Biomedical research and Down syndrome
Professor Sue Buckley OBE
Prepared remarks for a speech at the meeting of a Roche Global Down Syndrome Advisory Board,
Basel, Switzerland, 12-13 March 2013.
Welcome and introduction
Good evening. It is wonderful to see many familiar faces from many advocacy groups around the world.
I would like to thank Hoffman La Roche for the invitation to speak this evening about Down syndrome research and - in particular - about recent advances in biomedical research. It is a personal and a professional privilege to be speaking to you this evening. I think the work that Roche is now undertaking is exciting and I would wish to congratulate them on deciding to invest in research which may lead to significant quality of life improvements for individuals with Down syndrome.
I think that the current knowledge based on animal work supports the view that it is time to start these human studies but success is no means certain. I think we will all need to work together and that there are significant challenges ahead for both the Roche team and the Down syndrome community, which I will use as a shorthand for people with Down syndrome, their families and advocacy groups. I will set out these challenges and hopefully set the scene for further thinking and discussion this evening and tomorrow.
Many of you will know that I have been active in the field of Down syndrome research for over 30 years, and that I have a daughter with Down syndrome - now 43 years old. I trained in clinical psychology, worked in services for people with intellectual disabilities, and taught psychology for many years at the University of Portsmouth in the United Kingdom. My research interests began with teaching reading to young children with Down syndrome and over the years have touched on many aspects of development, cognition and learning for young people with Down syndrome.
I have also had an interest in the nervous system and brain function since I was a student and taught brain and behavior courses to psychology students for a number of years. As I prepared this talk, I realized how the developmental and education work that I have actively focused on and the current point reached in biomedical science have come together and face at least some similar challenges.
For many years, Down syndrome research has encompassed many fields of inquiry - usually divided along the lines of traditional academic and professional disciplines. For example, genetics, medicine and psychology. In recent years, these areas of research have become increasingly intertwined as our understanding of genes and their functions, and of the nervous system and how it works, have begun to point to ways in which we can understand aspects of human development and behavior at a physiological level.
This increasingly interdisciplinary research is now leading to the identification of pharmaceutical compounds that might act on parts of the brain in ways that could improve mental function for people with Down syndrome. We have come together at this meeting to learn more about the early stage trials of these compounds.
I would like to briefly review the history of Down syndrome research and put the planned Roche studies in the context of the wider quest for a better understanding of what it means to be born with an extra copy of chromosome 21. Research in a number of fields has positively impacted the lives of people with Down syndrome - expectations are very different for a baby born now compared to the expectations for my daughter 43 years ago which led to her parents abandoning her in an institution - at least in some countries.
I also hope to show that the identification of possible pharmaceutical therapies for cognitive function is not a radical departure from the efforts of researchers, clinicians, therapists and teachers to find new and better ways to improve life for people with Down syndrome. Rather, it is the natural progression of the science in many fields and the anticipated result of advances in genetics, biology, neuroscience and psychology.
That said, pharmaceutical therapies for cognitive function are largely untried, and the limited human studies conducted to date have not been encouraging. Pharmaceutical therapies do represent a different approach to improving development and learning for people with Down syndrome from those we have today, such as specialized medical care, early intervention and adapted therapy and teaching techniques. And, they are not without important ethical and safety concerns.
I will touch on these as I outline what will be required to evaluate these therapies, and identify some of the formidable challenges that lie ahead.
A brief history of Down syndrome research
Down syndrome research has progressed alongside and in response to more general scientific advances since the mid-19th century.[ 1] This is unsurprising: the more we understand about typical human development, the better we can identify what is similar and what differs for people with Down syndrome.
John Langdon Down first published a description of the condition that now bears his name in 1866 - a year after Gregor Mendel published his laws of genetics. By 1920, it was generally accepted that chromosomes carried genes and by 1958 there was good evidence that most humans carried 46 chromosomes in their cells. In 1959, two research teams reported that people with Down syndrome had an extra copy of chromosome 21.
