Levodopa Shows No Disease-modifying Effects in Parkinson’s, Study Finds

levodopa study

Levodopa/carbidopa treatment is effective in managing Parkinson’s motor symptoms, but does not protect against disease progression among patients with early disease, a study shows.

The research, “Randomized Delayed-Start Trial of Levodopa in Parkinson’s Disease” was published in The New England Journal of Medicine.

Levodopa is the main treatment for Parkinson’s disease. However, neurologists might delay prescribing levodopa for different reasons, including concern about the development of levodopa-induced dyskinesias (abnormal, uncontrolled, involuntary movements), which is one of the most common dose-limiting side effects of this treatment approach.

However, almost all patients eventually receive levodopa to control their motor symptoms.

In an earlier clinical trial, called ELLDOPA , 361 patients with early Parkinson’s disease received levodopa or placebo for 40 weeks. Two weeks after that, clinical examination showed that the participants who had received levodopa had a slower disease progression than those on placebo. However, brain imaging studies revealed that levodopa had either accelerated the death of dopaminergic neurons, or it had modified the protein responsible for the transport of dopamine in brain nerve cells.

“Therefore, whether levodopa has an effect on the progression of Parkinson’s disease beyond its immediate benefit with respect to symptoms remains unknown,” scientists wrote.

Now, researchers from the University of Amsterdam designed a multicenter, randomized, placebo-controlled, delayed-start trial to assess levodopa’s effect on patients with early Parkinson’s disease who had insufficient disability to receive anti-Parkinson medication: the Levodopa in Early Parkinson’s Disease (LEAP) study (ISRCTN30518857).

Patients who had received their diagnosis within the previous two years were randomly assigned to an early-start group (207 subjects): levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) for 80 weeks; or to a delayed-start group (210 participants): placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks.

During Phase 1 (the first 40 weeks of the trial), patients received levodopa or placebo. During Phase 2 (the second 40 weeks) patients in both trial groups received levodopa. Assessments were made at baseline (trial initiation) and at weeks 4, 22, 40, 44, 56, 68, and 80.

The study’s primary endpoint (goal) was the difference in the mean change, from trial initiation to week 80, in the total score on the Unified Parkinson’s Disease Rating Scale (UPDRS). That tool assesses both motor and non-motor symptoms associated with Parkinson’s disease (higher scores indicate more severe disease).

Secondary outcomes included the progression of symptoms between weeks 4 and 40 and between weeks 44 and 80, as measured by the category scores on the UPDRS; disability; cognitive impairment; depression; and disease-related quality of life.

At week 80, there was no significant difference between the early-start and delayed-start group regarding motor and non-motor symptoms, as measured by the UPDRS, indicating that levodopa had no disease-modifying effect.

To test if early treatment initiation was prognostically better than a delayed one or vice-versa, scientists compared symptoms’ progression rate in week 4-40 and week 44-80. Once again, no significant changes were observed between groups in either study period.

No significant changes in therapy-related motor fluctuations, including dyskinesias, were found between groups. During the first 40 weeks, patients on the early-start group complained more of nausea (23%), compared to the participants on the delayed-start group (14.3%).

Also, no significant differences were observed regarding disability, cognitive impairment, depression and disease-related quality of life between the groups.

“We conclude that treatment with levodopa at a dose of 100 mg three times per day in combination with carbidopa at a dose of 25 mg three times per day had no disease-modifying effect, either beneficial or detrimental, on early Parkinson’s disease among patients who were evaluated over the course of 80 weeks. Whether higher doses of the drug, longer periods of administration, or initiation of the drug at later stages of the disease could alter the course of Parkinson’s disease warrants evaluation in future trials,” researchers concluded.

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Gut Bacteria Affect Metabolism of Parkinson’s Therapy Levodopa, Study Shows

gut bacteria

Levodopa, one of the main medicines used to treat Parkinson’s symptoms, can be converted into dopamine by gut bacteria, researchers report.

