Head Cases

Milk.

New research conducted at the University of Kansas Medical Center has found a correlation between milk consumption and the levels of a naturally-occurring antioxidant called glutathione in the brain in older, healthy adults.

In-Young Choi, Ph.D., an associate professor of neurology at KU Medical Center, and Debra Sullivan, Ph.D., professor and chair of dietetics and nutrition at KU Medical Center, worked together on the project. Their research, which was published in The American Journal of Clinical Nutrition, suggests a new way that drinking milk could benefit the body.

“We have long thought of milk as being very important for your bones and very important for your muscles,” Sullivan said. “This study suggests that it could be important for your brain as well.”

Choi’s team asked the 60 participants in the study about their diets in the days leading up to brain scans, which they used to monitor levels of glutathione, a powerful antioxidant, in the brain.

The researchers found that participants who had indicated they had drunk milk recently had higher levels of glutathione in their brains. This is important, the researchers said, because glutathione could help stave off oxidative stress and the resulting damage caused by reactive chemical compounds produced during the normal metabolic process in the brain. Oxidative stress is known to be associated with a number of different diseases and conditions, including Alzheimer’s disease, Parkinson’s disease and many other conditions, said Dr. Choi.

“You can basically think of this damage like the build-up of rust on your car,” Sullivan said. “If left alone for a long time, the build-up increases and it can cause damaging effects.

Few Americans reach the recommended daily intake of three dairy servings per day, Sullivan said. The new study showed that the closer older adults came to those servings, the higher their levels of glutathione were.

“If we can find a way to fight this by instituting lifestyle changes including diet and exercise, it could have major implications for brain health,” Choi said.

An editorial in the same edition of The American Journal of Clinical Nutrition said the study presented “a provocative new benefit of the consumption of milk in older individuals,” and served as a starting point for further study of the issue.

“Antioxidants are a built-in defence system for our body to fight against this damage, and the levels of antioxidants in our brain can be regulated by various factors such as diseases and lifestyle choices,” Choi said.

For the study, researchers used high-tech brain scanning equipment housed at KU Medical Center’s Hoglund Brain Imaging Center. “Our equipment enables us to understand complex processes occurring that are related to health and disease,” Choi said. “The advanced magnetic resonance technology allowed us to be in a unique position to get the best pictures of what was going on in the brain.”

A randomized, controlled trial that seeks to determine the precise effect of milk consumption on the brain is still needed and is a logical next step to this study, the researchers said.

Power Cut.

An experimental drug that attacks brain tumour tissue by crippling the cells’ energy source called the mitochondria has passed early tests in animal models and human tissue cultures, say Houston Methodist scientists.

As reported on the cover of the April 2015 ChemMedChem (early online), Houston Methodist Kenneth R. Peak Brain & Pituitary Tumor Center Director David S. Baskin, M.D., and Peak Center Head of Research Martyn Sharpe, Ph.D. designed a drug called MP-MUS that destroyed 90 to 95 percent of malignant glioma cells, yet in other experiments did not seem to adversely affect healthy human brain cells (in vitro). This compliments a soon to be published extensive study showing the same drug can treat human brain cancer grown in the brains of mice. Researchers hope to begin testing the drug in human clinical trials in 2016 or 2017

“We are very optimistic that we’ll get there,” said Baskin, also Vice Chair of the Department of Neurosurgery at Houston Methodist Hospital. “Our past work has shown that MP-MUS has very low toxicity until it gets into tumour cells. Once it arrives, it is changed to its active form, doing a lot of damage where we want it to, leaving healthy brain cells alone, a bit like a ‘smart bomb.’ To our knowledge, this is the first known example of selective mitochondrial chemotherapy, which we believe represents a powerful new approach to brain cancer.”

Medical options for brain tumour patients are woeful, Baskin said. “It’s a horrible diagnosis. Because of where the tumours are located, and because of the way they can infiltrate healthy tissue, surgery is often not helpful long term. The most effective chemotherapy drug available right now, temozolomide, only extends life from 9 to 15 months, and patients’ quality of life during that period isn’t very good.”

For that reason, Baskin said, he and researchers around the world have been looking for new treatment approaches, such as vaccines intended to aid the body’s immune system’s recognition and removal of tumour cells, gene therapy and, in the present case, targeting tumor cell mitochondria.

