Jacob, a child with Down Syndrome, enjoying a family holiday and browsing in shops, like any other 5 year old child wouldJacob looking at books and watching TV at age 6 years - Down Syndrome doesn't stop normal development, but social attitudes do. - Jacob, a baby with Down Syndrome - Jacob at one year of age

Down Syndrome Cure

I asked Dr A. Kirchgessner, professor and neurologist, to investigate cures for Down Syndrome. Down Syndrome cures was, from the start, to be a look at possible future cures for Down Syndrome, as no cure for Down Syndrome yet exists.

What became apparent to Dr. Kirchgessner, is that people with Down Syndrome have so many and varied intellectual and medical concerns, that to talk of a cure for Down Syndrome as such, was, well, so far into the future to be just fantasy.

However, it was apparent that cures did exist for many of the complaints that afflicted those with Down Syndrome, particularly the physical complaints.

For example, heart defects common to those with Down Syndrome can be cured by and large, and this has resulted in a much longer life span for those with Down Syndrome.

Generally speaking, as medical science keeps making inroads into curing dieases and conditions, it will keep making inroads into the physical healing of complaints sufferred by those with Down Syndrome.

So, the neurologist then altered the direction of the assignment to cover the cures for Down Syndrome that related specifically to memory and learning, and which would likely appear before 2020 AD.

Anyway, here is her report on Cures for Down Syndrome:

Improving Memory and Learning in Individuals with Down Syndrome

Down syndrome, or trisomy 21, as it is called in the medical community, is caused by an extra copy of human chromosome 21, a single DNA molecule contained within each cell that contains many genes.i An error in cell division happens at the moment of conception for reasons we still don’t understand resulting in 3 copies (instead of 2) of all or part of the genes contained within chromosome 21. Human chromosome 21 encodes 231 genes.ii However, the characteristic features of Down syndrome can be achieved by having 3 copies of the genes contained within chromosomal band 21q22, a critical region researcher’s zeroed in on, which contains 33 genesiii and has become known as the Down syndrome critical region (DSCR). Thus, Down syndrome’s genetic origin is clear. However, exactly how these duplicate genes influence development is not well understood. This article will discuss recent progress in identifying critical genes that may contribute to defects in learning and memory in Down syndrome and how this information could identify targets for novel treatments to improve cognitive function.

 

How Common is Down Syndrome?

Down syndrome is the most frequently occurring genetic disorder in humans, with an incidence of 1 in 800 live births.iv A genetic disorder is an illness caused by abnormalities in genes or chromosomes. Down syndrome is the most common genetic cause of intellectual disability and is also associated with many other health problems including heart disease, leukemia, and early onset Alzheimer disease. On the other hand, people with Down syndrome seem to be at a decreased risk of certain cancers. Solid tumors are very rare in people with Down syndrome. Why? The answer almost certainly lies among the genes overproduced when they inherit their extra copy of chromosome 21.v

 

Impact on Learning

Although the extent and severity of the abnormalities is highly variable, all individuals with Down syndrome have some level of intellectual disability that is associated with specific brain regions and the performance of cognitive tasks. Attention, learning, memory, and judgment are all of what we call “cognition”. This means basically that someone who has Down syndrome will have trouble learning and functioning in everyday life. Having an intellectual disability doesn’t mean a person can’t learn. But they will most definitely have trouble learning.

Individuals with Down syndrome have IQ ranges between 30 and 70. Interestingly, the average IQ is 70 at 1 year, by school age it’s around 50. Thus, Down syndrome is characterized by a delayed cognitive development, leading to mild-moderate mental retardation and a decrease of the IQ from early in the first year to late childhood.

Down syndrome individuals have impaired memory span, particularly verbal short-term memory – the ability to hold spoken words and sentences and numbers for brief periods of time, in the left hemisphere (side) of the brain.

In a typical memory span experiment, subjects hear a sequence of digits and have to repeat them back in the same order as they heard them. A normal person has a memory span of 7 plus or minus 2, but an individual with Down syndrome has a verbal short-term memory span of only 1-2.

 

Alterations in Brain Structure – The Synapse

All people with Down syndrome have a mild-to-moderate learning disability that is mainly a consequence of functional and developmental alterations in the brain. The brain of a child with Down syndrome develops differently from a normal one. There’s a reduction in brain volume, the size of the hippocampus being particularly affected.vi The hippocampus is a brain region essential for learning and memory. It’s one of the major areas studied by scientists to determine which network of cells is affected in cognition in Down syndrome.

