Looking at Parkinson’s Potential Links to the Gut Microbiome

microbiome

I wonder if my dad’s battle with ulcerative colitis is linked to his struggles with Parkinson’s disease. Because of a series of medical complications, he’s missing his colon, a vital part of the digestion process. This affects how he digests food and medicine, which in turn affects his intestinal microbiome.

Recent research looks at how the microbiome might be linked to Parkinson’s disease. The idea seems understandable enough: You are what you eat, right? But you are what your body can process as well. Which makes me wonder: Is he alone in having both ulcerative colitis and Parkinson’s?

How might ulcerative colitis and Parkinson’s be related?

According to one recent study, those who have ulcerative colitis had a 30 percent higher risk of Parkinson’s disease than the control group. My dad seems to fall in the 30 percent group.

Not everyone with ulcerative colitis loses the colon. But my dad did, which seems to add another layer to his relationship with Parkinson’s disease. The colon helps the body during the final stage of digestion, preparing you to dispose of waste while collecting the remaining fluids.

If someone were to lose their colon to a disease like ulcerative colitis, the loss would affect the final stages of digestion. And this process likely would affect the intestinal microbiome. So, how might the intestinal microbiome relate to Parkinson’s?

A 2017 study in the journal npj Parkinson’s Disease discusses a link between the intestinal microbiome and disease: “Changes in the composition of intestinal bacterial populations have been associated with a wide array of conditions including neurological and neurodevelopmental disorders such as multiple sclerosis, autism, depression, schizophrenia and PD, and studies are beginning to explore some of the mechanisms that contribute to the powerful influence of the microbiota.”

If ulcerative colitis affects the intestinal microbiome, and the microbiome is linked with Parkinson’s disease, ulcerative colitis could be related to Parkinson’s.

Gut microbiome and disease prevention

If the gut microbiome is related to the development of certain illnesses, can those illnesses be prevented? According to a 2016 study in the journal Pharmacology & Therapeutics, “The interaction between the host and its gut microbiome is a complex relationship whose manipulation could prove critical to preventing or treating not only various gut disorders, like irritable bowel syndrome (IBS) and ulcerative colitis (UC), but also central nervous system (CNS) disorders, such as Alzheimer’s and Parkinson’s diseases.”

The npj Parkinson’s Disease study also raises the possibility of diagnosing Parkinson’s at an earlier stage by monitoring the bowels. Its authors noted: “Meta-analyses suggest that constipation is more than twice as common in people who develop PD compared to those who do not, and that constipated individuals are twice as likely to develop PD within 10 years of their evaluation.” By recognizing the relationship between the brain and the gut, we might be able to better understand the link between digestion and the central nervous system. This knowledge could help in developing a treatment at an earlier stage of the disease.

Additionally, we don’t know whether Parkinson’s might be a cause or an effect of the microbiome’s status. It’s possible that Parkinson’s affects the gut. Per the same study: “At this time, it is not clear whether the observed changes in microbiota in PD patients are an initial occurrence that contributes to the development of neurological dysfunction and degeneration, or if they emerge in response to PD-related pathology in the enteric and/or the CNSs that impairs peristaltic activity and induces inflammation.” But my dad had ulcerative colitis many years before the first signs of PD showed.

I’m interested in seeing what developments will occur as we begin to better understand Parkinson’s disease. Perhaps emerging science will discredit the relationship between the microbiome and Parkinson’s disease. But these statements and statistics seem to hint at a significant relationship between the digestive process and the nervous system.

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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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Finding Joy in Giving Thanks

joy

How can we experience real joy when we struggle to be thankful? Dealing with difficult circumstances, particularly when living with a chronic illness such as Parkinson’s disease, can lead us to have a grim outlook on life. We can become embittered when things don’t go as we’d expected or wanted.

What do we expect? Do we think that things will never go wrong because we try to do everything right? Do we expect a situation to go our way because we feel that we are undeserving of bad things?

Learn to be content

Discontentment can stem from a lack of peace and grow due to continual worry about the things over which we have no control. Discontentment can arise from hopes being dashed or unrealized expectations of what we thought our lives would be. Simply put, discontentment is void of joy.

Serenity is the opposite of discontentment. It is a state of calm and peace. Discontentment cannot coexist with serenity. Serenity is grounded in a trust that is bigger than ourselves and goes beyond our understanding. We welcome such trust instead of succumbing to worry about every little thing that ultimately leads to our unhappiness.

