Power chords: Music program gives people with speech challenges the gift of song

Rosalind Duane / North Shore News
MAY 5, 2017

Tony Burrows participates in a theatre sports game called “Passing the Mask,” which is meant to stimulate facial muscles. photo Paul McGrath, North Shore News 

It’s called “Passing the Mask.”

One person hides their face behind their hands, turns to the person sitting beside them, then opens their hands to reveal an obvious expression.

The next person sitting in the circle then covers their face and turns to share the same expression, and so on until everyone in the group has had a chance to pass it on.

It’s an exercise meant to stimulate facial muscles and is particularly useful for people with conditions such as Parkinson’s disease, which causes muscle rigidity and can result in a loss of facial expression (what is sometimes referred to as “masked faces”).

Some people with Parkinson’s also experience speech changes such as speaking softly, quickly, slurring or hesitating before talking. Speech may also be more monotone without usual inflections.

That’s something Joani Bye can empathize with. The longtime North Vancouver resident has been singing professionally since her first year at the University of British Columbia.

Initially a student in the music program, she switched to voice in her second year, and has performed with a variety of well-known acts over the years, including Cher, INXS, and on Bon Jovi’s “Livin’ On A Prayer.”

“That’s me screaming in the background,” she says with a laugh, adding, “I’ve done a lot of work. I’ve been around a long time.”

After a friend was diagnosed with Parkinson’s, Bye became involved with the Parkinson’s Society of B.C. and participates in annual fundraising events.

Last year, she saw an email from the organization asking for volunteers to attend a training course to become instructors for SongShine. The email called for people with a background in music, theatre, physical therapy, or speech therapy.

Bye knew immediately she wanted to do it.

Started in the U.S. in 2002, SongShine incorporates breathing and relaxation exercises, theatre sports, role playing, vocal exercises, and singing in a curriculum designed for anyone with some form of speech loss or speech changes caused by medical conditions or even just an aging voice.

The idea behind the program is to stimulate alternative brain pathways to help facilitate speech recovery and speaking confidence, explains Bye.

It’s a concept pulled from the relatively new theory of neuroplasticity, which suggests that the brain has the ability to create new neural pathways to work around damage or injury.

“Your voice is a big part of your identity and, (not just) for me in particular but for anybody, losing your ability to communicate is devastating,” she says.

The program is not a replacement for speech therapy but serves to complement it, similar to doing physical therapy and also taking yoga classes.

In January, Bye led her first 10-week SongShine program at North Shore Neighbourhood House with Penelope Bacsfalvi, a speech pathologist.

She recounts a special moment from that course involving a stoke survivor who could not speak clearly.

North Vancouver singer and musician Joani Bye leads a SongShine course at North Shore Neighbourhood House in April. The program uses a variety of exercises, including music, aimed at building confidence and improving communication in people experiencing speech changes due to medical conditions or injury. photo Paul McGrath, North Shore News

“We were singing the song ‘When I Fall in Love,’” recalls Bye. “It’s a difficult melody and I was teaching it to the class one line at a time.”

She demonstrates by singing the first line:

“When I fall in love. ...”

The class repeated the line.

“It will be forever. ...”

The class again repeated. Then something a little magical happened.

“He finished the whole song,” she notes, referring to the stroke survivor. “The class was completely silent and when he finished, everybody clapped.”

Many of the people who attend SongShine have trouble with speech volume, forming words, and finding words. But if the brain can’t find a single word, sometimes it can find a whole song, suggests Bye.

“Music is powerful and it’s the power of music that’s being used,” she says.

Sue Chalmers was diagnosed with lupus 20 years ago. The disease affected her brain function, leaving her word-depleted with a toneless voice and delayed thought processing.

“After two years and three months of day rehab at Lions Gate Hospital, I was ready to go to classes at North Shore Neighbourhood House,” she says in an email.

Chalmers attended the first SongShine session and reports the facilitators were “amazing.”

“I love this class. After an hour of SongShine, people’s spirits are lifted. To regain speech, singing comes easier than speaking. I’ve heard and seen gains in each participant. Aside from skill-building, the course helps develop confidence and camaraderie,” she says. “Participants are taught to comfortably breathe deeply after gentle stretch exercises, and this aids volume without straining. The SongShine program is scientifically formed with each step made towards a gain. Incorporated are games, which ultimately result in class laughter while learning.”

Bye explains that the camaraderie comes easily.

“Everyone in the room is in the same situation in one way or another and they’re so supportive of each other that it’s a very comfortable, trusting feeling in that class,” she says, adding it’s also important that participants enjoy the experience. “We always have fun. There’s always laughter at some point in the class.”

Tony Burrows attended the same session of SongShine at North Shore Neighbourhood House. Diagnosed with Parkinson’s disease six years ago, Burrows was then diagnosed with a related condition called multiple system atrophy (MSA) two years ago, which has made his voice weak.

