Study suggests sleep clears brain of damaging toxins
A good night’s rest may literally clear the mind. Using mice, researchers showed for the first time that the space between brain cells may increase during sleep, allowing the brain to flush out toxins that build up during waking hours. These results suggest a new role for sleep in health and disease. The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS).
“Sleep changes the cellular structure of the brain. It appears to be a completely different state,” said Maiken Nedergaard, M.D., D.M.Sc., co-director of the Center for Translational Neuromedicine at the University of Rochester Medical Center in New York, and a leader of the study.
For centuries, scientists and philosophers have wondered why people sleep and how it affects the brain. Only recently have scientists shown that sleep is important for storing memories. In this study, Dr Nedergaard and her colleagues unexpectedly found that sleep may be also be the period when the brain cleanses itself of toxic molecules.
Their results, published in Science, show that during sleep a plumbing system called the glymphatic system may open, letting fluid flow rapidly through the brain. Dr Nedergaard’s lab recently discovered the glymphatic system helps control the flow of cerebrospinal fluid (CSF).
“It’s as if Dr Nedergaard and her colleagues have uncovered a network of hidden caves and these exciting results highlight the potential importance of the network in normal brain function,” said Roderick Corriveau, Ph.D., a program director at NINDS. Initially the researchers studied the system by injecting dye into the CSF of mice and watching it flow through their brains while simultaneously monitoring electrical brain activity.
The dye flowed rapidly when the mice were unconscious, either asleep or anesthetized. In contrast, the dye barely flowed when the same mice were awake. “We were surprised by how little flow there was into the brain when the mice were awake,” said Dr Nedergaard. “It suggested that the space between brain cells changed greatly between conscious and unconscious states.”
To test this idea, the researchers inserted electrodes into the brain to directly measure the space between brain cells. They found that the space inside the brains increased by 60% when the mice were asleep or anesthetized.
“These are some dramatic changes in extracellular space,” said Charles Nicholson, Ph.D., a professor at New York University’s Langone Medical Center and an expert in measuring the dynamics of brain fluid flow and how it influences nerve cell communication. Certain brain cells, called glia, control flow through the glymphatic system by shrinking or swelling. Noradrenaline is an arousing hormone that is also known to control cell volume.
Similar to using anaesthesia, treating awake mice with drugs that block noradrenaline induced unconsciousness and increased brain fluid flow and the space between cells, further supporting the link between the glymphatic system and consciousness.
Previous studies suggest that toxic molecules involved in neurodegenerative disorders accumulate in the space between brain cells. In this study, the researchers tested whether the glymphatic system controls this by injecting mice with labelled beta-amyloid, a protein associated with Alzheimer’s disease, and measuring how long it lasted in their brains when they were asleep or awake. Beta-amyloid disappeared faster in mice brains when the mice were asleep, suggesting sleep normally clears toxic molecules from the brain.
“These results may have broad implications for multiple neurological disorders,” said Jim Koenig, Ph.D., a program director at NINDS. “This means the cells regulating the glymphatic system may be new targets for treating a range of disorders.” The results may also highlight the importance of sleep. “We need sleep. It cleans up the brain,” said Dr Nedergaard.
Study finds Polypill improves patient compliance
People are much more likely to take preventive medicines if they’re combined in one pill, an international study has found. The findings were published 3 September 2013 in the Journal of the American Medical Association. Taking aspirin, cholesterol-lowering and blood pressure-lowering drugs long-term more than halves heart attack and stroke recurrence.
However, only about 50 per cent of people with cardiovascular disease in high-income countries take all recommended preventive medications. In lowand middle-income countries, only five to 20 per cent do. This leaves tens of millions of people undertreated. In the first study to test the impact of a fixed-dose combination pill - called a polypill - in people with cardiovascular disease, 2,004 participants in the UK, Ireland, the Netherlands and India were randomly assigned either the polypill, or their normal combination of medicines.
After an average of 15 months’ followup, the proportion of participants in the polypill group who were taking medications regularly was a third higher than in the group receiving usual care.
The polypill group also had lower blood pressure and cholesterol measurements. Lead author, Professor Simon Thom, from the National Heart and Lung Institute at Imperial College London, said: “The reality is that large numbers of people who have already suffered heart attacks or strokes either don’t receive these medications or get out of the habit of taking them. The findings of this study suggest that providing them in a single pill is a helpful preventive step.”
