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Click the links below to get answers to some of our research-focused Frequently Asked Questions:
Isn't Down syndrome too complex to treat?
For many years, scientists believed that Down syndrome was too complex to understand, and they believed that there was no way to reverse or reduce the cognitive impairment. However, scientific advances have made it possible to understand how specific genes are linked to specific abnormalities in the structure and function of the brain. Although the 21st chromosome has hundreds of genes, researchers believe that there may be only a handful that significantly effect cognition. Using advanced techniques and methods, researchers believe they will be able to isolate the effects of these specific genes and determine how their expression in the brain can cause problems with cognition. Once researchers define the mechanisms responsible for cognitive dysfunction, they can begin the process of discovering treatments that enhance brain function, including cognition. Specifically, researchers believe that if they can find a drug that can "turn down" the over-expression of certain genes in the brain, they will be able to restore or significantly improve cognitive functioning in persons with Down syndrome. Today we can boldly predict that Down syndrome is not too complex to understand and it is not too difficult to treat.
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Is a treatment a cure?
No. Once a baby is born with Down syndrome, he or she will always have an extra chromosome. However, research may be able to reverse or ameliorate the affects of the extra chromosome, particularly with regard to the degree of mental retardation. No one can say for sure how much cognition could be improved. However, even a modest improvement of 10 IQ points could have enormous impact on the life of a person with Down syndrome. Because the majority of individuals with Down syndrome fall into the mild to moderate range of cognitive impairment, an extra 10 IQ points would enable most persons with Down syndrome to function much more independently in school and the workplace.
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What is DSRTF's Research Focus?
DSRTF believes that the most promising and cutting-edge Down syndrome research today involves understanding the underlying genetic, biological and neurological processes in Down syndrome and how they relate to one another to cause cognitive dysfunction. The area of the brain of most interest to researchers is the hippocampus, which is essential for learning and memory. Of particular interest in this region of the brain are the areas between brain cells, where information is transferred between neurons. These areas are called synapses, and evidence suggests that the structure and function of synapses in a Down syndrome brain are abnormal, causing cognitive deficits. Defining these brain abnormalities, documenting the time of their occurrence, and developing methods to evaluate them are an important focus of current Down syndrome research.
The underlying genetic and biological causes of the brain abnormalities are another focus of current research. Researchers hypothesize that the activity of one or more genes on chromosome 21 causes the structure and function of the hippocampus to be abnormal. They have begun to identify the genes responsible for certain critical brain abnormalities and to study how an over-expression in the brain can affect cognition. The next step is to identify pharmaceutical agents that can turn down or turn off the expression of these genes in critical areas of the brain with the hope of restoring the brain to normal function.
DSRTF also recognizes, that in order for successful clinical trials of potential treatments to take place, there needs to be a generally accepted cognitive benchmark. DSRTF has encouraged and supports the current discussions with experts in human cognitive function about what tests might best be used to characterize cognition in people with DS, with a view toward preparing for pilot studies.
DSRTF also supports certain epidemiological research at the National Center on Birth Defects and Developmental Disabilities at the Centers for Disease Control that are critical to advancing Down syndrome research in general. DSRTF has worked with Congress to fund studies to estimate the number of people in the United States with Down syndrome by age and ethnic group and to document the onset and course of secondary and related developmental and mental disorders in people with Down syndrome.
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What are recent findings in Down syndrome cognition research?
Background:
All brain functions are accomplished through the operation of circuits. Each circuit is composed of neurons that are arranged in series. For example, a three neuron circuit would have neuron #1 connected to neuron #2 and neuron #2 in turn connected to neuron #3. Each neuron receives information on its dendrite and conveys information to the next neuron through an electrical signal that is sent down its axon. The electrical signal causes the release of a small molecule called a neurotransmitter. This occurs at the synapse, which is the point of contact between neurons. The synapse consists of two elements, a presynaptic element which represents the axon of the neuron immediately upstream in the circuit. The second element that is the dendrite of the neuron immediately downstream. The point at which the dendrite receives synaptic contacts is often on a specialization called a dendritic spine. The release of the neurotransmitter from the presynaptic element allows it to diffuse to a specific receptor on the postsynaptic element. This causes electrical stimulation and allows for the signal to be passed along. Some synapses are excitatory and others are inhibitory.
The operation of circuits is especially vulnerable at synapses. Disruption of synaptic contacts disables circuits and causes problems in learning and memory. Indeed, disruption of synapses in any circuit will cause failure of that circuit. Studies published some time ago showed that synapses are abnormal in people with Down syndrome.
