ScienceDaily (July 9, 2012) — Alzheimer’s disease is one of the most dreaded and debilitating illnesses one can develop. Currently, the disease afflicts 6.5 million Americans and the Alzheimer’s Association projects it to increase to between 11 and 16 million, or 1 in 85 people, by 2050.

Cell death in the brain causes one to grow forgetful, confused and, eventually, catatonic. Recently approved drugs provide mild relief for symptoms but there is no consensus on the underlying mechanism of the disease.

"We don’t know what the problem is in terms of toxicity," said Joan-Emma Shea, professor of chemistry and biochemistry at the University of California, Santa Barbara (UCSB). "This makes the disease difficult to cure."

Accumulations of amyloid plaques have long been associated with the disease and were presumed to be its cause. These long knotty fibrils, formed from misfolded protein fragments, are almost always found in the brains of diseased patients. Because of their ubiquity, amyloid fibrils were considered a potential source of the toxicity that causes cell death in the brain. However, the quantity of fibrils does not correspond with the degree of dementia and other symptoms.

New findings support a hypothesis that fibrils are a by-product of the disease rather than the toxic agent itself. This paradigm shift changes the focus of inquiry to smaller, intermediate molecules that form and dissipate quickly. These molecules are difficult to perceive in brain tissue.

Read more …

July 10, 2012 by Anne Trafton

A clinical trial of an Alzheimer’s disease treatment developed at MIT has found that the nutrient cocktail can improve memory in patients with early Alzheimer’s. The results confirm and expand the findings of an earlier trial of the nutritional supplement, which is designed to promote new connections between brain cells.

A graphic depicting a synapse, a connection between brain cells. Graphic: Christine Daniloff

Alzheimer’s patients gradually lose those connections, known as synapses, leading to memory loss and other cognitive impairments. The supplement mixture, known as Souvenaid, appears to stimulate growth of new synapses, says Richard Wurtman, a professor emeritus of brain and cognitive sciences at MIT who invented the nutrient mixture.

“You want to improve the numbers of synapses, not by slowing their degradation — though of course you’d love to do that too — but rather by increasing the formation of the synapses,” Wurtman says.

To do that, Wurtman came up with a mixture of three naturally occurring dietary compounds: choline, uridine and the omega-3 fatty acid DHA. Choline can be found in meats, nuts and eggs, and omega-3 fatty acids are found in a variety of sources, including fish, eggs, flaxseed and meat from grass-fed animals. Uridine is produced by the liver and kidney, and is present in some foods as a component of RNA.

These nutrients are precursors to the lipid molecules that, along with specific proteins, make up brain-cell membranes, which form synapses. To be effective, all three precursors must be administered together.

Results of the clinical trial, conducted in Europe, appear in the July 10 online edition of the Journal of Alzheimer’s Disease. The new findings are encouraging because very few clinical trials have produced consistent improvement in Alzheimer’s patients, says Jeffrey Cummings, director of the Cleveland Clinic’s Lou Ruvo Center for Brain Health.

“Memory loss is the central characteristic of Alzheimer’s, so something that improves memory would be of great interest,” says Cummings, who was not part of the research team.

Plans for commercial release of the supplement are not finalized, according to Nutricia, the company testing and marketing Souvenaid, but it will likely be available in Europe first. Nutricia is the specialized health care division of the food company Danone, known as Dannon in the United States.

Making connections

Wurtman first came up with the idea of targeting synapse loss to combat Alzheimer’s about 10 years ago. In animal studies, he showed that his dietary cocktail boosted the number of dendritic spines, or small outcroppings of neural membranes, found in brain cells. These spines are necessary to form new synapses between neurons.

Following the successful animal studies, Philip Scheltens, director of the Alzheimer Center at VU University Medical Center in Amsterdam, led a clinical trial in Europe involving 225 patients with mild Alzheimer’s. The patients drank Souvenaid or a control beverage daily for three months.