These early advances in our understanding of Down syndrome did little to improve life for people with the condition. John Langdon Down published his description of Down syndrome in the midst of debates about evolution that preceded the rise of eugenics in the first half of the 20th century. Within ten years of the discovery that Down syndrome resulted from an additional chromosome, prenatal diagnosis from cell samples obtained from fetuses via amniocentesis entered clinical practice.[ 2]
Perhaps the most significant scientific breakthroughs of the 20th century for people with Down syndrome were the discovery of antibiotics in 1929 and the invention of open heart surgery in 1953. In 1929, the average life expectancy for people with Down syndrome was estimated to be 9 years. That had risen little by 1949 when it was estimated to be 12 years. Over the next 20 years, average life expectancy jumped to 30 years and it has continued to rise to over 60 years today.[ 3]
The application of clinical advances to benefit people with Down syndrome depended on a better understanding of their particular medical and developmental needs. This research really began in earnest towards the end of the 1970s - around the time I too began my first study of reading development. By 1981, sufficient evidence and experience existed for Dr Mary Coleman to develop the first healthcare guidelines.[ 4]
Genetics research also began to accelerate from the late 1970s when the first gene located on human chromosome 21 was found to correspond with a gene on mouse chromosome 16 and Charles Epstein proposed that mouse models could be useful in the study of Down syndrome. The first mouse model - the Ts16 - did not survive beyond birth, so its uses were limited. In 1990, researchers reported that they had created a mouse carrying additional copies of many of the genes comparable to those on human chromosome 21 that did survive and that displayed learning and memory difficulties compared to typical mice. There are other models, but to date this model - the Ts65Dn - has been the most extensively studied.
From the mid-1990s efforts began to document the genetic code contained on chromosome 21. In 2000, the DNA sequence of human chromosome 21 was published, providing a critical reference for Down syndrome research.[ 5] Over the past two decades our understanding of the genes found on chromosome 21 and their function has steadily improved, though much work remains.[ 6]
Developmental and educational research also accelerated from the late 1970s. Researchers began to study the cognitive and physical development of people with Down syndrome. We soon discovered that many traditional assumptions were wrong and that when given appropriate opportunities young people with Down syndrome could learn more than previously thought possible. Researchers began to characterize specific differences in the function and development of different aspects of cognition, including language, speech, reading and memory when compared to typical development and development for children with other causes of intellectual disabilities.
This research is continuing to build a more nuanced view of the intellectual disabilities associated with Down syndrome. People with Down syndrome do not experience global mental delays and deficits, but rather the delays and deficits they experience vary across different mental functions and processes.[ 7] For example, while short term memory function is impaired in people with Down syndrome, verbal short term memory is more impaired than visuospatial short term memory.[ 8] Another example is that language development is usually more delayed than other areas of cognitive development.[ 9]
By pinpointing particular areas of relative strengths and weaknesses we can target therapies more effectively. For example, we can draw on visual teaching techniques to overcome verbal processing difficulties, or target training activities at specific memory deficits. In recent years, trials of targeted educational interventions and therapies for young people with Down syndrome have begun[ 10, 11] and are already informing better teaching practice in schools.[ 12]
Scientific research is therefore yielding results and advancing our understanding of Down syndrome. Clinical research has dramatically improved life expectancy and quality of life for people with Down syndrome. Educational and developmental research is helping many young people achieve more today than ever before. Biological and genetics research is starting to uncover some of the basic mechanisms affected by the extra chromosome and new possibilities are emerging for possible pharmaceutical therapies that may further improve life for people with Down syndrome.
Despite these tremendous advances, we need to be cautious. There are many things we still do not understand about Down syndrome.
Few, if any, precisely defined outcomes for people with Down syndrome are dictated solely by the presence of an additional copy of chromosome 21. Even congenital problems are not an inevitable consequence of trisomy 21. Heart defects are much more common among babies with Down syndrome, but still only approximately half of them. Trisomy 21 alone does not cause heart defects - it just increases the chance they will occur.
