to people with Parkinson’s about the need for clinically validated medical marijuana and hemp-derived [cannabidiol] CBD treatment alternatives,” he said.

Zelira and the foundation will jointly develop the survey — which will be sent to patients — and review results in preparation for a clinical trial on the safety and efficacy of medical cannabis in PD.

Separately, Zelira will use survey results to inform development of clinically validated medical cannabis and hemp-derived cannabidiol medicines for PD patients, and to help guide patients in considering such alternative treatments. (Cannabidiol, or CBD, is a non-psychoactive marijuana extract.)

“Many people with Parkinson’s disease are seeking help with their symptoms by trying various forms of medical cannabis,” said John Lehr, president and CEO of the Parkinson’s Foundation. “The volume and frequency of questions Parkinson’s Foundation receive from people with Parkinson’s regarding the safety and impact of medical cannabis and CBD has led us to examine this public health issue more fully, and to seek collaborations with leaders in the field from academia, government, advocacy groups and industry to provide the most accurate information possible.”

Zelira, he added, is devoted to helping patients understand the role that medical cannabis might play in managing daily symptoms.

“This effort is consistent with our focus on patients and our desire to provide them with as many treatment options as possible,” said Osagie Imasogie, Zelira’s founder and chairman.

Currently, evidence is lacking to support the use of medical marijuana in managing Parkinson’s symptoms. The issue is being researched, but mostly in small studies with and without control groups, so that results are conflicting, the foundation said in an article that followed the 2019 conference and cites a need for larger and more rigorously conducted research.

Observational studies have shown that cannabinoids — the active molecules in marijuana — may help with non-motor PD symptoms, including pain, anxiety, weight loss and problems sleeping. Controlled clinical trials have reported mixed results for treating motor symptoms such as tremor and rigidity.

In related news, an animal study reported that a compound affecting some of the same brain receptors as cannabis could help ease dyskinesia, the uncontrolled and involuntary movements that can follow levodopa treatment in Parkinson’s.

This disease is estimated to affect about 1 million U.S. residents and 10 million people globally.

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High Blood Levels of Liver Enzyme Linked to Sex-specific Parkinson’s Risk in Korean Study

sex-specific disease risk

Elevated blood levels of the liver enzyme gamma-glutamyltransferase (GGT), a marker for liver disease, was found to be associated with an increased risk of Parkinson’s disease in Korean women and a lower risk in Korean men, a large-scale study  found.

These sex-specific associations held after adjusting for factors that influence GGT levels, such as age, income status, body mass index (BMI), smoking habits, and alcohol consumption.

Although this study was conducted only in a Korean population, its results suggest that blood tests for GGT may be a useful marker for Parkinson’s disease risk.

The study, “Serum gamma-glutamyltransferase activity and Parkinson’s disease risk in men and women,” was published in Nature Scientific Reports

A process known as oxidative stress is thought to be one of the underlying mechanisms that lead to nerve cell damage or death in Parkinson’s. 

Oxidative stress occurs when there is an imbalance in the production of reactive oxygen molecules — called free radicals — and molecules that neutralize free-radicals, known as antioxidants. An excess of free radicals can oxidize proteins, lipids, and DNA, damaging the cellular components. 

Gamma-glutamyltransferase (GGT) is an enzyme primarily located in the membrane of liver cells, and is a blood marker for various conditions affecting the liver. Elevated levels of GGT in the blood are also associated with conditions like heart disease and stroke, as well as with metabolic syndrome (high blood pressure, high blood sugar, and excess body fat) and dementia.

GGT has also been implicated in oxidative stress, and given the connection between oxidative stress and Parkinson’s disease, GGT may also be a blood marker for Parkinson’s. 

To determine if such a relationship exists, researchers at Seoul National University College of Medicine in South Korea designed a study tracking millions of Korean citizens via use of that country’s National Health Insurance Service (NHIS) database.

