Small study could lead to identification of treatable diseases for some with chronic pain syndrome

About half of a small group of patients with fibromyalgia – a common syndrome that causes chronic pain and other symptoms – was found to have damage to nerve fibers in their skin and other evidence of a disease called small-fiber polyneuropathy (SFPN). Unlike fibromyalgia, which has had no known causes and few effective treatments, SFPN has a clear pathology and is known to be caused by specific medical conditions, some of which can be treated and sometimes cured. The study from Massachusetts General Hospital (MGH) researchers will appear in the journal PAIN and has been released online.

"This provides some of the first objective evidence of a mechanism behind some cases of fibromyalgia, and identifying an underlying cause is the first step towards finding better treatments," says Anne Louise Oaklander, MD, PhD, director of the Nerve Injury Unit in the MGH Department of Neurology and corresponding author of the Pain paper.

The term fibromyalgia describes a set of symptoms – including chronic widespread pain, increased sensitivity to pressure, and fatigue – that is believed to affect 1 to 5 percent of individuals in Western countries, more frequently women. While a diagnosis of fibromyalgia has been recognized by the National Institutes of Health and the American College of Rheumatology, its biologic basis has remained unknown. Fibromyalgia shares many symptoms with SFPN, a recognized cause of chronic widespread pain for which there are accepted, objective tests.

Designed to investigate possible connections between the two conditions, the current study enrolled 27 adult patients with fibromyalgia diagnoses and 30 healthy volunteers. Participants went through a battery of tests used to diagnose SFPN, including assessments of neuropathy based on a physical examination and responses to a questionnaire, skin biopsies to evaluate the number of nerve fibers in their lower legs, and tests of autonomic functions such as heart rate, blood pressure and sweating.

The questionnaires, exam assessments, and skin biopsies all found significant levels of neuropathy in the fibromyalgia patients but not in the control group. Of the 27 fibromyalgia patients, 13 had a marked reduction in nerve fiber density, abnormal autonomic function tests or both, indicating the presence of SFPN. Participants who met criteria for SFPN also underwent blood tests for known causes of the disorder, and while none of them had results suggestive of diabetes, a common cause of SFPN, two were found to have hepatitis C virus infection, which can be successfully treated, and more than half had evidence of some type of immune system dysfunction.

"Until now, there has been no good idea about what causes fibromyalgia, but now we have evidence for some but not all patients. Fibromyalgia is too complex for a ‘one size fits all’ explanation," says Oaklander, an associate professor of Neurology at Harvard Medical School. "The next step of independent confirmation of our findings from other laboratories is already happening, and we also need to follow those patients who didn’t meet SFPN criteria to see if we can find other causes. Helping any of these people receive definitive diagnoses and better treatment would be a great accomplishment."

(Source: massgeneral.org)

More study is needed, but isoflurane might provide alternative to electroconvulsive therapy

Although electroconvulsive therapy (ECT) has long been considered the most effective treatment of medication-resistant depression, millions of people who could benefit don’t take advantage of it because of the treatment’s side effects and public misperception of the procedure.

If the results of a campus-wide collaboration of University of Utah researchers are borne out by larger studies and trials, patients with refractory depression might one day have an alternative that is as effective as ECT but without the side effects – the surgical anesthetic drug isoflurane. 

“We need to expand our research into a larger, multicenter trial, but if the results of our pilot study pan out, it would change the face of treating depression,” says Howard R. Weeks, M.D., assistant professor of psychiatry and first author on a study published July 26, 2013, in PLOS ONE online.

Also known as shock therapy, ECT is effective in 55 percent to 90 percent of depression cases, with significant reductions in symptoms typically occurring within two to four weeks. When medications work, they can take six to eight weeks to become effective. But ECT is associated with side effects including amnesia, concentration and attention problems, and other cognitive issues. Many people also mistakenly believe ECT is painful and causes brain damage, which has given the treatment a social stigma that makes millions of patients reluctant to have it. Isoflurane potentially offers an alternative to ECT that could help many of those people, according to Weeks and his colleagues from eight University of Utah departments and programs. 

In a pilot study with 20 patients who received ECT treatments compared to eight patients who received the isoflurane treatments, the researchers found that both therapies provided significant reduction in symptoms of depression. Immediately following the treatments, ECT patients showed declines in areas of memory, verbal fluency, and processing speed. Most of these ECT-related deficits resolved by four weeks. However, autobiographical memory, or recall of personal life events, remained below pretreatment levels for ECT patients four weeks after the treatment. In contrast, the patients treated with isoflurane showed no real impairment but instead had greater improvements in cognitive testing than ECT patients both immediately and four weeks after the treatments. 