This is even truer of mental function. In all areas of cognitive development we see wide variation in levels of achievement and skills among people with Down syndrome. Again, having an extra chromosome 21 undoubtedly affects development but it does not alone determine outcomes.
We therefore need to be careful of over simplifying the mechanistic links between genes, biochemistry, neurological function and real world outcomes for people with Down syndrome. The biology is clearly important, but cognitive development is a complex and iterative process that depends on input. Input and practice changes the structure and function of areas of the brain.
Take language, for example. We are not born with language, but rather we are born with the brain 'machinery' needed to learn language. The language we learn depends on the language in which we are immersed. For young people with Down syndrome, that brain 'machinery' does not seem to work as well as for typically developing children - at least in response to typical environmental input or teaching methods. Clearly, if we can make basic cell function in the brain work better with pharmaceutical interventions we should expect to see improvements in specific learning outcomes, but not necessarily in the absence of effective teaching and support.
Recent advances in Down syndrome research
In recent years, scientists have identified differences in how nerve cells function in the Ts65Dn mouse compared to typical mice and have explored how these differences impact learning. One of several areas of particular interest is GABA receptor antagonism.[ 13]
Signals are transmitted between neurons by chemicals called neurotransmitters which act by binding to receptors on the surface of the cells. Some neurotransmitters encourage (or excite) signaling between neurons and some discourage (or inhibit) signaling Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in mammals. It binds to GABA receptors.
Studies of Ts65Dn mice show that excess GABA-mediated inhibition is associated with learning and memory problems. This suggests that treatments targeting GABA receptors may improve learning. In a study published in 2007, Fabian Fernandez and colleagues at Stanford University, reported that treating Ts65Dn mice with compounds that counter GABA-mediated inhibition improved their performance in tests of memory and learning.
Promising as these findings were, the GABA antagonists used with the mice are associated with heightened anxiety and convulsions.[ 14] People with Down syndrome are more prone to seizures, and are particularly sensitive to epilepsy-inducing drugs.[ 13] Researchers therefore began to search for compounds that could target GABA-mediated neurotransmission in ways that are less likely to cause serious side effects.
During this meeting, we are learning about Roche's research into compounds targeting GABA-mediated neurotransmission. Whereas previously-studied drugs act on GABA receptors generally, Roche's compounds act on a subset of GABA receptors that are present in parts of the brain linked with memory and learning. Two weeks ago, scientists in Spain and at Roche published a study reporting that treatment with a compound targeting specific GABA receptors improved learning and memory in Ts65Dn mice without causing any observable indications of elevated anxiety or seizures.[ 14]
The hippocampi are parts of the brain involved in short and long term memory. There is evidence that abnormalities in the hippocampus of Ts65Dn mice are linked with memory and learning difficulties.[ 13] There is also some evidence that people with Down syndrome experience memory problems thought to be linked to the hippocampus.[ 8, 13]
In summary, at this time there are candidate pharmaceutical therapies for which there is evidence suggesting they might alleviate problems with specific neurological functions in parts of the brain thought to be involved in some of the learning difficulties associated with Down syndrome.
So far, the only experimental evidence for improvements in learning and memory resulting from these compounds is from studies of mice carrying extra copies of genes similar to those found on human chromosome 21. What might this tell us about the possible benefits for people with Down syndrome?
Experiments with mice examine learning and memory using a variety of tests. For example, spatial learning and memory can be assessed using the Morris Water Maze in which mice are placed in pool of cloudy water and have to swim around to find a slightly submerged platform onto which they can climb from the water. Visual cues are placed around the pool. The mice swim around the pool until they find the platform. As the test is repeated, they learn to find the platform more quickly, presumably by learning its location in relation to the visual cues. Ts65Dn mice perform less well than typical mice in this test, presumably because their visuospatial memory is impaired.