Registration in the NHIS database has been mandatory for all citizens since 1989, and people over the age of 40 are advised to undergo a health screening every two years. The database accordingly holds detailed patient information, including demographics, blood tests (including of liver enzymes), health habits, body measurements, and factors like heart attack and stroke risk.

These data allowed investigators to follow almost 6.1 million adults (6,098,405) from 2009 through 2016. They recorded newly diagnosed cases of Parkinson’s to compare with levels of GGT from blood tests. 

During a median follow-up of 6.4 years, 20,895 Koreans developed Parkinson’s disease. Of these, 9,512 were men (0.33%) and 11,383 were women (0.35%). 

Higher levels of GGT in women were found to be significantly associated with an increased risk of Parkinson’s, while in men, elevated GGT in men was significantly linked to a lower risk of developing the disease. 

Women with the highest GGT levels had a hazard ratio of 1.33, with ratios above 1 representing a higher Parkinson’s risk. But men with the highest GGT levels had a hazard ratio of 0.67, indicating a lower risk. 

An initial analysis of the data found blood levels of GGT varied based on factors such as age, income status, body mass index (BMI), smoking, and alcohol consumption. 

When the team statistically adjusted for these factors, and for exercise, high GGT levels still showed a significant link to Parkinson’s disease risk, with that risk again being greater in women and lesser in men. 

This relationship remained after analyzing this sex-specific association across age groups, except for men older than 80. 

“The biological mechanism of serum GGT in these conditions is suggested to be associated with inflammation and oxidative stress,” the study noted. “Because abnormal protein aggregation, mitochondrial dysfunction resulting in oxidative stress, and neuroinflammation are the possible pathogenic mechanism of PD, GGT may be linked to the risk of PD development through inflammatory and oxidative stress reactions.”

As GGT levels may be related to the presence of fatty liver, investigators also looked for a possible link between GGT and obesity or metabolic syndrome and the risk of Parkinson’s.

For both men and women, a risk of Parkinson’s was seen to be greater in those who were obese or had metabolic syndrome. This finding was in line with previous research. 

But while no significant link between GGT levels and obesity with Parkinson’s was seen in men, a positive significant association was identified for women.

Estrogen, the primary female sex hormone, may be a reason for these sex-specific differences, the researchers said. Previous studies suggest this hormone is protective against Parkinson’s, but as women in middle-age go through menopause, their estrogen levels fall.

GGT blood levels are also known to be “inversely associated with estrogen,” the researchers wrote, speculating that “this could partially explain the sex-specific relationship between GGT and PD.”

They concluded, “this nationwide big data cohort analysis showed that the serum GGT level has a significant impact on the risk of PD, with a differential association in men and women.”

Further research is now needed to validate “serum GGT as a marker predicting PD risk in other ethnic populations.”

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Nonprofits RARE Courage, All Wheels Up Partner on Survey Seeking to Improve Air Travel for Wheelchair Users

RARE Courage survey

Kevin Schaefer hadn’t been in an airport since he was 4 years old, so he had been looking forward to flying from his home in Cary, North Carolina, to Anaheim, California, in June for the 2019 Cure SMA Conference. As it turned out, his experience didn’t go as expected. Airport workers dropped his wheelchair three times during the trip, causing serious damage.

Schaefer, who is forums director for BioNews Services (publisher of this website) and a columnist for SMA News Today, has spinal muscular atrophy (SMA) type 2; he uses a customized chair that weighs nearly 400 pounds, typical for such specialized equipment.

“I saw it from the window. Because they don’t know how to properly handle the chairs, they dropped mine once on the way there and twice on the way back,” he said. “By the time I got home, it was barely drivable.”

What happened to Schaefer is not unusual, however. Because wheelchairs must be stowed in the cargo areas of commercial planes — they aren’t permitted in cabins — the possibility of damage is one of many issues regularly faced by wheelchair users.

In a collaborative effort to bring about change, nonprofit RARE Courage is launching a survey about assistive devices and passenger air travel geared toward those with neuromuscular diseases, including Parkinson’s disease. The survey is available here.

