Amarantus Announces Publication in BRAIN of Eltoprazine Phase 2a Clinical Study for Treating Parkinson's Disease Levodopa-Induced Dyskinesia

• Eltoprazine demonstrated significant beneficial anti-dyskinesia effect at 5 and 7.5 mg doses, with no reduction of levodopa efficacy 
• Eltoprazine was well tolerated at all dose levels, with no major adverse effects reported
• Results support advancing eltoprazine into Phase 2b chronic dosing, clinical studies, as a treatment for patients with Parkinson's disease levodopa-induced dyskinesia

SAN FRANCISCO and GENEVA, Feb. 10, 2015 (GLOBE NEWSWIRE) -- Amarantus BioSciences Holdings, Inc. (OTCQB:AMBS), a biotechnology company focused on developing diagnostics in neurology, and therapeutic products with the potential for orphan drug designation in the areas of neurology, psychiatry, ophthalmology and regenerative medicine, announced that the publication of the results of a Phase 2a study of eltoprazine in Parkinson's disease levodopa-induced dyskinesias (PD-LID). The paper titled, "Eltoprazine Counteracts L-DOPA-induced Dyskinesias in Parkinson's Disease: A Dose-Finding Study," has been published in Oxford Journals (Oxford University Press) online and will appear shortly in a future print edition of BRAIN - A Journal of Neurology.

Eltoprazine is a small-molecule 5-HT_1A/1B serotonin receptor agonist, investigational drug candidate, with a well-established safety profile. A Phase 2a dose-finding study was conducted with eltoprazine to determine its effect against levodopa-induced dyskinesia, in patients with Parkinson's disease (PD). The double-blind, randomized, placebo-controlled clinical study was led by Professor Per Svenningsson, M.D., Ph.D., Centre for Molecular Medicine, Karolinska Institutet, Professor Anders Björklund, Ph.D., Faculty of Medicine at Lund University, and Professor Håkan Widner, M.D., Ph.D., Faculty of Medicine at Lund University. The study was partially supported by a grant from The Michael J. Fox Foundation for Parkinson's Research.

Some researchers believe that, in the advanced stages of PD, as dopamine nerve terminals are lost, serotonergic terminals take up levodopa and convert it to dopamine instead. Unlike in dopamine nerve endings, the serotonin nerve terminals do not have a negative feedback loop, possibly causing an excessive release of dopamine and resulting in the development of abnormal involuntary hyperkinetic movements, known as levodopa-induced dyskinesias (LID). Pre-synaptic activation of serotonin receptors using a 5HT_1A/1B agonist may dampen this excessive dopamine release. In animal model studies of LID previously conducted in Professor Björklund's laboratory, simultaneous activation of 5-HT_1A and 5-HT_1B receptors was shown to effectively block LID. The Phase 2a dosing trial with eltoprazine was conducted as an initial clinical pharmacology study to determine if activation of 5-HT_1A/1Breceptors in Parkinson's disease subjects may replicate the effects of serotonin receptor activation seen in pre-clinical dyskinesia studies.

The study in 22 subjects with long standing PD-LID was a randomized, four-way crossover design in which patients received a single dose of placebo and eltoprazine, at 2.5, 5 and 7.5 mg, in combination with a challenge dose of levodopa (1.5 times usual dose), on four different days, separated by an interval of a week. Data from the study demonstrated that eltoprazine significantly reduced peak dose dyskinesia at both the 5 and 7.5 mg doses using the Combined Dyskinesia Rating Scale. The 5 mg dose also showed a significant anti-dyskinetic effect on other measures of dyskinesia, including the Rush dyskinesia rating scale. Importantly, there were no adverse effects on levodopa efficacy at any dose level as evidenced by United Parkinson's Disease Rating Scale (UPDRS Part III) observation. Additionally, all dose levels of eltoprazine were well tolerated with no major adverse effects reported.

"Eltoprazine's anti-dyskinetic effect is promising, especially given the reduction in dyskinesia following a levodopa challenge at one and a half times greater than the regular levodopa dose," said Charlotte Keywood, M.D., Chief Medical Officer at Amarantus. "Levodopa treatment is the current standard of care for patients to manage PD motor symptoms, despite the occurrence of dyskinesia with long-term use. Thus, we were very pleased to see that normal motor responses to levodopa, measured by UPDRS III, remained unchanged in all patients treated with eltoprazine."

The Phase 2a study also included a pharmacokinetic (PK) evaluation of eltoprazine. The data show that the PK characteristics of eltoprazine in PD patients are the same as those found in healthy subjects. Given the positive PK profile in PD patients and the acute anti-dyskinesia effect seen with the 5 and 7.5 mg doses, further advancement of eltoprazine into Phase 2b chronic dosing clinical studies to treat patients with PD-LID is warranted.

"We are pleased to have the eltoprazine study results published in this prestigious peer-reviewed journal," said Dr. Keywood. "The results of this proof of concept, first trial in PD-LID patients, support the findings of the non-clinical pharmacology studies conducted using animal models of PD-LID and show the predictive value of these models in aiding human drug development."

"The data from this study show an acute antidyskinetic effect of eltoprazine with no detriment to levodopa efficacy. With these data at hand, we are confident moving forward into longer-term dosing studies to further evaluate the utility of eltoprazine as a treatment for levodopa-induced dyskinesia," concluded Dr. Keywood.

Amarantus expects to file its Investigational New Drug Application (IND) with the U.S. Food and Drug Administration (FDA) and commence its Phase 2b study of eltoprazine in PD-LID subjects in the first quarter of 2015.

"Dyskinesia impacts quality of life of people with Parkinson's disease, and is therefore a top priority for the Foundation," commented Maurizio Facheris, M.D., M.Sc., Associate Director of research programs at The Michael J. Fox Foundation. "We are glad to see this project moving further through clinical testing and closer to patients' hands."