There are very few conclusions we can draw from these experiments in relation to what benefits we might expect for people with Down syndrome. We know that people with Down syndrome experience memory difficulties and these difficulties seem likely to affect language development and many aspects of everyday learning and function. If these pharmaceutical therapies can improve memory function for people with Down syndrome in similar ways to the mouse models, then we might see gains in certain skills that could improve the quality of life for people with the condition. Even modest improvements in short or long term memory function could be helpful. However, until we test the compounds with humans with Down syndrome we cannot tell if they will have an effect, nor precisely what the effect will be.
Should we be intervening?
Before turning to the challenges involved in evaluating pharmaceutical therapies in people with Down syndrome, I want to briefly touch on the question of whether we should be trying at all. Some people are rightly very cautious about using pharmaceutical compounds targeting brain function. The brain is hugely complex and the effects that an extra copy of chromosome 21 have on the brain are also hugely complex. It is therefore reasonable to ask if we really know what we are doing interfering with the brains of people with Down syndrome in this way.
Moreover, some people argue that we should not wish to 'cure' people with Down syndrome - that their genetic makeup and its consequences for cognition and development are part of who they are as individual human beings.
I do not think that 'curing' people of Down syndrome is a realistic goal, nor will it ever be. The compounds being evaluated in mouse models are not 'cures' - and while they may offer 'treatments' for some specific problems associated with Down syndrome, they are not treatments for Down syndrome per se. The question, therefore, that we should focus on is to what extent should we help people with Down syndrome lead more rewarding and fulfilling lives? My answer to this question is we should help as much as is practically possible and pharmaceutical interventions are as important as educational ones.
Surely, no one would argue that we should not take advantage of modern surgical techniques to correct cardiac defects in babies with Down syndrome? This has clear benefits - as is evidence by marked increases in survival and longevity among people with Down syndrome. I do not think most people would argue we do not treat an underactive thyroid or a hearing loss. Few would argue that we should not take advantage of therapies and early interventions that can improve cognition and learning outcomes for people with Down syndrome.
Some of these therapies and interventions target specific brain functions in ways similar to these new pharmaceutical approaches. For example, researchers at Down Syndrome Education International recently completed a trial of computer based memory training.[ 11] This intervention is designed to improve specific cognitive functions by exercising them in ways that are hoped to leave lasting benefits after the training period, presumably by altering neurological structures in ways not dissimilar from how pharmaceutical therapies might be expected to work. New learning is stored by changing the structure and function of neurons.
That said, there are challenges that are unique to biomedical research and pharmaceutical therapies, and they are important.
First, much of what we understand about the biochemistry and neurological effects of extra copies of genes found on chromosome 21 is based on studies of mouse models with generally only limited correlations to observations in humans.[ 13] Just because a mouse model exhibits certain neurological features does not prove that the same features are present in people with Down syndrome. Just because a treatment works in a mouse, does not mean it will work in humans. In fact, the odds are it will not: biomedical research is littered with examples of promising findings in mice that are then not replicated in humans.
In keeping with this caution, the few pharmaceutical therapies that have to date been evaluated in humans have not had promising results. For example, studies with mouse models suggested that memantine improved performance in tests of learning and memory. However, recently, a large randomized controlled trial found it to be ineffective as a treatment of cognitive impairment and dementia in people with Down syndrome aged over 40 years.[ 15] More recently, a study of younger adults, aged 18 to 32 years and without dementia found limited evidence of improvements on a range of psychological tests with only one measure reaching statistical significance.[ 16] Similarly, despite encouraging biological evidence, trials of cholinesterase inhibitors have found no benefit for children with Down syndrome aged 10 to 17 years[ 17] and only limited evidence of benefits for young adults.[ 18]
Second, the brain is complex and interconnected. Just because we have evidence about what we are doing in a particular part of the brain, does not mean that we understand how we may impact other parts of the brain. It is quite possible that efforts to normalize neurological function in one part of the brain could adversely affect function in another part of the brain. As I commented earlier, one of the promising features of the compounds being investigated by Roche is that they target the activity of receptors thought to be most active in one part of the brain. However, we cannot rule out the possibility that pharmaceutical therapies targeting one aspect of cognitive function may have unintended consequences on others. These effects may be modest and difficult to detect and we may find ourselves having to accept trade-offs - as we do for most medicines.
