Stephen Hawking’s Beautiful Message For Anyone With Depression.


Stephen Hawking has one of the greatest minds of our time. He is well known for his work in theoretical physics, and was born on January 8, 1942, (300 years after the death of Galileo) in Oxford, England. As a young child, he wanted to study mathematics, but once he began college, he studied Natural Sciences. Then, during his first year in Cambridge at the age of 21, Hawking began to have symptoms of ALS (amyotrophic lateral sclerosis). Doctors gave him two and a half years to live.

Now, at the age of 74, he continues to teach, research, and provide the world with beautiful messages. He says that his expectations were reduced to zero when he was given the ALS diagnosis. Ever since then, every aspect of his life has been a bonus.

One of the most brilliant minds did not allow these life challenges to stop him. He continued studying. Hawking has twelve honorary degrees. He has dedicated his life to finding answers about the universe, the Big Bang, creation and scientific theories.He cannot speak or move, bounded to a wheelchair, but he has found ways to inspire the world, encouraging us to find the mysticism in the stars. He says:

 “Remember to look up at the stars and not down at your feet. Never give up work. Work gives you meaning and purpose and life is empty without it. If you are lucky enough to find love, remember it is there and don’t throw it away.”

Recently during a lecture in January at the Royal Institute in London, Hawking compared black holes to depression, making it clear that neither the black holes or depression are impossible to escape. “The message of this lecture is that black holes ain’t as black as they are painted. They are not the eternal prisons they were once thought. Things can get out of a black hole both on the outside and possibly to another universe. So if you feel you are in a black hole, don’t give up; there’s a way out,” he said.

 When asked about his disabilities, he says: “The victim should have the right to end his life, if he wants. But I think it would be a great mistake. However bad life may seem, there is always something you can do, and succeed at. While there’s life, there is hope.” He continues with an inspiring message about disabilities:
“If you are disabled, it is probably not your fault, but it is no good blaming the world or expecting it to take pity on you. One has to have a positive attitude and must make the best of the situation that one finds oneself in; if one is physically disabled, one cannot afford to be psychologically disabled as well. In my opinion, one should concentrate on activities in which one’s physical disability will not present a serious handicap. I am afraid that Olympic Games for the disabled do not appeal to me, but it is easy for me to say that because I never liked athletics anyway. On the other hand, science is a very good area for disabled people because it goes on mainly in the mind. Of course, most kinds of experimental work are probably ruled out for most such people, but theoretical work is almost ideal.

My disabilities have not been a significant handicap in my field, which is theoretical physics. Indeed, they have helped me in a way by shielding me from lecturing and administrative work that I would otherwise have been involved in. I have managed, however, only because of the large amount of help I have received from my wife, children, colleagues and students. I find that people in general are very ready to help, but you should encourage them to feel that their efforts to aid you are worthwhile by doing as well as you possibly can.”

Stephen Hawking does not only encourage the scientific minds to pay attention, but inspires the rest of us to take notice that there is connection between the stars and each one of us. His disabilities have not stopped his curious mind and sense of wonder.

His daughter, Lucy, shared with the crowd at the lecture, “He has a very enviable wish to keep going and the ability to summon all his reserves, all his energy, all his mental focus and press them all into that goal of keeping going. But not just to keep going for the purposes of survival, but to transcend this by producing extraordinary work writing books, giving lectures, inspiring other people with neurodegenerative and other disabilities.”

Study shows more patients with ALS have genetic origin than previously thought


DNA illustration.

Investigators Also Find That ALS Patients With Mutations in Multiple Genes Experience Earlier Disease Onset

Genetics may play a larger role in causing amyotrophic lateral sclerosis (ALS) than previously believed, potentially accounting for more than one-third of all cases, according to one of the most comprehensive genetic studies to date of patients who suffer from the condition.

The study, conducted by investigators at Cedars-Sinai and Washington University in St. Louis, also showed that patients with defects in two or more ALS-associated genes experience disease onset about 10 years earlier than patients with single-gene mutations.

“These findings shed new light on the genetic origins of ALS, especially in patients who had no prior family history of the disease,” said Robert H. Baloh, MD, PhD, director of neuromuscular medicine in the Department of Neurology and director of the ALS Program at Cedars-Sinai. Baloh is senior author of the study, published online in Annals of Neurology.

