Exercise That’s Tailored and Routine Can Help Patients at All Disease Stages, Therapist Says

exercise and Parkinson's

Although exercise is beneficial for patients at all stages of Parkinson’s disease, a regular routine should be in place before movement issues become pronounced, an expert who led a presentation hosted by The Parkinson Voice Project advises.

The theme of the free Feb. 9 talk by Michael Braitsch, a kinesiology professor, board-licensed doctor of physical therapy,  and certified fight referee, was “Packing Some ‘Punch’ Into Your Parkinson’s Exercise Routine.”

Part of the Parkinson’s Lecture Series that features disease experts, the presentation is available online, complete with explanatory graphics and videos of patient testimonials. The lecture was held at the Project’s Clark and Brigid Lund Parkinson’s Education Center in Richardson, Texas. Presentations may be viewed in person or through the website.

The most important thing for Parkinson’s patients is to get moving, often, and earlier rather than later, said Braitsch, who treats individual patients in addition to leading group exercise programs to help those with chronic conditions move and feel better.

“A lot of folks in the medical community would wait until people start falling, or until they’re having major problems with mobility, to prescribe physical therapy,” he said. “A lot of people are more forward thinking now.”

Braitsch said that while exercise is good for everyone, it’s particularly valuable for those with movement disorders. Exercise can slow disease progression, and help to improve patients’ quality of life.

“While we know that exercise is medicine for anyone, for people with Parkinson’s it’s so much more important than for the Average Joe,” he said, adding that Parkinson’s motor symptoms mimic normal aging in many ways — only they’re sped up and intensified.

Key factors in any exercise program include repetition, intensity, task duration, and consistency. “Stick with it, keep going, do not quit,” he said. “You can make big changes.”

The trick to consistency often is finding a routine that’s safe, fun and relatively quick, said Braitsch, a board member of the Adaptive Martial Arts Association and the University of Texas Southwestern Medical Center Adaptive Sports Expo.

Because each patient experiences Parkinson’s uniquely, tailored and one-on-one routines are best. Still, he said, group programs with skilled leaders are also worthwhile, fostering consistency, motivation, performance, community, camaraderie, support and idea sharing.

“Depression, isolation, it starts a negative feedback loop. So, that’s where a tribe helps,” said Braitsch, who offers Tai Chi and Southpaws boxing classes for people with Parkinson’s. “Strength in numbers means we all do better together.”

For many Parkinson’s patients, regular exercise is typically prompted by a recent status change, a propensity to fall, freezing episodes, weakness, balance problems, issues with gait, or an acute flair up of chronic episodes, Braitsch said.

Workouts can prevent or alleviate those and other motor symptoms, including slowness of movement (bradykinesia), loss of spontaneous and voluntary movement, rigidity, resting tremors, uncontrollable movement, postural instability, and coordination issues, he said. Along with the body’s core, chronically weak muscle groups for Parkinson’s often include the neck, shoulders, legs, back and hips.

Aerobic exercise also promotes better sleep, boosts energy, improves moods, blood flow and cognitive performance, he added. Non-motor Parkinson’s symptoms can range from depression and anxiety to hallucinations, memory problems and dementia.

“There are two categories of patients,” Braitsch said, “those who exercise and those who don’t. Those who do tend to do much better.”

While those living with Parkinson’s should not think of exercise as replacing the need for medicine, Braitsch said research shows that aerobic exercise helps reduce the amount of carbidopa-levodpa necessary to manage symptoms. This treatment works to increase dopamine levels in the brain to make movement easier, but it cannot salvage damaged neurons.

“People tell me that when they exercise they feel more awake and more with it,” he said, adding that many patients begin to feel better within the first few weeks of a regular routine. “That’s the aerobic training effect.”

While specific training is encouraged for specific ailments, exercise programs should generally focus on flexibility and strengthening what’s physically weak, Braitsch said. Key elements of an effective program includes weight shifting, dynamic movement, multiple planes of motion and direction, and axial rotation.

Non-contact boxing training, which includes cross training and tempo training, also offers intensity, the satisfaction that accompanies skill acquisition, footwork, dynamic movement and weight shifting, he said. 

Likewise, Tai Chi, yoga, Pilates and stretching are particularly conducive to flexibility. For strength, Braitsch suggests adding supervised workouts with free weights or weight machines. For balance and posture, engage back and core muscles. Dancing, running, walking, cycling and even kickboxing — if it’s safe — can also reap significant dividends.

