Neuroscience
Month
To handle large amounts of data from detailed brain models, IBM, EPFL, and ETH Zürich are collaborating on a new hybrid memory strategy for supercomputers. This will help the Blue Brain Project and the Human Brain Project achieve their goals.
Motivated by extraordinary requirements for neuroscience, IBM Research, EPFL, and ETH Zürich through the Swiss National Supercomputing Center CSCS, are exploring how to combine different types of memory – DRAM, which is standard for computer memory, and flash memory that is akin to USB sticks – for less expensive and optimal supercomputing performance.
The Blue Brain Project, for example, is building detailed models of the rodent brain based on vast amounts of information – incorporating experimental data and a large number of parameters – to describe each and every neuron and how they connect to each other. The building blocks of the simulation consist of realistic representations of individual neurons, including characteristics like shape, size, and electrical behavior.
Given the roughly 70 million neurons in the brain of a mouse, a huge amount of data needs to be accessed for the simulation to run efficiently.
“Data-intensive research has supercomputer requirements that go well beyond high computational power,” says EPFL professor Felix Schürmann of the Blue Brain Project in Lausanne. “Here, we investigate different types of memory and how it is used, which is crucial to build detailed models of the brain. But the applications for this technology are much broader.”
70 Million Neurons for the New IBM Blue Gene/Q
The Blue Brain Project has acquired a new IBM Blue Gene/Q supercomputer to be installed at CSCS in Lugano, Switzerland. This machine has four times the memory of the supercomputer used by the Blue Brain Project up to now, but this still may not be enough to model the mouse brain at the desired level of detail.
The challenge for scientists is to modify the supercomputer so that it can model not only more neurons—as many as the 70 million in the mouse brain—but with even more detail while using fewer resources. The researchers aspire to do just that by engineering different types of memory. The Blue Gene/Q comes equipped with 64 terabytes of DRAM memory. But this type of memory, which is ubiquitous in personal computers, loses data almost instantaneously when the power is turned off.
The scientists plan to boost the supercomputer’s capacity by combining DRAM with another type of memory that has made its way into everyday devices, from cameras to mobile phones: flash memory. Unlike DRAM, flash memory can retain information, even without power, and is much more affordable. The Blue Brain Project’s new supercomputer efficiently integrates 128 terabytes of flash memory with the 64 terabytes of DRAM memory.
“These technological advancements will not only help scientists model the brain, but they will also contribute to future evidence-based systems,” says IBM Research computational scientist Alessandro Curioni, who is based in Zurich.
To take full advantage of this novel mix of memory, IBM has been developing a scalable memory system architecture, while EPFL and ETH Zürich researchers are working on high-level software to optimize this hybrid memory for large-scale simulations and interactive supercomputing.
“The resulting machine may not necessarily be the fastest supercomputer in the world, but it will certainly open up new avenues for data-intensive science,” says ETH Zürich professor and CSCS director Thomas Schulthess. “The results of this collaboration will support scientific investigations across all types of data intensive applications including astronomy, geosciences and healthcare.”
Towards the Human Brain
The Blue Brain Project has recently become the core of an even more ambitious project, the European Flagship Human Brain Project, also coordinated by EPFL. The Human Brain Project faces the daunting task of providing the technical tools to integrate as much data as possible into detailed models of the human brain by 2023. Estimated at 90 billion neurons, the human brain compared to that of a mouse contains roughly a thousand times more neurons. The new strategy to use hybrid memory is an important step towards helping the Human Brain Project meet its 10-year goal.
As it goes with research and innovation, a scientific pursuit is pushing the boundaries of technology, leading to new and more powerful tools. The Blue Brain and Human Brain Projects have brought into perspective the need to deal with complex and unusual calculations, requiring supercomputer technology where speed is simply not enough.
A 350-year-old mathematical mystery could lead toward a better understanding of medical conditions like epilepsy or even the behavior of predator-prey systems in the wild, University of Pittsburgh researchers report.
The mystery dates back to 1665, when Dutch mathematician, astronomer, and physicist Christiaan Huygens, inventor of the pendulum clock, first observed that two pendulum clocks mounted together could swing in opposite directions. The cause was tiny vibrations in the beam caused by both clocks, affecting their motions.
The effect, now referred to by scientists as “indirect coupling,” was not mathematically analyzed until nearly 350 years later, and deriving a formula that explains it remains a challenge to mathematicians still. Now, Pitt professors apply this principle to measure the interaction of “units”—such as neurons, for example—that turn “off” and “on” repeatedly. Their findings are highlighted in the latest issue of Physical Review Letters.
“We have developed a mathematical approach to better understanding the ‘ingredients’ in a system that affect synchrony in a number of medical and ecological conditions,” said Jonathan E. Rubin, coauthor of the study and professor in Pitt’s Department of Mathematics within the Kenneth P. Dietrich School of Arts and Sciences. “Researchers can use our ideas to generate predictions that can be tested through experiments.”
More specifically, the researchers believe the formula could lead toward a better understanding of conditions like epilepsy, in which neurons become overly active and fail to turn off, ultimately leading to seizures. Likewise, it could have applications in other areas of biology, such as understanding how bacteria use external cues to synchronize growth.
Together with G. Bard Ermentrout, University Professor of Computational Biology and professor in Pitt’s Department of Mathematics, and Jonathan J. Rubin, an undergraduate mathematics major, Jonathan E. Rubin examined these forms of indirect communication that are not typically included in most mathematical studies owing to their complicated elements. In addition to studying neurons, the Pitt researchers applied their methods to a model of artificial gene networks in bacteria, which are used by experimentalists to better understand how genes function.
“In the model we studied, the genes turn off and on rhythmically. While on, they lead to production of proteins and a substance called an autoinducer, which promotes the genes turning on,” said Jonathan E. Rubin. “Past research claimed that this rhythm would occur simultaneously in all the cells. But we show that, depending on the speed of communication, the cells will either go together or become completely out of synch with each another.”
To apply their formula to an epilepsy model, the team assumed that neurons oscillate, or turn off and on in a regular fashion. Ermentrout compares this to Southeast Asian fireflies that flash rhythmically, encouraging synchronization.
“For neurons, we have shown that the slow nature of these interactions encouraged ‘asynchrony,’ or firing at different parts of the cycle,” Ermentrout said. “In these seizure-like states, the slow dynamics that couple the neurons together are such that they encourage the neurons to fire all out of phase with each other.”
The Pitt researchers believe this approach may extend beyond medical applications into ecology—for example, a situation in which two independent animal groups in a common environment communicate indirectly. Jonathan E. Rubin illustrates the idea by using a predator-prey system, such as rabbits and foxes.
