FoxFeed Blog: Parkinson's Doctors in Training Leading New Research Frontiers

Posted by  Rachel Dolhun, MD, May 13, 2019

The Edmond J. Safra Fellowship in Movement Disorders, a collaboration between The Michael J. Fox Foundation and longtime partner the Edmond J. Safra Foundation, trains neurologists to care for people with Parkinson's and other movement disorders as well as to lead studies into these conditions. Over two years and under the guidance of experienced clinicians and researchers at top-tier medical centers across the world, fellows develop skills in both treating patients and leading research projects. By working as physicians and researchers at the same time, these specialists are able to ask -- and answer -- questions that are critical to better understanding and treatment of their patients' diseases.

Members of the Class of 2019, who are nearing graduation, recently shared learnings from studies they've led during their training on an MJFF-hosted webinar.

Katherine Amodeo, MD; University of Rochester; Rochester, New York

Dr. Amodeo researches memory and thinking (cognitive) changes in Parkinson's disease, dementia with Lewy bodies and related dementias. She has led two small case studies, which suggest that treatment approaches and medication effects vary among people who have dementia with Lewy bodies, and that low blood pressure (orthostatic hypotension) may affect cognition in people with Lewy body dementia. Katie will continue deeper research on these topics in the near future. 

Sarah Horn, MD; University of Pennsylvania; Philadelphia

Dr. Horn studies psychosis -- hallucinations (seeing things that aren't there) and delusions (believing things that aren't true) -- in Parkinson's disease and dementia with Lewy bodies. She conducted a medical chart review to evaluate the effectiveness of Nuplazid (pimavanserin) versus Seroquel (quetiapine) on treating psychosis. Her results suggest that Nuplazid may more promptly control symptoms with fewer bothersome side effects. Larger, controlled trials are necessary to confirm results and guide care.

Katherine Leaver, MD; Icahn School of Medicine at Mount Sinai; New York, New York

Dr. Leaver is interested in genetics and Parkinson's. She wanted more data to guide her Parkinson's patients who have a LRRK2 genetic mutation and are candidates for deep brain stimulation (DBS). She compared the medical records of patients with a LRRK2 mutation who had DBS with records from those who did not undergo surgery. She also looked at records from people with Parkinson's but without a LRRK2 mutation who had DBS. In her study, people with LRRK2 mutations who had DBS were more likely to have a longer course of disease and to be referred to surgery for dyskinesia. Leaver continues to collect genetic data to learn more about disease and inform treatment decisions.

Natalie Witek, MD; Rush University; Chicago, Illinois

Natalie focuses on ataxia (impaired coordination of walking, speech or other processes). She looked at whether it's better to admit patients to the hospital or work them up as outpatients to optimally evaluate this symptom. Through a chart review, she noted those who were admitted to the hospital received a faster diagnosis and treatment. Natalie plans to continue research and care for people with ataxia.

Irene Hegeman Richard, MD, a movement disorder specialist who researches Parkinson's mood changes and serves as Amodeo's fellowship mentor at the University of Rochester in New York, offered the presenters and their peers practical advice on early career development.

Listen to the webinar :https://www.michaeljfox.org/files/Spring_Webinar_April_2019_The_Edmond_J._Safra_Fellowship_in_Movement_Disorders.mp4

https://www.michaeljfox.org/foundation/news-detail.php?parkinson-doctors-in-training-leading-new-research-frontiers

Levodopa-Sparing Medications May Help Patients in Early Stages of Parkinson’s, Study Suggests

MAY 13, 2019   BY ANA PENA IN NEWS.

Neurologists treating patients with early-stage Parkinson’s disease should prescribe more often therapies that spare patients from starting levodopa too soon in order to delay onset of side effects associated with long-term use of the medicine, findings from a study conducted in Romania suggest.