“It is the most frustrating thing in the world, not being able to communicate with people not only verbally but also through script as this MSA has also stripped me of the ability to be able to communicate through handwriting,” says Burrows via email.

The North Vancouver resident has started learning sign language to help him communicate and uses an app on his iPad as well.

“I think that the overall (SongShine) program is tremendous at voice activating, and I would personally recommend it to anybody who has trouble verbally communicating as a result of whatsoever life has thrown their way,” says Burrows.

When asked about the possibility of his voice returning to full strength, Burrows is optimistic. “I think that this is entirely up to me and how hard I want to push myself, but I think that with the magical combination of these classes along with a concerted effort on my part, I firmly believe that anything can happen.”

The next session of SongShine is currently being held at Highlands United Church in North Vancouver, and there are still spots available.

Anyone interested in attending or getting more information about the program can contact Bye directly at joanibye@icloud.com.

http://www.nsnews.com/living/health-wellness/power-chords-music-program-gives-people-with-speech-challenges-the-gift-of-song-1.18514460

Patients with Parkinson’s Get Their Say on Device Trial Design

May 5, 2017  By Marie Thibault

The first-of-its-kind research collaboration between the Medical Device Innovation Consortium, The Michael J. Fox Foundation, FDA, and others is one step closer to designing trials with significance levels that dial in patient preferences.

What might medical device clinical trials of the future look like? It’s a timely question, given the recent New England Journal of Medicine editorial from FDA leaders on the topic.

In another sign that device trials are evolving, the first phase of a novel project to adapt clinical trial design to better reflect patient preferences and risk tolerances has been completed. The effort, a collaboration between the Medical Device Innovation Consortium (MDIC), The Michael J. Fox Foundation for Parkinson’s Research (MJFF), FDA, RTI Health Solutions, and the Massachusetts Institute of Technology (MIT), is intended to determine significance levels for medical device trials that incorporate patients’ views. If, for instance, there are few or no effective treatment options for a disease, patients may be willing to take on more risk to gain a benefit from a new treatment. As MD+DI reported previously, this undertaking is focused first on Parkinson’s disease.

“We’ve just completed aim one, an important foundational step to the entire effort, which was to identify the attributes that were most important to Parkinson’s patients,” said Stephanie Christopher, MDIC program director.

Pinpointing the key issues that matter to patients with Parkinson’s disease meant the MDIC and FDA worked closely with the MJFF Patient Council to learn more. Margaret Sheehan, JD, a partner at Ashurst LLP and a member of the MJFF Patient Council, was one of seven people who agreed to contribute to the project as patient scientists. She told MD+DI that the patient scientists took part in detailed calls every two week to discuss what it meant to have Parkinson’s.

“MDIC has really appreciated the opportunity to work with the Fox Foundation on this,” Christopher said. “This has been the first time that we’ve been able to do a project like this where we’ve worked so directly with a patient group and a group of patient scientists to really provide us direct input on the work we’re doing.”

The calls were a way to expand the understanding of Parkinson’s disease. Sheehan explained that while many people consider the disease to be primarily a motor sensory disorder that is evidenced by symptoms like tremors, there are many symptoms that are not well understood.

“You could see you were having an impact because they’d ask a question one week and you’d say, ‘Well really, the worst problem I have is getting out of bed in the morning,’” Sheehan said of the calls. “And the next week, getting out of bed in the morning would be on the list.”

These discussions led to a narrowed list of nine attributes—though there could have been dozens, Sheehan noted—that matter to patients with Parkinson’s disease, including sleep, depression, and frequency of urination. These attributes will be part of a large-scale patient preference survey that will be conducted through the MJFF Fox Insight website this summer.

The survey, which could reach thousands of patients with Parkinson’s, “will really help us identify on a large scale where patient preferences lie in this space,” Christopher said. “We want to capture [the experiences of] a wide range of patients, including a wide range of age of patients and a wide range of where they are in their disease state, from the newly diagnosed patients to patients who have had Parkinson’s for 10, 15, or even more years.”

This summer’s survey will be step two of the effort. After that, MIT researchers will evaluate the results and determine how patients’ risk tolerance would impact the statistical design of clinical trials. Once the novel approach for a trial design is determined, its acceptability will need to be evaluated by key stakeholders.

“This is research to see whether this kind of model of taking patient preference information to inform the clinical trial design could work,” Christopher explained.

The collaborative project is scheduled for completion in the first quarter of 2018, though potential impact to clinical trial design is likely to come later. Christopher noted that while this method is first being evaluated in Parkinson’s disease, there is interest in similar research for other diseases.

Sheehan acknowledged the challenge of using subjective values like symptoms and risk tolerance to define objective measurements. “When you mess around with [the p-value], you better be darn sure that you can defend what you’ve done,” she said. “That is very, very, very hard.”