A lesson from the birds

Birds don’t worry about where their next meal is coming from. They know that they can always find food. They don’t spend their time in a state of worry, and their songs reflect their lifestyle.

The key to being content, a foundational component to joy, is: Do not worry.

The Serenity Prayer, thought to have been written by the American theologian Reinhold Niebuhr, is widely known and used by support groups and addiction recovery 12-step programs. We would do well to heed its wisdom when it comes to practicing contentment: “God, grant me the serenity to accept the things I cannot change, the courage to change the things I can, and the wisdom to know the difference.”

Develop an attitude of gratitude

With Thanksgiving almost a week away, our thoughts turn to moments of gratefulness. Now would be a good time to start a Thanksgiving list. When we take time to reflect on the good things that happened in our day and the lessons we learned from the not-so-good things, being grateful will come more naturally and frequently.

When we count our blessings and start a habit of reflecting on the things for which we can be thankful, our outlook and attitude will begin to change. We will find more to be thankful for, and our state of thankfulness will encourage joy to flourish.

The magic of music

When we are striving for joy — and not merely happiness, which can be fleeting — music can be a bridge to get there. A singing or whistling person is rarely a discontented one. Music can help to instill peace, hope, lightheartedness, and a light at the end of the tunnel. Where peace and hope exist, healing music and joy are found. 

Joy overrules discontentment any day. But that doesn’t mean sorrow or grief won’t come our way. We will get through the darkest days, undefeated, and ready to overcome our challenges with a heart filled with thankfulness and joy.

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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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Metabolism of Metals in Blood May Be Affected by Parkinson’s Disease, Study Says

blood and metal concentrations

Cooper concentrations are significantly affected in the blood serum of Parkinson’s patients, suggesting this metal metabolism could somewhat influence the mechanisms behind this neurodegenerative disorder, a study reports.

The results, “Assessment of copper, iron, zinc and manganese status and speciation in patients with Parkinson’s disease: A pilot study,” were published in the Journal of Trace Elements in Medicine and Biology.

Environmental factors are thought to contribute to Parkinson’s disease (PD). Metals such as copper, iron, zinc, and manganese are known to be neurotoxic. Evidence indicates that metal exposure can contribute to Parkinson’s-related neurodegeneration, mainly by modulating alpha-synuclein protein aggregation — one of the key events in the development of PD.

For instance, higher-than-usual iron levels have been found in a brain region important to motor control, called the substantia nigra, of Parkinson’s patients. This brain area is one of the most affected by the disease.

High levels of zinc and copper have also been found in the cerebrospinal fluid (surrounds the brain and spinal cord) of people with Parkinson’s. In addition, severe manganese overexposure can cause Parkinson’s-like symptoms. Manganese is a compound present in ground water.

Although metal exposure is known to play some role in neurodegeneration, available data on their trace amounts in Parkinson’s patients are rather contradictory.

A team of researchers in Russia assessed the levels of iron, copper, zinc, and manganese in the hair, blood serum, and urine of 13 patients, as well as the species of these metals in patients’ serum.

These 13 people (nine women and four men; mean age of 73.6) and 14 gender-matched healthy controls had their serum, urine, and hair metal content analyzed. Scientists also assessed the specific forms/species of iron, copper, zinc, and manganese that were present in participants’ serum samples.

Several exclusion criteria were used in the study to “decrease the impact of side factors.” Namely, these factors are the presence of other neurological disorders; being a vegetarian; endocrine (hormone imbalance) disorders; recurrent gastrointestinal problems; acute infectious, surgical and traumatic diseases;  metallic implants; smoking and alcohol use; and occupational or environmental exposure to metals.

While no significant differences were found in hair, urine and serum metal levels between these two groups, “a trend towards decreased hair (−22%) and urine (−41%) copper levels was observed in PD patients as compared to controls,” the researchers wrote.

Hair iron and manganese levels showed a tendency to rise in the Parkinson’s group: iron concentrations in patients exceeded those of controls by 24% and manganese levels by 21%.

Urine iron and zinc levels were 38% and 47% lower in the patient than control group. Blood serum metal levels were almost similar across the two.

