MS reversed in mice / Single dose ( Calcitriol ) Vitamin D followed by Vitamin D supplements

Contact: Colleen Hayes cehayes@wisc.edu 608-263-6387 University of Wisconsin-Madison

Mouse studies reveal promising vitamin D-based treatment for MS

MADISON — A diagnosis of multiple sclerosis (MS) is a hard lot. Patients typically get the diagnosis around age 30 after experiencing a series of neurological problems such as blurry vision, wobbly gait or a numb foot. From there, this neurodegenerative disease follows an unforgiving course.

Many people with MS start using some kind of mobility aid — cane, walker, scooter or wheelchair — by 45 or 50, and those with the most severe cases are typically bed-bound by 60. The medications that are currently available don’t do much to slow the relentless march of the disease.

In search of a better option for MS patients, a team of University of Wisconsin-Madison biochemists has discovered a promising vitamin D-based treatment that can halt — and even reverse — the course of the disease in a mouse model of MS. The treatment involves giving mice that exhibit MS symptoms a single dose of calcitriol, the active hormone form of vitamin D, followed by ongoing vitamin D supplements through the diet. The protocol is described in a scientific article that was published online in August in the Journal of Neuroimmunology.

“All of the animals just got better and better, and the longer we watched them, the more neurological function they regained,” says biochemistry professor Colleen Hayes, who led the study.

MS afflicts around 400,000 people nationwide, with 200 new cases diagnosed each week. Early on, this debilitating autoimmune disease, in which the immune system attacks the myelin coating that protects the brain’s nerve cells, causes symptoms including weakness, loss of dexterity and balance, disturbances to vision, and difficulty thinking and remembering. As it progresses, people can lose the ability to walk, sit, see, eat, speak and think clearly.

Current FDA-approved treatments only work for some MS patients and, even among them, the benefits are modest. “And in the long term they don’t halt the disease process that relentlessly eats away at the neurons,” Hayes adds. “So there’s an unmet need for better treatments.”

While scientists don’t fully understand what triggers MS, some studies have linked low levels of vitamin D with a higher risk of developing the disease. Hayes has been studying this “vitamin D hypothesis” for the past 25 years with the long-term goal of uncovering novel preventive measures and treatments. Over the years, she and her researchers have revealed some of the molecular mechanisms involved in vitamin D’s protective actions, and also explained how vitamin D interactions with estrogen may influence MS disease risk and progression in women.

In the current study, which was funded by the National Multiple Sclerosis Society, Hayes’ team compared various vitamin D-based treatments to standard MS drugs. In each case, vitamin D-based treatments won out. Mice that received them showed fewer physical symptoms and cellular signs of disease.

First, Hayes’ team compared the effectiveness of a single dose of calcitriol to that of a comparable dose of a glucocorticoid, a drug now administered to MS patients who experience a bad neurological episode. Calcitriol came out ahead, inducing a nine-day remission in 92 percent of mice on average, versus a six-day remission in 58 percent for mice that received glucocorticoid.

“So, at least in the animal model, calcitriol is more effective than what’s being used in the clinic right now,” says Hayes.

Next, Hayes’ team tried a weekly dose of calcitriol. They found that a weekly dose reversed the disease and sustained remission indefinitely.

But calcitriol can carry some strong side effects — it’s a “biological sledgehammer” that can raise blood calcium levels in people, Hayes says — so she tried a third regimen: a single dose of calcitriol, followed by ongoing vitamin D supplements in the diet. This one-two punch “was a runaway success,” she says. “One hundred percent of mice responded.”

Hayes believes that the calcitriol may cause the autoimmune cells attacking the nerve cells’ myelin coating to die, while the vitamin D prevents new autoimmune cells from taking their place.

While she is excited about the prospect of her research helping MS patients someday, Hayes is quick to point out that it’s based on a mouse model of disease, not the real thing. Also, while rodents are genetically homogeneous, people are genetically diverse.

“So it’s not certain we’ll be able to translate (this discovery to humans),” says Hayes. “But I think the chances are good because we have such a broad foundation of data showing protective effects of vitamin D in humans.”