Typically, researchers classify 90 percent of ALS cases as “sporadic,” meaning they occur in patients without a family history of the disease. In their study, however, the researchers found a significant degree of genetic involvement in patients with no family history. Examining DNA from 391 individuals, they identified numerous new or very rare ALS gene mutations in such people. Added to the 10 percent of cases already known to be genetic because of family history, the study suggested that more than one-third of all ALS could be genetic in origin.

Baloh said the presence of the new and rare mutations, found among 17 genes already known to be associated with ALS, does not necessarily mean they all cause the disease. But they are considered likely suspects — especially in combination. ALS often is caused by well-known defects in single genes, but recent studies have suggested that some cases could be brought on by the simultaneous occurrence of two or more “lesser” genetic defects. In theory, each mutation alone might be tolerated without initiating disease, but in combination they exceed the threshold required for disease development.

This study strengthens that possibility: Fifteen patients — nine of whom had no previous family history of ALS — had mutations in two or more ALS-associated genes. The research also takes an important next step, showing that multiple genetic defects can influence the way disease manifests in individual patients. Those with mutations in two or more genes had onset about 10 years earlier than those with defects in only one gene.

Matthew B. Harms, MD, assistant professor of neurology at Washington University and co-corresponding author of the article, said that unknown factors still accounted for the majority of ALS cases.

“This tells us that more research is needed to identify other genes that influence ALS risk, and that ultimately, individuals may have more than one gene contributing toward developing disease,” Harms said.

ALS is an incurable, virtually untreatable neurodegenerative disease that attacks motor neurons — nerve cells responsible for muscle function — in the brain and spinal cord. It causes progressive weakness and eventual failure of muscles throughout the body; patients typically survive three to five years after onset.

Investigators in this study used new-generation technology that quickly and efficiently determines the organizational structure of large numbers of genes. They expect this and similar research to usher in personalized medicine in ALS that will allow healthcare teams to analyze a patient’s entire genetic makeup and deliver gene-specific therapies to correct detected defects. Cedars-Sinai researchers recently conducted a disease-in-a-dish study with cells from patients with defects in a gene that commonly causes ALS. Using small segments of genetic material to target the defects, they showed that this type of gene therapy can improve neurons from patients with the disease.

These individualized-treatment studies recently received a $1.6-million boost from the ALS Association, which awarded the funds to the Cedars-Sinai Board of Governors Regenerative Medicine Institute as part of an initial distribution of money raised by the ALS Ice Bucket Challenge. With this funding, investigators will employ a specialized stem cell process to create motor neurons from a large number of patients with ALS.

ALS: Renewing brain’s aging support cells may help neurons survive


Thick section of mammalian brain, gold stained for astrocytes.

ALS research shows that aging astrocytes lose the ability to protect motor neurons, but replacing old cells with younger ones engineered to restore an important protein may improve neuron survival

Amyotrophic lateral sclerosis (ALS), attacks motor neurons in the brain, brainstem and spinal cord, leading to progressive weakness and eventual paralysis of muscles throughout the body. Patients typically survive only three to five years after diagnosis.

Now, with publication of a study by investigators at the Cedars-Sinai Board of Governors Regenerative Medicine Institute, ALS researchers know the effects of the attack are worsened, at least in part, by the aging and failure of support cells called astrocytes, which normally provide nutrients, housekeeping, structure and other forms of assistance for neurons.

Earlier studies suggested the possible involvement of these support cells in ALS development and progression, but the new research is believed to be the first to directly measure the effects of aging on the ability of astrocytes to sustain motor neurons. Results are published online inNeurobiology of Aging.

The Cedars-Sinai researchers first tried to repeat previous studies showing that astrocytes from laboratory animals with an ALS mutation failed to support normal motor neurons. They were surprised to find that very young ALS astrocytes were supportive, but ALS astrocytes from older animals were not. More surprisingly, it wasn’t just diseased astrocytes that were affected by age. The scientists discovered — and reported for the first time — that even normal aging of astrocytes reduces their ability to support motor neurons.

“Aging astrocytes lose their ability to support motor neurons in general, and they clearly fail to help those attacked by ALS,” said Clive Svendsen, PhD, professor and director of the Board of Governors Regenerative Medicine Institute, the article’s senior author.

