Posts tagged down syndrome
Articles and news from the latest research reports.
New insight on why people with Down syndrome invariably develop Alzheimer’s disease
A new study by researchers at Sanford-Burnham Medical Research Institute reveals the process that leads to changes in the brains of individuals with Down syndrome—the same changes that cause dementia in Alzheimer’s patients. The findings, published in Cell Reports, have important implications for the development of treatments that can prevent damage in neuronal connectivity and brain function in Down syndrome and other neurodevelopmental and neurodegenerative conditions, including Alzheimer’s disease.
Down syndrome is characterized by an extra copy of chromosome 21 and is the most common chromosome abnormality in humans. It occurs in about one per 700 babies in the United States, and is associated with a mild to moderate intellectual disability. Down syndrome is also associated with an increased risk of developing Alzheimer’s disease. By the age of 40, nearly 100 percent of all individuals with Down syndrome develop the changes in the brain associated with Alzheimer’s disease, and approximately 25 percent of people with Down syndrome show signs of Alzheimer’s-type dementia by the age of 35, and 75 percent by age 65. As the life expectancy for people with Down syndrome has increased dramatically in recent years—from 25 in 1983 to 60 today—research aimed to understand the cause of conditions that affect their quality of life are essential.
"Our goal is to understand how the extra copy of chromosome 21 and its genes cause individuals with Down syndrome to have a greatly increased risk of developing dementia," said Huaxi Hu, Ph.D., professor in the Degenerative Diseases Program at Sanford-Burnham and senior author of the paper. "Our new study reveals how a protein called sorting nexin 27 (SNX27) regulates the generation of beta-amyloid—the main component of the detrimental amyloid plaques found in the brains of people with Down syndrome and Alzheimer’s. The findings are important because they explain how beta-amyloid levels are managed in these individuals."
Beta-Amyloid, Plaques and Dementia
Xu’s team found that SNX27 regulates beta-amyloid generation. Beta-amyloid is a sticky protein that’s toxic to neurons. The combination of beta-amyloid and dead neurons form clumps in the brain called plaques. Brain plaques are a pathological hallmark of Alzheimer’s disease and are implicated in the cause of the symptoms of dementia.
"We found that SNX27 reduces beta-amyloid generation through interactions with gamma-secretase—an enzyme that cleaves the beta-amyloid precursor protein to produce beta-amyloid," said Xin Wang, Ph.D., a postdoctoral fellow in Xu’s lab and first author of the publication. "When SNX27 interacts with gamma-secretase, the enzyme becomes disabled and cannot produce beta-amyloid. Lower levels of SNX27 lead to increased levels of functional gamma-secretase that in turn lead to increased levels of beta-amyloid."
SNX27’s Role in Brain Function
Previously, Xu and colleagues found that SNX27 deficient mice shared some characteristics with Down syndrome, and that humans with Down syndrome have significantly lower levels of SNX27. In the brain, SNX27 maintains certain receptors on the cell surface—receptors that are necessary for neurons to fire properly. When levels of SNX27 are reduced, neuron activity is impaired, causing problems with learning and memory. Importantly, the research team found that by adding new copies of the SNX27 gene to the brains of Down syndrome mice, they could repair the memory deficit in the mice.
The researchers went on to reveal how lower levels of SNX27 in Down syndrome are the result of an extra copy of an RNA molecule encoded by chromosome 21 called miRNA-155. miRNA-155 is a small piece of genetic material that doesn’t code for protein, but instead influences the production of SNX27.
With the current study, researchers can piece the entire process together—the extra copy of chromosome 21 causes elevated levels of miRNA-155 that in turn lead to reduced levels of SNX27. Reduced levels of SNX27 lead to an increase in the amount of active gamma-secretase causing an increase in the production of beta-amyloid and the plaques observed in affected individuals.
"We have defined a rather complex mechanism that explains how SNX27 levels indirectly lead to beta-amyloid," said Xu. "While there may be many factors that contribute to Alzheimer’s characteristics in Down syndrome, our study supports an approach of inhibiting gamma-secretase as a means to prevent the amyloid plaques in the brain found in Down syndrome and Alzheimer’s."
"Our next step is to develop and implement a screening test to identify molecules that can reduce the levels of miRNA-155 and hence restore the level of SNX27, and find molecules that can enhance the interaction between SNX27 and gamma-secretase. We are working with the Conrad Prebys Center for Chemical Genomics at Sanford-Burnham to achieve this," added Xu.