The findings might explain why levodopa treatment is less effective in some patients.

The study, “Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease,” was published in Nature Communications.

Parkinson’s disease is characterized by low levels of dopamine, a chemical brain messenger essential for neurons involved in movement control.

In terms of treatment, patients cannot take dopamine directly, as the compound is broken down by the body before it reaches the brain. Levodopa crosses the blood-brain barrier and is taken up by dopaminergic neurons, which convert the chemical into dopamine, which helps manage disease-related motor symptoms.

Studies have suggested that gut bacteria can affect treatment effectiveness in several diseases; particularly in Parkinson’s, the amount of levodopa that reaches the brain varies among patients.

“It is well established that gut bacteria can affect the brain,” assistant professor in microbiology Sahar El Aidy, PhD, and this study’s lead investigator, said in a press release. “There is a continuous chemical dialogue between gut bacteria and the brain, the so-called gut-brain axis.”

However, it remains to be explained if inter-patient variations in gut bacteria composition and functionality contribute to treatment response fluctuations in Parkinson’s disease patients who require a higher daily treatment dosage regimen.

Researchers from the University of Groningen in The Netherlands analyzed the effect of levodopa metabolizing bacteria in the middle section of the small intestine (jejunum), where levodopa is absorbed.

Using rat jejunum bacteria samples, researchers saw that an enzyme called tyrosine decarboxylase, which normally converts tyrosine into tyramine, also efficiently converted levodopa to dopamine in the gut. Enterococcus bacteria, commonly found in the intestines, were responsible for such enzymatic activity.

To understand if they could somehow inhibit levodopa’s conversion, the Dutch team “fed” the bacteria with a high concentration of the amino acid tyrosine, the main substance that tyrosine decarboxylase acts on, but tyrosine’s abundance did not prevent levodopa’s metabolization.

As part of their treatment regimen, Parkinson’s patients are given a decarboxylase inhibitor, like carbidopa, to block peripheral metabolism of levodopa to dopamine, allowing a greater concentration of levodopa to reach the brain.

Scientists studied the effect of human decarboxylase inhibitors, including carbidopa, benserazide, and methyldopa, on the bacterial tyrosine decarboxylase. None of the tested inhibitor compounds blocked levodopa’s enzymatic transformation.

“It turned out that, for example, the inhibitor carbidopa is over 10,000 times more potent in inhibiting the human decarboxylase,” said El Aidy. This could be due to species-specific changes in carbidopa’s chemical structure, indicating that a more effective levodopa treatment could be achieved by co-administration of tyrosine decarboxylase inhibitor targeting both human and bacterial forms of the enzyme.

“[C]ommonly applied inhibitors of human DOPA [levodopa] [tyrosine] decarboxylase in levodopa combination therapy do not inhibit bacterial TDC [tyrosine decarboxylase] dependent levodopa conversion, implying levodopa/carbidopa (levodopa) combination therapy for PD [Parkinson’s disease] patients would not affect the efficacy of levodopa in situ [locally] by small intestinal bacteria,” researchers wrote.

These findings confirm the gut bacteria’s ability to influence local levels of levodopa treatment and suggest that the presence of tyrosine decarboxylase could reduce the amount of levodopa available in the bloodstream of Parkinson’s patients.

To test the latter hypothesis, investigators analyzed stool samples from patients who were on a normal or high dose of levodopa. They reported a strong positive correlation between the relative abundance of the bacterial gene encoding for tyrosine decarboxylase and the need for a higher levodopa/carbidopa treatment dose, as well as with disease duration.

To further understand the concept that the amount of tyrosine decarboxylase in jejunum’s bacteria affects bloodstream levels of levodopa/carbidopa and dopamine, scientists orally administered levodopa plus carbidopa to 18 wild-type (healthy) rats and analyzed animals’ blood 15 minutes after administration (time point when levodopa is at its higher concentration in rats).