Researchers believe that even if a doctor believes a patient’s clinical situation required management with levodopa, they should first try to combine it with other antiparkinsonian therapies — such as other dopamine agonists or monoamine oxidase B inhibitors — in order to allow lower levodopa doses.

These findings resulted from a study, “Therapeutic strategies in the early stages of Parkinson’s disease: a cross-sectional evaluation of 15 years’ experience with a large cohort of Romanian patients,” which was published in the journal Neuropsychiatric Disease and Treatment.

Currently, the most effective and cost-saving therapy for lessening Parkinson’s symptomsis substitution therapy with levodopa. However, a major drawback of this therapy is the side effects associated with its long-term use.

After four to six years of treatment with levodopa, many patients may start experiencing spontaneous involuntary movements (dyskinesia), with some patients also having impulsive and compulsive behaviors. Its effectiveness can also reduce over time, causing patients to experience wearing-off effects, meaning that the therapy loses its ability to effectively manage Parkinson’s symptoms before it is time for the next dose.

Some clinical evidence seems to indicate that in many cases “if the therapy is started too early and with high doses, these complications may appear earlier and can be more severe, especially in younger patients,” the researchers wrote. This leads clinicians to try to avoid these side effects and adverse reactions by limiting levodopa doses as much as possible.

Based on clinical efficacy data from newer antiparkinsonian therapies in younger patients (under 60 years), European guidelines propose the use of levodopa-sparing medications as a first option for early-stage patients to delay the onset of motor and non-motor complications. But there is little real-world data to confirm how these therapeutic recommendations are being applied in clinical practice.

Therefore, the researchers reviewed the medical records of patients with early-stage Parkinson’s hospitalized between 2003 and 2017 at Târgu Mures Emergency County Hospital, in Romania, to gather real-world data on the use of levodopa and alternative therapies.

During this 15-year period, a total of 2,379 patients with Parkinson’s were hospitalized, of whom 1,237 had received the diagnosis for five years or less. The researchers justified this time window because most practicing neurologists consider that the efficacy of levodopa-sparing treatment strategies is significantly reduced after a five-year period. Only patients with early-stage disease were included in the study.

In this group, 18 patients (1.5%) were receiving monoamine oxidase-B inhibitors (MAO-Bi). A total of 665 patients were taking dopamine agonists, of whom 120 were taking the therapy alone (9.7%) and  83 patients (6.7%) in combination with MAO-Bi. Many of the patients (42%) were only taking levodopa, while 481 patients (38.8%) were taking levodopa in combination with other antiparkinsonian therapies.

Assessment of levodopa daily doses, either alone or in combination with other therapies, did not reveal any significant differences between patients grouped by age (younger than 50, 50–65, or older than 65).

“The therapeutic strategies used in the early stages of Parkinson’s disease in the study period are similar to those found in the literature,” the researchers wrote. Still, they recommend that “neurologists treating this disease should, with due diligence, apply a greater proportion of different levodopa-sparing combinations, especially if they are not financially burdensome.”

What makes clinicians decide to prescribe levodopa or other dopamine agonists in the first place is difficult to access through this study, and can be influenced by a number of factors, the researchers said.

“Because our study looks at a long period it is hard to retrospectively assess how much of the clinical decisions was influenced by the early optimism (as reflected in the initial studies) regarding the potential disease-modifying effect as well as the magnitude of the clinical efficacy of dopamine agonists,” they added.

Still, “if the severity of the clinical image requires substitution therapy, the use of combined therapies can significantly reduce levodopa doses and thus the requirement to use the minimum efficient levodopa dose can be achieved,” they concluded.

https://parkinsonsnewstoday.com/2019/05/13/levodopa-sparing-medications-should-be-prescribed-early-stage-parkinsons-study-suggests/

Scientists Develop HANABI Device to Identify Toxic Aggregates in Parkinson’s Patients’ Brains

 MAY 13, 2019 JOANA CARVALHO

A new test can analyze cerebrospinal fluid samples and help measure how many toxic aggregates of alpha-synuclein can be found in the brains of patients with Parkinson’s disease.