Down syndrome helps researchers understand Alzheimer’s disease
The link between a protein typically associated with Alzheimer’s disease and its impact on memory and cognition may not be as clear as once thought, according to a new study from the University of Wisconsin-Madison’s Waisman Center. The findings are revealing more information about the earliest stages of the neurodegenerative disease.
The researchers — including lead study author Sigan Hartley, UW-Madison assistant professor of human development and family studies, and Brad Christian, UW-Madison associate professor of medical physics and psychiatry and director of PET Physics in the Waisman Laboratory for Brain Imaging and Behavior — looked at the role of the brain protein amyloid-β in adults living with Down syndrome, a genetic condition that leaves people more susceptible to developing Alzheimer’s. They published their findings in the September issue of the journal Brain.
"Our hope is to better understand the role of this protein in memory and cognitive function," says Hartley. "With this information we hope to better understand the earliest stages in the development of this disease and gain information to guide prevention and treatment efforts."
However, the findings of their study not only may help scientists better understand the condition as it impacts those living with Down syndrome, but they are also relevant to adults without the genetic syndrome.
"There are many unanswered questions about at what point amyloid-β, together with other brain changes, begins to take a toll on memory and cognition and why certain individuals may be more resistant than others," says Hartley.
The UW-Madison scientists, along with collaborators at the University of Pittsburgh, studied 63 healthy adults with Down syndrome, aged 30 to 53, who did not exhibit clinical signs of Alzheimer’s or other forms of dementia. They found that many adults with Down syndrome had high levels of amyloid-β protein but did not suffer the expected negative consequences of the elevated protein.
Alzheimer’s disease is the sixth leading cause of death in the U.S. People with Down syndrome are born with an extra copy of the 21st chromosome, where the gene that codes for the amyloid-β protein resides.
For the study, which was conducted over the course of two days, researchers used magnetic resonance imaging (MRI) and positron emission tomography (PET) scans to capture images of the participants’ brains. Twenty-two of the 63 participants had elevated levels of amyloid-β but showed no evidence of diminished memory or cognitive function when compared to those without elevated levels of the protein. The researchers controlled for differences in age and intellectual level.
Similarly, when assessed as a continuous measure, amyloid-β levels were not tied to differences in memory or cognitive ability, such as changes in visual and verbal memory, attention and language.
(Source: news.wisc.edu)
(Image caption: LB1 in three different views to illustrate facial asymmetry. A is the actual specimen, B is the Right side doubled at the midline and mirrored, and C is the left side doubled and mirrored. Differences in left and right side facial architectures are apparent, and illustrate growth abnormalities of LB1. Credit: A, E. Indriati, B and C, D.W. Frayer)
Flores bones show features of Down syndrome, not a new “hobbit” human
In October 2004, excavation of fragmentary skeletal remains from the island of Flores in Indonesia yielded what was called “the most important find in human evolution for 100 years.” Its discoverers dubbed the find Homo floresiensis, a name suggesting a previously unknown species of human.
Now detailed reanalysis by an international team of researchers including Robert B. Eckhardt, professor of developmental genetics and evolution at Penn State, Maciej Henneberg, professor of anatomy and pathology at the University of Adelaide, and Kenneth Hsü, a Chinese geologist and paleoclimatologist, suggests that the single specimen on which the new designation depends, known as LB1, does not represent a new species. Instead, it is the skeleton of a developmentally abnormal human and, according to the researchers, contains important features most consistent with a diagnosis of Down syndrome.
"The skeletal sample from Liang Bua cave contains fragmentary remains of several individuals," Eckhardt said. "LB1 has the only skull and thighbones in the entire sample."
No substantial new bone discoveries have been made in the cave since the finding of LB1.
Initial descriptions of Homo floresiensis focused on LB1’s unusual anatomical characteristics: a cranial volume reported as only 380 milliliters (23.2 cubic inches), suggesting a brain less than one third the size of an average modern human’s and short thighbones, which were used to reconstruct a creature standing 1.06 meters (about 3.5 feet tall). Although LB1 lived only 15,000 years ago, comparisons were made to earlier hominins, including Homo erectus and Australopithecus. Other traits were characterized as unique and therefore indicative of a new species.
A thorough reexamination of the available evidence in the context of clinical studies, the researchers said, suggests a different explanation.
The researchers report their findings in two papers published today (Aug. 4) in the Proceedings of the National Academy of Sciences (1, 2).
In the first place, they write, the original figures for cranial volume and stature are underestimates, “markedly lower than any later attempts to confirm them.” Eckhardt, Henneberg, and other researchers have consistently found a cranial volume of about 430 milliliters (26.2 cubic inches).
"The difference is significant, and the revised figure falls in the range predicted for a modern human with Down syndrome from the same geographic region," Eckhardt said.
