Posts tagged science
Articles and news from the latest research reports.
Researchers Investigate Mechanism of Alzheimer’s Therapy
Researchers at the University of Kentucky Sanders-Brown Center on Aging, led by faculty member Donna Wilcock, have recently published a new paper in the Journal of Neuroscience detailing an advance in treatment of Alzheimer’s disease.
Gammagard™ IVIg is a therapy that has been investigated for treatment of Alzheimer’s. Despite small clinical studies that have reported efficacy of the approach, the mechanism of action is poorly understood.
The UK researchers set out to investigate the mechanism by which the treatment may act in the brain to lower amyloid deposition (amyloid deposits being a key pathology in Alzheimer’s).
To conduct their investigation, researchers introduced IVIg directly into the brains of mice which carry a human gene causing them to develop amyloid plaques. They found that IVIg lowers amyloid deposits in the brains of the mice over the course of seven days. Their data suggest that the modulation of inflammation in the brain by IVIg is a key event that leads to the reduction in amyloid deposition.
The scientists hypothesize that the IVIg acts as an immune modulator, and this immune modulation is responsible for the reductions in amyloid pathology.
The data suggests that modulating the immune response in the brain may help ameliorate the Alzheimer’s pathology. Researchers are currently investigating other ways to produce the same modulation of the immune response because the access of IVIg to the brain when administered peripherally is very limited.
University experts spot early signs of Alzheimer’s
Early signs of Alzheimer’s disease can be detected years before diagnosis, according to researchers at Birmingham City University.
The study found that sufferers of a specific type of cognitive impairment have an increased loss of cells in certain parts of the brain, which can be vital in detecting which patients will progress to a diagnosis of Alzheimer’s.
A team of researchers from Birmingham City University (UK), in association with colleagues from Lanzhou University (China) and the Alzheimer’s Disease Neuroimaging Initiative, conducted a brain scan analysis over two years, of patients suffering from amnestic mild cognitive impairment (aMCI) – a condition involving the diminishing of cognitive abilities, from which 80% of patients progress to a diagnosis of Alzheimer’s.
Scans showed that the loss of grey matter in the left hemisphere of the brain was particularly widespread and degenerative for those patients at high risk of developing Alzheimer’s, compared with those with no active neurological disorders.
This region of the brain has been associated with language, decision making, expressing personality, executing movement, planning complex cognitive behaviour and moderating social behaviour.
One of the researchers involved in the study, Professor Mike Jackson, from Birmingham City University, said: “Continuous loss of cells within the regions of the brain highlighted in this study should act as alarm bells for doctors, as they may indicate that the patient is on course to developing Alzheimer’s.”
The brains parahippocampal gyrus, a region which is known to be related to memory encoding and retrieval, was highlighted as an area that should be looked at carefully when examining brain scans to detect early signs of the disease.
Treating Alzheimer’s early is thought to be vital to prevent damage to memory and thinking. Although treatments are available to temporarily ease symptoms, there has been little in the way of success in slowing down the cognitive decline in patients with mild to moderate Alzheimer’s, which has been partly put down to the late timing of the diagnosis.
Experts at Birmingham City University hope that this study will aid other researchers to find an effective clinical treatment to delay the conversion to Alzheimer’s.
Robot mom would beat robot butler in popularity contest
If you tickle a robot, it may not laugh, but you may still consider it humanlike — depending on its role in your life, reports an international group of researchers.
Designers and engineers assign robots specific roles, such as servant, caregiver, assistant or playmate. Researchers found that people expressed more positive feelings toward a robot that would take care of them than toward a robot that needed care.
"For robot designers, this means greater emphasis on role assignments to robots,” said S. Shyam Sundar, Distinguished Professor of Communications at Penn State and co-director of University’s Media Effects Research Laboratory. “How the robot is presented to users can send important signals to users about its helpfulness and intelligence, which can have consequences for how it is received by end users.”
To determine how human perception of a robot changed based on its role, researchers observed 60 interactions between college students and Nao, a social robot developed by Aldebaran Robotics, a French company specializing in humanoid robots.
Each interaction could go one of two ways. The human could help Nao calibrate its eyes, or Nao could examine the human’s eyes like a concerned eye doctor and make suggestions to improve vision.