To access the online version of the paper titled, "Eltoprazine Counteracts L-DOPA-induced Dyskinesias in Parkinson's Disease: A Dose-Finding Study," please click here.

To access the Karolinska Institutet press release titled, "New therapeutic principle for Parkinsonian dyskinesia shows clinical effect," regarding the publication in BRAIN, please click here.

About Eltoprazine

Eltoprazine is a small molecule 5HT_1A/1B partial agonist in clinical development for the treatment of Parkinson's disease levodopa-induced dyskinesia (PD-LID) and Adult Attention Deficit Hyperactivity Disorder (ADHD). Eltoprazine has been evaluated in over 600 human subjects to date, and has a well-established safety profile. Eltoprazine was originally developed by Solvay Pharmaceuticals for the treatment of aggression. Upon Solvay's merger with Abbott Pharmaceuticals, the Eltoprazine program was out-licensed to PsychoGenics. PsychoGenics licensed Eltoprazine to Amarantus following successful proof-of-concept trials in PD-LID and adult ADHD.

About Parkinson's disease and levodopa-induced dyskinesia (PD-LID) 

Parkinson's disease is a chronic, progressive neurological disorder that causes motor symptoms such as tremors, rigidity and slowed movements as well as non-motor symptoms including cognitive impairment and autonomic dysfunction. The Parkinson's Disease Foundation estimates that there are approximately one million people living with Parkinson's disease in the United States and seven to 10 million PD patients worldwide. The most commonly prescribed treatments for Parkinson's disease are levodopa-based therapies. In the body, levodopa is converted to dopamine to replace the dopamine loss caused by the disease. As dopamine neurons in the brain are lost the therapeutic efficacy of levodopa attenuates, and increased use is associated with a side effect of dyskinesias. These are involuntary, uncontrollable and often exaggerated and jerky movements. They are distinct from the static, rhythmic tremor as a symptom of Parkinson's disease. Levodopa-induced dyskinesia can be severely disabling, rendering patients unable to perform routine daily tasks.

About Amarantus BioScience Holdings, Inc.

Amarantus BioScience Holdings (AMBS) is a biotechnology company focused on developing diagnostics in neurology, and therapeutic products with the potential for orphan drug designation in the areas of neurology, psychiatry, ophthalmology and regenerative medicine. AMBS has licensed Eltoprazine, a Phase 2b ready small molecule indicated for Parkinson's disease Levodopa-induced dyskinesia and adult ADHD. AMBS has an exclusive worldwide license to the Lymphocyte Proliferation test, (LymPro Test^®), which was developed by Prof. Thomas Arendt, Ph.D., from the University of Leipzig, for Alzheimer's disease and owns the intellectual property rights to a therapeutic protein known as mesencephalic-astrocyte-derived neurotrophic factor ("MANF") and is developing MANF-based products as treatments for brain and ophthalmic disorders. AMBS also owns intellectual property for the diagnosis of Parkinson's disease (NuroPro) and the discovery of neurotrophic factors (PhenoGuard^™).

In November 2014, AMBS entered into an exclusive option agreement with Lonza Walkersville, Inc., a subsidiary of Lonza Group Ltd., to acquire Cutanogen Corporation, a subsidiary of Lonza Walkersville, to develop Engineered Skin Substitute (ESS-W), an autologous skin replacement product for the treatment of Stage 3 and Stage 4 intractable severe burns.

On January 12, 2015, AMBS announced the acquisition of DioGenix, Inc., a specialized neuro-diagnostics company, and owns the rights to MSPrecise^®, a proprietary next-generation DNA sequencing (NGS) assay for the identification of patients with relapsing-remitting multiple sclerosis (RRMS) at first clinical presentation. On January 15, 2015, AMBS executed a one-year exclusive option agreement with Georgetown University to enter into a license for the patent rights related to certain blood based biomarkers for memory loss and Alzheimer's disease jointly owned by Georgetown University and University of Rochester. For further information please visit www.Amarantus.com, or connect with the Company on Facebook, LinkedIn, Twitter and Google+.

About Our Collaboration Partners

Karolinska Institutet is one of the world's leading medical universities. Its vision is to significantly contribute to the improvement of human health. Karolinska Institutet accounts for over 40 percent of the medical academic research conducted in Sweden and offers the country's broadest range of education in medicine and health sciences. The Nobel Assembly at Karolinska Institutet selects the Nobel laureates in Physiology or Medicine.

The Faculty of Medicine at Lund University works to understand, explain and improve human health. As a part of Lund University we create unique interdisciplinary collaborations for scientific breakthroughs and innovations. Lund University was founded in 1666 and is consistently ranked among the world's top 100 universities.

Forward-Looking Statements

Certain statements, other than purely historical information, including estimates, projections, statements relating to our business plans, objectives, and expected operating results, and the assumptions upon which those statements are based, are forward-looking statements. These forward-looking statements generally are identified by the words "believes," "project," "expects," "anticipates," "estimates," "intends," "strategy," "plan," "may," "will," "would," "will be," "will continue," "will likely result," and similar expressions. Forward-looking statements are based on current expectations and assumptions that are subject to risks and uncertainties which may cause actual results to differ materially from the forward-looking statements. Our ability to predict results or the actual effect of future plans or strategies is inherently uncertain. Factors which could have a material adverse effect on our operations and future prospects on a consolidated basis include, but are not limited to: changes in economic conditions, legislative/regulatory changes, availability of capital, interest rates, competition, and generally accepted accounting principles. These risks and uncertainties should also be considered in evaluating forward-looking statements and undue reliance should not be placed on such statements.