Pharmaceutical therapies may also have more serious side effects. I have already touched on risks of elevated anxiety and convulsions relating to some compounds used with mouse models. Obviously, we need to certain that these compounds are safe in humans.
I hope that my brief review of Down syndrome research and the promise and the challenges of recent advances in proposed pharmaceutical therapies for learning and memory have been helpful for setting the scene.
I would like to conclude this talk by looking ahead.
Trials are beginning to evaluate some of these therapies with people with Down syndrome. What will be involved in these trials and how should the Down syndrome community be engaged?
These trials will take time. First, preliminary trials must assess the safety of a compound - usually with relatively small numbers of people. If these are successful, larger trials can take place to evaluate if the compound has the desired effect and to further monitor safety. If these are positive, then full scale clinical trials can take place with larger numbers of patients. The entire process can take many years.
These trials will require extensive collaboration: collaboration between scientists working in different fields, collaboration between clinicians and researchers, and collaboration between the Down syndrome community and researchers. These trials will likely take place in multiple countries, so these collaborations will need to be international.
The Down syndrome community will need to work with researchers to define the outcomes that matter. Developmental scientists and clinical practitioners experienced at working with people with Down syndrome will need to collaborate with biomedical researchers to develop the measures and assessment protocols necessary to accurately assess these outcomes.
This is not a trivial undertaking. There are substantial challenges involved in developing assessments that are reliable and sensitive enough to demonstrate treatment effects - and this applies to educational and pharmaceutical interventions so developing better measures will help us all.
These trials will need to demonstrate significant enhancements in function that lead to notable improvements in the lives of people with Down syndrome. One of the criticisms of memory training research similar to the work we have recently undertaken with children with Down syndrome is that it is not enough to show an improvement in narrow measures of memory function, but rather the benefits must transfer to broader measures of function - for example, language development or mathematical ability - for the intervention to be of value.[ 19, 20]
I would agree with this argument. Our goal is to achieve real world improvements in the lives of people with Down syndrome. Just because a pharmaceutical therapy or an education intervention improves a person's ability to recall a sequence of digits or symbols, it does not necessarily mean that they will develop better language skills or learn more in the classroom. These are these ultimate measures of success.
The Down syndrome community must be involved in setting these goals. What levels of gain in what functions would be sufficient to warrant the use of pharmaceutical therapies? Only people with Down syndrome and their families can answer these questions.
Developmental and learning outcomes are influenced by the type, intensity and the quality of the therapies and education provided to people with Down syndrome.[ 10, 21-23] Evaluating a pharmaceutical therapy with people with Down syndrome receiving poor quality support may find no effect, whereas the same therapy might be additionally beneficial for those receiving higher quality support. Pharmaceutical trials will need to take these issues into account.
It may be that pharmaceutical therapies are less effective than developmental interventions. For example, one study of computer based memory training with children with ADHD reported more pronounced effects of training than medication.[ 24]
It may also be that pharmaceutical therapies are most effective when combined with targeted developmental interventions, and perhaps more so during specific periods of development.
We should also expect therapies to work for some, but not all individuals. Determining the factors influencing response to intervention will be important. Particular health problems, sleep disturbance and additional diagnoses may all play roles.
The community will need to consider all of these issues and weigh the relative risks and benefits of differing therapies.
Finally, the international Down syndrome must play a crucial role in providing clear and balanced information about this research to families and people with Down syndrome. We should be engaged in recruiting study participants and I would encourage participation in any properly conducted and regulated scientific studies. However, we have a responsibility to provide accurate information, and to be cautious about the eventual benefits that this research may lead to.
I look forward to exploring these issues with you all during the course of this meeting.
Professor Sue Buckley has provided and continues to provide consulting services to F. Hoffman-La Roche Ltd., and receives compensation for these services. Down Syndrome Education International has been engaged to provide advisory services to F. Hoffman-La Roche Ltd., and received compensation for out-of-pocket expenses relating to these services. These disclosures were correct at the time of publication.
