214CNO14SEP2015
CNO Report 214
Release Date 14 SEP 2015
Draft Report Compiled by
Ralph Turchiano
In This Issue:
1. Antipsychotics inappropriately prescribed to people with intellectual disabilities
2. Statin side effects linked to off-target reaction in muscle mitochondria
3. Blueberry extract could help fight gum disease and reduce antibiotic use
4. Survey reinforces further understanding of dietary deficiencies and optimum nutrition needed
5. Keeping older muscles strong
6. Natural compound could reduce breast cancer risk in some women
7. How the ‘heat’ compound from chili peppers could help kill cancer cells
8. Cocoa flavanols lower blood pressure and increase blood vessel function in healthy people
9. Melatonin and multiple sclerosis: Why MS symptoms may improve as the days get shorter
10. Resveratrol impacts Alzheimer’s disease biomarker
Public Release: 1-Sep-2015
Antipsychotics inappropriately prescribed to people with intellectual disabilities
Large numbers of people with intellectual disabilities are being inappropriately prescribed antipsychotic drugs, finds a new UCL study
University College London
Large numbers of people with intellectual disabilities in the UK are being inappropriately prescribed antipsychotic drugs, finds a new UCL study.
Intellectual disability is a lifelong condition that begins before the age of 18 and is characterised by limitations in intellectual functioning (generally indicated by an IQ under 70) and difficulties with one or more life skills. Around 1% of the population has an intellectual disability.
The new study, published in The BMJ, looked at anonymised GP records of 33,016 UK adults with intellectual disabilities between 1999 and 2013. It found that over one-quarter had been prescribed antipsychotic drugs, of whom 71% had no record of severe mental illness.
Antipsychotic drugs are designed to treat severe mental illnesses such as schizophrenia. There is very little evidence that they help to address behavioural problems not due to mental illness in people with intellectual disability. Despite this, the study found that antipsychotics were often prescribed to people with behaviour problems who had no history of severe mental illness. Behaviour problems that might be seen in people with intellectual disability include aggression, self-injury, destruction to property and other behaviours outside social norms.
People with intellectual disability who also had autism or dementia were also more likely to receive an antipsychotic drug, as were older people.
“The number of people with intellectual disabilities who have been prescribed antipsychotics is greatly disproportionate to the number diagnosed with severe mental illness for which they are indicated.” explains study author Dr Rory Sheehan (UCL Psychiatry). “People who show problem behaviours, along with older people with intellectual disability or those with co-existing autism or dementia, are significantly more likely to be given an antipsychotic drug, despite this being against clinical guidelines and risking possible harm.”
However, the study also found that the rate of prescribing of antipsychotic drugs to people with intellectual disability had fallen gradually but consistently over the past 15 years, indicating that alternative therapies are being utilised and GPs are changing their practice.
Other classes of drugs used to treat mental illness were also prescribed to people with intellectual disability in large numbers. Drugs used to treat anxiety were the most frequently prescribed, followed by the antidepressants (used to treat depression). Like the antipsychotic group, both of these types of drug were given at substantially higher rates than mental disorders were recorded. This suggests that these drugs might also be prescribed inappropriately in some cases. The researchers paid particular attention to investigating the use of antipsychotics due to their risk of serious side-effects.
Side-effects of antipsychotic drugs include sedation, weight gain, metabolic changes that can ultimately lead to diabetes, and movement problems such as restlessness, stiffness and shakiness.
“Side-effects can be managed, but the risks and benefits must be carefully considered before prescribing antipsychotics to people without severe mental illness,” says Dr Sheehan. “Research evidence does not support using antipsychotics to manage behaviour problems in people with intellectual disabilities. Many people with intellectual disability and behaviour disturbance have complex needs and other interventions, such as looking at the support people receive and their communication needs, should be prioritised. Antipsychotics, or indeed any medications, should not be prescribed lightly and are no substitute for comprehensive care.”