Participants then filled out a questionnaire about their feelings toward Nao. Researchers used these answers to calculate the robot’s perceived benefit and social presence in both scenarios. They published their results in the current issue of Computers in Human Behavior.
"When (humans) perceive greater benefit from the robot, they are more satisfied in their relationship with it, and even trust it more," Sundar said. "In addition, we found that when the robot cares for you, it seems to have greater social presence."
A robot with a strong social presence behaves and interacts like an authentic human, according to Ki Joon Kim, doctoral candidate in the department of interaction science, Sungkyunkwan University, Korea, and lead author of the journal article.
The research team found that when participants perceived a strong social presence, they considered the caregiving robot smarter than the robot in the alternate scenario. Participants were also more likely to attribute human qualities to the caregiving robot.
"Social presence is particularly important in human-robot interactions and areas of artificial intelligence because the ultimate goal of designing and interacting with social robots is to provide users with strong feelings of socialness,” said Kim.
The next immediate goal is to confirm these experimental findings in real-life situations where caretaker robots are already working. Examining how other robot roles influence human perception toward them is also important.
"We have just finished collecting data at a local retirement village in State College with the Homemate robot which we brought in from Korea,” said Sundar. “In that study, we are examining differences in user reactions to a robot that is an assistant versus one that is framed as a companion.”
Peering into the Protein Pathways of a Cell
As a cell’s central power plant, the mitochondrion is a busy place.
Specially-coded proteins from the nucleus are constantly being ferried across the mitochondrion’s inner membrane, where they help the mighty organelle do its work – producing the cell’s high-energy molecules, carrying out signaling duties, and controlling cell growth.
Scientists have long known that the central channel through which most of these proteins must pass – a critical gatekeeper known as the translocase of the inner mitochondrial membrane 23 or TIM23 for short – requires an electrical field for its gating capabilities to function. But they weren’t quite sure how the whole process worked.
Until now.
Using highly sensitive fluorescent probes, a team of scientists based at UConn has managed to peer deep into the inner workings of a cell, capturing the never-before-seen structural dynamics of the TIM23 channel complex while it functioned in its natural environment.
In doing so, the team, led by Nathan N. Alder, an assistant professor in the Department of Molecular and Cell Biology in the College of Liberal Arts and Sciences, discovered that the TIM23 complex not only opens and closes in response to fluctuations in the energized state of the mitochondrion’s inner membrane, as the scientific community suspected, it also changes its very structure – altering the helical shape of protein segments that line the channel – as the electrical field across the membrane drops.
The research, which appears this week in the peer-reviewed journal Nature Structural & Molecular Biology, explains how the energized state of the membrane drives the structural dynamics of membrane proteins and sheds new light on how cellular transport systems harness energy to perform their work inside the cell. It also shows how fluorescent mapping at the subcellular level may reveal new insights into the underlying causes of neurodegenerative and metabolic disorders associated with mitochondrial function.
In an overview of the research accompanying the paper’s publication, Nikolaus Pfanner of the University of Freiburg, Germany, an international leader in the field of cellular protein trafficking, and several members of his research group, called the study “a major step towards a molecular understanding of a voltage-gated protein translocase.”
“The molecular nature of voltage sensors in membrane proteins is a central question in biochemical research,” Pfanner and his colleagues said. “The study … is not only of fundamental importance for our understanding of mitochondrial biogenesis, but also opens up new perspectives in the search for voltage-responsive elements in membrane proteins.”
Applying a new technique
The fluorescent mapping technique used in the research was a key to the project’s success. Alder says he first realized the application’s potential when he successfully mapped channel proteins in a functioning mitochondrion in 2008. In the current study, he advanced the process further, using probes to capture the behavior of a particular segment of the TIM23 channel complex as it was impacted by voltage changes in the membrane’s electrical field.
“Fluorescent mapping made this possible,” says Alder, who, as a post-doctoral student, worked with protein fluorescent labeling pioneer Arthur E. Johnson of Texas A&M’s Health Science Center. “It allowed us to peer into the functioning dynamics of a protein import channel complex that is responsible for building up the power plant of the cell … What we found was that these protein-trafficking complexes are certainly not static. This is a very, very dynamic channel.”
To monitor the fluorescence probes inside the mitochondria, the research team used advanced spectrofluorimeters equipped with xenon lamps and laser diodes to measure steady-state and time-resolved fluorescence, respectively.
