Posts Tagged ‘Parkinson’s disease’

A promising molecule has offered hope for a new treatment that could stop or slow Parkinson’s, something no treatment can currently do.

Researchers from the University of Helsinki found that molecule BT13 has the potential to both boost levels of dopamine, the chemical that is lost in Parkinson’s, as well as protect the dopamine-producing brain cells from dying.

The results from the study, co-funded by Parkinson’s UK and published online today in the journal Movement Disorders, showed an increase in dopamine levels in the brains of mice following the injection of the molecule. BT13 also activated a specific receptor in the mouse brains to protect the cells.

Typically, by the time people are diagnosed with Parkinson’s, they have already lost 70-80 per cent of their dopamine-producing cells, which are involved in coordinating movement.

While current treatments mask the symptoms, there is nothing that can slow down its progression or prevent more brain cells from being lost, and as dopamine levels continue to fall, symptoms get worse and new symptoms can appear.

Researchers are now working on improving the properties of BT13 to make it more effective as a potential treatment which, if successful, could benefit the 145,000 people living with Parkinson’s in the UK.

The study builds on previous research on another molecule that targets the same receptors in the brain, glial cell line-derived neurotrophic factor (GDNF), an experimental treatment for Parkinson’s which was the subject of a BBC documentary in February 2019. While the results were not clear cut, GDNF has shown promise to restore damaged cells in Parkinson’s.

However, the GDNF protein requires complex surgery to deliver the treatment to the brain because it’s a large molecule that cannot cross the blood-brain barrier – a protective barrier that prevents some drugs from getting into the brain.

BT13, a smaller molecule, is able to cross the blood-brain barrier – and therefore could be more easily administered as a treatment, if shown to be beneficial in further clinical trials.

Professor David Dexter, Deputy Director of Research at Parkinson’s UK, said:

“People with Parkinson’s desperately need a new treatment that can stop the condition in its tracks, instead of just masking the symptoms.

“One of the biggest challenges for Parkinson’s research is how to get drugs past the blood-brain barrier, so the exciting discovery of BT13 has opened up a new avenue for research to explore, and the molecule holds great promise as a way to slow or stop Parkinson’s.

“More research is needed to turn BT13 into a treatment to be tested in clinical trials, to see if it really could transform the lives of people living with Parkinson’s.”

Dr Yulia Sidorova, lead researcher on the study, said: “We are constantly working on improving the effectiveness of BT13. We are now testing a series of similar BT13 compounds, which were predicted by a computer program to have even better characteristics.

“Our ultimate goal is to progress these compounds to clinical trials in a few coming years.”

Molecule offers hope for halting Parkinson’s


Nourianz is the first adenosine A2A receptor antagonist approved for use in Parkinson Disease

By Brian Park

The Food and Drug Administration (FDA) has approved Nourianz (istradefylline; Kyowa Kirin) tablets as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson disease (PD) experiencing “off” episodes.

Nourianz is an oral selective adenosine A2A receptor antagonist and non-dopaminergic pharmacologic option. Adenosine A2A receptors are found in the basal ganglia of the brain where degeneration or abnormality is noted in PD; the basal ganglia are involved in motor control.

The approval was based on data from four 12-week, randomized, placebo-controlled clinical trials that evaluated the efficacy and safety of Nourianz in 1143 patients with PD taking a stable dose of levodopa/carbidopa with or without other PD medications.

Results from all 4 studies have demonstrated a statistically significant decrease from baseline in daily “off” time in patients treated with Nourianz compared with placebo. Regarding safety, the most common treatment-emergent adverse reactions were dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia.

“Istradefylline is an Adenosine A2A receptor antagonist, and is a novel non-dopaminergic pharmacologic approach to treating OFF episodes for people living with PD,” said Dr Stuart Isaacson, MD, Parkinson’s Disease and Movement Disorders Center of Boca Raton, Florida. “Based on data from four clinical studies, istradefylline taken as an adjunct to levodopa significantly improved OFF time and demonstrated a well-tolerated safety profile. Istradefylline represents an important new treatment option for patients with Parkinson’s disease who experience ‘OFF’ episodes.”

The FDA had accepted the resubmitted NDA for Nourianz in April 2019 after previously rejecting the submission in 2008 due to concerns over efficacy findings.

For more information visit kyowakirin.com.

