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NLX-112 Eases L-dopa Dyskinesia in Marmosets With Parkinson’s, Study Says

dyskinesia

An investigational therapy known as NLX-112 (befiradol) may hold promise to treat levodopa-induced dyskinesia, a complication of long-term levodopa therapy that affects people with Parkinson’s disease, a study found.

The study, “The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets,” was published in Neuropharmacology.

Motor symptoms of Parkinson’s disease include tremor; slow movement (bradykinesia); stiffness (rigidity); uncontrolled, involuntary movements that can affect the arms, legs, head, or the whole body (dyskinesia); and poor balance.

As the disease progresses, patients typically need to gradually increase treatment doses for maximum benefit. Even after that, symptoms sometimes reappear or worsen due to the dopaminergic therapy’s gradual loss of efficiency.

Dyskinesia is one of the complications of long-term levodopa therapy that affects many patients with advanced Parkinson’s disease. Currently, the main medication available to manage dyskinesia is amantadine. However, it can have side effects and may not be effective for every patient.

Studies indicate that Parkinson’s progression and symptoms may be associated with impaired signals from another important brain chemical, serotonin. Serotonin is involved in smooth muscle contraction, and serves as the “feel-good” chemical in the brain, influencing one’s sense of well-being and happiness.

Serotonin-producing neurons have an enzyme that is crucial to producing dopamine. This enzyme can be stored in vesicles and released as a “false neurotransmitter.” This results in excessive and inappropriate dopamine release, which generates dyskinesia.

NLX-112 (also known as befiradol or F13640) is an experimental medicine being developed by Neurolixis that activates a type of serotonin receptor called 5-HT1A. This investigational therapy has been shown to inhibit the “false neurotransmitter” release, thereby minimizing or even abolishing dyskinesia in rodent models of Parkinson’s disease.

In a study funded by Parkinson’s Virtual Biotech, the drug development arm of Parkinson’s UK, researchers tested NLX-112 in a marmoset model of levodopa-induced dyskinesia.

Animals were treated with 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that induces the death of dopamine-producing neurons and mimics Parkinson’s symptoms. Dyskinesia was then induced by chronic levodopa/benserazide combination therapy administered up to twice daily for up to a month.

NLX-112 treatment was administered alone or in combination with levodopa twice a week. Scientists also tested levodopa therapy combined with (+)8-OH-DPAT, another compound that activates the serotonin receptor 5-HT1A.

When administered together with levodopa at three different doses (0.025, 0.1 and 0.4 mg/kg ), NLX-112 reduced dyskinesia in a time and dose-dependent manner. The most prominent effects were at a dosage of 0,4 mg/kg.

In addition, NLX-112 was found to marginally interfere with the anti-parkinsonian effects of levodopa, unlike (+)8-OH-DPAT, which lessened levodopa-induced dyskinesia but also eliminated levodopa’s therapeutic efficacy.

When given alone (not combined with dopaminergic therapy), NLX-112 elicited anti-parkinsonian-like activity, easing disease-related motor disability in marmosets modeling Parkinson’s.

“Interestingly, the higher dose of NLX-112 (0.4 mg/kg) appeared less active than the lower doses, only reducing disability at a single, early time-point, suggesting an inverted dose-response relationship,” the researchers wrote.

Both NLX-112 and (+)8-OH-DPAT produced dose-dependent unusual behavior in marmosets, including sedation, scratching, wet-dog shakes, and sustained muscle contractions in the tail. These manifestations are all consistent with serotonin syndrome, a disorder that can occur when taking serotonin-boosting medications, and manifests itself with both behavioral and other general symptoms such as sweating and diarrhea.

Despite its effects, NLX-112 was not kept in animals’ blood circulation for long, which may limit its pharmacological effects in this particular species.

“This promising research on NLX-112 offers hope that we can find a treatment that can tackle dyskinesia, which can make everyday tasks, such as eating, writing, and walking, extremely difficult,” Arthur Roach, PhD, director of research at Parkinson’s UK, said in a press release.

“People with Parkinson’s tell us it is one of the most critical issues that impacts quality of life, so we’re delighted that this project is progressing so positively,” Roach said. “With 145,000 people living with Parkinson’s in the UK, we are desperately in need of a breakthrough treatment, and we’re committed to delivering one by 2024.”