The new assessment strategy was developed by Japanese researchers and was reported in a study, “Ultrasonication-based rapid amplification of α-synuclein aggregates in cerebrospinal fluid,” published in Nature Scientific Reports.

Parkinson’s disease is a neurodegenerative disorder mainly resulting from the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for controlling body movements.

Overproduction of the protein alpha-synuclein in nerve cells of the brain, another hallmark of the disease, leads to the formation of small toxic deposits called Lewy bodies that will gradually damage and kill nerve cells. Growing evidence has demonstrated that these alpha-synuclein aggregates are associated with Parkinson’s onset and progression.

A therapy that would be able to prevent the accumulation of these protein aggregates in nerve cells could become a potential treatment for people with Parkinson’s disease.

However, to accurately test the efficacy of such therapies, clinicians must be able to tell how many alpha-synuclein aggregates are present in a patient’s brain before and after treatment. Until now, no specific method assessing the degree of protein accumulation in the brain had been successfully established.

But this may be about to change. A group of researchers from Japan’s Osaka Universitydeveloped the first strategy that is able to measure the exact amount of alpha-synuclein aggregate buildup in the brain.

The HANdai Amyloid Burst Inducer (HANABI) assay is a fully automated tool that can detect the number of alpha-synuclein aggregates in a patient’s cerebrospinal fluid (CSF) — the liquid that circulates in the brain and spinal cord — using a technique called ultrasonication.

Ultrasonication is a technique in which sound waves are transformed into mechanical disruptive energy. Researchers are able to measure the rate at which alpha-synuclein clumps together to form toxic protein aggregates, a process known as alpha-synuclein seeding activity.

Investigators showed that the seeding activity of alpha-synuclein was higher among 44 patients with a diagnosis of confirmed or probable Parkinson’s disease who participated in a prospective observational study, compared with 17 participants who did not have any neurodegenerative or neuroinflammatory disease.

“This system has the potential to distinguish patients with Parkinson’s disease from controls based on seeding activity of alpha-synuclein aggregates in cerebrospinal fluid,” Hideki Mochizuki, MD, PhD, senior author of the study, said in a news release. “This tells us that the HANABI device is sensitive enough to have real clinical potential, and supports the idea that alpha-synuclein aggregation is a marker of the disease.”

The team also found that the seeding activity of alpha-synuclein in CSF was linked to the uptake of 123I-meta-iodobenzylguanidine (MIBG), a radioactive compound whose low uptake has been linked to neurodegeneration and is considered an important clinical feature of Parkinson’s.

“Therefore, our data, showing a correlation between the HANABI assay and MIBG uptake, suggest that the seeding activity of CSF from patients with Parkinson’s disease could reflect the progression of Lewy body [disease],” researchers said.

Scientists said one of the advantages of using the HANABI assay is the speed at which it can measure alpha-synuclein aggregates in the CSF, surpassing other methods by a large margin.

“The HANABI device was developed to overcome limitations of existing methods and process multiple samples simultaneously,” said Keita Kakuda, lead author of the study. “This has allowed us to drastically shorten the time to perform the assay, from around 10 days to only several hours.”

Further studies are still needed to confirm the clinical relevance of these findings. The team is hoping the new assay might be used to aid clinicians diagnosing, assessing disease severity, and selecting the best course of treatment for patients.

https://parkinsonsnewstoday.com/2019/05/13/new-device-hanabi-recognizes-alpha-synuclein-aggregates-in-the-brain/

Finding the Little Surprises in Life MAY 13, 2019 BY SHERRI WOODBRIDGE

MAY 13, 2019 BY "SHERRI WOODBRIDGE"

My youngest grandson is 4. He loves to do whatever we’re doing, whether it’s cooking with Grandpa, changing the oil in his dad’s truck, or planting seeds in the garden with me, Grammy. 

