Neuroscience

In a new study, post-menopausal women on testosterone therapy showed a significant improvement in verbal learning and memory, offering a promising avenue for research into memory and ageing.

Led by Director of the Women’s Health Research Program at Monash University, Professor Susan Davis, and presented at ENDO 2103, the research is the first large, randomised, placebo-controlled investigation into the effects of testosterone on cognitive function in postmenopausal women.

Testosterone has been implicated as being important for brain function in men and these results indicate that it has a role in optimising learning and memory in women.

Dementia, which was estimated to affect more than 35 million people worldwide in 2010, is more common in women than men. There are no effective treatments to prevent memory decline.

In the study, 96 postmenopausal women recruited from the community were randomly allocated to receive a testosterone gel or a visually identical placebo gel to be applied to the skin. Participants underwent a comprehensive series of cognitive tests at the beginning of the study and 26 weeks later.

All women performed in the normal range for their age at the beginning of the trial. There was a statistically significant and clinically meaningful improvement in verbal learning and memory amongst the women using the testosterone gel after 26 weeks.

Professor Davis said the results indicated that testosterone played an important role in women’s health. 

"Much of the research on testosterone in women to date has focused on sexual function. But testosterone has widespread effects in women, including, it appears, significant favourable effects on verbal learning and memory," Professor Davis said. 

"Our findings provide compelling evidence for the conduct of larger clinical studies to further investigate the role of testosterone in cognitive function in women.

Androgen levels did increase in the cohort on testosterone therapy, but on average, remained in the normal female range. No negative side-effects of the therapy were observed.

A synthetic compound is able to turn off “secondary” vacuum cleaners in the brain that take up serotonin, resulting in the “happy” chemical being more plentiful, scientists from the School of Medicine at The University of Texas Health Science Center San Antonio have discovered. Their study, released June 18 by The Journal of Neuroscience, points to novel targets to treat depression.

Serotonin, a neurotransmitter that carries chemical signals, is associated with feelings of wellness. Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressants that block a specific “vacuum cleaner” for serotonin (the serotonin transporter, or SERT) from taking up serotonin, resulting in more supply of the neurotransmitter in circulation in the extracellular fluid of the brain.

Delicate balance

"Serotonin is released by neurons in the brain," said Lyn Daws, Ph.D., professor of physiology and pharmacology in the School of Medicine. "Too much or too little may be a bad thing. It is thought that having too little serotonin is linked to depression. That’s why we think Prozac-type drugs (SSRIs) work, by stopping the serotonin transporter from taking up serotonin from extracellular fluid in the brain."

A problem with SSRIs is that many depressed patients experience modest or no therapeutic benefit. It turns out that, while SSRIs block the activity of the serotonin transporter, they don’t block other “vacuum cleaners.” “Until now we did not appreciate the presence of backup cleaners for serotonin,” Dr. Daws said. “We were not the first to show their presence in the brain, but we were among the first show that they were limiting the ability of the SSRIs to increase serotonin signaling in the brain. The study described in this new paper is the first demonstration of enhancing the antidepressant-like effect of an SSRI by concurrently blocking these backup vacuum cleaners.”

Serotonin ceiling

Even if SERT activity is blocked, the backup vacuum cleaners (called organic cation transporters) keep a ceiling on how high the serotonin levels can rise, which likely limits the optimal therapeutic benefit to the patient, Dr. Daws said.

"Right now, the compound we have, decynium-22, is not an agent that we want to give to people in clinical trials," she said. "We are not there yet. Where we are is being able to use this compound to identify new targets in the brain for antidepressant activity and to turn to medicinal chemists to design molecules to block these secondary vacuum cleaners."

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have found a compound that could counter Parkinson’s disease in two ways at once.

In a new study published recently online ahead of print by the journal ACS Chemical Biology, the scientists describe a “dual inhibitor”—two compounds in a single molecule—that attacks a pair of proteins closely associated with development of Parkinson’s disease.

“In general, these two enzymes amplify the effect of each other,” said team leader Phil LoGrasso, a TSRI professor who has been a pioneer in the development of JNK inhibitors for the treatment of neurodegenerative diseases. “What we were looking for is a high-affinity, high-selectivity treatment that is additive or synergistic in its effect—a one-two punch.”

That could be what they found.

This new dual inhibitor attacks two enzymes—the leucine-rich repeat kinase 2 (LRRK2) and the c-jun-N-terminal kinase (JNK)—pronounced “junk.” Genetic testing of several thousand Parkinson’s patients has shown that mutations in the LRRK2 gene increase the risk of Parkinson’s disease, while JNK has been shown to play an important role in neuron (nerve cell) survival in a range of neurodegenerative diseases. As such, they have become highly viable targets for drugs to treat disorders such as Parkinson’s disease.

A dual inhibitor ultimately would be preferred over separate individual JNK and LRRK2 inhibitors because a combination molecule would eliminate complications of drug-drug interactions and the need to optimize individual inhibitor doses for efficacy, the study noted.

Now the team’s new dual inhibitor will need to be optimized for potency, high selectivity (which reduces off-target side effects) and bioavailability so it can be tested in animal models of Parkinson’s disease.

No matter how we jump, roll, sit, or lie down, our brain manages to maintain a visual representation of the world that stays upright relative to the pull of gravity. But a new study of rider experiences on the Hong Kong Peak Tram, a popular tourist attraction, shows that specific features of the environment can dominate our perception of verticality, making skyscrapers appear to fall.

The study is published in Psychological Science, a journal of the Association for Psychological Science.

The Hong Kong Peak Tram to Victoria Peak is a popular way to survey the Hong Kong skyline and millions of people ride the tram every year.

“On one trip, I noticed that the city’s skyscrapers next to the tram started to appear very tilted, as if they were falling, which anyone with common sense knows is impossible,” says lead researcher Chia-huei Tseng of the University of Hong Kong. “The gasps of the other passengers told me I wasn’t the only one seeing it.”

The illusion was perplexing because, in contrast with most illusions studied in the laboratory, observers have complete access to visual cues from the outside world through the tram’s open windows.