Public Release: 1-Sep-2015
Statin side effects linked to off-target reaction in muscle mitochondria
Cell Press
Statins are a popular and easy-to-swallow option for people looking to lower their cholesterol. But for a quarter of patients, statins come with muscle pain, stiffness, cramps, or weakness without any clear signs of muscle damage. These symptoms may affect daily activities so much that people stop using the drugs. In Cell Metabolism on September 1, Dutch researchers show, in mice and humans, that statins yield an off-target reaction that disrupts muscle mitochondria function, possibly causing the side effects.
“Adverse drug effects, like those of statins and many other drugs, have been linked to mitochondria–the cell’s powerhouses–though the exact mechanisms are often unknown,” says co-senior study author Frans Russel of the Nijmegen Center for Mitochondrial Disorders at the Radboud University Medical Center in the Netherlands. “This research leads to several opportunities to synthesize new classes of cholesterol-lowering drugs without the unwanted muscle effects, as well as the development of new avenues to counteract these effects, both of which we are currently investigating.”
Statins exist in the body in two chemical forms, acid and lactone. Most statins are administered (as a tablet) in their acid form, which slows down the production of cholesterol in the liver. The acid form can turn into the lactone form within the body, but the lactone form has no therapeutic effect.
Russel, along with co-senior author Jan Smeitink, postdoctoral researcher Tom Schirris, and colleagues, found that lactones can, however, unintentionally interfere with a mitochondrial pathway that produces the cell’s energy currency, ATP. In mouse muscle cells, lactones were about three times more potent at disturbing mitochondrial function than their acid forms. These findings could be confirmed in muscle biopsies of patients suffering from statin-induced side effects, in which ATP production (via lactone inhibition of the Qo site of complex III of the mitochondrial oxidative phosphorylation system) was reduced, as compared to healthy control subjects.
“Further independent studies are needed on the effects of the different statins on mitochondrial function and to indicate the usefulness of complex III activity as a predictive marker for statin-induced myopathies,” Russel says. “Interindividual differences in the enzymatic conversion of the acid into the lactone form could be an explanation for the differences between patients in susceptibility for statin-induced muscle pain.”
The researchers are also excited to explore whether current statins can be improved or supplemented without impacting muscles in the future. In their study, they were able to reduce lactone’s ability to interfere with mitochondrial function, which is early evidence that side effects could be prevented or reversed.
Public Release: 2-Sep-2015
Blueberry extract could help fight gum disease and reduce antibiotic use
American Chemical Society
Gum disease is a common condition among adults that occurs when bacteria form biofilms or plaques on teeth, and consequently the gums become inflamed. Some severe cases, called periodontitis, call for antibiotics. But now scientists have discovered that wild blueberry extract could help prevent dental plaque formation. Their report in ACS’ Journal of Agricultural and Food Chemistry could lead to a new therapy for periodontitis and a reduced need for antibiotics.
Many people have had some degree of gum inflammation, or gingivitis, caused by dental plaque. The gums get red and swollen, and they bleed easily. If left unchecked, the condition can progress to periodontitis. The plaque hardens into tartar, and the infection can spread below the gum line and destroy the tissue supporting the teeth. To treat this condition, dentists scrape off the tartar and sometimes have to resort to conventional antibiotics. But recently, researchers have started looking at natural antibacterial compounds to treat gum disease. Daniel Grenier and colleagues wanted to see if blueberry polyphenols, which work against foodborne pathogens, could also help fight Fusobacterium nucleatum, one of the main species of bacteria associated with periodontitis.
In the lab, the researchers tested extracts from the wild lowbush blueberry, Vaccinium angustifolium Ait., against F. nucleatum. The polyphenol-rich extracts successfully inhibited the growth of F. nucleatum, as well as its ability to form biofilms. It also blocked a molecular pathway involved in inflammation, a key part of gum disease. The researchers say they’re developing an oral device that could slowly release the extract after deep cleaning to help treat periodontitis.