“With an increase in rabbits will come an increase in foxes, as they’ll have plenty of prey,” said Jonathan E. Rubin. “More rabbits will get eaten, but eventually the foxes won’t have enough to eat and will die off, allowing the rabbit numbers to surge again. Voila, it’s an oscillation. So, if we have a fox-rabbit oscillation and a wolf-sheep oscillation in the same field, the two oscillations could affect each other indirectly because now rabbits and sheep are both competing for the same grass to eat.”
There is growing evidence that a gene variant that reduces the plasticity of the nervous system also modulates responses to treatments for mood and anxiety disorders. In this case, patients with posttraumatic stress disorder, or PTSD, with a less functional variant of the gene coding for brain-derived neurotrophic factor (BDNF), responded less well to exposure therapy.
This gene has been implicated previously in treatment response. Basic science studies have convincingly shown that BDNF levels are an important modifier of the therapeutic effects of antidepressants in animal models. Other researchers have made similar findings in a small group of depressed patients treated with the rapid-acting antidepressant ketamine. Low BDNF plasma levels also have been linked to poorer effects of cognitive rehabilitation in schizophrenia. BDNF infused directly into the infralimbic prefrontal cortex in rats was found to extinguish conditioned fear, and BDNF levels were found to modulate the amount of fear extinction.
"Findings are accumulating to suggest that BDNF is an important modifier of the responses to a number of clinical interventions, presumably because BDNF is such an important regulator of neuroplasticity, i.e., the ability of the brain to adapt," said Dr. John Krystal, Editor of Biological Psychiatry.
In this study, researchers from Australia and Puerto Rico teamed up to investigate the influence of the BDNF Val66Met genotype on response to exposure therapy in patients with PTSD. They recruited 55 patients, all of whom participated in an 8-week exposure-based cognitive behavior therapy program.
Exposure therapy is currently the most effective treatment for PTSD, although it does not work for everyone. This type of therapy is delivered over multiple one-on-one sessions with a trained therapist, with a goal of reducing patients’ fear and anxiety.
They found that patients with the Met-66 allele of BDNF, compared with patients with the Val/Val allele, showed poorer response to exposure therapy.
"This paper reflects an important and significant advance, in translating recent ground-breaking findings in animal and human neuroscience into clinically anxious populations," said first author Dr. Kim Felmingham.
She added, “Findings from this study support a widely held, but largely untested, hypothesis that extinction is necessary for exposure therapy. It also provides evidence that genotypes influence response to cognitive behavior therapy.”
This finding supports prior evidence and highlights the importance of considering genotypes as potential predictor variables in clinical trials of exposure therapy.
Study is the first to show association between mother’s chemical exposure and fetal motor activity and heart rate
A study led by researchers at the Johns Hopkins Bloomberg School of Public Health has for the first time found that a mother’s higher exposure to some common environmental contaminants was associated with more frequent and vigorous fetal motor activity. Some chemicals were also associated with fewer changes in fetal heart rate, which normally parallel fetal movements. The study of 50 pregnant women found detectable levels of organochlorines in all of the women participating in the study—including DDT, PCBs and other pesticides that have been banned from use for more than 30 years. The study is available online in advance of publication in the Journal of Exposure Science and Environmental Epidemiology.
“Both fetal motor activity and heart rate reveal how the fetus is maturing and give us a way to evaluate how exposures may be affecting the developing nervous system. Most studies of environmental contaminants and child development wait until children are much older to evaluate effects of things the mother may have been exposed to during pregnancy; here we have observed effects in utero,” said Janet A. DiPietro, PhD, lead author of the study and Associate Dean for Research at the Bloomberg School of Public Health.
For the study, DiPietro and her colleagues followed a sample of 50 high- and low- income pregnant women living in and around Baltimore, Md. At 36 weeks of pregnancy, blood samples were collected from the mothers and measurements were taken of fetal heart rate and motor activity. The blood samples were tested for levels of 11 pesticides and 36 polychlorinated biphenyl (PCB) compounds.
According to the findings, all participants had detectable concentrations of at least one-quarter of the analyzed chemicals, despite the fact that they have been banned for more than three decades. Fetal heart rate effects were not consistently observed across all of the compounds analyzed; when effects were seen, higher chemical exposures were associated with reductions in fetal heart rate accelerations, an indicator of fetal wellbeing. However, associations with fetal motor activity measures were more consistent and robust: higher concentrations of 7 of 10 organochlorine compounds were positively associated with one of more measures of more frequent and more vigorous fetal motor activity. These chemicals included hexachlorobenzene, DDT, and several PCB congeners. Women of higher socioeconomic status in the study had a greater concentration of chemicals compared to the women of lower socioeconomic status
“There is tremendous interest in how the prenatal period sets the stage for later child development. These results show that the developing fetus is susceptible to environmental exposures and that we can detect this by measuring fetal neurobehavior. This is yet more evidence for the need to protect the vulnerable developing brain from effects of environmental contaminants both before and after birth,” said DiPietro.
“Fetal heart rate and motor activity associations with maternal organochlorine levels: results of an exploratory study” was written by Janet A. DiPietro, Meghan F. Davis, Kathleen A. Costigan, and Dana Boyd Barr.
Low baseline diastolic blood pressure (DBP) appears to be associated with brain atrophy in patients with arterial disease, whenever declining levels of blood pressure (BP) over time among patients who had a higher baseline BP were associated with less progression of atrophy, according to a report published Online First by JAMA Neurology, a JAMA Network publication.
(Image: Wikimedia Commons)
“Studies have shown that both high and low blood pressure (BP) may play a role in the etiology of brain atrophy. High BP in midlife has been associated with more brain atrophy later in life, whereas studies in older populations have shown a relation between low BP and more brain atrophy. Yet, prospective evidence is limited, and the relation remains unclear in patients with manifest arterial disease,” according to the study.
Hadassa M. Jochemsen, M.D., of University Medical Center Utrecht, the Netherlands, and colleagues examined the association of baseline BP and change in BP over time with the progression of brain atrophy in 663 patients (average age 57 years; 81 percent male). The patients had coronary artery disease, cerebrovascular disease, peripheral artery disease or abdominal aortic aneurysm.
According to the results, patients with lower baseline DBP or mean arterial pressure (MAP) had more progression of subcortical (the area beneath the cortex of the brain) atrophy. In patients with higher BP (DBP, MAP or systolic BP), those with declining BP levels over time had less progression of subcortical atrophy compared with those with rising BP levels.
“This could imply that BP lowering is beneficial in patients with higher BP levels, but one should be cautious with further BP lowering in patients who already have low BP,” the study authors conclude.