The original estimate of 3.5 feet for the creature’s height was based on extrapolation combining the short thighbone with a formula derived from an African pygmy population. But humans with Down syndrome also have diagnostically short thighbones, Eckhardt said.
Though these and other features are unusual, he acknowledged, “unusual does not equal unique. The originally reported traits are not so rare as to have required the invention of a new hominin species.”
Instead, the researchers build the case for an alternative diagnosis: that of Down syndrome, one of the most commonly occurring developmental disorders in modern humans.
"When we first saw these bones, several of us immediately spotted a developmental disturbance," said Eckhardt, "but we did not assign a specific diagnosis because the bones were so fragmentary. Over the years, several lines of evidence have converged on Down syndrome."
The first indicator is craniofacial asymmetry, a left-right mismatch of the skull that is characteristic of this and other disorders. Eckhardt and colleagues noted this asymmetry in LB1 as early as 2006, but it had not been reported by the excavating team and was later dismissed as a result of the skull’s being long buried, he said.
A previously unpublished measurement of LB1’s occipital-frontal circumference — the circumference of the skull taken roughly above the tops of the ears — allowed the researchers to compare LB1 to clinical data routinely collected on patients with developmental disorders. Here too, the brain size they estimate is within the range expected for an Australomelanesian human with Down syndrome.
LB1’s short thighbones not only match the height reduction seen in Down syndrome, Eckhardt said, but when corrected statistically for normal growth, they would yield a stature of about 1.26 meters, or just over four feet, a figure matched by some humans now living on Flores and in surrounding regions.
These and other Down-like characteristics, the researchers state, are present only in LB1, and not in the other Liang Bua skeletal remains, further evidence of LB1’s abnormality.
"This work is not presented in the form of a fanciful story, but to test a hypothesis: Are the skeletons from Liang Bua cave sufficiently unusual to require invention of a new human species?" Eckhardt said.
"Our reanalysis shows that they are not. The less strained explanation is a developmental disorder. Here the signs point rather clearly to Down syndrome, which occurs in more than one per thousand human births around the world."
'Support cells' in brain play important role in Down syndrome
Researchers from UC Davis School of Medicine and Shriners Hospitals for Children – Northern California have identified a group of cells in the brain that they say plays an important role in the abnormal neuron development in Down syndrome. After developing a new model for studying the syndrome using patient-derived stem cells, the scientists also found that applying an inexpensive antibiotic to the cells appears to correct many abnormalities in the interaction between the cells and developing neurons.
The findings, which focused on support cells in the brain called astroglial cells, appear online today in Nature Communications.
“We have developed a human cellular model for studying brain development in Down syndrome that allows us to carry out detailed physiological studies and screen possible new therapies,” said Wenbin Deng, associate professor of biochemistry and molecular medicine and principal investigator of the study. “This model is more realistic than traditional animal models because it is derived from a patient’s own cells.”
Down syndrome is the most common chromosomal cause of mild to moderate intellectual disabilities in the United States, where it occurs in one in every 691 live births. It develops when a person has three copies of the 21st chromosome instead of the normal two. While mouse models have traditionally been used in studying the genetic disorder, Deng said the animal model is inadequate because the human brain is more complicated, and much of that complexity arises from astroglia cells, the star-shaped cells that play an important role in the physical structure of the brain as well as in the transmission of nerve impulses.
“Although neurons are regarded as our ‘thinking cells,’ the astroglia have an extremely important supportive role,” said Deng. “Astroglial function is increasingly recognized as a critical factor in neuronal dysfunction in the brain, and this is the first study to show its importance in Down syndrome.”
Creating a unique human cellular model
To investigate the role of astroglia in Down syndrome, the research team took skin cells from individuals with Down syndrome and transformed them into stem cells, which are known as induced pluripotent stem cells (iPSC). The cells possess the same genetic make-up as the donor and an ability to grow into different cell types. Deng and his colleagues next induced the stem cells to develop into separate pure populations of astroglial cells and neurons. This allowed them to systematically analyze factors expressed by the astroglia and then study their effects on neuron development.
They found that a certain protein, known as S100B, is markedly increased in astroglial cells from patients with Down syndrome compared with those from healthy controls. S100B released by astroglial cells promotes harmful astroglial activation (astrogliosis) and adversely affects neurons, causing them to die at increased rates or develop in multiple dysfunctional ways.
The investigators obtained further evidence of the critical role of astroglial cells in Down syndrome by implanting the skin-cell derived astroglial cells from Down syndrome patients into mice. Those mice then developed the neuropathological phenotypes of Down syndrome, while mice implanted with Down syndrome neurons did not.