That study, first reported in 2008, found that 40 percent of patients who consumed the drink improved in a test of verbal memory, while 24 percent of patients who received the control drink improved their performance.

The new study, performed in several European countries and overseen by Scheltens as principal investigator, followed 259 patients for six months. Patients, whether taking Souvenaid or a placebo, improved their verbal-memory performance for the first three months, but the placebo patients deteriorated during the following three months, while the Souvenaid patients continued to improve. For this trial, the researchers used more comprehensive memory tests taken from the neuropsychological test battery, often used to assess Alzheimer’s patients in clinical research.

Patients showed a very high compliance rate: About 97 percent of the patients followed the regimen throughout the study, and no serious side effects were seen.

Both clinical trials were sponsored by Nutricia. MIT has patented the mixture of nutrients used in the study, and Nutricia holds the exclusive license on the patent.

Brain patterns

In the new study, the researchers used electroencephalography (EEG) to measure how patients’ brain-activity patterns changed throughout the study. They found that as the trial went on, the brains of patients receiving the supplements started to shift from patterns typical of dementia to more normal patterns. Because EEG patterns reflect synaptic activity, this suggests that synaptic function increased following treatment, the researchers say.

Patients entering this study were in the early stages of Alzheimer’s disease, averaging around 25 on a scale of dementia that ranges from 1 to 30, with 30 being normal. A previous trial found that the supplement cocktail does not work in patients with Alzheimer’s at a more advanced stage. This makes sense, Wurtman says, because patients with more advanced dementia have probably already lost many neurons, so they can’t form new synapses.

A two-year trial involving patients who don’t have Alzheimer’s, but who are starting to show mild cognitive impairment, is now underway. If the drink seems to help, it could be used in people who test positive for very early signs of Alzheimer’s, before symptoms appear, Wurtman says. Such tests, which include PET scanning of the hippocampus, are now rarely done because there are no good Alzheimer’s treatments available.

Provided by Massachusetts Institute of Technology

Source: medicalxpress.com

ScienceDaily (July 6, 2012) — In a forthcoming issue of Topics in Cognitive Science researchers from the University of Amsterdam (UvA) argue that at least two, seemingly trivial musical skills can be considered fundamental to the evolution of music: relative pitch — the skill to recognise a melody independent of its pitch level — and beat induction — the skill to pick up regularity (the beat) from a varying rhythm. Both are considered cognitive mechanisms that are essential to perceive, make and appreciate music, and, as such, could be argued to be conditional to the origin of music.

While it recently became quite popular to address the study of the origins of music from an evolutionary perspective, there is still little agreement on the idea that music is in fact an adaptation, that it influenced our survival, or that it made us sexually more attractive. Music appears to be of little use. It doesn’t quell our hunger, nor do we live a day longer because of it. So why argue that music is an adaptation? There are even researchers who claim that studying the evolution of cognition is virtually impossible (Lewontin, 1998; Bolhuis & Wynne, 2009).

Distinguishing between music and musicality

The alternative that Henkjan Honing and Annemie Ploeger of the UvA propose is, first, to distinguish between the notion of ‘music’ and ‘musicality’, with musicality being defined as a natural, spontaneously developing trait based on and constrained by our cognitive system, and music as a social and cultural construct based on that very musicality. And secondly, to collect accumulative evidence from a variety of sources (e.g., psychological, physiological, genetic, phylogenetic, and cross-cultural evidence) to be able to show that a specific cognitive trait is indeed an adaptation.

Both relative pitch and beat induction are suggested as primary candidates for such cognitive traits, musical skills that are considered trivial by most humans, but that turn out to be quite special in the rest of the animal world.

Once these fundamental cognitive mechanisms are identified, it becomes possible to see how these might have evolved. In short: the study of the evolution of music cognition is conditional on a characterisation of the basic mechanisms that make up musicality.