Over 100 years ago psychologist Carl Gustav Jung penned his theory of ‘complexes’ where he explained how unconscious psychological issues can be triggered by people, events, or Jung believed, through word association tests.
New research in the Journal of Analytical Psychology is the first to reveal how modern brain function technology allows us to see inside the mind as a ‘hot button’ word triggers a state of internal conflict between the left and right parts of the brain.
The study revealed that some words trigger a subconscious internal conflict between our sense of selves and downloaded brain programs referring to “other” beings.
Analysis showed how this conflict takes place between the left and the right brain over three seconds, after which the left brain takes over to ensure ‘hot buttons’ will continue to be active.
"We found that when a complex is activated, brain circuits involved in how we sense ourselves, but also other people, get activated," said Dr. Leon Petchkovsky. "However, as there is no external person, the ‘other’ circuits really refer to internalized programs about how an ‘other’ person might respond. When a hot button gets pressed, ‘internal self’ and ‘internal other’ get into an argument."
"If we can manage to stay with the conflict rather than pseudo-resolve it prematurely, it may be possible to move beyond it," said Petchkovsky. "We can do this in psychotherapy, or by developing ‘mindfulness’ meditation skills. This makes for fewer ‘hot-buttons’ and a happier life."
Further research into this technology may help to develop an office-based test for condtions such as schizophrenia. Jung noticed that when schizophrenic patients responded to the word association test, their complexes tended to predominate for a much longer time and they would often get a burst of auditory hallucinations when they hit complexed responses.
In Dr Petchkovsky’s research with two schizophrenic patients found that their right brain activity persists for much longer than other patients and they reported an increase in auditory hallucination activity when complexes are struck.
Findings may have implications for treating compulsive behavior associated with psychiatric disease and eating disorders
What started as an experiment to probe brain circuits involved in compulsive behavior has revealed a surprising connection with obesity.
The University of Iowa-led researchers bred mice missing a gene known to cause obesity, and suspected to also be involved in compulsive behavior, with a genetic mouse model of compulsive grooming. The unexpected result was offspring that were neither compulsive groomers nor obese.
The study, published the week of June 10 in the online early edition of the Proceedings of the National Academy of Sciences (PNAS), suggests that the brain circuits that control obsessive-compulsive behavior are intertwined with circuits that control food intake and body weight. The findings have implications for treating compulsive behavior, which is associated with many forms of psychiatric disease, including obsessive-compulsive disorder (OCD), Tourette syndrome, and eating disorders.
UI neuro-psychiatrists Michael Lutter, M.D., Ph.D. and Andrew Pieper, M.D., Ph.D. led the study. The team also included researchers from Stanford University School of Medicine, University of Texas Southwestern Medical Center, Beth Israel Deaconess Medical Center, and Harvard Medical School.
Lutter, an assistant professor of psychiatry, and Pieper, an associate professor of psychiatry and neurology at the UI Carver College of Medicine, both recently arrived at the UI and use mouse models in their laboratories to study human disorders and conditions.
Pieper is interested in compulsive behavior. His mouse model of compulsivity lacks a brain protein called SAPAP3. These mice groom themselves excessively to the point of lesioning their skin, and their compulsive behavior can be effectively treated by fluoxetine, a drug that is commonly used to treat OCD in people.
Lutter works with a mouse that genetically mimics an inherited form of human obesity. This mouse lacks a brain protein known a MC4R. Mutations in the MC4R gene are the most common single-gene cause of morbid obesity and over-eating in people.
“I study MC4R signaling pathways and their involvement in the development of obesity,” Lutter explains. “I’m also interested in how these same molecules affect mood and anxiety and reward, because it’s known that there is a connection between depression and anxiety and development of obesity.”
An old study hinted that in addition to its role in food intake and obesity, MC4R might also play a role in compulsive behavior, which got Lutter and Pieper thinking of ways to test the possible interaction.
"We knew in one mouse you could stimulate excessive grooming through this MC4R pathway and in another mouse a different pathway (SAPAP3) caused compulsive grooming," Lutter says. "So, we decided to breed the two mice together to see if it would have an effect on compulsive grooming."
The experiment proved their original hypothesis—knocking out the MC4R protein in the OCD mouse normalized grooming behavior in the animals. In addition, chemically blocking MC4R in the OCD mice also eliminated compulsive grooming. The rescued behavior is mirrored by normalization of a particular pattern of brain cell communication linked to compulsive behavior.
However, the breeding experiment revealed another totally unexpected result. Loss of the SAPAP3 protein from the mice that were obese due to lack of MC4R produced mice of normal weight.
"We had this other, completely shocking finding—we completely rescued body weight and food intake in the double null mouse," Lutter says. "So, not only were we affecting the brain regions involved in grooming and behavior, but we also affected the brain regions involved in food intake and body weight."
Although obesity and obsessive-compulsive behavior may seem unrelated, Lutter suggests that the connection may be rooted in the evolutionary need to eat safe, clean food in times of a food abundance, and to lessen this drive when food is scarce.
"Food safety has been an issue through the entire course of human evolution—refrigeration is a relatively recent invention," he says. "Obsessive behavior, or fear of contamination, may be an evolutionary protection against eating rotten food."
Oils and fats have lots of calories and nutrients but they also spoil much more easily than less nutrient- and calorie-dense foods like potatoes, onions, or apples.
"I think this circuit that we have uncovered is probably involved in determining whether or not people should eat calorically dense foods," he says.
Lutter suggests that slight perturbations in this system might lead, on one hand, to disorders that link anxiety and obsessive behavior to limited food selection or intake, such as anorexia nervosa, Tourette syndrome, or OCD, and on the other hand, to obesity, where people over-consume high-fat foods and may have decreased obsessive behavior and anxiety.
“The next step will be to determine how these two pathways communicate with one another, in hopes of identifying new ways to develop drugs to treat either of these disorders,” says Pieper.
An interesting new report of animal research published in Biological Psychiatry suggests that common antidepressant medications may impair a form of learning that is important clinically.
(Photo: ALAMY)
Selective serotonin reuptake inhibitors, commonly called SSRIs, are a class of antidepressant widely used to treat depression, as well as a range of anxiety disorders, but the effects of these drugs on learning and memory are poorly understood.
In a previous study, Nesha Burghardt, then a graduate student at New York University, and her colleagues demonstrated that long-term SSRI treatment impairs fear conditioning in rats. As a follow-up, they have now tested the effects of antidepressant treatment on extinction learning in rats using auditory fear conditioning, a model of fear learning that involves the amygdala. The amygdala is a region of the brain vitally important for processing memory and emotion.
They found that long-term, but not short-term, SSRI treatment impairs extinction learning, which is the ability to learn that a conditioned stimulus no longer predicts an aversive event.
