Parkinson's: New treatment approach shows promise in brain cells

 Ana Sandoiu        October 18, 2019

New research shows that an innovative strategy for treating Parkinson's disease has proven successful in neurons that derive from people living with the condition.

Parkinson's disease affects dopamine producing neurons, illustrated here.

Dr. Dimitri Krainc, chair of neurology and director of the Center for Neurogenetics at Northwestern University Feinberg School of Medicine in Chicago, IL, is the last and corresponding author of the study, which appears in the journal Science Translational Medicine.

Parkinson's disease is a neurodegenerative condition affecting more than 1 million people in the United States and 4 million adults or more across the world.

Although most Parkinson's cases occur in people without a family history of the disease, understanding the genetic risk factors is critical. This fact is true because, even in such "sporadic" cases, the inheritance pattern may still exist — although it may be unknown.

Furthermore, when genetic mutations do raise the risk of Parkinson's, "the inheritance pattern is usually unknown," according to the National Institutes of Health (NIH).

Alterations in the GBA1 gene, in particular, are "important risk factors" for the development of Parkinson's disease. The GBA1 gene encodes the so-called lysosomal enzyme glucocerebrosidase (GCase), an enzyme that is key for normal neuronal function.

As the authors of the new study explain in their paper, previous research has suggested that targeting GCase could have therapeutic benefits.

However, while past research and experimental treatments have suggested fixing the mutated enzymes, the new study suggests an alternative approach: activating and enhancing healthy, nonmutated ones.

Activating wild type GCase may work

Krainc and colleagues write that GBA1 mutations "represent the most common risk factor for Parkinson's disease."

Mutations in this gene can produce defects in GCase enzymes, which then contribute to the toxic buildup of protein in the dopamine producing neurons that Parkinson's typically affects.

Dr. Krainc explains that most drug development for Parkinson's has so far relied on stabilizing the mutated gene, but such treatments would only work in a limited number of Parkinson's cases.

"Instead, activating wild type [i.e., not mutated] GCase may be more relevant for multiple forms of PD that exhibit reduced activity of wild type GCase," Dr. Krainc explains.

In the paper, the researchers show that they developed and used a new range of chemical compounds that activated and amplified normal, wild type GCase.

Experiments revealed that doing so improved cellular function in neurons collected from people with Parkinson's.

The authors conclude, "Our findings point to activation of wild type GCase by small molecule modulators as a potential therapeutic approach for treating familial and sporadic forms of [Parkinson's disease] that exhibit decreased GCase activity."

The corresponding researcher also says that the chemical modulators, or activators, alleviated cellular dysfunction that various types of Parkinson's induced, suggesting that the approach could work in people with different versions of the condition.

"This study highlights wild type GCase activation as a potential therapeutic target for multiple forms of Parkinson's disease," says Dr. Krainc.

"Our work points to the potential for modulating wild type GCase activity and protein levels in both genetic and idiopathic forms of [Parkinsons's disease] and highlights the importance of personalized or precision neurology in development of novel therapies."

Dr. Dimitri Krainc

More research is necessary, and Dr. Krainc emphasizes the need to use human neurons when trying to develop new drugs for Parkinson's, as some features of the disorder only manifest in human neurons and not in rodent models.

https://www.medicalnewstoday.com/articles/326719.php

Neuroscientists to introduce new approach to assess brain damage in Parkinson's patients

October 18, 2019

TSU neuroscientists and their colleagues from SibSMU plan to introduce a new approach to studying brain damage in patients with Parkinson's disease. They will analyze the condition of myelin - the main substance of the membranes of nerve fibers, on which the proper transmission of signals between neurons depends. A unique non-invasive method developed under the supervision of Vasily Yarnykh, scientific coordinator of the Laboratory of Neurobiology, Professor at TSU and the University of Washington, will help neuroscientists assess the degree of damage to the nerve membranes.

