Research Features - Issue 105

ISSN 2399-1542 ISSUE 105

AMERICAN SOCIETY OF HUMAN GENETICS Executive Vice President, Joseph D McInerney, discusses the work of the organisation and outlines the hopes and concerns he has for future genetic research

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WINGS FOR LIFE

Jean Georges, Executive Director, explains how they are improving care and treatment of Alzheimer’s patients and reflects on how awareness of the disease has changed throughout the last 20 years

Set up to bridge a critical funding gap, the charity has established itself as a significant force in spinal cord research and fundraising Research Features 3 – CEO Anita Gerhardter explains how and discusses how close we might be to a cure

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This Issue

TO ISSUE 105

The value of basic research, the critical need for rigorous data analysis, the importance of translating from bench to bedside – the researchers featured in this issue acknowledge the wider impact and context of their research. We have also heard from several thought leaders who are at the forefront of funding and directing research in diverse areas of health sciences.

Joseph D McInerney from the American Society of Human Genetics discusses the society’s long history and its work. He also shares some of his hopes and concerns for the future of genetic research.

With Alzheimer’s disease affecting more people each year, we spoke to Jean Georges, Executive Director of Alzheimer Europe about how awareness of the disease has changed. And a change of attitude is exactly what Dr Samuel Ball, CEO and President of The National Center on Addiction and Substance Abuse is hoping for – he explains how understanding addiction as a disease, not a failing, is a key step in improving the surrounding policy and practice.

Raising awareness is also a key remit for Wings for Life, the spinal cord research charity. CEO Anita Gerhardter details the progress they have made so far and their plans to continue funding key research into spinal cord injury.

The scientists in this issue are passionate about their research and we are just as passionate about sharing the valuable work they do.

Neuroscience, child health, spinal cord injury, epidemiology... join our readers across the globe to discover the exciting health science research taking place every day around the world.

Published by: Research Publishing International Publisher: Simon Jones simon@researchfeatures.com Editorial Director: Emma Feloy emma@researchfeatures.com Editorial Assistant: Patrick Bawn patrick@researchfeatures.com Editorial Assistant: Miranda Airey miranda@researchfeatures.com Designer: Christine Burrows design@researchfeatures.com Head of Marketing: Alastair Cook audience@researchfeatures.com Project Managers: Annie Venables annie@researchfeatures.com John French John@researchfeatures.com Julian Barrett Julian@researchfeatures.com Kate Rossiter Kate@researchfeatures.com Contributors: Alex Davey, Barney Leeke, Ella Gilbert, Kate Feloy, Kate Porter

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CONTENTS

30 06 12 18 22

ASHG: Continually advancing genetic discoveries

Diagnosis in the genomics era Lost for words: investigating specific language impairments Juvenile Idiopathic Arthritis and sleep disorders – a co-morbid nightmare

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Exposing the mechanisms of sexbiased childhood developmental disorders

30

Alzheimer Europe: The importance of awareness in dementia

34

Newly identified pathways could advance understanding of neurodegenerative diseases and define novel therapeutic strategies

62 42 46 50

CASA: Addiction is a disease, not a choice The complex web of addiction, disease and mental health

Explaining the unexplained: the link between panic and noncardiac chest pain

54 58 62

A technology-based future for psychotherapy

Wings for Life: The backbone of spinal cord research Treating the wounded: neuroprotection strategies in spinal cord injury

66 70

Learning from the best

Generating novel insights into the consequences of diabetes by integrating clinical, biomarker and genetic data in large cohorts

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Communicating Science: Animation vs Textbooks

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38

Down syndrome accelerates Alzheimer's disease onset

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Thought Leadership

ASHG: Continually advancing genetic discoveries

Joseph D. McInerney is the current Executive Vice President of the American Society of Human Genetics – a long established organisation which provides expertise and a base for scientists in the field of genetic research. He recently sat down with us at Research Features to discuss the work of the organisation and to outline the hopes and concerns he has for future genetic research.

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rom Watson and Crick’s uncovering of DNA’s double helix structure in 1953, to the initial use of gene editing in 1987, to the completion of the human genome project 16 years later in 2003 – genetics is an area of continual scientific excitement and discovery.

Its research has helped to determine cures and treatments for a number of different genetic disorders and its application is now utilised throughout the world of scientific research. As such, it is vital for scientists to work collaboratively – sharing ideas, data and their research findings.

With this in mind, the American Society of Human Genetics was first established back in 1948 – five years prior to Watson and Crick’s ground-breaking discovery. Research Features spoke to Joe McInerney, their current Executive Vice President, to discuss the organisation’s heritage and ascertain how the landscape of genetics research has changed since its inception.

What does your role as Executive Vice President of the American Society of Human Genetics (ASHG) involve?

I became a member of the society in 1980 and it has been my major professional home ever since. In 2013, I took on the role of ASHG Executive Vice President, and now I get to see the organisation operate from the inside, which I was not able to do as a member.

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Could you tell us about the ASHG’s background and the aims of the society?

The ASHG was established in 1948 and our first president was Nobel Laureate, Hermann Muller. The intent at the time was to create a forum where like-minded people could communicate with one another and support one another, and to help direct the growth of the field.

The formal mission of the society is to advance human genetics in science, health and society through excellence in research, education and advocacy, and our tagline derives from that.

The tagline is ‘Discover, Educate, Advocate.’

Our membership is international. We have around 8,000 members and we have an increasing number of collaborations with other societies, including international societies such as the European Society of Human Genetics. ASHG is the largest professional genetics society in the world.

What impact do you think the ASHG has had on human genetics research since it was first established in 1948?

It is hard to quantify our contribution, but I think it is very safe to say that our members have been involved in the creation of much of the new knowledge in the field and have been responsible for many of the central advances, including much of the science and technology related to genome science and to investigations of the relationship between genetics and health and disease.

Senator James Cowan of Canada, recipient of ASHG’s 2016 Advocacy Award, chats with meeting attendees about his efforts to prevent genetic discrimination

Our members have been working for a very long time on population genetics and human evolution, human history, the architecture of the human population. Our members helped to establish the first three departments in medical genetics in the United States in the 1950s, one at Johns Hopkins University, one at the University of Michigan and one at the University of Washington.

Are there any of the organisation's accomplishments that you are particularly proud of?

There are many. One is our high quality journal and the role it plays in the dissemination of cutting edge research around the world.

There is our meeting too, which is another forum for the dissemination of research and the exchange of ideas, and for networking and building collaborations. The meeting is really quite impressive, it is the largest genetics

meeting in the world, each year attracting between 7,000 and 8,000 people.