“It is vital we continue to work with biotech companies like Neurolixis to drive forward new treatments that may slow, stop, or reverse Parkinson’s, and also those, like NLX-112, that could bring relief from symptoms or side effects,” said Roach.

“We are excited that NLX-112 has shown such positive results in reducing dyskinesia in marmosets,” said Adrian Newman-Tancredi, PhD, co-founder and CEO of Neurolixis. “If the striking preclinical data are reproduced in clinical trials, NLX-112 could significantly alleviate the troubling dyskinesia that prevent many Parkinson’s patients from performing routine daily tasks, thereby improving their quality of life.”

“We are currently making plans and seeking funding to take NLX-112 into clinical trials, and hope to be able to initiate these before the end of 2020,” Newman-Tancredi said.

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Parkinson’s Foundation Grants $250K for Parkinson’s UK Treatment Project

Parkinson’s Foundation

As part of a new partnership with Parkinson’s UK, the Parkinson’s Foundation has granted the nonprofit $250,000 toward a prospective new treatment linked to mitochondrial function that is being developed in the Parkinson’s Virtual Biotech program.

The grant will help advance a project aimed at uncovering new methods of potentially impeding brain cell death through stabilization of the source of energy necessary for cell survival — the mitochondria. It’s the first international funding for the Parkinson’s UK-led program and marks the beginning of a collaborative effort to move forward promising Parkinson’s (PD) treatment research.

“We are pleased to partner with Parkinson’s UK to further innovative research that will help the international PD community,” John Lehr, president and CEO of the Parkinson’s Foundation, said in a press release. “This collaboration will help us better serve people living with Parkinson’s today while furthering the promise of a cure tomorrow.”

Parkinson’s UK and its supporters and collaborators each year invest more than $5 million in Parkinson’s Virtual Biotech — the organization’s drug discovery and development arm — focusing on projects with the potential to transform patients’ lives. Fueled by project-specific partnerships with some of the world’s top research organizations, the program’s goal is to invest $29 million by the end of 2021.

“We are delighted to receive this investment from the Parkinson’s Foundation to support a growing portfolio of projects in our Virtual Biotech,” said Steve Ford, chief executive of Parkinson’s UK. “While we have made huge strides in our research efforts, we have long recognized that we can’t do it alone. The Parkinson’s Foundation shares this philosophy that we’re better together, and their investment marks a new chapter that will help ensure the Parkinson’s community receives the new treatments it needs.”

With its grant, the Parkinson’s Foundation is focusing on a £98,000 (about $126,000) year-long project with the University of Sheffield that began in August called “Novel Mitochondrial Rescue Compounds.”

Through compound modification, scientists will seek to discover and develop a potential therapy that could protect the dopamine-producing brain cells affected by Parkinson’s. The hope is that the most promising study compound ultimately will result in prospective brain cell-protecting treatments that could slow PD progression and enhance patients’ lives.

Parkinson’s is caused by the death or malfunction of dopaminergic neurons, which regulate muscle movement and coordination. To do their job, these nerve cells require large amounts of mitochondra-provided energy. Studies have widely suggested that mitochondrial dysfunction plays a central role in the development of PD.

To date, the Parkinson’s Virtual Biotech program has invested in seven drug discovery and development projects.

In addition to this collaboration, the two PD organizations also are working together on Parkinson’s Revolution, an indoor cycling fundraiser slated for Feb. 8 across the United States, the United Kingdom and Canada. The event is designed to highlight the benefits of exercise in PD while also raising funds for research and programs.

Since 1957, the Parkinson’s Foundation has invested more than $353 million in PD research and clinical care. Parkinson’s UK is Europe’s largest charitable funder of Parkinson’s research.

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Study Will Test Brain’s Natural ‘Plumbing System’ in Parkinson’s, Alzheimer’s Mice

Parkinson's

Parkinson’s UK and Alzheimer’s Research UK have teamed up to help fund a project that will test whether a “waste disposal system” in the brain could be exploited to help in the understanding and treatment of these diseases, Parkinson’s UK announced.

The new project, which is expected to take about three years to complete, will focus specifically on the glymphatic system. This system, which was  discovered only recently, helps to remove waste products from the brain.