RARE Courage was incubated by a group of patients and columnists within BioNews. As the nonprofit arm of the company, RARE Courage is just beginning its work in advocacy on behalf of rare disease communities. It operates as a standalone entity independent of BioNews and has applied for 501(c)(3) status, according to Chris Comish, BioNews founder and CEO.

Coordinating with RARE Courage on the project is another nonprofit, All Wheels Up, which is working with airline carriers and aircraft manufacturers to make airplanes accessible for the 4 million wheelchair users in the United States — and millions more around the world — who depend on wheelchairs for mobility and safe seating.

Produced largely by the RARE Courage travel accommodations subcommittee, the survey will include about 25 questions regarding airlines, travel frequency, required travel accommodations, and assistive equipment use, storage, damage and repair.

“RARE Courage is proud to join with Wheels Up in helping to raise awareness of accessibility issues associated with air travel,” Comish said. “We applaud the efforts of Wheels Up and look forward to elevating the patient voice in support of this initiative.”

The partnership began when Michael Morale, BioNews’ senior director of multichannel content and the survey’s lead writer, contacted Michele Erwin, founder and president of All Wheels Up, about the organization’s work. That led to more discussions about a possible collaboration between the two organizations.

“Those of us in wheelchairs have always had the desire and sometimes the need to travel, but due to our limited mobility and being limited by the airline industry, we haven’t been able to do it,” said Morale, who has SMA type 3 and also has experienced damage to his electric wheelchair during air travel.

“Our goal at RARE Courage is to help facilitate change so that those of us who are in chairs have the same freedoms as able-bodied people have. We’re not asking for any kind of royal treatment. I think this partnership can make things happen,” Morale said.

Erwin started All Wheels Up after encountering several problems trying to arrange a trip to Disney World for her son Greyson, now 13, who has SMA type 2 and uses a wheelchair.

“Our organization is always looking to collaborate when it comes to accessible air travel, because for one thing, it raises awareness,” said Erwin, who spoke about accessible air travel at a U.S. House of Representatives hearing last fall. “Unless you’re within the reduced-mobility community, there’s little awareness about issues like damage to wheelchairs.”

From January through August 2019, U.S. carriers reported mishandling at least 7,747 wheelchairs — an average of 29 daily, according to a recent story in USA Today.  According to Erwin, airlines spend millions annually in repairs to the chairs, which cost at least $20,000 new and are only replaceable under government or private insurance every five years.

Beyond wheelchairs being damaged, or even sent to the wrong airport, those who use motorized or properly modified manual chairs can experience discomfort or worse in equipment that doesn’t meet their needs.

What typically happens at airports is, while a wheelchair is being lifted to cargo, its owner is switched to a transfer chair that does not have restraints or prescribed support such as a headrest or protective gel cushion.

“If someone has a severe physical disability, it can be unsafe for them to be outside their custom wheelchair,” Erwin said. “They can’t sit up, and their limbs are being exposed to being broken.”

After the chair transfer, individuals are wheeled by flight attendants onto the aircraft, where they must sit in a regular seat. Those with neuromuscular diseases such as Parkinson’s, SMA, or muscular dystrophy must be accompanied by someone who can hold them upright during takeoff, turbulence, and landing. Then there’s the wait for the transfer chair and their own, hopefully undamaged, wheelchair.

“People want the dignity to be able to roll onto a plane in their own chair,” Morale said. “That’s the bottom line.”

For that to happen, Erwin is proposing that, similar to accommodations in many public bus systems, carriers set aside one space per plane for a wheelchair, which would remain restrained during flight. An animation of the proposed setup can be viewed here.

All Wheels Up’s primary goal is to prove to airlines and manufacturers that wheelchairs can pass safety regulations for air travel. While the fight has been long and hard, there is progress. In 2018, the Federal Aviation Administration Reauthorization Act was signed into law with the organization’s amendment requiring study into in-cabin wheelchair restraint systems.