To conduct the study, Alder incorporated cysteine residues modified with a fluorescent probe at specific positions along a transmembrane segment of a TIM23 complex derived from a common species of yeast, Saccharomyces cerevisiae. The team then monitored the probes in real time to observe how the channel’s voltage-gating and structure responded to induced changes in the inner membrane’s electrical field.
“It’s an indirect way of looking at the structure of something, but because we are able to look into an actually functioning mitochondrion, it’s given us a whole world of new information,” says Alder.
“That the magnitude of the voltage gradient across the membrane could play a significant role in defining the structure of these proteins is probably one of the most significant elements of this research,” he adds.
A defining moment
Watching the process was, for Alder, a defining moment in his professional career.
“When I first saw a certain kind of structure that told me I was in the middle of a channel, that was one of the most exciting times in my professional life,” he says. “I knew I was getting insight into a fundamental natural phenomenon, something no one has ever seen before.”
When Alder saw the protein-conducting channel bending and collapsing in response to changes in the membrane’s voltage levels, he was equally thrilled.
“That was one of those rare technical moments in my professional life that showed we were really getting insight into a fundamental process going on inside a cell,” he says. “It’s always been known that you need an energized membrane to make these channels work, but no one had a clue why.”
Joining Alder on the project were UConn graduate students Ketan Malhotra and Murugappan Sathappa and research associate Judith S. Landin. Johnson, Alder’s former mentor at Texas A&M, is also listed as a co-author. The work in the Alder Lab was funded by the National Science Foundation; work done in the Johnson Lab was additionally sponsored by the National Institutes of Health and the Robert A. Welch Foundation.
Alder says the next phase of the research will look toward isolating the TIM23 protein channel complex in an artificial system to see if it continues to respond to voltage fluctuations outside of its natural habitat. The research team is also hoping to identify the particular parts of the protein complex that are acting as voltage sensors.
“Once we start to identify exactly what is the voltage sensor, we will have a better understanding of the translocase process, and ultimately we can apply this knowledge to other kinds of protein transporters whose dysfunction has been implicated in the etiology of diseases such as cardiovascular disease and cancer,” Alder says. “If their function is tied to the energized state of the membrane, we’ll be able to see whether defects in that ability to couple to the membrane might be associated with the pathogenesis of these diseases.”
Researchers Identify “Switch” for Long-term Memory
Calcium signal in neuronal cell nuclei initiates the formation of lasting memories
Neurobiologists at Heidelberg University have identified calcium in the cell nucleus to be a cellular “switch” responsible for the formation of long-term memory. Using the fruit fly “Drosophila melanogaster” as a model, the team led by Prof. Dr. Christoph Schuster and Prof. Dr. Hilmar Bading investigates how the brain learns. The researchers wanted to know which signals in the brain were responsible for building long-term memory and for forming the special proteins involved. The results of the research were published in the journal “Science Signaling”.
The team from the Interdisciplinary Center for Neurosciences (IZN) measured nuclear calcium levels with a fluorescent protein in the association and learning centres of the insect’s brain to investigate any changes that might occur during the learning process. Their work on the fruit fly revealed brief surges in calcium levels in the cell nuclei of certain neurons during learning. It was this calcium signal that researchers identified as the trigger of a genetic programme that controls the production of “memory proteins”. If this nuclear calcium switch is blocked, the flies are unable to form long-term memory.
Prof. Schuster explains that insects and mammals separated evolutionary paths approximately 600 million years ago. In spite of this sizable gap, certain vitally important processes such as memory formation use similar cellular mechanisms in humans, mice and flies, as the researchers’ experiments were able to prove. “These commonalities indicate that the formation of long-term memory is an ancient phenomenon already present in the shared ancestors of insects and vertebrates. Both species probably use similar cellular mechanisms for forming long-term memory, including the nuclear calcium switch”, Schuster continues.
The IZN researchers assume that similar switches based on nuclear calcium signals may have applications in other areas – presumably whenever organisms need to adapt to new conditions over the long term. “Pain memory, for example, or certain protective and survival functions of neurons use this nuclear calcium switch, too”, says Prof. Bading. This cellular switch may no longer work as well in the elderly, which Bading believes may explain the decline in memory typically observed in old age. Thus, the discoveries by the Heidelberg neurobiologists open up new perspectives for the treatment of age- and illness-related changes in brain functions.