He said old astrocytes and ALS-affected astrocytes have lower death rates in the petri dish than younger ones — they seem to hang around longer and accumulate. But while older astrocytes and those with the ALS mutation live longer, they appear to have significant damage to their DNA. Instead of being cleared away for replacement by new, healthy cells, the old, defective cells become useless clutter, producing chemicals that cause harmful inflammation. The process is accelerated in ALS astrocytes.

“Our findings have implications for scientists studying neurodegenerative diseases like ALS and Alzheimer’s and the aging process in general. In younger animals modeling ALS and in older ‘normal’ animals, the accumulations of defective astrocytes in the nervous system look similar,” said Melanie Das, PhD, a student in the Cedars-Sinai Graduate Program in Biomedical Science and Translational Medicine, the article’s first author.

After establishing the effects of aging on astrocytes, the researchers took another step — evaluating the potential therapeutic effects of a specially engineered protein.

“We found that by culturing aging astrocytes and those harboring the ALS mutation with a neuron-protective protein called GDNF, we could increase motor neuron survival. We already knew that GDNF was protective directly on motor neurons, but we believe this is the first time that the delivery of GDNF has been shown to have a direct beneficial effect on astrocytes, perhaps resetting their aging clock, which ultimately benefits neurons,” Svendsen said.

Svendsen and scientists in his laboratory have studied GDNF extensively, devising experimental methods to restore beneficial levels in the brain and spinal cord — where the disease originates — and in muscles, at the point where nerve fibers connect with muscle fibers to stimulate muscle action. Several large GDNF-related research projects taking shape at Cedars-Sinai are funded by the California Institute for Regenerative Medicine.

“Our major CIRM-funded programs, aimed at engineering young stem cell-derived astrocytes to secrete GDNF, then transplanting those cells back into patients, take on even greater importance, given this aging phenomenon,” said Svendsen, the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine.

Scientists identify spark plug that ignites nerve cell demise in ALS


myelin

False-colored scanning electron micrograph of myelinated nerve fibers.

Scientists from Harvard Medical School have identified a key instigator of nerve cell damage in people with amyotrophic lateral sclerosis, or ALS, a progressive and incurable neurodegenerative disorder.

Researchers say the findings of their study, published Aug. 5 in the journal Science, may lead to new therapies to halt the progression of the uniformly fatal disease that affects more than 30,000 Americans. One such treatment is already under development for testing in humans after the current study showed it stopped nerve cell damage in mice with ALS.

The onset of ALS, also known as Lou Gehrig’s disease, is marked by the gradual degradation and eventual death of neuronal axons, the slender projections on nerve cells that transmit signals from one cell to the next.

The HMS study reveals that the aberrant behavior of an enzyme called RIPK1 damages neuronal axons by disrupting the production of myelin, the soft gel-like substance enveloping axons to insulate them from injury.

“Our study not only elucidates the mechanism of axonal injury and death but also identifies a possible protective strategy to counter it by inhibiting the activity of RIPK1,” said the study’s senior investigator Junying Yuan, the Elizabeth D. Hay Professor of Cell Biology at HMS.

The new findings come on the heels of a series of pivotal discoveries made by Yuan and colleagues over the last decade revealing RIPK1 as a key regulator of inflammation and cell death. But up until now, scientists were unaware of its role in axonal demise and ALS.

Experiments conducted in mice and in human ALS cells reveal that when RIPK1 is out of control, it can spark axonal damage by setting off a chemical chain reaction that culminates in stripping the protective myelin off of axons and triggering axonal degeneration–the hallmark of ALS.

RIPK1, the researchers found, inflicts damage by directly attacking the body’s myelin production plants–nerve cells known as oligodendrocytes, which secrete the soft substance, rich in fat and protein that wraps around axons to support their function and shield them from damage.

Building on previous work from Yuan’s lab showing that the activity of RIPK1 could be blocked by a chemical called necrostatin-1, the research team tested how ALS cells in lab dishes would respond to the same treatment. Indeed, necrostatin-1 tamed the activity of RIPK1 in cells of mice genetically altered to develop ALS.

In a final set of experiments, the researchers used necrostatin-1 to treat mice with axonal damage and hind leg weakness, a telltale sign of axonal demise similar to the muscle weakness that occurs in the early stages of ALS in humans. Necrostatin-1 not only restored the myelin sheath and stopped axonal damage but also prevented limb weakness in animals treated with it.