Exploring the illusion under various conditions, Tseng and colleagues found that the perceived, or illusory, tilt was greatest on night-time rides, perhaps a result of the relative absence of visual-orientation cues or a heightened sense of enclosure at night. Enhancing the tilted frame of reference within the tram car — indicated by features like oblique window frames, beams, floor, and lighting fixtures — makes the true vertical of the high rises seem to tilt in the opposite direction.

The illusion was significantly reduced by obscuring the window frame and other reference cues inside the tram car, by using wedges to adjust observers’ position, and by having them stand during the tram ride.

But no single modification was sufficient to eliminate the illusion.

“Our findings demonstrate that signals from all the senses must be consonant with each other to abolish the tilt illusion,” the researchers write. “On the tram, it seems that vision dominates verticality perception over other sensory modalities that also mediate earth gravity, such as the vestibular and tactile systems.”

The robustness of the tram illusion took the researchers by surprise:

“We took the same tram up and down for hundreds of trips, and the illusion did not reduce a bit,” says Tseng. “This suggests that our experiences and our learned knowledge about the world — that buildings should be vertical — are not enough to cancel our brain’s wrong conclusion.”

People can plan strategic movements to several different targets at the same time, even when they see far fewer targets than are actually present, according to a new study published in Psychological Science, a journal of the Association for Psychological Science.

A team of researchers at the Brain and Mind Institute at the University of Western Ontario took advantage of a pictorial illusion — known as the “connectedness illusion” — that causes people to underestimate the number of targets they see.

When people act on these targets, however, they can rapidly plan accurate and strategic reaches that reflect the actual number of targets.

Using sophisticated statistical techniques to analyze participants’ responses to multiple potential targets, the researchers found that participants’ reaches to the targets were unaffected by the presence of the connecting lines.

Thus, the “connectedness illusion” seemed to influence the number of targets they perceived but did not impact their ability to plan actions related to the targets.

These findings indicate that the processes in the brain that plan visually guided actions are distinct from those that allow us to perceive the world.

“The design of the experiments allowed us to separate these two processes, even though they normally unfold at the same time,” explained lead researcher Jennifer Milne, a PhD student at the University of Western Ontario.

“It’s as though we have a semi-autonomous robot in our brain that plans and executes actions on our behalf with only the broadest of instructions from us!”

According to Mel Goodale, professor at the University of Western Ontario and senior author on the paper, these findings “not only reveal just how sophisticated the visuomotor systems in the brain are, but could also have important implications for the design and implementation of robotic systems and efficient human-machine interfaces.”

One in four people who survive a stroke or transient ischemic attack (TIA) suffer from symptoms of post-traumatic stress disorder (PTSD) within the first year post-event, and one in nine experience chronic PTSD more than a year later. The data suggest that each year nearly 300,000 stroke/TIA survivors will develop PTSD symptoms as a result of their health scare. The study, led by Columbia University Medical Center researchers, was published today in the online edition of PLOS ONE.

“This work builds on recent findings of ours that PTSD is common among heart attack survivors and that it contributes to a doubled risk of a future cardiac event or of dying within one to three years. Our current results show that PTSD in stroke and TIA survivors may increase their risk for recurrent stroke and other cardiovascular events,” said first author Donald Edmondson, PhD, MPH, assistant professor of behavioral medicine (Center for Behavioral Cardiovascular Health) at CUMC. “Given that each event is life-threatening and that strokes/TIAs add hundreds of millions of dollars to annual health expenditures, these findings are important to both the long-term survival and health costs of these patient populations.”

“PTSD is not just a disorder of combat veterans and sexual assault survivors, but strongly affects survivors of stroke and other potentially traumatic acute cardiovascular events as well,” said Ian M. Kronish, MD, MPH, assistant professor of medicine (Center for Behavioral Cardiovascular Health) and the study’s senior author. “Surviving a life-threatening health scare can have a debilitating psychological impact, and health care providers should make it a priority to screen for symptoms of depression, anxiety, and PTSD among these patient populations.”

Stroke is the fourth-leading cause of death and the top cause of disability in the United States. According to data from the American Stroke Association, nearly 795,000 Americans each year suffer a new or recurrent stroke, and up to an additional 500,000 suffer a TIA.

PTSD is an anxiety disorder initiated by exposure to a traumatic event. Common symptoms include nightmares, avoidance of reminders of the event, and elevated heart rate and blood pressure. Chronic PTSD is a duration of these symptoms for three months or longer (as defined by the DSM-IV).

Since only a few studies have assessed PTSD due to stroke, Drs. Edmondson and Kronish and their colleagues performed the first meta-analysis of clinical studies of stroke- or TIA-induced PTSD. The nine studies in the meta-analysis included a total of 1,138 stroke or TIA survivors.

The study found that 23 percent, or roughly one in four, of the patients developed PTSD symptoms within the first year after their stroke or TIA, with 11 percent, or roughly one in nine, experiencing chronic PTSD more than a year later.

“PTSD and other psychological disorders in stroke and TIA patients appear to be an under-recognized and undertreated problem,” said Dr. Kronish.

“Fortunately, there are good treatments for PTSD,” said Dr. Edmondson. “But first, physicians and patients have to be aware that this is a problem. Family members can also help. We know that social support is a good protective factor against PTSD due to any type of traumatic event.”

“The next step is further research to assess whether mental health treatment can reduce stroke- and TIA-induced PTSD symptoms and help these patients regain a feeling of normalcy and calm as soon as possible after their health scare,” said Dr. Edmondson.

A line of genetically modified mice that Western University scientists call “Forrest Gump” because, like the movie character, they can run far but they aren’t smart, is furthering the understanding of a key neurotransmitter called acetylcholine (ACh). Marco Prado, PhD, and his team at Robarts Research Institute say the mice show what happens when too much of this neurotransmitter becomes available in the brain. Boosting ACh is a therapeutic target for Alzheimer’s disease because it’s found in reduced amounts when there’s cognitive failure. Prado’s research is published in the Journal of Neuroscience.