In circulation, cooper is usually carried by ceruloplasmin, the major copper-carrying protein in the blood. This protein also plays a role in iron metabolism. In Parkinson’s, the binding of copper to ceruloplasmin is reduced, this way increasing the pool of free cooper available in the blood. Free cooper is thought to play a significant role in neurodegeneration, mainly by promoting oxidative stress: cellular damage as a consequence of high levels of oxidant molecules.

According to the researchers, “reduced ceruloplasmin levels may ultimately lead to increased iron sequestration in brain structures including substantia nigra.”

Speciation analysis — a process by which one can identify the quantities and concentrations of individual elements in a sample — revealed a significant decrease in the molecular binding of copper to ceruloplasmin, resulting in “a nearly ten-fold increase in serum free copper levels in PD patients.”

These results need to be interpreted carefully, as the levels of free copper in both groups were still within normal range, the researchers said.

Though metal speciation appears to be significantly affected in the serum of Parkinson’s patients, how these molecular changes impact the patients’ disease course remains to be understood.

The scientists believe that their “findings are indicative of the potential role of metal metabolism and PD pathogenesis [its origin and progression], although the exact mechanisms of such associations require further detailed studies.”

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Video Games Created for Parkinson’s Rehab Can Help in Strengthening Limbs, Study Suggests

video games and rehab

Video games carefully designed to improve the upper limbs — including grip strength, dexterity, and coordination — may be a rehabilitation aid for people with Parkinson’s disease (PD), a small study in patients suggests.

The study, “Leap motion controlled video game-based therapy for upper limb rehabilitation in patients with Parkinson’s disease: a feasibility study,” was published in the Journal of NeuroEngineering and Rehabilitation.

Rehabilitation is an important therapy approach in addressing motor symptoms in PD. In recent years, video games that use virtual reality technologies have grown in interest in this field — the basic idea being that these games, which involve the player moving their body as a means to play, allows for rehab-like tasks to be done in a more fun and engaging setting.

However, common commercial systems — like the Nintendo Wii, Playstation Move, and Kinect plus XBOX 360 — aren’t especially well-suited for Parkinson’s rehabilitation; they tend to move too quickly or be too difficult. The need, instead, is for “specific serious” video games, which the researchers defined as, “games designed for a primary purpose other than that of pure entertainment, and which promote learning and behavior changes for PD patients.”

For the study, 23 people (11 male, 12 female; average age 66.65) with PD were recruited from a Parkinson’s association based in Madrid. All had disease stages of 2, 3, or 4 based on the Hoehn and Yahr scale (a 0–5 scale, with higher stages correlating with more advanced disease).

Patients were divided into two groups; 11 completed upper limb-focused conventional physical therapy as a control group, while 12 played serious video games designed by the researchers. Both groups had two 30-minute sessions of their respective therapy each week for six weeks.

These video games utilized the Leap Motion Controller System (LCM), which tracks an individual’s hands as the means of controlling the game, without the need for additional sensors or controllers. “This system presents important advantages over other motion capture systems, namely thanks to its portability, ease of use, commercial availability, low cost and non-invasive nature,” the researchers wrote.

They designed six “serious” games, each of which involved performing tasks akin to what is done in conventional therapy. For instance, one involves playing a virtual piano, which necessitates flexing individual fingers. In another game, players must move virtual blocks into a particular order, requiring the player to reach for different blocks. The researchers noted that “different interventions can be designed by combining two or more games that focus on a specific pathology and patient population.”

Both before and after the six-week intervention, participants underwent a battery of tests assessing physical abilities.

Both groups showed significant improvements in grip strength on both sides of the body.

Scores on the Purdue Pegboard Test (PPT, which measures coordination and dexterity) improved significantly in both groups. But in the control group, only the more affected side of the body showed a significant improvement, whereas significant improvements were seen on both body sides in the video game group.

Although both groups’ scores before the intervention were similar, PPT scores in the video games group were significantly higher than in the conventional therapy group after the respective interventions.

Significant improvements on the Box and Blocks Test (BBT, another coordination test) were also seen in both groups, but only on the more heavily impaired side of the body.

Both groups reported high subjective satisfaction with their therapy. “Furthermore,” the researchers wrote, “compliance to the interventions was excellent (100%) and no adverse side-effects were observed for both groups.”

This study has some limitations, the researchers noted: it was done in quite a small sample size, and only on people with mild-to-moderate PD. As such, more studies are needed to validate its findings.