Neuroprotective effects of antibiotics
The research team also screened candidate drugs using a ‘disease-in-a-dish’ model. When they administered minocycline — a tetracycline antibiotic with anti-inflammatory properties commonly used to treat bacterial infections, acne and arthritis — many of the abnormalities in the astroglial cells were corrected and there were more healthy interactions between the astroglia and neurons compared to the control cells without the defect.
“The advent of induced pluripotent stem cell technology has created exciting new approaches to model neurodevelopmental and neurodegenerative diseases for the study of pathogenesis and for drug screening,” said David Pleasure, professor of neurology and pediatrics and a co-author of the study. “Using this technology, the study is the first to discover the critical role of astroglial cells in Down syndrome as well as identify a promising pathway for exploring how a drug such as minocycline may offer an effective way to help treat it.”
Pleasure, who is research director at Shriner’s Hospital for Children Northern California and also directs the Institute for Pediatric Regenerative Medicine, noted that considerable research interest has arisen about the use of minocycline for diseases of the central nervous system because of the increasing evidence about its neuroprotective effects. Unlike many drugs, minocycline can cross from the bloodstream into the brain so that it can act on the astroglial cells. The drug has never been tested as a treatment for Down syndrome, and both Pleasure and Deng cautioned that its safety and efficacy will require clinical trials in people with Down syndrome.
Currently, Deng’s laboratory is conducting additional preclinical studies using the human-derived stem cells from Down syndrome patients and mouse models to determine whether cellular and behavioral abnormalities can be improved with minocycline therapy and other candidate drugs.
“The abnormalities we identified occur in the early stages of Down syndrome,” said Deng. “While much more research is needed, it is exciting to consider that pharmacological intervention in these cellular processes might help slow or even prevent disease progression.”
(Image: iStockphoto)
New research suggests connection between white matter and cognitive health
A multidisciplinary group of scientists from the Sanders-Brown Center on Aging at the University of Kentucky have identified an interesting connection between the health of the brain tissue that supports cognitive functioning and the presence of dementia in adults with Down syndrome.
Published in the Neurobiology of Aging, the study, which focused on detecting changes in the white matter connections of the brain, offers tantalizing potential for the identification of biomarkers connected to the development of dementia, including Alzheimer’s disease.
"We used magnetic resonance imaging to compare the health of the brain’s white matter and how strongly it connects different parts of the brain," explains Elizabeth Head, Ph.D., the study’s senior author. "The results indicate a compelling progression of deterioration in the integrity of white matter in the brains of our study participants commensurate with their cognitive health."
Research team member David Powell, PhD, compared the brain scans of three groups of volunteers: persons with Down syndrome but no dementia, persons with Down syndrome and dementia, and a healthy control group.
Using MRI technologies, brain scans of subjects with Down syndrome showed some compromise in the tissues of brain’s frontal lobe compared to those from the control group. When people with Down syndrome and dementia were compared to people with Down syndrome without dementia, those same white matter connections were even less healthy.
Perhaps the most intriguing aspect of the study was the correlation between the cognitive abilities of participants with Down Syndrome and the integrity of their white matter– those who had higher motor skill coordination and better learning and memory ability had healthier frontal white matter connections.
Persons with Down syndrome are at an extremely high risk for developing Alzheimer’s disease after the age of 40. The team hopes their work might eventually lead to the identification of biomarkers for the development of Alzheimer’s disease in people with Down syndrome and, potentially, extend that to the general population as well.
Head cautions that these results are to some extent exploratory due to the small cohort of 30 participants. But, she says, “If we are able to identify people who, based on biomarkers, have a higher risk of developing Alzheimer’s disease, we might be able to intervene at an earlier point to retard the progression of the disease.”
Faulty stem cell regulation may contribute to cognitive deficits associated with Down syndrome
The learning and physical disabilities that affect people with Down syndrome may be due at least in part to defective stem cell regulation throughout the body, according to researchers at the Stanford University School of Medicine. The defects in stem cell growth and self-renewal observed by the researchers can be alleviated by reducing the expression of just one gene on chromosome 21, they found.
The finding marks the first time Down syndrome has been linked to stem cells, and addresses some long-standing mysteries about the disorder. Although the gene, called Usp16, is unlikely to be the only contributor to the disease, the finding raises the possibility of an eventual therapy based on reducing its expression.
“There appear to be defects in the stem cells in all the tissues that we tested, including the brain,” said Michael Clarke, MD, Stanford’s Karel H. and Avice N. Beekhuis Professor in Cancer Biology. The researchers conducted their studies in both mouse and human cells. “We believe Usp16 overexpression is a major contributor to the neurological deficits seen in Down syndrome.”