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Public Release: 8-Sep-2015
Survey reinforces further understanding of dietary deficiencies and optimum nutrition needed
New data finds most adults believe their diets meet nutritional requirements, despite prevalence of diseases associated with deficiencies
Tonic Life Communications USA
September 8, 2015, New York, New York- Data from a three-country survey seeking to understand beliefs of adults on the role of diet for optimal health, as well as consumption of key micronutrients including Omega-3 and Vitamin D, will be published in the November/December issue of Nutrition Today. The survey of 3,000 American, British and German adults found that 72 percent reported having a “healthy” or “optimal” diet and more than half (52 percent) believed they consume all the key nutrients needed for optimal nutrition through food sources alone. However, the prevalence of chronic diseases in these countries suggests respondents may be overestimating how healthy their diets are. While research indicates that Omega-3s can provide a beneficial advantage for those predisposed to cardiovascular diseases , it remains the leading cause of death in the U.S., U.K. and Germany. The survey was commissioned by the Global Nutrition and Health Alliance (GNHA).
“Regardless of country, most consumers know optimal nutrition is important. A nutrient rich diet is the foundation for a healthy life,” said GNHA founding member Suzanne Steinbaum, DO, Director & Attending Cardiologist, Women and Heart Disease Center, Lenox Hill Hospital. “Omega-3s are proven to be beneficial for cardiovascular health, as well as cognitive function, but far too often, people do not consume the amount needed for the greatest benefit. That is why I recommend all my patients take an Omega-3 supplement.”
In terms of supplementation of Omega-3 and Vitamin D, the survey also found that less than a third (32 percent) of those polled were actively taking a supplement.
“Preaching about proper diet is not enough. Perceptions of a healthy diet and the fact that it is very difficult to consume the recommended intake of nutrients such as Omega-3 and Vitamin D via diet alone, require us to rethink that approach,” said GNHA founding member Nigel Denby, RD, Head of Dietetics at Grub4Life in London. “Additional studies are needed to demonstrate the truth behind what people report they are consuming and what they really are eating. These types of studies would help further discussion about the role of vitamin and mineral supplementation as part of a healthy diet.”
Survey outcomes by country include:
Americans:
· 73% believe they have a “healthy” or “optimal” diet
· 81% realize Omega-3s are important to one’s health
· 65% aren’t sure if they are getting enough from their diet
· Only 45% regularly take an Omega-3 supplement
· Less than half (48%) consume enough Vitamin D via diet
· 62% take a Vitamin D supplement
British:
· 72% believe they have a “healthy” or “optimal” diet
· 72% realize Omega-3s are important to one’s health
· 23% aren’t sure if they are getting enough from their diet
· Only 29% regularly take an Omega-3 supplement
· Less than half (44%) consume enough Vitamin D via diet
· 32% take a Vitamin D supplement
Germans:
· 70% believe they have a “healthy” or “optimal” diet
· 80% realize Omega-3s are important to one’s health
· 34% aren’t sure if they are getting enough from their diet
· Only 24% regularly take an Omega-3 supplement
· Less than half (42%) consume enough Vitamin D via diet
· 31% take a Vitamin D supplement
Public Release: 8-Sep-2015
Keeping older muscles strong
University of Iowa scientists discover cause of and potential treatment for muscle weakness and loss due to aging
University of Iowa Health Care
As we grow older, we lose strength and muscle mass. However, the cause of age-related muscle weakness and atrophy has remained a mystery.
Scientists at the University of Iowa have discovered the first example of a protein that causes muscle weakness and loss during aging. The protein, ATF4, is a transcription factor that alters gene expression in skeletal muscle, causing reduction of muscle protein synthesis, strength, and mass. The UI study also identifies two natural compounds, one found in apples and one found in green tomatoes, which reduce ATF4 activity in aged skeletal muscle. The findings, which were published online Sept. 3 in the Journal of Biological Chemistry, could lead to new therapies for age-related muscle weakness and atrophy.