Sheehan added, “The commitment and the prioritization and the robustness of everything that FDA and MDIC and RTI are doing is just astounding . . . It’s just been incredibly well thought out.”

http://www.mddionline.com/article/patients-parkinsons-get-their-say-device-trial-design-05-05-17

Study sniffing out Parkinson’s disease

May 5, 2017  by: Chris Lambie

Can losing the sense of smell be used as an early warning sign that a person will develop Parkinson’s disease? That’s one of the questions Kim Good is trying to answer in her lab at Dalhousie University.

Professor Kim Good, with the Dalhousie University departments of psychiatry and psychology and neurosciences, is conducting a study examining the connection between a poor sense of smell and Parkinson's disease. (ERIC WYNN / Local XPress)

Can losing the sense of smell be used as an early warning sign that a person will develop Parkinson’s disease?

That’s one of the questions Kim Good is trying to answer in her lab at Dalhousie University.

“Parkinson’s is a disease of the motor system. So people start to have a tremor or they’re having trouble eating or chewing. They go to see their doctor and the doctor says, ‘Oh, you have Parkinson’s disease,’ ” Good, a clinical neuroscientists, said Friday.

“It usually comes as a big surprise to people. The thing is, with Parkinson’s disease there’s lots of data that suggests the disease actually starts a lot earlier than when these motor symptoms start.”

There might be a clue, however, in an area of the brain that controls the sense of smell.

“It’s been known for quite some time that people who have Parkinson’s disease, almost all of them have very, very poor sense of smell,” Good said. “The problem is your sense of smell tends to deteriorate after the age of 65.”

There are lots of reasons people could lose their sense of smell.

“If somebody was punched in the face when they were 20 that could account for an olfactory deficit at the age of 60,” Good said.

Plus, there are other disorders associated with losing the sense of smell, including Alzheimer’s disease, which means doctors can’t use that as sure-fire proof that someone has Parkinson’s.

“So we have used (the sense of smell) and a very specific type of brain scanning technique in order to try to identify changes in the brain that happen in patients with Parkinson’s disease in the earliest stages, with the hopes that if we get a protocol sorted, that we might be able to screen people who are at risk and be able to determine prior to when these motor symptoms start, whether or not they are destined to develop Parkinson’s disease,” said Good, an associate professor in Dal’s departments of psychiatry and psychology and neurosciences.

She’s running a study that aims to test people’s sense of smell using scratch and sniff cards.

Some of subjects are more likely to develop Parkinson’s “because they have a first-degree relative who has Parkinson’s disease,” she said. “So either their mother, their father, sister or brother.”

That pre-disposition isn’t a requirement for the study, she said.

“That’s the group that we think will be the most interesting because they have about a five per cent chance of developing Parkinson’s.”

Good is hoping to recruit 1,200 people between the ages of 40 and 70 for the study, which starts with taking the scratch and sniff test at home and mailing the results back to her lab. The test involves answering multiple-choice questions identifying 40 different smells.

The 10 per cent who score the best and the 10 per cent who do the worst at identifying odours are brought in for further testing.

“We’re only choosing those people we call super smellers — so the people who are really, really good smellers — and those who are at the poorest or the lowest level of performance. And we ask them to come in for MRI scanning.”

The scans will look at the area that connects participants’ noses to their brains.

That’s where a protein called alpha-synuclein is deposited in people with Parkinson’s, Good said.

“It’s not really known what this protein does. But it messes up how the brain basically connects different brain regions together. And early on in the disorder, it’s thought that this pathway between the nose and the brain is affected. So that’s really what we’re looking at. We’re looking to see whether or not the connections are, not scrambled so much, but there are fewer connections between the nose and the brain compared to what should be there in similarly aged people that don’t have Parkinson’s.”

So far, Good’s recruited about 500 people for the study. To learn more about participating in the research, go to predictparkinsons.com.

The study will also look at people’s sleep history and problems with constipation, which can also be clues that Parkinson’s might be in their future.

“There’s this triad of problems that people tend to have,” Good said.

In terms of sleep history, she’s looking for people who have rapid eye movement, or REM, behaviour disorder.

“They have problems with their sleeping patterns in that, when they’re dreaming, they tend to act out their dreams,” Good said.

“In healthy people who have normal dreams you have this paralysis that comes over you in REM sleep — that’s your dream sleep — and in people with REM behaviour disorder that paralysis no longer keeps them from acting out their dreams. So they may thrash around in bed, they may punch their partner, they may do all sorts of things. And the reason why this group is so interesting is, depending on how long you follow these people forward, they are extraordinarily likely to eventually develop Parkinson’s.”

She hopes to follow the test subjects for a decade to identify who develop Parkinson’s.

“The aim of our study is to basically get a number of biomarkers sorted so that people who may be at risk of developing Parkinson’s disease can get, maybe not diagnosed early, but at least have the information prior to any kind of motor symptoms that start.”