Clarke is the senior author of the research, published Sept. 11 in Nature. Postdoctoral scholar Maddalena Adorno, PhD, is the lead author.
“Conceptually, this study suggests that drug-based strategies to slow the rate of stem cell use could have profound effects on cognitive function, aging and risk for Alzheimer’s disease in people with Down syndrome,” said co-author Craig Garner, PhD, who is the co-director of Stanford’s Center for Research and Treatment of Down Syndrome and a professor of psychiatry and behavioral sciences.
Down syndrome, which is caused by an extra copy of chromosome 21, affects about 400,000 people in the United States and 6 million worldwide. It causes both physical and cognitive problems. While many of the physical issues, such as vulnerability to heart problems, can now be treated, no treatments exist for poor cognitive function.
The new study’s findings suggest answers to many long-standing mysteries about the condition, including why people with Down syndrome appear to age faster and exhibit early Alzheimer’s disease.
“This study is the first to provide a possible explanation for these tendencies,” said Garner. The fact that people with Down syndrome have three copies of chromosome 21 and the Usp16 gene “accelerates the rate at which stem cells are used during early development, which likely exhausts stem cell pools and impairs tissue regeneration in adults with Down syndrome. As a result, their brains age faster and are susceptible to early onset neurodegenerative disorders.”
The researchers didn’t confine their studies to laboratory mice. They also investigated the effect of Usp16 overexpression in human cells. Adorno and colleagues in the laboratory of co-author Samuel Cheshier, MD, assistant professor of neurosurgery, found that the presence of excess Usp16 caused skin cells from unaffected people to grow more slowly. Furthermore, neural progenitor cells (those self-renewing cellular factories responsible for the development and maintenance of many of the cell types in the brain) were less able to form balls of cells called neurospheres — a laboratory test that reflects the number and robustness of nerve stem cells in a culture. Conversely, reducing Usp16 expression in skin and nerve-progenitor cells from people with Down syndrome allowed the cells, which usually proliferate slowly, to assume normal growth patterns.
“This gene is clearly regulating processes that are central to aging in mice and humans,” said Clarke, “and stem cells are severely compromised. Reducing Usp16 expression gives an unambiguous rescue at the stem cell level. The fact that it’s also involved in this human disorder highlights how critical stem cells are to our well-being.”
Adorno and Clarke didn’t set out to study Down syndrome. Clarke’s past research has focused on how normal stem cells and cancer stem cells regenerate themselves, and Adorno was searching for genes that could inhibit a specific molecular pathway involved in the self-renewal of these cells. Understanding how normal stem cells regenerate themselves could help to repair tissue and organ damage from disease, and understanding how cancer stem cells maintain themselves could help explain why they are unusually resistant to chemotherapy or radiation therapy — often resulting in a patient’s relapse after seemingly successful treatment. Usp16 seemed to fit the bill; it plays a critical role in a self-renewal pathway previously identified by Clarke and his colleagues.
But Adorno and Clarke soon realized that Usp16 had another interesting property: in humans, it is found on chromosome 21.
They turned to Garner and Cheshier to help them evaluate a possible link to Down syndrome. Garner supplied two strains of mice commonly used to study the condition. One, Ts65Dn, has three copies of 132 genes found on human chromosome 21 — including Usp16. The second, Ts1Cje, has three copies of 79 genes from the chromosome, but only two copies of Usp16. Although both mice display some symptoms of the disorder, Ts65Dn more closely mimics the craniofacial structure and learning and memory disabilities seen in affected humans.
Colleagues in the Cheshier laboratory found that neural stem cells from the more-severely affected Ts65Dn mice were less able to self-renew and grow normally than were cells from the Ts1Cje mice. Reducing the expression of Usp16 in the cells from the Ts65Dn mice to more normal levels largely corrected these functional defects.
“We demonstrated that central nervous system stem cells in Down syndrome mice were defective in their ability to self-renew — the process by which stem cells regenerate themselves upon cell division. Blocking Usp16 expression in these cells restored this ability,” said Cheshier. “We hope in the future that correcting this Usp16 defect can lead to therapeutics that will ameliorate the central nervous system defects seen in patients with Down syndrome.”
Finally, the researchers created a new, Ts65Dn-derived mouse strain in which one of the three copies of Usp16 was mutated. This normalized the level of expression of that gene, without affecting the overexpression of the other 131 triplicated genes in these mice. Nerve progenitor cells from these mice were equally able as normal cells to form neurospheres. The researchers are now continuing their studies of these mice.