CONTACT: Investor and Media Contact: Jenene Thomas Jenene Thomas Communications, LLC Investor Relations and Corporate Communications Advisor T: (US) 908.938.1475 E: jenene@jenenethomascommunications.com

Source:Amarantus BioScience Holdings, Inc.

The Stigma of Parkinson’s Disease

FoxFeed Blog

Posted by  Rachel Dolhun, MD, February 09, 2015

The hallmark signs of Parkinson’s disease — tremor, stiffness, slowness and/or walking problems — are fairly obvious to the outside observer. Less apparent non-motor symptoms, such as depression, anxiety and apathy, are also often present.

Both aspects of Parkinson’s — visible and invisible — can be misinterpreted, causing a stigma sometimes associated with neurological disease.  Slowness of movement or speech may be perceived as intellectual disability, imbalance as intoxication, masked facial expression as an unfriendly demeanor, and tremor as nervousness. Internalizing these judgments or trying to hide the disease to avoid discrimination only make symptoms worse.

Nancy Mulhearn, a person living with Parkinson’s disease, recently shared her approach to challenging social stigma with Neurology Now:

                     “I recommend surrounding yourself with a network of people dealing with the same
                      problem… I didn't want to be pitied or stared at, and I didn't want the world to change
                      for me and my condition,” she explains.

By openly sharing their personal experiences with Parkinson’s, people like Nancy are helping to educate others. One person and one story at a time, we can work to gradually dissolve the social stigma associated with neurological diseases like Parkinson’s..

Turn Staring Into Caring: The stigma of a neurologic disorder can be stressful—and can make symptoms worse. Patients and doctors teach us how to turn negative reactions into positive encounters.

Neurology Now

February/March 2015

 

Volume 11(1)

 

p 34–38

Stephens, Stephanie

Illustrations by Brian Stauffer

Back to top

When Stephanie Schroeder rolls and blinks her eyes, shrugs her shoulders, or opens her mouth and stretches her tongue, people sometimes stare, and she feels it.

“People may think my contacts are bothering me or that I have a neck ache,” says 51-year-old Schroeder, of Brooklyn, NY. “When I first moved to New York, kids on the subway would laugh and point. Riding the subway definitely gave me a pretty thick skin.”

That thick skin helps protect Schroeder from the unwelcome reactions of strangers to the visible symptoms of Tourette syndrome, with which she was diagnosed 24 years ago. She's happy to “tell all” to those who ask about her tics and is often amused by the responses. “Once I told someone at work and he just chuckled uncomfortably, ‘That's cool. I don't know anybody else with Tourette's.’”

Of course, the discomfort others feel toward her tics hasn't always been so benign. In fact, she thinks she has probably failed in job interviews because of her condition. “I just knew they wouldn't hire me, even though I have no proof of that. Maybe they thought, ‘Why is this crazy lady moving around so much?’” (For more information about workplace discrimination, see “Work Disclosure: When Is It Safe?” on page 38.)

Tourette's is just one of many neurologic conditions with visible symptoms that can make strangers uncomfortable, afraid, or react inappropriately. And dealing with those negative reactions can be upsetting for the recipients—and can even exacerbate certain symptoms.

STIGMA CAUSES STRESS

“If you come see me as an adult patient and you have frequent and noticeable motor and/or vocal tics, I know you've probably been the victim of a fair amount of stigma,” says James Frederick Leckman, MD, a professor of pediatrics and psychiatry and the Neison Harris Professor in the Child Study Center at Yale School of Medicine. Being repeatedly singled out and mimicked can even cause a form of post-traumatic stress disorder, or PTSD, he says. He's known patients to report flashbacks and nightmares. Some avoid places where they experienced painful teasing, while others remain wary and watchful and have trouble concentrating.

Sometimes even well-meaning people can contribute to the stigma, says Dr. Leckman. A teacher who doesn't understand or recognize the symptoms of Tourette's, for instance, may ask a child to “stop” his or her “bad” behavior. If the teacher subsequently disciplines that child, the teacher may be unknowingly encouraging other kids in class to mistreat that student, causing more stress and potentially making the tics worse.

USING FAME TO COUNTER SHAME

Parkinson's disease is another neurologic disorder with outward symptoms that are frequently misinterpreted. A tremor can be misread as anxiety or nervousness, an unsteady gait can mistakenly convey intoxication, and slurred speech may falsely suggest intellectual disability, all of which can make social interaction difficult, says Rachel Dolhun, MD, a medical communications specialist for the Michael J. Fox Foundation for Parkinson's Research. In some cases, the disease can cause a loss of facial expression, making it difficult for Parkinson's patients to convey their emotions, which others may interpret as unfriendly or standoffish, she adds.

The stigma of the disease may have been why Michael J. Fox, the Back to the Future actor and one of the more famous faces of the disease, waited seven years before disclosing his condition. Since going public and christening his foundation 14 years ago, Fox has earned international respect for his efforts to find a cure and eradicate stigma by being open and honest and by raising public awareness. As he told a New York Times op-ed columnist, “many Parkinson's sufferers feel shame,” and he has worked to help take the shame out of the disease.

n his television comedy, The Michael J. Fox Show, which aired on NBC between September 2013 and January 2014, his character, Mike Henry, had Parkinson's. Like the actor, Henry openly acknowledged his condition, as well as the unwanted attention it brought, often with humor.

During an appearance last November on NBC's Today show with co-host Willie Geist, whose father, CBS Morning correspondent Bill Geist, has the disease, Fox acknowledged the shame that accompanies having any illness, including Parkinson's. But he said he's proud to be the public face of the disease. “Since I made my diagnosis known, it's been a tremendous opportunity and a tremendous privilege,” he said.