Results showed that higher abundance of bacterial tyrosine decarboxylase in the rats’ jejunum decreased plasma levels of levodopa. The ratio between dopamine and levodopa/carbidopa levels in the small intestine positively correlated with bacterial enzyme amount.

Researchers then treated 10 rats with a subtype of Enterococcus bacteria known as Enterococcus faecalis that did not have the tyrosine decarboxylase gene and compared their levodopa/carbidopa plasma levels with 10 other rats that were given wild-type (normal, positive for the tyrosine decarboxylase gene) Enterococcus faecalis cells.

As expected, animals treated with wild-type cells had significant lower plasma levels of levodopa/carbidopa than the ones treated with mutant cells.

“Collectively, our data show that levodopa conversion by bacterial [tyrosine decarboxylase] in the small intestine should be considered as a significant explanatory factor for the increased levodopa/carbidopa dosage regimen required in a subset of [Parkinson’s disease] patients,” researchers wrote.

“This is considered to be a problem for Parkinson’s disease patients, because a higher dose will result in dyskinesia, one of the major side effects of levodopa treatment,” El Aidy said, referring to the involuntary, jerky movements patients experience.

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World War II Chemical Weapon Antidote May Also Fight Parkinson’s, Researchers Suggest

dimercaprol for Parkinson's

Dimercaprol, an antidote to a World War II chemical weapon, was shown to be effective in removing a neurotoxin associated with Parkinson’s, revealing it as a possible treatment for the neurodegenerative disease.

Purdue University researchers report that the antidote can safely and effectively remove acrolein, a neurotoxic substance, from the body. Earlier this year, the researchers from the laboratory of professor Riyi Shi, MD, PhD, published their results on the chemical warfare antidote as a potential Parkinson’s treatment in the Journal of Neurochemistry.

Acrolein is a neurotoxin generated in the body after nerve cells are damaged and is directly linked to Parkinson’s disease. Exposure to acrolein increases pain and triggers a cascade of biochemical events thought to increase the severity of Parkinson’s and other neurodegenerative diseases.

The researchers administered dimercaprol to rats with increased levels of acrolein and nerve damage, a model applicable to Parkinson’s disease, and tested the ability of dimercaprol to block acrolein and neurodegenerative disease progression.

They observed that dimercaprol neutralized acrolein and eliminated it from the brain. Importantly, adding dimercaprol led to an increased survival rate of neurons, improved mobility, and less pain. They also demonstrated that dimercaprol could effectively neutralize acrolein in human cells.

Dimercaprol has several advantages over other chemicals that isolate and eliminate acrolein, including fewer side effects and being easily processed by the body and eliminated via the urine.

“Our studies show that by removing the toxin (acrolein) from the brain, we are not just reducing the symptoms of Parkinson’s disease but also significantly reversing the damage of Parkinson’s disease. This could actually provide a new treatment for Parkinson’s patients,” said Shi, a professor of neuroscience and biomedical engineering in Purdue’s Department of Basic Medical Sciences, College of Veterinary Medicine, and Weldon School of Biomedical Engineering.

Dimercaprol is already approved by the U.S. Food and Drug Administration to treat heavy metal poisoning, so it is known to be safe when administered to humans. Future clinical trials are necessary to test the effectiveness of dimercaprol as a treatment for patients with Parkinson’s and other neurodegenerative diseases.

“We believe that the drug’s classification and method of administration are what make it an attractive therapy option,” Shi said. “By systematically injecting the antidote drug directly into the abdominal cavity, it can be absorbed by the bloodstream and then travel to the brain, where the disease is most harmful and where the drug can most benefit the patient.”

The research was funded by grants from the National Institutes of Health, the Indiana State Department of Health, and the Indiana CTSI Collaboration in Biomedical Translational Research Pilot Program.