Connecting the Dots

At the outset of their experiments, investigators homed in on a gene called optineurin (OPTN). Past research had revealed the presence of OPTN defects in people with both inherited and sporadic forms of ALS, but scientists were not sure whether and how OPTN was involved in the development of the disease. To find out, researchers created mice genetically altered to lack OPTN. Examining spinal cord cells under a microscope, the scientists noticed that the axons of mice missing the OPTN gene were swollen, inflamed and far fewer in number, compared with spinal cord cells obtained from mice with the OPTN gene. These axons also bore signs of myelin degradation. Strikingly, the researchers noticed the same signs of axonal demise in spinal cord cells obtained from human patients with ALS. Mice with OPTN deficiency also exhibited loss of strength in their hind legs. Further experiments revealed that lack of OPTN was particularly harmful to myelin-secreting cells. Thus, the researchers concluded, OPTN deficiency was directly incapacitating the nervous system’s myelin factories. But one question remained: How did the absence of OPTN damage these cells?

A Smoking Gun

Looking for the presence of chemicals commonly seen during inflammation and cell death, the researchers noticed abnormally high levels of RIPK1–a known promoter of cell death–in spinal cord cells from mice lacking OPTN. Moreover, the scientists observed traces of other damaging chemicals often recruited by RIPK1 to kill cells.

“It was as if we saw the chemical footprints of cell death left behind by RIPK1 and its recruits,” Yuan said.

That observation, Yuan added, was the smoking gun linking RIPK1’s misbehavior to OPTN deficiency. In other words, researchers said, when functioning properly, the OPTN gene appears to regulate the behavior of RIPK1 by ensuring its levels are kept in check, that it is broken down fast and that it is cleared out of cells in a timely fashion. In the absence of such oversight, however, RIPK1 appears to get out of control and cause mischief.

In a closing set of experiments, the researchers examined neurons obtained from mice with the most common inherited form of ALS, one caused by mutations in a gene called SOD1. Indeed, RIPK1 levels were elevated in those cells too. Thus, the investigators said, OPTN may not be the sole gene regulating RIPK1’s behavior. Instead, RIPK1 appears to fuel axonal damage across various forms of inherited and acquired forms of ALS.

The findings suggest that RIPK1 may be involved in a range of other neurodegenerative diseases marked by axonal damage, including multiple sclerosis, certain forms of spinal muscular atrophy and even Alzheimer’s disease.

The Harvard Office of Technology Development (OTD) and collaborating institutions have developed a patent portfolio for RIPK1 modulating compounds. Harvard OTD has licensed the patent to a biotechnology company.

Environmental Pollutants May Be Linked to ALS


Pesticide exposure and pollutants were measured in patients’ blood.

A study appearing in JAMA Neurology links environmental pollutants to the development of amyotrophic lateral sclerosis. In this 150-second video analysis, MedPage Today clinical reviewer F. Perry Wilson MD, addresses the three issues with risk factor research exemplified in this study.

Importance  Persistent environmental pollutants may represent a modifiable risk factor involved in the gene-time-environment hypothesis in amyotrophic lateral sclerosis (ALS).

Objective  To evaluate the association of occupational exposures and environmental toxins on the odds of developing ALS in Michigan.

Design, Setting, and Participants  Case-control study conducted between 2011 and 2014 at a tertiary referral center for ALS. Cases were patients diagnosed as having definitive, probable, probable with laboratory support, or possible ALS by revised El Escorial criteria; controls were excluded if they were diagnosed as having ALS or another neurodegenerative condition or if they had a family history of ALS in a first- or second-degree blood relative. Participants completed a survey assessing occupational and residential exposures. Blood concentrations of 122 persistent environmental pollutants, including organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and brominated flame retardants (BFRs), were measured using gas chromatography–mass spectrometry. Multivariable models with self-reported occupational exposures in various exposure time windows and environmental toxin blood concentrations were separately fit by logistic regression models. Concordance between the survey data and pollutant measurements was assessed using the nonparametric Kendall τ correlation coefficient.

Main Outcomes and Measures  Occupational and residential exposures to environmental toxins, and blood concentrations of 122 persistent environmental pollutants, including OCPs, PCBs, and BFRs.