With input from All Wheels Up, the United States Access Board is leading the project that will assess the feasibility of equipping passenger planes with systems to secure passengers so they can remain in their wheelchairs on flights.

An independent federal agency that promotes equality for those with disabilities through accessible design and guidelines and standards development, the Access Board will conduct the study through the National Academy of Sciences’ Transportation Research Board.

Erwin will head to Washington, D.C., next month to address a meeting of the board’s committee. There, she plans to present preliminary findings of the RARE Courage survey in a white paper.

“My organization is the only one coming to the table with something other than theory or opinion,” she said, adding that donations would help fund future research papers and budget impact models. “We want to show that airlines can have increased income through increased travel, and no lawsuits for injuries and disability from people lifting these wheelchairs.”

Jenn Powell, a RARE Courage member and MS News Today columnist who has progressive multiple sclerosis, said she expects the survey and All Wheels Up collaboration to advance the conversation about air travel.

“The time for change was yesterday,” she said. “For most people, the loss of personal comfort and the ability to travel is incomprehensible. Wheels Up will help us make our voices heard.”

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Treating Stem Cells with Fasudil Eases Parkinson’s Symptoms in Mouse Model, Study Finds

mouse stem cell study

Bone marrow stem cells treated with fasudil and administered via the nose (intranasal) to mice in a model of Parkinson’s disease led to evidence of better motor abilities and a reduced of dopaminergic neurons,  a recent study from China reports.

These results suggest that fasudil’s use and intranasal delivery could lead to better stem cells treatments for Parkinson’s.

The research, “Intranasal Delivery of Bone Marrow Stromal Cells Preconditioned with Fasudil to Treat a Mouse Model of Parkinson’s Disease,” was published in Dove Press.

Stem cell therapy is a promising approach for various illnesses, but getting cells into the brain is a challenge. Current techniques like intravenous (IV) injection either fail to cross the blood brain barrier (BBB), while others are highly invasive, as with intraventricular injections (directly into the brain). The BBB, a semipermeable membrane that’s essential in protecting the brain from blood-borne threats like viruses, can also prevent treatments from reaching the brain and central nervous system — areas they need to reach to work as intended.

To understand whether a different route of stem cell administration would be more effective, researchers at Fudan University in Shanghai used bone marrow stromal cells (BMSCs). BMSCs are those stem cells derived from bone marrow that can differentiate into several types of cells, including neural cells.

These cells were delivered through the nose to mice engineered to develop symptoms that mimic Parkinson’s. Three experimental groups were treated: mice given intranasal administration of unconditioned BMSCs, those given BMSCs treated with fasudil, and those given BMSCs conditioned with an inert liquid called PBS, commonly used as an experimental control.

Fasudil belongs a class of molecules that enhances the growth and differentiation of stem cells, and has been shown to improve their ability to be grafted onto new tissue and survive transplantation. It is used in China and Japan to treat cerebral vasospasm (hemorrhage) and some types of stroke, but is not approved in the U.S. or Europe.

Unconditioned and fasudil-conditioned BMSCs migrated to the substantia nigra and olfactory bulbs within the animals’ brains. Dopamine-producing (dopaminergic) neurons die in both of these structures during Parkinson’s, contributing to disease progression.

Fasudil-conditioned stem cells effectively prevented dopaminergic neuron loss within the substantia nigra of treated mice, the researchers reported. This benefit was not observed in the other experimental groups.

Mere survival of dopaminergic neurons would do little to improve Parkinson’s symptoms without also making and releasing dopamine: a neurotransmitter essential for muscle and mood control. Mice treated with fasudil-BMSCs showed higher concentrations of dopamine and its metabolites, and a greater neurotransmitter release than either of the other two groups.

Fasudil-BMSC treatment also significantly reduced neuroinflammation and increased the release of BDNF, a signaling molecule important to neuronal cell survival. Neuroinflammation has been implicated in the progression of Parkinson’s disease, and controlling it eases many of its symptoms.