Brain Structural Deficits May Contribute to Increased Functional Connections Between Brain Regions Implicated in Depression
Major depressive disorder is associated with a dysregulation of brain regions including the prefrontal cortex and limbic system. The relationship between structural and functional abnormalities in these brain regions in depressed patients is far from clear. However, both types of changes are assumed to underlie the symptoms of this disorder.
This lack of understanding prompted Dr. Bart de Kwaasteniet at the Academic Medical Center in Amsterdam and his colleagues to use a multimodal neuroimaging approach to further investigate this relationship.
The researchers, led by Professor Damiaan Denys, recruited 18 patients with major depressive disorder and 24 healthy individuals, all of whom underwent multiple neuroimaging scans. They specifically focused on the structural and functional connectivity between the subgenual anterior cingulate cortex (ACC) and the medial temporal lobe, two regions that are connected by a white matter tract called the uncinate fasciculus. These regions are known to be involved in the regulation of emotion and memory.
de Kwaasteniet explained their findings: “We identified decreased structural integrity of the uncinate fasciculus connecting the medial temporal lobe and the subgenual ACC. Furthermore, we identified an increased functional connection between these regions in major depression relative to controls. Importantly, we identified a negative correlation between the integrity of this white matter tract and the functional connection between the subgenual ACC and bilateral hippocampus in major depression.”
These results suggest that structural disturbances in the uncinate fasciculus contribute to abnormally high functional interactions among brain circuits associated with the symptoms of depression. “This leads to the hypothesis that abnormalities in brain structure lead to differences in connectivity between brain areas in depressive disorder,” added de Kwaasteniet.
However, they also hypothesized that the reverse may be true as well. In other words, that the increased functional connectivity among these brain regions leads to structural changes in the brain’s white matter fibers by means of an abnormally increased signal transduction. This hypothesis is supported by recent studies in schizophrenia which suggest that circuit hyperactivity may be a predictor of subsequent cortical atrophy.
"This interesting study suggests that abnormalities in the structural connections between brain regions, the white matter, are associated with abnormal activity within a brain circuit implicated in the symptoms of depression. This observation raises an important question about the implications of treating the circuit functional abnormalities without fixing the underlying brain structure," commented Dr. John Krystal, Editor of Biological Psychiatry. “Perhaps the structural abnormalities contribute to the risk for the relapse of depression among individuals whose brain circuit activity has responded to antidepressant medications.”
More research will be necessary to test the theories generated from the findings of this study.
Exposure to Stress Even Before Conception Causes Genetic Changes to Offspring
A female’s exposure to distress even before she conceives causes changes in the expression of a gene linked to the stress mechanism in the body — in the ovum and later in the brains of the offspring from when they are born, according to a new study on rats conducted by the University of Haifa.
“The systemic similarity in many instances between us and mice raises questions about the transgenerational influences in humans as well, for example, the effects of the Second Lebanon War or the security situation in the South on the children of those who went through those difficult experiences,” the researchers said. “If until now we saw evidence only of behavioral effects, now we’ve found proof of effects at the genetic level.”
In previous studies in Prof. Micah Leshem’s lab, it was found that exposing rats to stress before they had even conceived (and even at their “teen” stage) influences the behavior of their offspring. This study, conducted in the lab of Dr. Inna Gaisler-Salomon by PhD student Hiba Zaidan, in cooperation with Prof. Leshem, the researchers sought to examine whether there was an influence on genetic expression.
In the study, which was recently published in the journal Biological Psychiatry, the researchers focused on the gene known as CRF-1, a gene linked to the body’s stress-control system that expresses itself in many places in the brain under stress.
The researchers took female rats that were 45 days old, which is parallel to human adolescence. Some of the rats were exposed to “minor” stress, which included changes in temperature and daily routine for seven days, and compared them to a control group that was not exposed to stress at all. The rats were mated and conceived two weeks later.
In the first part of the study, the researchers examined the ova of the rats that were exposed to stress even before they conceived, and they found that at that stage there was enhanced expression of the CRF-1 gene. For the second part, the researchers examined the brains of newborn rats immediately after birth, before the mother could have any influence on them, and found that even at the neonatal stage, there was enhanced expression of the CRF-1 gene in the brains of the rats born to mothers who had been exposed to stress.