“We are really interested in learning how other genes in this chromosomal region may be affecting stem cell renewal,” said Clarke. “We also want to understand how much we’re able to rescue the neurological defect by normalizing the expression of Usp16 in this mouse model. How does this compare to what is happening in humans? We’re sure it plays some significant role.”
(Source: med.stanford.edu)
Experimental Compound Reverses Down Syndrome-Like Learning Deficits In Mice
Researchers at Johns Hopkins and the National Institutes of Health have identified a compound that dramatically bolsters learning and memory when given to mice with a Down syndrome-like condition on the day of birth. As they report in the Sept. 4 issue of Science Translational Medicine, the single-dose treatment appears to enable the cerebellum of the rodents’ brains to grow to a normal size.
The scientists caution that use of the compound, a small molecule known as a sonic hedgehog pathway agonist, has not been proven safe to try in people with Down syndrome, but say their experiments hold promise for developing drugs like it.
“Most people with Down syndrome have a cerebellum that’s about 60 percent of the normal size,” says Roger Reeves, Ph.D., a professor in the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins University School of Medicine. “We treated the Down syndrome-like mice with a compound we thought might normalize the cerebellum’s growth, and it worked beautifully. What we didn’t expect were the effects on learning and memory, which are generally controlled by the hippocampus, not the cerebellum.”
Reeves has devoted his career to studying Down syndrome, a condition that occurs when people have three, rather than the usual two, copies of chromosome 21. As a result of this “trisomy,” people with Down syndrome have extra copies of the more than 300 genes housed on that chromosome, which leads to intellectual disabilities, distinctive facial features and sometimes heart problems and other health effects. Since the condition involves so many genes, developing treatments for it is a formidable challenge, Reeves says.
For the current experiments, Reeves and his colleagues used mice that were genetically engineered to have extra copies of about half of the genes found on human chromosome 21.
The mice have many characteristics similar to those of people with Down syndrome, including relatively small cerebellums and difficulty learning and remembering how to navigate through a familiar space. (In the case of the mice, this was tested by tracking how readily the animals located a platform while swimming in a so-called water maze.)
Based on previous experiments on how Down syndrome affects brain development, the researchers tried supercharging a biochemical chain of events known as the sonic hedgehog pathway that triggers growth and development. They used a compound — a sonic hedgehog pathway agonist — that could do just that.
The compound was injected into the Down syndrome-like mice just once, on the day of birth, while their cerebellums were still developing. “We were able to completely normalize growth of the cerebellum through adulthood with that single injection,” Reeves says.
But the research team went beyond measuring the cerebellums, looking for changes in behavior, too. “Making the animals, synthesizing the compound and guessing the right dose were so difficult and time-consuming that we wanted to get as much data out of the experiment as we could,” Reeves says. The team tested the treated mice against untreated Down syndrome-like mice and normal mice in a variety of ways, and found that the treated mice did just as well as the normal ones on the water maze test.
Reeves says further research is needed to learn why exactly the treatment works, because their examination of certain cells in the hippocampus known to be involved in learning and affected by Down syndrome appeared unchanged by the sonic hedgehog agonist treatment. One idea is that the treatment improved learning by strengthening communication between the cerebellum and the hippocampus, he says.
As for the compound’s potential to become a human drug, the problem, Reeves says, is that altering an important biological chain of events like sonic hedgehog would likely have many unintended effects throughout the body, such as raising the risk of cancer by triggering inappropriate growth. But now that the team has seen the potential of this strategy, they will look for more targeted ways to safely harness the power of sonic hedgehog in the cerebellum. Even if his team succeeds in developing a clinically useful drug, however, Reeves cautions that it wouldn’t constitute a “cure” for the learning and memory-related effects of Down syndrome. “Down syndrome is very complex, and nobody thinks there’s going to be a silver bullet that normalizes cognition,” he says. “Multiple approaches will be needed.”
(Source: newswise.com)
Technique inactivates Down-causing chromosome
Borrowing a trick from nature, researchers have switched off the extra chromosome that causes Down syndrome in cells taken from patients with the condition.
Though not a cure, the technique, reported July 17 in Nature, has already produced insights into the disorder. In the long run it might even make the flaw that causes Down syndrome correctable through gene therapy.
“Gene therapy is now on the horizon,” says Elizabeth Fisher, a molecular geneticist at University College London. “But that horizon is very far away.”
Down syndrome, also called trisomy 21, occurs when people inherit three copies of chromosome 21 instead of the usual two. It is the most common chromosomal condition, affecting around one in every 700 babies born in the United States. People with the disorder typically have both physical and cognitive complications of having an extra chromosome.
