Neuroscience

Mice with many of the pathologies of Alzheimer’s Disease showed fewer signs of the disease when given a protein-restricted diet supplemented with specific amino acids every other week for four months.

Mice at advanced stages of the disease were put on the new diet. They showed improved cognitive abilities over their non-dieting peers when their memory was tested using mazes. In addition, fewer of their neurons contained abnormal levels of a damaged protein, called “tau,” which accumulates in the brains of Alzheimer’s patients.

Dietary protein is the major dietary regulator of a growth hormone known as IGF-1, which has been associated with aging and diseases in mice and several diseases in older adults.

Upcoming studies by USC Professor Valter Longo, the study’s corresponding author, will attempt to determine whether humans respond similarly – while simultaneously examining the effects of dietary restrictions on cancer, diabetes and cardiac disease.

"We had previously shown that humans deficient in Growth Hormone receptor and IGF-I displayed reduced incidence of cancer and diabetes. Although the new study is in mice, it raises the possibility that low protein intake and low IGF-I may also protect from age-dependent neurodegeneration," said Longo, who directs the Longevity Institute of the USC Davis School of Gerontology and has a joint appointment the USC Dornsife College of Letters, Arts and Sciences.

Longo worked with Pinchas Cohen, dean of the USC Davis School, as well as USC graduate students Edoardo Parrella, Tom Maxim, Lu Zhang, Junxiang Wan and Min Wei; Francesca Maialetti of the Istituto Superiore di Sanità in Rome; and Luigi Fontana of Washington University in St. Louis.

"Alzheimer’s Disease and other forms of neurodegeneration are a major burden on society, and it is a rising priority for this nation to develop new approaches for preventing and treating these conditions, since the frequencies of these disorders will be rising as the population ages over the next several decades," said Cohen, who became dean of the School of Gerontology in summer 2012. "New strategies to address this, particularly non-invasive, non-pharmacological approaches such as tested in Dr. Longo’s study are particularly exciting."

The results of their study were published online by Aging Cell last month.

The team found that a protein-restricted diet reduced levels of IGF-1 circulating through the body by 30 to 70 percent, and caused an eight-fold increase in a protein that blocks IGF-1’s effects by binding to it.

IGF-1 helps the body grow during youth but is also associated with several diseases later in life in both mice and humans. Exploring dietary solutions to those diseases as opposed to generating pharmaceuticals to manipulate IGF-1 directly allows Longo’s team to make strides that could help sufferers today or in the next few years.

"We always try to do things for people who have the problem now," Longo said. "Developing a drug can take 15 years of trials and a billion dollars.

"Although only clinical trials can determine whether the protein-restricted diet is effective and safe in humans with cognitive impairment, a doctor could read this study today and, if his or her patient did not have any other viable options, could consider introducing the protein restriction cycles in the treatment – understanding that effective interventions in mice may not translate into effective human therapies," he said.

Many elderly individuals may have already be frail, have lost weight or may not be healthy enough to eat a protein-restricted diet every other week. Longo strongly insisted that any dieting be monitored by a doctor or registered dietician to make sure that patients do not become amino acid deficient, lose additional weight or develop other side effects.

New research sheds light on how the brain encodes objects with multiple features, a fundamental task for the perceptual system. The study, published in Psychological Science, a journal of the Association for Psychological Science, suggests that we have limited ability to perceive mixed color-shape associations among objects that exist in several locations.

Research suggests that neurons that encode a certain feature — shape or color, for example — fire in synchrony with neurons that encode other features of the same object. Psychological scientists Liat Goldfarb of the University of Haifa and Anne Treisman of Princeton University hypothesized that if this neural-synchrony explanation were true, then synchrony would be impossible in situations in which the same features are paired differently in different objects.

Say, for example, a person sees a string of letters, “XOOX,” and the letters are printed in alternating colors, red and green. Both letter shape and letter color need to be encoded, but the associations between letter shape and letter color are mixed (i.e., the first X is red, while the second X is green), which should make neural synchrony impossible.

“The perceptual system can either know how many Xs there are or how many reds there are, but it cannot know both at the same time,” Goldfarb and Treisman explain.

The researchers investigated their hypothesis in two experiments, in which they presented participants with strings of green and red Xs and Os and asked them to compare the number of Xs with the number of red letters (i.e., more Xs, more reds, or the same).

Participants’ responses to unique color-shape associations were significantly faster and more accurate than were their responses to displays with mixed color-shape associations.

The results show that relevant color and shape dimensions could be synchronized when the pairings between color and shape were unique, but not when the pairings were mixed.

These findings demonstrate a new behavioral principle that governs object representation. When shapes are repeated in several locations and have mixed color-shape associations, they are hard to perceive.