FDA Approves New Adjunct Treatment for Parkinson Disease

by DAVID NIELD

Dosing medicines can be a tricky process: How much of a medication actually ends up hitting its target can vary a lot between patients, sometimes for mysterious reasons. As it turns out, even the things living in our bodies could be gobbling up our drugs.

In a series of experiments with levodopa (L-dopa) drug treatments for Parkinson’s, a new study has found that the gut microbes Enterococcus faecalis and Eggerthella lenta can intercept L-dopa and chemically transform it before it reaches the brain.

While this research only focuses on a specific treatment for one condition, the team behind the work thinks we might be underappreciating the role that our gut microbiome plays in controlling the efficacy and potency of medicines.

“Maybe the drug is not going to reach its target in the body, maybe it’s going to be toxic all of a sudden, maybe it’s going to be less helpful,” says chemical biologist Maini Rekdal from Harvard University.

The job of L-dopa is to deliver dopamine to the brain, replacing the dopamine eaten up by Parkinson’s. However, since the introduction of L-dopa in the 1960s, scientists have known that enzymes in the gut can stop this delivery from happening, leading to some nasty side effects as dopamine “spills out” before reaching the brain.

A second drug, carbidopa, was introduced to keep L-dopa intact, but it doesn’t always seem to help. Even with this additional drug, the effectiveness of L-dopa can vary between patients. What this new research does is identify the specific bacteria to blame, out of trillions of potential species.

With reference to the Human Microbiome Project, the team found that not only our own gut enzymes can wreak havoc on the medication, but the bacterium E. faecalis can also convert L-dopa to dopamine before it reaches the brain. Sure enough, it ate up all the L-dopa in lab tests.

Using faecal samples and supplies of dopamine, the researchers identified that another strain of gut bacteria, E. lenta, then consumes the converted dopamine and produces the neuromodulator meta-thyramine as a byproduct.

Thus, E. faecalis and E. lenta are apparently working as a sort of microbe tag team, preventing the medication from reaching its target. Furthermore, while carbidopa is used to stop a human gut enzyme from converting L-dopa to dopamine in the digestive system, it doesn’t seem to work on the E. faecalis enzyme that’s doing the same.

The good news is that the researchers have already found a molecule, alpha-fluoromethyltyrosine (AFMT), that can stop E. faecalis from breaking down L-dopa without destroying the bacterium itself, by targeting a non-essential enzyme.

Ultimately, we might end up with a way of making L-dopa significantly more effective as a Parkinson’s treatment, without as many of the side effects – but that’s still a long way off.

“All of this suggests that gut microbes may contribute to the dramatic variability that is observed in side effects and efficacy between different patients taking L-dopa,” says chemical biologist Emily Balskus from Harvard University.

Even if we can’t fix the problem just yet, we now have a proof of concept that particular combinations of gut microbes can indeed cause havoc with our meds. Hopefully, this will give other researchers food for thought and we might see similar investigations of other medicines, too.

The research has been published in Science.

https://www.sciencealert.com/gut-microbes-could-be-eating-up-our-meds-before-they-get-chance-to-work


The research has presented strong evidence that Parkinson’s disease begins in the gastrointestinal tract and spreads via the vagus nerve to the brain. Many patients have also suffered from gastrointestinal symptoms before the Parkinson’s diagnosis is made. The image is for illustrative purposes only.

A major epidemiological registry-based study from Aarhus University and Aarhus University Hospital indicates that Parkinson’s disease begins in the gastrointestinal tract; the study is the largest in the field so far.

The chronic neurodegenerative Parkinson’s disease affects an increasing number of people. However, scientists still do not know why some people develop Parkinson’s disease. Now researchers from Aarhus University and Aarhus University Hospital have taken an important step towards a better understanding of the disease.

New research indicates that Parkinson’s disease may begin in the gastrointestinal tract and spread through the vagus nerve to the brain.

“We have conducted a registry study of almost 15,000 patients who have had the vagus nerve in their stomach severed. Between approximately 1970-1995 this procedure was a very common method of ulcer treatment. If it really is correct that Parkinson’s starts in the gut and spreads through the vagus nerve, then these vagotomy patients should naturally be protected against developing Parkinson’s disease,” explains postdoc at Aarhus University Elisabeth Svensson on the hypothesis behind the study.