“We wanted to know what happens if you have more of the gene which controls how much acetylcholine is secreted by neurons,” says Prado, a Robarts scientist and professor in the Departments of Physiology and Pharmacology and Anatomy and Cell Biology at Western’s Schulich School of Medicine & Dentistry. “The response was the complete opposite of what we expected. It’s not a good thing. Acetylcholine release was increased threefold in these mice, which seemed to disturb cognitive function. But put them on a treadmill and they can run twice as far as normal mice before tiring. They’re super-athletes.” In addition to its function in modulating cognitive abilities, ACh drives muscle contraction which allowed for the marked improvement in motor endurance.

One of the tests the scientists, including first author Benjamin Kolisnyk, used is called the touch screen test for mice which uses technology similar to a tablet. After initiating the test, the mice have to scan five different spots on the touch screen to see a light flash, and then run and touch that area. If they get it right they get a reward.  Compared to the control mice, the “Forrest Gump” mice failed miserably at the task.  The researchers found the mice, which have the scientific name ChAT-ChR2-EYFP, had terrible attention spans, as well as dysfunction in working memory and spatial memory.

Prado interprets the research as showing ACh is very important for differentiating cues. So if your brain is presented with a lot of simultaneous information, it helps to pick what’s important. But when you flood the brain with ACh, your brain loses the ability to discern what’s relevant. This study was funded mainly by the Canadian Institutes of Health Research.

The protein mSYD1 has a key function in transmitting information between neurons. This was recently discovered by the research group of Prof Peter Scheiffele at the Biozentrum, University of Basel. The findings of the investigations have been published in the scientific journal “Neuron”.

Synapses are the most important sites of information transfer between neurons. The functioning of our brain is based on the ability of the synapses to release neurotransmitter substances in a fraction of a second, so that neuronal signals can be rapidly propagated and integrated. Peter Scheiffele’s team has now identified a new mechanism, which ensures that synaptic vesicles, the carrier of the transmitter substances, are concentrated at their designated place, thereby contributing to rapid signal transmission.

mSYD1 as organizer of synaptic structures
The speed and precision of synaptic transmission is based on a highly complex protein apparatus in the synapse. A concentration of synaptic vesicles is found at the synaptic contact sites between neurons. When a nerve cell is activated, vesicles fuse with the edge of the synapse, the so-called active zone, and send neurotransmitters to the neighboring cells.

Peter Scheiffele’s research group has now identified a previously unknown protein called mSYD1, which regulates the deposition of the vesicles at the active zone. In nerve cells, in which no mSYD1 protein is present, synaptic contacts continue to be formed but the accumulation of the synaptic vesicles at the active zone is disrupted. This results in a significant reduction of synaptic transmission.

Inactive mSYD1 in autistic disorders
These findings provide important new insights into the mechanisms underlying the formation of functional neuronal networks. In patients with a developmental disorder belonging the autism spectrum, mSYD1 is one of a group of genes that are inactivated. In further investigations, the research group is now looking at how the inactivation of mSYD1 affects the behavior of mice, in order to gain insights into the fundamental neuronal defects associated with autism.

A chemical hormone released in the body as a reaction to stress could be a key trigger of the mechanism for the late onset of Alzheimer’s disease, according to a study by researchers at Temple University.

Previous studies have shown that the chemical hormone corticosteroid, which is released into the body’s blood as a stress response, is found at levels two to three times higher in Alzheimer’s patients than non-Alzheimer’s patients.

“Stress is an environmental factor that looks like it may play a very important role in the onset of Alzheimer’s disease,” said Domenico Praticò, professor of pharmacology and microbiology and immunology in Temple’s School of Medicine, who led the study. “When the levels of corticosteroid are too high for too long, they can damage or cause the death of neuronal cells, which are very important for learning and memory.”

In their study, “Knockout of 5-lipoxygenase prevents dexamethasone-induced tau pathology in 3xTg mice,” published in the journal Aging Cell, the Temple researchers set up a series of experiments to examine the mechanisms by which stress can be responsible for the Alzheimer’s pathology in the brain.

Using triple transgenic mice, which develop amyloid beta and the tau protein, two major brain lesion signatures for Alzheimer’s, the Temple researchers injected one group with high levels of corticosteroid each day for a week in order to mimic stress.

While they found no significant difference in the mice’s memory ability at the end of the week, they did find that the tau protein was significantly increased in the group that received the corticosteroid. In addition, they found that the synapses, which allow neuronal cells to communicate and play a key role in learning and memory, were either damaged or destroyed.

“This was surprising because we didn’t see any significant memory impairment, but the pathology for memory and learning impairment was definitely visible,” said Pratico. “So we believe we have identified the earliest type of damage that precedes memory deficit in Alzheimer’s patients.”
Pratico said another surprising outcome was that a third group of mice that were genetically altered to be devoid of the brain enzyme 5-lipoxygenase appeared to be immune and showed no neuronal damage from the corticosteroid.

In previous studies, Pratico and his team have shown that elevated levels of 5-lipoxygenase cause an increase in tau protein levels in regions of the brain controlling memory and cognition, disrupting neuronal communications and contributing to Alzheimer’s disease. It also increases the levels of amyloid beta, which is thought to be the cause for neuronal death and forms plaques in the brain.

Pratico said the corticosteroid causes the 5-lipoxygenase to over-express and increase its levels, which in turn increases the levels of the tau protein and amyloid beta.

“The question has always been what up-regulates or increases 5-lipoxygenase, and now we have evidence that it is the stress hormone,” he said. “We have identified a mechanism by which the risk factor — having high levels of corticosteroid — could put you at risk for the disease.

“Corticosteroid uses the 5-lipoxygenase as a mechanism to damage the synapse, which results in memory and learning impairment, both key symptoms for Alzheimer’s,” said Pratico. “So that is strong support for the hypothesis that if you block 5-lipoxygenase, you can probably block the negative effects of corticosteroid in the brain.”

Diapocynin, a synthetic molecule derived from a naturally occurring compound (apocynin), has been found to protect neurobehavioral function in mice with Parkinson’s disease symptoms by preventing deficits in motor coordination.

The findings are published in the May 28, 2013 edition of Neuroscience Letters.