"This impairment may have important consequences clinically, since extinction-based exposure therapy is often used to treat anxiety disorders and antidepressants are often administered simultaneously," said Dr. Burghardt. "Based on our work, medication-induced impairments in extinction learning may actually disrupt the beneficial effects of exposure-therapy."
This finding is consistent with the results of several clinical studies showing that combined treatment can impede the benefits of exposure therapy or even natural resilience to the impact of traumatic stress at long-term follow-up.
The authors also suggest a mechanism for this effect on fear learning. They reported that the antidepressants decreased the levels of one of the subunits of the NMDA receptor (NR2B) in the amygdala. The NMDA receptor is critically involved in fear-related learning, so these reductions are believed to contribute to the observed effects.
Dr. John Krystal, Editor of Biological Psychiatry, commented, “We know that antidepressants play important roles in the treatment of depression and anxiety disorders. However, it is important to understand the limitations of these medications so that we can improve the effectiveness of the treatment for these disorders.”
New findings provide vital step towards exploring pain medications that may lower risks of prescription drug abuse and side effects of painkillers
For patients managing cancer and other chronic health issues, painkillers such as morphine and Vicodin are often essential for pain relief. The body’s natural tendency to develop tolerance to these medications, however, often requires patients to take higher doses – increasing risks of harmful side effects and dependency.
Now, new research from the University of Michigan Health System and a major pharmaceutical company has identified a novel approach to moderate and severe pain therapy that paves the way for lower dosage painkillers. The findings appear in Proceedings of the National Academy of Sciences of the United States of America.
Drugs such as hydrocodone (the main ingredient of Vicodin) and oxycodone (Oxycontin) are often the best options for the treatment of moderate to severe pain for patients facing medical conditions ranging from a wisdom tooth extraction to cancer. The drugs bind to specific molecules (opioid receptors) on nerve cells in the brain and spinal cord to prevent the feeling of pain.
“We have for the first time discovered compounds that bind to an alternative site on the nerve opioid receptors and that have significant potential to enhance the drug’s positive impact without increasing negative side effects,” says co-author John Traynor, Ph.D., professor of pharmacology at the U-M Medical School.
“We are still in the very early stages of this research with a long way to go, but we believe identifying these compounds is a key step in revolutionizing the treatment of pain. This opens the door to developing pain relief medications that require lower doses to be effective, helping address the serious issues of tolerance and dependence that we see with conventional pain therapy.”
Conventional drug treatments for pain work by targeting the so-called orthosteric site of the opioid receptor that provides pain relief. Targeting this site, however, is a double-edged sword because it is also responsible for all of the drug’s unwanted side effects, such as constipation and respiratory depression. Tolerance also limits chronic use of the drugs because higher doses are required to maintain the same effect.
Using cell systems and mouse brain membranes, researchers have identified compounds that bind to a physically distinct and previously unknown “allosteric” site on the opioid receptor- a site that fine-tunes the activity of the receptor. Not only do these compounds act at a location that hasn’t been studied as a drug target before but they bind to the receptor in a new way to enhance the actions of morphine – which means lower doses can have the same impact.
“The newly-discovered compounds bind to the same receptor as morphine but appear to act at a separate novel site on the receptor and therefore can produce different effects. What’s particularly exciting is that these compounds could potentially work with the body’s own natural painkillers to manage pain,” Traynor says.
“We know that conventional strong pain medications ultimately increase the risk of withdrawal symptoms and addiction, which is an especially serious issue with the current prescription drug abuse epidemic in our country. The implications of this work, if it translates to animal studies and then to humans, are highly significant to this area of study.”
In 2010, China had more people living with Alzheimer’s disease than any other country in the world – and twice as many cases of Alzheimer’s and other kinds of dementia as the World Health Organization thought.
Cases of all kinds of age-related dementia in the country rose from 3.7 million in 1990 to 9.2 million in 2010. This is the finding of the first comprehensive analysis of Chinese epidemiological research, made possible by the recent digitisation of Chinese-language research papers. Previous estimates, based on English-language papers, seem to have under-reported the number of cases by half.
"We are now only beginning to comprehend the enormous value in this ‘parallel universe’ of information," says Igor Rutan of the University of Edinburgh, UK, who was part of the team that carried out the research.
The figures are bad news for a country where 90 per cent of the elderly must be cared for by their families – old people who still have family members living are not allowed to be admitted to a nursing home – even as widespread migration to cities has disrupted the traditional family structure.
Population bulge
The findings are a reflection of China’s ageing population, and its policies.
As countries modernise, death rates fall, and later on birth rates fall as more people take up birth control. Between the two events, though, there is a “bulge” of births, the source of the modern world’s population explosion. Eventually birth and death rates roughly equalise, but the birth bulge remains as an age bulge in the population.
This reached an extreme in China, where a surge in births in the 1950s and 1960s was followed by plummeting birth rates in the 1970s, later reinforced by China’s one-child policy. “Family planning policy means China is becoming an ageing country much faster than other middle-income countries such as India,” says co-author Wei Wang of Edith Cowan University in Perth, Australia.
In its youth, the bulge underpinned China’s economic development. But by 2033, it is predicted that working-age people will be outnumbered by dependents, mostly the elderly.
The new research shows that they will need more care than China was expecting. Dementia rises in an ageing population: cases increased from 4.9 to 6.3 million in the greying European Union between 2004 and 2010.
Unhealthy lifestyle
"The rates in China are similar or even higher than rates in Europe and the US," says Wang.
And they are rising. In 1990, the team estimates, 1.8 per cent of Chinese aged 65 to 69, and 42.1 per cent aged 95 to 99, had dementia. In 2010 those figures were 2.6 and 60.5 per cent, respectively. If similar rates hold in other middle-income countries, there might be 20 per cent more cases of Alzheimer’s worldwide – five million more – than now estimated, the authors calculate.
The increase in China might reflect better diagnosis, but an urbanising lifestyle could also be causing more dementia. “Obesity, diabetes and suboptimal health contribute,” says Wang.
Martin Prince of King’s College London, who is organising another survey for dementia in China, says that if midlife obesity is a risk factor for dementia, then future rates in China could be 20 per cent higher than estimated.
Expert Panel of Physicians and Neuroscientists Announce International Guidance on Using Neurostimulation to Significantly Reduce the Need for Opioids in Chronic Pain
Recognizing that treatment of chronic pain can be confounding, the Neuromodulation Appropriateness Consensus Committee (NACC), an international group of more than 60 leading pain specialists, has created the first consensus guidelines for the use of neurostimulation in chronic pain.