Behaviorally, mice given fasudil-treated BMSCs also had better scores on the Rotarod test, a common laboratory measure of motor function. In contrast, mice in the PBS control and the unconditioned stem cell groups showed no improvements in motor abilities.

Exactly how BMSCs travel from the nasal passages to the brain is not yet understood. But this study provides further evidence that such travel takes place, and treating cells with fasudil may be beneficial.

Its results also support fasudil-treated BMSCs being useful in several areas of future Parkinson’s therapy, including enhancing the survival of functional dopaminergic neurons, and suppressing immune and inflammatory responses.

If proven to work well in further studies, intranasal stem cell administration (perhaps through a spray) could be a convenient and non-invasive way of delivering stem cell therapy.

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Seelos Set to Begin Animal Studies for SLS-007 Using Gene Therapy Approach

SLS-007

Seelos Therapeutics will begin animal studies to test a gene therapy approach to deliver its investigational candidate SLS-007 for Parkinson’s disease.

SLS-007, originally developed by scientists at the University of California, Los Angeles, is intended to lessen the aggregation, or clumping, of alpha-synuclein protein — a major component of the Lewy bodies found in Parkinson’s patients.

The investigational therapy consists of a family of peptide blockers that specifically target a central region of alpha-synuclein called the non-amyloid component core, which is particularly prone to aggregation.

In preclinical studies, SLS-007 was able to slow disease progression, including stopping alpha-synuclein propagation and seeding — a process in which a “seed” provides the template for the aggregation of normal protein into clumps. This occurred when scientists used fibril preparations and alpha-synuclein seeds collected from patients with Parkinson’s or Lewy body dementia.

Now, the researchers at Seelos will test a modified, harmless form of a virus, called an adeno-associated virus, or AAV, as a vehicle to deliver SLS-007. In preparation, the company currently is producing the viral vectors and preparing the animals for its preclinical study.

“Identifying the AAV vector as the optimal route of systemic administration of SLS-007 may ultimately yield a convenient one-time delivery of the peptides,” Raj Mehra, PhD, chairman and CEO of Seelos, said in a press release.

“This is a novel method of viral delivery that has been a collaboration between our R&D team and key opinion leaders that, if successful, could be a major advancement in the field,” Mehra said.

The aim of the animal studies is to test the best route of administration, establish the pharmacokinetic and pharmacodynamic profiles of SLS-007, and assess parameters of target engagement to alpha-synuclein. In pharmacokinetics, researchers evaluate the movement of a compound into, through, and out of the body —essentially how the body affects a medicine. Pharmacodynamics determines the interactions between the body and a compound.

“The study will include measurements of several key biomarkers that will assess the extent of alpha-synuclein (α-synuclein) aggregates expression in key target areas of the brain, such as the forebrain and the substantia nigra,” said Tim Whitaker, MD, Seelos’ head of research and development.

“These outcomes will help determine key target engagement and set the stage for our next steps with the program,” he added.

The results from these studies, namely delivery and target engagement, are expected in the second half of this year.

Seelos also is developing SLS-004, its other candidate to treat Parkinson’s disease. SLS-004 uses another modified, harmless form of a virus, known as a lentivirus, to deliver an enzyme called DNA methyltransferase 3A. This targets a particular region of the SCNA gene, which provides the instructions for making alpha-synuclein, and limits the protein’s production.

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Taking the Day Off from Parkinson’s

day off

I had a pretty good day recently. It was better than I’d had in a long while. I remember thinking that I could forget I had Parkinson’s disease if every day was like that day.

But every day isn’t like that one. Every other day usually begins with being slow and rigid. If I didn’t have Parkinson’s disease, I would jump out of bed and skip to the bathroom. It would be the beginning of a new day.

If I was taking the day off from having Parkinson’s disease, I would take my morning medicinal cocktail and not feel nauseous at all. But wait — if I didn’t have Parkinson’s, I wouldn’t need a medicinal cocktail.