The essence of the method is the special mathematical processing of MRT (magnetic resonance tomography) data, which helps to build myelin maps and quantify them, - explains Marina Khodanovich, head of the Laboratory of Neurobiology of the TSU Research Institute of Biology and Biophysics. - This method opens up new possibilities in obtaining additional diagnostic information about patients with some serious diseases in which the main destructive process is demyelination (destruction of the myelin sheath of neurons).

In 2019, for the first time in world clinical practice, TSU neuroscientists used a new tool to assess the severity of pathological changes in the membranes of nerve fibers in people with Parkinson's disease.

In the next stage, neuroscientists will process MRT images and receive MPF (maturation promoting factor) maps of myelin in the brain, which helps to estimate the amount of myelin and the condition of the nerve membranes in patients with Parkinson's.

The researchers expect to receive additional information that is important for clarifying the diagnosis, choosing treatment tactics, and understanding the pathological processes that lead to a complete loss of human capacity.

"It is important to understand how recovery occurs, in particular, to study the migration of young nerve cells replacing dead neurons."

Marina Khodanovich, TSU Research Institute of Biology and Biophysics

In most patients, recovery is extremely slow. It is necessary to distinguish between zones in which there is a positive dynamic, from those where it is absent. Perhaps the new data on neurogenesis will help create approaches that accelerate the rehabilitation of people who have suffered a vascular catastrophe.

The effectiveness of the new approach has been proved by the results of several projects implemented with the support of the Russian Science Foundation. In particular, scientists conducted a study of the reliability of the method on a model of stroke in rats. Neuroscientists analyzed the change in myelin dynamics (every other day, on the third and tenth days), and received data on how neuron death, growth of inflammation, and destruction of myelin occur. The results of postmortem histological studies confirmed the scientists’ conclusions.

Source:

Tomsk State University

https://www.news-medical.net/news/20191018/Neuroscientists-to-introduce-new-approach-to-assess-brain-damage-in-Parkinsons-patients.aspx

Making Meaning of It All

OCTOBER 18, 2019 Dr. C

Wellness map in hand, I pass through the fog of conflict that is my life and agree to enter sanctuary. I surrender myself to experiences of bliss and well-being.

Caressed by calmness, the fog has lifted. Like a crisp fall day, the colors are vibrant and the view breathtaking. In the distance is something not seen before. This is the destination toward which I must strive. It beckons to me, constantly whispering in my ear, “Come to me and discover what you need.”

It’s all making sense.

Our brains are wired to make connections. Not just neural ones, but associative ones. When we have a new experience, we associate it with memories of similar events. The further the new experience is from the known, the more difficult the association.

An experience that supports our well-being can be so different from any in our history that an association is difficult. It is so difficult that we procrastinate. “I can’t make sense of this, so I’m not going to do anything about it until I can.” It’s a cautious approach I’ve taken many times in my life. Eventually, I get splinters from sitting on the fence too long.

Greek philosopher Epicurus believed that happiness comprises friendship, freedom from everyday life and politics, and time and space to think things through. Epicurus would not advise spending money as temporary relief for a bad day. He would suggest taking time to reflect and contemplate.

Socrates had a different stance, as evidenced by his dictum: “The unexamined life is not worth living.” Socrates believed you should review and examine every aspect of your life to get the best out of it. A life bereft of meaning and purpose lacks action guided by that purpose. Meaning and purpose are part of a healthy self-concept.

Making sense of a well-being moment can be challenging. They are often scarce, and we have little experience with them. But well-being moments always come with useful information. Without that, they are just “feel-good” moments.

Taking that information and turning it into wisdom for a lifetime requires wrestling with it, using it, and integrating it into life — use it or lose it. It helps to have an experienced guide. Teachers of mystic traditions suggest mentoring in a sanctuary as one way to assist in the meaning-making process.

How we make sense of everything is vital to our movement forward, against the challenges, the setbacks, and the frailty that we encounter. Making sense of it gives us meaning and purpose throughout our journey with Parkinson’s disease, and the rest of our lives.