Brian Dranka, PhD, postdoctoral fellow at the Medical College of Wisconsin (MCW), is the first author of the paper.  Balaraman Kalyanaraman, PhD, Harry R. & Angeline E. Quadracci Professor in Parkinson’s Research, Chairman and Professor of Biophysics, and Director of the MCW Free Radical Research Center, is the corresponding author.

In a specific type of transgenic mouse called LRRK2R1441G, the animals lose coordinated movements and develop Parkinson’s-type symptoms by ten months of age.  In this study, the researchers treated those mice with diapocynin starting at 12 weeks. That treatment prevented the expected deficits in motor coordination.  

“These early findings are encouraging, but in this model, we still do not know how this molecule exerts neuroprotective action. Further studies are necessary to discover the exact mode of action of the diaopocynin and other molecules with a similar structure,” said Dr. Kalyanaraman.

Clinicians have expressed a need for earlier disease detection in Parkinson’s disease patients; the researchers believe further study of this specific mouse model may allow them to identify new biomarkers that would enable early disease detection, and ultimately allow for better patient care and quality of life.

Researchers have identified a new virus in patients with severe brain infections in Vietnam. Further research is needed to determine whether the virus is responsible for the symptoms of disease.

The virus was found in a total of 28 out of 644 patients with severe brain infections in the study, corresponding to around 4 per cent, but not in any of the 122 patients with non-infectious brain disorders that were tested.

Infections of the brain and central nervous system are often fatal, and patients who survive - often young children and young adults - are left severely disabled. Brain infections can be caused by a range of bacterial, parasitic, fungal and viral agents; however, doctors fail to find the cause of the infection in more than half of all cases, despite extensive diagnostic efforts. Not knowing the causes of these brain infections makes public health and treatment interventions impossible.

Researchers at the Oxford University Clinical Research Unit, the Wellcome Trust South East Asia Major Overseas Programme and the Academic Medical Center at the University of Amsterdam identified the virus, tentatively named CyCV-VN, in the fluid around the brain of two patients with brain infections of unknown cause. The virus was subsequently detected in an additional 26 out of 642 patients with brain infections of known and unknown causes.

Using next-generation gene sequencing techniques, the team sequenced the entire genetic material of the virus, confirming that it represents a new species that has not been isolated before. They found that it belongs to a family of viruses called the Circoviridae, which have previously only been associated with disease in animals, including birds and pigs.

Dr Rogier van Doorn, Head of Emerging Infections at the Wellcome Trust Vietnam Research Programme and Oxford University Clinical Research Unit Hospital for Tropical Diseases in Vietnam, explains: “We don’t yet know whether this virus is responsible for causing the serious brain infections we see in these patients, but finding an infectious agent like this in a normally sterile environment like the fluid around the brain is extremely important. We need to understand the potential threat of this virus to human and animal health.”

The researchers were not able to detect CyCV-VN in blood samples from the patients, but it was present in 8 out of 188 faecal samples from healthy children. The virus was also detected in more than half of faecal samples from chickens and pigs taken from the local area of one of the patients from whom the virus was initially isolated, which may suggest an animal source of infection.

Dr Le Van Tan, Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, said: “The evidence so far seems to suggest that CyCV-VN may have crossed into humans from animals, another example of a potential zoonotic infection. However, detecting the virus in human samples is not in itself sufficient evidence to prove that the virus is causing disease, particularly since the virus could also be detected in patients with other known viral or bacterial causes of brain infection.

"While detection of this virus in the fluid around the brain is certainly remarkable, it could still be that it doesn’t cause any harm. Clearly, we need to do more work to understand the role this virus may play in these severe infections."

The researchers are currently trying to grow the virus in the laboratory using cell culture techniques to develop a blood assay to test for antibody responses in patient samples, which would indicate that the patients had mounted an immune response against the virus. Such a test could also be used to study how many people in the population have been exposed to CyCV-VN without showing symptoms of disease.

The team are collaborating with scientists across South-east Asia and in the Netherlands to determine whether CyCV-VN can be detected in patient samples from other countries and better understand its geographical distribution.

Professor Menno de Jong, head of the Department of Medical Microbiology of the Academic Medical Centre in Amsterdam, said: “Our research shows the importance of continuing efforts to find novel causes of important infectious diseases and the strength of current technology in aid of these efforts.”

The distribution of white matter brain abnormalities in some patients after mild traumatic brain injury (MTBI) closely resembles that found in early Alzheimer’s dementia, according to a new study published online in the journal Radiology.

“Findings of MTBI bear a striking resemblance to those seen in early Alzheimer’s dementia,” said the study’s lead author, Saeed Fakhran, M.D., assistant professor of radiology in the Division of Neuroradiology at the University of Pittsburgh School of Medicine. “Additional research may help further elucidate a link between these two disease processes.”

MTBI, or concussion, affects more than 1.7 million people in the United States annually. Despite the name, these injuries are by no means mild, with approximately 15 percent of concussion patients suffering persistent neurological symptoms.

“Sleep-wake disturbances are among the earliest findings of Alzheimer’s patients, and are also seen in a subset of MTBI patients,” Dr. Fakhran said. “Furthermore, after concussion, many patients have difficulty filtering out white noise and concentrating on the important sounds, making it hard for them to understand the world around them. Hearing problems are not only an independent risk factor for developing Alzheimer’s disease, but the same type of hearing problem seen in MTBI patients has been found to predict which patients with memory problems will go on to develop Alzheimer’s disease.”

For the study, Dr. Fakhran and colleagues set out to determine if there was a relationship between white matter injury patterns and severity of post-concussion symptoms in MTBI patients with normal findings on conventional magnetic resonance imaging (MRI) exams. The researchers studied data from imaging exams performed on 64 MTBI patients and 15 control patients, using an advanced MRI technique called diffusion tensor imaging, which identifies microscopic changes in the brain’s white matter.

The brain’s white matter is composed of millions of nerve fibers called axons that act like communication cables connecting various regions of the brain. Diffusion tensor imaging produces a measurement, called fractional anisotropy, of the movement of water molecules along axons. In healthy white matter, the direction of water movement is fairly uniform and measures high in fractional anisotropy. When water movement is more random, fractional anisotropy values decrease.