A hypothesis that turned out to be correct:

“Our study shows that patients who have had the the entire vagus nerve severed were protected against Parkinson’s disease. Their risk was halved after 20 years. However, patients who had only had a small part of the vagus nerve severed were not protected. This also fits the hypothesis that the disease process is strongly dependent on a fully or partially intact vagus nerve to be able to reach and affect the brain,” she says.

The research project has just been published in the internationally recognised journal Annals of Neurology.

The first clinical examination

The research has presented strong evidence that Parkinson’s disease begins in the gastrointestinal tract and spreads via the vagus nerve to the brain. Many patients have also suffered from gastrointestinal symptoms before the Parkinson’s diagnosis is made.

“Patients with Parkinson’s disease are often constipated many years before they receive the diagnosis, which may be an early marker of the link between neurologic and gastroenterologic pathology related to the vagus nerve ,” says Elisabeth Svensson.

Previous hypotheses about the relationship between Parkinson’s and the vagus nerve have led to animal studies and cell studies in the field. However, the current study is the first and largest epidemiological study in humans.

The research project is an important piece of the puzzle in terms of the causes of the disease. In the future the researchers expect to be able to use the new knowledge to identify risk factors for Parkinson’s disease and thus prevent the disease.

“Now that we have found an association between the vagus nerve and the development of Parkinson’s disease, it is important to carry out research into the factors that may trigger this neurological degeneration, so that we can prevent the development of the disease. To be able to do this will naturally be a major breakthrough,” says Elisabeth Svensson.

https://neurosciencenews.com/parkinsons-gastrointestinal-tract-neurology-2150/

181307_web-1

Whiile human genetic mutations are involved in a small number of Parkinson’s disease (PD) cases, the vast majority of cases are of unknown environmental causes, prompting enormous interest in identifying environmental risk factors involved. The link between Helicobacter pylori (H. pylori) and gastric ulcers has been known for several decades, but new evidence suggests that this harmful bacterium may play a role in PD as well. A new review in the Journal of Parkinson’s Disease summarizes the current literature regarding the link between H. pylori and PD and explores the possible mechanisms behind the association.

In a comprehensive review of prior studies, investigators uncovered four key findings:

People with PD are 1.5-3-fold more likely to be infected with H. pylori than people without PD.
H. pylori-infected PD patients display worse motor functions than H. pylori-negative PD patients.
Eradication of H. pylori improved motor function in PD patients over PD patients whose H. pylori was not eradicated.
Eradication of H. pylori improved levodopa absorption in PD patients compared to PD patients whose H. pylori was not eradicated.
“This is an in-depth and comprehensive review that summarizes all the major papers in the medical literature on Parkinson’s disease and H. pylori, the common stomach bacterium that causes gastritis, ulcers and stomach cancer,” explained lead investigator David J. McGee, PhD, Associate Professor, Department of Microbiology and Immunology, LSU Health Sciences Center-Shreveport, Shreveport, LA, USA. “Our conclusion is that there is a strong enough link between the H. pylori and Parkinson’s disease that additional studies are warranted to determine the possible causal relationship.”

Investigators also analyzed existing studies to try and find possible testable pathways between the bacterial infection and Parkinson’s to lay the groundwork for future research. They found four main possible explanations for the association:

Bacterial toxins produced by H. pylori may damage neurons.

The infection triggers a massive inflammatory response that causes damage to the brain.

H. pylori may disrupt the normal gut microbial flora.

The bacteria might interfere with the absorption properties of levodopa, the medication commonly used to treat the symptoms of Parkinson’s disease.

The onset of PD is often preceded by gastrointestinal dysfunction, suggesting that the condition might originate in the gut and spread to the brain along the brain-gut axis. In the review, investigators note that this has been documented in rats.

Screening PD patients for the presence of H. pylori and subsequent treatment if positive with anti-H. pylori triple drug therapy, may contribute to improved levodopa absorption and ultimately improvement of PD symptoms, potentially leading to a longer life span in patients with PD.

“Evidence for a strong association among H. pylori chronic infection, peptic ulceration and exacerbation of PD symptoms is accumulating,” concluded Dr. McGee.

“However, the hypotheses that H. pylori infection is a predisposing factor, disease progression modifier, or even a direct cause of PD remain largely unexplored. This gut pathology may be multifactorial, involving H. pylori, intestinal microflora, inflammation, misfolding of alpha-synuclein in the gut and brain, cholesterol and other metabolites, and potential neurotoxins from bacteria or dietary sources. Eradication of H. pylori or return of the gut microflora to the proper balance in PD patients may ameliorate gut symptoms, L-dopa malabsorption, and motor dysfunction.”

https://scienmag.com/eradicating-helicobacter-pylori-infections-may-be-a-key-treatment-for-parkinsons-disease/

SS39069

By Alan Mozes

People with attention-deficit/hyperactivity disorder (ADHD) may be more than twice as likely to develop an early onset form of Parkinson’s, new research warns.

