Drug may increase cognition for people with Down syndrome

ScienceDaily (Aug. 1, 2011) — A University of Colorado School of Medicine scientist is completing a major clinical trial on a drug that could boost cognitive function in those with Down syndrome, significantly improving their quality of life and representing a potential milestone in research on this genetic condition.

"We are hoping to enhance memory and learning in those with Down syndrome," said Alberto Costa, MD, PhD, an associate professor of medicine and the neuroscientist leading the effort. "We have been studying this drug for three years and are now ready to analyze the data on our trial. Our team at the University of Colorado and Children's Hospital Colorado expects to have the results in the next two or three months."

Costa, whose work was recently chronicled in New York Times Magazine, is testing the drug memantine, currently used to relieve symptoms of Alzheimer's disease, in 39 people with Down syndrome. About half received the drug and the others a placebo. In 2007, Costa demonstrated that memantine could improve memory function in mice with Down syndrome.

And now, for the first time, he is taking a drug effective in the treatment of learning and memory deficits in mice with Down syndrome and applying it to humans, a move described by the New York Times as "a milestone in the history of Down syndrome research."

Costa is no disinterested researcher. His 16-year-old daughter Tyche -- named for the Greek goddess of Fortune -- has Down syndrome. Like others with the condition, she faces the specter of a steady decline in mental functioning as she gets older and a roughly 20 percent chance of getting Alzheimer's in her 50's. After that diagnosis, death is often just five years away.

"I feel I am racing the clock to find something that will at least keep her functioning at the level she is at now," Costa said. "As they age, parts of their brain will shrink and their functions will diminish."

Costa is actively pursuing links between Down and Alzheimer's disease. He says babies born with Down often carry the biological markers for Alzheimer's.

"They have the disease from the get go," he said.

Costa says the world is awash in false assumptions about Down syndrome ranging from distortions on life expectancy to educational limitations. In fact, depending on the severity of their condition, those with Down can live into their 70s, attend college, live independently and hold down jobs.

"If we are successful, it will increase hope and expectations for those with Down syndrome," Costa said. "Right now there are drugs for the signs and symptoms of medical conditions more frequent in those with Down syndrome, but nothing to improve brain function. In fact, the prevailing wisdom has been that there is essentially nothing you can do to boost memory and learning in this group. Hopefully, we can prove them wrong."

But he and other Down researchers face an overall lack of federal funding, especially when compared to other diseases and disorders.

Costa has been supported by Forest Pharmaceuticals which is funding the clinical trial, the Linda Crnic Institute for Down Syndrome, the Coleman Institute for Cognitive Disabilities and the National Institute of Child Health and Development, part of the National Institutes of Health.

"Clearly these funding sources are the unsung heroes," Costa said. "They may not get the attention or publicity but I can assure you that our efforts and the future of those with Down syndrome would be seriously compromised without their continued generosity."

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Colorado Denver, via EurekAlert!, a service of AAAS.

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Brain connectivity disrupted in patients with post-concussive syndrome

ScienceDaily (July 26, 2011) — A new study has found that patients with mild traumatic brain injury (MTBI) exhibit abnormal functional connectivity in the thalamus, a centrally located relay station for transmitting information throughout the brain. The results of the study appear online in the journal Radiology.

"Using resting-state functional MRI, we found increased functional connectivity of thalamocortical networks in patients following MTBI, due to the subtle injury of the thalamus," said study co-author Yulin Ge, M.D., associate professor in the Department of Radiology at NYU Langone Medical Center. "These findings hold promise for better elucidating the underlying cause of a variety of post-traumatic symptoms that are difficult to spot and characterize using conventional imaging methods."

According to the Centers for Disease Control and Prevention, each year in the U.S. 1.5 million people sustain traumatic brain injuries, resulting from sudden trauma to the brain. MTBI, or concussion, accounts for at least 75 percent of all traumatic brain injuries. Following a concussion, some patients experience a brief loss of consciousness. Other symptoms include headache, dizziness, memory loss, attention deficit, depression and anxiety. Some of these conditions may persist for months or even years. Typically in patients with MTBI, there are no structural abnormalities visible on the brain, so researchers have begun using specialized imaging exams to detect abnormalities in how the brain functions.

Comparing levels of activity among different groups of brain cells helps identify which brain networks are communicating with one another. Some brain networks, known as resting state networks (RSNs) and baseline brain activities can be detected when the brain is at rest. These networks include the parts of the brain associated with working memory.

"The RSNs have great potential for studying thalamic dysfunction in several clinical disorders including traumatic brain injury," Dr. Ge said.

Resting-state functional MRI (RS-fMRI) has rapidly emerged as a novel informative tool for investigating brain connectivity between regions that are functionally linked. RS-fMRI provides insight into functional activity and communication between brain regions, which play key roles in cognitive performance.

"The disruption of such functional properties is better characterized by RS-fMRI than by conventional diagnostic tools," Dr. Ge said.

Dr. Ge and colleagues used RS-fMRI to study the brain activity of 24 patients with MTBI and 17 healthy control patients. A normal pattern of thalamic RSNs with relatively symmetric and restrictive connectivity was demonstrated in the healthy control group. In the patients with MTBI, this pattern was disrupted, with significantly increased thalamic RSNs and decreased symmetry. These findings correlated with clinical symptoms and diminished neurocognitive functions in the patients with MTBI.

"The thalamic functional networks have multiple functions, including sensory information process and relay, consciousness, cognition, and sleep and wakefulness regulation," Dr. Ge said. "The disruption of thalamic RSNs may result in a burning or aching sensation, accompanied by mood swings and sleep disorders, and can contribute to certain psychotic, affective, obsessive-compulsive, anxiety and impulse control disorders. These symptoms are commonly seen in MTBI patients with post-concussive syndrome."