Of the MTBI patients, 42 (65.6 percent) were men, and the mean age was 17. Sports injury was the reason for concussion in two-thirds of the patients. All patients underwent neurocognitive evaluation with Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT). The researchers analyzed correlation between fractional anisotropy values, the ImPACT total symptom score, and findings of sleep-wake disturbances.

Sleep-wake disturbances are among the most disabling post-concussive symptoms, directly decreasing quality of life and productivity and magnifying post-concussion memory and social dysfunction.

The results showed a significant correlation between high ImPACT total symptom score and reduced fractional anisotropy at the gray-white junction, most prominently in the auditory cortex. Significantly decreased fractional anisotropy was found in patients with sleep-wake disturbances in the parahippocampal gyri relative to patients without sleep-wake disturbances.

“When we sleep, the brain organizes our experiences into memories, storing them so that we can later find them,” Dr. Fakhran said. “The parahippocampus is important for this process, and involvement of the parahippocampus may, in part, explain the memory problems that occur in many patients after concussion.”

According to Dr. Fakhran, the results suggest that the true problem facing concussion patients may not be the injury itself, but rather the brain’s response to that injury.

“Traditionally, it has been believed that patients with MTBI have symptoms because of abnormalities secondary to direct injury,” he said. “Simply put, they hit their head, damaged their brain at the point of trauma and thus have symptoms from that direct damage. Our preliminary findings suggest that the initial traumatic event that caused the concussion acts as a trigger for a sequence of degenerative changes in the brain that results in patient symptoms and that may be potentially prevented. Furthermore, these neurodegenerative changes are very similar to those seen in early Alzheimer’s dementia.”

The researchers hope that these findings may lead to improved treatments in the future.

“The first step in developing a treatment for any disease is understanding what causes it,” Dr. Fakhran said. “If we can prove a link, or even a common pathway, between MTBI and Alzheimer’s, this could potentially lead to treatment strategies that would be potentially efficacious in treating both diseases.”

Memory improves in older, overweight women after they lose weight by dieting, and their brain activity actually changes in the regions of the brain that are important for memory tasks, a new study finds. The results were presented at The Endocrine Society’s 95th Annual Meeting in San Francisco.

(Image: Corbis)

“Our findings suggest that obesity-associated impairments in memory function are reversible, adding incentive for weight loss,” said lead author Andreas Pettersson, MD, a PhD student at Umea University, Umea, Sweden.

Previous research has shown that obese people have impaired episodic memory, the memory of events that happen throughout one’s life.

Pettersson and co-workers performed their study to determine whether weight loss would improve memory and whether improved memory correlated with changes in relevant brain activity. A special type of brain imaging called functional magnetic resonance imaging (functional MRI) allowed them to see brain activity while the subjects performed a memory test.

The researchers randomly assigned 20 overweight, postmenopausal women (average age, 61) to one of two healthy weight loss diets for six months. Nine women used the Paleolithic diet, also called the Caveman diet, which was composed of 30 percent protein; 30 percent carbohydrates, or “carbs”; and 40 percent unsaturated fats. The other 11 women followed the Nordic Nutrition Recommendations of a diet containing 15 percent protein, 55 percent carbs and 30 percent fats.

Before and after the diet, the investigators measured the women’s body mass index (BMI, a measure of weight and height) and body fat composition. They also tested the subjects’ episodic memory by instructing them to memorize unknown pairs of faces and names presented on a screen during functional MRI. The name for this process of creating new memory is “encoding.” Later, the women again saw the facial images along with three letters. Their memory retrieval task, during functional MRI, was to indicate the correct letter that corresponded to the first letter of the name linked to the face.

Because the two dietary groups did not differ in body measurements and functional MRI data, their data were combined and analyzed as one group. The group’s average BMI decreased from 32.1 before the diet to 29.2 (below the cutoff for obesity) after six months of dieting, and their average weight dropped from 188.9 pounds (85 kilograms) to 171.3 pounds (77.1 kilograms), the authors reported. This study was part of a larger, diet-focused study funded by the Swedish Research Council and the Swedish Heart-Lung Foundation.

Memory performance improved after weight loss, and Pettersson said the brain-activity pattern during memory testing reflected this improvement. After weight loss, brain activity reportedly increased during memory encoding in the brain regions that are important for identification and matching of faces. In addition, brain activity decreased after weight loss in the regions that are associated with retrieval of episodic memories, which Pettersson said indicates more efficient retrieval.

“The altered brain activity after weight loss suggests that the brain becomes more active while storing new memories and therefore needs fewer brain resources to recollect stored information,” he said.

A missing brain enzyme increases concentrations of a protein related to pain-killer addiction, according to an animal study. The results were presented at The Endocrine Society’s 95th Annual Meeting in San Francisco.

Opioids are pain-killing drugs, derived from the opium plant, which block signals of pain between nerves in the body. They are manufactured in prescription medications like morphine and codeine, and also are found in some illegal drugs, like heroin. Both legal and illegal opioids can be highly addictive.

In addition to the synthetic opioids, natural opioids are produced by the body. Most people have heard of the so-called feel-good endorphins, which are opioid-like proteins produced by various organs in the body in response to certain activities, like exercise.

Drug addiction occurs, in part, because opioid-containing drugs alter the brain’s biochemical balance of naturally produced opioids. Nationwide, drug abuse of opioid-containing prescription drugs is skyrocketing, and researchers are trying to identify the risk factors that differentiate people who get addicted from those who do not.

In this particular animal model, researchers eliminated an enzyme called prohormone convertase 2, or PC2, which normally converts pre-hormonal substances into active hormones in certain parts of the brain. Previous research by this team demonstrated that PC2 levels increase after long-term morphine treatment, according to study lead author Theodore C. Friedman, MD, PhD, chairman of the internal medicine department at Charles R. Drew University of Medicine and Science in Los Angeles.

“This raises the possibility that PC2-derived peptides may be involved in some of the addiction parameters related to morphine,” Friedman said.