Neurostimulation is an established and growing area of pain therapy that treats nerves with electrical stimulation rather than drugs. The NACC findings, announced at the International Neuromodulation Society (INS) 11th World Congress, address provider training, patient screening, and treatment recommendations.
While the extent and suffering of chronic pain is becoming better recognized, the danger of opioids for addiction, diversion or misuse is well known. Long-term opioid use can lead to the need for escalating doses to bring relief, and raises the risk of physical dependence, overdose, weight gain, depression, and immune and hormone system dysfunction.
“Many studies contain insufficient evidence to prove the safety or effectiveness of any long-term opioid regimen for chronic pain,” said study lead author Dr. Timothy Deer, INS president-elect and director of the Center for Pain Relief in Charleston, W. Va. “Indeed, many patients discontinue long-term opioid therapy due to insufficient pain relief or adverse events.”
Neurostimulation has been shown in clinical studies to be safe and effective for properly selected patients, and is approved by the FDA to treat chronic pain of the trunk and limbs. It belongs to a family of therapies known as neuromodulation because they modulate, or alter, the function of nerves, such as nerves that may have become hypersensitized or damaged, or are otherwise sending pain signals long past the initial injury. Since the components of neurostimulators bear some resemblance to heart pacemakers, they are sometimes called pain pacemakers.
The NACC recommends neurostimulation be used earlier in the treatment of some kinds of chronic pain, such as failed back surgery syndrome and complex regional pain syndrome. A study being presented at the world congress shows neurostimulation effectiveness correlates with early use in those conditions, with the added benefit of shortening the time patients spend trying other methods and containing long-term costs of managing chronic pain.
The most common form of neurostimulation, spinal cord stimulation (SCS), was introduced in 1967 and is now implanted in some 4,000 patients annually in the United States. With SCS, appropriately selected patients who have had back and/or leg pain longer than six months often find their symptoms relieved by 50 percent or more. The therapy uses slender electrical leads placed beneath the skin along the spinal cord and connected to a compact pulse generator, about the size of a pocket watch, that sends mild current along the leads to elicit a natural biological response and limit pain messages sent to the brain. Patients try the minimally invasive technique to see if it works for them before receiving a permanent implant.
“The lessons learned over the last few decades of clinical practice have influenced neurostimulator design, placement, and programming – and added new insights into spinal anatomy and pain physiology,” said INS President Dr. Simon Thomson, consultant in in pain medicine and neuromodulation at Basildon and Thurrock University NHS Trust in the United Kingdom.
Although neurostimulation devices may seem novel at first, using electrical current to limit pain dates back to antiquity, when standing on an electric fish was one remedy. Use of modern neurostimulation devices is likely to expand as the aging populace lives longer with chronic conditions, while technological refinements and clinical evidence continue to accumulate.
“A reduction in opioid use among patients treated with spinal cord stimulation was shown in a several studies, notably a 2005 randomized controlled clinical trial led by Dr. Richard North under the auspices of the Johns Hopkins University School of Medicine,” commented INS Secretary and study co-author Dr. Marc Russo, director of the Hunter Pain Clinic in New South Wales, Australia. “Broad-based studies show that within two years, using spinal cord stimulation rather than repeat back surgery is not only a more cost-effective use of health resources, it also is correlated with higher rates of return to work.”
Consensus committee authors believe that when appropriately applied, neurostimulation to target treatment directly to nerves can improve productivity and quality of life for chronic pain patients, offering a potentially less costly and risky option than repeat surgery or long-term painkiller use. They recommend:
Creative types are often seen as rather flaky — their minds leaping wildly from one bizarre idea to another, ever seeking inspiration. But a new study suggests that people who actually achieve creative success have minds that stubbornly cling to ideas, even to the point where it impairs their ability to shift focus.
In one experiment, researchers at Northwestern University in Illinois selected 34 students out of more than 300 who completed a questionnaire on creative achievement, ultimately including 19 who had outstanding achievements in music, art, science, writing or other areas and 15 of those whose scores ranked them as being among the least creative.
“We preselected people with very high and very low creative achievement,” says lead author Darya Zabelina, a graduate student at Northwestern. The research was published in Frontiers in Psychology.
During the study, participants had to shift their attention from a global level of processing to a local one, by focusing on different aspects of patterns. In some cases, they were asked to identify a large letter made up of smaller ones (for example, an “S” pattern made up of smaller “e’s”). In other instances, the correct answer was the opposite one — identifying the smaller letter.
“It’s a little counter-intuitive,” says Zabelina, “but people with high creativity actually perform badly on this test.” In fact, they made more than twice as many errors as the less creative group — and even after controlling for overall intelligence, the creative people still did less well.
A second experiment involved the same task, performed by another 39 high, moderate or low scorers in creative achievements. Again, the more creative people scored lower. And in both experiments, there was no difference in performance whether people had to shift from the “forest” focus of the larger letters to the “tree level” of the smaller ones or whether the shift was in the opposite direction. That suggests that the lower scores were not related to creative people being more focused specifically on either detail or on general patterns.
The research may help explain why autistic people, who tend to focus obsessively, can often be highly creative. Paradoxically, it may also help explain the link between attention deficit/hyperactivity disorder (ADHD) and creative success.
“The general idea is that [people with ADHD] are not able to focus on anything,” says Zabelina, “But really there are two different parts of the disorder, and one is that if they really get interested in something, they become almost like autistic people: really focused, so much so that they are not able to practice anything else.” Indeed, between 30% and 50% of autistic people also have ADHD.
The combination of an ability to range widely from one thought to another and to focus when a good idea occurs may be the sweet spot for creative success. The trick is in the timing: to mind-wander enough when seeking ideas to hit on the best ones and then to zoom in and persist once the right solution has been found.
But the study makes clear that creative achievement may come with some trade-offs in mental flexibility, when the time comes to actually shift focus. Persistence certainly matters in creative achievement — but some creative folks may not know when to stop.
Phase 1 trial safely resets patients’ immune systems, reduces attack on myelin protein
A phase 1 clinical trial for the first treatment to reset the immune system of multiple sclerosis (MS) patients showed the therapy was safe and dramatically reduced patients’ immune systems’ reactivity to myelin by 50 to 75 percent, according to new Northwestern Medicine research.
In MS, the immune system attacks and destroys myelin, the insulating layer that forms around nerves in the spinal cord, brain and optic nerve. When the insulation is destroyed, electrical signals can’t be effectively conducted, resulting in symptoms that range from mild limb numbness to paralysis or blindness.
“The therapy stops autoimmune responses that are already activated and prevents the activation of new autoimmune cells,” said Stephen Miller, the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. “Our approach leaves the function of the normal immune system intact. That’s the holy grail.”