Recent Research Findings:
Scientists have been studying a mouse model of Down syndrome called the Ts65Dn mouse. This mouse has an extra copy of the mouse chromosome that corresponds to human chromosome 21. Just as people with Down syndrome are trisomic for chromosome 21, so the mice are trisomic for the corresponding mouse chromosome.
Their studies on Ts65Dn mice indicated that both the presynaptic elements and the postsynaptic elements are enlarged in many brain regions. Motor cortex, sensory cortex, and hippocampus are all affected. In many cases enlarged axonal terminals are in contact with enlarged dendritic spines. The changes are present early in development and persist throughout the life of the mouse. By using the electron microscope, these findings have been confirmed and show that the actual point of synaptic contact is enlarged.
Researchers began trying to understand why this change occurs and what it means for brain function. Their findings suggested there is an overall decrease in the activity of synapses.
Another structural change involving synapses is a decrease in the density of synaptic contacts in a certain part of the hippocampus. This change recapitulates a similar finding in the brains of people with Down syndrome. Taken together with the increase in the size of synapses, these findings provide compelling evidence that studies in mouse models can teach us about the operation of brain circuits in Down syndrome.
The most important question, of course, is what changes in synaptic structure mean for the function of brain circuits. It is known that the hippocampus of a Down syndrome mouse model of Down syndrome learns less well than a normal mouse. Certain electrophysiological studies can be done to understand the ability of hippocampal circuits to learn. In essence, one stimulates these circuits and asks if they become more efficient. An increase in efficiency, sometimes referred to as synaptic plasticity, is evidence that circuits can learn. These changes are believed to reflect at a physiological level what goes on during learning in living subjects. Stanford researchers found that synaptic plasticity was markedly suppressed in the hippocampus of the Ts65Dn mouse. To understand the mechanism, they asked whether there were alterations in the baseline properties of the circuits. They found no such changes. However, they did discover decreased current flow through a certain kind of receptor and, through a series of studies, discovered that this was because of increased inhibition.
In the mouse model of Down syndrome, it appears that inhibitory synapses are too strong. If blocked experimentally, researchers saw restoration of the ability of hippocampal neurons to learn. In essence, researchers now believe that increased inhibition is responsible for the failure of synaptic plasticity to increase. More importantly, they believe that increased inhibition may well be responsible for difficulties in learning and memory not just in the mice, but also in people with Down syndrome.
The mechanism for increased inhibition and how to regulate it is a current topic of research. To date, scientists have discovered that it may be due, at least in part, to increased release of the inhibitory neurotransmitter GABA from presynaptic terminals. However, they have not ruled out other abnormalities and are actively pursuing this question. Interestingly, in morphological studies, it appears that there has been a redistribution of inhibitory synapses so that they now are in a position to more effectively inhibit excitatory neurotransmission. In time, scientists hope to understand exactly how these changes occur and what their significance is for understanding and treating abnormal cognition in people with Down syndrome.
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What are our research objectives for the near term?
Future research objectives focus on defining in detail the abnormalities in brain structure and function that could be responsible for cognitive problems in Down syndrome and explaining their genetic and cellular basis. Current studies are carried out in mouse models of Down syndrome, but in the future researchers hope to have access to brain tissue from people with Down syndrome so that ideas can be tested and refined.
In the near term, scientists will continue to define abnormalities in synaptic structure and function that are relevant in Down syndrome. They will develop as much information as to when and where these abnormalities occur.
In parallel, investigations are taking place to identify specific gene(s) responsible for particular abnormalities and cognitive deficits. As these are found scientists then turn their attention to identifying compounds that can regulate the expression of the targeted gene(s). The goal is for researchers to design treatments that enhance cognition.
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How are Down syndrome and Alzheimer's disease connected?
It is an interesting and surprising finding that every person with Down syndrome develops by age 40 the brain pathological changes of people with Alzheimer's disease. Moreover, most people with Down syndrome in old age - i.e., beyond age 60 - show further cognitive decline. This is a devastating aspect of Down syndrome and one that is quite disconcerting for those that care for elderly individuals with Down syndrome.
The question is how to explain the link between Down syndrome and Alzheimer's disease. There is no certain view at this time. However, some recent findings are very exciting. They point to a specific gene that is present in three copies in Down syndrome, which is known to be linked to Alzheimer's disease. In ongoing studies, researchers are testing how this gene might contribute to the development of Alzheimer's disease in people with Down syndrome.