“The LMC system and the serious games designed and used in this study represent a rehabilitation tool that may benefit certain PD patients for the improvement of coordination, speed of movements and fine dexterity in [upper limb] interventions,” the researchers concluded.

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Gut Inflammation May Increase Risk for Parkinson’s Disease, Review Study Suggests

gut inflammation

Inflammation in the gut, a hallmark of autoimmune disorders such as inflammatory bowel disease, may contribute to an earlier risk of developing Parkinson’s disease (PD), according to a recent review of genetic, epidemiological and animal model studies.

The risk, however, is very small with only 3% to 5% of patients with IBD eventually getting a Parkinson’s diagnosis.

The review, ”Inflammatory Bowel Diseases and Parkinson’s Disease,” was published recently in the Journal of Parkinson’s Disease.

PD is characterized by a range of inflammatory processes in the brain, including the release of pro-inflammatory signaling molecules (cytokines) and infiltration of immune cells.

Increasing evidence, however, suggests that PD starts in the gastrointestinal system, with symptoms such as chronic constipation often emerging before motor symptoms develop.

“Experimental, clinical and epidemiological data suggest that intestinal inflammation contributes to the pathogenesis of PD,” the researchers wrote.

Gut infections are then thought to trigger alpha-synuclein release and subsequent aggregation, with the disease then spreading to the central nervous system (brain and spinal cord), where it promotes neurodegeneration. Alpha-synuclein is the protein that in PD becomes misfolded and forms toxic aggregates or clumps, which are the main component of Lewy bodies and greatly contribute to neurodegeneration.

“Parkinsonism is probably not just a brain disorder, but a group of diseases that may have their onset in the periphery, particularly in the gastrointestinal tract,” Tomasz Brudek, PhD, at the Copenhagen University Hospital and author of the review, said in a press release.

Inflammatory bowel disease (IBD) is triggered by prolonged inflammation of the digestive tract due to an imbalanced immune response. The two most common forms of IBD are ulcerative colitis and Chron’s disease.

Chronic inflammation of the gut is likely a predisposing factor for people to develop PD.

Genome-wide association studies (GWAS) have identified links between IBD and PD. Using GWAS, researchers analyzed the whole human genome searching for genetic changes associated with the disease. Mutations in the LRRK2 gene were found to be “a common susceptibility-factor” in both PD and Crohn’s disease, which may indicate a potential genetic link and common disease mechanisms.

An analysis of 138,511 genomes (our complete genetic “set”) from participants with European ancestry identified 17 genetic changes that occurred in both PD and autoimmune diseases, including ulcerative colitis and Crohn’s disease. Additional diseases included celiac disease, rheumatoid arthritis, type 1 diabetes, multiple sclerosis and psoriasis.

Several epidemiological studies also have shown a link between IBD and PD but with conflicting results. A meta-analysis of different population studies revealed that IBD patients had a 46% increased risk of having PD compared to controls. This association was still significant if ulcerative colitis and Chron’s disease patients were analyzed separately; those with Crohn’s had a 28% increased risk of PD, while those with ulcerative colitis had a 30% increased risk of PD when compared to healthy controls.

However, the authors noted that only a very small proportion of IBD patients will develop PD. “While IBD patients are more likely to get PD, the risk is still very small. For a given IBD patient, the probability of not getting the diagnosis is 95%–97%,” Brudek said.

The association of Parkinson’s disease with IBD may not be due to the disease specifically, but to gut inflammation in general.

“Inflammation of the gut is only one of many symptoms on the list of changes in the gut and is associated with neural structures in PD patients. Thus, IBD might be just one of many sources of intestinal inflammation,” Brudek said.

Animal studies have shown that inflammation in the gut can lead to the death of dopaminergic neurons — those that are mainly affected in Parkinson’s disease — supporting a link between gastrointestinal inflammation as a factor contributing to PD.

A recent study using a PD mouse model showed that alpha-synuclein aggregation occurred in the large intestine. This also was the case in wild-type (control) mice that were induced to develop colitis (inflammation of the gut).

When researchers induced colitis in the PD mouse model at a young age, they saw that mice went on to develop severe neurodegeneration later in life.

Several studies involving the post-mortem analysis of PD patients have reported the existence of alpha-synuclein aggregates in patients’ enteric nervous system (ENS) —  the network of nerves that innervate the gastrointestinal tract — along with the brain.