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Michael J. Fox Foundation Offering $7.5M in Funding for Parkinson’s Research Projects

MJFF research funding

The Michael J. Fox Foundation is continuing to support the advancement of Parkinson’s disease research by investing up to $7.5 million in projects proposed by investigators, the nonprofit recently announced.

Funding will be considered for projects aimed at the following four areas: exploring new biological targets for therapeutic development; identifying biomarkers to objectively measure disease progression; testing potential new treatments; and determining preventive factors.

“Our core goals are to better understand, measure, treat and — most significantly — prevent Parkinson’s disease,” Todd Sherer, PhD, the foundation’s CEO, said in a press release. “We ask scientists to bring us their promising, innovative projects in these areas to move the needle closer to cures and better quality of life for people with this disease today.”

Scientists can submit their proposals through Sept. 26, with funds anticipated in May 2019.

The foundation has divided each of the research areas into four programs for which investigators can apply for grants.

To find new biological targets of the disease, the Target Advancement Program will focus on the identification of proteins and pathways that are involved in the onset and progression of Parkinson’s.

Finding these targets will not only shed light on neurodegeneration and motor and non-motor dysfunction and symptoms, but it will also enable the development of potential new therapies to slow or stop disease progression.

The Improved Biomarkers and Clinical Outcome Measures program is intended to identify biomarkers associated with the disease that can be effectively quantified using objective tests, and accelerate the development of new therapies. These tests are expected to improve diagnosis, track disease progression, and monitor treatment response.

The Therapeutic Pipeline program seeks to develop new therapies that can change the course of the disease and improve treatment beyond the current standards of care. Existing treatments alleviate symptoms, but do not address several aspects of the disease, and can result in serious side effects.

A fourth program is centered on Parkinson’s prevention. By using epidemiological factors, such as lifestyle behaviors (e.g. diet and exercise), medication taken or other types of treatments, the foundation hopes to identify which factors can decrease the risk of Parkinson’s disease.

Each of the four programs will receive a total of $1.5 million of the grant money, with the exception of the Therapeutic Pipeline program, which will receive $3 million to fund preclinical and clinical studies.

Applications for project submissions are now open. Both academic and industry scientists worldwide are invited to apply.

The foundation will host a webinar at 12 p.m. EST Sept. 6 to review the goals of the programs, explain the funding process, and answer applicant questions. For more information and to register for the webinar, visit here.

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Russian Researchers Create Software that Predicts Parkinson’s Symptoms

software program predictive

A new software can predict with an accuracy of 96 percent the form of Parkinson’s disease and future symptoms that a patient may experience.

The software was the result of a collaboration between researchers at Peter the Great St. Petersburg Polytechnic University (SPbPU), the Institute of Experimental Medicine, and ITMO University, in Russia.

This technology may improve early diagnosis, promote preventive care, and ultimately enhance patients’ overall health.

The program was developed based on a discriminant analysis method that allows researchers to dissect a great amount of data more easily and create groups that share similar features. The technology combines clinical information, test results, and disease progression data, which may provide common patterns used to identify patients or particular features according to those specific characteristics.

This strategy allows clinicians to evaluate which treatments would be more likely to work for a patient or group of patients. Also, the software could predict if patients were likely — or not — to develop certain disorders or symptoms.

For instance, in a previous study researchers found that Parkinson’s patients who have very low blood levels of copper have increased chances of developing abnormal posture.  “If a doctor knows about a potential threat in advance, he or she can start preparing for the treatment beforehand,” Marina Karpenko, PhD, associate professor at the biophysics department of SPbPU, said in a press release.

Built on the basis of artificial intelligence, the software has the capacity to constantly improve its predictive abilities, as Karpenko explained: “The program can be ‘trained’: the more information is uploaded in it, the more precise conclusions and recommendations it will provide,” she said.

Overall, the software may empower clinicians to diagnose Parkinson’s disease earlier, which will support prompt and targeted treatments to provide the best patient care and outcomes.

Researchers expect to make the software available in the near future, in a format that can be installed in any computer or smartphone.