This research expands on Anne Treisman’s groundbreaking research on feature integration in visual perception, which shows that humans can encode characteristics such as color, form, and orientation, even in the absence of spatial attention.

Treisman is one of 12 scientists who received the National Medal of Science at the White House on February 1, 2013. The National Medal of Science, along with the National Medal of Technology and Innovation, is the highest honor that the US government grants to scientists, engineers, and inventors.

For many patients with difficult-to-treat neuropathic pain, deep brain stimulation (DBS) can lead to long-term improvement in pain scores and other outcomes, according to a study in the February issue of Neurosurgery, official journal of the Congress of Neurological Surgeons. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.

About two-thirds of eligible patients who undergo DBS achieve significant and lasting benefits in terms of pain, quality of life, and overall health, according to the report by Sandra G.J. Boccard, PhD, and colleagues of University of Oxford, led by Tipu Aziz FMedSci and Alex Green, MD. Some outcomes show continued improvement after the first year, according to the new report, which is one of the largest studies of DBS for neuropathic pain performed to date.

Most Patients Benefit from DBS for Neuropathic Pain

The authors reviewed their 12-year experience with DBS for neuropathic pain. Neuropathic pain is a common and difficult-to-treat type of pain caused by nerve damage, seen in patients with trauma, diabetes, and other conditions. Phantom limb pain after amputation is an example of neuropathic pain.

In DBS, a small electrode is surgically placed in a precise location in the brain. A mild electrical current is delivered to stimulate that area of the brain, with the goal of interrupting abnormal activity. Deep brain stimulation has become a standard and effective treatment for movement disorders such as Parkinson’s disease. Although DBS has also been used to treat various types of chronic pain, its role in patients with neuropathic pain remains unclear.

Between 1999 and 2011, that authors’ program evaluated 197 patients with chronic neuropathic pain for eligibility for DBS. Of these, 85 patients proceeded to DBS treatment. The remaining patients did not receive DBS—most commonly because they were unable to secure funding from the U.K. National Health Service or decided not to undergo electrode placement surgery.

The patients who underwent DBS were 60 men and 25 women, average age 52 years. Stroke was the most common cause of neuropathic pain, followed by head and face pain, spinal disease, amputation, and injury to nerves from the upper spinal cord (brachial plexus).

In 74 patients, a trial of DBS produced sufficient pain relief to proceed with implantation of an electrical pulse generator. Of 59 patients with sufficient follow-up data, 39 had significant improvement in their overall health status up to four years later. Thus, 66 percent of patients “gained benefit and efficacy” by undergoing DBS.

Benefits Vary by Cause; Some Outcomes Improve with Time

The benefits of DBS varied for patients with different causes of neuropathic pain. Treatment was beneficial for 89 percent for patients with amputation and 70 percent of those with stroke, compared to 50 percent of those with brachial plexus injury.

On average, scores on a 10-point pain scale (with 10 indicating the most severe pain) decreased from about 8 to 4 within the first three months, remaining about the same with longer follow-up. Continued follow-up in a small number of patients suggested further improvement in other outcomes, including quality-of-life scores.

Deep brain stimulation has long been regarded as potentially useful for patients with severe neuropathic pain that is not relieved by other treatments. However, because of the difficulties of performing studies of this highly specialized treatment, there has been relatively little research to confirm its benefits; only about 1,500 patients have been treated worldwide. The new study—accounting for about five percent of all reported patients—used up-to-date DBS technologies, imaging, and surgical techniques.

Dr. Boccard and coauthors acknowledge some important limitations of their study—especially the lack of complete patient follow-up. However, they believe their experience is sufficiently encouraging to warrant additional studies, especially with continued advances in stimulation approaches and technology. The researchers conclude, “Clinical trials retaining patients in long-term follow-up are desirable to confirm findings from prospectively assessed case series.”

A new type of prophylactic treatment for brain injury following prolonged epileptic seizures has been developed by Emory University School of Medicine investigators.

Status epilepticus, a persistent seizure lasting longer than 30 minutes [check this, some people say FIVE], is potentially life-threatening and leads to around 55,000 deaths each year in the United States. It can be caused by stroke, brain tumor or infection as well as inadequate control of epilepsy. Physicians or paramedics now treat status epilepticus by administering an anticonvulsant or general anesthesia, which stops the seizures.

Researchers at Emory have been looking for something different: anti-inflammatory compounds that can be administered after acute status epilepticus has ended to reduce damage to the brain. They have discovered a potential lead compound that can reduce mortality when given to mice after drug-induced seizures.

The results are scheduled for publication Monday in Proceedings of the National Academy of Sciences Early Edition.