Overall, these results support the existence of “connection between the intestinal environment and the CNS, [central nervous system], the so-called ‘gut-brain axis theory’ with a bi-dircetional communication between both,” Brudek wrote.

Similar to IBD patients, the gut microbiome — the natural community of microbes living in the gut — also is altered in people with PD, with an enrichment of a pro-inflammatory microbiome signature.

“Taken together, all data, including human, animal, and microbiome studies, suggest quite strongly that individuals with an increased tendency for peripheral inflammation have a higher risk to acquire PD. Given the potentially critical role of gut pathology in the pathogenesis of PD, there is reason to suspect that IBD may impact PD risk,” Brudek said.

Brudek proposed that future studies are required to identify risk factors associated with early (prodromal) PD that will support the development of therapeutic interventions for patients at higher risk of developing the disease.

Moreover, he added, it is important that clinicians recognize early the symptoms of PD in IBD, but also in patients with other chronic inflammatory disorders.

“We should direct our focus on the immune system in all Parkinsonian disorders, and further investigate the role of systemic inflammation and the immune system as such in these neurological diseases,” he said, adding that a “clear knowledge of the mechanisms implicated in gut/immune/nervous communication could help improve the prognostic and therapeutic tools leading to better quality of life for patients, reducing the exacerbation of PD symptoms, and delaying the progression of the disease.”

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Review Highlights Questions That Remain for Fecal Transplant in Parkinson’s

fecal transplant

There currently is not enough data to support the use of fecal transplants as a treatment in Parkinson’s disease, a new review suggests.

Published in the Journal of Parkinson’s Disease, the review is titled “Faecal Transplantation, Pro- and Prebiotics in Parkinson’s Disease; Hope or Hype?

The gut microbiome — the bacteria that live in the gut — have a documented impact on human health. Recent research has suggested that the gut microbiome in people with Parkinson’s disease (PD) is dysregulated and does not work properly. However, the exact changes that happen in PD are still unclear, with many studies finding conflicting results, and none able to demonstrate a cause-and-effect relationship between Parkinson’s and bacteria, one way or the other.

Fecal microbiome transplantation (FMT) is a category of procedures that aim to transplant fecal material — and, by extension, gut bacteria — from healthy individuals into sick people. The treatment is designed to put “good” bacteria back into the digestive tract, helping to replenish the bacterial balance.

In the new review, the researchers assessed the current state of evidence for the use of FMT, also called bacteriotherapy, and other gut-bacteria-targeted treatment strategies in Parkinson’s.

“FMT is an interesting option for restoring the changes in the microbiome of PD patients. It is an attractive technique because the administration is relatively simple and in general it has only a mild pattern of adverse effects,” Teus van Laar, MD, PhD, a professor at the University of Groningen, director of the Parkinson Expertise Center Groningen, and co-author of the review, said in a press release.

“However, no rigorous clinical trials have been performed yet, which leaves multiple questions open about the presumed optimal content of FMT, the route of administration, the volume of FMT and the long-term effects,” van Laar said.

There is virtually no available data on FMT in Parkinson’s, the researchers noted.

“References [in published scientific literature] to the potential use of FMT in PD are restricted to a recent Chinese case study on a PD patient with severe constipation,” they said. While this patient experienced improvement in both constipation and PD symptoms, it is virtually impossible to draw any conclusions from a sample size of one.

The researchers further noted that basic questions about using fecal transplant in PD still need to be addressed. For instance, FMT requires a “healthy’ donor” — but exactly what that means could be debated. This is especially true given that fact that the actual changes in gut microbiome that happen in PD aren’t fully understood.

Additionally, practical issues, like the best route — enema, nasogastric tube, etc. — or frequency of administration, will need to be worked out before FMT can be confidently recommended in PD.

The first clinical trial of FMT in 40 people with Parkinson’s (NCT03808389) is currently ongoing and is scheduled to be completed at the end of 2019. That trial, currently enrolling in Belgium, aims to recruit 40 Parkinson’s patients who will receive FMT from healthy donors while a control group receives autologous (self) FMT.

The results from this trial may help answer some of the questions researchers have about fecal transplant — in particular, whether it is beneficial at all for a significant portion of people with PD. However, many questions will remain unanswered following this study. For instance, the researchers noted that the inclusion criteria for Parkinson’s patients “do not in- or exclude constipation, which may complicate the interpretation of results.”