Testosterone deficiency not only cause of age-associated changes in men
Just as the symptoms of menopause in women are attributed to a sharp drop in oestrogen production, symptoms often seen in middle-aged men – changes in body composition, energy, strength and sexual function – are usually attributed to the less drastic decrease in testosterone production that typically occurs in the middle years. However, a study by Massachusetts General Hospital (MGH) researchers finds that insufficient oestrogen could be at least partially responsible for some of these symptoms.
“This study establishes testosterone levels at which various physiological functions start to become impaired, which may help provide a rationale for determining which men should be treated with testosterone supplements,” says Joel Finkelstein, MD, of the MGH Endocrine Unit, corresponding author of the study in the September 12, 2013 New England Journal of Medicine.
“But the biggest surprise was that some of the symptoms routinely attributed to testosterone deficiency are actually partially or almost exclusively caused by the decline in oestrogen that is an inseparable result of lower testosterone levels.” Traditionally a diagnosis of male hypogonadism – a drop in reproductive hormone levels great enough to cause physical symptoms – has been based on a measure of blood testosterone levels alone.
Although such diagnoses have increased dramatically – leading to a 500% increase in U.S. testosterone prescriptions between 1993 and 2000, the authors note – there has been little understanding of the levels of testosterone needed to support particular functions. In addition to its direct action on some physical functions, a small portion of the testosterone that men make is normally converted into oestrogen by an enzyme called aromatase.
The higher the testosterone level in a normal man, the more is converted into oestrogen. Since any drop in testosterone means that there is less to be converted into oestrogen, men with low testosterone also have low oestrogen levels, making it unclear which hormones support which functions.
The MGH team set out to determine the levels of hormone deficiency at which symptoms begin to occur in men and whether those changes are attributable to decreased levels of testosterone, oestrogen or both. The study enrolled two groups of men with normal reproductive function, ages 20 to 50, and all participants were first treated with a drug that suppresses normal production of all reproductive hormones. Men in the first group were randomly assigned to receive daily doses of testosterone gel at one of four dosage levels or a placebo gel for 16 weeks.
Men in the second group received the same testosterone doses along with an aromatase inhibitor which markedly suppressed conversion of testosterone into oestrogen. More than 150 men in each group completed the study, including monthly visits for blood tests and questionnaires about their overall health and sexual function. Body composition and leg strength were assessed at the beginning and end of the study period.
Among participants in whom oestrogen production was not blocked, increases in body fat were seen at what would be considered a mild level of testosterone deficiency. Decreases in lean body mass, the size of the thigh muscle and leg strength did not develop until testosterone levels became quite low.
In terms of sexual function, sexual desire was reported to decrease progressively with each drop in testosterone levels, whereas erectile function was preserved until testosterone levels were extremely low. In participants also receiving the aromatase inhibitor, increases in body fat were seen at all testosterone dose levels, but suppressing oestrogen production had no effect on lean mass, muscle size or leg strength.
Adverse effects on sexual function were much more obvious when oestrogen synthesis was suppressed regardless of participants’ testosterone levels. Overall the results imply that testosterone levels regulate lean body mass, muscle size and strength, while oestrogen levels regulate fat accumulation. Sexual function – both desire and erectile function – is regulated by both hormones.
Dr Finkelstein notes that decisions about whether an individual is a candidate for testosterone replacement should be made based on his symptoms and not just his testosterone level. The findings regarding oestrogen’s effects suggest that the forms of testosterone used for therapy should be capable of being aromatized into oestrogen, he adds.
Researchers look for Alzheimer’s disease before symptoms start
Johns Hopkins researchers say that by measuring levels of certain proteins in cerebrospinal fluid (CSF), they can predict when people will develop the cognitive impairment associated with Alzheimer’s disease years before the first symptoms of memory loss appear. Identifying such biomarkers could provide a long-sought tool to guide earlier use of potential drug treatments to prevent or halt the progression of Alzheimer’s while people are still cognitively normal.
To date, medications designed to stop the brain damage have failed in clinical trials, possibly, many researchers say, because they are given to those who already have symptoms and too much damage to overcome. “When we see patients with high blood pressure and high cholesterol, we don’t say we will wait until you get congestive heart failure before we treat you.
Early treatments keep heart disease patients from getting worse, and it’s possible the same may be true for those with pre-symptomatic Alzheimer’s,” says Marilyn Albert, Ph.D., a professor of neurology at the Johns Hopkins University School of Medicine. She is primary investigator of the study whose results are published in the October 16, 2013 issue of the journal Neurology.