I think the emphasis we have placed on our trainees, our young people, our doctoral students, our postdocs, and graduate students is another important accomplishment. As the career landscape changes significantly, many of our young people indicate that they do not see themselves moving into academic positions and are looking for opportunities elsewhere, including increasingly in industry, and we have done our best to support our trainees when they are facing those kinds of decisions.

I am really proud of our role in policy and advocacy, and in education. We have very strong education programmes here at a variety of levels. We also have a very good policy and advocacy history. I am proud of the role we played in the case of Myriad vs the

The formal mission of the society is to advance human genetics in science, health and society through excellence in research, education and advocacy 8

Association for Molecular Pathology. The case, addressed by the Supreme Court in 2013, resulted in the barring of patents on human genes and it helped to make BRCA testing, a test for susceptibility to breast cancer, more widely available.

Very significant too was our support for the Genetic Information Nondiscrimination Act, which prevents the use of genetic information in decisions related to health insurance and employment.

You mentioned that a lot of young people would rather go into industry than academia.

Is that a problem for academia?

I do not think it is a problem for academia, except in the sense that I think people in academia have to begin to think a little bit differently about the kind of training and mentorship they are providing to young scientists. If more and more young scientists are not going to move into the academic setting, then there are a number of reasons for that which need to be considered. I think much of it has to do with funding opportunities and the fact that young people see themselves doing a five-year PhD and then two three-year postdocs, and they are facing the prospect of an ever more competitive funding climate

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Thought Leadership

with organisations that are not formally genetics groups. For example, we are now in the middle of a collaboration with the American Physiological Society, one of the oldest professional societies in the United States, founded in the late 1800s.

We have just been working with them on a collaborative symposium on cardiovascular genetics.

We also are working on collaborations with some of the Asian genetics societies and we are active in the International Federation of Human Genetics Societies as well. We are also increasingly encouraging collaborations between genetics professionals and those from non-genetics groups.

ASHG is one of 30 scientific societies which belong to FASEB and is headquartered at the FASEB campus in Bethesda, Maryland

and they might not end up getting their first R01 grants, here in the US, from NIH (Research Project Grants for health-related research and development) until their late 30s. I think more and more young people are saying that they are not willing to sign up for that path, and they are looking for opportunities elsewhere. Not everyone, but certainly an increasingly large number of trainees do not see themselves going into the academic setting and I do not think that is necessarily a bad thing, but it certainly presents a new set of challenges for those of us involved in training and mentoring young people.

What are your goals for the ASHG while you serve as the society’s Executive Vice President?

My first overarching goal is to make sure that we as a society remain relevant to all segments of the field as it undergoes rapid growth and specialisation. I want to make sure that we remain the ‘big tent’ for all genetics individuals, including those who are going into highly specialised areas of genetics and also those who may not consider themselves geneticists, but who certainly are using genetic and genomic tools as they investigate important questions in basic biology, and in health and disease.

The National Institutes of Health (NIH) here has more than 30 institutes and centres, and there is only one that is formally called the National Human Genome Research Institute and has genetics in the title, but virtually every one of those institutes is involved in genetics research in one way or another. The people in those institutes might not see themselves

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as geneticists. They may be developmental biologists, cardiologists, specialists in addiction, specialists in ageing, for example, but they are all using genetic tools and I want to make sure that those individuals see the American Society of Human Genetics as a potential home for them to collaborate with individuals who are formally trained in research.

I am trying to find ways to keep our young people engaged as well, to ensure that they remain members of the society once they have completed their training. We have a lot of programmes underway for trainees and we recently instituted a new membership category for early career investigators, because we know that as people make the transition from formal training into their first professional positions their finances are constrained.

Finally, trying to make genetics attractive to under-represented minorities is an ongoing, major challenge, not only for us, but for all of science.

You have already mentioned the ASHG’s Annual Meeting. What else does the ASHG do to encourage interaction among human genetics professionals?

We continue to work on building collaborations with other groups. For example, we have joined symposia with other societies. We began this with a session that we call Building Bridges, with the European Society. We also have joint memberships with the European Society of Human Genetics.

Increasingly, we are initiating collaborations

What are key considerations in the formation of science policy, and what involvement does the ASHG have in this field?

My colleagues who are heavily involved in science policy have said to me over the years that there are a few questions to ask upfront if you are thinking about the determination of new policy. Firstly, you need to consider whether the situation is truly in need of a policy solution. Secondly, you need to ask if there is an appropriate policy solution that one could construct that would be acceptable to the various stakeholders. There is the classic example here in the United States with prohibition - the policy was an abject failure because it was not acceptable to the various stakeholders, that is, those of us who like to drink Irish whisky. I am being a little glib here, but you can come up with examples in biology and medicine as well.

Another important issue in thinking about policy is, is the policy enforceable? Do you actually have the mechanisms to ensure that the policy works and that the people it is intended to influence abide by it and obey it? When policy-related issues come to our attention, we apply those criteria and others and we then ask ourselves whether we can make a helpful and credible contribution given the expertise available to us. We also look at what is important to our members.

Are there issues that are important to the members where we can help promote their interests from an advocacy stand point?

Things like making policy statements about the importance of research funding, access to reproductive services, those kinds of things.

Our policy staff have developed a new policy platform that is now available on our website and it lays out the broad areas where we will be attending to policy-related issues. These

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Thought Leadership

Our members have been involved in the creation of new knowledge in the genetics field and have been responsible for many central advances, particularly related to genome science and the relationship between genetics and health and disease are the conduct of genetic research, the use of genetics in health care, the use of genetics in society, and then issues related to genetic literacy across the board.

Research on the human genome generates some important ethical questions. How does the ASHG go about identifying and addressing these issues?

These kinds of issues come to us in a variety of ways, but generally they emerge from the advances in science and technology that often become evident to our members first, usually before they get to the general public.

Sometimes we can see them coming. For example, if you were paying attention to what was happening in genetics in the 1970s and 80s, you could see that the growth of prenatal diagnosis at that time was going to raise some important ethical issues. Things like prenatal diagnosis for sex election and therapeutic abortion in the case of genetic diagnosis.

A while back, people who were working in ethics came up with a term that I really like, ‘anticipatory ethics’. It is about trying to stay ahead of the curve and anticipate what is coming down the pipe, anticipate what the issues are, anticipate the groups that might be affected, who the stakeholders are, who has the requisite expertise to help us through these issues.

Sometimes you can see what is coming and hope to prepare for it, but sometimes we are taken a little bit by surprise, as with the rapid expansion of gene-editing technology over the last couple of years, and its potential application to germ line genome editing (a technique to modify reproductive cells). We are currently working on a policy statement about that.

Another example was genetic testing in children, in the wake of whole genome sequencing and whole exome sequencing.