***

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.

https://parkinsonsnewstoday.com/2019/10/18/well-being-moments-journey/

Stool Calprotectin May Be Used as Marker of Bowel Inflammation in Parkinson’s Patients, Study Finds

OCTOBER 18, 2019 BY JOANA CARVALHO, MSC

The levels of calprotectin — a protein whose levels increase in response to tissue inflammation — in the stool may be used as a marker of bowel inflammation in patients with Parkinson’s disease, according to a recent study.

The results, “Fecal Calprotectin as a Marker of the Gut Immune System Activation Is Elevated in Parkinson’s Disease,” were published in Frontiers in Neuroscience.

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

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

It also is thought that lesions in the ENS may be linked to bowel inflammation, dysmotility(impairment of GI tract muscles) and high intestinal permeability, all of which contribute to gastrointestinal symptoms of Parkinson’s disease, such as constipation.

In this study, researchers from Wrocław Medical University in Poland set out to explore the usefulness of calprotectin and zonulin — two proteins whose levels tend to increase in the presence of inflammation and immune system dysfunction — as markers of bowel inflammation and impaired intestinal permeability in patients with Parkinson’s disease.

To that end, they gathered stool samples from 35 patients with Parkinson’s disease who were either hospitalized or routinely followed at the Department of Neurology at Wrocław Medical University, and 20 healthy individuals (controls).

The levels of calprotectin and zonulin in the stool were measured by Enzyme-Linked Immunosorbent Assay (ELISA), a technique that allows researchers to measure the amount of a specific protein of interest using an enzymatic reaction. All study participants were asked to complete a short questionnaire regarding their GI symptoms.

Results showed the median levels of calprotectin found in the stools of patients with Parkinson’s disease were much higher compared to those found in the stools of healthy individuals (54.5 μg/g versus 9.7 μg/g), indicating the presence of bowel inflammation.

“Additionally, we evaluated the percentage of subjects with abnormal results considering the following age-dependent upper cut-off values of normal fecal calprotectin: 51 μg/g for subjects below 60 years of age, and 112 μg/g for subjects above 60 years. Abnormal fecal calprotectin level was found in 43% of all PD patients and in none of the control subjects,” the researchers stated.

Additionally, abnormal calprotectin levels were found more often among patients younger than 60 (50%) than among those who were older than 60 (39%).

No correlations were found between the levels of calprotectin found in the stool of patients and disease duration. Unlike calprotectin, no significant differences were found in the levels of zonulin between the two groups.

The most frequent GI symptoms patients reported in questionnaires included constipation (69%), feeling of incomplete evacuation (51%), bloating (51%), abdominal pain (20%), and changes in bowel movements (17%).

“The results of the present study confirm that [Parkinson’s disease] is characterized by the gut immune system activation,” the researchers said.

“The evaluation of fecal calprotectin level may be a useful tool to detect the signs of gut immune system activation present in a remarkable number of [Parkinson’s disease] patients, also in the early stage of the disease. Calprotectin may constitute a critical link between amyloid formation and neuroinflammatory cascades serving as a prospective diagnostic and therapeutic target,” they added.

https://parkinsonsnewstoday.com/2019/10/18/stool-calprotectin-may-be-a-marker-of-bowel-inflammation-in-parkinsons/

Parkinson’s Foundation Opens Campaign to Support Newly Diagnosed

 OCTOBER 18, 2019 BY MARY CHAPMAN IN NEWS.

To provide new patients with the information, tools and resources they need to best manage their health, the Parkinson’s Foundation has launched a campaign to close the gap between learning of an illness and knowing how and where to find help.

Called “Newly Diagnosed: Building a Better Life with Parkinson’s Disease,” the effort is said to be the first such national campaign designed to reach the 60,000 people in the U.S. estimated to be diagnosed with Parkinson’s (PD) every year.

“In an effort to help provide better outcomes from the beginning of their journey, the Parkinson’s Foundation is whole-heartedly committed to connecting sooner with those facing a life-changing diagnosis,” John L. Lehr, the foundation’s president and CEO, said in a news release. “Our goal is to empower everyone new to our community to build a better life with Parkinson’s from day one while addressing their unmet needs.”