Results  Participants included 156 cases (mean [SD] age, 60.5 [11.1] years; 61.5% male) and 128 controls (mean [SD] age, 60.4 [9.4] years; 57.8% male); among them, 101 cases and 110 controls had complete demographic and pollutant data. Survey data revealed that reported pesticide exposure in the cumulative exposure windows was significantly associated with ALS (odds ratio [OR] = 5.09; 95% CI, 1.85-13.99; P = .002). Military service was also associated with ALS in 2 time windows (exposure ever happened in entire occupational history: OR = 2.31; 95% CI, 1.02-5.25; P = .046; exposure ever happened 10-30 years ago: OR = 2.18; 95% CI, 1.01-4.73; P = .049). A multivariable model of measured persistent environmental pollutants in the blood, representing cumulative occupational and residential exposure, showed increased odds of ALS for 2 OCPs (pentachlorobenzene: OR = 2.21; 95% CI, 1.06-4.60; P = .04; and cis-chlordane: OR = 5.74; 95% CI, 1.80-18.20; P = .005), 2 PCBs (PCB 175: OR = 1.81; 95% CI, 1.20-2.72; P = .005; and PCB 202: OR = 2.11; 95% CI, 1.36-3.27; P = .001), and 1 BFR (polybrominated diphenyl ether 47: OR = 2.69; 95% CI, 1.49-4.85; P = .001). There was modest concordance between survey data and the measurements of persistent environmental pollutants in blood; significant Kendall τ correlation coefficients ranged from −0.18 (Dacthal and “use pesticides to treat home or yard”) to 0.24 (trans-nonachlor and “store lawn care products in garage”).

Conclusions and Relevance  In this study, persistent environmental pollutants measured in blood were significantly associated with ALS and may represent modifiable ALS disease risk factors.

Read the full article in JAMA. URL: http://archneur.jamanetwork.com/article.aspx?articleid=2519875

How Has Stephen Hawking Lived Past 70 with ALS?


An expert on Lou Gehrig’s disease explains what we know about this debilitating condition and how Hawking has beaten the odds
stephen hawking
Stephen Hawking turns 70 on Sunday, beating the odds of a daunting diagnosis by nearly half a century.

The famous theoretical physicist has helped to bring his ideas about black holes and quantum gravity to a broad public audience. For much of his time in the public eye, though, he has been confined to a wheelchair by a form of the motor-neuron disease amyotrophic lateral sclerosis (ALS). And since 1985 he has had to speak through his trademark computer system—which he operates with his cheek—and have around-the-clock care.

But his disease seems hardly to have slowed him down. Hawking spent 30 years as a full professor of mathematics at the University of Cambridge. And he is currently the director of research at the school’s Center for Theoretical Cosmology.

But like his mind, Hawking’s illness seems to be singular. Most patients with ALS—also known as Lou Gehrig’s disease, for the famous baseball player who succumbed to the disease—are diagnosed after the age of 50 and die within five years of their diagnosis. Hawking’s condition was first diagnosed when he was 21, and he was not expected to see his 25th birthday.

Why has Hawking lived so long with this malady when so many other people die so soon after diagnosis? We spoke with Leo McCluskey, an associate professor of neurology and medical director of the ALS Center at the University of Pennsylvania, to find out more about the disease and why it has spared Hawking and his amazing brain.

[An edited transcript of the interview follows.]

What is ALS—and is there more than one form of it?
ALS, which is also known as a motor-neuron disease—and colloquially as Lou Gehrig’s disease in the U.S.—is a neurodegenerative disease. Each muscle is controlled by motor neurons that reside in the brain in the frontal lobe. These are controlled electrically and are synaptically connected to motor neurons that reside lower down in the brain—as well as motor neurons that reside in the spinal cord. The guys in the brain are called the upper motor neurons, and the guys in the spine are called the lower motor neurons. The disease causes weakness of either upper motor neurons or lower motor neurons or both.

It’s been known for quite some time that there are variants of ALS. One is referred to as progressive muscular atrophy, or PMA. It appears to be an isolated illness of the lower motor neurons. However, pathologically, if you do an autopsy of a patient, they will have evidence of deterioration of upper motor neurons.

There is also primary lateral sclerosis—PLS—and clinically it looks like an isolated upper motor-neuron disorder. However, pathologically they also have lower motor-neuron disorder.

The other classic syndrome is called progressive baldor palsy—or progressive supranuclear palsy—which is weakening of cranial muscles, like the tongue, face and swallowing muscles. But it pretty much always spreads to limb muscles.