When he comes into the house, he almost immediately climbs onto the bar stool, ready to “mix stuff.” He mixes up anything he can get his hands on: flour, sugar, salt, oil, milk, or eggs. When he goes home, a sign of the day’s activities usually is stashed somewhere in our house. For example, after he left today, I was getting something out of the cupboard and found his cooking tongs sitting on a shelf in the pantry.

I love finding little surprises like that. They are little surprises that remind me where he had been or what he was doing. It made me think of how God leaves little surprises — little reminders — of what He is doing in our lives. 

For those of us living with a chronic illness, sometimes it can be difficult to see anything good happening in our lives.

We can often dread each day instead of looking forward to it with anticipation. When our day consists of trying to stay upright and being clearly understood, or dealing with relentless pain, it’s hard to find nice surprises awaiting us.

Living with Parkinson’s disease, sometimes it’s hard to see reminders of where God is working in our lives because often it can feel as though He isn’t working — the way we want Him too, anyhow.

We want to be nicely surprised that our medications are lasting longer and are working better. We want to be surprised that the exercises we just started are making a noticeable difference and are proving to be beneficial. We want the nutritional changes we have made to make us feel better. We want a cure. We want to be surprised with a miracle of being healed. 

When we fail to see anything much changing for the better in our lives, we eventually stop looking for anything better.

We tend to lose hope. And then one day, we open a cupboard door and see a yellow bottle of pills on the shelf and realize we forgot to take the last dose, which in turn makes us realize we went longer than usual before needing the next dose.

A nice surprise.

Another day, we notice we are jumping farther than we have ever jumped before in exercise class, and that is another nice surprise. We notice that the pain we were fighting last week has eased up some, and that is another very nice surprise. And suddenly, where we were once starting to feel defeated, we again have hope. All because our day was sprinkled with unexpected surprises. Surprises that God hid in the little places of our lives, in order to remind us that He’s still working — and He’s full of surprises.

***

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/2019/05/13/finding-life-surprises-everyday-activities-positivity/

Stopping inflammation in its tracks: A leap forward for new anti-inflammatory drugs

MAY 13, 2019      by University of Queensland

Associate Professor Kate Schroder and Dr. Rebecca Coll from UQ's Institute for Molecular Bioscience are working towards the anti-inflammatory drugs of the future. Credit: University of Queensland

Treatments for chronic inflammatory diseases are one step closer as University of Queensland researchers discover a way to stop inflammation in its tracks.

Associate Professor Kate Schroder and Dr. Rebecca Coll from UQ's Institute for Molecular Bioscience and Professor Avril Robertson from UQ's School of Chemistry and Molecular Biosciences led the study, which will inform the design of new drugs to stop the formation of a protein complex, called the inflammasome, which drives inflammation.

Dr. Coll, who is now a Lecturer at the Wellcome-Wolfson Institute for Experimental Medicine at Queen's University Belfast, said the inflammasome was important in protecting our bodies from infection, but is also a key driver of unhealthy inflammation.

"Inflammation helps our bodies heal following infection, but when the inflammasome is not switched off, inflammation becomes damaging.

"Uncontrolled inflammation results in chronic diseases, such as Parkinson's disease, Alzheimer's disease and respiratory diseases such as asthma," she said.

Associate Professor Schroder said the team's exciting discovery gave new insight into how to stop inflammation at the molecular level.

"We previously identified a small molecule, MCC950, that inhibits the inflammasome to block inflammation in disease but, until now, we did not understand how it worked," she said.

"We discovered that MCC950 binds directly to the inflammasome and inactivates it, turning off inflammation.

"Now that we understand how a small molecule can inhibit the inflammasome, we are very excited about the potential of inflammasome inhibitors as anti-inflammatory drugs.

Professor Robertson said "UQ start-up Inflazome Ltd, which is developing targeted therapies for inflammatory diseases, had announced its plans to commence clinical trials of their inflammasome inhibitors in 2019, and other companies are competing in this space.