Defects are also found at the cellular level as reflected by an alteration in neurogenesis and synaptogenesis. Neurogenesis is the process by which neurons are created. Down syndrome brains exhibit a lower weight with reduced neuronal number regardless of age. Synaptogenesis is the formation of chemical synapses through which neurons signal to each other and to non-neuronal cells such as those in muscles and glands. Synapses are not made correctly in a Down syndrome brain- their structure and function is different and as a result, synapses don’t work correctly in a Down syndrome brain. When synapses fail, neurons degenerate (die). Thus, if we could discover treatments to prevent degeneration of neurons we might be able to improve learning and memory. By examining synapses in the hippocampus, scientists hope to find out more about what is different in Down syndrome brains.

 

Early Onset Alzheimer’s Disease

People with Down syndrome have a greatly increased risk of developing early onset Alzheimer’s disease. Alzheimer’s disease is diagnosed in about 22-25% of people with Down syndrome who are 40 or more years old, compared to about 2-3% of people with other developmental disabilities. By the age of 60, between 50-70% of people with Down syndrome develop dementia. Why?

The know risk factor for Alzheimer’s disease, amyloid precursor protein (APP) is processed or encoded on chromosome 21. Trisomy (3 copies) of APP is likely to make a significant contribution to the increased frequency of dementia in people with Down syndrome. Indeed, triplication of a short segment of human chromosome 21 that includes APP in people without Down syndrome has been shown to be associated with early onset Alzheimer’s disease.

 

The Importance of Genes

We know that Down syndrome produces abnormalities in the structure and functioning of the brain regions that affect cognition. We also know that because there are more chromosome 21 genes in people with Down syndrome, there is increased gene activity. It’s very likely that the activity of one or more of these extra genes leads to cognitive impairment. Thus, treatments directed at reducing the activity of the extra gene(s) will prevent or reverse the deficit.

 

Mouse Models of Down Syndrome

One strategy for investigating genetic influences on human cognition is to examine the actions of genes in other species. The most extensively studied animal “model” of Down syndrome is the Ts65Dn mouse.vii

The Ts65Dn mouse strain carries an extra copy of mouse chromosome 16 which is very similar to chromosome 21 in humans. A number of features observed in these mice show similarities to characteristics that are common among people with Down syndrome. These include certain anatomical features (such as aspects of facial shape), differences in the connections between certain brain cells, and behavioral characteristics, including learning difficulties.

Studies of Ts65Dn mice have identified problems with the “strengthening” of connections between brain cells (synapses) in the hippocampus – a part of the brain that is linked with aspects of learning and memory. This “strengthening” of synaptic connections between brain cells (known as “long-term potentiation”) is widely thought to support memory formation. Long term potentiation is absent in the hippocampus of Down syndrome miceviii and appears to be due to chronic over-inhibition of signals between these brain cells by the neurotransmitter gamma-aminobutyric acid (GABA). It’s thought that Down syndrome patients have too much GABA-related inhibition, making it difficult to process information.

In other words, learning involves neuronal excitation in certain parts of the brain and inhibition in other areas. Normal brains maintain a balance between neuronal excitation and inhibition that allows efficient learning. For example, caffeine, which is a stimulant, can make us more attentive and aware, and enhance learning. Conversely, alcohol or sedatives impair our ability to learn.

 

Treatment of Cognitive Dysfunction in Individuals with Down Syndrome

Researchers have investigated the effects of drugs that decrease the effects (known as antagonists) of the inhibitory GABA neurotransmitter in Ts65Dn mice. The first two drugs tested were picrotoxin and bilobalide.ix Bilobalide is a substance found in Ginkgo biloba leaf extracts. It is widely used to improve memory and/or prevent dementia.

After 2 weeks treatment, both drugs were shown to improve novel object recognition with Ts65Dn mice achieving test scores similar to those achieved by typical mice.

Unfortunately, picrotoxin is not considered a good drug for humans and bilobalide is not approved by the FDA, so the researchers tried another GABAA antagonist – pentylenetetrazole (PTZ).

Ts65Dn mice given PTZ were able to identify novel objects and navigate a maze – tasks that simulate difficulties faced by individuals with Down syndrome. Moreover, the treated mice performed as well as their normal counterparts for up to two months after drug treatment was discontinued. This suggests that some type of long-lasting neuronal adaptation was occurring.

A key component of enduring neural change associated with memory is long term potentiation. In general terms, once a threshold of activation is achieved, a neuron becomes permanently more sensitive to excitation. Long term potentiation was absent in Down syndrome mice but it approached near normal levels after chronic PTZ treatment and remained comparable to that in wild-type mice for up to 3 months after PTZ was discontinued. These results are exciting and illustrate the potential of neuropsychological research to improve our understanding of Down syndrome.