Those are the four classic motor-neuron disorders that have been described. And it was thought for quite some time that these disorders were limited to motor neurons. It’s now clear that that’s not true. It’s now well recognized that 10 percent of these patients can develop degeneration in another part of the brain, such as other parts of the frontal lobe that don’t contain the motor neurons or the temporal lobe. So some ofthese patients can actually develop dementia, called frontal-temporal lobe dementia.

One of the misconceptions about ALS is that it’s only a motor-neuron disease, and that’s not true.

What has Stephen Hawking’s case shown about the disease?
One thing that is highlighted by this man’s course is that this is an incredibly variable disorder in many ways. On average people live two to three years after diagnosis. But that means that half the people live longer, and there are people who live for a long, long time.

Life expectancy turns on two things: the motor neurons running the diaphragm—the breathing muscles. So the common way people die is of respiratory failure. And the other thing is the deterioration of swallowing muscles, and that can lead to malnutrition and dehydration. If you don’t have these two things, you could potentially live for a long time—even though you’re getting worse. What’s happened to him is just astounding. He’s certainly an outlier.

Has he lived so long because he got the disease when he was young and had the juvenile-onset type?
Juvenile-onset is diagnosed in the teenage years, and I don’t know enough about his course to say. But it’s probably something similar to juvenile-onset disorder, which is something that progresses very, very, very slowly. I have patients in my clinic who were diagnosed in their teens and are still alive in their 40s, 50s or 60s. But not having ever examined him or taken a history, it’s a little hard for me to say.

He’s a very good example of the sparing of the non-motor parts of the brain that can occur.

How frequent are these cases of very slow-progressing forms of ALS?
I would say probably less than a few percent.

How much do you think Stephen Hawking’s longevity has been due to the excellent care that he has received versus the biology of his particular form of ALS?
It’s probably a little bit of both. I just know him from television, so I don’t know what kind of interventions he’s had. If he really isn’t on a ventilator, then it’s his biology—it’s the biology of his form of the neurodegenerative disease that determines how long he will live. For trouble swallowing you can elect to have a feeding tube placed, which basically takes malnutrition and dehydration off the table. But mostly it’s about the biology of the disease.

Hawking obviously has quite the active mind, and previous statements that he has made seem to indicate he has a pretty positive mental outlook, despite his condition. Is there any evidence that lifestyle and psychological well-being do much to help with patients’ outcomes? Or is the disease usually too quick for that to make a difference?
I don’t believe that adds to longevity.

ALS still doesn’t have a cure. What have we learned about the disease recently that might help us find one—or at least better treatments?
Beginning in 2006 it became clear that like a lot of other neurodegenerative diseases, ALS was determined by the accumulation of abnormal proteins in the brain. Ten percent of ALS is genetic and based on a gene mutation. I’m sure there are also at-risk genes for ALS, but there are now multiple genes that have been identified as potentially causing the disease. Each one of them are interesting in that they lead to the accumulation of different proteins in the brain. Knowing specific genes gives us particular mechanisms in the brain, and would potentially give us targets for therapies. But none of this has given us any robust therapies yet.

What does Stephen Hawking’s case mean for people who have the disease?
It’s just an incredible, incredible example of the variability of the disease—and the hope for patients who have it that they could also live a long life. Unfortunately, it’s a small percentage of people for whom that actually happens.

Momentum of Ice Bucket Challenge Continues


As of Friday, August 15, 2014, The ALS Association has received $9.5 million in donations compared to $1.6 million during the same time period last year (July 29 to August 15). These donations have come from existing donors and 184,812 new donors to The Association.

ALS, also known as Lou Gehrig’s Disease, is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Eventually, people with ALS lose the ability to initiate and control muscle movement, which often leads to total paralysis and death within two to five years of diagnosis. There is no cure and only one drug approved by the U.S. Food and Drug Administration (FDA) that modestly extends survival. Veterans are twice as likely be diagnosed with the disease.

“We’re heartened that the momentum of this incredible visibility continues,” said Barbara Newhouse, President and CEO of The ALS Association. “We are so thankful for the generous outpouring of donations and people’s interest in learning more about ALS.”

The ALS Association’s mission includes providing care services to assist people with ALS and their families through a network of chapters working in communities across the nation, and a global research program focused on the discovery of treatments and eventually a cure for the disease. In addition, The Association’s public policy efforts empower people to advance public policies in our nation’s Capital that respond to the needs of people with ALS.