The next step is human clinical trials, a step that must be taken by a medical doctor, a neurologist. If the treatment works in people, patients with early symptoms of MS may never need to receive an official diagnosis.

“It’s my hope that one day doctors will be able to say, ‘We’re going to give you an oral calcitriol dose and ramp up the vitamin D in your diet, and then we’re going to follow you closely over the next few months. You’re just going to have this one neurological episode and that will be the end of it,'” says Hayes. “That’s my dream.”

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Nicole Miller nemiller2@wisc.edu 608-262-3636

Can vitamin B supplements help stave off stroke? ( 7% reduction in 6 months )

Contact: Rachel Seroka rseroka@aan.com 612-928-6129 American Academy of Neurology

MINNEAPOLIS – New evidence suggests that taking vitamin B supplements may help reduce the risk of stroke. The research appears in the September 18, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Previous studies have conflicting findings regarding the use of vitamin B supplements and stroke or heart attack,” said author Xu Yuming, with Zhengzhou University in Zhengzhou, China. “Some studies have even suggested that the supplements may increase the risk of these events.”

For the research, scientists analyzed 14 randomized clinical trials with a total of 54,913 participants. All of the studies compared B vitamin use with a placebo or a very low-dose B vitamin. Participants were then followed for a minimum of six months. There were 2,471 strokes throughout the studies, all of which showed some benefit of taking vitamin B.

Vitamin B lowered the risk of stroke in the studies overall by seven percent. However, taking supplements did not appear to affect the severity of strokes or risk of death from stroke.

Folic acid, a supplemental form of folate (vitamin B9), which is often found in fortified cereals, appeared to reduce the effect of vitamin B. Researchers did not find a reduction in stroke risk for vitamin B12.

“Based on our results, the ability of vitamin B to reduce stroke risk may be influenced by a number of other factors such as the body’s absorption rate, the amount of folic acid or vitamin B12 concentration in the blood, and whether a person has kidney disease or high blood pressure,” said Yuming. “Before you begin taking any supplements, you should always talk to your doctor.”

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To learn more about stroke, please visit http://www.aan.com/patients.

The American Academy of Neurology, an association of more than 26,000 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, brain injury, Parkinson’s disease and epilepsy.

For more information about the American Academy of Neurology, visit http://www.aan.com or find us on Facebook, Twitter, Google+ and YouTube.

Media Contacts: Rachel Seroka, rseroka@aan.com, (612) 928-6129 Michelle Uher, muher@aan.com, (612) 928-6120

Head injury + pesticide exposure = Triple the risk of Parkinson’s disease

Contact: Rachel Seroka
rseroka@aan.com
612-928-6129
American Academy of Neurology

MINNEAPOLIS – A new study shows that people who have had a head injury and have lived or worked near areas where the pesticide paraquat was used may be three times more likely to develop Parkinson’s disease. The study is published in the November 13, 2012, print issue of Neurology®, the medical journal of the American Academy of Neurology. Paraquat is a herbicide commonly used on crops to control weeds. It can be deadly to humans and animals.

“While each of these two factors is associated with an increased risk of Parkinson’s on their own, the combination is associated with greater risk than just adding the two factors together,” said study author Beate Ritz, MD, PhD, of UCLA’s Fielding School of Public Health. “This study suggests that the physiological process that is triggered by a head injury may increase brain cells’ vulnerability to attacks from pesticides that can be toxic to the brain or the other way around, for example, chronic low dose exposure to pesticides may increase the risk of Parkinson’s after a head injury.”

The study involved 357 people with Parkinson’s disease and 754 people without the disease, all of whom lived in an agricultural area in central California. The participants reported any head injuries they had ever received with a loss of consciousness for more than five minutes.

The researchers determined participants’ exposure to the weed killer based on a 500-meter area around their home and work addresses, using a geographic information system (GIS) that combined data on paraquat use collected by the state of California’s Pesticide Use Reporting system with land use maps.