Because what it means to work out intensely varies from patient to patient, it’s important to self-monitor, he said. “You might burn through medications and cause a spike in symptoms,” he said, stressing that patients should consult their movement specialist before starting any exercise program.

“Doing it is the key, and doing it safely and consistently,” he said.

In preclinical and early Parkinson’s stages, exercise offers an abundance of neuroprotection, Braitsch said. For those in the early to middle disease stages, workouts can optimize brain function, make repairs, and strengthen neural pathways overall. In later stages, goals should emphasize adaptation, maximizing function, and preventing further problems associated with a sedentary lifestyle.

“Everyone can do better and everyone can improve something,” he said, noting that wheelchair-bound patients also benefit from exercise. “It’s never too late and never too early to take action.”

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Next 20 Years Expected to Bring ‘Message of Hope’ to Parkinson’s Patients, Review Study Finds

hope and Parkinson's

Discoveries into molecular mechanisms, risk factors — especially genetic — and advances in potential and repurposed therapies for Parkinson’s disease over the last 20 years are reason to believe that major breakthroughs await the next two decades, a review article by two researchers states.

The review article, “Therapies to Slow, Stop, or Reverse Parkinson’s Disease” was published in a supplement of the Journal of Parkinson’s Disease.

The development of better laboratory models, especially animal models that capture the slowly progressive nature of Parkinson’s, together with data resulting from scientific research and early clinical trials “strongly justifies sending this message of hope,” the authors write, explaining that the mechanisms underlying this neurodegenerative disease are gradually being deciphered.

The researchers, Tom Foltynie at University College London and J. William Langston at Stanford University, highlighted possible therapies that are most likely to emerge as disease-modifying treatments for Parkinson’s, despite the considerable challenges that remain in bringing a treatment successfully through a clinical study.

Based on the knowledge that mutations in the LRRK2 gene are one of the most common genetic causes of Parkinson’s disease, researchers have focused on therapies that can inhibit (block) LRRK2. But these efforts have been hindered by lung complications (lung toxicity) in primates exposed to inhibitor candidates, and scientists are exploring more selective ways of delivering such medications to avoid toxicity.

Questions also remain as to whether the brain is the prime target for LRRK2 activity, with some evidence pointing to the gut as well.

Treatments targeting the GBA gene, which encodes an enzyme called beta-glucocerebrosidase, may be relevant for people with sporadic forms of the disease in whom low levels of beta-glucocerebrosidase have been observed. This enzyme plays an important role in the mobilization and processing of alpha synuclein, which is low in GBA mutation carriers.

Ambroxol, an approved treatment for respiratory diseases associated with sticky or excessive mucus, is known to boost beta-glucocerebrosidase activity. However, it remains to be determined if Parkinson’s patients can tolerate the dose required for this therapy to reach the central nervous system. Other molecules that work in the body in ways similar to Ambroxol have been identified.

Since most available Parkinson’s therapies aim to ease motor symptoms, targeting non-motor features like cognition, speech, gait, balance difficulties and autonomic failure (or problems with regulating blood pressure and other process controlled by the autonomic nervous system) is important, given that many of these may precede motor onset. This could allow treatments to be started earlier, possibly delaying or preventing the onset of motor symptoms.

One approach to slowing disease progression gaining interest is that of “repurposing” medications already approved for diseases other than Parkinson’s. Preclinical studies found that type 2 diabetes medications — scientifically known as glucagon-like peptide 1 (GLP-1) receptor agonists — protect against alpha-synuclein-induced neurodegeneration. Various ongoing Phase 2 trials are assessing the effect of various GLP-1 receptor agonists (liraglutide, lixisenatide and semaglutide ) in Parkinson’s disease patients — NCT03659682NCT03439943NCT02953665). Plans for a Phase 3 trial of exenatide, another GLP-1 agonist, are underway.

Medicines used to treat primary biliary cirrhosis (an autoimmune disease of the liver; ursodeoxycholic acid), chronic myelocytic leukemia (nilotinib) and asthma (salbutamol and clenbuterol) also hold promise for Parkinson’s as they seem to contribute to nerve cell survival, eliminate toxic alpha-synuclein buildup, and modulate alpha-synuclein production, respectively.

Various studies have linked alpha-synuclein-induced neuroinflammation to Parkinson’s disease. As such, immunomodulatory therapies can be a treatment option. Evidence suggests a person’s immune system can react to toxic forms of alpha-synuclein and trigger an inflammatory reaction, which can speed disease progression. Azathioprine and sargramostim, both immunomodulatory medications, are being considered as potential candidates for slowing Parkinson’s progression.