Source: Science Daily

ScienceDaily (July 6, 2012) — If you’re concerned about losing your hearing because of noise exposure (earbud deafness syndrome), a new discovery published online in the FASEB Journal offers some hope. That’s because scientists from Germany and Canada show that the protein, AMPK, which protects cells during a lack of energy, also activates a channel protein in the cell membrane that allows potassium to leave the cell. This activity is important because this mechanism helps protect sensory cells in the inner ear from permanent damage following acoustic noise exposure.

This information could lead to new strategies and therapies to prevent and treat trauma resulting from extreme noise, especially in people with AMPK gene variants that may make them more vulnerable to hearing loss.

"Future research on the basis of the present study may lead to the development of novel strategies preventing noise-induced hearing loss or accelerating recovery from acoustic trauma," said Florian Lang, Ph.D., a researcher involved in the work from the Department of Physiology at the University of Tübingen, in Tübingen, Germany.

To make this discovery, Lang and colleagues compared two groups of mice. The first group was normal and the second lacked the AMPK protein. Hearing of the mice was tested by measuring sound-induced brain activity. All mice were exposed to well-defined noise causing an acoustic trauma and leading to hearing impairment. Prior to noise exposure, the hearing ability was similar in normal mice and mice lacking AMPK. After exposure, the hearing of the normal mice mostly recovered after two weeks, but the recovery of hearing in AMPK-deficient mice remained significantly impaired.

"When it comes to preventing hearing loss, keeping the volume down is still the best strategy, and this discovery doesn’t prevent loud music from beating on our ear drums," said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal. “This discovery does help explain why some people seem more likely to lose their hearing than others. At the same time, it also provides a target for new preventive strategies — and perhaps even a treatment — for earbud deafness syndrome.”

Source: Science Daily

July 6, 2012

(Medical Xpress) — Scientists at the University of Liverpool have found that a protein produced by a gene identified in fruitflies, is responsible for communication between nerve cells in the brain.

Dr Stephen Royle: “This research is another step towards fully understanding the complexities of the human brain.”

The ‘stoned’ gene was discovered in fruitflies by scientists in the 1970s. When this gene was mutated, the flies had problems walking and flying, giving rise to the term ‘stoned’ gene. The same gene was found in mammals some years later, but until now scientists have not known precisely what this gene is responsible for and why it causes problems with physical functions when it mutates.

‘Packets of chemicals’

Scientists at Liverpool have found that the protein the gene expresses in mammals, called stonin2, is responsible for retrieving ‘packets’ of chemicals that nerve cells in the brain release in order to communicate with each other.  The inability of the gene to express this protein in the fruitfly study, suggests why the insect appeared not to be able to walk or fly normally.

The team used advanced techniques to inactivate stonin2 for short and long periods of time in animal cells grown in the laboratory. The cells used where from an area of the brain associated with learning and memory.  They showed that without stonin2 the nerve cells could not retrieve the ‘packets’ needed to transport the chemicals required for communications between nerve cells.

Dr Stephen Royle, from the University’s Institute of Translational Medicine, explains: “Nerve cells in the brain communicate by releasing ‘packets’ of chemicals.  These ‘packets’ must be retrieved and refilled with chemicals so that they can be used once again. This recycling programme is very important for nerve cells to keep communicating with each other. 

“We have shown that a protein called stonin 2 is needed for the packets to be retrieved. There is currently no evidence to suggest that the gene which expresses this protein is mutated in human disease, but any failure in its function would be disastrous.  The research is another step towards fully understanding the complexities of the human brain.”

The research is published in the journal, Current Biology.

Provided by University of Liverpool

Source: medicalxpress.com

ScienceDaily (July 6, 2012) — Yona Goldshmit, Ph.D., is a former physical therapist who worked in rehabilitation centers with spinal cord injury patients for many years before deciding to switch her focus to the underlying science.

"After a few years in the clinic, I realized that we don’t really know what’s going on," she said.