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Dopamine Agonists Linked to Impulse Control Disorders in Parkinson’s Patients, Study Finds

impulse control disorder

More than half of Parkinson’s patients who have been treated with a dopamine agonist may develop impulse control disorders over time, according to recent research.

The study, “Longitudinal analysis of impulse control disorders in Parkinson disease,” was published in the journal Neurology.

Impulse control disorders are characterized by the inability to resist impulses or to control specific behaviors. These include compulsive gambling, shopping, eating, and sexual behaviors, which can lead to serious financial, legal, or social problems.

These types of disorders are common among Parkinson’s patients. The use of dopamine agonists — which act as a substitute for dopamine in the brain — has been suggested as a main risk factor; however, scientific evidence has been controversial, and this relationship had not yet been fully established.

In this observational study (NCT01564992), researchers analyzed the incidence of impulse control disorders among 411 Parkinson’s patients who had been diagnosed with the disease for five years or less, followed up annually for up to five years.

Approximately 86.6% of the patients reported taking a dopamine agonist at least once since disease onset, and 71.9% continued treatment with a dopamine agonist for an average of three years.

In the beginning of the study, 19.7% of patients were diagnosed with an impulse control disorder. Compulsive gambling affected 3.9% of the patients, compulsive shopping 4.6%, compulsive or binge eating 10.5%, and 8.5% had compulsive sexual behaviors. About 6.3% of patients had more than one compulsive disorder.

Those with impulse control disorders were found to be younger, had longer disease duration, and took dopamine agonists more frequently and at higher doses than those without these issues.

No differences in frequency and dosage of levodopa were found between the two groups.

Over the course of the study, the incidence of impulse control disorders among participants increased from the initial 19.7% to 32.8% after the five years of follow-up.

For people who had never taken dopamine agonists, 12.4% developed compulsive disorders compared with 51.5% of those who had ever used the therapy.

“Our study suggests that impulse control disorders are even more common than we thought in people who take dopamine agonists,” Jean-Christophe Corvol, MD, PhD, lead author of the study and a professor at Pitié-Salpêtrière Hospital and Pierre and Marie Curie University, said in a press release.

Higher doses of the therapies and longer treatment periods made people more likely to develop impulse control disorders.

Two specific dopamine agonists, Mirapex (pramipexole) and Requip (ropinirole), were associated with the highest risk of developing impulse control disorders: 4.67 times higher for Mirapex, and 4.86 times higher for Requip. Others therapies such as Apokyn (apomorphine), Pardocel (bromocriptine), Neupro (rotigotine), and Piribedil (piribedil) were associated with a 2.74 times increased risk.

During the study, 30 patients discontinued dopamine agonist therapy, which led to a progressive resolution of compulsive disorders. After one year, 50% of these patients no longer had the behavioral disorder they were previously diagnosed with.

Similar analysis with other antiparkinsonian drugs were performed, and failed to reveal any association with the incidence of these behavioral disorders.

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Cerium Oxide Nanoparticles Hold Therapeutic Potential for Parkinson’s, Study Finds

cerium oxide nanoparticles

Very tiny particles of cerium oxide — a compound with antioxidant effects — can prevent the toxic effects of alpha-synuclein in the brain, which may represent a new therapeutic option for Parkinson’s disease, a study suggests.

The study, “Nano-particle mediated inhibition of Parkinson’s disease using computational biology approach,” was published in Scientific Reports.

Several factors contribute to Parkinson’s disease progression, including the accumulation of alpha-synuclein proteins inside nerve cells and the formation of toxic protein aggregates called Lewy bodies.

Efforts have been made to develop pharmacological approaches to fight Parkinson’s, but no completely effective solution has been found yet.

Most pharmacological compounds are not specific and may result in severe side effects. Additionally, most available compounds are unable to cross the blood-brain barrier — a semipermeable membrane that protects the brain — and are not able to reach the nerve cells affected by Parkinson’s.