My shower time would be halved, and I wouldn’t have to worry about being off balance in the shower or falling when stepping out of it. 

I would sit down at my computer, and instead of my fingers seizing up, feeling like popsicle sticks, and refusing to be obedient to my brain, they would begin to type. One word, two words, three words, four — just like the old times. 

What if?

But if it were like “old times,” I would most likely still be working. I would be sitting at my desk taking phone calls, encouraging people, and leading a children’s choir. Or I would be running my business again, making wooden figurines for Christmas, Thanksgiving, and Easter scenes. 

Perhaps I would have retired by now and would be watching my grandkids full-time instead of a few hours, two days a week. And I wouldn’t need a nap (or two) during the day.

If I had escaped the Parkinson’s monster, I would be able to drive myself wherever I wanted to go. I would be able to do laundry anytime and not just when I’m “on.” I could fold clothes and carry out other household chores without any help.

If I didn’t have Parkinson’s disease, I wouldn’t have to deal with my medications being “off” or “on.” I could float through my day. 

Life would be good.

Don’t misunderstand me

My life is good in spite of Parkinson’s disease. I have so much to be thankful for that I once may have taken for granted. Family and friends are so much more precious and valuable to me now.

Daily doses of dopamine may be the norm now, or adjusting deep brain stimulation settings, but I still get those priceless hours with my grandkids, and the medication still works when I take it. So, even if I can’t really take the day off from having Parkinson’s, some days are better than others, and I’ll take what I can get.

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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.

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FDA Response Bolsters Affiris’ Plans for Potential Parkinson’s Vaccine Affitope

Affitope response

The U.S. Food and Drug Administration (FDA) has responded to Affiris‘  pre-investigational new drug (IND) submission regarding a planned Phase 2 clinical trial of the potential Parkinson’s vaccine Affitope (PD01A).

After reviewing previous preclinical and clinical data, the FDA answered questions posed by the company and provided guidance related to designing the upcoming trial.

Based on that response, Affiris intends to initiate the Phase 2 study in the U.S. and Europe in the second half of this year.

In the brains of people with Parkinson’s disease, the protein alpha-synuclein forms into spherical clumps called Lewy Bodies, which are toxic to neurons. It is widely believed that therapies that reduce this accumulation of alpha-synuclein could be beneficial for Parkinson’s.

Affitope is designed to induce the body’s immune system to make antibodies — molecules that recognize specific targets — against alpha-synuclein. By encouraging one’s body to develop its own defenses against molecules that contribute to Parkinson’s, Affitope works like a vaccine against the disease.

In theory, this could cause the immune system to reduce alpha-synuclein, without the need for repeated administration of medication.

The experimental therapy was previously tested in a series of Phase 1 clinical trials in patients with Parkinson’s disease (NCT01568099NCT01885494NCT02618941NCT02758730, and NCT02216188). Results showed Affitope was well-tolerated, with the only reported treatment-related adverse side effects being mild injection site reactions. Lab tests also showed that the vaccine did trigger the production of antibodies against alpha-synuclein.

Those early trials were not designed to detect a change in Parkinson’s symptoms.

Details of the planned Phase 2 trial. trial design and objectives have not yet been released by Affiris, but in general, Phase 1 trials are designed primarily to evaluate safety, whereas Phase 2 trials are more concerned with finding appropriate dosages and obtaining preliminary data on effectiveness.

“We are pleased to have completed the pre-IND process, with the FDA providing helpful guidance for the continued advancement of Affitope PD01 for the treatment of Parkinson’s disease, an indication with an urgent and significant unmet medical need,” Noel Barrett, PhD, CEO at Affiris, said in a press release. “We appreciate the FDA’s feedback as we endeavour to provide patients with a potentially disease-modifying immunotherapy utilizing our proprietary patented Affitome technology.”