Now a scientist working with Peter Currie, Ph.D., at Monash University in Australia, Dr. Goldshmit is studying the mechanisms of spinal cord repair in zebrafish, which, unlike humans and other mammals, can regenerate their spinal cord following injury. On June 23 at the 2012 International Zebrafish Development and Genetics Conference in Madison, Wisconsin, she described a protein that may be a key difference between regeneration in fish and mammals.

One of the major barriers to spinal regeneration in mammals is a natural protective mechanism, which incongruously results in an unfortunate side effect. After a spinal injury, nervous system cells called glia are activated and flood the area to seal the wound to protect the brain and spinal cord. In doing so, however, the glia create scar tissue that acts as a physical and chemical barrier, which prevents new nerves from growing through the injury site.

One striking difference between the glial cells in mammals and fish is the resulting shape: mammalian glia take on highly branched, star-like arrangements that appear to intertwine into dense tissue. Fish glia cells, by contrast, adopt a simple elongated shape — called bipolar morphology — that bridges the injury site and appears to help new nerve cells grow through the damaged area to heal the spinal cord.

"Zebrafish don’t have so much inflammation and the injury is not so severe as in mammals, so we can actually see the pro-regenerative effects that can happen," Dr. Goldshmit explained.

Studies in mice have found that mammalian glia can take up the same elongated shape, but in response to the environment around the injury they instead mature into scar tissue that does not allow nerve regrowth.

Dr. Goldshmit and her colleagues have focused on a family of molecules called fibroblast growth factors (Fgf), which have shown some evidence of improving recovery in mice and humans with spinal cord damage. The Monash University group found that Fgf activity around the damage site promotes the bipolar glial shape and encourages nerve regeneration in zebrafish.

Preliminary results in mice show that Fgf injections near a spinal injury increase both the number of glia cells at the site and the elongated morphology. Their evidence suggests that Fgfs may work to create an environment more supportive of regeneration in mammals as well and could be a valuable therapeutic target.

Spinal injury patients usually have few options, Dr. Goldshmit emphasized, and development of new, biologically-based approaches will be critical.

"This is a nice example of how we can use the zebrafish model," she said. "When we learn from the zebrafish what to look at, we can find things that give us hope for finding therapeutic approaches for spinal cord injury in humans."

Source: Science Daily

July 6, 2012 by Nancy Owano

(Phys.org) — Talk about fMRI may not be entirely familiar to many people, but that could change with new events that are highlighting efforts to link up humans and machines. fMRI (Functional Magnetic Resonance Imaging) is a promising technology that can help human move beyond joysticks to control robots via brain scanners instead. Now a research project exploring ways to develop robot surrogates with whom humans can interact has turned a corner. A university student‘s ability to make his robot surrogate move around, using fMRI technology, was successful. The experiment linked up Israeli student Tirosh Shapira in a lab at Bar-Ilan University, Israel, with a small robot in another lab far away at Beziers Technology Institute in France.

Shapira merely had to think about moving his arms or legs and the robot, with a camera on its head with an image displayed in front of Shapira, successfully would do the same. If Shapira thought about moving forward or backward, the robot responded accordingly.

fmri monitors blood flowing through the brain and can spot when areas associated with certain actions, such as movement, are in use. The fMRI read the student’s thoughts, which were translated via computer into commands relayed across the Internet to the robot in France.

There is much more work to be done to advance this approach, however. The researchers seek to devise a different type of scanning. An fMRI scanner is an expensive piece of equipment but the scientists believe that improvements in software might allow for a head-mounted device. Another research goal is to see if they can get humans to speak via the robot. The size of the robot will need modification, closer to the size and movement of a human, and engineered with a wider range of movement that would include hand gestures. In sum, according to the researchers, this experiment is only one of many steps ahead.

Medical applications for this technology are seen as promising, especially as scientists explore how patients with paralysis can interface with robots so that the patients can reconnect to the world. Another suggested application has been in the military, where robot surrogates rather than soldiers would be sent into battle.