During the third stage, the researchers exposed the offspring – both those whose mothers had been exposed to stress and those whose mothers were not – to stress when they reached adulthood. It emerged that the expression of CRF-1 among the offspring was dependent on three factors: The sex of the offspring, the stress undergone by the mother and the stress to which the offspring were exposed. The female rats whose mothers had been exposed to stress and who themselves underwent a “stressful” behavioral test showed higher levels of CRF-1 than other groups.
“This is the first time that we showed that the genetic response to stress in rats is linked to the experiences their mothers underwent long before they even got pregnant with them,” the researchers said. “We are learning more and more about intergenerational genetic transfer and in light of the findings, and in light of the fact that in today’s reality many women are exposed to stress even before they get pregnant, it’s important to research the degree to which such phenomenon take place in humans.”
(Image: iStockphoto)
…treating neurological diseases and computers that see!
Some 165 million Europeans are likely to experience some form of brain-related disease during their life. As the population ages, Alzheimer’s and other neurodegenerative or age-related mental disorders are affecting more people and contributing to higher health costs. Finding better ways of preventing and treating brain diseases is therefore becoming urgent, and understanding how our brains work is important to keep our economies at the forefront of new information technologies and services. EU-funded research is answering these challenges.
As mentioned in the first part of this article, this May the European Commission announced EUR 150 million of funding for 20 new ICT research projects expected to deliver new insights and innovations relating to traumatic brain injury, mental disorders, pain, epilepsy and paediatric conduct disorders.
The European Commissioner for Research, Innovation and Science, Máire Geoghegan-Quinn has said, ”Treating those affected (by brain-related disease) is already costing us EUR 1.5 million every minute […] Brain research could help alleviate the suffering of millions of patients and those that care for them. Unlocking the secrets of how the brain works could also open up a whole new universe of services and products for our economies.”
Treating neurological diseases
Stroke is the most common neurological disease to afflict people, causing cognitive problems - such as difficulties with attention, memory or language - or severe physical disability. The incidence increases with age, making it the most frequent cause of life-long impairment in adulthood.
These effects tend to increase patients” dependence on other people, and this lost autonomy can then lead to depression. The CONTRAST project seeks to bridge the gap between institutional rehabilitation and monitoring of the patient at home.
The project is developing an adaptive ”human-computer interface” (HCI) to improve cognitive functioning, offering training modules that improve the recovery of attention and memory. Patients will be able to go through an individually tailored rehabilitation process at home at the computer, while their doctor provides home-based training and monitors their progress from the clinic.
A third of stroke patients will experience long-term physiological or cognitive disabilities - preventing them from maintaining independent lives. COGWATCH aims to enhance the rehabilitation of stroke patients with symptoms of ”apraxia and action disorganisation syndrome” (AADS). Such patients retain their motor capabilities but commit cognitive errors during every-day goal-oriented tasks.
The project is developing intelligent tools and objects, portable and wearable devices, and ambient systems to provide personalised cognitive rehabilitation at home for stroke patients with AADS symptoms. By providing persistent feedback, the system will help to re-train patients on how to carry out the everyday activities they need to be independent.
Parkinson’s disease is another neurodegenerative disorder that is growing in incidence as our population ages - it particularly affects areas of the brain that are involved in movement control. The CUPID project aims to develop innovative, personalised rehabilitation at home for people with Parkinson”s disease, based on the patient”s needs.
The CUPID service will employ wearable sensors, audio biofeedback, virtual reality and external cueing to provide intensive motivating training that is suited to the patient and monitored remotely - decreasing the need for travel to a rehabilitation centre.
By the end of its first year, in December 2012, the project had designed the rehabilitation exercises and developed prototype virtual games for these exercises, as well as the telemedicine infrastructure needed for remote supervision.
Epilepsy is another common neurological disorder that, despite progress in treatment, is still incurable. Nowadays, pharmaceutical treatment can reduce or remove the symptoms, but this needs life-long continuous adjustment in order to be effective. The condition therefore requires monitoring of multiple parameters for accurate diagnosis, prediction, alerting and prevention, as well as treatment follow-up and presurgical evaluation.