“But it has been hard to see Alzheimer’s disease coming, even though we believe it begins developing in the brain a decade or more before the onset of symptoms,” she adds.
For the new study, the Hopkins team used CSF collected for the Biomarkers for Older Controls at Risk for Dementia (BIOCARD) project between 1995 and 2005, from 265 middle-aged healthy volunteers. Some three-quarters of the group had a close family member with Alzheimer’s disease, a factor putting them at higher than normal risk of developing the disorder.
Annually during those years and again beginning in 2009, researchers gave the subjects a battery of neuropsychological tests and a physical exam. They found that particular baseline ratios of two proteins – phosphorylated tau and beta amyloid found in CSF – were a harbinger of mild cognitive impairment (often a precursor to Alzheimer’s) more than five years before symptom onset. They also found that the rate of change over time in the ratio was also predictive.
The more tau and the less beta amyloid found in the spinal fluid, the more likely the development of symptoms. And, Albert says, the more rapidly the ratio of tau to beta amyloid goes up, the more likely the eventual development of symptoms. Researchers have known that these proteins were in the spinal fluid of patients with advanced disease.
“But we wondered if we could measure something in the cerebral spinal fluid when people are cognitively normal to give us some idea of when they will develop difficulty,” Albert says. “The answer is yes.” Alzheimer’s disease disrupts critical metabolic processes that keep neurons healthy.
These disruptions cause neurons to stop working, lose connections with other nerve cells, and finally die. The brains of people with Alzheimer’s have an abundance of two abnormal structures – amyloid plaques and “tangles” made of tau.
The plaques are sticky accumulations of beta-amyloid that build up outside of the neurons, while the tangles form inside the neurons. When there are too many tangles inside the cells, the cells start to die. In a normal brain, tau helps the skeleton of the nerve cell maintain itself. When too many phosphate groups attach themselves to tau, too much of the protein develops and tangles form.
Albert says researchers believe that the relative amount of beta-amyloid in the spinal fluid decreases as Alzheimer’s progresses because it is getting trapped in the plaques and therefore isn’t entering the fluid. Though the BIOCARD study has been going on for nearly two decades, this is some of the first predictive data to come out of it, Albert says, owing to the length of time it takes for even high-risk middle-aged people to progress to dementia.
Only 53 of the original patients have progressed to mild cognitive impairment or dementia, giving a sample size just large enough to draw some preliminary conclusions. These first symptoms include memory disruptions such as repeating oneself, forgetting appointments, and forgetting what others have said.
Propofol discovery may lead to new anaesthetics
New research on the most commonly used anaesthetic drug could help to unravel a long-standing mystery about how it induces a pain-free, sleep-like state. General anaesthetics are administered to tens of millions of people every year in hospitals, where they are used to sedate patients undergoing surgery. Despite this, scientists have yet to understand how the drug interacts with its targets in brain cells to achieve this effect.
Following years of research on propofol, which has become the most commonly used anaesthetic since it was introduced in the 1980s, researchers at Imperial College London and Washington University School of Medicine have published a study in the journal Nature Chemical Biology in which they identify exactly how the drug acts in the brain.
Researchers had already identified the receptor that propofol interacts with in the brain. Having a more detailed picture of exactly how propofol works on a molecular level may help scientists to design new versions of the drug that reduce the risks involved in surgery and ultimately improve patient safety.
“The job of the skilled anaesthetist is so important because in addition to the desirable effects of anaesthetics which make surgery possible, current anaesthetics can have unwanted effects on the heart, on blood pressure and can also interfere with breathing during surgery,” said the study’s co-principal investigator Professor Nick Franks from the Department of Life Sciences at Imperial College London.
“Whilst propofol is the best anaesthetic we have today, it is important for patient safety that we come up with new versions of the drug that work just as well or better as anaesthetics, but have fewer or less dangerous side effects.”
“For many years, the mechanisms by which anaesthetics act have remained elusive,” explained co-principal investigator Alex S Evers, MD, the Henry E. Mallinckrodt Professor and head of the Department of Anesthesiology at Washington University. “We knew that intravenous anaesthetics, like propofol, act on an important receptor on brain cells called the GABAA receptor, but we didn’t really know exactly where they bound to that receptor.”
In an attempt to understand how propofol induces anaesthesia during surgery, scientists have tried to identify how and where it interacts with receptors in the brain called gamma-aminobutyric acid type A (GABAA) receptors. Activating these receptors – with propofol for example – stops a nerve cell communicating with its neighbours, leading to unconsciousness.