The general idea behind the project is that, since both neurological diseases are associated with the abnormal and toxic buildup of “clumps” of protein in the brain (tau for Alzheimer’s and alpha-synuclein for Parkinson’s), activating the glymphatic system could help remove these clumps and, by extension, fight the disease.

“Studying how the glymphatic system affects the clearance of two distinct protein species that both accumulate in the brain and cause neurodegeneration means we’ll be able to understand how best to harness the power of the system. This will hopefully allow us to provide a new therapeutic target for treatment of the conditions,” Ian Harrison, PhD, said in a press release. Harrison, a professor at University College London, will lead the project.

The glymphatic system is a functional waste clearance pathway for the central nervous system (brain and spinal cord); it works as the brain’s unique method to remove waste. It consists of a “plumbing system” that takes advantage of the brain’s blood vessels and pumps cerebral spinal fluid through the brain’s tissue, flushing away waste.

This system is highly active during sleep, clearing away toxins responsible for Parkinson’s and other neurological disorders.

Using mouse models, Harrison and other researchers will track how tau and alpha-synuclein spread in the brain after the glymphatic system’s activity has been altered (either diminished or increased). It also will determine the effect this change has on mouse behaviors that are related to neurological diseases, such as memory and movement capabilities.

Previous research has suggested that sleep, exercise and low levels of alcohol could help activate the glymphatic system. The new project will build on these findings; researchers also will investigate potential new therapies to target this system.

“This is the first time we’ll be studying the glymphatic system’s role in clearing toxic proteins, and the potential it provides for developing new treatments which are urgently needed by people living with Parkinson’s,” said David Dexter, PhD, deputy director of research at Parkinson’s UK.

Sara Imarisio, PhD, the head of research at at Alzheimer’s Research UK, added: “The causes of Alzheimer’s disease are complex. While there are many differences between Parkinson’s and Alzheimer’s, common biology between both diseases means that research into one condition can provide important insights into the other. This new research could shed light on a disease process that holds potential as a target for future drugs, and that could change the course of Alzheimer’s and other neurodegenerative diseases.”

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Safety and Efficacy of Oral Cannabidiol in Treating Parkinson’s Psychosis Focus of Phase 2 Study in UK

cannabidiol

A planned Phase 2 clinical trial will assess the safety and effectiveness of pharmaceutical-grade cannabidiol (CBD) in treating Parkinson’s-related psychosis.

The trial was announced by Parkinson’s UK, which is investing £1.2 million (roughly $1.5 million) to support the study, due to begin enrolling patients in 2020.

Psychosis is estimated to affect more than half of people with Parkinson’s disease. It is characterized by hallucinations (seeing, hearing, or feeling things that are not really there) and delusions (fixed beliefs that are demonstrably untrue).

These symptoms are typically managed by reducing or stopping the use of medications used to treat Parkinson’s, but such choices have the obvious drawback of arresting any benefits those treatments provide. Antipsychotics are sometimes also used, but they can carry side effects or worsen motor symptoms.

Nuplazid (pimavanserin, by Acadia Pharmaceuticals) is the only medicine currently approved to treat Parkinson’s-related psychosis in the United States; no approved therapies for this condition are available in the United Kingdom.

“Current treatments prescribed by clinicians for psychosis typically work by blocking dopamine receptors, which can increase the problems people with Parkinson’s experience with movement and other symptoms of the condition,” Sagnik Bhattacharya, a professor at King’s College London who will help lead the trial, said in the press release.

This trial will “will determine, for the first time, whether CBD can correct the abnormal functioning of the brain that is causing symptoms such as hallucinations and delusions,” Bhattacharya added.

Cannabidiol is a non-psychoactive component of the cannabis plant, meaning it is found in cannabis, but unlike tetrahydrocannabinol or THC does not induce a feeling of being “high.” CBD is currently undergoing a renaissance of interest for its potential medical uses.

“We know from a recent survey we carried out, that people with Parkinson’s would continue to use, or start using, cannabis-derived products if robust evidence became available that they are safe and effective in treating Parkinson’s symptoms,” said Arthur Roach, PhD, the director of research at Parkinson’s UK. “One of the key questions this clinical trial will address is if CBD is safe to use for Parkinson’s-related psychosis, which has never been done before.”