Currently, there are no disease-modifying drugs for people with Parkinson’s.

“But that doesn’t mean that there aren’t going to be,” Good said.

If they’re invented, in order to test them we’ll need a way to identify people who are pre-destined to develop Parkinson’s, she said.

“We’re kind of putting the cart before the horse, but at the same time, if these drugs do come into testing or on the market, then we’ll be able to identify people who might benefit from them.”

About one per cent of the population develops Parkinson’s, she said.

“Of course, as the population is aging, the number of people who have the disorder is going to increase,” Good said.The usual age of onset is between 50 and 60, she said.“So it’s a little bit earlier than Alzheimer's,” Good said.

“It kind of comes on without people really realizing because sense of smell deficits are not something that you tend to be aware of. Typically what we have is partners saying to us, ‘Yes, for about about 10 years now my partner’s had to put lots of condiments on their food. That may be the first indicator that something is not quite right.”Individuals might want prepare if they learn Parkinson’s is in their future, she said.

“Maybe people don’t want to know, but you can make lots of decisions, you can change your lifestyle around if you know that there is the possibility that you might not be as mobile in the next five to 10 years, or 10 to 15,” Good said.

“And who knows? There may be a treatment coming right down the pipeline we don’t know about yet.”

https://www.localxpress.ca/local-news/study-sniffing-out-parkinsons-disease-607450

Michael J. Fox Foundation Awards 3 Trial Centers $125,000 in New Parkinson’s Trial Recruitment Program

MAY 4, 2017   BY CAROLINA HENRIQUES IN NEWS.

The Michael J. Fox Foundation for Parkinson’s Research (MJFF) is giving three clinical trial centers a $125,000 incentive to increase accessibility and volunteer enrollment in Parkinson’s disease (PD) studies as part of its new Parkinson’s Disease Trial Recruitment Innovation (PD-TRI) program.

The centers – Barrow Neurological Institute in Phoenix, Arizona; Beth Israel Deaconess Medical Center in Boston, Massachusetts; and Oregon Health and Science University in Portland, Oregon – were selected due to their comprehensive clinical research portfolio, strong infrastructure for executing Parkinson’s trials, and commitment to provide innovative solutions for recruiting research volunteers.

Clinical trials are essential to finding new and better treatments for Parkinson’s disease. Having volunteer participants is fundamental to completing trials successfully and to develop new therapies; however, finding participants is challenging and often leads to increased costs and even to studies being abandoned.

Not knowing about research opportunities, having negative perceptions of the trial process, and having poor choices of transportation have been shown to be significant barriers to bringing eligible individuals to clinical trials.

The PD-TRI program hopes to improve the recruitment of volunteers and consequently advance research by rewarding centers working to overcome these challenges.

As part of the PD-TRI program, each center will address the above-mentioned main barriers to trial participation by promoting:

• The creation of a clinical trial referral network of local practitioners;
• The use of behavioral economics principles to build bridges between volunteer awareness and trial opportunities;
• The engagement of caregivers to make trials more accessible to patients with Parkinson’s cognitive impairment;
• Free transportation to and from study sites in partnership with Lyft Concierge, a transportation service that works to meet the needs of an aging population.

Each trial center will evaluate the impact of their selected interventions by performing ongoing qualitative and quantitative assessments. The sites will submit their experiences to peer-reviewed journals to inform trial recruitment practices elsewhere and accelerate Parkinson’s research.

“Clinical trial sites enroll, on average, only one volunteer per month,” Sohini Chowdhury, MJFF’s deputy CEO, said in a press release. “This contributes to the lengthy process of Parkinson’s drug development, and PD-TRI aims to advance understanding of recruitment to address this challenge.”

Last year, the American Parkinson Disease Association (APDA) launched a series of in-person educational seminars titled “Parkinson’s Disease: Spotlight on Clinical Trials — What You Need to Know” to spread vital information about PD trials across the United Sates.

The program was designed to provide an expert perspective on the importance of clinical trials for the advancement of Parkinson’s research and to help those affected by the disease better understand what clinical trials are, why they are so important, and the different ways one can become a trial participant.

A summary of the information discussed in these seminars, with information on how to find and participate in a clinical trial is available:

https://www.apdaparkinson.org/webinar/spotlight-parkinsons-clinical-trials/

https://parkinsonsnewstoday.com/2017/05/04/michael-j-fox-foundation-awards-3-trial-centers-125000-parkinsons-trial-recruitment-program/

How Parkinson’s Disease Affects Your Body

MAY 4, 2017  BY WENDY HENDERSON

https://youtu.be/Cp6LfcLrosU

In this video from Consumer Health Digest, Dr. Ron Desi talks about the basics of Parkinson’s disease and how the progressive neurodegenerative disease affects the body.