For this study, Friedman and his co-researchers analyzed the effects of morphine on the brain after knocking out the PC2 enzyme in mice. Morphine normally binds to a protein on cells known as the mu opioid receptor, or MOR. They found that MOR concentrations were higher in mice lacking PC2, compared to other mice.

To analyze the effects of PC2 elimination, the researchers examined MOR levels in specific parts of the brain that are related to pain relief, as well as to behaviors associated with reward and addiction. They measured these levels using a scientific test called immunohistochemistry, which uses specific antibodies to identify the cells in which proteins are expressed.

“In this study, we found that PC2 knockout mice have higher levels of MOR in brain regions related to drug addiction,” Friedman said. “We conclude that PC2 regulates endogenous opioids involved in the addiction response and in its absence, up-regulation of MOR expression occurs in key brain areas related to drug addiction.”

Rett Syndrome is a neurological disorder that affects about 1 in 10,000 girls. Back in 1992, University of Edinburgh researcher Adrian Bird discovered that the protein, MeCP2, plays a major role in the disease. The story of MeCP2 is in many ways a microcosm of human genetics. It has become the showcase gene for many complex epi-genetic phenomena including X-linked inactivation, DNA methylation, and genomic imprinting. These gender-specific bargaining chips provide compatibility in an evolutionary system where sex-chromosome provisioning is inherently assymetric. In two new papers, one in Nature and the the other in Nature Neuroscience, Bird and collaborator Michael Greenberg, show how mutations found in Rett Syndrome affect the interaction of MeCP2 with a key regulatory protein known as NCoR.

Nearly all cases of Rett Syndrome are caused by mutations at various postions in the MeCP2 gene. Bird and Greenberg analyzed the locations of these mutations using the RettBase MeCp2 database, and found they cluster to two primary locations—the well-known methyl-CpG binding domain, and a new hotspot within a transcriptional repressor domain (TRD). When they compared these locations with mutations found in the general population by using the Exome Variant Server, they found no overlap. This suggests the that the MeCP2 and TRD regions are the primary regions involved in Rett’s.

The researchers hypothesized that the newly found TRD region must act through a unknown regulator of MeCP2 function. Using mass spectrometry, they were able to identify several factors which they had purified from Mecp2-EGFP “knock-in” mice. Most of these factors turned out to be subunits of the co-repressor, NCoR, which was previously known to interact with MeCP2. This is the first identified example of a protein-protein interaction known to be disrupted in Rett’s.

In the Nature paper, the researchers further report that activity-dependent phosphorylation of MeCP2 mediates its interaction with NCoR. They used a technique known as phosphotryptic mapping to identify three sites that are directly phosphorylated in MeCP2 as a result of elevation in cAMP or BDNF. More generally, they showed that membrane depolarization, and therefore activity, results in the phosporylation.

One confounding factor in trying to pinpoint the mechanisms underlying Rett Syndrome is that both loss of MeCP2, and overexpression of MeCP2, can lead to the disease. In mouse models of the disease, this could be accounted for by the observation that both loss of NCoR binding, and constitutive binding of NCoR can lead to disease symptoms. While not a complete explanation of the role of MeCP2 in the disease, it provides some clues to help dissect the involvement of the many different kinds of mutations involved.

Despite the rarity of Rett’s syndrome, its impact on our understanding of human genetics and neural development should not be underestimated. As one of the autistic spectrum disorders, research on Rett’s helps connect molecular mechanics to behavior. For example, when MeCP2 is bound to DNA it can cause condensation of the chromatin structure, and also form complexes with histone deacetylaces. In demostrating that neural activity, and subsequent signal tranduction pathways, lead to modifications of MeCP2, the researchers have revealed a path from the environment directly to the genes.

The X-linked inactivation of one copy of the MeCP2 gene in females adds another layer of complexity to the disease. The celluar mosiac formed by the pattern of inactivation, particularly in the brain, needs more study to be undersatood. The fact that Rett’s symptoms can be “rescued” in mice by the expression of MeCP2 in postmitotic neurons is encouraging. In humans, Rett’s is frequently not observed untill the first or second year of life. As MeCP2 activation correlates with this period of rapid neural maturation, Rett’s is generally considered to be neurodevelopmental disease, as opposed to a neurodegenerative disease.

Rett’s is hardly ever observed in males for the simple reason that they fail to thrive long before birth. In those rare cases that a presumably XXY male child is rescued by the additional X chromsome, as in Klinefelder’s disease, rare opportunity to study the disease etiology is afforded. The efforts of these researchers, and the larger Rett’s community, together with the insights afforded by massive data collation have turned a rare disease into a primary source of knowledge about how evolution proceeds through the interplay of the sexes at the genetic and epigenetic levels.

TAU researcher says mannitol could prevent aggregation of toxic proteins in the brain

Mannitol, a sugar alcohol produced by fungi, bacteria, and algae, is a common component of sugar-free gum and candy. The sweetener is also used in the medical field — it’s approved by the FDA as a diuretic to flush out excess fluids and used during surgery as a substance that opens the blood/brain barrier to ease the passage of other drugs.

Now Profs. Ehud Gazit and Daniel Segal of Tel Aviv University’s Department of Molecular Microbiology and Biotechnology and the Sagol School of Neuroscience, along with their colleague Dr. Ronit Shaltiel-Karyo and PhD candidate Moran Frenkel-Pinter, have found that mannitol also prevents clumps of the protein α-synuclein from forming in the brain — a process that is characteristic of Parkinson’s disease.

These results, published in the Journal of Biological Chemistry and presented at the Drosophila Conference in Washington, DC in April, suggest that this artificial sweetener could be a novel therapy for the treatment of Parkinson’s and other neurodegenerative diseases. The research was funded by a grant from the Parkinson’s Disease Foundation and supported in part by the Lord Alliance Family Trust.

Seeing a significant difference

After identifying the structural characteristics that facilitate the development of clumps of α-synuclein, the researchers began to hunt for a compound that could inhibit the proteins’ ability to bind together. In the lab, they found that mannitol was among the most effective agents in preventing aggregation of the protein in test tubes. The benefit of this substance is that it is already approved for use in a variety of clinical interventions, Prof. Segal says.