“Many of us know from our own experiences that muscle weakness and atrophy are big problems as we become older,” says Christopher Adams, MD, PhD, UI professor of internal medicine and senior study author. “These problems have a major impact on our quality of life and health.”
Previously, Adams and his team had identified ursolic acid, which is found in apple peel, and tomatidine, which comes from green tomatoes, as small molecules that can prevent acute muscle wasting caused by starvation and inactivity. Those studies set the stage for testing whether ursolic acid and tomatidine might be effective in blocking the largest cause of muscle weakness and atrophy: aging.
In their latest study, Adams’ team found that ursolic acid and tomatidine dramatically reduce age-related muscle weakness and atrophy in mice. Elderly mice with age-related muscle weakness and atrophy were fed diets lacking or containing either 0.27 percent ursolic acid, or 0.05 percent tomatidine for two months. The scientists found that both compounds increased muscle mass by 10 percent, and more importantly, increased muscle quality, or strength, by 30 percent. The sizes of these effects suggest that the compounds largely restored muscle mass and strength to young adult levels.
“Based on these results, ursolic acid and tomatidine appear to have a lot of potential as tools for dealing with muscle weakness and atrophy during aging,” Adams says. “We also thought we might be able to use ursolic acid and tomatidine as tools to find a root cause of muscle weakness and atrophy during aging.”
Adams’ team investigated the molecular effects of ursolic acid and tomatidine in aged skeletal muscle. They found that both compounds turn off a group of genes that are turned on by the transcription factor ATF4. This led them to engineer and study a new strain of mice that lack ATF4 in skeletal muscle. Like old muscles that were treated with ursolic acid and tomatidine, old muscles lacking ATF4 were resistant to the effects of aging.
“By reducing ATF4 activity, ursolic acid and tomatidine allow skeletal muscle to recover from effects of aging,” says Adams, who also is a member of the Fraternal Order of Eagles Diabetes Research Center at the UI and a staff physician with the Iowa City Veterans Affairs Medical Center.
The UI study was done in collaboration with Emmyon, Inc., a UI-based biotechnology company founded by Adams, that is now working to translate ursolic acid and tomatidine into foods, supplements, and pharmaceuticals that can help preserve or recover strength and muscle mass as people grow older.
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In addition to Adams, the UI team included Michael Dyle, Steven Bullard, Jason Dierdorff, Daryl Murry, Daniel Fox, Kale Bongers, Vitor Lira, and David Meyerholz, as well as Scott Ebert and John Talley at Emmyon, Inc.
The study was funded by a Small Business Innovation Research (SBIR) grant to Emmyon, Inc. from the National Institute on Aging, as well as grants from the Department of Veterans Affairs and the Fraternal Order of Eagles Diabetes Research Center at the University of Iowa
Public Release: 9-Sep-2015
Natural compound could reduce breast cancer risk in some women
Luteolin may inhibit growth of human breast cancer cells in postmenopausal women taking hormone replacement therapy
University of Missouri-Columbia
COLUMBIA, Mo. – More than 100 women die from breast cancer every day in the United States. The odds increase in postmenopausal women who have taken a combined estrogen and progestin hormone replacement therapy; these women also have an increased risk of developing progestin-accelerated breast tumors. Now, University of Missouri researchers have found that luteolin, a natural compound found in herbs such as thyme and parsley as well as vegetables such as celery and broccoli, could reduce the cancer risk for women who have taken hormone replacement therapy.
“In most circumstances, hormone replacement therapies improve the lives of menopausal women and achieve excellent results,” said Salman Hyder, the Zalk Endowed Professor in Tumor Angiogenesis and professor of biomedical sciences in the College of Veterinary Medicine and the Dalton Cardiovascular Research Center. “Nevertheless, research has proven that a higher incidence of breast cancer tumors can occur in women receiving therapies that involve a combination of the natural component estrogen and the synthetic progestin.