These types of sequencing will reveal genetic variants related to disorders that clinicians would not generally test for in children and

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adolescents. That landscape is changing considerably because of the availability of this type of testing, and so we were obliged to go back and revisit a statement that we had developed a number of years ago, to update our own thinking about genetic testing in children and adolescents in the wake of new technology. We try to make informed judgements about these ethical questions and consider where the expertise of our members can be most helpful. There are a lot of issues out there and we cannot take all of them on, so it is also important to identify those that are most in need of our attention.

Stories about designer babies and other headline-grabbing portrayals of the impact of genetic engineering appear from time to time in the popular press. What steps does the ASHG take to reframe public debate on genetic advances?

We see our role as helping to ensure that the treatment of genetics is reality-based. A lot of the things we hear about designer babies are simply not possible. So we try to work with the press to say what is possible and what is not possible. The notion at the moment, that you can make a series of decisions and apply a series of genetic tools that will ensure you have a child with any particular trait, like enhanced intelligence – that is simply not reality. So we work with the press to reframe what the public debate should really be about, and to keep it reality-based.

One of the aims of the ASHG in promoting the science of human genetics is to encourage its application for the common good, how does it go about this?

The intent to increase our store of basic knowledge – I think that is an essential benefit to humanity. Even just knowing more is good, and then we promote the responsible application of human genetics in personal and public health through our policy and advocacy efforts. We also have many different educational activities to help with the appropriate integration of genetics into the public sphere, into public thinking, and also

into application. We have educational programmes ranging from high school up to education for practising health care providers, to help ensure the appropriate integration of genetics into mainstream health care.

What developments do you see happening in the field of genetic research over the next ten years?

I have to be careful here because we in the genetics community have been criticised for trying to over sell the fruits of genetic research, especially where personal and public health are concerned, even though we have made good progress in that field.

But I will talk a little bit about what might be coming down the road.

Certainly our Precision Medicine Initiative here in the United States, which was an initiative of our former president Barack Obama, will continue. It is a research project, created in 2015, with the aim of advancing tailored medical care for the individual. As part of the project, genetic and health data is being collected from one million people.

Genetic and genomic tools will be employed to investigate the distribution of disease in society and the association of identified genetic variance with predisposition to disease, and to provide insights into treatment and prevention.

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Joseph McInerney (right) discusses ASHG programmes with Dr Hudson Freeze, ASHG member and FASEB president, at ASHG’s exhibit booth at the Society’s 2016 annual meeting, in Vancouver

There is a philosopher and neuroscientist, Sam Harris, who wrote not long ago that the core of science is not controlled experiments or mathematical modelling, it is intellectual honesty. Creationism and other pseudosciences are simply intellectually dishonest, and they confuse people and politicians, often with false equivalents. For example, there are not two co-equal sides in the evolution–creation debate. One side has rigorously vetted evidence, derived from the well established methods of science. The other has revealed knowledge, often from scripture, that is completely bereft of scientific evidence and requires faith-based acceptance. These are not equal ways of looking at the world.

They do not produce knowledge of equal value when one is thinking about the natural world.

Certainly there will be an ongoing consideration in the future of the relationship between one’s genes and one’s environment.

I also think we will see a greater involvement of global populations in genetics research to ensure that our research truly reflects the variation that is out there around the world.

I think you will see insight into common complex diseases that are major causes of mortality and morbidity around the world – cancer, heart disease, diabetes, psychiatric illness – I expect there to be continued insights into those maladies.

I am also sure you will see a continued focus on how we manage big data. The Human Genome Project – a research programme which aimed to map and understand all the genes of human beings – has received a lot of attention. However, the scientific community has sequenced the genomes of thousands of other species now, and so there is an enormous avalanche of genomic data that we have to figure out how to manage appropriately. Not only how to share the data effectively, but how to mine it in the most appropriate way to answer the questions we want to ask. So you will see lots of focus on computational biology and the management of big data. We never know where the next big technological breakthroughs will occur, but we will certainly see continued investigation into gene regulation and expression.

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A further major area of activity is the continued exploration of the genetic architecture of our species, its population history. What does the species look like from a population genetics standpoint? And of course that provides insights into our own history, into human evolution. How we came to be what we are. Those are some of the things I see happening in the next ten years.

Before taking up your current post at the ASHG you were the recipient of the society’s Excellence in Education Award in 2005.

This was in partial recognition of the key role you played in keeping evolution in high school biology texts, which you carried out in the face of strong opposition from those trying to introduce creationism into high school science teaching. Why was it so important to you personally to stand up for science generally, and science education in particular?

I am very passionate about this. I have been involved in the evolution–creation issue for more than 30 years. For me the heart of this issue is the recognition that science is really a unique and powerful way of asking questions and seeking answers, and we do significant damage to science when individuals or groups try to impose non-scientific ways of thinking about the process for reasons of ideology, whether the ideology is religious or political.

Science education in schools is the only place where most of the public encounters the methods and habits of mind of scientific enquiry, and gets an exposure to a thoroughgoing scepticism, the notion that we should question everything, and I think we need to protect that educational process from ideologically-driven challenges.

• If you would like to find any more information about the American Society of Human Genetics, please visit their website at http://www.ashg.org/.

Contact American Society of Human Genetics 9650 Rockville Pike, Bethesda, MD 20814, USA W: www.ashg.org E: society@ashg.org

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Diagnosis in the genomics era Rady Children’s Institute for Genomic Medicine in San Diego, California, has a pioneering programme, headed by Dr Stephen Kingsmore, president and CEO, that delivers life-changing genetic diagnoses for severely ill newborn babies.

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ach year, hundreds of thousands of children are born with unidentified genetic diseases, and many of them end up in neonatal or paediatric intensive care units with difficulty feeding, epileptic seizures, or other serious issues. In fact, more than 20% of infant deaths are ascribed to genetic disease, yet the gene at fault is often not obvious looking at the child.

A NEEDLE IN A HAYSTACK There are around 20,000 genes in the human genome, so searching for a disease-causing

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mutation is like seeking a needle in a haystack: a painstaking process that, for many children, simply cannot be completed fast enough to deliver life-saving treatment.

But, thanks to Dr Kingsmore, Dr Dimmock, and their growing team of expert colleagues, all this is changing. The world-renowned paediatric specialists have devoted themselves to creating a super-team that develops and deploys novel techniques for ultra-rapid whole genome sequencing and analysis, to achieve rapid genetic diagnoses in acutely ill babies

and infants. In fact, last year the team achieved the Guinness World Record for the fastest genetic diagnosis, taking just 26 hours. On average, a full genome sequence for most infants can be generated and analysed in around two or three days.

The impact of diagnosis by whole genome sequencing is often life-changing. The team now routinely test their critically ill patients for over 5,000 diseases, of which over 500 have highly effective treatments. Crucially, in at least 70 of these not found by routine

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Child Health

newborn screening, the early initiation of treatment prevents serious disability or death.