Dr. Desi explains that Parkinson’s disease usually develops in middle to late age and that the risk of the disease increases with age, typically striking people in their 60s. It’s characterized by slow, imprecise movements and tremors. The symptoms will differ from person to person, but patients often experience tremors in the limbs and the face, rigidity, and impaired balance.

The exact cause of Parkinson’s disease is unknown, but researchers think it’s a combination of environmental factors, genetics and the presence of a protein in the nerve cells called “lewy bodies.” There is no cure for Parkinson’s disease, but there are treatments that can help improve quality of life and manage the symptoms of the disease.

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.

https://parkinsonsnewstoday.com/2017/05/04/parkinsons-disease-affects-body/

6 Things to Know About Using Medicinal Marijuana

 MAY 4, 2017  BY WENDY HENDERSON

Using cannabis or marijuana for medicinal purposes is a hot topic right now among patients and health practitioners. It’s regularly touted as either a cure or a pain reliever for many chronic illnesses, including Parkinson’s disease.

According to the National Cancer Institute, here are some of the facts about medical marijuana and its suggested uses:

It’s grown all over the world.

The plant is grown in various places around the world but originated in central Asia. The resin of the plant contains compounds called cannabinoids which are active chemicals that affect the brain and central nervous system.

The key is cannabinoids.

Two of the active cannabinoids that are useful in medical marijuana are delta-9-THC and cannabidiol. Delta-9-THC is psychoactive and is the property that gives users the “high,” whereas cannabidiol can help the central nervous system and immune system by decreasing inflammation without any high for the user. Cannabinoids can be taken in several ways: inhaled, sprayed under the tongue, ingested or smoked.

It’s been used for thousands of years. 

Cannabis has been used for medicinal purposes in some civilizations for thousands of years, but it’s only been since the late 19th century that western medicine has started to see the potential for cannabis to be used as a pain reliever.

Medical marijuana is legal in some states. 

Recreational use of cannabis is illegal in the United States, but many states now allow the use of medicinal marijuana for patients who are registered.

Cannabinoids can help with the side effects of chemotherapy.

It’s thought that cannabinoid drugs may offer pain relief for cancer patients and help with some of the side effects of treatment, including chemotherapy. Though as of right now, there’s no hard evidence to support the use of ingesting or smoking cannabis to treat nausea and sickness from chemotherapy.

Cannabis has killed cancer cells in laboratory tests.

There has been clinical research which shows that cannabis has been able to kill cancer cells in laboratory tests, but cannabis has not been approved by the FDA as a treatment for cancer.

Parkinson’s Disease 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.

https://parkinsonsnewstoday.com/2017/05/04/6-things-know-using-medicinal-marijuana/

In Huntington's disease, traffic jams in the cell's control center kill brain cells

May 4, 2017

Nuclear transport protein RanGAP1 (red) clumps up with mutant Huntingtin protein (green) in neurons. Credit: Cell Press, Neuron April 5, 2017

Working with mouse, fly and human cells and tissue, Johns Hopkins researchers report new evidence that disruptions in the movement of cellular materials in and out of a cell's control center—the nucleus—appear to be a direct cause of brain cell death in Huntington's disease, an inherited adult neurodegenerative disorder.

Moreover, they suggest, laboratory experiments with drugs designed to clear up these cellular "traffic jams" restored normal transport in and out of the nucleus and saved the cells.

In the featured article published online on April 5 in Neuron, the researchers also conclude that potential treatments targeting the transport disruptions they identified in Huntington's disease neurons may also work for other neurodegenerative diseases, such as ALS and forms of dementia.

Huntington's disease is a relatively rare fatal inherited condition that gradually kills off healthy nerve cells in the brain, leading to loss of language, thinking and reasoning abilities, memory, coordination and movement. Its course and effects are often described as Alzheimer's disease, Parkinson's disease and ALS rolled into one, making Huntington's disease a rich focus of scientific investigation.

"We're trying to get at the heart of the mechanism behind neurodegenerative diseases and with this research believe we've found one that seems to be commonly disrupted in many of them, suggesting that similar drugs may work for some or all of these disorders," says Jeffrey Rothstein, M.D., Ph.D., a professor of neurology and neuroscience, and director of the Brain Science Institute and the Robert Packard Center for ALS Research at the Johns Hopkins University School of Medicine.

In 2015, Rothstein's team found out how a mutation in a gene—implicated in 40 percent of inherited ALS cases and 25 percent of inherited frontotemporal dementia cases—gums up transport in and out of the nucleus in neurons, ultimately shutting the cell down and leading to its death. The mutant gene makes RNA molecules that stick to a transport protein, RanGAP1. RanGAP1 in turn helps move molecules through nuclear pores that serve as passageways in the nucleus, letting proteins and genetic material flow in and out of it. Jonathan Grima, currently a fourth-year neuroscience graduate student in Rothstein's laboratory, learned that this same mutation is also the most common cause of another disorder in which patients have Huntington's -like symptoms without having the causative 

Huntington's disease mutation. Additionally, he realized that other researchers previously showed that mutations in the nuclear pore protein NUP62 caused Huntington's disease-like pathology. Because of such clues from others' research, Grima took on the task of investigating whether problems with nuclear transport and the nuclear pores also happened in neurons with Huntington's disease.