People with Parkinson’s disease were twice as likely to have had a head injury with loss of consciousness for more than five minutes as people who did not have the disease. Of the 357 people with Parkinson’s disease, 42, or 12 percent, reported ever having had such a head injury, compared to 50 of the 754 people without the disease, or 7 percent.

People with Parkinson’s disease were 36 percent more likely to have exposure to paraquat than those who did not have the disease. Of those with Parkinson’s, 169 had exposure to the weed killer, or 47 percent, compared to 291 of those without the disease, or 39 percent.

 

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The study was supported by the National Institute of Environmental Health Science, National Institute of Neurological Disorders and Stroke, National Institutes of Health and American Parkinson Disease Association.

To learn more about Parkinson’s disease, visit http://www.aan.com/patients.

The American Academy of Neurology, an association of more than 25,000 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, brain injury, Parkinson’s disease and epilepsy. For more information about the American Academy of Neurology, visit http://www.aan.com or find us on Facebook, Twitter, Google+ and YouTube.

Media Contacts:

Rachel Seroka, rseroka@aan.com, (612) 928-6129

Angela Babb, APR, ababb@aan.com, (612) 928-6102

Children with MS were 1.74 times more likely to have received a certain type of hepatitis B vaccine, called Engerix B®. Those children with MS developed symptoms three or more years after the vaccine.

Public release date: 25-Sep-2008 Re-Posted for Filing

Contact: Rachel Seroka
rseroka@aan.com
651-695-2738
American Academy of Neurology

Majority of children vaccinated against hepatitis B not at increased risk of MS

ST. PAUL, Minn. – The majority of children vaccinated against hepatitis B are not at an increased risk of developing multiple sclerosis (MS), according to a study to be published in the October 8, 2008, online issue of Neurology®, the medical journal of the American Academy of Neurology.

The study based in France involved 349 children with MS and 2,941 children without the disease. The children were all under the age of 16. A total of 24.4 percent of the children with MS were vaccinated for hepatitis B in the three years before the study, compared to 27.3 percent for the children without MS.

Although the study found that hepatitis B vaccination does not generally increase the risk of multiple sclerosis, the children with MS were 1.74 times more likely to have received a certain type of hepatitis B vaccine, called Engerix B®. Those children with MS developed symptoms three or more years after the vaccine. The risk was only found for this specific type of hepatitis B vaccine and not found for all vaccines against hepatitis B.

This association cannot be taken as confirmation that the vaccine caused MS. Further studies are needed to determine whether this is a causal relationship.

 

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The American Academy of Neurology, an association of more than 21,000 neurologists and neuroscience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer’s disease, epilepsy, Parkinson’s disease, and multiple sclerosis.

For more information about the American Academy of Neurology, visit www.aan.com.

Statins have unexpected effect on pool of powerful brain cells : Reduces Glial progenitor cells

Re-post 34th HRR 2008

Contact: Tom Rickey
tom_rickey@urmc.rochester.edu
585-275-7954
University of Rochester Medical Center

Cholesterol-lowering drugs known as statins have a profound effect on an elite group of cells important to brain health as we age, scientists at the University of Rochester Medical Center have found. The new findings shed light on a long-debated potential role for statins in the area of dementia.

Neuroscientists found that statins, one of the most widely prescribed classes of medication ever used, have an unexpected effect on brain cells. Researchers looked at the effects of statins on glial progenitor cells, which help the brain stay healthy by serving as a crucial reservoir of cells that the brain can customize depending on its needs. The team found that the compounds spur the cells, which are very similar to stem cells, to shed their flexibility and become one particular type of cell.

The new findings come at a time of increasing awareness among neurologists and cardiologists of the possible effects of statins on the brain. Several studies have set out to show that statins provide some protection against dementia, but the evidence has been inconclusive at best. Meanwhile, there is some debate among physicians about whether statins might actually boost the risk of dementia. The new research published in the July issue of the journal Glia by Steven Goldman, M.D., Ph.D., and first author Fraser Sim, Ph.D., provides direct evidence for an effect of statins on brain cells.

“There has been a great deal of discussion about a link between statins and dementia, but evidence either way has been scant,” said Goldman, a neurologist who led the team. “This new data provides a basis for further exploration.