Miller is the co-senior author of a paper on the study, which was published June 5 in the journal Science Translational Medicine. The study is a collaboration between Northwestern’s Feinberg School, University Hospital Zurich in Switzerland and University Medical Center Hamburg-Eppendorf in Germany.
The human trial is the translation of more than 30 years of preclinical research in Miller’s lab.
In the trial, the MS patients’ own specially processed white blood cells were used to stealthily deliver billions of myelin antigens into their bodies so their immune systems would recognize them as harmless and develop tolerance to them.
Current therapies for MS suppress the entire immune system, making patients more susceptible to everyday infections and higher rates of cancer.
While the trial’s nine patients — who were treated in Hamburg, Germany — were too few to statistically determine the treatment’s ability to prevent the progression of MS, the study did show patients who received the highest dose of white blood cells had the greatest reduction in myelin reactivity.
The primary aim of the study was to demonstrate the treatment’s safety and tolerability. It showed the intravenous injection of up to 3 billion white blood cells with myelin antigens caused no adverse affects in MS patients. Most importantly, it did not reactivate the patients’ disease and did not affect their healthy immunity to real pathogens.
As part of the study, researchers tested patients’ immunity to tetanus because all had received tetanus shots in their lifetime. One month after the treatment, their immune responses to tetanus remained strong, showing the treatment’s immune effect was specific only to myelin.
The human safety study sets the stage for a phase 2 trial to see if the new treatment can prevent the progression of MS in humans. Scientists are currently trying to raise $1.5 million to launch the trial, which has already been approved in Switzerland. Miller’s preclinical research demonstrated the treatment stopped the progression of relapsing-remitting MS in mice.
“In the phase 2 trial we want to treat patients as early as possible in the disease before they have paralysis due to myelin damage.” Miller said. “Once the myelin is destroyed, it’s hard to repair that.”
In the trial, patients’ white blood cells were filtered out, specially processed and coupled with myelin antigens by a complex GMP manufacturing process developed by the study co-senior authors, Roland Martin, Mireia Sospedra, and Andreas Lutterotti and their team at the University Medical Center Hamburg-Eppendorf. Then billions of these dead cells secretly carrying the myelin antigens were injected intravenously into the patients. The cells entered the spleen, which filters the blood and helps the body dispose of aging and dying blood cells. During this process, the immune cells start to recognize myelin as a harmless and immune tolerance quickly develops. This was confirmed in the patients by immune assays developed and carried out by the research team in Hamburg.
This therapy, with further testing, may be useful for treating not only MS but also a host of other autoimmune and allergic diseases simply by switching the antigens attached to the cells. Previously published preclinical research by Miller showed the therapy’s effectiveness for type 1 diabetes and airway allergy (asthma) and peanut allergy.
The MS human trial relates directly to Miller’s recently published research in mice in which he used nanoparticles — rather than a patient’s white blood cells — to deliver the myelin antigen. Using a patient’s white blood cells is a costly and labor-intensive procedure. Miller’s study showed the nanoparticles, which are potentially cheaper and more accessible to a general population, could be as effective as the white blood cells as delivery vehicles. This nanoparticle technology has been licensed to Cour Pharmaceutical Development Company and is in preclinical development.
Miller’s research represents several pillars of Northwestern’s Strategic Plan by discovering new ways to treat disease in the biomedical sciences and translating those discoveries into ideas and products that make the world a better place for everyone.
The presence of Lewy bodies in nerve cells, formed by intracellular deposits of the protein α-synuclein, is a characteristic pathologic feature of Parkinson’s Disease (PD). In the quest for an animal model of PD that mimics motor and non-motor symptoms of human PD, scientists have developed strains of mice that overexpress α-synuclein. By studying a strain of mice bred to overexpress α-synuclein via the Thy-1 promoter, scientists have found these mice develop many of the age-related progressive motor symptoms of PD and demonstrate changes in sleep and anxiety. Their results are published in the latest issue of Journal of Parkinson’s Disease.
PD is the second most common neurodegenerative disorder in the United States, affecting approximately one million Americans and five million people worldwide. Its prevalence is projected to double by 2030. The most obvious symptoms are movement-related, such as involuntary shaking and muscle stiffness; non-motor symptoms, such as increases in anxiety and sleep disturbances, can appear prior to the onset of motor symptoms. Although the drug levodopa can relieve some symptoms, there is no cure – intensifying the pressure to find an animal model that can help clarify the pathological processes underlying human PD and find new medications to treat the pathology and/or relieve symptoms.
Investigators at the National Institute on Aging compared wild type mice with specially bred mice that were transgenic for the A53T mutation of the human α-synuclein (SNCA) gene under the control of a human thymus cell antigen 1, theta (THY-1) promoter. As the mice aged, their motor performance on a rotarod test (which measures how long the mouse can remain on a rotating rod) became impaired and the length of their strides were significantly shorter than the wild type control mice.
The study also found that SNCA mice displayed fragmented nighttime activity patterns compared to wild type controls and appeared to have a reduced overall sleep time. “Despite the prevalence of abnormal sleep patterns in PD, very few studies to date have outlined sleep disturbances in animal models of PD,” says Sarah M. Rothman, PhD, a researcher with the National Institute on Aging, in Baltimore, MD.
Many PD patients typically show an increase in anxiety and depression, and in this respect the SNCA mouse model did not replicate the human condition. SNCA mice displayed an early and significant decrease in anxiety-like behavior that persisted throughout their lifespan, as shown by both open field and elevated plus maze tests (in which mice have the choice of spending time in open or closed arms of a maze). Other rodent models that utilize changes in expression of α-synuclein have also reported lower anxiety levels. The authors suggest that higher levels of serotonin found in the hypothalamus of the SNCA mice may be associated with the reduced anxiety observed.
The authors say it is important to remember that the SNCA “model utilizes the presence of a mutation that only occurs very rarely in PD. While all PD patients display α-synuclein pathology, they do not all express the mutated form of the protein,” says Dr. Rothman.
Researchers in Spain have found that a drug used to control Type II diabetes can help repair the spinal cords of mice suffering from the inherited disease adrenoleukodystrophy which, untreated, leads eventually to a paralysis, a vegetative state and death. They believe that their findings may be relevant to other neurodegenerative diseases. A Phase II trial will be starting shortly. The research is published simultaneously on line in the journal Brain.
A drug used to control Type II diabetes can help repair the spinal cords of mice suffering from the inherited disease adrenoleukodystrophy which, untreated, leads eventually to a paralysis, a vegetative state and death. This is an important step along the road to the development of a therapy for the human disease for which current treatment options are scarce and only partially effective, the annual conference of the European Society of Human Genetics will hear tomorrow (Sunday).