The use of nanoparticles loaded with an active agent have shown some promise in overcoming these limitations. The surface of these particles can contain small markers that allow them to pass through the blood-brain barrier and gain access to the central nervous system, specifically anchoring to the intended target cells and releasing their active pharmacological agent.

Now researchers are proposing the use of nanoparticles to target abnormal alpha-synuclein proteins.

The team designed a complete computer-based analysis of all known mechanisms concerning alpha-synuclein involvement in Parkinson’s to find the most suitable nanoparticle.

They compared three different nanoparticles: gold nanoparticles which have been shown to prevent alpha-synuclein aggregation; graphene and superparamagnetic iron-oxide nanoparticles that have also been reported to prevent fibrils formation; and cerium oxide nanoparticles that have been shown to have neuroprotective activity due to their antioxidant and anti-apoptotic effects.

Their analysis was based on compiled information about drug design and effects, disease diagnosis and features, as well as molecular target interactions and systems biology data.

Using computer simulation methods and protein modeling analysis, the team found that cerium oxide nanoparticles had a greater affinity toward alpha-synuclein, while sustaining good stability and overall response.

The analysis also revealed that cerium oxide could prevent the aggregation of alpha-synuclein, and promote the activation of dopamine receptors and the regulation of signaling pathways and genes important in Parkinson’s disease.

Based on these preclinical results, the researchers proposed cerium oxide nanoparticles “as [a] potential inhibitor of alpha-synuclein” that can “be employed as [a] nano-drug against Parkinson’s disease.”

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Enzyme May Be Early Biomarker of Parkinson’s and Treatment Target for Patients, Scientist Suggests

sEH enzyme and Parkinson's

Ways of better diagnosing and treating Parkinson’s patients may lie in developing biomarkers, inhibitors, and stem cells therapies that are based on an enzyme newly identified in research into this disease, called soluble epoxide hydrolase (sEH), a commentary article suggests.

The opinion piece, “Fatty acid chemical mediator provides insights into the pathology and treatment of Parkinson’s disease,” was written by Cesar V. Borlongan, director of the Center of Excellence for Aging & Brain Repair at the University of South Florida, and published in Proceedings of the National Academy of Sciences (PNAS) of the United Stated of America.

Parkinson’s disease is characterized by progressive loss of brain cells — in particular, those that produce dopamine — as well as by the accumulation of abnormal protein aggregates, including alpha-synuclein and Lewy bodies.

Brain cells most affected by the disease are located in the substantia nigra, a basal ganglia structure in the midbrain that is rich in dopamine neurons, but other brain areas are also impacted both at Parkinson’s onset and throughout disease progression.

The accumulation of toxic alpha-synuclein aggregates has been pinpointed as the major player in nerve cell degeneration.

But several studies report that other mechanisms, including calcium imbalance, neuroinflammation, and increased oxygen-mediated stress, are also directly linked to Parkinson’s.

“Unfortunately, despite these scientific advances in our knowledge of the disease pathology [mechanisms], there is no cure for Parkinson’s disease, only relief from its symptoms,” Borlongan wrote.

Hs commentary focused on a recent study published in PNAS that highlighted the important role of the soluble epoxide hydrolase (sEH) enzyme plays in neuroinflammation and the death of dopaminergic nerve cells in the brain, seen by its researchers working in multiple animal models of Parkinson’s and in patients’ cells.

They demonstrated that sEH contributes to the transformation of alpha-synuclein to a toxic element in brain cells. Additional studies also show that alpha-synuclein mediates the loss of nerve cells in the periphery, suggesting that sEH — similar to what happens in the brain — may also modify alpha-synuclein in peripheral nerve cells (peripheral being the gastrointestinal track and enteric, or intrinsic, nervous system that governs that track).

Importantly, this phenomenon could occur at very early disease stages, before nerve cell damage is established.