"For adults who experience a period of status epilepticus longer than one hour, more than 30 percent die within four weeks of the event, making this a major medical problem," says Ray Dingledine, PhD, chair of the Department of Pharmacology at Emory University School of Medicine. "Medications that would reduce the severe consequences of refractory status epilepticus have been elusive. We believe we have an effective route to minimizing the brain injury caused by uncontrolled status epilepticus."

Dingledine’s laboratory has identified compounds that block the effects of prostaglandin E2, a hormone involved in processes such as fever, childbirth, digestion and blood pressure regulation. Prostaglandin E2 is also involved in the toxic inflammation in the brain arising after status epilepticus.

The first author of the paper is postdoctoral fellow Jianxiong Jiang, PhD, and the medicinal chemist largely responsible for developing the compounds is Thota Ganesh, PhD.

Jiang and colleagues induced status epilepticus in mice with the alkaloid drug pilocarpine, and gave them a compound, TG6-10-1, starting four hours later and again at 21 and 30 hours. TG6-10-1 blocks signals from EP2, one of four receptors for prostaglandin E2.

Among animals that received the EP2 blocker, 90 percent survived after one week, while 60 percent of a control group survived. The scientists also used nest-building behavior and weight loss as gauges of damage to the brain. Four days after status epilepticus, all the animals that received TG6-10-1 displayed normal nest-building, but more than a quarter of living control animals were not able to build nests. In addition, the brains of TG6-10-1-treated mice had reduced levels of inflammatory messenger proteins called cytokines, less brain injury and less breach of the blood-brain-barrier.

Consequences of refractory status epilepticus can include brain damage, difficulty breathing, abnormal heart rhythms and heart failure.

Dingledine says the first clinical test of an EP2 blocking compound would probably be as an add-on treatment for prolonged status epilepticus, several hours after seizures have ended. It could also be tested in similar situations such as subarachnoid hemorrhage, prolonged febrile seizures or medication-resistant epilepsy, he says.

Dingledine and his colleagues have a patent pending for novel technology related to this research. Under Emory policies, they are eligible to receive a portion of any royalties or fees received by Emory from this technology.

Vascular brain injury from conditions such as high blood pressure and stroke are greater risk factors for cognitive impairment among non-demented older people than is the deposition of the amyloid plaques in the brain that long have been implicated in conditions such as Alzheimer’s disease, a study by researchers at the Alzheimer’s Disease Research Center at UC Davis has found.

Published online early today in JAMA Neurology (formerly Archives of Neurology), the study found that vascular brain injury had by far the greatest influence across a range of cognitive domains, including higher-level thinking and the forgetfulness of mild cognitive decline.

The researchers also sought to determine whether there was a correlation between vascular brain injury and the deposition of beta amyloid (Αβ) plaques, thought to be an early and important marker of Alzheimer’s disease, said Bruce Reed, associate director of the UC Davis Alzheimer’s Disease Research Center in Martinez, Calif. They also sought to decipher what effect each has on memory and executive functioning.

“We looked at two questions,” said Reed, professor in the Department of Neurology at UC Davis. “The first question was whether those two pathologies correlate to each other, and the simple answer is ‘no.’ Earlier research, conducted in animals, has suggested that having a stroke causes more beta amyloid deposition in the brain. If that were the case, people who had more vascular brain injury should have higher levels of beta amyloid. We found no evidence to support that.”

"The second,” Reed continued, “was whether higher levels of cerebrovascular disease or amyloid plaques have a greater impact on cognitive function in older, non-demented adults. Half of the study participants had abnormal levels of beta amyloid and half vascular brain injury, or infarcts. It was really very clear that the amyloid had very little effect, but the vascular brain injury had distinctly negative effects.” 

“The more vascular brain injury the participants had, the worse their memory and the worse their executive function – their ability to organize and problem solve,” Reed said.

The research was conducted in 61 male and female study participants who ranged in age from 65 to 90 years old, with an average age of 78. Thirty of the participants were clinically “normal,” 24 were cognitively impaired and seven were diagnosed with dementia, based on cognitive testing. The participants had been recruited from Northern California between 2007 to 2012.

The study participants underwent magnetic resonance imaging (MRI) ― to measure vascular brain injury ― and positron emission tomography (PET) scans to measure beta amyloid deposition: markers of the two most common pathologies that affect the aging brain. Vascular brain injury appears as brain infarcts and “white matter hyperintensities” in MRI scans, areas of the brain that appear bright white.

The study found that both memory and executive function correlated negatively with brain infarcts, especially infarcts in cortical and sub-cortical gray matter. Although infarcts were common in this group, the infarcts varied greatly in size and location, and many had been clinically silent. The level of amyloid in the brain did not correlate with either changes in memory or executive function, and there was no evidence that amyloid interacted with infarcts to impair thinking.