“These findings were made through experiments done in cell culture using human brain cells and exposing them to doses of statins used widely in patients. But this research was not done in people. There are a great number of questions that need to be explored further before anyone considers changing the way statins are used,” Goldman added.

Goldman’s team is recognized as a leader identifying and directing the molecular signals that direct the development of stem cells and their daughter cells, known as progenitor cells. In this study, Sim ran a genomic screen to see which genes are more active in these cells compared to other brain cells. Sim and Goldman found several related to cholesterol, including the enzyme HMG-CoA reductase, which is central to making cholesterol and is the main target of statins.

“It was quite surprising that the cholesterol-signaling pathways are so active in these cells,” Goldman said. “Since such signaling is blocked with compounds used literally by millions of patients every day, we decided to take a closer look.”

The team measured the effects of two widely used statins, simvastatin and pravastatin, on glial progenitor cells, which can become either astrocytes or oligodendrocytes. The team looked at progenitor cells from 16 patients who had brain tissue removed during surgery to treat epilepsy, tumors, or vascular problems.

Scientists found that both compounds, when used at doses that mimic those that patients take, spur glial progenitor cells to develop into oligodendrocytes. For example, in one experiment, they found about five times as many oligodendrocytes in cultures of human progenitor cells exposed to pravastatin compared to cultures not exposed to the substance. Similarly, they found that the number of progenitor cells was just about one-sixth the level in cultures exposed to simvastatin compared to cultures not exposed to the compound.

To understand the process, think of a baseball team raising a group of great young prospects. They run fast, they throw hard, they hit well. Most teams will tailor their players to the positions the team needs – a few pitchers, for instance, and several batters. Any team that suddenly found itself with all pitchers or all hitters would be ill prepared to compete.

The Rochester team discovered that statins essentially push most of the raw talent in one direction.

Scientists don’t really know the long-term effects of such a shift. Physicians are looking at statins as a possible treatment for multiple sclerosis, where the myelin coating that covers nerve cells in the central nervous system is damaged. Myelin is produced by oligodendrocytes – so spurring the development of oligodendrocytes might provide one way to reduce or repair the damage seen in M.S.

But the body maintains a pool of uncommitted glial progenitor cells for a reason. The body normally turns to that reservoir of cells when it needs to repair damage from a variety of causes, such as an infection, hemorrhage, a serious blow to the head, or inflammation within the brain, such as in patients with multiple sclerosis. No one knows the consequences if such cells weren’t available when needed, though increased cognitive impairment might be one possibility.

“These are the cells ready to respond if you have a region of the brain that is damaged due to trauma, or lack of blood flow like a mini-stroke,” said Sim, assistant professor of Neurology. “Researchers need to look very carefully at what happens if these cells have been depleted prematurely.”

Glial progenitor cells are distributed throughout the brain and, according to Sim, make up about 3 percent of our brain cells. While true stem cells that can become any type of cell are very rare in the brain, their progeny, progenitor cells, are much more plentiful. They are slightly more specialized than stem cells but can still develop into different cell types.

The work may be relevant to drugs commonly used by diabetics as well. That’s because the team discovered that a signaling molecule called PPAR gamma is central to the effect of statins on glial progenitor cells. When PPAR gamma was blocked, the statins no longer had the effect. Since PPAR gamma is the main target of diabetes medications such as Avandia and Actos, which trigger the molecule, Goldman said it’s likely that those medications have the same effect on progenitor cells. He also noted that many patients are on both diabetes drugs and statins, which could increase the effect.

“Our results suggest the need for awareness of the possible toxicities accruing to long-term statin use, and identify one such potential toxicity, the premature differentiation and attendant long-term depletion of oligodendrocyte progenitor cells of the adult brain,” conclude the authors in their Glia paper.

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Besides Sim and Goldman, other authors include medical student Jennifer Lang, technical associate Tracy Ali, Cornell scientist Neeta Roy, and neurosurgeons Edward Vates, M.D., and Webster Pilcher, M.D. The National Institute of Neurological Disorders and Stroke and the National Multiple Sclerosis Society funded the work