For more information, please contact Carrie Munk at cmunk@alsa-national.org.

About The ALS Association
The ALS Association is the only national non-profit organization fighting Lou Gehrig’s Disease on every front.  By leading the way in global research, providing assistance for people with ALS through a nationwide network of chapters, coordinating multidisciplinary care through Certified Treatment Centers of Excellence, and fostering government partnerships, The Association builds hope and enhances quality of life while aggressively searching for new treatments and a cure.  For more information about The ALS Association, visit our website at www.alsa.org.

ALS Linked to 3-D Changes in DNA Health Agencies Update.


 

A mutation that alters the shape of DNA makes cells more vulnerable to stress and death and contributes to the development of a genetic form of amyotrophic lateral sclerosis (ALS), according to a study funded by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke.

Neurons from a patient with amyotrophic lateral sclerosis show signs of nuclear damage linked to a mutation that alters the shape of DNA.

http://jama.jamanetwork.com/Mobile/article.aspx?articleid=1861778&utm_campaign=social_050214&utm_medium=facebook&utm_source=jama_fb

From the desk of Zedie.

‘INDIVIDUALIZED’ THERAPY FOR THE BRAIN TARGETS SPECIFIC GENE MUTATIONS CAUSING DEMENTIA AND ALS.


Stem cell-based approach manipulates brain cells in test tube studies

Johns Hopkins scientists have developed new drugs that — at least in a laboratory dish — appear to halt the brain-destroying impact of a genetic mutation at work in some forms of two incurable diseases, amyotrophic lateral sclerosis (ALS) and dementia.

They made the finding by using neurons they created from stem cells known as induced pluripotent stem cells (iPS cells), which are derived from the skin of people with ALS who have a gene mutation that interferes with the process of making proteins needed for normal neuron function.

“Efforts to treat neurodegenerative diseases have the highest failure rate for all clinical trials,” saysJeffrey D. Rothstein, M.D., Ph.D., a professor of neurology and neuroscience at the Johns Hopkins University School of Medicine and leader of the research described online in the journal Neuron. “But with this iPS technology, we think we can target an exact subset of patients with a specific mutation and succeed. It’s individualized brain therapy, just the sort of thing that has been done in cancer, but not yet in neurology.”

Scientists in 2011 discovered that more than 40 percent of patients with an inherited form of ALS and at least 10 percent of patients with the non-inherited sporadic form have a mutation in the C9ORF72 gene. The mutation also occurs very often in people with frontotemporal dementia, the second-most-common form of dementia after Alzheimer’s disease. The same research appeared to explain why some people develop both ALS and the dementia simultaneously and that, in some families, one sibling might develop ALS while another might develop dementia.

In the C9ORF72 gene of a normal person, there are up to 30 repeats of a series of six DNA letters (GGGGCC); but in people with the genetic glitch, the string can be repeated thousands of times. Rothstein, who is also director of the Johns Hopkins Brain Science Institute and the Robert Packard Center for ALS Research, used his large bank of iPS cell lines from ALS patients to identify several with the C9ORF72 mutation, then experimented with them to figure out the mechanism by which the “repeats” were causing the brain cell death characteristic of ALS.

In a series of experiments, Rothstein says, they discovered that in iPS neurons with the mutation, the process of using the DNA blueprint to make RNA and then produce protein is disrupted. Normally, RNA-binding proteins facilitate the production of RNA. Instead, in the iPS neurons with the C9ORF72 mutation, the RNA made from the repeating GGGGCC strings was bunching up, gumming up the works by acting like flypaper and grabbing hold of the extremely important RNA binding proteins, including one known as ADARB2,  needed for the proper production of many other cellular RNAs. Overall, the C9ORF72 mutation made the cell produce abnormal amounts of many other normal RNAs and made the cells very sensitive to stress.

To counter this effect, the researchers developed a number of chemical compounds targeting the problem. This compound behaved like a coating that matches up to the GGGGCC repeats like velcro, keeping the flypaper-like repeats from attracting the bait, allowing the RNA-binding protein to properly do its job.

Rothstein says Isis Pharmaceuticals helped develop many of the studied compounds and, by working closely with the Johns Hopkins teams, could begin testing it in human ALS patients with the C9ORF72 mutation in the next several years. In collaboration with the National Institutes of Health, plans are already underway to begin to identify a group of patients with the C9ORF72 mutation for future research.