Gliomas (a type of brain tumour), develop from brain cells called astrocytes. Gliomas account for as much as 20 to 30 percent of all tumours of the brain and central nervous system.

Mitochondria are often referred to as the “powerhouses” of cells, including misbehaving cancer cells, because they help cells create energy. In cancer cells this feature is partially switched off, causing cells to rely on other systems that generate energy. The numerous pill-shaped mitochondria in each cell perform a number of other crucial functions, however, and even cancer cells cannot grow and divide without healthy mitochondria.

As luck would have it, an enzyme called MAO-B is over-expressed in brain tumor cells, which is the target of MP-MUS. This means that healthy cells are only exposed to low levels of MP-MUS and their mitochondria to very low levels of P+-MUS, Baskin says. On the other hand, in tumour cells the vast majority of the pro-drug is converted into P+-MUS, which essentially traps the drug inside their mitochondria where it attacks the mitochondrial DNA.

“We found that we could achieve profound effects with MP-MUS at very low concentrations, around 75 micromolar,” said Baskin, Professor of Neurological Surgery, Weill Cornell Medical College. “By contrast, temozolomide must be used at concentrations two to three times that to be of any use to patients. Our approach is designed to capitalise on what is going inside the cells. Tumour cells have much more MAO-B, and when challenged, make even more MAO-B as a sort of defensive response. We hope that we are one step ahead of the cancer cells, as we are using that very fact to kill them.”

The researchers reported MP-MUS’s toxicity to healthy cells remained low at concentrations as high as 180 micromolar. This information will be useful to the researchers as they consider safety and efficacy trials in human patients.

Memory Gain.

Memory and as well as connections between brain cells were restored in mice with a model of Alzheimer’s given an experimental cancer drug, Yale School of Medicine researchers reported in the journal Annals of Neurology.

The drug, AZD05030, developed by Astra Zeneca proved disappointing in treating solid tumours but appears to block damage triggered during the formation of amyloid-beta plaques, a hallmark of Alzheimer’s disease. The new study, funded by an innovative National Institutes of Health (NIH) program to test failed drugs on different diseases, has led to the launch of human trials to test the efficacy of AZD05030 in Alzheimer’s patients.

“With this treatment, cells under bombardment by beta amyloid plaques show restored synaptic connections and reduced inflammation, and the animal’s memory, which was lost during the course of the disease, comes back,” said Stephen M. Strittmatter, the Vincent Coates Professor of Neurology and senior author of the study.

In the last five years, scientists have developed a more complete understanding of the complex chain of events that leads to Alzheimer’s disease. The new drug blocks one of those molecular steps, activation of the enzyme FYN, which leads to the loss of synaptic connections between brain cells. Several other steps in the disease process have the potential to be targets for new drugs, Strittmatter said.

“The speed with which this compound moved to human trials validates our New Therapeutic Uses program model and serves our mission to deliver more treatments to more patients more quickly,” said Christopher P. Austin, M.D., director of NIH’s National Center for Advancing Translational Sciences (NCATS), which funded the work.

Mind Reading.

It sounds like the stuff of science fiction: researchers slice a brain into thin little sections and just by measuring the properties of specific neurons, they can determine what an organism learned before it died. In fact, this sort of mind reading has become a reality. In work published in Nature, researchers at Cold Spring Harbor Laboratory (CSHL) describe how postmortem brain slices can be “read” to determine how a rat was trained to behave in response to specific sounds. The work provides one of the first examples of how specific changes in the activity of individual neurons encode particular acts of learning and memory in the brain.

“Neuroscientists have previously identified brain areas involved in learning something,” says CSHL Professor Anthony Zador, who led the team of researchers on this current work. “But we wanted to drill down further and identify how changes at specific connections encode a particular behavioral response.”

To do this, the team focused on how rats translate sound cues into behavior. The researchers trained rats to associate a specific tone with a reward. Changes in the tone, like the difference between a tuba and a flute, signaled the animal to look for the reward either on the left or right side of a training box.

In previous work, the team discovered that activity in a specific population of neurons was crucial for animals to perform the task. This neuronal population transmitted information from one auditory brain region (the auditory cortex) to another (the auditory striatum).