“Down syndrome has been one of those disorders where people say, ‘Oh, there’s nothing you can do about it,’ ” says Jeanne Lawrence, a chromosome biologist and genetic counselor at the University of Massachusetts Medical School in Worcester, who led the study with colleagues Lisa Hall and Jun Jiang.
The researchers decided to see whether they could shut down the extra chromosome by drawing on a biological process called X inactivation. Women have two X chromosomes and men have only one X and a Y. To halve the amount of X chromosome products, female cells shut down one copy. Cells do that using a chunk of RNA called XIST, which is made by one X chromosome but not the other. The RNA works by pulling in proteins that essentially board up the chromosome like an abandoned building. The other X stays on by making a different RNA.
Lawrence and Hall thought that if they put XIST on another chromosome, it might shut that one down too. So Jiang put the gene for XIST onto one of the three copies of chromosome 21 carried by stem cells grown from a man with Down syndrome. That copy of the chromosome got switched off.
“It’s kind of surprising that it wasn’t done before. I’m smacking my own forehead and saying, ‘duh,’ ” says Roger Reeves, a geneticist at Johns Hopkins University.
One idea about why an extra chromosome 21 causes cognitive problems is that it may slow down the growth of brain cells. Jiang grew nerve cells from the Down patient’s stem cells to see how cells with one shut-down chromosome developed compared with cells bearing three active copies. The cells with only two working chromosomes grew faster, forming clusters of neurons in a day or two, while the uncorrected cells needed four or five days.
The work is an enormous step forward in Down syndrome research, Fisher says, and “may take us much closer to understanding the molecular basis of the disorder.” The technique could allow researchers to figure out which genes are involved in Down syndrome and how extra copies affect cells and ultimately the body, she says.
Reeves wants to use the technology in animal experiments, a critical step in determining whether it could find use as gene therapy for people with Down syndrome. He plans to work with Lawrence’s group to switch off the extra chromosome in mice engineered to have a disorder that simulates some features of Down syndrome.
But Reeves doubts that scientists could use the method to switch off the extra chromosome in every cell in the body. Doing so would probably require gene therapy at a very early stage of pregnancy, something scientists don’t know how to do. “I just don’t see how we would get there from where we are today,” Reeves says.
Such universal silencing of the extra chromosome may be necessary to forestall developmental problems. But other problems associated with Down syndrome might be prevented or reversed by shutting down the extra chromosome after birth. For instance, people with Down syndrome are at high risk of developing childhood leukemia and of getting Alzheimer’s disease. Gene therapy to turn off the extra chromosome in the bone marrow or the brain might prevent those problems.
Therapeutic possibilities are still far in the future and may never pan out, says William Mobley, a neurologist and neuroscientist at the University of California, San Diego. “We have to move cautiously and deliberately and not say that a cure for Down syndrome is on the horizon,” he says. “It’s not true, but gosh is there excitement that progress is being made.”
(Source: sciencenews.org)
Cry analyzer seeks clues to babies’ health
Researchers at Brown University and Women & Infants Hospital have developed a new tool that analyzes the cries of babies, searching for clues to potential health or developmental problems. Slight variations in cries, mostly imperceptible to the human ear, can be a “window into the brain” that could allow for early intervention.
To parents, a baby’s cry is a signal of hunger, pain, or discomfort. But to scientists, subtle acoustic features of a cry, many of them imperceptible to the human ear, can hold important information about a baby’s health.
A team of researchers from Brown University and Women & Infants Hospital of Rhode Island has developed a new computer-based tool to perform finely tuned acoustic analyses of babies’ cries. The team hopes their baby cry analyzer will lead to new ways for researchers and clinicians to use cry in identifying children with neurological problems or developmental disorders.
“There are lots of conditions that might manifest in differences in cry acoustics,” said Stephen Sheinkopf, assistant professor of psychiatry and human behavior at Brown, who helped develop the new tool. “For instance, babies with birth trauma or brain injury as a result of complications in pregnancy or birth or babies who are extremely premature can have ongoing medical effects. Cry analysis can be a noninvasive way to get a measurement of these disruptions in the neurobiological and neurobehavioral systems in very young babies.”
The new analyzer is the result of a two-year collaboration between faculty in Brown’s School of Engineering and hospital-based faculty at Women & Infants Hospital. A paper describing the tool is in press in the Journal of Speech, Language and Hearing Research.