Next, to test the capabilities of mannitol in the living brain, the researchers turned to transgenic fruit flies engineered to carry the human gene for α-synuclein. To study fly movement, they used a test called the “climbing assay,” in which the ability of flies to climb the walls of a test tube indicates their locomotive capability. In the initial experimental period, 72 percent of normal flies were able to climb up the test tube, compared to only 38 percent of the genetically-altered flies.

The researchers then added mannitol to the food of the genetically-altered flies for a period of 27 days and repeated the experiment. This time, 70 percent of the mutated flies could climb up the test tube. In addition, the researchers observed a 70 percent reduction in aggregates of α-synuclein in mutated flies that had been fed mannitol, compared to those that had not.

These findings were confirmed by a second study which measured the impact of mannitol on mice engineered to produce human α-synuclein, developed by Dr. Eliezer Masliah of the University of San Diego. After four months, the researchers found that the mice injected with mannitol also showed a dramatic reduction of α-synuclein in the brain.

Delivering therapeutic compounds to the brain

The researchers now plan to re-examine the structure of the mannitol compound and introduce modifications to optimize its effectiveness. Further experiments on animal models, including behavioral testing, whose disease development mimics more closely the development of Parkinson’s in humans is needed, Prof. Segal says.

For the time being, mannitol may be used in combination with other medications that have been developed to treat Parkinson’s but which have proven ineffective in breaking through the blood/brain barrier, says Prof. Segal. These medications may be able to “piggy-back” on mannitol’s ability to open this barrier into the brain.

Although the results look promising, it is still not advisable for Parkinson’s patients to begin ingesting mannitol in large quantities, Prof. Segal cautions. More testing must be done to determine dosages that would be both effective and safe.

The lipidation states (or modifications) in certain proteins in the brain that are related to the development of Alzheimer disease appear to differ depending on genotype and cognitive diseases, and levels of these protein and peptides appear to be influenced by diet, according to a report published Online First by JAMA Neurology, a JAMA Network publication.

Sporadic Alzheimer disease (AD) is caused in part by the accumulation of β-amyloid (Αβ) peptides in the brain. These peptides can be bound to lipids or lipid carrier proteins, such as apolipoprotein E (ApoE), or be free in solution (lipid-depleted [LD] Αβ). Levels of LD Αβ are higher in the plasma of adults with AD, but less is known about these peptides in the cerebrospinal fluid (CSF), the authors write in the study background.

Angela J. Hanson, M.D., Veterans Affairs Puget Sound Health Care System and the University of Washington, Seattle, and colleagues studied 20 older adults with normal cognition (average age 69 years) and 27 older adults with amnestic mild cognitive impairment (average age 67 years).

The patients were randomized to a diet high in saturated fat content (45 percent energy from fat, greater than 25 percent saturated fat) with a high glycemic index or a diet low in saturated fat content (25 percent of energy from fat, less than 7 percent saturated fat) with a low glycemic index. The main outcomes the researchers measured were lipid depleted (LD) Αβ42 and Αβ40 and ApoE in cerebrospinal fluid.

Study results indicate that baseline levels of LD Αβ were greater for adults with mild cognitive impairment compared with adults with normal cognition. The authors also note that these findings were more apparent in adults with mild cognitive impairment and the Ɛ4 allele (a risk factor for AD), who had higher LD apolipoprotein E levels irrespective of cognitive diagnosis. Study results indicate that the diet low in saturated fat tended to decrease LD Αβ levels, whereas the diet high in saturated fat increased these fractions.

The authors note the data from their small pilot study need to be replicated in a larger sample before any firm conclusions can be drawn.

“Overall, these results suggest that the lipidation states of apolipoproteins and amyloid peptides might play a role in AD pathological processes and are influenced by APOE genotype and diet,” the study concludes.

Editorial: Food for Thought

In an editorial, Deborah Blacker, M.D., Sc.D., of the Massachusetts General Hospital/Harvard Medical School, Boston, writes: “The article by Hanson and colleagues makes a serious effort to understand whether dietary factors can affect the biology of Alzheimer disease (AD).”

“Hanson et al argue that the changes observed after their two dietary interventions may underlie some of the epidemiologic findings regarding diabetes and other cardiovascular risk factors and risk for AD. The specifics of their model may not capture the real underlying biological effect of these diets, and it is unclear whether the observed changes in the intermediate outcomes would lead to beneficial changes in oligomers or plaque burden, much less to decreased brain atrophy or improved cognition,” she continues.

“At some level, however, the details of the biological model are not critical; the important lesson from the study is that dietary intervention can change brain amyloid chemistry in largely consistent and apparently meaningful ways – in a short period of time. Does this change clinical practice for those advising patients who want to avoid dementia? Probably not, but it adds another small piece to the growing evidence that taking good care of your heart is probably good for your brain too,” Blacker concludes.

Researchers have discovered a pathway by which the brain controls a molecule critical to forming long-term memories and connected with bipolar disorder and schizophrenia.

The discovery was made by a team of scientists led by Alexei Morozov, an assistant professor at the Virginia Tech Carilion Research Institute.

The mechanism – a protein called Rap1 – controls L-type calcium channels, which participate in the formation of long-term memories. Previous studies have also linked alterations in these ion channels to certain psychiatric disorders. The discovery of the channels’ regulation by Rap1 could help scientists understand the physiological genesis of bipolar disorder and schizophrenia.

"People with genetic mutations affecting L-type calcium channels have higher rates of bipolar disorder and schizophrenia," said Morozov. "This suggests that there might be a relationship between the activation of L-type calcium channels and these psychiatric disorders. Understanding how these ion channels are controlled is the first step to determining how their functioning or malfunctioning affects mental health."

A single neuron in the brain can have thousands of synapses, each of which can grow, strengthen, weaken, and change structurally in response to learning new information. Electric signals traveling from neuron to neuron jump across these synapses through chemical neurotransmitters. The release of these chemicals is caused by the flow of electrically charged atoms through a particular subset of ion channels known as voltage-gated calcium channels.