What’s more, among “those ADHD patients who had a record of being treated with amphetamine-like drugs — especially Ritalin [methylphenidate] — the risk dramatically increased, to between eight- to nine-fold,” said senior study author Glen Hanson.

But his team did not prove that ADHD or its medications actually caused Parkinson’s risk to rise, and one ADHD expert noted that the absolute risk of developing Parkinson’s remains very small.

For the study, researchers analyzed nearly 200,000 Utah residents. All had been born between 1950 and 1992, with Parkinson’s onset tracked up until the age of 60.

Prior to any Parkinson’s diagnosis, roughly 32,000 had been diagnosed with ADHD.

Hanson, a professor of pharmacology and toxicology at the University of Utah, said that ADHD patients were found to be “2.4 times more likely to develop Parkinson’s disease-like disorders prior to the age of 50 to 60 years,” compared with those with no history of ADHD. That finding held up even after accounting for a number of influential factors, including smoking, drug and alcohol abuse, and other psychiatric disorders.

“Although we cannot accurately say how much time elapsed between ADHD and [a] Parkinson’s-like disorder diagnosis, it was probably between 20 to 50 years,” he said.

As to what might explain the link, Hanson said that both ADHD and most forms of Parkinson’s source back to a “functional disorder of central nervous system dopamine pathways.”

In addition, Hanson said that “the drugs used to treat ADHD apparently work because of their profound effects on the activity of these dopamine pathways.” Theoretically, the treatment itself might trigger a metabolic disturbance, promoting dopamine pathway degeneration and, ultimately, Parkinson’s, he explained.

Still, Hanson pointed out that, for now, “we are not able to determine if the increased risk associated with stimulant use is due to the presence of the drug or the severity of the ADHD,” given that those treated with ADHD drugs tend to have more severe forms of the disorder.

And while demonstrating “a very strong association” between ADHD and Parkinson’s risk, the findings are preliminary, the study authors added.

Also, the absolute risk of developing Parkinson’s remained low, even in the most pessimistic scenario.

For example, the findings suggest that the risk of developing early onset Parkinson’s before the age of 50 would be eight or nine people out of every 100,000 with ADHD. This compares with one or two out of every 100,000 among those with no history of ADHD, the researchers said.

But the scientists noted that the results should raise eyebrows, because Parkinson’s primarily strikes people over the age of 60. Given the age range of those tracked so far in the study, Hanson said that his team was not yet able to ascertain Parkinson’s risk among ADHD patients after the age of 60.

Hanson also pointed out that because ADHD was only first diagnosed in the 1960s, only about 1.5 percent of the people in the study had an ADHD diagnosis, despite current estimates that peg ADHD prevalence at 10 percent. That suggests that the current findings may underestimate the scope of the problem.

“Clearly, there are some critical questions left to be answered concerning what is the full impact of this increased risk,” Hanson said.

Dr. Andrew Adesman is chief of developmental and behavioral pediatrics at Cohen Children’s Medical Center of New York with Northwell Health in New York City. He was not involved with the study and said the findings “surprised” him.

But, “we need to keep in mind that this study needs to be replicated and that the incidence of these conditions was very low, even among those with ADHD,” Adesman said. “The reality is that this would not affect 99.99 percent of individuals with ADHD.”

Meanwhile, Adesman said, “given that this study needs to be replicated, given that it is unclear whether ADHD medications further increase the risks of Parkinson’s, and given the very low risk in an absolute sense, I believe individuals with ADHD should not be hesitant to pursue or continue medical treatment for their ADHD.”

The report was published online Sept. 12 in the journal Neuropsychopharmacology.