In the mid-1980’s, researchers in Europe studied isoflurane as a potential depression therapy. Later studies by other scientists failed to confirm the results of the original work and isoflurane research fell out of favor. But these later studies didn’t adhere to the first study’s protocol regarding type of anesthetic, dosing size and number of treatments, according to Weeks, and he believes that’s why isoflurane’s antidepressant effects weren’t confirmed in subsequent trials. For their research, Weeks and his University of Utah colleagues followed the original study’s protocol. 

“Our data reconfirm that isoflurane had an antidepressant effect approaching ECT with less adverse neurocognitive effects, and reinforce the need for a larger clinical trial,” the researchers wrote. 

Researchers don’t know what produces the relief of depression symptoms from ECT or isoflurane. Weeks believes further research might identify a molecular pathway that both therapies target and is responsible for the improvement in depression. One common effect of both ECT and isoflurane treatments is a brief state of low electrical activity in which the brain becomes unusually quiet. ECT induces a seizure to reach that state, but isoflurane does not. After inhaling the anesthesia, patients are “under” for about 45 minutes, with 15 minutes of that time being a deep state of unconsciousness, according to Weeks. This period of electrical rest for the brain may be a potential explanation for why ECT and isoflurane improve depression. 

If isoflurane proves to be a viable alternative to ECT, a device invented by three University of Utah anesthesiology faculty members can make the anesthetic an even more attractive therapy. The Aneclear™ device (Anecare, Salt Lake City, UT) invented by Dwayne R. Westenskow, Ph.D., Derek J. Sakata, M.D., and Joseph A. Orr, Ph.D., from the University of Utah Department of Anesthesiology, uses hyperventilation and allows patients to rebreathe their own carbon dioxide (C02). Hyperventilation removes anesthesia from the lungs and C02 encourages blood flow to the brain, which encourages quicker removal of anesthetic. The Aneclear™ also minimizes or even eliminates vomiting, nausea, and extreme fatigue that some patients experience from anesthesia. 

“With the Aneclear™, we can wake people up from the anesthesia much quicker,” Weeks says. “This makes the treatment a potentially viable clinical treatment by reducing the time required in an operating room.” 

Weeks and his co-researchers now are looking for grants to fund a larger study that will include several U.S. centers.

(Source: healthcare.utah.edu)

Statins, a class of cholesterol-lowering drugs found in millions of medicine cabinets, may help treat Rett Syndrome, according to a study published today in Nature Genetics. The Rett Syndrome Research Trust (RSRT) funded this work with generous support from the Rett Syndrome Research Trust UK and Rett Syndrome Research & Treatment Foundation.

Rett Syndrome is a neurological disorder that affects girls. A seemingly typical toddler begins to miss developmental milestones. A regression follows as young girls lose speech, mobility, and hand use. Many girls have seizures, orthopedic and severe digestive problems, as well as breathing and other autonomic impairments. Most live into adulthood and require total, round-the-clock care. Rett Syndrome affects about 1 in 10,000 girls born in the U.S. each year.

The new study screened for randomly induced mutations in genes that modify the effect of the Rett gene, MECP2 (methyl-CpG-binding protein 2), in a mouse model. MECP2 turns other genes on or off by disrupting chromatin, the DNA-protein mix that makes up chromosomes.

The challenge of treating Rett Syndrome is what drove senior author Monica Justice, Ph.D., Professor in the Departments of Molecular and Human Genetics and Molecular Physiology and Biophysics at the Baylor College of Medicine, to look beyond MECP2, hoping to find new drug targets that might improve symptoms or even reverse the course of the disease. In 2007, Adrian Bird, Ph.D., Buchanan Professor of Genetics at the Wellcome Trust Centre for Cell Biology at the University of Edinburgh, showed that symptoms in mice are reversible regardless of the age of the animal.

Exploring cholesterol metabolism in neurological diseases is an emerging area, with statin drugs being tested in fragile X syndrome, neurofibromatosis, amyotrophic lateral sclerosis, and other conditions. But it hadn’t been on the radar for Rett Syndrome. “Our screen was to see if we could suppress the symptoms to reveal alternative pathways to treatment. The cholesterol hit was a big one,” Dr. Justice said. The screen was unbiased – the researchers were looking for any gene that would interact with MECP2 in a useful way, rather than employing a candidate gene approach based on hypotheses.