Previous studies have shown that blocking these ion channels inhibits the formation of long-term memories. Although it was known that L-type calcium channels are activated in response to learning, how they are controlled was a mystery.

In the experiment, Morozov and colleagues knocked out the gene responsible for coding the enzyme Rap1, which he suspected played a role in activating L-type calcium channels. The researchers then used live imaging techniques to monitor the release of neurotransmitters and electron microscopy to visualize L-type channels at synapses. They discovered that, without Rap1, the L-type calcium channels were more active and more abundant at synapses all the time, increasing the release of neurotransmitters. The results showed that Rap1 is responsible for suppressing L-type calcium channels, allowing them to activate only at the proper moments, possibly during long-term memory formation.

"Our next step is to determine whether this new signaling pathway is altered in cases of mental disease," said Morozov. "If so, it could help us gain a better understanding of the molecular underpinnings of channel-related psychiatric disorders, such as bipolar disorder and schizophrenia. Such knowledge would go a long way toward developing new therapeutic methods."

UCLA researchers now have the first evidence that bacteria ingested in food can affect brain function in humans. In an early proof-of-concept study of healthy women, they found that women who regularly consumed beneficial bacteria known as probiotics through yogurt showed altered brain function, both while in a resting state and in response to an emotion-recognition task.

The study, conducted by scientists with the Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, part of the UCLA Division of Digestive Diseases, and the Ahmanson–Lovelace Brain Mapping Center at UCLA, appears in the current online edition of the peer-reviewed journal Gastroenterology.

The discovery that changing the bacterial environment, or microbiota, in the gut can affect the brain carries significant implications for future research that could point the way toward dietary or drug interventions to improve brain function, the researchers said.

"Many of us have a container of yogurt in our refrigerator that we may eat for enjoyment, for calcium or because we think it might help our health in other ways," said Dr. Kirsten Tillisch, an associate professor of medicine in the digestive diseases division at UCLA’s David Geffen School of Medicine and lead author of the study. "Our findings indicate that some of the contents of yogurt may actually change the way our brain responds to the environment. When we consider the implications of this work, the old sayings ‘you are what you eat’ and ‘gut feelings’ take on new meaning."

Researchers have known that the brain sends signals to the gut, which is why stress and other emotions can contribute to gastrointestinal symptoms. This study shows what has been suspected but until now had been proved only in animal studies: that signals travel the opposite way as well.

"Time and time again, we hear from patients that they never felt depressed or anxious until they started experiencing problems with their gut," Tillisch said. "Our study shows that the gut–brain connection is a two-way street."

The small study involved 36 women between the ages of 18 and 55. Researchers divided the women into three groups: one group ate a specific yogurt containing a mix of several probiotics — bacteria thought to have a positive effect on the intestines — twice a day for four weeks; another group consumed a dairy product that looked and tasted like the yogurt but contained no probiotics; and a third group ate no product at all.

Functional magnetic resonance imaging (fMRI) scans conducted both before and after the four-week study period looked at the women’s brains in a state of rest and in response to an emotion-recognition task in which they viewed a series of pictures of people with angry or frightened faces and matched them to other faces showing the same emotions. This task, designed to measure the engagement of affective and cognitive brain regions in response to a visual stimulus, was chosen because previous research in animals had linked changes in gut flora to changes in affective behaviors.

The researchers found that, compared with the women who didn’t consume the probiotic yogurt, those who did showed a decrease in activity in both the insula — which processes and integrates internal body sensations, like those from the gut — and the somatosensory cortex during the emotional reactivity task.

Further, in response to the task, these women had a decrease in the engagement of a widespread network in the brain that includes emotion-, cognition- and sensory-related areas. The women in the other two groups showed a stable or increased activity in this network.

During the resting brain scan, the women consuming probiotics showed greater connectivity between a key brainstem region known as the periaqueductal grey and cognition-associated areas of the prefrontal cortex. The women who ate no product at all, on the other hand, showed greater connectivity of the periaqueductal grey to emotion- and sensation-related regions, while the group consuming the non-probiotic dairy product showed results in between.

The researchers were surprised to find that the brain effects could be seen in many areas, including those involved in sensory processing and not merely those associated with emotion, Tillisch said.

The knowledge that signals are sent from the intestine to the brain and that they can be modulated by a dietary change is likely to lead to an expansion of research aimed at finding new strategies to prevent or treat digestive, mental and neurological disorders, said Dr. Emeran Mayer, a professor of medicine (digestive diseases), physiology and psychiatry at the David Geffen School of Medicine at UCLA and the study’s senior author.

"There are studies showing that what we eat can alter the composition and products of the gut flora — in particular, that people with high-vegetable, fiber-based diets have a different composition of their microbiota, or gut environment, than people who eat the more typical Western diet that is high in fat and carbohydrates," Mayer said. "Now we know that this has an effect not only on the metabolism but also affects brain function."

The UCLA researchers are seeking to pinpoint particular chemicals produced by gut bacteria that may be triggering the signals to the brain. They also plan to study whether people with gastrointestinal symptoms such as bloating, abdominal pain and altered bowel movements have improvements in their digestive symptoms which correlate with changes in brain response.

Meanwhile, Mayer notes that other researchers are studying the potential benefits of certain probiotics in yogurts on mood symptoms such as anxiety. He said that other nutritional strategies may also be found to be beneficial.

By demonstrating the brain effects of probiotics, the study also raises the question of whether repeated courses of antibiotics can affect the brain, as some have speculated. Antibiotics are used extensively in neonatal intensive care units and in childhood respiratory tract infections, and such suppression of the normal microbiota may have long-term consequences on brain development.

Finally, as the complexity of the gut flora and its effect on the brain is better understood, researchers may find ways to manipulate the intestinal contents to treat chronic pain conditions or other brain related diseases, including, potentially, Parkinson’s disease, Alzheimer’s disease and autism.

Answers will be easier to come by in the near future as the declining cost of profiling a person’s microbiota renders such tests more routine, Mayer said.