Rita Sattler, Ph.D., an assistant professor of neurology at Johns Hopkins and the co-investigator of the study, says without iPS technology, the team would have had a difficult time studying the C9ORF72 mutation. “Typically, researchers engineer rodents with mutations that mimic the human glitches they are trying to research and then study them,” she says. “But the nature of the multiple repeats made that nearly impossible.” The iPS cells did the job just as well or even better than an animal model, Sattler says, in part because the experiments could be done using human cells.

“An iPS cell line can be used effectively and rapidly to understand disease mechanisms and as a tool for therapy development,” Rothstein adds. “Now we need to see if our findings translate into a valuable treatment for humans.”

The researchers also analyzed brain tissue from people with the C9ORF72 mutation who died of ALS. They saw evidence of this bunching up and found that the many genes that were altered as a consequence of this mutation in the iPS cells were also abnormal in the brain tissue, thereby showing that iPS cells can be a faithful tool to study the human disease and discover effective therapies.

In the future, the scientists will look at cerebral spinal fluid from ALS patients with the C9ORF72 mutation, searching for proteins that were found both in the fluid and the iPS cells. These may pave the way to develop markers that can be studied by clinicians to see if the treatment is working once the drug therapy is moved to clinical trials.

ALS, sometimes known as Lou Gehrig’s disease, named for the Yankee baseball great who died from it, destroys nerve cells in the brain and spinal cord that control voluntary muscle movement. The nerve cells waste away or die, and can no longer send messages to muscles, eventually leading to muscle weakening, twitching and an inability to move the arms, legs and body. Onset is typically around age 50 and death often occurs within three to five years of diagnosis. Some 10 percent of cases are hereditary. There is no cure for ALS and there is only one FDA-approved drug treatment, which has just a small effect in slowing disease progression and increasing survival, Rothstein notes.

Evaluation of Potential Infectivity of Alzheimer and Parkinson Disease Proteins in Recipients of Cadaver-Derived Human Growth Hormone.


Importance  Growing evidence of cell-to-cell transmission of neurodegenerative disease (ND)–associated proteins (NDAPs) (ie, tau, , and α-synuclein) suggests possible similarities to the infectious prion protein (PrPsc) in spongiform encephalopathies. There are limited data on the potential human-to-human transmission of NDAPs associated with Alzheimer disease (AD) and other non-PrPsc ND.

Objective  To examine evidence for human-to-human transmission of AD, Parkinson disease (PD), and related NDAPs in cadaveric human growth hormone (c-hGH) recipients.

Design  We conducted a detailed immunohistochemical analysis of pathological NDAPs other than PrPsc in human pituitary glands. We also searched for ND in recipients of pituitary-derived c-hGH by reviewing the National Hormone and Pituitary Program (NHPP) cohort database and medical literature.

Setting  University-based academic center and agencies of the US Department of Health and Human Services.

Participants  Thirty-four routine autopsy subjects (10 non-ND controls and 24 patients with ND) and a US cohort of c-hGH recipients in the NHPP.

Main Outcome Measures  Detectable NDAPs in human pituitary sections and death certificate reports of non-PrPsc ND in the NHPP database.

Results  We found mild amounts of pathological tau, Aβ, and α-synuclein deposits in the adeno/neurohypophysis of patients with ND and control patients. No cases of AD or PD were identified, and 3 deaths attributed to amyotrophic lateral sclerosis (ALS) were found among US NHPP c-hGH recipients, including 2 of the 796 decedents in the originally confirmed NHPP c-hGH cohort database.

Conclusions and Relevance  Despite the likely frequent exposure of c-hGH recipients to NDAPs, and their markedly elevated risk of PrPsc-related disease, this population of NHPP c-hGH recipients does not appear to be at increased risk of AD or PD. We discovered 3 ALS cases of unclear significance among US c-hGH recipients despite the absence of pathological deposits of ALS-associated proteins (TDP-43, FUS, and ubiquilin) in human pituitary glands. In this unique in vivo model of human-to-human transmission, we found no evidence to support concerns that NDAPs underlying AD and PD transmit disease in humans despite evidence of their cell-to-cell transmission in model systems of these disorders. Further monitoring is required to confirm these conclusions.

Source: JAMA