Dr. Justice and her team injected healthy male mice with a chemical called ENU (a form of nitrosourea) that mutates sperm stem cells randomly, then mated the males to Rett females. The researchers then looked for offspring that should have developed the syndrome (according to their genes), but didn’t (according to their good health).

Key to the investigation was being able to tell sick mice from healthy ones. Fortunately this turned out to be easy. The rescued mice didn’t develop the characteristic tremor, trouble breathing, poor limb-clasping, and general scruffiness of their affected cage-mates. They moved around more, performed better on mobility tests and lived longer.

Once the rescued mice had been identified the random gene mutations from the 24,000 genes that make up the mouse genome had to be pinpointed. “With next generation DNA sequencing, we are finding mutations so easily and quickly. It’s amazing,” said Dr. Justice, compared to the old days of setting up many more generations of crosses to narrow down a part of the genome harboring a gene of interest.

“We are only15% of the way through the screen, and so far we have identified 5 modifiers. The most drug-targetable is a gene called squalene epoxidase (Sqle), which encodes a rate-limiting enzyme in the cholesterol biosynthetic pathway. Frankly, this discovery was a surprise,” Dr. Justice said.  It’s important to note that this enzyme is different from the rate-limiting enzyme (HMG CoA reductase) influenced by statin drugs.

Cholesterol is of course best known for its negative effects on the cardiovascular system, but the lipid has multiple roles in the brain: it helps to form the myelin insulation on neurons and takes part in membrane trafficking, dendrite remodeling, synapse formation, signal transduction, and neuropeptide synthesis.

The next step was to test several statins (fluvastatin and lovastatin) on Rett mice. Like the Sqle mutation, the drugs improved symptoms. Treated mice performed well on mobility and gross motor tests, had better overall health scores and lived longer. The drugs didn’t, however, improve breathing.

“When we saw the mutation in a cholesterol pathway enzyme, we immediately thought of statin drugs. Now that our eyes have opened to what is going on, we have a multitude of drugs that modulate lipid metabolism that we can try in addition to statins,” said first author Christie Buchovecky, graduate student in the Justice lab.

With additional RSRT funding, pediatric neurologist and Director of the Tri-State Rett Syndrome Center in the Bronx Dr. Sasha Djukic undertook a detailed review of lipid data in girls with Rett Syndrome. She found that a subset have elevated cholesterol levels which normalize as they age. These data are not included in the Nature Genetics publication but will be part of a subsequent paper. Dr. Djukic is now planning a clinical trial.

Drs. Justice and Djukic caution that carefully designed and rigorously executed clinical trials are essential to test whether what works in mice will also work in girls with Rett Syndrome. Clinical trials should also determine the most effective timeframe for treatment, ways to identify which girls are most likely to respond, (for example, will statins help girls with Rett who do not have elevated cholesterol?), which drugs to trial and what dosages are effective but not toxic.

“Although statins are blockbuster drugs taken by a large percentage of the population they are not without risks and side-effects, and data on statins in the general pediatric population are quite limited. One of the key objectives of the clinical trial will be to determine correct dosages for Rett symptoms. It’s important to note that the mice in Dr. Justice’s study received very low doses of statins. I urge parents to resist any temptation to medicate their children with off-label statins,” cautions Dr Djukic. “The only way to know if this class of drugs will be efficacious in Rett is through controlled trials. Working with Dr. Justice and RSRT we will be bringing families additional information as soon as possible.”

“The biggest finding is the discovery that this pathway is so important to the pathology of the disorder; it suggests new directions for trying to learn more about Rett Syndrome,” Dr. Justice explains. “Emerging evidence from both mice and humans suggest that Rett Syndrome may have a component of disease that is metabolic. Certainly, this study will further clarify our data, and may suggest avenues for treatment that were previously unexplored.”

(Source: rsrt.org)

Neuroscientist Sarah Laszlo wants to understand what’s going on in children’s brains when they’re reading. Her research may untangle some of the mysteries surrounding dyslexia and lead to new methods of treating America’s most common learning disorder.

“The brain can reveal things that aren’t necessarily visible on the surface,” she says. “It can tell you things about what’s going wrong that you can’t find out by giving a kid a test or asking him to read out loud.”

Laszlo, who joined Binghamton’s psychology department in 2011, recently received a five-year, $400,763grant from the National Science Foundation’s Early Career Development (CAREER) Program, the agency’s most prestigious award for young researchers. The funding will enable her to conduct a five-year brain activity study of 150 children with and without dyslexia.