The organization surveyed more than 1,100 PD patients in January to better understand the needs and priorities of the newly diagnosed. Results showed that 42 percent of patients and 45 percent of their care partners had received no educational materials about Parkinson’s within six months of diagnosis.

Those findings led to the campaign, which seeks to not only connect with new patients early, but to provide ongoing support. The effort will include a free Newly Diagnosed Kit that may be ordered or downloaded:(https://www.parkinson.org/newlydiagnosed) programs focused on care and research, funding for community grants that help the newly diagnosed, relevant podcasts, and an online community to be launched later this year aimed at establishing peer-to-peer connections.

“Early in my diagnosis with Young Onset Parkinson’s, I realized that I couldn’t find all of the answers I was looking for,” said Christina Korines, who was diagnosed at 33. “I needed a partner to help me navigate my diagnosis, and the Parkinson’s Foundation is the go-to partner for anyone diagnosed with Parkinson’s, especially the newly diagnosed.”

The organization now offers has a video and other information: (https://www.parkinson.org/newlydiagnosed#) for new patients, including Five Steps to Living Well. More information is also available by calling the Parkinson’s Foundation Helpline at 800-4PD-INFO.

Parkinson’s disease affects nearly 1 million U.S. residents and nearly 10 million people globally. After Alzheimer’s, it’s the second most common neurodegenerative disorder in the U.S.

https://parkinsonsnewstoday.com/2019/10/18/parkinsons-foundation-campaign-supports-newly-diagnosed/

Can We Repair the Brain in Parkinson's Disease?

October 17, 2019

Who's speaking at this Webinar?

Roger Barker

Professor of Clinical Neuroscience/Honorary Consultant Neurologist, University of Cambridge

 

Parkinson's Disease (PD) is a common neurodegenerative disorder of the brain that is characterised pathologically by the loss of nigral dopaminergic neurons. Whilst motor features of the disease respond well to current dopaminergic treatments, side effects such as dyskinesia and neuropsychiatric problems are common over time. These problems could, in theory, be avoided through targeted delivery of dopamine to the dorsal striatum as is possible with neuronal replacement approaches or growth factor (GDNF) delivery.

These strategies have been tried over the last 20-30 years and shown long-term clinical benefit in some patients. But efficacy is inconsistent, and these new therapies often have their own side effects.

In this webinar, the University of Cambridge’s Professor Roger Barker will discuss the history, current status and potential of growth factor- and cell-based therapies for PD. 

Attend this webinar to hear:

• The latest advances in cell-based treatments for PD
• The potential of stem cell therapies for brain repair

To register:     https://go.technologynetworks.com/repair-the-brain-parkinsons-disease

https://www.technologynetworks.com/neuroscience/webinars/can-we-repair-the-brain-in-parkinsons-disease-325873

Despite Damning Scientific Evidence, EPA Dismisses Link Between Parkinson’s and Exposure to the Herbicide Paraquat

Beyond Pesticides, October 17, 2019

 The U.S. Environmental Protection Agency (EPA) is downplaying the connection between exposure to the herbicide paraquat and the development of Parkinson’s disease, per registration review documents released by the agency this week. Although unsurprising given the current administration’s track record of defending some of the most heinous chemicals still on the market, the review nonetheless marks a low point for scientific integrity within EPA’s Office of Pesticide Programs, according to advocates. Health and environmental advocates have already discounted EPA’s industry-biased review, and are instead pushing hard for Congressional action – namely HR 3817, the Protect Against Paraquat Act, introduced by Congresswoman Nydia Velazquez (D-NY).

Under federal law, pesticides are required to undergo reevaluation every 15 years. Paraquat is a potent restricted use herbicide, not available to be applied by residential users, but permitted for use on multiple agriculture crops. Over the last decade, independent peer-reviewed scientific studies have repeatedly found strong associations between paraquat to the development of Parkinson’s disease. Many of these studies have been covered in Beyond Pesticides’ Daily News or are recorded in the Pesticide-Induced Diseases Database.