Huntington's disease is caused by a mutation in the Huntingtin protein, resulting in too many repeats of the amino acid glutamine in the protein's sequence, making the protein sticky and clumpy.

Grima used two mouse models of Huntington's disease: one with a human version of the mutant Huntingtin protein and another with an aggressive form of the disease that contains only the first portion of the mouse Huntingtin protein. By using antibodies with glowing markers that bind to specific proteins and viewing the neurons under the microscope, Grima saw that the mutant Huntingtin protein clumped up in the same location of the cell as abnormal clumps of RanGAP1, the nuclear transport protein. It also clumped up in the same location as abnormal clumps of nuclear pore proteins NUP88 and NUP62. "This finding was quite tantalizing given the fact that mutations in the NUP62 protein were shown by other researchers to cause an infantile form of Huntington's disease called infantile bilateral striatal necrosis," says Grima.

Grima also observed this same clumping of Huntingtin protein with RanGAP1 and nuclear pore proteins to the wrong place in the cell in brain tissue and cultured brain cells derived from deceased patients with Huntington's disease.

To further explore nuclear transport's role in Huntington's disease, Grima took lab-grown mouse neurons and used chemical switches to a) turn on both an additional healthy copy of the RanGAP1 gene and a mutant version of Huntingtin; b) just turn on the mutant Huntingtin; or c) just turn on a healthy version of Huntingtin.

He then measured cell death and found that neurons with the healthy version of Huntingtin had about 17 percent of the neurons die off. Neurons with only the mutant version of Huntingtin were more likely to die, with about 33 percent dying off, but in neurons with both the mutant Huntingtin and the RanGAP1, only 24 percent of the neurons died off. The researchers think that some of the extra healthy RanGAP1 they introduced into diseased cells wasn't bound up to the mutant Huntingtin and resumed normal nuclear transport.

Next, Grima looked at cell death in cultured neurons with a healthy or a mutant form of Huntingtin, or with a mutant form of Huntingtin that was treated with small amounts of an experimental drug called KPT-350, one that prevents a nuclear export protein, Exportin-1, from shuttling proteins and RNA out of the nucleus. Neurons with the healthy version of Huntingtin had about 18 percent die off, and neurons with the mutant version of Huntingtin had about 38 percent die off. Those treated with the nuclear export blocking drug had improved survival, with only about 22 percent of the cells die off. Blocking nuclear export seemed to prevent cells from dying and counteracted the defects in neurons with mutant Huntingtin, the researchers say.

"Our studies show that broken-down components of the nuclear transport machinery lead to traffic jams within brain neurons of essential information and eventually brain cell death," says Grima. "We believe that the reestablishment of proper cell transport could provide a promising therapeutic target for Huntington's disease, and potentially other neurodegenerative disorders."

"Although the disrupted nuclear transport seems to be killing neurons in multiple neurodegenerative diseases, these diseases have very different properties and symptoms," cautions Rothstein. "We need to do more work to find out why one disease causes a certain set of symptoms and another disease causes others with respect to what is happening with nuclear transport."

According to the researchers, there is an average of 2000 nuclear pores per cell and each individual nuclear pore consists of multiple copies of more than 30 different proteins that each serve different functions. It may be that nuclear pores on neurons and other types of brain cells like glia are constructed of different combinations of these proteins, some of which may be more or less critical in various neurodegenerative diseases.

Grima is currently working on answering this question using a new mouse model developed at Johns Hopkins that will allow him to isolate these nuclear pore proteins from different cell types in the mouse brain to identify whether these nuclear pore components are in fact different based on brain cell types and brain locations.

"We sincerely hope our new findings may help bring us a step closer to treating this and potentially other horrific neurodegenerative disorders," says Grima.

According to the Huntington's Society of America, about 30,000 people in the United States have Huntington's symptoms and 200,000 people are at risk of inheriting the disease from a parent.