The two-part study will begin with a six-week pilot phase to evaluate the safety, tolerability and effectiveness of CBD in people with Parkinson’s-related psychosis. Participants will be given daily oral CBD capsules at doses up to 1 gram per day to find the optimum dose. Then, 120 patients will be randomized to treatment with either CBD or a placebo for 12 weeks.

In addition to safety, trial goals (endpoints) will include a detailed assessment of psychotic, motor and non-motor symptoms, as well as brain imaging.

“We will be assessing how safe CBD is for people with Parkinson’s, what the correct dosage is and how it is tolerated alongside the different medications someone with the condition may already be on,” Bhattacharya said. “The study will also look at the effect of CBD on other symptoms which will pave the way for scientists to investigate the potential of the compound in treating these in future studies.

“We hope that this will progress to large-scale clinical trials — the final step towards becoming a new treatment that will improve the lives of people with Parkinson’s,” Bhattacharya added.

If successful, this study “could result in a regulated cannabinoid-based medicine being prescribed and used in the clinic, as opposed to self-administration of expensive supplements that have not been monitored for their composition or effects,” Roach said.

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Parkinson’s UK Awards Scientist £100,000 to ID Ways of Protecting Dopamine-producing Neurons

Parkinson's UK grant

A scientist at the University of Sheffield in England has been awarded a £100,000 grant by Parkinson’s UK to develop a treatment that might slow or stop the progression of Parkinson’s disease and protect brain cells.

The one-year grant, worth about $120,000, was given to Heather Mortiboys, a senior research fellow at the university’s Institute for Translational Neuroscience (SITraN), by Parkinson’s Virtual Biotech Programme, the British charity’s therapeutic development arm.

“All the clinical treatments for people living with Parkinson’s at the moment are based on easing these sometimes devastating symptoms,” Mortiboys said in a press release. “With this new funding award … we have the potential to go on to develop a drug treatment which will actively address the root cause of these symptoms to slow, or halt the progression of Parkinson’s for the first time.”

Mitochondria, power factories for cells that include dopamine-producing brain cells, don’t work as they should in people with Parkinson’s disease.  Resulting shortages in cellular energy cause neurons to fail and ultimately die, particularly dopamine neurons. Those nerve cells are responsible for movement and coordination, and rely on mitochondria to function.

In her previous work, Mortiboys developed a model of dopamine brain cells — using skin cells from patients — that allows researchers to test potential therapies. Her research team was able to grow high numbers of brain cells derived from these skin cells. They used them to identify compounds that support dopamine neurons and their mitochondrial function, and potentially lessen cell death.

With this award, Mortiboys and her team will try to pinpoint the molecules in these compounds that are of greatest benefit to mitochondria in producing the energy needed to support these brain cells. Working in collaboration with the National Institute of Health Research (NIHR) Sheffield Biomedical Research Centre, the scientists will then move the molecules into a drug discovery phase.

“There is an urgent need for treatments to protect the nerve cells that become damaged in patients with Parkinson’s disease, which will have a crucial impact in slowing the progression of the condition and improving the quality of life” said Pamela Shaw, director of SITraN and and the university’s new Neuroscience Institute.

Potential treatments identified through this process will be further developed through a partnership with the NIHR Biomedical Research Centre at the Royal Hallamshire Hospital, a Sheffield teaching hospital, Shaw said, adding “[w]e are hugely grateful to Parkinson’s UK for supporting this important translational research.”

“We are delighted to partner and work with Dr Heather Mortiboys and her team at the University of Sheffield. Through our Virtual Biotech initiative, we are committed to accelerating promising and breakthrough treatments for Parkinson’s,” said Richard Morphy, drug discovery manager at Parkinson’s UK.

“This is an exciting new approach that could rescue defective mitochondria inside neurons to prevent dysfunction and degeneration of dopamine-producing brain cells,” Morphy said.

Parkinson’s UK, which invests about $4.8 million a year in work that advances potential treatments, estimates that about 148,000 people in the U.K. have this neurodegenerative disease.

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Grant from MS Society, Parkinson’s UK to Establish Digital Brain Bank

digital brain bank

The Multiple Sclerosis (MS) and Parkinson’s Tissue Bank at Imperial College London, is the largest repository of brain and spinal cord tissue samples in Europe.