- Patterson D, Costa AC. (2005) Down syndrome and genetics - a case of linked histories. Nature Reviews Genetics, 6(2), 137-147. https://dx.doi.org/10.1038/nrg1525
- Nadler HL, Gerbie, AB. (1970) Role of Amniocentesis in the Intrauterine Detection of Genetic Disorders. New England Journal of Medicine , 282, 596-599. https://dx.doi.org/10.1056/NEJM197003122821105
- Bittles AH, Glasson EJ. (2004). Clinical, social, and ethical implications of changing life expectancy in Down syndrome. Developmental Medicine and Child Neurology, 46, 282-286. https://dx.doi.org/10.1111/j.1469-8749.2004.tb00483.x
- Cohen WI and the Down Syndrome Medical Interest Group. (1999). Health Care Guidelines for Individuals with Down Syndrome. Down Syndrome Quarterly, 4(3).
- Hattori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park HS, Toyoda A, Ishii K, Totoki Y, Choi DK, Groner Y, Soeda E, Ohki M, Takagi T, Sakaki Y, Taudien S, Blechschmidt K, Polley A, Menzel U, Delabar J, Kumpf K, Lehmann R, Patterson D, Reichwald K, Rump A, Schillhabel M, Schudy A, Zimmermann W, Rosenthal A, Kudoh J, Schibuya K, Kawasaki K, Asakawa S, Shintani A, Sasaki T, Nagamine K, Mitsuyama S, Antonarakis SE, Minoshima S, Shimizu N, Nordsiek G, Hornischer K, Brant P, Scharfe M, Schon O, Desario A, Reichelt J, Kauer G, Blocker H, Ramser J, Beck A, Klages S, Hennig S, Riesselmann L, Dagand E, Haaf T, Wehrmeyer S, Borzym K, Gardiner K, Nizetic D, Francis F, Lehrach H, Reinhardt R, Yaspo ML; Chromosome 21 mapping and sequencing consortium. (2000). The DNA sequence of human chromosome 21. Nature, 405, 311-319. https://dx.doi.org/10.1038/35012518
- Antonarakis SE, Lyle R, Dermitzakis ET, Reymond A, Deutsch S. (2004) Chromosome 21 and down syndrome: from genomics to pathophysiology. Nature Reviews Genetics, 5(10), 725-38. https://dx.doi.org/10.1038/nrg1448
- Fidler, D. J. and Nadel, L. (2007). Education and children with Down syndrome: Neuroscience, development, and intervention. Mental Retardation and Developmental Disabilities Research Reviews, 13, 262-271. https://dx.doi.org/10.1002/mrdd.20166
- Jarrold, C., Nadel, L., Vicari, S. (2008). Memory and neuropsychology in Down syndrome. Down Syndrome Research and Practice. https://library.down-syndrome.org/reviews/2068/
- Abbeduto, L., Warren, S. F. and Conners, F. A. (2007). Language development in Down syndrome: From the prelinguistic period to the acquisition of literacy. Mental Retardation and Developmental Disabilities Research Reviews, 13, 247-261. https://dx.doi.org/10.1002/mrdd.20158
- Burgoyne, K., Duff, F. J., Clarke, P. J., Buckley, S., Snowling, M. J. and Hulme, C. (2012). Efficacy of a reading and language intervention for children with Down syndrome: a randomized controlled trial. Journal of Child Psychology and Psychiatry, 53, 1044-1053. https://dx.doi.org/10.1111/j.1469-7610.2012.02557.x
- Bennett, S., Holmes, J., Buckley, S. (2013). Computerized memory training leads to sustained improvement in visuo-spatial short term memory skills in children with Down syndrome. American Journal on Intellectual and Developmental Disabilities (in press).
- Burgoyne, K., Duff, F. J., Clarke, P. J., Smith, G., Buckley, S., Snowling, M. J. and Hulme, C. (2012) Reading and Language Intervention for Children with Down Syndrome: Teacher's Handbook. Cumbria, UK: Down Syndrome Education International.