Rather than lumping all children with dyslexia into one group, as many previous brain-imaging studies have done, Laszlo’s project will help to establish types and degrees of the disorder.

Her lab uses electroencephalography, or EEG, as a non-invasive way to measure the electrical signals sent between brain cells when they’re communicating with each other. Study participants — kids in kindergarten through fourth grade — wear a cap outfitted with special sensors while playing a computerized reading game.

These scans produce massive amounts of data: The cap’s 10 sensors collect readings 500 times per second for 45 minutes. That’s one reason that brain activity studies are expensive and time-consuming. It’s also the reason that a study of just 150 children is the largest study of its kind.

Kara Federmeier, a professor of psychology at the University of Illinois, says it’s not just the scale of the study that’s impressive; it’s also the project’s duration. “Sarah will be able to assess how the brain transitions from immature reading processes to mature reading processes,” Federmeier says. “Her project promises to provide important, novel data that may be critical for informing educational practices about teaching reading and clinical practices for assessing reading-related difficulties.”

Why study this disorder in particular? Laszlo notes that there are significant, sometimes lifelong consequences of growing up with dyslexia. Many dyslexic children don’t do as well in school as they might otherwise, which limits their career opportunities. Some also encounter social problems. “This has the potential to help a lot of people,” she says.

Laszlo hopes to identify the brain signatures of people with dyslexia and have a clear idea of how to help them. “Once you understand what’s going on in the brain,” she says, “you can do a better job of designing treatments.”

Today, the best-case scenario is that children with dyslexia receive interventions that enable them to get up to speed on reading aloud. But they may continue to lag behind their peers when it comes to comprehension, fluency and speed. “The treatments we have now don’t always fix the underlying problem,” Laszlo says. “They just put a Band-Aid on it. And when you go to do more complicated things, like reading larger passages, the Band-Aid doesn’t help.”

(Source: discovere.binghamton.edu)

Researchers at McMaster University have discovered a solution to a long-standing medical mystery in Huntington’s disease (HD).

HD is a brain disease that can affect 1 in about 7,000 people in mid-life, causing an increasing loss of brain cells at the centre of the brain. HD researchers have known what the exact DNA change is that causes Huntington’s disease since 1993, but what is typically seen in patients does not lead to disease in animal models. This has made drug discovery difficult.

In this week’s issue of the science journal, the Proceedings of the National Academy of Sciences, professor Ray Truant’s laboratory at McMaster University’s Department of Biochemistry and Biomedical Sciences of the Michael G. DeGroote School of Medicine reveal how they developed a way to measure the shape of the huntingtin protein, inside of cell, while still alive. They then discovered was that the mutant huntingtin protein that causes disease was changing shape. This is the first time anyone has been able to see differences in normal and disease huntingtin with DNA defects that are typical in HD patients.

They went on to show that they can measure this shape change in cells derived from the skin cells of living Huntington’s disease patients.

“With mouse models, we know that some drugs can stop, and even reverse Huntington’s disease, but now we know exactly why,” said Truant. “The huntingtin protein has to take on a precise shape, in order to do its job in the cell. In Huntington’s disease, the right parts of the protein can’t line up to work properly. It’s like trying to use a paperclip after someone has bent it out of shape.”

The research also shows that the shape of disease huntingtin protein can be changed back to normal with chemicals that are in development as drugs for HD.  “We can refold the paper clip,” said Truant.

The methods they developed have been scaled up and used for large scale robotic drug screening, which is now ongoing with a pharmaceutical company. They are looking for drugs that can enter the brain more easily. Furthermore, they can tell if the shape of huntingtin has been corrected in patients undergoing drug trials, without relying on years to know if the HD is affected yet.

This research was a concerted effort from many sources: funding from the Canadian Foundation Institute and the Ontario Innovation Trust for an $11M microscopy centre at McMaster in 2006, ongoing support from the Canadian Institutes of Health Research, and important funding from the Toronto-based Krembil Foundation. The project was initiated with charity grant support from the Huntington Society of Canada, which allowed them to show this method was promising for further support.

The last piece of the puzzle was from the Huntington’s disease patient community, with skin cell donations from living patients and unaffected spouses that allowed the team to look at real human disease.

More information about Huntington’s Disease can be found at HDBuzz.net, a global website in eleven languages that takes primary published research articles and explains them to plain language to more than 300,000 non-scientists per month.

There are eight other diseases that have a similar DNA defects as Huntington’s disease, Truant’s group is now using similar tools to develop assays to measure shape changes in those diseases, to see if this shapeshifting is common in other diseases.

(Source: newswise.com)