“Most older women normally have benign lesions in breast tissue,” Hyder said. “These lesions typically don’t form tumors until they receive the ‘trigger’– in this case, progestin–that attracts blood vessels to cells essentially feeding the lesions causing them to expand.” His newest study shows that when the supplement luteolin is administered to human breast cancer cells in the lab, benefits can be observed including the reduction of those vessels “feeding” the cancer cells causing cancer cell death.
Hyder’s lab has found that as human breast cancer cells develop, they tend to take on stem cell-like properties, which can make them harder to kill. Here, luteolin was used to monitor stem cell-like characteristics of breast cancer cells and his team saw a vast reduction in this phenomenon, further proving that the natural compound exerts its anti-tumor effects in a variety of ways.
Then, Hyder further tested laboratory mice with breast cancer and found that blood vessel formation and stem cell-like characteristics also were reduced in vivo, or inside the body.
“We feel that luteolin can be effective when injected directly into the bloodstream, so IV supplements may still be a possibility,” Hyder said. “But, until the supplement is tested for safety and commercialized, which we hope will happen after further testing and clinical trials, women should continue consuming a healthy diet with fresh fruits and vegetables.”
The early-stage results of this research are promising. If additional studies are successful within the next few years, MU officials will request authority from the federal government to begin human drug development (this is commonly referred to as the “investigative new drug” status). After this status has been granted, researchers may conduct human clinical trials with the hope of developing new treatments for breast cancer in women who have taken combined estrogen and progestin hormone replacement therapies.
Researchers involved with the study included Matthew T. Cook, a recent doctoral graduate and research scientist at Dalton Cardiovascular Research Center; Cynthia Besch-Williford, associate professor of veterinary pathobiology; Yayun Liang, a research associate professor of biomedical sciences in the College of Veterinary Medicine at MU; and Sandy Goyette and Benford Mafuvadze, who are graduate students in biomedical sciences.
The research recently was published in the journal Springer Plus through the generosity of numerous donors to the Ellis Fischel Cancer Center at MU.
Public Release: 9-Sep-2015
How the ‘heat’ compound from chili peppers could help kill cancer cells
American Chemical Society
Capsaicin, the compound responsible for chilis’ heat, is used in creams sold to relieve pain, and recent research shows that in high doses, it kills prostate cancer cells. Now researchers are finding clues that help explain how the substance works. Their conclusions suggest that one day it could come in a new, therapeutic form. Their study appears in ACS’ The Journal of Physical Chemistry B.
About 10 years ago, researchers reported that capsaicin can kill prostate cancer cells in mice while leaving healthy cells unharmed. But translating that dose to humans would require them to eat a huge number of chili peppers per day. Figuring out how capsaicin works could help researchers transform it into an effective drug in the form of an injection or pill.
Researchers have figured out that the molecule binds to a cell’s surface and affects the membrane, which surrounds and protects the cell. That finding prompted Ashok Kumar Mishra and Jitendriya Swain to try to gain a deeper understanding of capsaicin’s effects so it might be harnessed in the future for new medicines.
The scientists were able to detect how the compound interacts with cell membranes by monitoring its natural fluorescence. The study showed that capsaicin lodges in the membranes near the surface. Add enough of it, and the capsaicin essentially causes the membranes to come apart. With additional research, this insight could help lead to novel tools against cancer or other conditions.
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Public Release: 10-Sep-2015 Cocoa flavanols lower blood pressure and increase blood vessel function in healthy people
New studies by the EU-funded FLAVIOLA research consortium show that cocoa flavanols could help maintain cardiovascular health as we age
University Hospital Düsseldorf
Two recently published studies in the journals Age and the British Journal of Nutrition (BJN) demonstrate that consuming cocoa flavanols improves cardiovascular function and lessens the burden on the heart that comes with the ageing and stiffening of arteries. The studies also provide novel data to indicate that intake of cocoa flavanols reduces the risk of developing cardiovascular disease (CVD).