Now, the MS Society and Parkinson’s UK has announced a £3 million grant (about $3.6 million) to support its transition into a digital brain bank powered by a virtual reality platform, which will provide new tools for researchers around the world with the ultimate goal of stopping Parkinson’s and other neurological diseases.

These new technologies will be used to create high-definition pictures of brain tissue donated by people with Parkinson’s and multiple sclerosis (MS) after their death.

The Tissue Bank, established in 2009, originated from The UK Multiple Sclerosis Tissue Bank and the UK Parkinson’s Disease Society Tissue Bank, both located at the Imperial College in London. Over the years, this repository has collected samples from patients with MS and Parkinson’s disease, as well as healthy donors. Their collection has a large number of well-documented clinical cases that have been used in more than 700 research projects.

The funding from the two leading neurological charities will total £3 million (about $3.6 million) over a period of five years.

“The Parkinson’s UK Brain Bank has played a vital role in advancing our understanding of Parkinson’s so far. Through these new technological initiatives, we will be able to expand the reach and impact of the bank, and enable the best researchers from across the world to study the samples,” professor David Dexter, deputy director of research at Parkinson’s UK, said in a press release.

The new digital tissue bank will grant researchers access to tissue images, as well as the opportunity to explore the brain’s structures in a 3-D interactive section.

“This holds huge potential for speeding up access to better treatments and ultimately a cure for the 148,000 people with Parkinson’s in the UK. In addition to providing tissue to researchers worldwide, this project will now also give them access to an immense library of tissue images that can be studied indefinitely. Sharing and storing tissue samples in this way means each individual brain can be used more extensively, benefitting future projects as well as current ones,” Dexter said.

Moreover, virtual visits will allow potential donors to understand how the bank works and what happens to the donated tissues. In this way people are allowed to make a more informed decision about their donation.

Among other projects, this grant will fund genetic screenings so that researchers can understand how a patient’s genetics contributes for disease development.

David Burrows was a patient who died from Parkinson’s disease 10 years ago. He donated his brain to the bank.

His wife, Deborah Burrows, said “Right from the start, David said he wanted to donate his brain to research. I was pleased — this was typical of David as he always wanted to help others. He worked as a car mechanic, and would always (sometimes literally) go that extra mile for people.”

“I feel so proud of David for his decision — he is a real inspiration to me. One brain can provide around 250 samples that can be used in many different research projects. So, David is still helping people now by ensuring that research to find better treatments for people with Parkinson’s can continue,” she said.

Professor Richard Nicholas, the scientific director of MS Studies at the tissue bank said, “it’s a privilege to have the support of organizations like the MS Society and Parkinson’s UK, who do everything they can to ensure the work of the scientific community reflects the needs of people living with the neurological conditions (…) The charities recognize that if we’re going to revolutionize the way these conditions are treated — and find treatments for everyone — scientists need the right tools.”

“This investment will ensure all researchers have access to high quality brain and spinal cord tissue from people with MS and Parkinson’s, and marks an important development in the UK research landscape. We’re excited to see where it takes us,” Nicholas said.

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Parkinson’s UK Continues to Support Keapstone’s Quest to Develop Treatments for MND and Parkinson’s

With its recent award of £1 million (about $1.3 million USD), Parkinson’s UK continues to invest in Keapstone Therapeutics, bringing the biotechnology company closer to developing treatments for Parkinson’s and motor neuron disease (MND), it was announced.
Keapstone officials also hope the funding, which will go toward specific preclinical packages, will attract further investment. Its focus is developing a disease-altering therapeutic approach to the diseases.
With an initial investment of £1 million (about $1.3 million USD), Parkinson’s UK and the University of Sheffield established Keapstone last March to create treatments for Parkinson’s. In addition to funding, the university contributes its research. So far, Sheffield-based Keapstone has secured £2.4 million (about $3.1 million USD). 
“Keapstone was the very first company that we helped launch as part of the Parkinson’s Virtual Biotech program to accelerate promising research and bring forward better treatments or a cure for Parkinson’s,” said Arthur Roach, director of research at Parkinson’s UK.
“We are very pleased with the progress of Keapstone’s work so far, and we are hopeful that these molecules could be the key in creating treatments for Parkinson’s that could slow or even stop the progression of the condition.”
Keapstone aims to use proprietary chemistry and biology to deliver certain molecules that can penetrate the central nervous system and target disease-modifying mechanisms. These compounds inhibit a molecule known as KEAP1 and activate Nrf2 signaling, which can protect neurons from Parkinson’s and MND, also known as amyotrophic lateral sclerosis (ALS).
Parkinson’s affects approximately 145,000 people in the UK and nearly 7 million globally. Existing Parkinson’s treatments only help manage symptoms.
Parkinson’s Virtual Biotech, the drug discovery and development arm of Parkinson’s UK, aims to build a portfolio of studies worth £11 million (about $14.4 million USD) by 2020. So far, it has invested £1.2 million (almost $1.6 million USD) in research to create drugs that could alleviate symptoms and slow the advancement of Parkinson’s.
Parkinson’s UK is a nonprofit organization that promotes better care, treatments and quality of life for Parkinson’s patients. It has invested more than £85 million (about $111 million USD) in research. Currently, Parkinson’s UK is funding about 50 projects investigating everything from gut bacteria to stem cells.
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Source: Parkinson's News Today