For instance, if genome sequencing uncovers a mutation in a gene for digestion, causing a baby to be unable to process a particular nutrient which then effectively becomes a poison, a simple change of diet can halt the disease: the sooner the condition is diagnosed, the less long-term organ damage the child will suffer. Minutes matter.

UNRAVELLING THE GENOME In a series of clinical trials funded by the United States National Institutes of Health, the Rady Children’s Institute team are analysing the clinical and social benefits of rapid genome sequencing for diagnosis in newborns. They reason that sequencing the whole genome identifies disease-causing mutations overlooked by other approaches which sequence only the protein-coding regions of the genome, known as ‘exomes’.

Paradoxically, sequencing the whole genome is also faster by one day than exome sequencing. Days matter.

The Rady Children’s team’s world-recordbreaking diagnostic speed was achieved by harnessing two main factors: improved technologies for genome sequencing, and increased understanding of what matters to physicians treating acutely ill infants, which enables the genome to be interpreted in the context of disease.

The first of these – genome sequencing technology – took the form of three state-ofthe-art ‘next generation’ DNA sequencing machines made by San Diego-based Illumina, purchased through a $120 million gift to establish the Institute from philanthropists Ernest and Evelyn Rady. Just one of these machines can sequence three genomes in a day which means the team can simultaneously obtain the genome of both a child and its parents, which may be crucial to finding the genetic cause of a disease.

The second key factor is to use artificial intelligence, combined with physician expertise, to create a highly customised disease suspects list for each patient, which is then compared with the genome sequencing results. The AI system compares the symptoms exhibited by a patient with a database of over 5000 genetic diseases, to produce a shortlist of genes that might be at the root of his or her illness, which can then be studied in detail by the team once the genome is sequenced.

Dr Kingsmore in front of the Acute Care Pavilion at Rady Children’s Hospital where the neonatal intensive care unit is located

Another key part of the Rady Children’s approach is the team of experts – not just medics but also computer scientists – that Kingsmore has assembled. These handpicked scientists fine-tuned the computer hardware and software used – known as ‘DRAGEN’, developed by another San Diego company, Edico Genome – to enable analyses to be conducted in minutes rather than days, and with greater sensitivity than standard methods.

The overall protocol that the Rady Children’s team has deployed, incorporating sequencing, computation, analysis, and clinical interpretation, enables them to quickly ‘zero in’ on a child’s condition, delivering targeted information of immediate, vital clinical use. The final, critical element is telementoring, where the Rady Children’s team provides diagnostic results in the setting of recommendations for treatment of these individually rare disorders. It is often the case that physicians may never have had a newborn diagnosed with that disorder before, and so need help figuring out the best therapeutic approach.

CLINICAL AND CULTURAL ADVANCES Rady Children’s Institute has an inclusive and outward-looking ethos that includes not only conducting cutting-edge genomic medicine research, but also working in tandem with the Rady Children’s Hospital – the largest paediatric hospital in the state of California – to translate these advances into revolutionary new standards of patient care.

The Institute’s stated goals therefore include conducting research to enable the prevention,

diagnosis, treatment and cure of childhood disease, contributing to knowledge and data-sharing among like-minded researchers, and establishing a strategy for geneticallypersonalised medicine in the broader community.

The impacts on paediatric healthcare are already being felt, with over 50% of babies tested getting a diagnosis and this figure set to rise. Even if a genetic diagnosis does not lead to a cure, the psychological impact upon families of having a name for their child’s disorder should not be underestimated. The value of the Rady Children’s approach is that it comprises a single, broad test, rather than the traditional approach of sequential testing for different syndromes, which can ‘prolong the agony’ for worried families seeking a diagnosis.

The Rady Children’s Institute’s Clinical Genome Center can currently process over a thousand genomes a year, but Dr Kingsmore would like to see the technique becoming much more prevalent, practised in neonatal and paediatric intensive care units across the world. Of course, widespread adoption requires intensive investment, and Kingmore and team are constantly pursuing philanthropic funding to extend the programme to every Children’s Hospital with a neonatal intensive care unit world-wide.

Although the research is at a pioneering stage, Dr Kingsmore and the Rady Children’s team clearly have great ambitions. Their work and intentions can only be to the benefit of those parents desperately seeking answers for their children.

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with Drs Stephen Kingsmore and David Dimmock

Dr Kingmore, what first drew you to the area of genomic medicine? How did you first get involved?

Stephen: Well it happened by accident.

All my career I’ve been working on applications of new technologies that may have a bearing on medicine, and over the last decade it became increasingly apparent that genome sequencing was going to transform health care dramatically.

Decoding genomes of acutely ill infants seems to be the biggest opportunity today.

And what would you say have been the key advances leading to the ability to achieve a diagnosis in just 26 hours?

I think the key thing has been speed. A variety of advances have come together to allow incredibly fast genomes – and diagnoses. In order to make a diagnosis you used to test diseases one at a time.

Since there are over 5,000 diseases and for any given baby there’s a list of a couple of hundred that might be causing their symptoms, it was remarkably difficult to make a diagnosis before the child either died or was sent home. Next-generation sequencing is an incredible thing – it allows all diseases to be tested at once, and that’s a complete paradigm shift.

And then the second thing has been that internet-based cloud computing and software improvements allow us to analyse genomes almost instantaneously. The first human genome took about 13 years to complete, and our world record was 26 hours! But on a routine basis we can do it in roughly two days if we really need to.

How many patients have you diagnosed so far using this current approach?

Seven months after starting at Rady Children’s, we’ve diagnosed 26 of 58 babies. Before that we also diagnosed 32 of 72 babies at Children’s Mercy Hospital.

What’s different in San Diego is that we’ve established a team with some of the best people in the world - guys like David Dimmock, Joe Gleeson, Narayanan Veeraraghavan, Matthew Bainbridge, Yan

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Ding, Shimul Chowdhury and Shareef Nahas – who have immense combined experience in doing this.

What is it about the Rady Children’s Institute that makes it better placed than other institutes to conduct this kind of research and translate it into benefits for patients? Presumably the team you have built is one of the key points?

Yes. We really are a team of exceptional people and I’m just privileged to be called the boss of this revolutionary new approach to saving children’s lives. How did we get them to Rady Children’s? I think it’s a combination of things truthfully, and sometimes it’s a bit of a mystery to me how we manage it.

Undoubtedly, I had a reputation and that helped a wee bit. Of course, having a total endowment of $170 million helps a big bit.

It means people know that there’s a strong financial footing, and that something big is going to happen. I think also that what we’re trying to do is something that resonates because there’s nobody else in the world currently focused on it. Of course, we live in San Diego which is starting to become recognised as the world’s centre for genomic medicine, and that helps a lot.