Journal reference: Neuron

Provided by: Johns Hopkins University School of Medicine 

https://medicalxpress.com/news/2017-05-huntington-disease-traffic-cell-center.html

Parkinson: Weight gain after deep brain stimulation

May 4, 2017

A SISSA study unveils some of the causes behind weight gain in Parkinsonian patients with deep brain stimulation providing important elements for preventative purposes

SCUOLA INTERNAZIONALE SUPERIORE DI STUDI AVANZATI

It was already known that people affected by Parkinson's disease, when subjected to deep brain stimulation, gained weight, but it was less clear why that was so. Thanks to new research by the International School for Advanced Studies - SISSA in Trieste (Italy), it has been realized that the weight gain after implant has a multifactorial origin. The study, published on the scientific journal Cortex, monitored for the first time a group of patients before and after the intervention, assessing cognitive, psychological and behavioural aspects. The results show that weight gain is associated with an increased desire for food and level of impulsiveness, as well as with the duration of the disease and the reduction of pharmacological treatment, thereby providing important elements for preventative purposes.

"The alteration of body weight is one of the potential complications of deep brain stimulation as a treatment of Parkinson's disease", explains Marilena Aiello, SISSA researcher and first author of the research. "The origin was initially traced to the substantial reduction in motor symptoms, overlooking the role of the brain stimulation area -- the subthalamic nucleus -- in the reward system. Our intention was to assess the overall picture before and after the operation, from a clinical as well as a cognitive, psychological and behavioural viewpoint".

The study -- conducted in collaboration with the Santa Maria della Misericordia University Hospital in Udine, under the leadership of Raffella Rumiati, in charge of SISSA neuroscience and society lab -- has involved 18 Parkinsonian patients who underwent deep brain stimulation and 18 healthy volunteers. 

"The patients have been assessed in three distinct phases: prior to the operation, 5 days after the operation, and 3 months thereafter. They were always under pharmacological treatment, gradually reduced, whereas, at the time of the latest survey, the stimulator, too, was active" Aiello went on to state. 

Participants were subjected to some questionnaires used at clinical level to assess their levels of depression, anhedonia -- i.e. the inability to experience pleasure -- and impulsiveness. In addition, they undertook some tasks assessing food reward sensitivity and impulsive reactions to food.

"Our results have confirmed a significant weight gain during the months following the operation. In line with an alteration of the reward system, the weight variation has proved more consistent in those patients who, after the operation, have displayed an increased desire for food. However, we have also noted the importance of individual characteristics, such as attentional impulsiveness - i.e. the tendency to take sudden decisions -- and of characteristics related to the disease, such as its duration and the reduction in the pharmacological load".

The researcher concludes thus: "Our results have proved the multifactorial nature of the post-operation weight gain, and offer important tools to identify the patients under greatest risk and accordingly prevent an excessive or anyway debilitating weight gain".

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Full paper: http://www.sciencedirect.com/science/article/pii/S0010945217301193

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https://www.eurekalert.org/pub_releases/2017-05/sisd-pwg050417.php

Researchers identify 6,500 genes that are expressed differently in men and women

NEUROSCIENCE NEWS
MAY 4, 2017

Summary: Findings point to males and females undergo an almost seperate, but interconnected evolution.

Source: Weizmann Institute of Science.

Yet another gene that was mainly expressed in women was active in the brain, and though its exact function is unknown, the scientists think it may protect the neurons from Parkinson’s — a disease that has a higher prevalence and earlier onset in men. NeuroscienceNews.com image is credited to Weizmann Institute of Science.

Genes that are mostly active in one sex or the other may play a crucial role in our evolution and health.

Men and women differ in obvious and less obvious ways — for example, in the prevalence of certain diseases or reactions to drugs. How are these connected to one’s sex? Weizmann Institute of Science researchers recently uncovered thousands of human genes that are expressed — copied out to make proteins — differently in the two sexes. Their findings showed that harmful mutations in these particular genes tend to accumulate in the population in relatively high frequencies, and the study explains why. The detailed map of these genes, reported in BMC Biology, provides evidence that males and females undergo a sort of separate, but interconnected evolution.

Several years ago, Prof. Shmuel Pietrokovski and Dr. Moran Gershoni of the Weizmann Institute’s Molecular Genetics Department asked why the prevalence of certain human diseases is common. Specifically, about 15% of couples trying to conceive are defined as infertile, which suggested that mutations that impair fertility are relatively widespread. This seems paradoxical: Common sense says that these mutations, which directly affect the survival of the species by reducing the number of offspring, should have been quickly weeded out by natural selection. Pietrokovski and Gershoni showed that mutations in genes specific to sperm formation persist precisely because the genes are expressed only in men. A mutation that is problematic for only half the population, no matter how detrimental, is freely passed on to the next generation by the other half.

In the present study, the researchers expanded their analyses to include genes that, though not necessary for fertility, are still expressed differently in the two sexes. To identify these genes, the scientists turned to the GTEx project — a very large study of human gene expression recorded for numerous organs and tissues in the bodies of close to 550 adult donors. That project enabled, for the first time, the comprehensive mapping of the human sex-differential genetic architecture.