SEEKING AND GIVING SUPPORT

“I recommend surrounding yourself with a network of people dealing with the same problem,” says Nancy Mulhearn of Asbury, NJ, who was diagnosed with Parkinson's in 2006 at age 44. That's what she did after years of denying the disease and hiding her symptoms. “I didn't want to be pitied or stared at, and I didn't want the world to change for me and my condition,” she explains.

Reach Out to Reduce Stigma

Limited communication and interaction between patients with neurologic disorders and the general public can increase the misunderstandings that lead to stigma, says Patrick Corrigan, PsyD, principal investigator at the National Consortium on Stigma and Empowerment and distinguished professor of psychology at the Illinois Institute of Technology.

Dr. Corrigan advocates for more “face time” between the two communities, advising people to “meet and get to know that person with the disorder. Sitting at church or working alongside someone can disarm prejudice and reframe misconceptions, while combining different points of view,” he says.

* Get Connected. Health care providers can help, too, says Deepa Rao, PhD, an associate professor in the departments of global health and psychiatry and behavioral sciences at the University of Washington. For example, they can connect patients with similar conditions who can support one another. That's what Dr. Rao sought out for her daughter, who has a medical condition; she asked her daughter's physician for the names of other families who were dealing with the same challenges.The Health Insurance Portability and Accountability Act (HIPAA), which governs patients' privacy rights, prevents physicians from sharing names, Dr. Rao notes. But patients can sign a privacy release form to give their doctor permission to share their names. “This helps us feel like we're not alone,” Dr. Rao says. “We all learn coping mechanisms by modeling each other's behaviors.”

* Be Kind to Yourself.“Self-stigma is an egregious impact of stigma in general, a diminished sense of self-esteem leading to a ‘Why try?’ attitude in many people,” says Dr. Corrigan. He thinks that the focus on “patient-centered outcomes” in the Affordable Care Act presents an opportunity for the health care profession to empower patients with neurologic disorders. “We can help them better determine their health care options and personal goals and learn to make decisions for themselves. All of that reduces self-stigma.”

* Dare to Share. Talking openly about symptoms can take a bite out of stigma and its effects. That's why Stephanie Schroeder does it. “My tics are part of who I am and don't really bother me unless I'm unduly stressed,” she says. “What does bother me is the amount of negative energy other people spend trying to shame me and others with Tourette's. It says more about them than about me or the disorder.”

When she could no longer disguise her symptoms, Mulhearn attended a Fox Foundation conference to learn more—and that changed her life. She says she was motivated and inspired to get involved by those she met at the conference. Now, at age 53, she's helped raise more than $100,000 for the foundation by organizing gala events. She's also a member of Team Fox, the grassroots community fundraising program, for which she mentors people who have been diagnosed with Parkinson's.

I've experienced every emotion: depression, denial, and more,” says Mulhearn. “I know what they are feeling and I can help.”

As for strangers' curiosity, she addresses it head on. “If I'm fumbling for change, I say, ‘I have Parkinson's disease,’” she explains. “I could go hide, but if other people see I'm OK with this, they're usually OK, too.”

COUNTERING THE CULTURE

Sometimes, people are frightened by neurologic illness simply because what they've heard about the condition and its symptoms is far worse than the reality. That's especially true with epilepsy, says Wendy Miller, PhD, RN, CCRN, an assistant professor at the Indiana University School of Nursing and a member of the professional advisory board for the Epilepsy Foundation.

“Movies and media can totally misrepresent epilepsy,” says Dr. Miller. “It's important to explain that, yes, you may have seizures, but that doesn't mean you'll soon be falling on the ground. You may just stare into space for a while.”

In 2013, Jerry Krill, the head coach of the University of Minnesota football team, noticed that his epileptic seizures were becoming more frequent. When he had one on the field during a game, some people called for his resignation.

The public outcry had a positive outcome. It forced Krill to reassess his workaholic habits and it prompted moral support from the university and the football team. Today, Krill eats healthier and gets enough sleep, and hasn't had a seizure in more than a year. And he has scored high points for helping to eradicate stigma.

The Epilepsy Foundation urges people with epilepsy to explain how their seizures look to those with whom they are in daily contact. “Tell them this is not a mental condition and it's not contagious,” Dr. Miller advises.

FIGHTING SKEPTICISM

A lifelong migraineur (a person who experiences migraines), Anjan Chatterjee, MD, MPH, MBA, is intimately familiar with the debilitating pain, nausea, vomiting, and sensitivity to light caused by migraine headaches, making him particularly empathetic to his migraine patients. He recalls the lack of sensitivity he encountered in medical school and during his residency, when studying for tests and working unreasonably long hours exacerbated his migraines and caused him to retreat for long periods of time.

That didn't go unnoticed, he says. “Even the most caring neurologist might say, ‘It's just a headache, now, isn't it?’ You may not be criticized if you had Parkinson's, but others may think a headache is just an excuse. People with migraine face that stigma time and time again and may worry about losing their jobs.”

That skepticism doesn't happen only at work, Dr. Chatterjee adds. “Patients have separated and divorced because their partners just don't believe them.”

When consulting with headache patients, Dr. Chatterjee, a member of the American Academy of Neurology and a Fellow of the American Headache Society, invites the entire family to learn more about what their loved one is experiencing. “I think 99 percent of the time, when you clearly explain this condition, a person's attitude changes from one of cynicism to extreme support,” he says. “Patients are the best people, even more so than health care professionals, to advise other patients about how to deal with stigma.”

BATTLING BIAS

Obvious symptoms often invite stares and whispers, but hidden symptoms such as some cognitive deficits associated with brain injury can be judged even more harshly, says Donna Langenbahn, PhD, a clinical associate professor at Rusk Rehabilitation at NYU Langone Medical Center. People with brain injuries—whether from car accidents, sports injuries, falls, or assaults—may be deemed “stupid or inept without an understanding of the underlying cause,” she says.