A link between metabolism products generated by gut bacteria and brain inflammation has also been identified, and scientists might look to manipulate the gut microbiome — the trillions of microorganisms and their genetic material that live in the intestinal tract — in Parkinson’s patients, study the effects of such manipulation on the neurodegeneration process.

Lastly, the authors highlighted the possible use of nanoparticles in the disease context, as these molecules have been shown to block the formation of toxic alpha-synuclein clusters and actively work against their aggregation. In theory, nanotechnology might hold the potential to accurately target Parkinson’s-related neuropathology.

“We now have better understanding of the processes involved in PD [Parkinson’s disease] degeneration and can therefore have greater confidence that laboratory data and positive results from early clinical trials will ultimately translate to therapies that slow down PD progression,” Foltynie and Langston said in a news release.

“There are currently no drugs that have been proven to slow down PD progression. Demonstrating that one or several of the candidate approaches is successful will lead to a frameshift in patient care,” they added. “Useful cooperation and coordination between investigators around the globe are significantly accelerating the path towards discovering agents that may slow, stop, or even reverse the progression of PD.”

Their review concluded by stressing the possible importance of combination treatments in future clinical trials.

“It is tempting to speculate that the future patient may be recruited into research reminiscent of the current state of play in HIV/cancer fields, e.g., where following genotyping/ microbiome testing, they are either given the curative enzyme corrective therapy or randomised to receive combination therapies rather than any/each of these alone,” they wrote.

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Holding On to Happiness, but Not Too Tightly

happiness

Life, liberty, and the pursuit of happiness. The H in the CHRONDI Creed refers to happiness. Happiness can be an elusive thing when battling a chronic disease like Parkinson’s. So many things can get in the way of experiencing happiness: pain, deep fatigue, irritability, the time consumed by the disease, and grief accompanying things stolen by the disease. Trying to hold on to even small moments of happiness is challenging. However, it is possible to experience moments of happiness in the face of chronic disease if one trains the brain to hold the moment gently — not too tightly.

Happiness is a state of mind and includes a broad range of phenomena, such as gratitude, inspiration, accomplishment, beauty, awe, laughter, compassion, tranquility, joy, love, exhilaration, ecstasy, and bliss. The experience of happiness can have a connection to one (or several) of these phenomena. Before you finish reading this column, let’s take a mental excursion together.

Visualize in your mind the last time you were happy and try to feel how you felt at that time. Try to hold the moment gently. Pause now to do that before reading on.

Were any of the above phenomena part of your memory? Remembering happiness is helpful in reminding us what it felt like and of what the experience may look like again. It can help us to see it in the smallest of moments throughout our lives. It is not a practice of grasping after happiness. Happiness is like a butterfly flitting from flower to flower. We take in the beauty and the rich, sensual experience and hold it gently in our mind. If we were to grasp the butterfly, we would destroy the experience.

Gently holding happiness without grasping is tied to a compassionate way of being. So much of our unhappiness is tied to grasping, to misperceptions, objectification, and poor communication in relationships. The practice of compassion is about experiencing the needs of others and then moving beyond suffering to a place of well-being. It is a shift in perception and out of suffering. Walking the path of the compassionate warrior is filled with happiness experiences accompanied by the knowledge of empathy, shifting perceptions, and shared well-being. Scrooge in Charles Dickens’ “A Christmas Carol” wasn’t happy until he experienced a shift in perception and became compassionate.

I don’t expect to experience happiness all the time. That’s just too unrealistic for where I am in my personal development as a compassionate warrior battling a chronic disease. I seek small moments each day, not by grasping for them but by looking for them, like looking at the butterfly, and then gently holding the moment in my mind. Then, I am very grateful for that moment and not sad when it naturally fades into the next experience as part of the day. This feeling of happiness is not induced by drugs or alcohol (which bring fake happiness and negative consequences). It is a happiness that comes from the practice of allowing the mind to experience both the large and small moments of happiness. I do my best to begin and end each day with a confirmation (a mantra or a prayer) of specific gratitude — not a statement of general gratitude but one aimed at something specific in my life. Gratitude is a way of holding the door open for those happiness moments.

Perhaps happiness brain training can be very helpful for those suffering from PD because of the link to dopamine production. I haven’t seen any research on this, but I find the practice to be quite helpful. What do you think? Are there methods you use to bring happiness into your life? Share them in the comments. Let’s pool together a collection of happiness tools for our readers.