The researchers also pointed out that, while FMT is generally regarded as a low-risk procedure, there have been reported instances of serious — even fatal — complications. As such, the safety profile of fecal transplant in PD will need further evaluation.

The review also touched on other techniques used to influence gut bacteria, namely the use of probiotics and prebiotics. Probiotics are the “good” bacteria of the kind found in yogurt — though again, such definitions are highly subjective and context-dependent. Forms of fiber, prebiotics can help facilitate the growth of certain types of bacteria, rather than administration of the bacteria themselves.

Several studies have demonstrated that some kinds of probiotics — namely the bacteria groups Lactobacillus and Bifidobacterium — can help alleviate constipation in PD, the researchers said. However, whether these treatments have any effect on other symptoms of PD is currently unknown.

Prebiotics have not been tested in humans with Parkinson’s. The researchers noted that, in animal models of the disease, prebiotic treatment has “indicated beneficial effects on the PD symptoms.” Much more research will need to be done, however, to determine whether this has any bearing on human health.

“FMT is a black box with too many unanswered questions at the moment, also with respect to safety concerns,” van Laar said. “FMT or the use of pro- and prebiotics might become standard treatments in selected subgroups of PD patients in the future, but there are no good data yet in the public domain to support their use in PD patients.”

The researchers called for new studies investigating the use of such transplants in Parkinson’s.

“We hope this review will activate colleagues to start proper research on this topic as soon as possible, rather than to begin therapy without conclusive clinical data,” van Laar said.

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Hiding Behind Parkinson’s Disease

shame

We often try to hide from the world when we feel inadequate, abnormal, or different. It’s a natural defense that can be destructive when it leads to feelings of shame.

Shame is an emotion we would rather avoid. It can come upon us unexpectedly. We tend to associate it with feelings of inadequacy or a poor self-image.

Odd but true

It might seem odd to think a disease would cause you to feel shame. With Parkinson’s disease, our bodies change as they become more rigid. They become more difficult for us to manage and we must rely on help from others. The lack of independence can be humiliating and lead to feelings of shame.

Negative feelings about our appearance or our capabilities affect our expectations. When shame is present, we fear being judged harshly. You feel as if you have breached an unspoken code of conduct for what others view as acceptable behavior in public.

We put pressure on ourselves by believing you have to walk a certain way, talk a certain way, and move a certain way to be normal. For someone with Parkinson’s disease, it might be impossible to live up to the code. It is easy to fall into the trap of feeling worthless and as if we have nothing to offer just because we have Parkinson’s. We can feel small and unimportant, and we may want to disappear.

I was talking to a neighbor one day and my hand began to shake quite a bit. She asked, “What’s the matter with you? Am I making you that nervous?” The way she asked was embarrassing for me. But that was the day she found out I had Parkinson’s disease.

Take off the mask

We want to hide because of how our disease makes us feel. Others want to hide from us because of how our abnormalities make them feel. It is uncomfortable for both sides. People don’t always know how to approach someone with Parkinson’s disease. They don’t know what to say or how to respond.

Don’t be embarrassed the next time you find yourself in a situation where someone is uncomfortable because of how you walk or talk. Enlighten them about the disease. Take off the mask of fear and shame and let others see you. There’s no reason for you to be ashamed.

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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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Using ENT-01 to Target Alpha-Synuclein Found in Gut May Help Slow Parkinson’s Progression, Review Finds

Parkinson's, ENT-01

Enterin’s ENT-01, a compound that targets and reduces the accumulation of alpha-synuclein in nerve cells found in the gut, may slow the progression of Parkinson’s disease, according to a review study.

The review, “Gastrointestinal Immunity and Alpha-Synuclein,” was published in the Journal of Parkinson’s Disease.

A hallmark feature of Parkinson’s is the progressive degeneration of brain cells due to the accumulation of toxic clumps of the protein alpha-synuclein, called Lewy bodies.

Some scientists believe Lewy bodies form in the enteric nervous system — the network of nerves that innervate the gastrointestinal (GI) tract — then spread to the brain, where they gradually damage and destroy brain cells.

For that reason, many researchers are now investigating the possibility of using compounds that specifically target and reduce the build-up of alpha-synuclein in nerve cells found in the gut to restore the function of the GI tract in people with Parkinson’s, and eventually slow down the progression of the disease in the central nervous system (composed of the brain and spinal cord).