As we age, our blood vessels become less flexible and less able to expand to let blood flow and circulate normally, and the risk of hypertension also increases. Arterial stiffness and blood vessel dysfunction are linked with cardiovascular disease — the number one cause of deaths worldwide. “With the world population getting older, the incidence of cardiovascular disease, heart attacks and stroke will only increase,” says Professor Malte Kelm, Professor of Cardiology, Pulmonary Diseases and Vascular Medicine at University Hospital Düsseldorf and Scientific Director of FLAVIOLA. “It is therefore pivotal that we understand the positive impact diet can have on cardiovascular disease risk. As part of this, we want to know what role flavanol-containing foods could play in maintaining the health of the heart and blood vessels.”
Cocoa flavanols are plant-derived bioactives from the cacao bean. Dietary intake of flavanols has been shown to have a beneficial effect on cardiovascular health but the compounds are often destroyed during normal food processing. Earlier studies have demonstrated that cocoa flavanol intake improves the elasticity of blood vessels and lowers blood pressure — but, for the most part, these investigations have focused on high-risk individuals like smokers and people that have already been diagnosed with conditions like hypertension and coronary heart disease. These two studies in Age and BJN are the first to look at the different effects dietary cocoa flavanols can have on the blood vessels of healthy, low-risk individuals with no signs or symptoms of cardiovascular disease.
Cocoa flavanols increase blood vessel flexibility and lower blood pressure
In the study published in Age, two groups of 22 young (<35 years of age) and 20 older (50-80 years of age) healthy men consumed either a flavanol-containing drink, or a flavanol-free control drink, twice a day for two weeks. The researchers then measured the effect of flavanols on hallmarks of cardiovascular aging, such as arterial stiffness (as measured by pulse wave velocity), blood pressure and flow-mediated vasodilation (the extent to which blood vessels dilate in response to nitric oxide).
They found that vasodilation was significantly improved in both age groups that consumed flavanols over the course of the study (by 33% in the younger age group and 32% in the older age group over the control intervention). In the older age group, a statistically and clinically significant decrease in systolic blood pressure of 4 mmHg over control was also seen.
Improving cardiovascular health and lowering the risk of CVD
In the second study, published in BJN, the researchers extended their investigations to a larger group (100) of healthy middle-aged men and women (35-60 years) with low risk of CVD. The participants were randomly and blindly assigned into groups that consumed either a flavanol-containing drink or a flavanol-free control drink, twice a day for four weeks. The researchers also measured cholesterol levels in the study groups, in addition to vasodilation, arterial stiffness and blood pressure.
“We found that intake of flavanols significantly improves several of the hallmarks of cardiovascular health,” says Professor Kelm. In particular, the researchers found that consuming flavanols for four weeks significantly increased flow-mediated vasodilation by 21%. Increased flow-mediated vasodilation is a sign of improved endothelial function and has been shown by some studies to be associated with decreased risk of developing CVD. In addition, taking flavanols decreased blood pressure (systolic by 4.4 mmHg, diastolic by 3.9 mmHg), and improved the blood cholesterol profile by decreasing total cholesterol (by 0.2 mmol/L), decreasing LDL cholesterol (by 0.17 mmol/L), and increasing HDL cholesterol (by 0.1 mmol/L).
The researchers also calculated the Framingham Risk Score – a widely used model to estimate the 10-year cardiovascular risk of an individual – and found that flavanol intake reduced the risk of CVD. “Our results indicate that dietary flavanol intake reduces the 10-year risk of being diagnosed with CVD by 22% and the 10-year risk of suffering a heart attack by 31%,” says Professor Kelm.
The combined results of these studies demonstrate that flavanols are effective at mitigating age-related changes in blood vessels, and could thereby reduce the risk of CVD in healthy individuals. The application of 10-year Framingham Risk Scores should be interpreted with caution as the duration of the BJN study was weeks not years and the number of participants was around 100, not reaching the scale of the Framingham studies. That being said, Professor Kelm comments that “the reduction seen in risk scores suggests that flavanols may have primary preventive potential for CVD.” Other longer-term studies, such as the 5-year COcoa Supplement and Multivitamin Outcomes Study (COSMOS) of 18,000 men and women, are now underway to investigate the health potential of flavanols on a much larger scale.