Source: PHYS.ORG

July 6, 2012

(Medical Xpress) — Researchers decode a molecular mechanism that sheds light on how trauma can become engraved in the brain

Scientists at the Universities of Bonn and Berlin have discovered a mechanism which stops the process of forgetting anxiety after a stress event. In experiments they showed that feelings of anxiety don’t subside if too little dynorphin is released into the brain. The results can help open up new paths in the treatment of trauma patients. The study has been published in the current edition of the Journal of Neuroscience.

Feelings of anxiety very effectively prevent people from getting into situations that are too dangerous. Those who have had a terrible experience initially tend to avoid the place of tragedy out of fear. If no other oppressive situation arises, normally the symptoms of fear gradually subside. “The memory of the terrible events is not just erased.” states first author, PD Dr. Andras Bilkei Gorzo, from the Institute for Molecular Psychiatry at the University of Bonn. “Those impacted learn rather via an active learning process that they no longer need to be afraid because the danger has passed.” But following extreme psychical stress resulting from wars, hostage-takings, accidents or catastrophes chronic anxiety disorders can develop which even after months don’t subside.

Body’s own dynorphin weakens fears

Why is it that in some people terrible events are deeply engraved in their memory, while after a while others seem to have completely put aside any anxiety related to the incident? Scientists in the fields of psychiatry, molecular psychiatry and radiology at the University of Bonn are all involved in probing this issue. “We were able to demonstrate by way of a series of experiments that dynorphin plays an important role in weakening anxiety,” says Prof. Dr. Andreas Zimmer, Director of the Institute for Molecular Psychiatry at the University of Bonn. The substance group in question is opiods which also includes, for instance, endorphins. The latter are released by the body of athletes and have an analgesic and euphoric effect. The reverse, however, is true of dynorphins: They are known for putting a damper on emotional moods.

Mice with disabled gene exhibit persistent anxiety

The team working with Prof. Zimmer tested the exact impact of dynorphins on the brain using mice whose gene for the formation of this substance had been disabled. After being exposed to a brief and unpleasant electric shock, the animals exhibited persistent anxiety symptoms, even if they hadn’t been confronted with the negative stimulus over a longer time. Mice exhibiting a normal amount of released dynorphin were anxious to begin with as well, but the symptoms quickly subsided. “This behavior is the same in humans: If you burn your hand on the stove once, you don’t forget the incident that quickly,” explains Prof. Zimmer. “Learning vocabulary, on the other hand, typically tends to be more tedious because it’s not tied to emotions.”

Results are transferrable to people

Next the researchers showed that these results can be transferred to people. “We took advantage of the fact that people exhibit natural variations of the dynorphin gene that lead to different levels of this substance being released in the brain,” reports Prof. Dr. Henrik Walter, Director of the Research Area Mind and Brain at the Psychiatric University Clinic at the Charité in Berlin, who also used to perform research in this area at the University Clinic in Bonn. A total of 33 healthy probands were divided into two groups: One with the genetically stronger dynorphin release and the other which exhibits less gene activity.

Unpleasant stimulus leads to stress reactions in the probands

Equipped with computer glasses the probands observed blue and green squares which appeared and then disappeared again in a magnetic resonance tomograph (MRT). When the green square was visible the scientists repeatedly gave probands an unpleasant stimulus on the hand using a laser. Scientists were able to prove that these negative stimuli actually led to a stress reaction given the increased sweat on the skin. At the same time, researchers recorded the activities of various brain areas with the tomograph. After this conditioning stage came part two of the experiment: The researchers showed the colored squares without any unpleasant stimuli and recorded how long the stress reaction acquired earlier lasted. The next day the experiment was continued without the laser stimulus in an effort to monitor the longer-term development.

New paths in the treatment of trauma patients

It became apparent that, as in mice human, probands with lower gene activity for dynorphin exhibited stress reactions lasting considerably longer than those probands who released considerably more. Moreover, in brain scans it could be observed that the amygdala – a brain structure in the temporal lobes that processes emotional contents - was also active even if in later testing rounds a green square was shown without the subsequent laser stimulus.