“There is growing evidence that [Parkinson’s disease] may start off in the gut,” Michael Zasloff, MD, PhD, founder of Enterin, scientific director of the MedStar Georgetown Transplant Institute and senior author of the study, said in a press release.

“The concept is that aggregates of the protein alpha-synuclein, thought to play a key role in the disease, arise within the enteric nervous system (ENS) and travel up the peripheral nerves to the central nervous system (CNS) where they ultimately cause inflammation and destruction of parts of the brain. Targeting the formation of alpha-synuclein aggregates in the ENS may therefore slow the progression of the disease,” Zasloff said.

In normal conditions, alpha-synuclein helps protect the nerve cells found in the GI tract from viral or bacterial infections by calling immune cells into action.

However, when a person develops chronic GI infections or their gut cells are no longer able to control which substances should be absorbed and which should be discarded as waste, alpha-synuclein may start to accumulate inside nerve cells from the gut, becoming highly toxic and possibly contributing to the onset of Parkinson’s.

“Based on this perspective, we are testing the hypothesis that by targeting the ENS with ENT-01, a compound that can inhibit the intracellular aggregation of [alpha-synuclein], we can restore ENS functioning in the short term, and possibly slow the progressive deterioration of the CNS in the long term,” the researchers wrote.

ENT-01 is an artificial compound derived from squalamine, a substance originally discovered in the liver and gall bladder of the dogfish shark. Preclinical studies have shown that ENT-01 is able to displace alpha-synuclein from the membranes of nerve cells found in the gut, restoring their normal electric activity and reducing the formation of toxic aggregates.

An open-label, Phase 2a clinical trial called RASMET (NCT03047629) in 2018 demonstrated that treatment with ENT-01 lessened constipation, a common GI symptom of Parkinson’s, in 80% of the 50 patients participating in the study.

“Surprisingly, we also observed benefits in both motor and non-motor symptoms. The RASMET study demonstrated that it is possible to correct long standing dysfunction of the ENS which might have been assumed to be irreversibly damaged,” the researchers wrote.

The team is currently leading a double-blind, placebo-controlled, Phase 2b trial called KARMET (NCT03781791) to investigate the effects of ENT-01 tablets on constipation and other neurologic symptoms of Parkinson’s in a group of 110 participants.

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Mouse Study Implicates Calcium Channel in Neuronal Death in Parkinson’s Disease

mouse study, Parkinson's

A calcium channel called Cav2.3 plays a role in neuronal death, and may be a useful therapeutic target in Parkinson’s disease, suggests a new study done primarily in mice.

The study, titled “Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease,” was published in Nature Communications.

Motor symptoms in Parkinson’s disease are caused primarily by the death of dopamine-producing (dopaminergic) neurons in a part of the brain called the substantia nigra (SN). It has been well-established that calcium signaling — that is, calcium ions moving in or out (but usually in) of a cell, which is mediated by specialized “channel” proteins — plays an important role in the functioning and survival of these neurons, but the precise mechanisms are still not fully understood.

In the new study, researchers began by measuring the levels of several different calcium channels in these neurons in the brains of mice. They were surprised to find higher levels of Cav2.3 than any other calcium channel; Cav2.3 has never been linked to neurodegeneration (neuron cell death) before.

The researchers then used mice that had been genetically engineered so they could not make Cav2.3 and treated them with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a chemical that is toxic to neurons and is “the standard model for preclinical testing of neuroprotective Parkinson’s disease therapies in animals,” the researchers wrote.

In wild-type (i.e. with functional Cav2.3) mice, MPTP treatment resulted in the death of about 40% of the dopaminergic neurons in the substantia nigra.

“In stark contrast, we observed no loss of SN dopaminergic neurons in Cav2.3 knockout animals after MPTP treatment,” the researchers wrote. “Taken together, these data identify Cav2.3 as mediator of SN dopaminergic neuron vulnerability to a degenerative stressor.”

The researchers then measured levels of other calcium-related proteins in neurons lacking Cav2.3, in order to identify possible mechanisms for this phenomenon. They found that these cells had increased levels (by about 40%) of a calcium-sensing protein called NCS-1, and they hypothesized that higher levels of this protein might lend the neurons protection from MPTP.