Public Release: 10-Sep-2015
Melatonin and multiple sclerosis: Why MS symptoms may improve as the days get shorter
New research from Brigham and Women’s Hospital offers an answer to the MS ‘seasonal paradox’
Brigham and Women’s Hospital
For patients and clinicians alike, it’s long been a mystery: why do symptoms of multiple sclerosis (MS) seem to get better in the winter and worse in the summer? A group led by Francisco Quintana, PhD, at the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital (BWH) and collaborators have found an explanation that could lead to a deeper understanding of the disease and more targeted treatment options for patients. By first looking broadly at possible environmental factors and then deeply at preclinical models of MS, the research team found that melatonin – a hormone involved in regulating a person’s sleep-wake cycle – may influence MS disease activity. The team reports its findings this week in Cell.
The researchers caution that this work does not mean MS patients should start taking supplements of melatonin – an imperfect drug. Instead, this new approach – which takes its lead from environmental observations – can be seen as a first step toward better and more targeted therapies.
“We know that for multiple sclerosis and most autoimmune diseases, both genetic and environmental factors play an important role, but in the last decade or so, most research has focused only on the genetic side of the equation,” said co-corresponding author Quintana, associate professor in the Ann Romney Center for Neurologic Diseases at BWH. “But we wanted to see what environmental factors would reveal to us about this disease. We knew that MS disease activity changed with the seasons. What we’ve uncovered offers an explanation for why that is the case.”
Working closely with colleagues at the Center for Research on Neuroimmunological Diseases (CIEN) at the Raul Carrea Institute for Neurological Research (FLENI) in Argentina, Quintana and his colleagues began by studying patients. The team found that during the fall and winter, the group of 139 relapsing remitting MS patients they studied experienced a significant improvement in symptoms (a phenomenon that’s been observed in previous studies). The team then explored a variety of environmental factors that have been proposed as possibly linked to MS symptoms, including vitamin D levels, UV incidence and upper respiratory tract infections. But the factor that was consistently associated with severity of MS symptoms was melatonin. Melatonin levels are known to correlate with day length – during the longer days of the spring and summer, levels are lower and during the shorter days of the fall and winter, levels are higher.
Based on this observation, the team tested this lead in the lab, studying the role that melatonin may play on a cellular level. Using both a mouse model and human cells, they investigated the effects of melatonin on certain types of cells, known to play a role in the immune response that leads to MS symptoms. The team found that melatonin affected the roles of two kinds of cells that are important in MS disease progression: pathogenic T cells that directly attack and destroy tissue and regulatory T cells, which are supposed to keep pathogenic T cells in check.
“We found that melatonin has a protective effect,” said Quintana. “It dampens the immune response and helps keep the bad guys – or pathogenic T cells – at bay.”
Although melatonin is available over the counter, it has significant drawbacks, including causing unwanted drowsiness. The team’s goal is to tease apart the molecular mechanisms that underlie melatonin’s role in order to develop targeted, non-toxic drugs that are safe and effective with minimal side effects.
“In the future, melatonin or its derivatives may be used in MS patients after appropriate clinical trials are conducted and dosage is established,” said Quintana. “However, extreme caution should be exercised: our data do not show that melatonin or its analogs are effective in treating MS.”
The team is currently working to establish a pilot clinical trial to study the effects of targeting melatonin signaling in MS patients and identify additional mechanisms of action.
Public Release: 11-Sep-2015
Resveratrol impacts Alzheimer’s disease biomarker
Georgetown University Medical Center
WASHINGTON (Sept. 11, 2015) — The largest nationwide clinical trial to study high-dose resveratrol long-term in people with mild to moderate Alzheimer’s disease found that a biomarker that declines when the disease progresses was stabilized in people who took the purified form of resveratrol.