While this discovery is important for the mechanistic and other insights it provides, it may also point to new ways of diagnosing and treating patients, Borlongan suggests.

“Whether sEH similarly initiates from the periphery and propagates to the brain in transporting α-synuclein will be of high clinical relevance, as it will allow early peripheral diagnosis of PD, which does not manifest its first motor symptoms until 80% of striatal dopamine is lost,” he wrote. “It may be possible to detect elevated sEH levels peripherally as a prelude to brain dopamine degeneration, thereby aiding in early intervention of the disease.”

For diagnosis, the research raises the possibility that increased levels of sEH in the periphery could be an early biomarker of brain cell degeneration, a disease marker before motor symptoms are evident.

“Of note, sEH activity can be measured in the intestines in other disease indications, suggesting its feasibility as a biomarker for Parkinson’s disease,” Borlongan said.

Therapeutic work might make use of a chemical inhibitor of sEH activity — much as the researchers did in their work, and which effectively reduced Parkinson’s-associated toxicity in both cells and animal models of the disease.

Medications that work as sEH blockers have already been tested in clinical trials for heart and lung diseases, facilitating their development as a Parkinson’s treatment, he said.

Likewise, sEH activity in stem cells collected from Parkinson’s patients was associated with the formation of alpha-synuclein aggregates, suggesting stem cell transplants could have the potential to lower sEH activity levels and prevent the accumulation of toxic alpha-synuclein toxic aggregates.

“It is conceivable that the development of sEH-based biomarkers, inhibitors, and stem cells may lead to new clinical products for inflammation-plagued disorders,” Borlongan concluded.

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With Parkinson’s, Slow Is the New Fast


There is no way I have Parkinson’s Disease (PD).

That river in Egypt (‘Da Nile’)

I will never forget the day I heard the words no one ever wants to hear: “You have an incurable, progressive disease.” Although I had two good friends with PD, I never thought we would have something like this in common.

In 2015, at my annual check-up, my primary care physician suggested I see a neurologist after I told her my handwriting was becoming illegible. Little did I know, this would mark the beginning of my PD journey. The first neurologist I saw told me I had PD but suggested I see a movement disorder specialist to confirm the diagnosis. Determined to prove him wrong, I made the appointment. After conducting the standard tests (which I felt were too subjective), she agreed with the first doctor’s diagnosis.

Still convinced that I did not have this disease, I sought out other medical opinions. After all, I ate well, exercised, and always got plenty of sleep — I did all the “right” things. How could I possibly be sick? Still in denial, I saw three other neurologists — all confirmed the PD diagnosis. One doctor prescribed a PET/CT scan of the brain, which offered further clinical proof of PD.

Medications … NOT!

Of course, the consensus of all the neurologists was that I should start taking prescription medication. Initially, I refused to follow their advice. I believed I could ease my symptoms through holistic measures, diet, physical and occupational therapy, and exercise.

I clearly remember what my life partner, Steve (lost to suicide), had dealt with while trying to find the right medications for his depression. There were numerous side effects and the multiple concurrent, prescribed treatments: “This drug doesn’t work, so add this drug to enhance the functioning of the first medication.” If there was still no improvement in symptoms, medication dosage would increase. Then there was the medication’s loss of efficacy over time. It could also take weeks or months to know if the drug was going to help. Even further alarming was that some of the side effects (suicide in the case of some antidepressants) were what the medication was trying to alleviate.

From what I read about PD medications, it seemed like I would experience a very similar situation to what Steve went through.

Am I depressed, or do I have PD?

Although I refused to take medications to alleviate my symptoms, I still continued my exercise routine (walking, yoga, weights, cycling). However, I was on high alert for changes in my body.

Other strange things were happening to me that I could not explain. While volunteering at a race, I was rolling posters for athlete giveaways. I could not understand why the other staff could roll five posters to my one. Why was I so slow at performing such a simple task? Rolling around in bed at night became a chore, and I felt I needed a forklift to change positions! My left foot kept falling out of my slip-on shoes. I had trouble keeping the shoe on, especially when going upstairs. Fatigue and lack of motivation plagued me.