So has San Diego being a centre for genomics helped you collaborate, for example with Illumina or other industry bodies, to bring the work on faster?

Absolutely. Quite a few of our team have been working alongside Illumina for as much as a decade. As we thought about moving here there was a lot of dialogue with guys like Dr Eric Topol at the Scripps Research Institute and with Illumina. There are 800 biotech companies in San Diego, many of them focused on genomics, and it really makes a huge difference to be surrounded by these companies. If you think about it, most of them have virtually no access to real-life patients and so they are very excited about their ability to test their new diagnostics and treatments with us. So, that truly has been a big benefit.

It also has an interesting side effect – genomics in general is a huge employer in our

The impact of diagnosis by whole genomesequencing can be life-changing region, and that means that our populous are somewhat unique in terms of their genomic literacy: they know what a genome is. That means that when we approach parents of a critically ill baby in an intensive care unit who are having the worst day of their life, they have a basic understanding of why somebody is approaching them and saying, “I think we can potentially help your kid if you’d like to enrol in this study”. That’s made a big difference in terms of our rate of enrolment of children.

Why is this method so helpful for babies in particular?

Babies are unique for several reasons. When a baby is born, it’s independent for the first time. It’s the first time its lungs have ever been used, at least to breathe, and the same with much of its metabolic status. Genetic diseases have been lingering there ever since the baby was formed, but it’s only at birth that many of them come to light because those organ systems have never been used before.

So, there’s a very high incidence of genetic diseases at birth. They’re the leading cause of death in infants (children up to one year of age). They’re also the leading cause of death in neonatal intensive care units (NICUs) and in paediatric intensive care units (PICUs).

When you’re able to give a diagnosis using this method, how does that help the infant and their family?

Let’s imagine that a baby is born and it has a disease. The baby winds up being transferred to a special unit, like a NICU, to receive treatment and a race is on to make a diagnosis. Now until you have a diagnosis, doctors use what is called a clinical diagnosis.

For example, this baby has a seizure disorder,

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What I really struggle with is the fact that in aggregate the world experience of this is probably only 150 babies, yet there are probably 80,000 babies a year in the US alone who could benefit from this, and really this is something that ought to be available to babies globally. We’re working with large children’s hospitals – such as Children’s Hospital Colorado, Children’s Hospital of Orange County, and Children’s Hospitals and Clinics of Minnesota – to grow to availability in five regional centres, and then 50, and then 500, and ultimately in about 5,000.

Above: Lab technician Luca Van Der Kraan prepares samples for testing Right: Shareef Nahas, Clinical Lab Director, Sergey Batalov, Senior Bioinformaticist, and Narayanan “Ray” Veeraraghavan, Director of Information Technology collaborate to complete the crucial final step of interpreting the sequenced data

or this baby has hypoglycaemia. That’s a clinical diagnosis and based on that you’ll follow the best treatment for that clinical diagnosis. Given that there are 5,000 genetic diseases, that treatment is rather empiric, rather generic and not specifically targeted to the underpinning cause of the disease.

So, when we get a molecular diagnosis by decoding the genome, we’re able to give specific targeted treatment for that child’s precise genetic changes.

protocol. We started that and the baby stopped seizing and is now at home. We had a baby with the same gene defect in our NICU a year ago, prior to rapid genome sequencing. That baby waited eight weeks to get a diagnosis and seized continually for eight weeks. That’s an example of what we’re dealing with and that’s why this is so revolutionary. Seizing is not good for a baby’s brain so a quick diagnosis can protect the brain from further damage.

So, let’s take seizure disorders. That’s something we see not every week, but nearly every week; babies are born and they have seizures. There are literally hundreds and hundreds of genetic disorders which can cause babies to start seizing at birth and to continue to seize. The treatments for infantile encephalopathy, this seizure phenomenon, are incredibly different. Some infants need special diets, some of them need antiepileptics. With anti-epileptics, these range enormously in terms of which ones you use.

Another time, we were able to confirm that surgeons should go ahead with a liver transplant – a costly and risky procedure in a newborn. And on a separate occasion we stopped a surgical procedure taking place based on a clinical diagnosis – the procedure was very risky and in that case wouldn’t have benefitted the infant. So, there are three examples just from the last month or so that help you understand why this is going to transform the medicine practised for newborns all over the world.

For example, we had a child just a couple of weeks ago. The baby was born seizing, continued to seize and within two days we were able to diagnose the child as having Otahara syndrome, and to find the specific genetic mutation. That particular disorder has a highly specific anti-epileptic treatment

Is the Rady Children’s Institute the only institute in the US offering this approach?

Almost, but not quite. We started this work at Mercy Children’s Hospital in Kansas City, and so my old team are still there and still doing this. In addition, there are other groups who are now emulating our approach.

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What do you think are the main barriers to rolling it out, across the US to begin with and then globally?

First, we need education and mentorship, so that neonatologists all over the world get up to speed on this. Second, we need hard evidence of clinical usefulness. Medicine always progresses based on hard evidence – clinical studies, ideally randomised controlled clinical trials – and typically you need several of these, and they need to be multicentre, so it takes quite a while. Third, implementing this approach is beyond the range of the vast majority of NICUs. It would be like saying, “Let’s do heart transplants at every children’s hospital in the world.” That’s not feasible, and so we need to figure out a regionalisation method whereby specialised centres can offer this to all local children’s hospitals world-wide.

You have won the Guinness World Record for the fastest whole genome sequencing. Do you think that has been helpful for raising awareness of your research, whether that’s within the public or among neonatologists?

The Guinness World Record’s a funny thing. They pinned my name on it, but honestly, it’s a team sport: Illumina were involved in that along with Edico Genome.

Illumina built the sequencer and then Edico Genome built the computer chip (both the Ferrari of their class), and then it was a team of folks including me who actually set the world record. It has been really helpful – if

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Child Health

we publish a paper in a scientific or a medical journal, that helps with a particular audience, but Guinness World Records are something that the public can latch onto. And that really does help, because at the end of the day, we can only do these types of things to the extent that parents say yes.

Obviously, the team effort is very important to your research. Who are some of the key players in the team?

We recruited David Dimmock from Medical College of Wisconsin. He was one of the first people to get started in paediatric genomic medicine, and we were very fortunate to recruit him. He’s a practising physician and many of us are technologists – it’s so important to have somebody like him to give us balance. He also helps give us credibility in the medical profession.

Another example is Todd Laird, our Chief Operating Officer. Todd has run huge commercial businesses in the biotech sector and then he decided to reinvent his career and help start a research institute. If you think about our ability to go from doing this in one children’s hospital to doing this globally, you need somebody who’s had global commercialisation experience.