Pietrokovski and Gershoni looked closely at around 20,000 protein-coding genes, sorting them by sex and searching for differences in expression in each tissue. They eventually identified around 6,500 genes with activity that was biased toward one sex or the other in at least one tissue. For example, they found genes that were highly expressed in the skin of men relative to that in women’s skin, and they realized that these were related to the growth of body hair. Gene expression for muscle building was higher in men; that for fat storage was higher in women.

Yet another difference

The two then looked at tendencies to accumulate mutations, to see if natural selection puts more or less pressure on genes that are specific to men or women. That is, to what extent are harmful mutations weeded out or tolerated in the population? Indeed, the researchers found that the efficiency of selection is weaker in many such genes. “The more a gene was specific to one sex, the less selection we saw on the gene. And one more difference: This selection was even weaker with men,” says Gershoni. Although they do not have a complete explanation for this additional difference, the researchers point to a theory of sexual evolution first proposed in the 1930s: “In many species, females can produce only a limited number of offspring while males can, theoretically, father many more; so the species’ survival will depend on more viable females in the population than males,” explains Pietrokovski. “Thus natural selection can be more ‘lax’ with the genes that are only harmful to males.”

Aside from the sexual organs, the researchers discovered quite a few sex-linked genes in the mammary glands — not so surprising, except that about half of these genes were expressed in men. Because men have fully fitted but basically nonfunctional mammary equipment, the scientists made an educated guess that some of these genes might suppress lactation.

Less obvious locations included genes that were found to be expressed only in the left ventricle of the heart in women. One of these genes, which is also related to calcium uptake, showed very high expression levels in younger women that sharply decreased with age; the scientists think that they are active in women up to menopause, protecting their hearts, but leading to heart disease and osteoporosis in later years when the gene expression is shut down. Yet another gene that was mainly expressed in women was active in the brain, and though its exact function is unknown, the scientists think it may protect the neurons from Parkinson’s — a disease that has a higher prevalence and earlier onset in men. The researchers also identified gene expression in the liver in women that regulates drug metabolism, providing molecular evidence for the known difference in drug processing between women and men.

“The basic genome is nearly the same in all of us, but it is utilized differently across the body and among individuals,” says Gershoni. “Thus, when it comes to the differences between the sexes, we see that evolution often works on the level of gene expression.” Pietrokovski adds: “Paradoxically, sex-linked genes are those in which harmful mutations are more likely to be passed down, including those that impair fertility. From this vantage point, men and women undergo different selection pressures and, at least to some extent, human evolution should be viewed as co-evolution. But the study also emphasizes the need for a better understanding of the differences between men and women in the genes that cause disease or respond to treatments.”

Prof. Shmuel Pietrokovski’s research is supported by the Leo and Julia Forchheimer Center for Molecular Genetics; and the estate of Georges Lustgarten. Prof. Shmuel Pietrovski is the incumbent of the Herman and Lilly Schilling Foundation Professorial Chair.

The Weizmann Institute of Science in Rehovot, Israel, is one of the world’s top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Source: Gizel Maimon – Weizmann Institute of Science 

Image Source: NeuroscienceNews.com image is credited to Weizmann Institute of Science.

Original Research: Full open access research for “The landscape of sex-differential transcriptome and its consequent selection in human adults” by Moran Gershoni and Shmuel Pietrokovski in BMC Biology. Published online February 7 2017 doi:10.1186/s12915-017-0352-z

Abstract

The landscape of sex-differential transcriptome and its consequent selection in human adults

Background

The prevalence of several human morbid phenotypes is sometimes much higher than intuitively expected. This can directly arise from the presence of two sexes, male and female, in one species. Men and women have almost identical genomes but are distinctly dimorphic, with dissimilar disease susceptibilities. Sexually dimorphic traits mainly result from differential expression of genes present in both sexes. Such genes can be subject to different, and even opposing, selection constraints in the two sexes. This can impact human evolution by differential selection on mutations with dissimilar effects on the two sexes.

Results

We comprehensively mapped human sex-differential genetic architecture across 53 tissues. Analyzing available RNA-sequencing data from 544 adults revealed thousands of genes differentially expressed in the reproductive tracts and tissues common to both sexes. Sex-differential genes are related to various biological systems, and suggest new insights into the pathophysiology of diverse human diseases. We also identified a significant association between sex-specific gene transcription and reduced selection efficiency and accumulation of deleterious mutations, which might affect the prevalence of different traits and diseases. Interestingly, many of the sex-specific genes that also undergo reduced selection efficiency are essential for successful reproduction in men or women. This seeming paradox might partially explain the high incidence of human infertility.

Conclusions

This work provides a comprehensive overview of the sex-differential transcriptome and its importance to human evolution and human physiology in health and in disease.

“The landscape of sex-differential transcriptome and its consequent selection in human adults” by Moran Gershoni and Shmuel Pietrokovski in BMC Biology. Published online February 7 2017 doi:10.1186/s12915-017-0352-z

http://neurosciencenews.com/genetics-sex-differences-6585/