In the current work, the team measured the strength of the connections between these two populations of neurons, as animals learned the task. “We found that there was a gradient in activity across the auditory striatum that corresponded to whether the animal was trained to go left or right for their reward.” explains Zador.

Based upon this information, the team reasoned that they might be able to use postmortem brain slices to “predict” (obviously, in retrospect) how these or other rats had been trained. As Zador describes, “We were amazed that in all cases, our predictions, left or right, were correct. We had deciphered a tiny piece of the neural code with which the animal encoded these memories. In essence, we could read the minds of these rats.”

“For decades scientists have been trying to map memories in the brain,” said James Gnadt, Ph.D., a program director at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS). “This study shows that scientists can precisely pinpoint the synapses where certain memories are expressed.”

According to Zador, the results are likely to be broadly applicable to other senses and parts of the brain. “We are excited to apply this method to more complex forms of learning, and to other sensory systems, like vision.”

Power Nap.

A team of researchers at Saarland University headed by Professor Axel Mecklinger have shown that a short nap lasting about an hour can significantly improve memory performance. The study, which was coordinated by graduate research student Sara Studte, involved examination of memory recall in 41 participants. The volunteers had to learn single words and word pairs. Once the learning phase was over, the participants were tested to determine how much information they could remember. About half of the participants were then allowed to sleep, while the others watched a DVD. After that, the participants were re-tested and those who had taken a nap were shown to have retained substantially more word pairs in memory than the participants in the control group who had watched a DVD.

The results of the study have been published in the journal Neurobiology of Learning and Memory.

Generations of school students have gone to bed the night before a maths exam or a vocabulary test with their algebra book or vocabulary notes tucked under their pillow in the hope that the knowledge would somehow be magically transferred into their brains while they slept. That they were not completely taken in by a superstitious belief has now been demonstrated by a team of neuropsychologists at Saarland University, who have shown that even a brief sleep can significantly improve retention of learned material in memory.

Sara Studte, a graduate biologist specializing in neuropsychology, working with her PhD supervisor Axel Mecklinger and co-researcher Emma Bridger, is examining how power naps influence memory performance. The results are clear: ‘Even a short sleep lasting 45 to 60 minutes produces a five-fold improvement in information retrieval from memory,’ explains Axel Mecklinger.

Strictly speaking, memory performance did not improve in the nap group relative to the levels measured immediately after the learning phase, but they did remain constant. ‘The control group, whose members watched DVDs while the other group slept, performed significantly worse than the nap group when it came to remembering the word pairs. The memory performance of the participants who had a power nap was just as good as it was before sleeping, that is, immediately after completing the learning phase, says Professor Mecklinger.

The researchers were particularly focused on the role of the hippocampus, a region of the brain in which memories are ‘consolidated’  the process by which previously learned information is transferred into long-term memory storage. ‘We examined a particular type of brain activity, known as “sleep spindles,” that plays an important role in memory consolidation during sleep,’ explains Sara Studte. A sleep spindle is a short burst of rapid oscillations in the electroencephalogram (EEG). ‘We suspect that certain types of memory content, particularly information that was previously tagged, is preferentially consolidated during this type of brain activity,’ says Mecklinger. Newly learned information is effectively given a label, making it easier to recall that information at some later time. In short, a person’s memory of something is stronger, the greater the number of sleep spindles appearing in the EEG.

In order to exclude the possibility that the participants only recall the learned items due to a feeling of familiarity, the researchers used the following trick: the test subjects were required to learn not only 90 single words, but also 120 word pairs, where the word pairs were essentially meaningless. Axel Mecklinger explains the method: ‘A word pair might, for example, be “milk-taxi.” Familiarity is of no use here when participants try to remember this word pair, because they have never heard this particular word combination before and it is essentially without meaning. They therefore need to access the specific memory of the corresponding episode in the hippocampus.’

The research teams draws a clear conclusion from its study: ‘A short nap at the office or in school is enough to significantly improve learning success. Wherever people are in a learning environment, we should think seriously about the positive effects of sleep,’ says Axel Mecklinger. Enhancing information recall through sleeping doesn’t require us to stuff bulky tomes under our pillow. A concentrated period of learning followed by a short relaxing sleep is all that’s needed.



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