Our Sequencing Operations Director, Yan Ding, ran the biggest medical genome centre in the US, Baylor College of Medicine Genome Sequencing Center, for 20 years, and she now manages our sequencing.

We have a team where every member is an expert in their field.

David, it would be great to hear more about your experience working on this project.

David: One of the things that was very obviously apparent in the beginning of the century was how difficult it was to figure out a child’s diagnosis. For quite a few genetic disorders, if you make the diagnosis early enough you can treat the disorder and save the kid’s life, or save their brain. But you need a reliable test. Right now, of the 5,000 plus genetic diseases we know of, we have about 30 conditions that are coupled with newborn screening in the US and I think about 12 in the UK – we’re barely scratching the surface in terms of newborn screening.

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Lab Technologists Laura Puckett and Luca Van Der Kraan, operating sequencing machines while Dr Yan Ding, Director of Sequencing Operations observes

The overall research protocol enables the team to quickly ‘zero in’ on a child’s condition, delivering targeted information that can be of immediate, vital clinical use Before I came to Rady Children’s, we started doing genome sequencing in the Children’s Hospital of Wisconsin in 2010. I think it’s the first place to do clinical genome sequencing for people that were sick. We sequenced about 22 children through that programme in the first year, and made some quite dramatic diagnoses. Then we moved towards more of a commercial diagnostic lab approach, where we were offering this testing more globally, worldwide. Over the next five-year period that I was in Wisconsin, we probably tested about 3,000 or 4,000 families and were making a diagnosis about a third of the time.

The trouble is that most of the children that were qualifying for the sequencing, were qualifying because people had failed to figure out what was going on and I think one of the worst feelings in the world is making a diagnosis on a child, when if you’d

known earlier you could’ve prevented the child from getting sick. So, the real appeal of Rady Children’s and what we’re doing here is the fact that we’re sequencing the children very early. Our target is to enrol kids within 96 hours of being born or arriving in our NICU, and the reason we’ve moved to that approach is that for many of these diseases that are treatable, they’re only treatable within a limited time window.

And so the real appeal of sequencing neonates is that you can actually get in early and change the long-term outcome.

As a clinician, you must be more involved with patients on a daily basis. How is it working somewhere where you’re working with patients and research in such a tight combination?

There has been a huge increase in the number of potential treatments available for kids with rare diseases. One of the best

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Detail That’s a genetic disease that normally wouldn’t have been noticed or at least not at that stage?

Yes, they wouldn’t have seen clinical geneticists. Nobody would have tested them, nobody would have even thought that they had a genetic disease. What we’re finding at Rady Children’s is that so many of these kids have genetic diseases. Then think about the 80,000 to 100,000 kids a year in the US who fit the exact category of the kids we’re sequencing and how a portion of those have a treatable, genetic condition.

These are kids with genetic diseases that are being born in the US without a diagnosis and without appropriate early treatment. So, the reason we talk about going to five hospitals, and 50 hospitals, and 500 hospitals is because we have this huge passion to try and save as many kids as we can.

parts of my day is being able to recommend new treatments for diseases for children who would otherwise die without the proper treatment. At Rady Children’s I have the pleasure of being able to mix improving diagnosis with trying out new treatments for diseases that would otherwise lead to lifelong disability or death.

At Rady Children’s one of the exciting things is that the research is currently being funded by an endowment. Previously, we’ve had to cobble together funding for the testing, either via insurance or the health care system, limiting the number of kids’ lives you can impact. You spend almost as much time trying to figure out where the money’s going to come from as you do actually taking care of the kid. But here, if kids meet our criteria we get to just go ahead and sequence them.

Previous studies looking at genetic testing in children have often selected kids to sequence because a clinical geneticist thought they had a genetic disease. What we’re doing at Rady Children’s now is sequencing almost all the kids that come into the NICU. I think the thing that has really shocked me is the fact that half the kids we’re sequencing have a genetic disease.

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For those children where you can provide a diagnosis but it’s not treatable, is there still a benefit, especially for the family, of knowing what it is?

I think that’s an important question.

When we talk about treatment, we mean that there is a specific therapy that is targeted at the underlying cause. That’s an important concept because being able to tell a family what condition their child has, and therefore what to expect for the future is very helpful.

With a portion of the kids we take care of, what the diagnosis does is provide a certainty to the parents around the prognosis. For example, I think for many parents, if they know that their child has a condition that is not compatible with long-term survival, it’s emotionally a lot easier for them to choose not to do certain things that are potentially unpleasant to the baby. So even in the situations where there is not a treatment that is targeted to the underlying cause, having a diagnosis can be hugely useful in taking care of that child and deciding what should and shouldn’t be done – you can make sure that the degree of harm or risk to which you’re putting the baby is proportionate with the potential benefits.

RESEARCH OBJECTIVES The team at Rady Children’s Institute for Genomic Medicine focus on increasing the speed and availability of genomic medicine for children. This includes the most rapid whole genome sequencing technology for use on neonates in order to detect and treat genetic disorders at the earliest opportunity and with the greatest precision.

FUNDING Rady Children’s Institute for Genomic Medicine; National Human Genome Research Institute; Eunice Kennedy Shriver National Institute for Child Health and Human Development.

KEY TEAM MEMBERS Illumina Inc., Edico Genome, OMICIA Inc., DNANexus, Children’s Mercy Hospital (Kansas City), Sanford Children’s Genomic Medicine Consortium BIO Led scientifically by Dr Stephen Kingsmore and Dr David Dimmock, the Rady Children’s Institute for Genomic Medicine was established in 2014.

Working alongside Rady Children’s Hospital, San Diego and the University of California, San Diego, the Institute houses a team of world leaders in genomic medicine for children.

CONTACT Rady Children’s Institute for Genetic Medicine 3020 Children’s Way, MC 5129 San Diego CA 92123 USA W: www.RadyGenomics.org E: rcigm_collaborations@rchsd.org

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Lost for words: investigating specific language impairments 18

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Child Health: Language

Centred around her lifelong interest in language development, Professor Mabel Rice, of the University of Kansas, studies children who struggle to learn and develop their native language. Her investigations into the genetic and neurological elements of language acquisition have important implications for speech and language intervention methods and, ultimately, the quality of life of those for whom language is an everyday challenge.

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earning your native tongue is a skill that many develop without really thinking about it. But, for those with a Specific Language Impairment, learning this skill can take a lot longer. Luckily, Professor Mabel Rice’s research is currently shedding light on this area of research, and her lifelong fascination with language acquisition has seen her dedicate her career to understanding how children learn and develop language.

In her early work, Professor Rice encountered children who struggled with simple tasks such as describing the colour or size of objects.

It was these encounters that motivated Professor Rice to carry out further research into delayed language development.