The system operates in two phases. During the first phase, the analyzer separates recorded cries into 12.5-millisecond frames. Each frame is analyzed for several parameters, including frequency characteristics, voicing, and acoustic volume. The second phase uses data from the first to give a broader view of the cry and reduces the number of parameters to those that are most useful. The frames are put back together and characterized either as an utterance — a single “wah” — or silence, the pause between utterances. Longer utterances are separated from shorter ones and the time between utterances is recorded. Pitch, including the contour of pitch over time, and other variables can then be averaged across each utterance.
In the end, the system evaluates for 80 different parameters, each of which could hold clues about a baby’s health.
“It’s a comprehensive tool for getting as much important stuff out of a baby cry that we can,” said Harvey Silverman, professor of engineering and director of Brown’s Laboratory for Engineering Man/Machine Systems.
To understand what important stuff to look for, Silverman and his graduate students Brian Reggiannini and Xiaoxue Li worked closely with Sheinkopf and Barry Lester, director of Brown’s Center for the Study of Children at Risk.
“We looked at them as the experts about the kinds of signals we might want to get,” Silverman said, “and we engineers were the experts on what we might actually be able to implement and methods to do so. So working together worked quite well.”
Lester, who has studied baby cries for years, says this vein of research goes back to the 1960s and a disorder called Cri du chat syndrome.
Cri du chat (cry of the cat) is caused by a genetic anomaly similar to Down syndrome. Babies who have it have a distinct, high-pitched cry. While the Cri du chat is unmistakable even without sensitive machinery, Lester and others wondered whether subtler differences in cry could also be indicators of a child’s health.
“The idea is that cry can be a window into the brain,” Lester said.
If neurological deficits change the way babies are able to control their vocal chords, those tiny differences might manifest themselves in differences in pitch and other acoustic features. Lester has published several papers showing that differences in cry are linked to medical problems stemming from malnutrition, prenatal drug exposure, and other risks.
“Cry is an early warning sign that can be used in the context of looking at the whole baby,” Lester said.
The tools used in those early studies, however, are primitive by today’s standards, Lester said. In early work, recorded cries were converted to spectrograms, visual readouts of pitch changes over time. Research technicians then read and coded each spectrogram by hand. Later systems automated the process somewhat, but the research was still slow and cumbersome.
This new automated analyzer enables researchers to evaluate cries much more quickly and in much greater detail. The Brown team plans to make it available to researchers around the world in the hopes of developing new avenues of cry research.
Sheinkopf, who specializes in developmental disorders, plans to use the tool to look for cry features that might correlate with autism.
“We’ve known for a long time that older individuals with autism produce sounds or vocalizations that are unusual or atypical,” Sheinkopf said. “So vocalizations in babies have been discussed as being useful in developing early identification tools for autism. That’s been a major challenge. How do you find signs of autism in infancy?”
The answer could be encoded in a cry.
“Early detection of developmental disorders is critical,” Lester added. “It can lead to insights into the causes of these disorders and interventions to prevent or reduce the severity of impairment.”
Drug improves cognitive function in mouse model of Down syndrome
An existing FDA-approved drug improves cognitive function in a mouse model of Down syndrome, according to a new study by researchers at the Stanford University School of Medicine.
The drug, an asthma medication called formoterol, strengthened nerve connections in the hippocampus, a brain center used for spatial navigation, paying attention and forming new memories, the study said. It also improved contextual learning, in which the brain integrates spatial and sensory information.
Both hippocampal function and contextual learning, which are impaired in Down syndrome, depend on the brain having a good supply of the neurotransmitter norepinephrine. This neurotransmitter sends its signal via several types of receptors on the neurons, including a group called beta-2 adrenergic receptors.
“This study provides the initial proof-of-concept that targeting beta-2 adrenergic receptors for treatment of cognitive dysfunction in Down syndrome could be an effective strategy,” said Ahmad Salehi, MD, PhD, the study’s senior author and a clinical associate professor of psychiatry and behavioral sciences. The study was published online July 2 in Biological Psychiatry.
Down syndrome, which is caused by an extra copy of chromosome 21, results in both physical and cognitive problems. While many of the physical issues, such as vulnerability to heart problems, can now be treated, no treatments exist for poor cognitive function. As a result, children with Down syndrome fall behind their peers’ cognitive development. In addition, adults with Down syndrome develop Alzheimer’s-type pathology in their brains by age 40. Down syndrome affects about 400,000 people in the United States and 6 million worldwide.
In prior Down syndrome research, scientists have seen deterioration of the brain center that manufactures norepinephrine in both people with Down syndrome and its mouse model. Earlier work by Salehi’s team found that giving a norepinephrine precursor could improve cognitive function in a mouse model genetically engineered to mimic Down syndrome.
(Source: med.stanford.edu)