The ARMOR project is designing a more holistic, personalised, medically efficient and economical monitoring system to analyse brain and body data from epilepsy patients. This portable system will provide more accurate diagnosis for individual patients, and allow better understanding and prediction of the time and type of their seizures - helping to give a warning and ensure the availability of medical assistance and advice if necessary.
Amputation of a limb is not just a traumatic physical experience. It can also lead to sensations - usually accompanied by pain - that seem to come from the missing body part, called a ”phantom limb”. The TIME project is developing an alternative treatment for phantom limb pain based on a new ”human-machine interface” (HMI) and selective, electrical stimulation of the peripheral nerves.
Using an implantable electrode placed inside the nerve, and electrical stimulators placed outside the body, the system will provide electrical micro stimulation to help reduce painful sensations - and may even have applications such as enabling amputees to sense virtual environments by touch.
Seeing things
The potential of such techniques doesn’t stop at monitoring, diagnosis and managing chronic conditions. The OPTONEURO project could ultimately help return functional sight to blind people.
”Optogenetics” is an exciting new gene therapy technique that makes nerve cells sensitive to particular colours of light. Simple pulses of intense light cause these photosensitised nerve cells to fire ”action potentials”, the carriers of information in the nervous system. To activate the nerve cells, however, the new therapy depends on high illumination densities - bright light shining on very small areas.
The OPTONEURO project therefore aims to develop the complementary optoelectronics needed to stimulate these photosensitised neurons. The system would be scalable for applications both in basic neuroscience research and in ”neuroprosthesis”. In particular, the optoelectronics should be used in a future optogenetic-optoelectronic retinal prosthesis - an artificial eye - for those blinded by the ”retinitis pigmentosa” disease.
The project requires a team of specialists in photonics, micro-optics and neurobiology to develop an array of ultra-bright electronically controlled micro-LEDs, which could also provide a new research tool for the neuroscience and neurotechnology community.
The SEEBETTER project is also looking to develop artificial vision prosthetics for the blind. Conventional image sensors have severe limitations, but ”silicon retina” vision sensors aim to mimic the biological retina”s information processing - computing both spatial and temporal aspects of the visual input. To date, these silicon retinas suffer from low quantum efficiency - meaning low light sensitivity - and an inability to combine both spatial and temporal processing on the same chip.
SEEBETTER’s team of experts - from biology and biophysics, as well as biomedical, electrical and semiconductor engineering - aim to use genetic and physiological techniques to understand better the function of the retina and model the retina’s vision processing. They will then design and build the first high-performance silicon retina, implemented on a single silicon wafer, specialised for both spatial and temporal visual processing.
Understand the neurobiological principles of seeing - beyond the functioning of the retina alone - may help us to replicate the success of human vision for computers and robots. The RENVISION project aims to achieve a comprehensive understanding of how the retina encodes visual information through the different cellular layers and to use such insights to develop a retina-inspired computational approach to computer vision.
Using high-resolution 3D microscopy will allow the researchers to make images of the inner retinal layers at near-cellular resolution. This new knowledge on retinal processing will help develop advanced pattern recognition and machine-learning technologies. The project could therefore solve some of the most difficult tasks in computer vision - such as automated scene categorisation and human action recognition - so that robots and computers can see and perceive what is happening in the images they receive.
These are just some of the EU-funded ICT projects using electronics and computing technologies to understand, augment and improve the human brain and its functioning. The results have the potential to reduce the impact of disability and disease, and improve our computing power, IT infrastructure and economy.
Clues about autism may come from the gut
Bacterial flora inhabiting the human gut have become one of the hottest topics in biological research. Implicated in a range of important activities including digestion, fine-tuning body weight, regulating immune response, and producing neurotransmitters that affect brain and behavior, these tiny workers form diverse communities. Hundreds of species inhabit the gut, and although most are beneficial, some can be very dangerous.
In new research appearing in the journal PLOS ONE, a team led by Rosa Krajmalnik-Brown, a researcher at Arizona State University’s Biodesign Institute, present the first comprehensive bacterial analysis focusing on commensal or beneficial bacteria in children with autism spectrum disorder (ASD).
After publishing earlier research exploring crucial links between intestinal microflora and gastric bypass, Krajmlanik-Brown convinced James Adams— director of the ASU Autism/Asperger’s Research Program—that similar high throughput techniques could be used to mine the microbiome of patients with autism. (Previously, Adams had been studying the relationship between the gut microbiome and autism using traditional culturing techniques.)