"We are keen to see results of these trials and hope that our discovery can lead to the efficient design of new molecules as anti-inflammatory drugs of the future," she said.

The research was published in the scientific journal Nature Chemical Biology.More information: MCC950 directly targets the NLRP3 ATPhydrolysis motif for inflammasome inhibition, Nature Chemical Biology (2019). DOI: 10.1038/s41589-019-0277-7 , https://www.nature.com/articles/s41589-019-0277-7

Journal information: Nature Chemical Biology 

Provided by University of Queensland 

https://medicalxpress.com/news/2019-05-inflammation-tracks-anti-inflammatory-drugs.html

How mutations lead to neurodegenerative disease

MAY 13, 2019    by Robyn Mills, University of Adelaide

Scientists have discovered how mutations in DNA can cause neurodegenerative disease. The discovery is an important step towards better treatment to slow the progression or delay onset in a range of incurable diseases such as Huntington's and motor neurone disease – possibly through the use, in new ways, of existing anti-inflammatory drugs.

The team of scientists has shown experimentally, for the first time, how mutations ultimately set off an anti-viral like inflammatory response in cells that leads to cell death and, over time, progressive neurological damage.

Led by the University of Adelaide, the study published in Human Molecular Genetics is the culmination of over a decade of research with researchers at the Victor Chang Research Institute in Sydney, seeking to understand how DNA mutations result in neurological damage.

This study investigates the outcomes of a mutation linked to Huntington's diseaseand 20 other neurodegenerative diseases, including some forms of motor neurone disease. But it also may have implications for the progression of neurodegenerative diseases which aren't necessarily inherited, such as Alzheimer's and Parkinson's, which evidence suggests are caused by a similar inflammatory response to environmental triggers.

"Together these conditions affect millions of families worldwide, and there are no cures or effective treatments," says project leader Rob Richards, Professor of Genetics in the University of Adelaide's School of Biological Sciences.

"If the new mechanism we have discovered proves to be correct, it will transform the field, providing a different way of thinking about these diseases and offering new opportunities for medical intervention."

The so-called 'DNA repeat diseases' – named because of the repeat sequences found in the DNA of patients – share many common features in their symptoms, but the mechanisms by which symptoms arise have previously been thought to be different for each.

"We've known what mutations are involved for some years, and the set of outcomes that result, but, until now, we've not known how one leads to the other. This new research shows us how each of these diseases can be caused by the same underlying cellular pathway."

The study results centre around RNA, the molecule in our cells which is the intermediate step between the DNA in chromosomes and the proteins that are the cells' main functional components.

The DNA provides a blueprint for producing RNA that is then normally 'bar-coded' to ensure cells recognise it as "self", distinguishing it from the RNA of a foreign invader, such as viruses. Using the experimental model fly Drosophila, Professor Richards and his team showed that the affected, 'double-stranded RNA' was instead recognised as foreign to the body, or "non-self".

"This elicits an anti-viral like, auto-inflammatory response that leads to neuronal destruction and death, in time causing progressive neurological damage," says Professor Richards. "The abnormal RNA is made from regions of repeated DNA sequences that are found in greater numbers in people affected with Huntington's and some other neurodegenerative diseases."

Professor Richards says there are existing drugs for other types of auto-inflammatory disease, which may prove to be effective in treating the symptoms of these diseases, by inhibiting the anti-viral inflammatory response.

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More information: Clare L Eyk et al. 'Non-self' Mutation: Double-stranded RNA elicits antiviral pathogenic response in a Drosophila model of expanded CAG repeat neurodegenerative diseases, 

Human Molecular Genetics (2019). DOI: 10.1093/hmg/ddz096

Journal information: Human Molecular Genetics 

Provided by University of Adelaide 

https://medicalxpress.com/news/2019-05-mutations-neurodegenerative-disease.html