“After the negative laser stimulus stopped this amygdala activity gradually became weaker. This means that the acquired anxiety reaction to the stimulus was forgotten,” reports Prof. Walter. This effect was not as pronounced in the group with less dynorphin activity and prolonged anxiety. “But the ‘forgetting’ of acquired anxiety reactions isn’t a fading, but, rather, an active process which involves the ventromedial prefrontal cortex,” emphasizes Prof. Walter. To corroborate this, researchers found that in the group with less dynorphin activity there was reduced coupling between the prefrontal cortex and the amygdala. “In all likelihood dynorphins affect fear forgetting in a crucial way through this structure,” says Prof. Walter. The scientists now hope that by using the results they will be able to develop long-term approaches for new strategies when it comes to the treatment of trauma patients.

Provided by University of Bonn

Source: medicalxpress.com

ScienceDaily (July 5, 2012) — A gene whose mutation results in malformed faces and skulls as well as mental retardation has been found by scientists.

They looked at patients with Potocki-Shaffer syndrome, a rare disorder that can result in significant abnormalities such as a small head and chin and intellectual disability, and found the gene PHF21A was mutated, said Dr. Hyung-Goo Kim, molecular geneticist at the Medical College of Georgia at Georgia Health Sciences University.

The scientists confirmed PHF21A’s role by suppressing it in zebrafish, which developed head and brain abnormalities similar to those in patients. “With less PHF21A, brain cells died, so this gene must play a big role in neuron survival,” said Kim, lead and corresponding author of the study published in The American Journal of Human Genetics. They reconfirmed the role by giving the gene back to the malformed fish — studied for their adeptness at regeneration — which then became essentially normal. They also documented the gene’s presence in the craniofacial area of normal mice.

While giving the normal gene unfortunately can’t cure patients as it does zebrafish, the scientists believe the finding will eventually enable genetic screening and possibly early intervention during fetal development, including therapy to increase PHF21A levels, Kim said. It also provides a compass for learning more about face, skull and brain formation.

The scientists zeroed in on the gene by using a distinctive chromosomal break found in patients with Potocki-Shaffer syndrome as a starting point. Chromosomes — packages of DNA and protein — aren’t supposed to break, and when they do, it can damage genes in the vicinity.

"We call this breakpoint mapping and the breakpoint is where the trouble is," said Dr. Lawrence C. Layman, study co-author and Chief of the MCG Section of Reproductive Endocrinology, Infertility and Genetics. Damaged genes may no longer function optimally; in PHF21A’s case it’s about half the norm.

"When you see the chromosome translocation, you don’t know which gene is disrupted," Layman said. "You use the break as a focus then use a bunch of molecular techniques to zoom in on the gene." Causes of chromosomal breaks are essentially unknown but likely are environmental and/or genetic, Kim said.

Little was known about PHF21A other than its role in determining how tightly DNA is wound in a package with proteins called histones. How tightly DNA is wound determines whether proteins called transcription factors have the access needed to regulate gene expression, which is important, for example, when a gene needs to be expressed only at a specific time or tissue. PHF21A is believed to primarily work by suppressing other genes, for example, ensuring that genes that should be expressed only in brain cells don’t show up in other cell types, Kim said.

Next steps include using PHF21A as a sort of geographic positioning system to identify other “depressor” genes it regulates then screening patients to look for mutations in those genes as well. “We want to find other people with different genes causing the same problem,” Layman said, and they suspect the genes PHF21A interacts with or regulates are the most likely suspects. It’s too early to know what percentage of Potocki-Shaffer syndrome patients have the PHF21A mutation, Kim noted. “Now that we know the causative gene, we can sequence the gene in more patients and see if they have a mutation,” Layman said.

They also want to look at less-severe forms of mental deficiency, including autism, for potentially milder mutations of PHF21A. More than a dozen of the 25,000 human genes are known to cause craniofacial defects and mental retardation, which often occur together, Kim said.

Source: Science Daily