“One of the reasons we started addressing this topic is the fact that autistic children have a lot of GI problems that can last into adulthood,” Krajmalnik-Brown says. “Studies have shown that when we manage these problems, their behavior improves dramatically.”
Following up on these tantalizing hints, the group hypothesized the existence of distinctive features in the intestinal microflora found in autistic subjects compared to typical children. The current study confirmed these suspicions, and found that children with autism had significantly fewer types of gut bacteria, probably making them more vulnerable to pathogenic bacteria. Autistic subjects also had significantly lower amounts of three critical bacteria, Prevotella, Coprococcus, and Veillonellaceae.
Krajmalnik-Brown, along with the paper’s lead authors Dae-Wook Kang and Jin Gyoon Park, suggest that knowledge gleaned through such research may ultimately be used both as a quantitative e diagnostic tool to pinpoint autism and as a guide to developing effective treatments for ASD-associated GI problems. The work also offers hope for new prevention and treatment methods for ASD itself, which has been on a mysterious and rapid ascent around the world.
A disquieting puzzle
Autism is defined as a spectrum disorder, due to the broad range of symptoms involved and the influence of both genetic and environmental factors, features often confounding efforts at accurate diagnosis. The diseases’ prevalence in children exceeds juvenile diabetes, childhood cancer and pediatric AIDS combined.
Controversy surrounds the apparent explosive rise in autism cases. Heightened awareness of autism spectrum disorders and more diligent efforts at diagnosis must account for some of the increase, yet many researchers believe a genuine epidemic is occurring. In addition to hereditary components, Western-style diets and overuse of antibiotics at an early age may be contributing to the problem by lowering the diversity of the gut microflora.
In terms of severe developmental ailments affecting children and young adults, autism is one of the most common, striking about 1 in 50 children. The disorder—often pitiless and perplexing—is characterized by an array of physical and behavioral symptoms including anxiety, depression, extreme rigidity, poor social functioning and an overall lack of independence.
To date, studies of the gut microbiome in autistic subjects have focused primarily on pathogenic bacteria, some of which have been implicated in alterations to brain function. One example involves gram-negative bacteria containing lipopolysaccharides in their cell walls, which can induce inflammation of the brain and lead to the accumulation of high levels of mercury in the cerebrum.
A new approach
Krajmalnik-Brown and lead author Dae-Wook Kang are researchers in the Biodesign Institute’s Swette Center for Environmental Biotechnology, which is devoted to the use of microbial communities for the benefit of human and environmental health. Their new study is the first to approach autism from a different angle, by examining the possible role of so-called commensal or beneficial bacteria.
Up to a quadrillion (1014) bacteria inhabit the human intestine, contributing to digestion, producing vitamins and promoting GI health. Genes associated with human intestinal flora are 100 times as plentiful as the body’s human genes, forming what some have referred to as a second genome. Various environmental factors can destabilize the natural microbiome of the gut, including antibiotics and specific diets.
In the current study, a cohort of 20 healthy and 20 autistic subjects between 3 and 16 years of age were selected and their gut microflora from fecal samples analyzed by means of a technique known as pyrosequencing. Pyrosequencing is a high-throughput method, allowing many DNA samples to be combined as well as many sequences per sample to be analyzed.
Lower diversity of gut microbes was positively correlated with the presence of autistic symptoms in the study. The authors stress that bacterial richness and diversity are essential for maintaining a robust and adaptable bacterial community capable of fighting off environmental challenges. “We believe that a diverse gut is a healthy gut,” Krajmalnik-Brown says.
The new study detected decreased microbial diversity in the 20 autistic subjects whose fecal samples were analyzed. Specifically, three bacterial genera—Prevotella, Coprococcus and Veillonellaceae—were diminished in subjects with autism, when compared with samples from normal children. (Surprisingly, these microbial changes did not seem directly correlated with the severity of GI symptoms.)
The three genera represent important groups of carbohydrate-degrading and/or fermenting microbes. Such bacteria could be critical for healthy microbial-gut interactions or play a supportive role for a wide network of different microorganisms in the gut. The latter would explain the decreased diversity observed in autistic samples.