That bias may render them “less of a person” in the eyes of others, says Dr. Langenbahn, who urges people to let go of their biases and learn more about brain injury and how it may affect aspects of life such as work, school, play, leisure, and intimacy. “That allows the person to maintain an active role in society and, ultimately, a sense of dignity.”

KNOW THE BASICS:

* Parkinson's Disease: The Basics—bit.ly/basics-PD

* Epilepsy: The Basics—bit.ly/Epilepsy-Basics

* Migraine: The Basics—bit.ly/Migraine-Basics

* Traumatic Brain Injury: The Basics—bit.ly/TBI-Basics

* Tourette Syndrome: AAN resources for patients —bit.ly/AAN-Tourette

Many people with a neurologic disorder who want and need to work are dogged by the question: to tell or not to tell? Indeed, there's a lot at stake, says Patrick Corrigan, PsyD, principal investigator at the National Consortium on Stigma and Empowerment and distinguished professor of psychology at the Illinois Institute of Technology.

“People who can hide a neurological disorder must decide carefully whether they want to [reveal their condition],” he says. “‘Coming out’ or disclosing can be a huge decision, especially if the condition is misunderstood. For example, just because I see you having symptoms, doesn't mean I understand what the disorder is or does. And just because the medical community understands, doesn't mean the public does.”

The employment arena is rife with discrimination, says Dr. Corrigan, who has published studies on the topic. “People with neurological conditions are less likely to be hired and less likely to be provided reasonable accommodations guaranteed by the Americans with Disabilities Act of 1990.”

The law prohibits discrimination and ensures equal opportunity for persons with disabilities in employment, state and local government services, public accommodations, commercial facilities, and transportation, he says. “If you're in a wheelchair, your employer is legally bound to provide accommodations for you, like revamping your workplace for accessibility. The same is legally true for people with neurologic disorders—those accommodations might include a job coach or a social worker.”

“Remember that you can't be fired for having a disability,” says Wendy Miller, PhD, RN, an assistant professor at the Indiana University School of Nursing and a member of the professional advisory board for the Epilepsy Foundation. “Not everyone you work with needs to know, but disclosing to those in close proximity may be a good idea to the degree that you're comfortable. The worst thing could be that no one knows you have the condition, and they don't know what to do when you need them.”

WEB EXTRAS:

* For how to combat stigma or to listen to a podcast about stigma and epilepsy, go to bit.ly/NN-stigma

http://patients.aan.com/resources/neurologynow/index.cfm?event=home.showArticle&id=ovid%2Ecom%3A%2Fbib%2Fovftdb%2F01222928-201511010-00017

Our Amazingly Plastic Brains

By 

NORMAN DOIDGE

WallStreet journal

Mental and physical exercise can keep the brain fit and help it recover capacities lost to disease and trauma

Feb. 6, 2015 5:34 p.m. ET

As people reach middle age, exercising the brain and the body to which it is attached—keeping both active—becomes more important.PHOTO: GETTY IMAGES

Can the brain heal and preserve itself—or even improve its functioning—as we get older? For some time, many scientists have tended to think of our brains as machines, most commonly as computers, destined to break down over time under the strain of age and use. In recent years, however, research in neuroscience has begun to show the inadequacy of this metaphor for describing the physiology of the brain. It turns out that our brains, like our bodies in general, are far more likely to waste away from underuse than to wear down from overuse. 

As people reach middle age, exercising the brain and the body to which it is attached—keeping both active—becomes more important. It is one of the few reliable ways to offset the natural wasting process and the damaging influence of our unnaturally sedentary modern lives. It also points to new possibilities for the brain to heal itself in the face of disease and trauma. 

For decades, physicians and scientists generally believed that the prognosis for most brain problems was grim. The standard view was that the brain had evolved to be so complex and specialized that we had to pay a price for its sophistication: It couldn’t repair or restore itself with replacement parts, as was possible with other organs, such as the skin, liver and blood. 

That view fit with, and partly stemmed from, an image that had prevailed since the days of the great French philosopher and scientist René Descartes, who described the brain as a glorious machine with discrete parts. Descartes’s heirs argued that each of these parts performed a single mental function in a single location. If a part was damaged—by a genetic fault, or stroke, or injury or disease—it was assumed that the body had no resources of its own to deal with the problem: After all, machines cannot repair themselves or spontaneously grow new parts. 

Once the electrical nature of the brain was delineated in the 19th century, scientists began speaking of it as a grander sort of machine, an electrical one, with “circuits”—a metaphor still very much with us. They came to see its circuits as analogous to those of electronic gadgets—unchangeable or “hard-wired.As the machine metaphor evolved, neuroscientists took to describing the brain as a computer. This “master analogy,” as computer scientist David Gelernter calls it (in criticizing this view), encourages us to see thought as “software” and the brain’s structure as “hardware.”

The unhappy practical implication of this view, for anyone wishing to maintain his or her brain, is clear: Hardware inevitably degenerates with time and use. The rule for a machine is, “Use it and lose it.” Many clinicians under the sway of this analogy saw patients’ attempts to resist their brains’ decline through activity and mental exercise as a harmless waste of time. 

Fortunately, a growing body of research suggests that this older view is wrong. It seems that a more accurate rule for our brains is “Use it or lose it.” 

In the late 1970s, research by Mark Rosenzweig of the University of California at Berkeley and Michael Merzenich of the University of California at San Francisco and others began to show that the brain’s circuitry changes microscopically with experience and activity.Dr. Rosenzweig and colleagues found that, with environmental stimulation, the brains of animals grew in key areas. Dr. Merzenich discovered that if an animal stopped using a body part, the brain area that processed sensory input from that part weakened or was taken over to perform another function. These findings have since been replicated many times. 