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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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Plasma Infusions from Young Donors Carry Risks, No Benefit, FDA Warns

FDA, plasma infusions

The U.S. Food and Drug Administration (FDA) is warning consumers, physicians, and health care providers that infusions of plasma from young donors for the treatment of normal aging or diseases such as Parkinson’s or Alzheimer’s are not approved and have not undergone the agency’s rigorous testing for efficacy and safety.

As a result, such a method — also used for multiple sclerosis, heart disease, or post-traumatic stress disorder — should not be regarded as safe or effective.

“There is no proven clinical benefit of infusion of plasma from young donors to cure, mitigate, treat, or prevent these conditions, and there are risks associated with the use of any plasma product,” read a statement from FDA Commissioner Scott Gottlieb, MD, and Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research.

The benefits of plasma, the liquid portion of the blood, are well-known, particularly in trauma or for abnormal blood clotting. The FDA-recognized Circular of Information for the Use of Human Blood and Blood Components details indications for safe and effective plasma use, where the treatment’s benefits outweigh its risks. But even in such cases plasma infusion still has risks, such as allergies and transfusion-related circulatory overload, resulting in pulmonary edema (swelling) and difficulty  breathing.

Besides a lack of clinical evidence, the FDA’s concerns also include the lack of data on appropriate dosing for the indications for which these treatments are being marketed in several states. Also, reports indicate that the infusion of large volumes of plasma may lead to infections and cardiovascular problems.

The agency cautions that plasma infusions for indications other than those approved should be done by a qualified investigator or sponsor with an active investigational new drug (IND) application with the agency. Clinical trials must be performed under an IND to make sure the treatment is safe.

“We strongly discourage consumers from pursuing this therapy outside of clinical trials under appropriate institutional review board and regulatory oversight,” Gottlieb and Marks stated. “We support sound, scientific research and regulation of medical treatments.”

They added, “We’re concerned that some patients are being preyed upon by unscrupulous actors touting treatments of plasma from young as cures and remedies.” The statement mentioned reports of clinics charging thousands of dollars for therapies with unproven benefits, with potential harmful effects and which have not been guided by well-controlled clinical studies.

Also, promoting plasma in such cases could discourage patients from being treated with appropriate treatments that may be available, the agency said.

The FDA is considering taking “regulatory and enforcement actions against companies that abuse the trust of patients” and jeopardize their health” by using uncontrolled manufacturing processes or  promoting therapies with no evidence of safety or efficacy.

If considering the use of plasma infusions for unapproved indications, the FDA strongly urges patients to consult with their health care providers to confirm whether the agency has reviewed the treatment. Patients should ask the clinical investigator for the IND number and a copy of the FDA-issued communication acknowledging the IND.

Patients and physicians should report any adverse events associated with plasma administration to the FDA’s MedWatch program. The agency continues to monitor this issue, along with state and local health departments, as well as blood establishments.

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Having a Heart, Lung, Kidney, or Bone-Marrow Transplant May Lower Risk of Developing Parkinson’s

transplant

People who have had kidney, heart, lung, or bone-marrow transplants are less likely to develop Parkinson’s disease than the general population, research suggests.

The study, “Transplant and risk of Parkinson disease” was published recently in Parkinsonism & Related Disorders

Chronic neuroinflammation is a hallmark of Parkinson’s disease with studies suggesting that inflammatory processes contribute to disease risk and progression, although such biological response is unlikely to be the primary cause of neuronal death. That is why researchers suspect that reducing inflammation in the brain has the potential to slow neurodegeneration.

Anti-rejection drugs, also known as immunosuppressant medications, inhibit the immune system’s activity and reduce overall inflammation in the body, including the central nervous system.

Patients who undergo organ transplants usually are given these types of medicines to lower their body’s ability to reject the transplanted organ.

“Because inflammation may play a role in the pathophysiology of PD [Parkinson’s disease], it is possible that immunosuppressants could reduce the risk” of the disease, researchers wrote.

A team led by Washington University School of Medicine in St. Louis researchers investigated the risk of Parkinson’s disease in relation to tissue transplant. This same team had shown previously that individuals taking selected immunosuppressants had a lower risk of Parkinson’s disease than the general population Medicare beneficiaries who were studied.

In the most recent study they assessed Medicare beneficiaries (age 66–90 years) data from 2004 to 2009 and identified 89,790 Parkinson’s disease cases. For the control group, researchers selected a 0.5% random sample of all Medicare beneficiaries included in the study period, totaling 118,095 subjects.