In response to this growing body of literature, EPA conducted an epidemiological evaluation of published studies on the link between paraquat and Parkinson’s. But, in a similar manner to how the agency conducted its epidemiological evaluation of pyrethroids, EPA made broad statements dismissing scientific evidence as insufficient.

While the chemical has been banned in the European Union since 2007, as a 2016 New York Times exposé found, millions of pounds are still being imported into the U.S. from other countries, sprayed on nearly 15 million acres of U.S. cropland. The Chinese government began a phase-out of the chemical in 2013, and Brazil is set to eliminate this chemical.

“America stands alone in functioning as a dumping ground for paraquat, a toxic herbicide other countries may produce, but refuse to expose their residents to,” said Drew Toher, community resource and policy director for Beyond Pesticides.

On the link between paraquat and Parkinson’s, “The data is overwhelming” said Samuel M. Goldman, MD, an epidemiologist in the San Francisco Veterans Affairs health system to the New York Times. “I’m not a farmer, I don’t need to kill weeds, but I have to believe there are less dangerous options out there.”

An EPA environmental review conducted as part of the reregistration process found evidence of significant reproductive harm to small mammals, and determined that songbirds may be exposed to levels well beyond lethal concentrations known to cause death. Threats to mammals and songbirds are particularly concerning in light of significant declines in these animal groups.

As EPA continues to damage public trust in its scientific review process, it is up to everyday citizens and residents of the US to correct course and push for health protective laws. Beyond Pesticides and other organizations stand ready to assist farming communities in transforming pest management by eliminating a reliance on toxic pesticides like paraquat and adopting organic practices.

Act to get paraquat out of America’s food system by encouraging your Congressional representative to cosponsor the Protect Against Paraquat Act.

The legislation is supported by the Unified Parkinson’s Advocacy Council – a group led by The Michael J. Fox Foundation for Parkinson’s Research – and supported by other health and environmental groups. 

https://beyondpesticides.org/dailynewsblog/2019/10/despite-damning-scientific-evidence-epa-dismisses-link-between-parkinsons-and-exposure-to-the-herbicide-paraquat/

New strategy to treat Parkinson's disease

OCTOBER 17, 2019      by Northwestern University

Immunohistochemistry for alpha-synuclein showing positive staining (brown) of an intraneural Lewy-body in the Substantia nigra in Parkinson's disease. Credit: Wikipedia

Northwestern Medicine scientists have used patient-derived neurons to develop and test a new strategy to treat Parkinson's disease by mitigating the effects of harmful genetic mutations, as detailed in a study published today (Oct. 16) in Science Translational Medicine.

Some experimental treatments for genetic disorders target mutated proteins or enzymes, but this study, led by Dr. Dimitri Krainc, took a different approach. Instead of trying to fix broken enzymes, the scientists amplified healthy ones, an approach that successfully alleviated symptoms of Parkinson's disease (PD) in human brain cells and in mouse models.

"This study highlights wild-type GCase activation as a potential therapeutic target for multiple forms of Parkinson's disease," said Krainc, who is chair of neurology and director of the Center for Neurogenetics at Northwestern University Feinberg School of Medicine

Parkinson's is the second-most common neurodegenerative disorder, predominately affecting neurons in an area of the brain called the substantia nigra. These neurons are responsible for producing dopamine—a chemical messenger used to transmit signals throughout the brain—and for relaying messages that plan and control body movement.

Mutations in the gene GBA1 represent the most common genetic risk factor for PD, according to the study, and GBA1 codes for an enzyme called glucocerebrosidase (GCase) that is important for neuronal function. PD-associated mutations can disable GBA1 and produce misshapen GCase enzymes, which contribute to an accumulation of toxic proteins in dopamine-producing neurons.

As this neuronal population dies, patients experience symptoms such as tremors and slowness of movement. While some medications can offer relief for these symptoms, there is no treatment that can stop or slow the disease.

According to Krainc, drug development for patients with GBA1-linked Parkinson's has largely focused on stabilizing mutated GCase and limiting its harmful effects. However, these treatments would be effective only in a few types of PD.