The mainstream view in neuroscience and medicine today is that the living brain is actually “neuroplastic”—meaning that its “circuits” are constantly changing in response to what we actually do out in the world. As we think, perceive, form memories or learn new skills, the connections between brain cells also change and strengthen. Far from being hard-wired, the brain has circuits that very rapidly form, unform and reform. 

This capacity is the foundation for the brain’s distinctive way of healing. If an area is damaged, new neurons can often take over old tasks. Nor are we just our neurons. Our memories and experiences are also encoded in the patterns of electrical energy produced by our brain cells, like a musical score. As with an orchestra, when one member of the string section is sick, the show can still go on if a replacement has access to the musical score.

This new “plastic” understanding has major practical implications for how we treat brain problems and maintain brain health. And it has led to some surprising discoveries.

Consider dementia, which in some form affects some 15% of people in the U.S. over age 70 and advances rapidly as we age. A brain with Alzheimer’s, the most common form of dementia, turns out, by various measures, to be a brain that is losing its overall plasticity. It shrinks and loses connections. But a growing body of research has found that exercise, both mental and physical, can lower the risk of experiencing dementia.

Last year, Peter Elwood and a team from the Cochrane Institute of Primary Care and Public Health at Cardiff University in the U.K. released results from the most detailed study ever done on the effect of lifestyle and exercise on the risk of getting dementia. The researchers followed 2,235 men—almost all the male inhabitants of Caerphilly, Wales, with initial ages between 45 and 59 years old—for 30 years.

They found that men who consistently did a few things reduced their risk for cognitive decline and dementia by a staggering 60%. These activities included eating a healthy diet (at least three to four servings of fruits and vegetables a day); maintaining a normal weight, with a body-mass index from 18 to under 25; limiting alcohol to about a glass of wine a day; and not smoking.But the activity with the biggest impact on risk was walking at least 2 miles a day, biking 10 miles a day or engaging in some other regular, vigorous physical exercise. All five of these factors have been found in other studies to promote the general health of two types of cells in the brain: neurons and glial cells (which interact with and protect neurons). 

Imagine if there were a drug that could reduce the risk of dementia by 60%. It would be the most talked-about drug in history, but this astonishing finding has been fairly quietly received. 

One reason is that many people assume that Alzheimer’s disease is “all in your genes.” But as neurologist and dementia researcher Tiffany Chow of the Rotman Research Institute and the University of Toronto points out, environmental factors “interact with…genetic makeup to eventually allow or deny dementia a foothold.” Even having multiple copies of the genetic materials associated with risk, Dr. Chow points out, “is not sufficient to produce Alzheimer’s disease.” For the majority of people, how they live matters. 

The research in Wales followed at least 10 other studies showing that exercise in midlife was associated or correlated with lower rates of dementia—and that a lack of regular exercise corresponded with higher rates of dementia. 

Another recent study—a randomized, controlled trial by Kirk Erickson of the University of Pittsburgh and colleagues published in the Proceedings of the National Academy of Sciences—shows that those without dementia who did aerobic exercise for a year showed significant hippocampal enlargement. The hippocampus is the brain region that turns short-term memories into long-term ones, and it is often the first to degenerate in Alzheimer’s cases and with age in general. Earlier studies showed aerobic exercise increased the brain’s gray and white matter in the frontal lobes, areas involved in planning and goal-directed activity.

How does this form of healing work? Exercise triggers the growth of new brain cells in the hippocampus. It also triggers the release of “neurotrophic growth factors”—a kind of brain fertilizer, helping the brain to grow, maintain new connections and stay healthy.

Frederick Gage of the Salk Institute, co-discoverer of stem cells in the brain, has suggested that new cells arise from long walks because, in an evolutionary sense, our bodies associate the exertion with moving from an existing territory, which had perhaps become depleted of food or too dangerous, to a new, unexplored territory whose details must be learned. In anticipation, the brain releases new cells and growth factors, which create a more plastic state and make possible new neural connections. This may be one of the mechanisms by which exercise helps to protect against diseases such as Alzheimer’s.

Recent studies have also found that exercise can reduce the symptoms of Parkinson’s—a degenerative disease that causes patients to gradually lose control of their muscles. Parkinson’s treatment has primarily focused on medication, with exercise as something of a distant runner-up.

But in 2011, a study of these issues was published in the journal Neurology. J. Eric Ahlskog of the Mayo Clinic reviewed the available evidence about exercise and Parkinson’s, in animals and humans. Vigorous exercise, for purposes of the study, included walking, swimming and “physical activity sufficient to increase heart rate and the need for oxygen.” He concluded that exercise deserved a “central place” in the treatment of Parkinson’s. 

A 2014 randomized study of Parkinson’s patients at the University of Iowa, led by researcher Ergun Uc, found that walking three times a week for 45 minutes for six months improved patients’ mood and Parkinsonian movement symptoms; the exercise also decreased their fatigue. Though the patients were on anti-Parkinson’s medication, the improvements could not be attributed to medication alone.

Parkinson’s patients are caught in a tightening noose. They may be helped by fast walking, but fast walking is precisely what they can no longer easily do. And the Parkinson’s patient who cannot walk does not “stay still”—his disease gets worse. Because our plastic brains are “use it or lose it” organs, when walking becomes more difficult, walking less will cause whatever walking circuits the patient still has to wither from disuse. 

When people with dormant brain circuits try to walk, they fail, “learn” that they can’t walk and stop trying. This is called “learned nonuse,” a phenomenon first seen in human beings who have suffered a stroke—caused by a blood clot or a bleed that cuts off the blood supply and oxygen to brain tissue and killing it. 