Professor Aurora Pujol, a research professor for the Catalan Government Research Body ICREA, working as Director of the Neurometabolic Diseases Laboratory at IDIBELL, Barcelona, Spain, investigated the role of mitochondria, the power plant of the cell, in adrenoleukodystrophy, a disease caused by the inactivation of the ABCD1 transporter of fatty acids in peroxisomes. This inactivation leads to the accumulation of fatty acids in organs and blood plasma, and causes spinal cord degeneration.
“ABCD1 is a protein located in the peroxisomes, compartments of the cell that detoxify chemicals and lipids, and thus the implication of mitochondria in such a disease was not obvious. But we knew from recent research that oxidative stress – where there is increased production of chemically active oxygen-containing molecules, and also significant decrease in the effectiveness of the body’s antioxidant defences – was involved. We also knew that bioenergetic failure appeared before disease symptoms. We therefore decided to investigate the role of the mitochondria”, Professor Pujol will say.
The group of diseases known as leukodystrophies are characterised by progressive loss of the myelin sheath, the fatty covering that acts as an insulator around nerve fibres. Damage to the myelin sheath impairs the conduction of signals in the affected nerves and leads to locomotor problems.
“We knew that early oxidative damage and bioenergetic dysfunction underlay the late onset degeneration of nerve fibres observed in the mouse model of X-linked adrenoleukodystrophy (X-ALD), the most frequently inherited leukodystrophy, so we looked at mitochondria for further clues. We found that the X-ALD mice showed a loss of mitochondria at 12 months of age, prior to disease symptoms, so this could not be a consequence of the disease, but rather a contributing factor. We also knew that the pathway involved in the mitochondrial loss could be treated by the use of the diabetes drug pioglitazone, so we decided to test its effect in the mice”, Professor Pujol will say.
Pioglitazone halted the nerve fibre degeneration by preventing the loss of mitochondria, and inhibiting metabolic failure and oxidative stress in the treated mice, and hence also halted locomotor disabilities. The researchers were able to prove this both through analysis of spinal cords post mortem, and in vivo by putting the mice through a number of physical tests.
Although X-ALD is a relatively rare disease with a minimum incidence of 1 in 17 000 males, there are other neurodegenerative disorders caused by myelin sheath degeneration, for example multiple sclerosis, and many others where impaired bioenergetics combined with oxidative stress and degeneration of axons are known to be involved. The latter category of disease includes Parkinson’s, Huntington’s, and Alzheimer’s. “It is possible that our findings may be relevant to these conditions as well,” says Professor Pujol.
“Following on from these promising results, together with Professor Patrick Aubourg from the Hôpital Bicêtre, Paris, we will shortly be starting a multi-centre phase II clinical trial of pioglitazone in adult patients suffering from a late onset variant of adrenoleukodystrophy. Our research has shown that it will be feasible to monitor the biological effects of the drug by looking for biomarkers of oxidative damage in blood cells or plasma. We are happy to have made a contribution to finding a simple and effective treatment to a group of devastating diseases”, she will conclude.
A gene linked to autism spectrum disorders that was manipulated in two lines of transgenic mice produced mature adults with irreversible deficits affecting either learning or social interaction.
The findings, published in the May 29 issue of the Journal of Neuroscience, have implications for potential gene therapies but they also suggest that there may be narrow windows of opportunity to be effective, says principal investigator Philip Washbourne, a professor of biology and member of the University of Oregon’s Institute of Neuroscience.
The research, reported by an 11-member team from three universities, targeted the impacts of alterations in the gene neuroligin 1 — one of many genes implicated in human autism spectrum disorders — to neuronal synapses in the altered mice during postnatal development and as they entered adulthood. One group over-expressed the normal gene, the other a mutated version.
Mice with higher-than-normal levels of the normal gene after a month had skewed synapses at maturity. Many were larger, appearing more mature, than normal. In these mice, Washbourne said, there were clear cognitive problems. “Behavior was just not normal. They didn’t learn very well, and they were slower to learn, but their social behavior was not impacted.”
Mice over-producing a mutated version of the gene reached adulthood with structurally immature synapses. “They were held back in development and behavior — the way they behave in terms of learning and memory, in terms of social interaction,” he said. “These were adult mice, three months old, but they behaved like normal mice at four weeks old. We saw arrested development. Learning is a little bit better, they are more flexible just like young mice, they learn faster, but their social interaction is off. To us, this looked more like Asperger’s syndrome.
"So with the same gene, doing two different manipulations — overexpressing the normal form or overexpressing a mutated form — we’ve gone to two different ends of the autism spectrum," said Washbourne, whose lab focuses on basic synapse formation and what goes wrong in relationship to autism. Work has been done in both mice and zebra fish.
"We made these mice so that we can turn the genes on and off as we want," Washbourne said. "Using an antibiotic, doxycycline, it turns off these altered genes that we inserted into their chromosomes. While on doxycycline, the mice are absolutely normal.”
However, if the inserted gene was turned off after the completion of development, mice still showed altered synapses and behavior. This result suggests that any kind of gene therapy may have to be applied to individuals with autism early on.
Effects seen in the social behavior of mice with the mutated gene, he said, are not unlike observations reported by parents of many autistic children. While normal mice prefer to engage with new mice entering their world rather than familiar others, or even a new inanimate object, these mice split their time equally. “It’s not a deficit in memory regarding which mouse is which, it’s more a weighting of their interaction. Does that mean they are autistic? I don’t know, but if you talk to parents of autistic children, one of the frustrating things they report is that their children treat complete strangers in exactly the same way that they treat them.”
While the findings provide new insights, Washbourne said, any translation into treatment could be decades away. “A problem with autism is there are many different genes potentially involved. It could be that some day, if you are diagnosed with autism, a mouth swab might allow for the identification of the exact gene that is mutated and allow for targeted therapy,” he said. “Genome sequencing already has turned up subtle mutations in lots of genes. Autism might be like cancer, with hundreds of potential combinations of faulty genes.”
A protein profile of people with restless leg syndrome (RLS), identifies factors behind disrupted sleep, cardiovascular dysfunction and pain finds research in BioMed Central’s open access journal Fluids and Barriers of the CNS. The research gives insights into the disorder, and could be useful in the development of new treatments.
It is not completely clear what causes RLS, also known as Willis Ekbom disease (WED), but in some people it is associated with iron deficiency in the brain, kidney failure, or low levels of the ‘pleasure’ neurotransmitter dopamine. It can also occur during pregnancy. It affects between 5 and 10% of the population and symptoms, which can range in severity, including sleep deprivation and decreased ability to work can lead to a reduction in quality of life. It is also a risk factor for cardiovascular disease.