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How can research in Alzheimer's disease help us understand and treat Down syndrome?
Because people with Alzheimer's disease and elderly people with Down syndrome have the same pattern of brain pathology, it is reasonable to suppose that advances in understanding Alzheimer's disease and new therapies to treat Alzheimer's disease can be applied to people with Down syndrome. Indeed, this is already happening. A number of studies are underway to test a role for cholinesterase inhibitors in people with Down syndrome. Cholinergic neurons are important for learning and memory and they are sick in both Alzheimer's disease and Down syndrome. They release a neurotransmitter called acetylcholine. The breakdown of acetylcholine is under the control of molecules called cholinesterases. Drugs that decrease the activity of these enzymes increase the level of acetylcholine. This helps increase memory in people with Alzheimer's disease, if only for a short time. Recent studies suggest that these drugs may also be used to treat Down syndrome. One can readily imagine that other therapies directed at Alzheimer's disease might be made available to people with Down syndrome.
Conversely, studies on mouse models of Down syndrome may well provide new insights into how best to treat people with Alzheimer's disease. Indeed, the research strategy for Down syndrome differs in some important ways from the typical strategy used to understand Alzheimer's disease. Work on Down syndrome might provide an important new way of thinking about what causes degeneration of neurons in Alzheimer's disease and how to treat or prevent it.
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Would Possible Treatments Be Just for Children?
No. Researchers believe that effective treatments could be developed for any person with Down syndrome - no matter what age they are.
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Why Are Mice Important for Our Research?
The progress of Down syndrome research on cognition is due largely to our ability to explore in great detail the abnormalities in the structure and function of the nervous system using mouse models. The mouse that researchers use for much of the research on Down syndrome is the Ts65Dn mouse. This mouse model is designed to have an extra copy of mouse chromosome that is very similar to chromosome 21 in humans. It has been very helpful in confirming that there are structural and functional changes in the synapses of hippocampus cells.
Unfortunately, the Ts65Dn mouse is difficult and expensive to breed. DSRTF has been working with Congress and the National Institutes of Health to increase the supply of these mice by increasing federal funding. Recently NIH approved more funding for production of the Ts65Dn mouse over a two-year period. It is hoped that this increased funding will lead to a greater supply of these mice for the research community.
Some exciting recent news is that researchers in the UK have developed a new mouse model of DS. Where the Ts65Dn mouse has an extra copy of chromosome 16, because that is the mouse chromosome that contains a significant number of the genes that are found on human chromosome 21, the new mouse model has a copy of the entire human chromosome 21. This mouse is expected to be a very powerful tool in helping researchers associate the specific genes that, by being present in a third copy, are responsible for impaired cognition in DS.
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Does the federal government fund cognition research for Down syndrome?
NIH funds Down syndrome research, but at the present time only a fraction of the funding is directed to bio-medical cognition research. NIH is best at promoting scientific discovery through investigator-initiated grants. It is less effective in ensuring that new knowledge advances the goal of achieving therapies. Private foundations like DSRTF can help "close the gap" between basic research and clinical applications by privately funding research where the goal is to produce treatments.
NIH reported that in fiscal year 2003 it spent approximately $30.6 million for research on Down syndrome. This money funded grants that cut across a broad spectrum, studying everything from better pre-natal screening techniques to how to improve motor fundtion in children with Down syndrome. DSRTF is encouraging NIH through its advocacy to fund more bio-medical research that is targeted at learning more about the cognitive impairment associated with Down syndrome and how to treat it.
In February DSRTF participated in a workshop held by NIH and led by Dr. William Mobley of the DSRTF-funded Stanford Center for DS Research and Treatment, to consider funding priorities for Down syndrome. DSRTF strongly advocated for increase funding for cognition related work.
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Does DSRTF advocate for both public and private funding for Down syndrome research?
Yes. DSRTF raises private funds for research and also advocates before Congress for increased federal funding for Down syndrome research.
During 2004, DSRTF successfully advocated before the Congress for increased funding for Down syndrome cognition research, and DSRTF received $150,000 in federal funding. NEWS: Congress Approves Funding for DSRTF
DSRTF also succeeded in getting congressional funding for two important Down syndrome studies at the Centers for Disease Control. NEWS: Congress Appropriates $1 Million for Down Syndrome Research
DSRTF also worked with the National Down Syndrome Society to encourage NIH to increase its funding for production of research mice. NIH has announced an additional $250,000 in funding for the production of the mice. NEWS: NIH Increases Funding for Mice
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