History of kidney, heart, lung, bone-marrow, pancreas or cornea transplant was then registered. There were 278 transplants in the Parkinson’s sample and 302 in the control group.

Statistical analysis revealed patients who underwent transplants had a 37% lower risk of developing Parkinson’s than the general Medicare population.

“Overall, patients who had undergone tissue transplant more than five years prior to PD [Parkinson’s disease] diagnosis or reference had lower risk of PD,” researchers wrote.

This correlation was consistent for kidney, heart, lung, and bone-marrow transplants. Liver or corneal (the transparent layer that makes up the front of the eye) transplant was not linked to Parkinson’s disease risk.

When adjusting for underlying cause of the transplants, such as valvular heart disease, diabetes with renal complications, or chronic hepatitis infection, organ transplant remained inversely correlated with Parkinson’s risk. However, the association with kidney transplant became statistically non-significant.

“This study provides evidence that tissue transplant may be associated with a lower PD [Parkinson’s disease] risk, warranting further investigation to identify factors that mediate this relationship, including a potential effect of immunosuppressive therapy on PD risk,” researchers concluded.

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Stem Cell Transplants Could Significantly Improve Parkinson’s Treatment, Study Suggests

stem cell transplant

Cell replacement therapies in which dopamine-producing stem cells are transplanted into Parkinson’s disease patients could improve motor symptoms, reducing or eliminating the need for dopaminergic medicines, a study suggests.

The study, “Repairing the Brain: Cell Replacement Using Stem Cell-Based Technologies,” was published in the Journal of Parkinson’s Disease.

Current available treatments to treat Parkinson’s focus on increasing dopamine levels in the brain, which alleviates motor symptoms. However, these treatments’ efficiency declines over time, and they are associated with various side effects.

“We are in desperate need of a better way of helping people with [Parkinson’s disease]. It is on the increase worldwide. There is still no cure, and medications only go part way to fully treat incoordination and movement problems,” Claire Henchcliffe MD, PhD, and Malin Parmar, PhD, co-authors of the study, said in a press release.

A possible long-term treatment for Parkinson’s is transplanting dopamine-producing stem cells into patients’ brains.

“If successful, using stem cells as a source of transplantable dopamine-producing nerve cells could revolutionize care of the [Parkinson’s disease] patient in the future. A single surgery could potentially provide a transplant that would last throughout a patient’s lifespan, reducing or altogether avoiding the need for dopamine-based medications,” Henchcliffe and Parmar said.

Previous transplantation studies in Parkinson’s disease used brain cells from aborted embryos. This approach could lead to long-term relief of motor symptoms and can reduce or even stop the need for medication.

However, there are some ethical and scientific issues related to this procedure, including the fact that fetal cells are scarce, their characteristics vary significantly, and some patients can develop side effects, such as dyskinesias (uncontrollable movements).

Using stem cells made in the lab for transplants would allow the production of enough cells to cover the current demand, ensure the number and type of transplanted cells are always the same, that they produce the desired amounts of dopamine, and that the risk rejection is low.

Two possible sources of cells could be used to perform the transplants: embryonic stem cell lines and induced pluripotent stem cells (iPSCs) — cells extracted from a patient’s blood or skin that are treated to become almost any type of cell in the body.

“With several research groups, including our own centers, quickly moving towards testing of stem cell therapies for PD, there is not only a drive to improve what is possible for our patients, but also a realization that our best chance is harmonizing efforts across groups,” said Henchcliffe, who is a neurologist at Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center in New York.

Several initiatives, both academic and in the industry, are moving toward testing stem cell therapies to treat Parkinson’s. The first clinical transplantation trials using pluripotent stem cells as donor tissue began in Japan last year.

“There is a long road ahead in demonstrating how well stem cell-based reparative therapies will work, and much to understand about what, where, and how to deliver the cells, and to whom. But the massive strides in technology over recent years make it tempting to speculate that cell replacement may play an increasing role in alleviating at least the motor symptoms, if not others, in the decades to come,” said Parmar, a professor at the Wallenberg Neuroscience Center and Lund Stem Cell Center at Lund University in Sweden.

New types of transplants focusing on non-motor symptoms could be developed if the initial trials with dopamine-producing cells are successful.