Comparing the cerebral spinal fluid (CSF) of women with and without RLS, researchers from the US and Korea discovered there was a significantly altered level of six specific proteins with RLS. Dr Stephanie Patton from Penn State University who led this study explained, “Our results reveal a protein profile in the RLS/WED CSF that is consistent with iron deficiency, dopamine dysregulation and inflammation.”
These proteins include a protein which transports vitamin D into cells and is involved in the regulation of dopamine levels, cystatin C – a biomarker for pain found in people with sciatica and during labor, and a neuromodulator (PTGDS) known to be involved in sleep disturbances. Levels of apolipoprotein (Apo) A1 were lower with RLS and may be related to the increased risk of cardiovascular disease.
The importance of iron’s role in RLS is highlighted by the presence of B-hemoglobin in the CSF of women with RLS, while levels of a glycoprotein (AGP) were reduced. AGP is involved in response to inflammatory damage and requires the presence of iron for it to be protective.
Dr Stephanie Patton continued, “Although a small study, this CSF protein profile is consistent with observed neuropathological findings and supports existing hypotheses about the biology behind RLS/WED, which could prove clinically important in developing new treatments.”
Unborn babies ‘practise’ facial expressions of pain in the womb, according to a study published today.
The researchers from Durham and Lancaster Universities suggest that fetuses’ ability to show a “pain” facial expression is a developmental process which could potentially give doctors another index of the health of a fetus.
The study is published in the prestigious academic journal, PLOS ONE, and was part funded by the Economic and Social Research Council (ESRC) and Durham University.
The study extends the findings of previous work demonstrating that the facial expressions of healthy fetuses develop and become more complex during pregnancy resulting in fetuses being able to show recognisable facial expressions.
The 4D scans of 15 healthy fetuses showed that they develop from making very simple one-dimensional expressions at 24 weeks, such as moving their lips in order to form a “smile”, to complex multi-dimensional expressions which can be recognised as “pain” expressions, by the time the mother is 36 weeks into her pregnancy.
The researchers suggest this is an adaptive process which enables the unborn baby to prepare themselves for life after birth when they have to communicate, for example if they feel hungry or uncomfortable, by making grimaces or crying.
The researchers used the video footage of 4D scans, observing repeatedly the facial expressions of eight female and seven male fetuses from the second to third trimester (24 to 36 weeks) of pregnancy.
Fetuses observed at 24 weeks gestation rarely showed a combination of facial movements which make up a ‘pain face’, such as lowering the eyebrows, wrinkling the nose and stretching the mouth. However, by 36 weeks gestation, a combination of at least four movements was seen rather more frequently, giving the impression that these older fetuses were capable of making a pain face.
Lead researcher Dr Nadja Reissland, of Durham University’s Department of Psychology, said: “It is vital for infants to be able to show pain as soon as they are born so that they can communicate any distress or pain they might feel to their carers and our results show that healthy fetuses ‘learn’ to combine the necessary facial movements before they are born.
“This suggests that we can determine the normal development of facial movements and potentially identify abnormal development too. This could then provide a further medical indication of the health of the unborn baby.
“It is not yet clear whether fetuses can actually feel pain, nor do we know whether facial expressions relate to how they feel. Our research indicates that the expression of fetal facial movements is a developmental process which seems to be related to brain maturation rather than being linked to feelings.”
Professor of Social Statistics at Lancaster University Brian Francis said: “Modern methods of data analysis enable the development of fetal pain faces to be clearly detected, with the complexity of facial movements making up a pain face increasing in the third trimester”.
Despite the advances in medical science, we still do not know very much about health indicators of fetal development or any warning signs of delayed or abnormal progress in the womb.
It is hoped that further research will test whether the development of facial expressions is delayed if fetuses experience unhealthy conditions in the womb, such as effects of smoking or alcohol, or where the fetus is undergoing invasive procedures.
From the neurons that enable thought to the keratinocytes that make toenails grow-a complex canopy of sugar molecules, commonly known as glycans, envelop every living cell in the human body.
These complex carbohydrate chains perform a host of vital functions, providing the necessary machinery for cells to communicate, replicate and survive. It stands to reason, then, that when something goes wrong with a person’s glycans, something goes wrong with them.
Now, researchers at the University of Georgia are learning how changes in normal glycan behavior are related to a rare but fatal lysosomal disease known as Niemann-Pick type C (NPC), a genetic disorder that prevents the body from metabolizing cholesterol properly. The findings were published recently in the PNAS Early Edition.
"We are learning that the problems associated with cholesterol trafficking in the cell lead to problems with glycans on the cell’s surface, and that causes a multitude of negative effects," said Geert-Jan Boons, professor of chemistry in the Franklin College of Arts and Sciences and researcher at UGA’s Complex Carbohydrate Research Center. "Now, for the first time, we can see what these problems are, which we hope will lead to a new understanding of diseases like NPC."
Because NPC patients are unable to metabolize cholesterol, the waxy substance begins to accumulate in the brain. This can lead to a host of serious problems, including neurodegeneration, which the researchers hypothesize may be caused by improper recycling of glycans on the surface of an NPC patient’s cells.
Glycans normally undergo a kind of recycling process when they enter the cell only to be returned to the surface recharged and ready to work. The researchers discovered that glycans in NPC cells do not do this.
"One of the secondary effects of NPC is the disruption of traffic pathways within the cell, and this can lead to altered recycling of glycans," said Richard Steet, associate professor of biochemistry and molecular biology and CCRC researcher. "The glycans come into the cell, but they won’t recycle back up to the cell’s surface where they must exist to function as receptors or ion channels."
"Basically, the machinery gets clogged up," Boons said.
Like downed phone lines and flooded roads in a thunderstorm, glycans get stuck inside the cell making communication and travel for these cells difficult or impossible. Without these basic abilities, the body’s motor, sensory and cognitive functions begin to suffer. This might explain why NPC patients suffer from such a wide variety of neurological and psychiatric disorders, such as uncoordinated limb movements, slurred speech, epilepsy, paralysis, psychosis, dementia and hallucinations.
The researchers made these observations in fibroblasts taken from diseased patients. These cells are most commonly found in connective tissues, and they play a vital role in wound healing. However, they hope to continue their investigation into the effects of NPC by studying glycan behavior in neural cells, which make up the human brain.
While they caution that much more work must be done, they hope that an improved understanding of the roles that glycans play in neural cells will lead to new therapeutics for NPC and other diseases like it.
"It is exciting to work on projects like these, because we believe glycobiology is the next frontier, the next level of complexity," Boons said. "The time is right for new discovery."