"Instead, activating wild-type GCase may be more relevant for multiple forms of PD that exhibit reduced activity of wild-type GCase," Krainc said.

In the current study, scientists developed a new series of chemical activators that stabilized and amplified normal GCase. The activator, a small molecule that binds to GCase, improved PD-related cellular dysfunction in patient derived neurons.

Importantly, these activators worked in several varieties of PD, showing this strategy could work for a wide range of patients, Krainc said.

"Our work points to the potential for modulating wild-type GCase activity and protein levels in both genetic and idiopathic forms of PD and highlights the importance of personalized or precision neurology in development of novel therapies," he said.

A 2017 study led by Krainc and published in Science found that some of the key pathological features of PD were only seen in human neurons and not in mouse models, further emphasizing the value of patient-derived neurons for drug development in Parkinson's disease.

"It will be important to examine human neurons to test any candidate therapeutic interventions that target midbrain dopaminergic neurons in PD," Krainc said.

More information: Lena F. Burbulla et al. A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson's disease, Science Translational Medicine (2019). DOI: 10.1126/scitranslmed.aau6870

Journal information: Science Translational Medicine 

https://medicalxpress.com/news/2019-10-strategy-parkinson-disease.html

Nourianz Now Available in US as Add-on to Carbidopa/Levodopa to Treat Parkinson’s Off Periods

OCTOBER 17, 2019   BY PATRICIA INACIO, PHD 

Kyowa Kirin’s Nourianz (istradefylline) tablets are now available in the United States as an add-on treatment for off periods in Parkinson’s disease patients on a carbidopa/levodopa regimen.

Off periods — when the effects of a medication wear off before a new dose can be taken — are characterized by the re-emergence of Parkinson’s motor symptoms and are typically more common as the disease progresses. Within five years of starting levodopa/carbidopa therapy, approximately 50% of patients may experience off periods.

“We are pleased to offer patients Nourianz, the first and only FDA-approved adenosine A2Areceptor antagonist treatment for ‘off’ time associated with [Parkinson’s],” Tom Stratford, president of Kyowa Kirin USA Holdings, said in a press release. “Nourianz administered with levodopa/carbidopa therapy can help reduce ‘off’ time and increase ‘on’ time without troublesome dyskinesia.”

Nourianz blocks a receptor, known as the adenosine A2A receptor, found at high levels in the basal ganglia, a region of the brain that controls movement. By blocking this receptor, Nourianz can alter the release of neurotransmitters — chemical substances produced in response to nerve signals that allow nerve cells to communicate — in the basal ganglia, regulating motor activity.

The U.S Food and Drug Administration (FDA) approved Nourianz in August based on the results of four randomized, placebo-controlled Phase 2 and 3 clinical trials (NCT00955526, NCT00455507, NCT01968031, and NCT00250393).

The trials assessed the safety and efficacy of two doses (20 mg and 40 mg) of Nourianz to reduce the mean total hours of awake time per day spent in the off state and also lessen motor symptoms.

A total of 1,143 Parkinson’s patients taking levodopa/carbidopa, levodopa/benserazide, or levodopa and any other dopa-decarboxylase inhibitor were recruited. Treatment with Nourianz significantly decreased daily off time, compared with patients on a placebo, and improved motor function.

The most common side effects of Nourianz included involuntary muscle movement (dyskinesia), dizziness, constipation, nausea, hallucinations, and insomnia.

“In my clinical practice, I see patients who experience the troublesome effects of Parkinson’s disease and ‘off’ episodes that interfere with activities of daily living,” said Peter A. LeWitt, MD, a professor of neurology at Wayne State University School of Medicine and director of the Parkinson’s Disease and Movement Disorders Program, Henry Ford Hospital.

“Nourianz represents an important milestone and provides U.S. patients and their caregivers with a nondopaminergic, once-a-day oral treatment option to significantly decrease the amount of ‘off’ time,” LeWitt added.

Nourianz has been marketed in Japan under the brand name Nouriast since May 2013.

https://parkinsonsnewstoday.com/2019/10/17/nourianz-now-available-us-add-on-parkinsons-off-periods/