Imaging Tracer with Potential to Bolster Clinical Trials of Parkinson’s and Its Treatments Favored by EMA

123I-FP-CIT SPECT tracer

The European Medicines Agency (EMA) endorsed an imaging test that can help in identifying Parkinson’ patients with early stage disease but likely to progress quickly — people who might be best suited to taking part in clinical trials.

Development of this clinical assessment tool — which targets disease biomarkers — came through collaborative work involving Critical Path for Parkinson’s (CPP) Consortium, a part of the Critical Path Institute (C-Path), the non-profit group Parkinson’s UK, and several pharmaceutical companies.

“This endorsement from the European Medicines Agency represents many years of hard work and incredible collaboration among companies, universities, and charities facilitated by the Critical Path Institute,” Diane Stephenson, executive director of CPP, who led the effort, said in a press release.

“Through our global project, we’ve been able to bring all the data and expertise together to make a powerful case, so we’re delighted that this endorsement from the EMA will improve the quality and chances of success for future trials of Parkinson’s treatments,” Stephenson added.

The method requires the intravenous injection of a radioactive tracer called 123I-ioflupane, or 123I-FP-CIT, which can be detected by single-photon emission computed tomography (SPECT) imaging. The tracer binds very specifically to dopamine transporter sites on the neurons that are lost to Parkinson’s disease, allowing scientists to detect alterations in dopamine transport — a hallmark event in the disease’s development.

Working as a kind of enrichment biomarker for early stages of Parkinson’s disease, the radioactive tracer helps to differentially diagnose between essential tremor and other parkinsonian disorders, such as progressive supranuclear palsy or multiple system atrophy, and Parkinson’s “subjects with high likelihood of progressing in clinical motor disability.”

The tracer has been available in the European Union since 2000 with the brand name DaTSCANTM, and in the United States since 2011 as DaTscan. In 2015, the U.S. Food and Drug Administration issued a letter of support for the use of this imaging biomarker as a “prognostic biomarker for enrichment in trials for Parkinson’s disease.”

“These brain scans in themselves are not new, but until now there has not been a clear consensus that they can and should be used to select participants for clinical trials,” Stephenson said.

“The use of these brain scans is already being included in new clinical trials at Biogen,” said Michael Ehlers, MD, PhD, executive vice president of research and development at Biogen. “We believe that this new approach will introduce greater efficiency in terms of cost and speed, while ensuring that the right patients are being included in our trials.”

Due to the progressive nature of Parkinson’s, the best approach to slow, stop, or reverse the disease would be by intervening as early as possible. But disease manifestations can be subtle in its early stages, complicating trial recruitment.

Previous reports suggest that up to 15 percent of patients taking part in trials of new Parkinson’s therapies may not be the best candidates to measure potential efficacy, because of scant change in their motor symptoms during the time-limited course of such studies. In its early stages, disease progression can be difficult to predict.

“Being able to rule out individuals who are unlikely to have Parkinson’s could be the difference between a successful trial and failure,” said David Dexter, PhD, a professor at Imperial College London and deputy research director of Parkinson’s UK. “This is a vital step forward in our mission to deliver, as quickly as possible, better treatments, and one day a cure, to people living with Parkinson’s.”

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Source: Parkinson's News Today