Because the causes of post-concussive syndrome are poorly understood, there is currently no treatment. But, according to Dr. Ge, the results of this study have implications for a new therapeutic strategy, based on sound understanding of the underlying mechanisms of thalamocortical disruption and post-concussive syndrome.

"Thalamic Resting-State Functional Networks: Disruption in Patients with Mild Traumatic Brain Injury." Collaborating with Dr. Ge on this paper were Lin Tang, Ph.D., Daniel K. Sodickson, M.D., Ph.D., Laura Miles, Ph.D., Yongxia Zhou, Ph.D., Joseph Reaume, B.S.R.T., and Robert I. Grossman, M.D.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Radiological Society of North America, via EurekAlert!, a service of AAAS.

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Researchers target, switch off serotonin-producing neurons in mice; New insights may be relevant to sudden infant death syndrome

ScienceDaily (July 28, 2011) — Researchers have developed a toolkit that enables them to turn off targeted cell populations while leaving others unaffected.

Led by Susan Dymecki, a professor of genetics at Harvard Medical School, the group focused on serotonin-producing neurons, observing how mice behave in a normal environment when suddenly their serotonin neurons are turned down. While their findings affirm earlier studies, the researchers used a technique that is non-invasive and does not require anesthesia, surgeries, or knocking out a gene -- each of which can cause problems when interpreting results.

"By selectively and abruptly switching off the serotonin-producing cells, we can get a definite idea of what bodily functions the serotonin cells specifically control," said Dymecki. "These findings and the new tools in neuroscience that it brings to the table will help us understand the role of serotonergic neurons in many human disorders."

One such disorder particularly relevant to these findings is Sudden Infant Death Syndrome, or SIDS.

These findings will appear in the July 29 edition of the journal Science.

The mammalian brain contains multiple chemical messengers, called neurotransmitters, which transfer information between nerve cells in order to regulate basic behaviors and functions like walking, eating, and sleeping. Serotonin is a major brain neurotransmitter produced solely by cells in the lower brain, or brainstem. Cells that make serotonin can convey information to large numbers of neurons distributed throughout the brain and can affect behavior as complex as mood.

In order to better understand how these serotonin-producing cells in the brain relate to basic physiology, Russell Ray and Rachael Brust, a postdoctoral researcher and a graduate student in Dymecki's lab, along with Jun Chul Kim, a prior postdoctoral fellow in Dymecki's lab who is now at the University of Toronto, and Andrea Corcoran, a postdoctoral researcher in the lab of Eugene Nattie at Dartmouth Medical School along with George Richerson, a professor of neurology at the University of Iowa, developed and characterized a method for selectively silencing neurons that produce serotonin.

The group began with a molecule genetically engineered by Bryan Roth and his colleagues at the University of North Carolina School of Medicine. Using a method that Dymecki's group had developed and optimized over the years called "intersectional genetics," they incorporated this molecule, a receptor, into the serotonin-producing brain cells in mice. As a result, the mice naturally generated this "unnatural" receptor on the surface of their serotoninergic neurons.

Receptors are key players in cellular communications, the initial recipients of chemical signals sent by other cells. Here, the researchers injected the mice with clozapine-N-oxide, a chemical compound designed to bind to and trigger the engineered receptor. Within minutes, the chemical and the foreign receptor acted together as a kind of dimmer switch, dampening the action of serotonin networks in the brains of these mice.

"This gave us the ability to selectively shut down serotonergic neuron function in the mouse brain," said Ray. "The mice remained awake, thus we could study their behavior in a normal environment."

When serotonergic neuron activity was diminished, the mice lost their capacity to maintain body temperature, and their temperatures plummeted to that of their surrounding environment.

Also, the ability of the mice to physiologically respond to elevations in carbon dioxide levels -- typically in the form of heavy, rapid breathing to rid the body of excessive carbon dioxide buildup before it might reach dangerous levels -- was roughly half that of normal mice when serotonergic neuron activity was low.

"What is particularly powerful to note is that we were able to study the mice both before and after we switched off the serotonergic neurons," said Ray. "We were able to demonstrate that prior to activating this foreign receptor switch -- that is prior to silencing the serotonin neurons -- the mice responded normally to temperature and carbon dioxide challenges."

The researchers believe this work may help us better understand the mechanisms underlying SIDS in humans.

Recent findings from the lab of Hannah Kinney at Children's Hospital Boston suggest that SIDS babies may have a deficiency of serotonin in circuits in the brainstem. Such deficiencies may lead directly to abnormal responses to elevated levels of carbon dioxide, such as when a baby rebreathes exhaled stale gases with high carbon dioxide levels while lying facedown.

"These infants may be vulnerable to sudden death due to impaired serotonin function in brainstem circuits important for protective responses to life threatening challenges, such as increased levels of carbon dioxide," said Dymecki. "What's more, a SIDS-vulnerable infant may be less equipped to maintain a normal body temperature."

Dymecki, along with her lab members and her colleagues at Dartmouth and University of Iowa, are now investigating how serotonergic neurons influence vital functions in young mice that are in the comparable age range to human infants at peak risk for SIDS. They also plan to use this genetic platform to selectively turn off subsets of serotonergic neurons, to better understand their specific functioning in health, and in other serotonin-linked disorders.

This research was funded by the National Institutes of Health.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Harvard Medical School. The original article was written by David Cameron.

Journal Reference:

R. S. Ray, A. E. Corcoran, R. D. Brust, J. C. Kim, G. B. Richerson, E. Nattie, S. M. Dymecki. Impaired Respiratory and Body Temperature Control Upon Acute Serotonergic Neuron Inhibition. Science, 2011; 333 (6042): 637 DOI: 10.1126/science.1205295

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Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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