We have known for more than a century that, after a stroke, the brain enters a state of shock: Neurons die, chemicals leak out of some cells and harm others, inflammation is very active, and blood flow around the dead tissue is interrupted. All of these events disrupt functioning not just where the stroke occurred but throughout the brain. The period typically lasts six weeks or longer. 

Physicians once treated such dire problems by waiting six weeks to see what mental functions their stroke patients still had. Since conventional medical wisdom held that the brain couldn’t “rewire” itself or develop new connections, physicians just wanted to discover which cognitive abilities remained after the shock wore off. The rehabilitation that patients underwent merely attempted to reawaken whatever circuits had been spared. 

But the plasticity of the brain provides better options. Edward Taub, a neuroscientist at the University of Alabama at Birmingham who discovered “learned nonuse,” has had striking results with patients who have lost the use of limbs from strokes and haven’t gotten better with conventional rehabilitation. He puts the patient’s good arm in a sling (so they can’t use it), for instance, and then incrementally and intensively trains the paralyzed or partially paralyzed arm. 

Brain-scan studies show that when patients recover under Dr. Taub’s treatment, neurons adjacent to the injury begin to take over from the damaged or dead neurons. More recently, the approach has worked with stroke patients who can no longer speak and with movement problems from multiple sclerosis, cerebral palsy and even movement problems that occur after radiation to the brain for cancer. Learned nonuse seems to occur in response to many brain problems, so dormant circuits, awaiting to be revived, are far more common than has been generally appreciated.

Among the most exciting new neuroplastic treatments are those that deal with “the noisy” brain—that is, neurons that fire out of sync or at the wrong rates in conditions like multiple sclerosis and Parkinson's disease, but also in traumatic brain injuries, learning disorders, conditions on the autism spectrum and some cases of chronic pain. 

A range of noninvasive methods has yielded radical improvements in all these diseases, allowing scientists and clinicians to “resynchronize” the noisy brain. Our brains work on patterns of electrical energy, and we can change the patterns of brain-firing with sensory input. When you hear a loud pounding beat, for instance, your neurons fire in sync to that frequency, a process called “entrainment.”

Using sound frequencies passed into the ears (which convert patterns of sound energy into patterns of electrical energy), it has been possible to cure some learning disorders and developmental delays, as well as to radically improve the lives of some autistic children. Scientists and doctors using mild forms of electricity to turn on touch receptors in the tongue have been able to reduce the symptoms of MS, Parkinson’s and brain injuries—and even to cure some strokes. 

Clinical work in Toronto and studies at Harvard and in Israel have shown that low-intensity lasers applied to the back of the neck can diminish stroke and brain-injury symptoms. And new forms of “conscious walking” that allow Parkinson’s patients to learn to use healthy parts of their brains to take over from damaged areas can sometimes get them moving again.

The basic neuroplastic principle of “use it or lose it” and the benefit of forming new brain connections through intensive learning also apply to people without brain problems. Physical exercise produces some new cells in the memory system, but mental exercise preserves and strengthens existing connections in the brain, giving a person a “cognitive reserve” to fend off future losses and to perfect skills. 

Brain exercises developed by the neuroscientist Dr. Merzenich have been evaluated in a National Institutes of Health study, published by George Rebok of the Johns Hopkins School of Medicine and colleagues in the Journal of the American Geriatrics Society. People who did the brain exercises—called Brain HQ—showed benefits 10 years later. They didn’t just improve on the brain exercises; their cognitive function improved in everyday life. Earlier studies showed that the exercises increased a person’s mental sharpness, so they could process information with the speed and accuracy they had when they were 10 years younger.

We still have a lot to learn about the brain and its powers of recovery, of course. But increasingly we have the evidence to conclude that we have been seeing our brains the wrong way for too long. Metaphors often conceal as much as they reveal. One day, we may well marvel at how odd it was that, for several centuries, we chose to view our ever-changing, activity-craving, animate brains as fixed, passive, inanimate machines. 

Dr. Doidge teaches in the University of Toronto’s department of psychiatry and is on the research faculty at Columbia University’s Center for Psychoanalytic Training and Research. His latest book is “The Brain’s Way of Healing” (Viking), from which this is adapted.

Corrections & Amplifications

An earlier version of this article incorrectly said that a study found a body-mass index of 18 and 25 beneficial for men; the article should have said the index ranged from 18 to under 25.

http://www.wsj.com/articles/our-amazingly-plastic-brains-1423262095

23andMe: Quest for Parkinson's cure opens door to genetic data mining

By Kim Smuga-Otto 

ksmugaotto@mercurynews.com

CREATED:   02/08/2015 04:20:34 PM PST

Members of a Parkinson's disease choir group practice at the Episcopal Church of St. John in Aptos, Calif., Thursday, Jan. 22, 2015. The choir group meets weekly and they find singing helps them manage their symptoms. (Patrick Tehan/Bay Area News Group) ( Patrick Tehan )

Even seated, Mary Haynes' body is perpetually in motion. Her torso lurches side to side when she speaks, while Mike Tossy's body is noticeably still. His eyes dart around, but his head rarely turns.

Both Haynes and Tossy suffer from Parkinson's disease -- a neurodegenerative disorder affecting nearly a million Americans. They are also two of 11,000 customers of 23andMe with Parkinson's participating in the DNA testing company's research program.

By analyzing the customers' DNA, the Mountain View company has helped discover eight new mutant genes linked to the disease. Now Haynes and Tossy could be asked to make their genetic codes available for deeper scrutiny -- a possibility that would test the boundaries of privacy in medical research.In January, the DNA testing firm announced a $10 million deal with Genentech to give the South San Francisco pharmaceutical company access to the genetic data of 23andMe's customers with Parkinson's.

It's a new Silicon Valley frontier: Just as marketing companies are mining your Internet browsing habits to design the killer ad, new technologies are allowing pharmaceutical companies like Genentech to mine our DNA to create the next generation of drugs.