To test this, the researchers treated mice that lacked NCS-1 with MPTP, which resulted in the death of about 60% of the dopaminergic neurons in the SN — significantly more than was seen in wild-type mice.

“NCS-1 thus emerges as protective factor during SN dopaminergic degeneration, of likely relevance to Parkinson’s disease,” the researchers wrote.

Finally, the researchers turned to human cells. They took skin cells from volunteers, and engineered these into a type of stem cell called induced pluripotent stem cells (iPSCs), which were subsequently induced to differentiate into neurons.

The researchers compared iPSC-derived neurons from people without Parkinson’s disease to those of a Parkinson’s disease patient who had a mutation in the GBA gene (such mutations are associated with a high risk of Parkinson’s disease).

No significant differences were found in the amount of Cav2.3 protein; however, levels of NCS-1 were about 40% lower in the neurons from the person with Parkinson’s. Although this does not provide definitive proof, it suggests that similar molecular mechanisms might be at play in human Parkinson’s disease.

“Collectively, our data strongly suggest opposing roles for Cav2.3 and NCS-1 in Parkinson’s disease,” the researchers said, adding that “Cav2.3 is neurodegenerative whereas NCS-1 is protective for SN dopaminergic neurons. Whether this involves any direct functional or molecular interactions between the two proteins must be clarified in future experiments.”

“Cav2.3 and NCS-1 thus emerge as potential targets for neuroprotective therapy,” they added.

Although a recent Phase 3 clinical trial (NCT02168842) using DynaCirc (isradipine) — a medicine used to treat high blood pressure — to block another type of calcium channel, called Cav1.3, showed that it did not protect against Parkinson’s disease, the authors believe that the therapeutic dose given may not have been sufficient to fully inihibit this channel in dopaminergic neurons. Alternatively, inhibiting this specific type of calcium channel may “be protective only under distinct conditions, e.g. before motor symptoms manifest, or in response to transiently elevated dopamine levels during dopamine replacement therapy,” they added.

Currently, the only available Cav2.3 inhibitor (SNX-482) is not suitable to be used in a clinical setting “due to off target effects.” As such, the “development of high affinity, brain-permeable, and selective Cav2.3 channel blockers is warranted,” the researchers said.

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Don’t Worry, Be Happy: Parkinson’s and the Limits of Positive Thinking

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I don’t want to take away from Mad magazine’s Alfred E. Neuman or singer-songwriter Bobby McFerrin, but the idea that a pair of rose-colored “don’t worry” glasses will change my life for the better has never sat well with me. Pollyanna is not a guest in my home.

“Look at all the wonderful things in your life. All your needs are provided for — no worries,” someone said to my wife and me recently as we described the temporary ruin of stagnation. But pouring saccharin sentiments over the burnt toast of my life won’t remove its acrid flavor.

I often write about having a positive action-based wellness plan. My approach is attitude plus behavior equal consequences. My positive outlook is wisdom-based and engaged in compassion and not on my ability to see a half-full glass. One can try to view the chronic disease glass as being half full, but the reality is that it is also half empty. I wish that my muscular problems and other Parkinson’s symptoms were absent. Viewing the glass as half full is not an action plan — it’s more of an “I’m tired of this right now” statement.

Many authors have extolled positive thinking: Norman Vincent Peale and Norman Cousins, among others. Choosing how to act, think, and feel creates patterns. We return to those patterns when times get tough. Another way of putting it is, “Fake it until you make it.” It seems vacuous to assume that “faking” happiness will remove the causes of unhappiness or make circumstances appear to be better than they are. Well-meaning people who propose the “don’t worry, be happy” solution don’t have a clear understanding of how Parkinson’s and other chronic diseases affect our daily lives. What we need is a well-designed and enacted wellness map — not rose-colored glasses.

Though my partner and I have moments of frustration and utter despair, we manage to pull ourselves up — as we have throughout our lives — to find the inner and spiritual strength that enables us to continue. It’s a lifelong habit for both of us, and as a team, we support each other through the continued challenges, taking turns with compassion and strength when the other one falters under the burden.

Do we worry? Yes, but we move gradually toward more acceptance. Are we happy? The glass remains half full, and we are grateful for the happiness and blessings in our lives. But it is now time to replenish the glass and move into deeper compassion, finding strength in the belief that all things happen for a reason and in their own time. We will not shy away from the work that needs to be done in our lives and for others with chronic diseases.

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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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