“This approach to brain repair in [Parkinson’s disease] definitely has major potential, and the coming two decades might also see even greater advances in stem cell engineering with stem cells that are tailor-made for specific patients or patient groups,” said Patrik Brundin, MD, PhD, and J. William Langston, MD, editors-in-chief of the Journal of Parkinson’s Disease. “At the same time, there are several biological, practical, and commercial hurdles that need circumventing for this to become a routine therapy.”

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Choosing to Build a Snowman

choices

Sherri Journeying Through

I watched “Harry Potter” last week for the first time. Many of the characters shared wisdom with those around them. My favorite piece of wisdom in “The Chamber of Secrets” was shared by Albus Dumbledore: “It is not our abilities that show what we truly are — it is our choices.”

I heard that and played it over once more in my mind. Then I realized why it intrigued me so much. Subconsciously, I had changed “abilities” to “disabilities” so that it became: “It is our choices, Sherri, that show what we truly are, far more than our disabilities.”

Many people with Parkinson’s disease live by the motto, “I have Parkinson’s, it doesn’t have me.” In my case, though, Parkinson’s does have me, even though I try not to let it take away as much as it tries to. Some days it feels like a burden pulling at the hem of my pants, making me drag it along wherever I go. But other days it feels like I can sneak away while it sleeps soundly in the closet, undisturbed.

Choices, choices, choices

What are we to do on a “free” day when given a reprieve from pain and sorrow?

It is winter where I am, snowing all over. My grandkids have had two snow days this last week. They’ve been outside making snowmen and inside drinking hot chocolate and reading books. They haven’t been sprawled out on the couch in front of the TV. Despite the limitations on their day, they’ve been living it. 

Choices

I’ve been given Parkinson’s, whether I want it or not. Now it is up to me to choose how I will deal with it. 

People look at us and often see our disability’s limitations and frustrations. Yet, the choices that we make in how we deal with those limitations and frustrations show those around us whether we are living under our disease, or above it, or in spite of it. I choose to live above it the best I can and build snowmen.

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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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Gene Variations Early in Life May Explain Vulnerability to Neurodegenerative Diseases

gene variations

Naturally occurring gene variations in brain cells may explain why dopamine-producing neurons are the first to die in people with Parkinson’s, according to a new study.

The findings also suggest that brain regions with a greater number of these variations are more likely to undergo cell death later in life in distinct neurodegenerative diseases.

The research, “Neurons with Complex Karyotypes Are Rare in Aged Human Neocortex,” was published in the scientific journal Cell Reports.

Unlike neuronal types, which are thought to be stable throughout life, the genetic makeup of nerve cells is variable. In the neocortex — a part of the cerebral cortex involved in functions such as sensory perception, motor function, thought, and language — the generation of copy-number variants (CNVs) due to imperfect DNA repair affects multiple genes and leads to significant diversity in a subset of neurons.

CNVs are genetic alterations where a certain section of the genome is repeated, making the number of repeats vary considerably among different neurons.

This genetic variation, called mosaicism, indicates the person is a mosaic — that is, composed of more than one genotype, or genetic constitution, although the person has developed from a single fertilized egg. In humans, all cells descending from the fusion of egg and sperm should contain an identical nuclear genome — our personal DNA signature.

“What’s really interesting about mosaicism is that it is fundamentally tweaking our assumptions about what nature is, because we’ve kind of always assumed that every cell in any given individual had the same genome,” Michael McConnell, PhD, the study’s senior author, said in a press release. “And now we’re showing that it’s different and what that might mean.”

The occurrence of CNVs during embryonic development has been associated with risk for schizophrenia, autism, and other neurological disorders. However, studies of CNVs specifically in nerve cells have not been able to determine whether the affected genes contribute to brain development, function, and disease.

“This has been a big open question in neuroscience, particularly in various neurodegenerative diseases,” McConnell said. “What is this selective vulnerability? What underlies it?”

Aiming to address these questions, scientists at the University of Virginia School of Medicine used a statistical analysis to assemble a brain atlas and assess how CNVs in neurons alter the genetic makeup of the human cerebral cortex.

Published data from 10 individuals were combined with a new dataset of over 800 neurons from five participants. All 15 individuals were healthy, ranging in age from one year to 95 years.

The results showed an atlas with 507 CNVs in nerve cells. It revealed that the frequency of neocortical neurons with complex karyotypes — the number and appearance of chromosomes in a cell — varies widely among individuals. Also, both the proportion of complex karyotypes and the size of CNVs were greater in neurons than in other cell types.