Glen Hanson, DDS, Ph.D., vice dean and professor, pharmacology, School of Dentistry, University of Utah, Salt Lake City; Andrew Adesman, M.D., chief, developmental and behavioral pediatrics, Steven & Alexandra Cohen Children’s Medical Center of New York, Northwell Health, New York City; Sept. 12, 2018, Neuropsychopharmacology, online

https://consumer.healthday.com/cognitive-health-information-26/parkinson-s-news-526/adhd-tied-to-raised-risk-of-early-parkinson-s-737637.html

Mit-Dopamine-Tracking_0

By Anne Trafton

Dopamine, a signaling molecule used throughout the brain, plays a major role in regulating our mood, as well as controlling movement. Many disorders, including Parkinson’s disease, depression, and schizophrenia, are linked to dopamine deficiencies.

MIT neuroscientists have now devised a way to measure dopamine in the brain for more than a year, which they believe will help them to learn much more about its role in both healthy and diseased brains.

“Despite all that is known about dopamine as a crucial signaling molecule in the brain, implicated in neurologic and neuropsychiatric conditions as well as our abilty to learn, it has been impossible to monitor changes in the online release of dopamine over time periods long enough to relate these to clinical conditions,” says Ann Graybiel, an MIT Institute Professor, a member of MIT’s McGovern Institute for Brain Research, and one of the senior authors of the study.

Michael Cima, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research, and Rober Langer, the David H. Koch Institute Professor and a member of the Koch Institute, are also senior authors of the study. MIT postdoc Helen Schwerdt is the lead author of the paper, which appears in the Sept. 12 issue of Communications Biology.

Long-term sensing

Dopamine is one of many neurotransmitters that neurons in the brain use to communicate with each other. Traditional systems for measuring dopamine — carbon electrodes with a shaft diameter of about 100 microns — can only be used reliably for about a day because they produce scar tissue that interferes with the electrodes’ ability to interact with dopamine.

In 2015, the MIT team demonstrated that tiny microfabricated sensors could be used to measure dopamine levels in a part of the brain called the striatum, which contains dopamine-producing cells that are critical for habit formation and reward-reinforced learning.

Because these probes are so small (about 10 microns in diameter), the researchers could implant up to 16 of them to measure dopamine levels in different parts of the striatum. In the new study, the researchers wanted to test whether they could use these sensors for long-term dopamine tracking.

“Our fundamental goal from the very beginning was to make the sensors work over a long period of time and produce accurate readings from day to day,” Schwerdt says. “This is necessary if you want to understand how these signals mediate specific diseases or conditions.”

To develop a sensor that can be accurate over long periods of time, the researchers had to make sure that it would not provoke an immune reaction, to avoid the scar tissue that interferes with the accuracy of the readings.

The MIT team found that their tiny sensors were nearly invisible to the immune system, even over extended periods of time. After the sensors were implanted, populations of microglia (immune cells that respond to short-term damage), and astrocytes, which respond over longer periods, were the same as those in brain tissue that did not have the probes inserted.

In this study, the researchers implanted three to five sensors per animal, about 5 millimeters deep, in the striatum. They took readings every few weeks, after stimulating dopamine release from the brainstem, which travels to the striatum. They found that the measurements remained consistent for up to 393 days.

“This is the first time that anyone’s shown that these sensors work for more than a few months. That gives us a lot of confidence that these kinds of sensors might be feasible for human use someday,” Schwerdt says.

Paul Glimcher, a professor of physiology and neuroscience at New York University, says the new sensors should enable more researchers to perform long-term studies of dopamine, which is essential for studying phenomena such as learning, which occurs over long time periods.

“This is a really solid engineering accomplishment that moves the field forward,” says Glimcher, who was not involved in the research. “This dramatically improves the technology in a way that makes it accessible to a lot of labs.”

Monitoring Parkinson’s

If developed for use in humans, these sensors could be useful for monitoring Parkinson’s patients who receive deep brain stimulation, the researchers say. This treatment involves implanting an electrode that delivers electrical impulses to a structure deep within the brain. Using a sensor to monitor dopamine levels could help doctors deliver the stimulation more selectively, only when it is needed.

The researchers are now looking into adapting the sensors to measure other neurotransmitters in the brain, and to measure electrical signals, which can also be disrupted in Parkinson’s and other diseases.

“Understanding those relationships between chemical and electrical activity will be really important to understanding all of the issues that you see in Parkinson’s,” Schwerdt says.

The research was funded by the National Institute of Biomedical Imaging and Bioengineering, the National Institute of Neurological Disorders and Stroke, the Army Research Office, the Saks Kavanaugh Foundation, the Nancy Lurie Marks Family Foundation, and Dr. Tenley Albright.

https://news.mit.edu/2018/brain-dopamine-tracking-sensors-0912