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Genetic Factors May Contribute to Young-onset Parkinson’s, Study Suggests

brain cells, young-onset Parkinson's

People who develop Parkinson’s disease before the age of 50 may have been born with the defective brain cells responsible for causing the illness, a study suggests.

These results also reveal that a medicine, which is already approved by the U.S. Food and Drug Administration (FDA) for treating pre-cancers of the skin, may be able to prevent the progress of the disease by interfering with several pathways related to Parkinson’s disease.

The study, “iPSC modeling of young-onset Parkinson’s disease reveals a molecular signature of disease and novel therapeutic candidates,” was published in the journal Nature Medicine.

In Parkinson’s disease, neurons that make dopamine — a neurotransmitter crucial for coordinating movement and regulating mood — start to die, causing a decrease in the amount of dopamine in the brain.

Often, exactly what is causing the neurons to die is not known, although the accumulation of toxic forms of the alpha-synuclein protein into clumps known as Lewy bodies is a possible culprit.

Most Parkinson’s patients get diagnosed when they are older than 60, but in 10% of cases, individuals are between 21 and 50 years old, referred to as young-onset Parkinson’s. More than 80% of these young patients do not have a family history of the disease, and none of the known Parkinson’s mutations are present in their DNA.

In this study, researchers at Cedars-Sinai Medical Center in Los Angeles used induced pluripotent stem cells (iPSCs) to study young-onset Parkinson’s disease.

iPSCs are a special type of stem cell that can be produced in the lab by using adult cells from a patient donor and reverting them back to a stem cell-like state. These cells then have the potential to develop into almost any type of cell in the body, similar to stem cells in an embryo.

The iPSC technique was used to convert blood cells from patients with young-onset Parkinson’s and no family history of the disease, as well as healthy volunteers, used as controls, into dopamine-producing neurons. Donor patients had no known Parkinson’s disease-related mutations.

“Our technique gave us a window back in time to see how well the dopamine neurons might have functioned from the very start of a patient’s life,” Clive Svendsen, PhD, a professor at Cedars-Sinai and senior author of the study, said in a press release.

The researchers noticed three key features in the iPSC-derived dopamine neurons from Parkinson’s patients that could be used to predict or diagnose new cases.

First, these nerve cells had higher levels of alpha-synuclein, a common occurrence in most forms of Parkinson’s. Second, lysosomes (structures in the cell used to capture and break down waste products) did not seem to be functioning properly, which could contribute to the buildup of alpha-synuclein. And third, levels of the protein kinase C (an enzyme that controls the function of other proteins in the cell) were higher than normal.

These findings indicate that young-onset Parkinson’s disease has a genetic contribution rather than occurring randomly as previously thought. This molecular signature had a 96% sensitivity in correctly identifying patients with early-onset disease.

Researchers hypothesized that the acute increase in alpha-synuclein does not cause dopamine neuron death in these patients. Instead, “an inability to degrade [alpha]-synuclein over many years leads to accumulation of insoluble [alpha]-synuclein in dopaminergic neurons, cellular death and Lewy body formation,” they wrote in the study.

“What we are seeing using this new model are the very first signs of young-onset Parkinson’s,” Svendsen said. “It appears that dopamine neurons in these individuals may continue to mishandle alpha-synuclein over a period of 20 or 30 years, causing Parkinson’s symptoms to emerge.”

Lysosome dysfunction could be a major contributor to Parkinson’s, according to the researchers. As such, they tested the effectiveness of different compounds known to activate lysosomes in the patient-derived dopaminergic neurons, in the hope that excess alpha-synuclein would get broken down.

A compound called PEP005, approved by the FDA for pre-cancers of the skin, was able to lower the levels of alpha-synuclein in these neurons. When injected into the brains of mice, PEP005 also significantly decreased alpha-synuclein levels.

Surprisingly, this compound reduced the levels of alpha-synuclein by activating another protein breakdown pathway, called proteasomal degradation, rather than lysosome degradation as initially expected.