The investigators then found that younger individuals had more variations in neurons than older people. This was in contrast to the team’s hypothesis that this mosaicism would increase with age, or that mutations would accumulate over time due to aging-associated cellular alterations.

“It showed a perfect correlation — a perfect anti-correlation — with age,” McConnell said. “Now, with our work, the hypotheses moving forward are that it could be that different regions of the brain actually have a different garden of these [variations] in young individuals and that sets up different regions for decline later in life.”

“This cross-sectional finding highlights the unmet need for an increased longitudinal understanding of human neuronal genome dynamics during an individual’s health span,” the scientists stated.

Looking ahead, the team will use a brain bank from the Lieber Institute to look at other brain areas, such as the temporal lobe, the site with the earliest neuronal death in Alzheimer’s. “So now I can really start to map things out more carefully, building an atlas of different brain regions from many individuals,” McConnell said.

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Inflammatory Signals from Non-neuronal Cells Linked to Neurodegeneration in Fly Study

Furin 1

The protein Furin 1, produced by dopaminergic neurons — nerve cells that synthesize the neurotransmitter dopamine — triggers a harmful inflammatory molecular cascade in neighboring non-neuronal cells that contributes to the degradation of these neurons over time, a study in flies found.

Because Furin 1 is controlled by LRRK2 — a major player in neurodegeneration in Parkinson’s disease — the findings begin to reveal how LRRK2 causes the loss of dopaminergic neurons in patients. Blocking this inflammatory signaling protected flies from age-dependent neurodegeneration.

The research, “A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration,” was published in Cell Reports.

Mutations in the LRRK2 gene are one of the most commonly known genetic causes of Parkinson’s disease and usually result in the malfunctioning of lysosomes — special compartments within cells that digest and recycle different types of molecules. Lysosomal dysfunction is involved in the formation of Lewy body protein aggregates and, therefore, neurodegeneration.

Glial cells — non-neuronal cells that provide support, protection, and nutrition for neurons — help neurons when they are in molecular distress. In certain conditions, glia become overly activated by these “mayday” callings and activate an inflammatory cascade, which contributes to the degradation of the distressed neurons.

Researchers from the Buck Institute for Research on Aging have previously identified Furin 1 as a mediator of LRRK2’s ability to regulate neuronal transmission in Drosophila melanogaster (fruit fly) larvae.

“Working in flies allowed us to identify a vicious cycle: stressed neurons signal to the glia and trigger inflammatory signals in the glia, which become harmful for the neuron as the brain ages. Interestingly, the genetic components of this crosstalk are conserved between flies and humans, boosting our enthusiasm and confidence that future work might lead to novel therapeutic paradigms,” Buck professor Pejmun Haghighi, PhD, senior author of the study, said in a news release.

In this study, investigators sought to test whether Furin 1 responds to LRRK2 in the adult fly brain and whether it is involved in mediating the toxic effect of LRRK2 mutations in dopamine-producing neurons.

The team generated two Parkinson’s disease fly models: one produced too much LRRK2 within neurons; the other had paraquat-induced dopaminergic neurodegeneration.

Paraquat is a toxic, fast-acting herbicide that when fed to flies induces the rapid degradation of dopamine-producing neurons and severely reduces their lifespan.

Fly brain tissue analysis revealed both LRRK2 overexpression and paraquat models had increased Furin 1 protein production in dopaminergic neurons. Furin 1 was found to be regulated by LRRK2 and the trigger of the inflammatory molecular cascade.

“Furin 1 is the real culprit in the interaction between the neurons and glial cells. It’s the ‘finger’ that pushes the switch on the signaling cascade,” said postdoctoral fellow Elie Maksoud, PhD, the study’s lead author.

Furthermore, reducing the amount of Furin 1 within neurons protected against toxicity.

Furin 1 acts on a molecule known as glass bottom boat (Gbb). Gbb binds to bone morphogenetic proteins (BMPs), a family of proteins that promote the formation of bone and the skeleton but are also essential for several neuronal processes. Various forms of these BMPs can be found in the form of molecular receptors in glial cells.

Scientists set up to investigate whether there was a genetic interaction between the overexpression of LRRK2 or Furin 1 and genes associated with BMP molecular pathways.

They reported that furin 1 toxicity was linked to increased BMP signaling in glial cells of both fruit fly models. By genetically silencing Gbb (reducing its production), researchers demonstrated that the action reversed the age-dependent loss of dopaminergic neurons and protected against LRRK2 protein toxicity.

Results suggest that the observed toxicity is mostly initiated by dopamine-producing neurons, which in turn activate BMP-mediated molecular communication with glial cells.