Could these symptoms be attributed to situational depression that resulted from Steve’s suicide, or was it PD? Should I consider medications for depression or PD?

A blessing and a curse

Having been an athlete most of my life — tennis player, weight trainer, roller-skater, race walker, dancer, and cyclist — I was very much in tune with my body and in touch with its capabilities. This has been both a blessing and a curse. The discipline to work out, along with the muscle memory I have built over the years, is serving me well in fighting PD. However, I am also very aware of how much ability I have lost. Before PD, my balance was excellent. Now it is probably closer to what someone my age has now. However, my frustration level is so high since I still expect to be able to accomplish what once came so naturally to me.

Where I was once strong, fluid, and graceful, I now feel weak, inflexible, rigid, and non-rhythmic. Most people who look at me see no signs of PD. However, I know what I have lost, and for me, that loss is huge.

Although I sometimes wish I had never been an athlete (you don’t know what you’ve got until its gone), I do accept that my years of training and athletics will be my saving grace in fighting this disease.

(Photos courtesy of Jean Mellano)


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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Targeting Enzyme in Immune Cells of Brain May Slow Parkinson’s Progression, Study Suggests

HDAC2 and microglia

Blocking the activity of an enzyme found in immune cells of the brain may prevent the degeneration and death of nerve cells seen in Parkinson’s disease, new research shows.

The study “Upregulation of HDAC2 in Laser Capture Nigral Microglia in Parkinson’s Disease,” was published in Neurobiology of Aging.

The enzyme being studied in this work, called HDAC2, regulates a critical cellular mechanism known as epigenetics. This is a mechanism that controls which genes are available to be read and translated into active proteins, and which genes are silenced and not available.

Because of its key role, HDAC2 — as well as other enzymes of its family — are seen as potential therapeutic targets for several  neurodegenerative diseases. But the relevance of HDAC2 to Parkinson’s is not clear.

Arizona State University-Banner Neurodegenerative Disease Research Center researchers, along with collaborators at Jiao Tong University School of Medicine in China, analyzed the levels and activity of HDAC2 in brain tissue samples from Parkinson’s patients and healthy controls.

The team used an advanced technique called laser captured microdissection, which allows the selection and separation of specific cells within a tissue sample.

Brain immune cells, called microglia, and dopamine-producing nerve cells collected from Parkinson’s patient samples were found to have high levels of HDAC2 compared to the levels of these cells in healthy samples.

Interestingly, HDAC2 levels correlated with the amount of LN3 — a marker of microglia activity — in the Parkinson’s samples but not in the controls. This suggests that HDAC2 may be linked to the greater pro-inflammatory and abnormal (deregulated) activity of microglia, as they transition from protective brain cells to ones that attack and damage healthy neurons.

To further test this hypothesis, the team used experimental cell lines that reproduced the behavior of microglia, the brain’s resident immune cells, and were chemically pushed into a pro-inflammatory state.

These experimental cells showed increased levels of HDAC2, similar to the pattern found in Parkinson’s patients. However, this effect was only observed when cells were exposed to higher levels of the chemical activator, suggesting that brain’s immune cells “may have an inflammatory threshold that must be met” before significant differences in HDAC2 levels are achieved, researchers wrote.

“It has been known for some time now that within pro-inflammatory environments, like the substantia nigra in Parkinson’s disease, microglia are responsible for the constant upregulation and release of neurotoxic cytokines,” Diego Mastroeni,  a study co-author and an assistant research professor in the ASU School of Life Sciences, said in a university news article.

These findings support HDAC2 as a specific target “that may be inhibited to reduce the expression of genes associated with neuroinflammation,” Mastroeni said. “The key will be targeting HDAC2 gene expression levels specifically in substantia nigra’s microglia.”

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Source: Parkinson's News Today