Reed said the study is important because there’s an enormous amount of interest in detecting Alzheimer’s disease at its earliest point, before an individual exhibits clinical symptoms. It’s possible to conduct a brain scan and detect beta amyloid in the brain, and that is a very new development, he said.

“The use of this diagnostic tool will become reasonably widely available within the next couple of years, so doctors will be able to detect whether an older person has abnormal levels of beta amyloid in the brain. So it’s very important to understand the meaning of a finding of beta amyloid deposition,” Reed said.

“What this study says is that doctors should think about this in a little more complicated way. They should not forget about cerebrovascular disease, which is also very common in this age group and could also cause cognitive problems. Even if a person has amyloid plaques, those plaques may not be the cause of their mild cognitive symptoms.”

Genes linked to autism and schizophrenia are only switched on during the early stages of brain development, according to a collaboration between researchers at Imperial College London, the University of Oxford and King’s College London.

This new study adds to the evidence that autism and schizophrenia are neurodevelopmental disorders, a term describing conditions that originate during early brain development.

The researchers studied gene expression in the brains of mice throughout their development, from 15-day old embryos to adults, and their results are published in Proceedings of the National Academy of Sciences.

The research focused on cells in the ‘subplate’, a region of the brain where the first neurons (nerve cells) develop. Subplate neurons are essential to brain development, and provide the earliest connections within the brain.

'The subplate provides the scaffolding required for a brain to grow, so is important to consider when studying brain development,' says Professor Zoltán Molnár, senior author of the paper from the University of Oxford, 'Looking at the pyramids in Egypt today doesn't tell us how they were actually built. Studying adult brains is like looking at the pyramids today, but by studying the developing brains we are able to see the transient scaffolding that has been used to construct it.'

The study shows that certain genes linked to autism and schizophrenia are only active in the subplate during specific stages of development. The data analysis was designed by Dr Enrico Petretto, Senior Lecturer in Genomic Medicine at Imperial College London. Dr Petretto said: “We looked at the full network of genes in the brain to identify which pathways play a role in early brain development. This allowed us to find coherent clusters of genes previously associated with susceptibility to autism spectrum disorders or schizophrenia. These results provide a unique resource for our understanding of how gene behaviour changes in the mouse subplate from the early embryonic stage to adulthood. This means we are better equipped to investigate how the gene network changes in the developing brain and identify any links with neurodevelopmental disorders.”

The team was able to map gene activity in full detail thanks to these new methods which allowed them to dissect and profile gene expression from small numbers of cells. This also enabled them to identify the different populations of subplate neurons more accurately.

Professor Hugh Perry, chair of the Medical Research Council’s Neuroscience and Mental Health Board, said: “By being able to pinpoint common genetic factors for neurological conditions such as autism and schizophrenia, scientists are able to understand an important part of the story as to why things go awry as our brains develop.  The Medical Research Council’s commitment to a broad portfolio of neuroscience and mental health research places us in a unique position to respond to the challenge of mental ill health and its relationship with physical health and wellbeing.”

A discovery using stem cells from a patient with motor neurone disease could help research into treatments for the condition.

The study used a patient’s skin cells to create motor neurons - nerve cells that control muscle activity - and the cells that support them called astrocytes.

Astrocyte death

Researchers studied these two types of cells in the laboratory. They found that a protein expressed by abnormalities in a gene linked to motor neurone disease, which is called TDP-43, caused the astrocytes to die.

The study, led by the University of Edinburgh and funded by the Motor Neurone Disease Association, provides fresh insight into the mechanisms involved in the disease.

Gene mutation

Although TDP-43 mutations are a rare cause of motor neurone disease (MND), scientists are especially interested in the gene because in the vast majority of MND patients, TDP-43 protein (made by the TDP-43 gene) forms pathological clumps inside motor neurons.

Motor neurones die in MND leading to paralysis and early death.

This study shows for the first time that abnormal TDP-43 protein causes death of astrocytes.

The researchers, however, found that the damaged astrocytes were not directly toxic to motor neurons.

Motor neurone disease is a devastating and ultimately fatal condition, for which there is no cure or effective treatment. -Professor Siddharthan Chandran (Director of the Euan Macdonald Centre for Motor Neurone Disease Research)

Implications

Better understanding the role of astrocytes could help to inform research into treatments for motor neurone disease (MND).

These findings, published in the journal Proceedings of the National Academy of Sciences, are significant as they show that different mechanisms are at work in different types of MND.

It is not just a question of looking solely at motor neurons, but also the cells that surround them, to understand why motor neurones die. Our aim is to find ways to slow down progression of this devastating disease and ultimately develop a cure. -Professor Siddharthan Chandran (Director of the Euan Macdonald Centre for Motor Neurone Disease Research)