For this study, the scientists created a molecule that closely resembles and mimics propofol but has an added hook that grabs onto the GABAA receptor and won’t let it go when it is activated by a bright light. They then extracted the receptor, cut it into pieces and identified the place on the protein that the propofol mimic had attached to.
Using the techniques they have developed, the scientists say they will now identify binding sites of other anaesthetics. They believe their approach also can be used to study other types of drugs, such as psychiatric agents and anti-seizure drugs.
Large study launched to check if vitamin D prevents diabetes
Researchers have begun the first definitive, large-scale clinical trial to investigate if a vitamin D supplement helps prevent or delay type 2 diabetes in adults who have prediabetes, who are at high risk for developing type 2. Funded by the US National Institutes of Health, the study is taking place at about 20 study sites across the United States.
The multiyear Vitamin D and Type 2 Diabetes (D2d) study will include about 2,500 people. Its goal is to learn if vitamin D – specifically D3 (cholecalciferol) – will prevent or delay type 2 diabetes in adults aged 30 or older with prediabetes. People with prediabetes have blood glucose levels that are higher than normal but not high enough to be called diabetes.
“This study aims to definitively answer the question: Can vitamin D reduce the risk of developing type 2 diabetes?” said Myrlene Staten, M.D., D2d project officer at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of NIH. “Vitamin D use has risen sharply in the U.S. in the last 15 years, since it has been suggested as a remedy for a variety of conditions, including prevention of type 2 diabetes.
But we need rigorous testing to determine if vitamin D will help prevent diabetes. That’s what D2d will do.” “Past observational studies have suggested that higher levels of vitamin D may be beneficial in preventing type 2 diabetes, but until this large, randomized and controlled clinical trial is complete, we won’t know if taking vitamin D supplements lowers the risk of diabetes,” said Anastassios G. Pittas, M.D., the study’s principal investigator at Tufts Medical Center, Boston. D2d is the first study to directly examine if a daily dose of 4,000 International Units (IUs) of vitamin D – greater than a typical adult intake of 600-800 IUs a day, but within limits deemed appropriate for clinical research by the Institute of Medicine – helps keep people with prediabetes from getting type 2 diabetes.
Based on observations from earlier studies, researchers speculate that vitamin D could reduce the diabetes risk by 25%. The study will also examine if sex, age or race affect the potential of vitamin D to reduce diabetes risk.
Scientists regenerate fully functional bioengineered saliva and tear glands
A research group headed by Professor Takashi Tsuji of Tokyo University of Science have successfully regenerated fully functional bioengineered salivary and lacrimal (tear) glands. The results signify a substantial advance in the development of next generation organ replacement regenerative therapies. The results are published in the scientific journal Nature Communications.
Organ replacement regenerative therapy has been proposed as having the potential to enable the replacement of organs that have been damaged by disease, injury or ageing. A research group led by Professor Takashi Tsuji (Professor in the Research Institute for Science and Technology, Tokyo University of Science, and Director of Organ Technologies Inc.) has provided a proof-of-concept for bioengineered organ replacement as the next step for regenerative therapy For the salivary glands, Dr. Tsuji’s research group (M. Ogawa et al.) reports the fully functional regeneration of a salivary gland that reproduces the morphogenesis induced by reciprocal epithelial and mesenchymal interactions through the orthotopic transplantation of a bioengineered salivary gland germ as a regenerative organ replacement therapy.
The bioengineered germ developed into a mature gland through acinar formations with the myoepithelium and innervation. The bioengineered submandibular gland produced saliva in response to the administration of pilocarpine and gustatory stimulation by citrate, protected against oral bacterial infection and restored normal swallowing in a salivary gland defect mouse model. Thus, this study provides a proof-of-concept for bioengineered salivary gland regeneration as a potential treatment for xerostomia.
For the lacrimal (tear) glands, Dr. Tsuji’s research group (M. Hirayama et al.,) reports the successful orthotopic transplantation of a bioengineered lacrimal gland germ into an adult extra-orbital lacrimal gland defect model mouse, which mimics the corneal epithelial damage caused by lacrimal gland dysfunction.
The bioengineered lacrimal gland germ and harderian gland germ both developed in vivo and achieved sufficient physiological functionality, including tear production in response to nervous stimulation and ocular surface protection. This study demonstrates the potential for bioengineered organ replacement to functionally restore the lacrimal gland.
Bioengineered salivary gland http://tinyurl.com/pufpx4y
Bioengineered lacrimal (tear) gland http://tinyurl.com/n9ayqwv
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