Ultimately, her research aims to broaden our understanding of why some children struggle to learn their native language, while for most children, the world over, this learning process happens automatically.

THE ART OF COMMUNICATION Children who are late to acquire language without an obvious reason for the delay, such as hearing loss or other developmental delays, are said to have Specific Language Impairment (SLI). Children with SLI have difficulties picking up, processing and interpreting language, and their overall language level (i.e., vocabulary size and ability to generate complete sentences) remains below the expected level throughout adolescence and adulthood. Subsequently, those with SLI often experience further complications, such as reading impairment, as well as significant challenges in their social, academic, personal and professional lives.

Evidence suggests that SLI is heritable, and Professor Rice studies the genetics and neural pathways of children with SLI and their families, in twins as well as single-born children.

EARLY IDENTIFICATION OF SLI Professor Rice’s lab at the University of Kansas takes a comprehensive and unique approach to their research, with an emphasis on the identification of a grammar marker, indicating

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the presence of SLI in preschool children. One important finding from her research has been that children with SLI particularly struggle within the domain of tense and agreement marking. This discovery led Professor Rice and her team to develop the Test of Early Grammatical Impairment (TEGI) and other experimental grammatical judgement tasks that can be used to identify young people with a history of SLI. In addition, the lab was also the first to discover that vocabulary deficits are more likely to persist later into adolescence in girls than boys. This finding has strong implications for how adolescent girls with SLI can be identified and supported.

UNIQUE LONGITUDINAL DATA Professor Rice is currently involved in a long-term collaborative project that studies the genetics and epigenetics (traits that are inherited, but not through DNA) of SLI. Four previous funding rounds have created a unique ongoing empirical archive of data comprised of 5000 children and their families. When these children reach adulthood, Professor Rice studies their children, providing a unique, multi-generational perspective on SLI. Using this data, the study has three principal aims: firstly, to document how language, speech and reading abilities develop over time for children with

SLI in comparison to their unaffected peers; secondly, to conduct family-based candidate gene investigations to identify the gene networks involved in language impairment; and, lastly, to carry out brain imaging studies to understand the neuroanatomy of language processing in children with and without SLI. For children with SLI, findings from this ongoing study show a consistent pattern of a delayed onset of language and language development on a parallel growth trajectory, but at lower performance levels to those without SLI. These lower levels persist through adolescence and are often accompanied by reading impairments. Family-wide investigations have found elevated rates of affectedness in family members. Related genetic studies suggest that it is a set of genes known to influence the development of the central nervous system that is responsible for language, speech and reading impairments. The continuation of this study will allow Professor Rice and her collaborators to expand on these findings, with the hope of ultimately identifying the components of the brain that can provide the missing link between DNA and the characteristics of how an individual learns and develops language.

STRONG PARTNERSHIPS Professor Rice also directs a study of twins, in collaboration with colleagues in Perth, Western Australia, that investigates how SLI manifests in twins. These two parallel longitudinal studies allow for a unique opportunity to investigate the extent to which SLI can be attributed to genetic variation, known as heritability. With data from 2,000 twin children, the study has provided the first robust empirical evidence that demonstrates delayed language acquisition in twins, in comparison to singleton children. Twins have comparatively delayed language skills at 24 months, with the gap reducing at four and six years, suggesting that twins are able to catch up

Professor Rice’s research aims to broaden understanding of why some children struggle to learn their native language, whilst for most children, the world over, this learning process happens automatically 19

What disadvantages and challenges are faced by those living with limited language capacities?

Good native language skills bring many advantages. Even preschool children like to be friends with others who have good language skills: those who can successfully verbally negotiate with the teacher and other children for favourite toys or activities and can build friendships through verbal interactions. Children who cannot easily do this are less likely to be preferred playmates and less likely to be teachers’ helpers. As children learn to read, they acquire many advantages academically, socially and, later, in the workplace or in higher education. About half the children with limited language capacity show difficulties in learning to read and may not reach age expectations, thereby limiting their educational or employment activities.

Because language acquisition is so easy for most children, those with limited language capacities can be perceived as not trying hard enough, not very smart, or not motivated to fit into the social group.

These assumptions can be, and often are, untrue, leaving persons with limited language capacity feeling misunderstood and at a marked disadvantage in changing peoples’ erroneous assumptions. Recent research shows that most children with limited language capacity do not “outgrow” the problem; instead, they learn to blend in with peers, although they lack the quick use of linguistic alternatives to negotiate conversations, disputes, and advocacy for their needs. This “invisible” but crucial requirement for social, academic, and employment opportunities can have profound effects: a recent study followed up on five-year-old girls identified with a language disorder when they were 31 years of age. They were almost three times more likely to report child sexual abuse than control children (43% vs 16%). Language ability is a highly valued human attribute that everyone wishes to have, especially those children and adults with a history of childhood language disorders such as SLI. Why is SLI often confused with Speech Sound Disorder (SSD) and why is it important to be able to differentiate between the two?

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Children who receive speech/language therapy are most likely to have SSD. This is because SSD is obvious to other children and adults – children with SSD can be difficult to understand or have an unexpected way of saying sounds in words. Technically, SSD is a condition in which sound production is not as expected for age level. Examples at the five-year-level are “top” for “stop”, “bawoon” for “balloon”; “wabbit” for “rabbit”; a lisp such as “theven” for “seven.” Prognosis for a child with SSD to resolve the speech problem is very good, especially with therapy. Those with SLI, on the other hand, have a problem with the language system.

There are, roughly, three major dimensions of the language system that can be affected: the level of vocabulary size which affects how many words a child has available to express an idea or request; grammar which affects how to formulate sentences, such as “Where does he like to play basketball?” not “Where him like played basketball?”; and social uses of language, such as how to tell a joke or when to use a title such as “Mrs” versus a woman’s first name. Language problems such as these usually do not affect intelligibility but they can leave an impression of immaturity, social awkwardness, or rude social interactions.

Because they usually appear to be typical children, the language problems of children with SLI are frequently unidentified as the key element of their difference from other children. The prognosis for improvement or spontaneous “outgrowing” of SLI is much more guarded than for SSD, and SLI is more likely to persist into adulthood.

Your study on individuals with SLI in Kansas is running in parallel with a study on twins with SLI in Perth. What allows the results of these two geographically separate studies to be directly compared?

The population demographics of the metropolitan area of Perth, Australia are very similar to Kansas City, Missouri, USA, the area where the Kansas study is based. The same standardised, norm-referenced tests for language acquisition and identification of language impairments are valid in both areas, making it possible to make meaningful comparisons across the two studies. Further, longitudinal studies of young twins are difficult to carry out in the USA given the

health care system, whereas when we started the twin study in Australia it was possible to recruit a relatively large sample of twins and follow them. In both areas families are likely to live in one region for long periods of time, a valuable demographic for longitudinal studies of children’s language acquisition.