- Dierssen, M. (2012). Down syndrome: the brain in trisomic mode. Nature Reviews Neuroscience, 13, 844-858. https://dx.doi.org/10.1038/nrn3314
- Martínez-Cué C, Martínez P, Rueda N, Vidal R, García S, Vidal V, Corrales A, Montero JA, Pazos A, Flórez J, Gasser R, Thomas AW, Honer M, Knoflach F, Trejo JL, Wettstein JG, Hernández MC. (2013). Reducing GABAA α5 Receptor-Mediated Inhibition Rescues Functional and Neuromorphological Deficits in a Mouse Model of Down Syndrome. The Journal of Neuroscience, 33(9), 3953-3966. https://dx.doi.org/10.1523/JNEUROSCI.1203-12.2013
- Hanney M., Prasher V., Williams N., Jones E.L., Aarsland D., Corbett A., Lawrence D., Yu L.M., Tyrer S., Francis P.T., Johnson T., Bullock R., Ballard C.; MEADOWS trial researchers. (2012). Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomized, double-blind, placebo-controlled trial. The Lancet, 379(9815), 528-536. https://dx.doi.org/10.1016/S0140-6736(11)61676-0
- Boada R, Hutaff-Lee C, Schrader A, Weitzenkamp D, Benke TA, Goldson EJ, Costa AC. (2012). Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial. Translational Psychiatry. 2012, 2, e141. https://dx.doi.org/10.1038/tp.2012.66
- Kishnani PS, Heller JH, Spiridigliozzi GA, Lott I, Escobar L, Richardson S, Zhang R, McRae T. Donepezil for treatment of cognitive dysfunction in children with Down syndrome aged 10-17. American Journal of Medical Genetics Part A, 152A(12), 3028-35. https://dx.doi.org/10.1002/ajmg.a.33730
- Kishnani PS, Sommer BR, Handen BL, Seltzer B, Capone GT, Spiridigliozzi GA, Heller JH, Richardson S, McRae T. (2009). The efficacy, safety, and tolerability of donepezil for the treatment of young adults with Down syndrome. A merican Journal of Medical Genetics Part A, 149A(8), 1641-54. https://dx.doi.org/10.1002/ajmg.a.32953
- Hulme C, Melby-Lervåg M. (2012). Current evidence does not support the claims made for CogMed working memory training. Journal of Applied Research in Memory and Cognition, 1(3), 197-200. https://dx.doi.org/10.1016/j.jarmac.2012.06.006
- Gathercole SE, Dunning DL, Holmes J. (2012). Cogmed training: Let's be realistic about intervention research. Journal of Applied Research in Memory and Cognition, 1(3), 201-203. https://dx.doi.org/10.1016/j.jarmac.2012.07.007
- Laws, G., Byrne, A., Buckley, S. (2000). Language and Memory Development in Children with Down Syndrome at Mainstream Schools and Special Schools: A comparison. Educational Psychology, 20(4), 447-457. https://dx.doi.org/10.1080/713663758
- Buckley S.J., Bird G., Sacks B., Archer T. (2006). A comparison of mainstream and special education for teenagers with Down syndrome: Implications for parents and teachers. Down Syndrome Research and Practice. 9(3), 54-67. https://dx.doi.org/10.3104/reports.295
- de Graaf, G., van Hove, G. and Haveman, M. (2013), More academics in regular schools? The effect of regular versus special school placement on academic skills in Dutch primary school students with Down syndrome. Journal of Intellectual Disability Research, 57, 21-38. https://dx.doi.org/10.1111/j.1365-2788.2011.01512.x
- Holmes, J., Gathercole, S. E., Place, M., Dunning, D. L., Hilton, K. A. and Elliott, J. G. (2010). Working memory deficits can be overcome: Impacts of training and medication on working memory in children with ADHD. Applied Cognitive Psychology, 24, 827-836. https://dx.doi.org/10.1002/acp.1589