PEP005 also worked by increasing the amount of tyrosine hydroxylase, an enzyme involved in the production of dopamine and whose deficiency has previously been linked to Parkinson’s.

Additionally, PEP005 lowered the levels of a specific type of protein kinase C. This is the first-time protein kinase C has been linked to Parkinson’s, so more research is needed to understand its exact role in this disease. The team now plans to validate protein kinase C as a marker of the disease by measuring the amount present in brain tissue sample from donor patients.

Because PEP005 is currently available as a gel that can be applied to the skin, a way to efficiently deliver it to the brain will need to be investigated to potentially develop it into a successful Parkinson’s treatment.

“Young-onset Parkinson’s is especially heartbreaking because it strikes people at the prime of life,” said study author Michele Tagliati, MD, professor in the Department of Neurology at Cedars-Sinai. “This exciting new research provides hope that one day we may be able to detect and take early action to prevent this disease in at-risk individuals.”

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FDA Extends Abbott’s Infinity DBS System Approval to Target Additional Brain Region

Infinity DBS system

The U.S. Food and Drug Administration (FDA) has expanded Abbott’s Infinity Deep Brain Stimulation (DBS) system approval to target a brain region critical for motor functions — the globus pallidus — as a way to lessen motor symptoms in Parkinson’s disease patients who still show impairments after medication.

This extended approval makes Abbott’s Infinity the only directional DBS system approved to target all three main brain regions used to treat Parkinson’s, essential tremor and movement disorders: the globus pallidus, the subthalamic nucleus, and the ventral intermediate nucleus.

DBS is an invasive surgical technique in which thin wires are implanted in the brain to deliver electrical pulses to certain areas. It is intended to ease motor symptoms in patients for whom standard medications, such as levodopa, are not effective, and stave off long-term motor complications, including tremors and dyskinesia (involuntary movements).

Traditional DBS systems are “omnidirectional,” meaning they don’t target specific parts of the brain. Abbott’s DBS system differs from others in that it’s designed to steer electrical current toward specific parts of the brain to lessen symptoms such as tremors.

Because the stimulation is more targeted, patients should be able to get meaningful symptom relief with less stimulation.

“The internal segment of the global pallidus, or GPi, is a well-established valuable DBS target for the management of the motor signs associated with Parkinson’s disease, and is a preferred target for many patients, particularly for those with troublesome medication induced dyskinesia,” Jerrold Vitek, MD, PhD, said in a press release. Vitek is director of the University of Minnesota Udall Center of Excellence for Parkinson’s Research, .

The Infinity DBS system uses a wireless Apple consumer device that allows doctors to perform upgrades and optimize programming settings without the need for surgery. Patients also are able to control their Infinity DBS System via a wireless touch controller.

“This approval expands the options for patients to tailor treatment to their unique needs, with the added benefits of being able to target precise areas and utilizing a patient-friendly iOS device,” Vitek said.

The ongoing PROGRESS trial (NCT02989610) is evaluating Abbott’s Infinity DBS system for treating Parkinson’s. The trial’s primary goal is to compare the therapeutic effectiveness of the Infinity DBS system compared to a conventional omnidirectional system.

Preliminary results from 66 Parkinson’s patients evaluated after three months of using the Infinity DBS system showed that most (89.4%) had a wider therapeutic window — an average increase of 35% — accompanied by an average decrease of 30% in the amount of stimulation needed to attain a therapeutic effect, compared with patients who were using a conventional omnidirectional system.

“Abbott’s PROGRESS study has led the way in establishing the value of directional DBS systems for targeted areas of the brain,” said Binith Cheeran, MD, director of medical affairs, deep brain stimulation, at Abbott.

“The approval of Abbott’s Infinity DBS system with targeted stimulation is a significant advancement for people living with Parkinson’s disease and their care teams. The ability to optimize the programming for each individual opens the door for a new standard of care for DBS therapy,” he said.

Abbott’s Infinity DBS system is available in nearly 30 countries.

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