Researchers believe that the key to the improvement lies in the fact that PTZ blocks the action of the inhibitory neurotransmitter called GABA. Normal brains maintain a balance between neuronal excitation and inhibition that allows efficient learning. It’s thought that Down syndrome patients have too much GABA-related inhibition, making it difficult to process information.

Learning in Ts65Dn mice also improved by memantine, an antagonist of N-methyl-D-aspartate (NMDA) type receptors. The results with memantine are particularly exciting because they demonstrate the rescue of learning/memory deficits as measured by three tests of hippocampal function. The rationale for using memantine is to reduce abnormal activation of the excitatory neurotransmitter glutamate and thus improve cognitive function. Several chromosome 21 proteins directly or indirectly impact NMDA function. Individuals with Down syndrome have increased NMDA receptor activity. Thus, memantine would be effective at decreasing receptor activity. Results from the one randomized controlled clinical trial for the treatment of cognitive dysfunction in Down syndrome are not yet available (expected 2009).

Could these findings be an important break-through in the search for pharmacological therapies to assist people with Down syndrome? Yes. However, it is too early to be certain that these drugs, or similar drugs, will prove to be effective for people with Down syndrome.

 

The DYRK1A Gene

Due to efforts in isolating the gene(s) responsible for cognitive dysfunction in Down syndrome, the DYRK1A gene was identified within the Down syndrome critical region on human chromosome 21. The DRYK1A enzyme plays a critical role in neurodevelopment. Mice overexpressing the DYRK1A protein showed significant hippocampal-dependent learning and memory deficits reminiscent of human Down syndrome. They also showed significant beta-amyloid production in the hippocampus which is a hallmark of Alzheimer disease. This suggests that up-regulation of DYRK1A may be closely associated with cognitive dysfunction and with the early onset of Alzheimer disease in Down syndrome.x

DYRK1A levels in brains of Down syndrome subjects were found approximately 1.5-fold higher than those in normal subjects indicating that this protein is overproduced in Down syndrome and may contribute to the cognitive defects in this disorder. Interestingly, green tea polyphenols rescued the brain defects caused by overexpression of DYRK1A in mice.xi

Natural polyphenol extracts are already used as dietary supplements for the treatment of various disorders and have been shown to be well tolerated. It has been suggested that oxidative stress plays an important role in Down syndrome.xii Oxidative stress response markers are increased in fetal Down syndrome tissues and upregulation of the chromosome 21 gene S100B causes an increase of reactive oxygen species leading to an increase in cell death. In addition, markers of oxidative stress have been measured in second trimester amniotic fluid samples from Down syndrome fetuses.xiii Anti-oxidants, such as polyphenols, may potentially by used to improve the cognitive performances of Down syndrome patients.

 

Effectiveness of Treatment in Down Syndrome

Very few clinical trials have been conducted to test the effectiveness of drugs, vitamins, and/or minerals on cognitive function in people with Down syndrome.xivxv The trials that were conducted had a small number of subjects and were very poorly designed. Thus there is no justification for the use of “miracle drugs” by the parents of children with Down syndrome.

A few drugs for Alzheimer’s disease were tried in Down syndrome patients, but the results were controversial.xvi Alzheimer’s dementia is the most common form of dementia in people with Down syndrome. In addition, people with Down syndrome tend to present with Alzheimer’s disease at a much younger age than the normal population. Although there is not cure for dementia, a number of anti-dementia drugs (e.g., rivastigmine,xvii galantamine,xviii donepezilxix ) have been developed which may slow the rate of decline and improve symptoms. Unfortunately, there is no evidence for the effectiveness of these drugs in Down syndrome or Down syndrome with manifestations of early onset Alzheimer’s disease. It appears to be the case that treatment of Down syndrome is in its infancy perhaps due to the difficulties encountered while conducting research in the learning disability population in general.

 

Memory Training

For more than 25 years we have known that children and adults with Down syndrome have specific impairments in working memory. In particular, they have difficulty with verbal short-term memory – the ability to hold spoken words in short-term storage- which is linked to language development and reading and math in childhood. A number of researchers have been interested in exploring ways to improve verbal short-term memory through memory training activities and recent work with both children with Down syndrome and non-disabled children has shown some positive results.xx

Parents were trained to carry out intervention programs with their children.xxi The verbal memory training was delivered entirely in an auditory/verbal mode – the children had to listen to digits spoken and then to say them, with the number of digits in the lists to be recalled increasing as children succeeded at a list length.