The collaboration between the two valley firms is aimed at uncovering proteins responsible for the disease, but it also raises some privacy concerns for customers of 23andMe who have previously agreed to give the company and its partners access to their genetic data -- and who may now be asked to release even more information about themselves.

Haynes, 69, of Capitola, is only partially wary. She says she realizes "it makes me kind of a guinea pig," but believes that "anything that moves us towards a cure is OK with me." And Tossy, a Soquel resident, feels the same way.

Members of a Parkinson's disease choir group practice at the Episcopal Church of St. John in Aptos, Calif., Thursday, Jan. 22, 2015. From left are: Suzanne Nickel, Mary Haynes, Mike Tossy and Robert Pardun. The choir group meets weekly and they find singing helps them manage their symptoms. (Patrick Tehan/Bay Area News Group) ( Patrick Tehan 

For now, Parkinson's is shrouded in mystery.

No single gene is responsible for the disorder. A few mutated genes have been linked to it, but the majority of those who suffer from Parkinson's have healthy versions of these genes. Scientists think it results from a subtle interplay between environmental factors and a multitude of genes that causes key neurons to die.

By the time symptoms -- a hand tremor or a stumbling gait -- appear, more than half of these cells are dead, or nonfunctioning.

Drugs like Levodopa or brain surgery can slow the progression, but eventually patients lose control over their bodies and need constant care.

Genentech hopes to use 23andMe's massive database to gain new insight about what may be breaking down inside the neurons. "We're hoping it gives a clue about Parkinson's genetic Achilles' heel," said Tim Behrens, Genentech's senior director of human genetics.

It was 23andMe's personal connection to Parkinson's that makes Haynes trust the company's intentions. The company's co-founder and CEO Anne Wojcicki's estranged husband, Google co-founder Sergey Brin, is a carrier for a mutant gene that increases his risk for Parkinson's. Brin's mother has the disease.

Scientists often talk of "reading" DNA. The human genome has about 3 billion "letters" -- the chemical subunits that make up someone's DNA -- but only a tiny fraction of these letters code our genes.

Currently, 23andMe uses DNA chips to analyze 750,000 letters, less than 1 percent. For the Genentech study, 23andMe will sequence the whole genomes of 3,000 customers.

"This will be one of the largest genetic studies that has ever been done in Parkinson's," said Todd Sherer, CEO of the Michael J. Fox Foundation.

When customers sign up for 23andMe's research group, they agree to allow the company or outside researchers to search for patterns in their DNA. Their account details -- names, email addresses and credit card numbers -- are separated from their genetic data and surveys that reveal their medical histories.

Right now, 23andMe researchers never have access to a single person's results. But they can, for example, compare women with Parkinson's who were diagnosed in their 50s and find out what percent have a particular gene variation.

The new deal with Genentech grants a different level of access.

Scientists will be able to explore an individual's DNA. Looking at Tossy's genome file, for example, they wouldn't know his name, but they would know that he was a 58-year-old male and they could identify the file of his mother -- a 23andMe customer with Parkinson's -- based on his DNA sequence.

To include Tossy, or his mother, in this research, both would have to sign new consent forms.

John Simpson, the privacy project director of Santa Monica-based Consumer Watchdog, believes such an "opt-in" approach is the right way to proceed, but he hopes the companies make data and approaches as transparent as possible. "They have a responsibility to keep the research subjects fully informed about where the research is headed," he said.

Tossy said he would be willing to give 23andMe that permission, but he'd want to know that his data would be used strictly for Parkinson's research.

There are several protections in place. Genentech will have exclusive access to data for a limited time. And the specifics of what they can review will be overseen by an independent institutional review board.

Parkinson's research and advocacy groups are enthusiastic about the possibilities of the collaboration. "We're excited to see the industry stepping in and making a major investment in Parkinson's," said Parkinson's Institute's CEO, Carolee Barlow.

For Tossy and Haynes, it's more personal. "The disease marches on," Haynes said, "and the part of our brain that is doing this is getting smaller and smaller."

Contact Kim Smuga-Otto at 408-920-5764. Follow her at Twitter.com/kim_smuga.

Singing therapy helps Parkinson's patients

Feb.8, 2015

Researchers at Iowa State University have been using music as therapy for

 patients with Parkinson’s disease.

Patients were first tested on pitch duration, vocal loudness, respiratory pressure

 and swallow control to set a baseline. Then, once a week for eight weeks, they

 all gathered together to sing simple songs. The end result? All showed

 significant improvement.

Since Parkinson’s is progressive, being able to maintain a function can be 

important for continued muscle control. Participants were shown to have 

positive changes in voice, speaking and breathing, and experienced reduced 

stress and anxiety, improved communication and well-being, and even better 

memory as they learned new songs.

The physical aspects aren’t the only areas that benefited. Interaction with others

 who have Parkinson’s has brought the group together socially. Even though the

 study is officially over, they still meet every week to keep singing ... because

 they know what it does for them.

The program has been so successful that researchers plan to do another study

 for a 10-week period. They’ll test this year’s participants to see if there are 

differences between those who continued to sing and those who didn’t.

Singing as therapy for Parkinson’s apparently isn’t new. As far back as 2011,

 Northwestern Memorial Hospital in Chicago has used music and drama for their 

therapeutic benefits to Parkinson’s patients. It has documented benefits in

 movement, posture, speech and voice, as well as mood and attitude, goal 

setting and encouraging others. In the drama section, the participants read

 scripts, which helps memory recall and articulation.

If you have Parkinson’s or know someone who does, investigate singing therapy 

in your area. If there isn’t a program, encourage the local hospital to begin one.

http://health.einnews.com/article/248762218/bNrOiWqikqQ_K3AH