Bacteria: in sickness and in health
Among the fully classified genera in the study, Prevotella was the most conspicuously reduced in autistic subjects. Prevotella is believed to play a key role in the composition of the human gut microbiome. For this reason, the group undertook a sub-genus investigation of autistic subjects. They found that a species known as Prevotella copri occurred only in very low levels in the autistic samples. The species is a common component in normal children exhibiting more diverse and robust microbial communities.
“We think of Prevotella as a healthy, good thing to have,” Krajmalnik-Brown notes. (Michael Polan’s recent New York Times Magazine story on the microbiome points to the fact that he is proud that his gut microbiome is rich in Prevotella regarding it as a possible sign of a healthy non-Western diet. )
Jin Gyoon Park (the other lead author), who works in the Virginia G. Piper Center for Personalized Diagnostics, under Joshua LaBaer’s direction, conducted a rigorous bioinformatic and statistical analysis of the intestinal microflora. He believes that the microbiome can be mined in future work to find diagnostic biomarkers for autism and many other diseases. Quantitative diagnoses of this sort have so far been lacking for autism, a disease for which subjective behavior indices are typically used to identify the disorder.
In describing the next steps for the research group, Kang and Park point to more detailed, gene-level analyses aimed at probing bacterial function and further illuminating relationships between human health and the complexities of the microbiome. Additionally, the group will use the current results as a guide for new treatment studies for autism aimed at modifying bacterial composition in the gut.
Dissecting the Distinctive Walk of Disease
Pitt multidisciplinary research team proposes mathematical model that examines multiple walking patterns and movements in adults older than 65
Older adults diagnosed with brain disorders such as Parkinson’s disease often feel a loss of independence because of their lack of mobility and difficulty walking. To better understand and improve these mobility issues—and detect them sooner—a University of Pittsburgh multidisciplinary research team is working toward building a more advanced motion test that addresses a wider range of walking patterns and movements.
In a recent issue of IEEE Transactions on Neural Systems and Rehabilitation Engineering, researchers from Pitt’s Swanson School of Engineering, School of Health and Rehabilitation Sciences, and School of Medicine propose a mathematical model that can examine multiple walking, or gait-related, features in healthy and clinical populations. To date, no study has brought together such a team to examine such a high number of movement features comparing healthy and clinical older adults. Previous studies have typically only measured one or two types of movement features in just one population.
“Right away, you can tell whether an older individual has difficulties walking by conducting a simple gait test,” said Ervin Sejdic, lead author of the paper and an assistant professor of engineering in the Swanson School. “But can we quantify these changes and document them earlier? That’s the biggest issue here and what we’re trying to model.”
Thirty-five adults older than 65 were recruited for the study, including 14 healthy participants, 10 individuals with Parkinson’s disease, and 11 adults who had impaired feeling in their legs owing to peripheral neuropathy (nerve damage). Walking trials were performed using a computer-controlled treadmill, and participants wore an accelerometer—a small box attached with a belt—and a set of reflective markers on their lower body that allowed for tracking of the participants’ movements through a camera-based, motion-analysis system. These two systems allowed the team to examine the torso and lower body movements of patients as they walked. Participants completed three walking trials on the treadmill—one at a usual walking pace, another while walking slowly, and another that included working on a task while walking (i.e. pushing a button in response to a sound).
The accelerometer signals were used to examine three aspects of movement: participants moving forward and backward, side to side, and up and down. The researchers then used advanced mathematical computations to extract data from these signals.
The results—integrated into the mathematical models—showed significant differences between the healthy and clinical populations. These metrics were able to discriminate between the three groups, identifying critical features in how the participants walked.
The Pitt team is now looking to conduct this type of study on a larger scale—evaluating the gait patterns of older adults residing within independent living facilities.
“Our results indicate that we can potentially develop these mathematical models as biomarkers to predict changes in walking due to diseases like Parkinson’s disease,” said Sejdic. “Now, we want to take it further. We’re especially hoping to help those individuals in independent living facilities by predicting the declines in their walking even earlier.”
“What also makes this study unique is the multidisciplinary team approach we used,” said Jennifer S. Brach (SHRS ’94G, ’00G) coprincipal investigator of the study and associate professor in Pitt’s Department of Physical Therapy. “Here we brought together a research team that included engineers, physical therapists, and experts in geriatrics to work on an important problem in older adults—changes in mobility.”
(Source: news.pitt.edu)