Firstly, the results showed that parents were able to implement the memory training at home and record progress. Second the memory training did lead to a small but significant increase in digit span for the group- with some kids making substantial progress and others less.

Clearly there is a need for further research into memory training which could lead to gains in memory, speech, and language for children with Down syndrome.

 

Is treatment a cure?

No. Treatment is not a cure. Once a baby is born with Down syndrome, he or she will always have an extra chromosome. However, treatment may be able to lessen or reverse the affects of the extra chromosome, particularly with regard to the degree of cognitive impairment. 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 persons with Down syndrome to function much more independently in school and the workplace.

 

i Patterson D, Costa A. Down syndrome and genetics – a case of linked histories. Nature Reviews Genetics. 2005;6;137-147.

ii Huang X, Gardiner K. Protein coding features and conservation of novel human chr21 transcript, in preparation.

iii Belichenko NP, Belichenko PV, Kleschevnikov AM, Salehi A, Reeves RH, Mobley WC. The Down syndrome critical region is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome. J Neurosci 2009; 29: 5938-5948.

iv Collins VR, Muggli EE, Riley M, Palma S, Halliday JL. Is Down syndrome a disappearing birth defect? J Pediatr 2008; 152: 20-4.

v Baek K-H et al. Down’s syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature 2009; 459: 1126-30.

vi Patterson D, Costa A. Down syndrome and genetics – a case of linked histories. Nature Reviews Genetics. 2005;6;137-147.

vii Sérégaza Z, Roubertoux PL, Jamon M, Soumireu-Mourat B. Mouse models of cognitive disorders in trisomy 21: a review. Behaviour Genetics. 2006;36(3);387-404.

 

viii Belichenko PV, Kleschevnikov AM, Salehi A, Epstein CJ, Mobley WC. Synaptic and cognitive abnormalities in mouse models of Down syndrome: exploring genotype-phenotype relationships. J Comp Neurol 2007; 504: 329-45.

ix Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka RC, Garner CC. Pharmacolotherapy for cognitive impairment in a mouse model of Down syndrome. Nat Neurosci 2007: 10: 411-3.

x Liu F, Liang Z, Wegiel J, Hwang YW, Igbal K, Grundke-Igbal I, Ramakrishna N, Gong CX. Overexpression of Dyrk1A contributes to neurofibrillary degeneration Down syndrome. FASEB J 2008; 22: 3224-33.

xi Guedj F et al. Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A. PloS One 2009; 4: e4606.

xii Zana M, Janka Z, Kalman J. Oxidative stress: a bridge between Down’s syndrome and Alzheimer’s disease. Neurobiol Aging 2007; 28: 648-676.

xiii Slonim DK, Koide K, Johnson KL, Tantravahi U, Cowan JM, Jarrah Z, Bianchi W. Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses. PNAS Early Edition 2009.

xiv Lobaugh NH, Karaskov V, Rombough V et al. Piracetam therapy does not enhance cognitive functioning in children with Down syndrome. Arch Pediatr Adolesc Med 2001; 155: 442-448.

xv Salman MS. Systematic review of the effect of therapeutic dietary supplements and drugs on cognitive function in subjects with Down syndrome. Eur J Ped Neurol 2002; 6: 213-219.

xvi Lott IT, Osann K, Doran E, Nelson L. Down syndrome and Alzheimer disease. Response to donepezil. Arch Neurol 2002; 59: 1133-1136.

xvii Mohan M, Bennett C, Carpenter PK. Rivastigmine for dementia in people with Down syndrome. Cochrane Database of Systematic Reviews 2009, Issue 1.

xviii Mohan M, Bennett C, Carpenter PK. Galantamine for dementia in people with Down syndrome. Cochrane Database of Systematic Reviews 2009, Issue 1.

xix Mohan M, Carpenter PK, Bennett C. Donepezil for dementia in people with Down syndrome. Cochrane Database of Systematic Reviews 2009; Issue 1.

xx Conners FA, Rosenquist CJ, Arnett L, Moore MS, Hume LE. Improving memory span in children with Down syndrome. J Intell Dis Res 2008; 52: 244-255.

xxi Buckley S. It is time to take memory training seriously. Down Syndrome Research Practice 2008; 12: 105-106.

Researched and written by Dr. Annette Kirchgessner, Phd (Neuroscience), medical university Professor, minor editing by Donald Urquhart (Psychologist).

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