Investigators hypothesize that these supportive non-neuronal cells might send inflammatory signals back to neurons, causing neurodegeneration.

“Furin 1 is a druggable target. Our hope is that treatments can be developed to reduce this toxic crosstalk before it becomes a serious problem for the dopaminergic neurons,” Maksoud said.

Haghighi said, “We have known for some time that different forms of genetic or environmental stress in neurons can trigger a response in glial cells; now we’ve been able to identify a molecular mechanism that explains how neuronal stress can lead to activation of inflammatory signals in glial cells.

“We’re looking at a new way to prevent Parkinson’s, especially in those who have risk factors for the disease. The effects of this toxic signaling are age-dependent, they accumulate over time. The goal is to intervene as early in the disease process as possible.”

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Patient-Derived Neurons Show Promise as Model for Parkinson’s Research, Study Finds

Stem cell-derived neurons, Parkinson's

Stem cell-derived neurons from patients with familial forms of Parkinson’s may be used as a valuable model to screen and develop novel therapies for this disease, according to a study.

The study, “T-type Calcium Channels Determine the Vulnerability of Dopaminergic Neurons to Mitochondrial Stress in Familial Parkinson Disease” was published in Stem Cell Reports.

While most Parkinson’s cases are sporadic, approximately 10% of them are caused by mutations in the PARK1, LRRK2, PARK2 and PARK6 genes. PARK2 and PARK6 are known to be involved in stress responses and molecular equilibrium within mitochondria (considered the power generators of cells).

Despite knowing multiple possible causes for Parkinson’s, scientists have not yet developed effective therapeutic treatments. Research findings obtained from cellular and animal models do not always reflect what occurs in people with hereditary Parkinson’s disease, “due to different cellular contexts or vulnerability to disease-relevant mutations,” wrote Keio University researchers, who have developed a model using human induced pluripotent stem cell (iPSC) technology.

iPSCs are derived from either skin or blood cells of patients. These cells are then reprogrammed back into a stem cell-like state, which allows for the development of an unlimited source of almost any type of human cell needed. Because they’re derived from patients, the “novel daughter cells” will carry the same genetic defects as those found in the original cells.

Using iPSCs, the team generated PARK2 patient-specific dopamine-producing neurons — those that are damaged in Parkinson’s — to model the disease in a laboratory setting.

The newly generated PARK2 mutant neurons were found to have high levels of oxidative stress, which causes cellular damage resulting from high levels of oxidant molecules. Oxidative stress is characterized by an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals are harmful to the cells and are associated with a number of diseases, including Parkinson’s.

Because studies have shown reduced mitochondria activity in the brains of Parkinson’s patients, the Japanese researchers exposed PARK2 mutant neurons to rotenone, a pesticide known to inhibit the function of mitochondria. As expected, these neurons were more susceptible to rotenone-induced cell death than healthy neurons.

To understand whether this cellular model could be used for drug discovery and to repurpose existing medicines, scientists screened several compounds that had already been approved by the U.S. Food and Drug Administration.

Candidates were shortlisted based on their ability to protect dopaminergic nerve cells against rotenone-induced death.

Benidipine — a calcium channel blocker that stabilizes calcium levels in the cell by blocking its influx through specific channels, known as T-type calcium channel — reduced rotenone-induced cell death. Two similar compounds did not: nifedipine and isradipine, which use a different channel subtype. These findings suggest that “the calcium channel subtype is important for neuroprotective effects against PARK2-(dopaminergic) neurons,” the researchers wrote.

In addition, benipidine rescued the compromised growth of neuronal projections — called neurites — in these PARK2 mutant neurons. These projections lead to the development of either axons or dendrites, which nerve cells use to transmit chemical signals and communicate.

To further validate benidipine’s effect, scientists examined the compound’s effect on neurons generated from patients with a different form of familial Parkinson’s — a mutation in the PARK6 gene.

As in PARK2 models, PARK6 nerve cells had reduced neuronal projections and elevated levels of oxidant molecules, compared with control dopamine-producing neurons. Rotenone treatment further increased oxidant molecule levels and cellular death in PARK6 neurons. The researchers found benipidine prevented rotenone-induced death in these neurons in a concentration-dependent manner.

They concluded that PARK2 and PARK6 dopamine-producing neurons mirror several molecular characteristics of Parkinson’s disease and thus can be used to search for potential therapeutic targets for this neurodegenerative disorder.

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