Resveratrol is a naturally occurring compound found in foods such as red grapes, raspberries, dark chocolate and some red wines.
The results, published online today in Neurology, “are very interesting,” says the study’s principal investigator, R. Scott Turner, MD, PhD, director of the Memory Disorders Program at Georgetown University Medical Center. Turner, who treats patients at MedStar Georgetown University Hospital, cautions that the findings cannot be used to recommend resveratrol. “This is a single, small study with findings that call for further research to interpret properly.”
The resveratrol clinical trial was a randomized, phase II, placebo-controlled, double blind study in patients with mild to moderate dementia due to Alzheimer’s disease. An “investigational new drug” application was required by the U.S. Food and Drug Administration to test the pure synthetic (pharmaceutical-grade) resveratrol in the study. It is not available commercially in this form.
The study enrolled 119 participants. The highest dose of resveratrol tested was one gram by mouth twice daily — equivalent to the amount found in about 1,000 bottles of red wine.
John Bozza, 80, participated in the study. Five years ago, his wife, Diana, began noticing “something wasn’t quite right.” He was diagnosed with mild cognitive impairment, but only a year later, his condition progressed to mild Alzheimer’s.
Diana, whose twin sister died from the same disease, says there are multiple reasons she and John decided to participate in the resveratrol study, and they now know he was assigned to take the active drug.
“I definitely want the medical community to find a cure,” she says. “And of course I thought there’s always a chance that John could have been helped, and who knows, maybe he was.”
Patients, like John, who were treated with increasing doses of resveratrol over 12 months showed little or no change in amyloid-beta40 (Abeta40) levels in blood and cerebrospinal fluid. In contrast, those taking a placebo had a decrease in the levels of Abeta40 compared with their levels at the beginning of the study.
“A decrease in Abeta40 is seen as dementia worsens and Alzheimer’s disease progresses; still, we can’t conclude from this study that the effects of resveratrol treatment are beneficial,” Turner explains. “It does appear that resveratrol was able to penetrate the blood brain barrier, which is an important observation. Resveratrol was measured in both blood and cerebrospinal fluid.”
The researchers studied resveratrol because it activates proteins called sirtuins, the same proteins activated by caloric restriction. The biggest risk factor for developing Alzheimer’s is aging, and studies with animals found that most age-related diseases–including Alzheimer’s–can be prevented or delayed by long-term caloric restriction (consuming two-thirds the normal caloric intake).
Turner says the study also found that resveratrol was safe and well tolerated. The most common side effects experienced by participants were gastrointestinal-related, including nausea and diarrhea. Also, patients taking resveratrol experienced weight loss while those on placebo gained weight.
One outcome in particular was confounding, Turner notes. The researchers obtained brain MRI scans on participants before and after the study, and found that resveratrol-treated patients lost more brain volume than the placebo-treated group.
“We’re not sure how to interpret this finding. A similar decrease in brain volume was found with some anti-amyloid immunotherapy trials,” Turner adds. A working hypothesis is that the treatments may reduce inflammation (or brain swelling) found with Alzheimer’s.
The study, funded by the National Institute on Aging and conducted with the Alzheimer’s Disease Cooperative Study, began in 2012 and ended in 2014. GUMC was one of 21 participating medical centers across the U.S.
Further studies, including analysis of frozen blood and cerebrospinal fluid taken from patients, are underway to test possible drug mechanisms.
“Given safety and positive trends toward effectiveness in this phase 2 study, a larger phase 3 study is warranted to test whether resveratrol is effective for individuals with Alzheimer’s — or at risk for Alzheimer’s,” Turner says.
Resveratrol and similar compounds are being tested in many age-related disorders including cancer, diabetes and neurodegenerative disorders. The study Turner led, however, is the largest, longest and highest dose trial of resveratrol in humans to date.