You are currently developing an app to aid your research. How does the app work?

The app is designed for mobile phone administration of simple grammar assessments based on the experimental measures developed in my lab. There is an assessment version in development, as well as a practice version. It will provide a method of grammar assessment that can be completed by anyone with a mobile phone, in any quiet place, and in a short time, with summary scores that are valid for detecting possible language impairments. It is intended to be a first step on the way to further treatment, much like the vision chart for eye assessments of children. The practice version will provide non-obtrusive ways to practice grammar tasks quietly and privately.

Do equivalent language issues exist across all languages?

At an abstract level, yes. At a specific level, languages differ in their sound, word, and sentence level requirements and these differences can influence which particular elements are easy or difficult for children with SLI. Are there any similar studies that investigate non-English language acquisition and development? Yes, although not nearly enough and not yet available across the long developmental arc as in the English studies. I know of very informative studies of Spanish, German, French, Norwegian, Swedish, Mandarin Chinese, Korean, Japanese, Italian, Greek and Dutch among others. There is a growing appreciation of how to carry out such studies and the need for better information about children with SLI and other forms of language disorders across languages and countries. There is also an emerging literature on bilingual or mulitilingual children with SLI that is very informative. As the world engages in more linguistic interactions across different languages it will be increasingly important to find ways to identify children with SLI, and parents with a history of SLI and unidentified language impairments as adults.

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Child Health: Language

Detail RESEARCH OBJECTIVES Professor Rice’s research focuses on how the human language capacity develops throughout life, from young children into adulthood. Her research looks at children with difficulties acquiring a language with no apparent reason behind the delay. She is currently working on a collaborative project looking at the epigenetics and neural pathways of children with SLI.

© Steve Puppe

FUNDING NIH: R01DC001803, R01DC005226, P30DC005803, R42DC013749, P30HD002528 and T32DC000052.

from an initially delayed start. Furthermore, the study found SLI to have relatively high heritability in twins and, as found in previous studies, this heritability increases with age.

This finding essentially suggests that, for SLI, an individual’s underlying genetic makeup exerts increasingly more influence than the environment, as age increases.

IT’S ALL IN THE DETAIL To investigate in more detail the influence of genetics on SLI, Professor Rice is currently collaborating with geneticists from multiple universities worldwide. These collaborations are exploring the genetics behind highlevel cognitive abilities such as language and how delayed language development is transmitted genetically through families.

Genetic studies in Professor Rice’s lab have documented growth curves for children with and without SLI. The similarities and differences between these curves have led to the hypothesis that malfunctioning inherited cell-level timing mechanisms could be responsible for how SLI develops and manifests throughout childhood, adolescence and into adulthood.

COMMUNICATION IS KEY One of the overriding objectives that persists throughout all of Professor Rice’s research is the dissemination of research findings to those working practically with SLI children. Providing accessible information on SLI will help teachers and medical practitioners to appreciate which children are different, allowing them to better plan for their specific needs. The research outcomes will also aid clinical intervention methods not only in language-related impairments but also associated disabilities, such as autism and intellectual impairments.

The ongoing work of Professor Rice and her team will make a great difference to children with language impairments whose differences are often misunderstood and underprovided for. Although Professor Rice and her team have already made great progress in this field, there is still some way to go before SLI can be fully understood.

However, the future looks promising and, in the words of Professor Rice herself: “We’re dedicated to doing it.”

Children with Specific Language Impairment have difficulties picking up, processing and interpreting language, and their overall language level remains below the expected level throughout adolescence and adulthood www.researchfeatures.com

COLLABORATORS USA: Lesa Hoffman and Hashim Raza, University of Kansas; Shelley Smith, University of Nebraska; Bradley Schlagger and Steven Petersen, Washington University; Richard Ellenson, Ellenson Enterprises; Russ Van Dyke, Tulane University, NIH Pediatric HIV/AIDS Cohort Study, Ken Wexler, MIT Australia: Steve Zubrick and Cate Taylor, University of Western Australia and Telethon Kids Institute; Stephen Crain and Rosalind Thornton, MacQuarie University ARC Centre of Excellence for Cognition and its Disorders Norway: Synnve Schjolberg and Kristian Tambs, Norwegian Institute for Public Health United Kingdom: Silvia Paracchini, St Andrews University BIO Professor Rice completed her BA and MA at the University of Northern Iowa.

She undertook a PhD at the University of Kansas where she currently works as the Director of the Child Language Doctoral Program. She is also the Fred and Virginia Merrill Distinguished Professor of Advanced Studies and Director of the Merrill Advanced Studies Center.

CONTACT Professor Mabel L Rice, PhD Dole Human Development Center Room 3031, University of Kansas 1000 Sunnyside Avenue Lawrence, KS 66045 USA E: mabel@ku.edu T: +1 785 864 4570

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Juvenile Idiopathic Arthritis and sleep disorders – a co-morbid nightmare Dr Teresa Ward, from the University of Washington, is researching the reasons why Juvenile Idiopathic Arthritis (JIA) children are more vulnerable to suffering from poor sleep health and sleep disordered breathing, a co-morbidity that can negatively affect child and family health outcomes.

Child Health

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uvenile arthritis is an extremely painful and debilitating disease and can even affect children as young as two years of age. Juvenile Idiopathic Arthritis (JIA) is the most common rheumatic disorder affecting an estimated 12,000 children under the age of 16 in the UK alone. However, the underlying cause and processes are poorly understood.

Symptoms can range from mild to severe and can include joint inflammation, pain, morning stiffness and mobility restrictions. As a result, some children are limited in the physical activities they can participate in, leading to anxiety, frustration, and emotional distress.

JIA peaks between one to four years or six to 12 years, depending on the type of JIA, and 20% of children experience long-term pain, impacting their lives well into adulthood.

There are seven subtypes of JIA (oligoarticular JIA [four or less joints]; rheumatoid factor positive or negative polyarticular JIA [five or more joints]; systematic JIA; enthesitis-related arthritis; psoriatic arthritis; and undifferentiated JIA), defined on the basis of the clinical and laboratory features present in the first six months of illness.

Dr Ward, an expert on sleep health, has investigated the intriguing relationship between JIA and the prevalence of sleep disordered breathing, such as Obstructive Sleep Apnoea (OSA). Research conducted by Dr Ward and her team indicated that OSA is more common in six to 11 year olds afflicted with JIA compared to typically developing control children. However, many questions remain unanswered: What is the prevalence of OSA in JIA? Why is OSA more prevalent in JIA patients? When does OSA emerge in these children? Does OSA treatment improve the quality of life of JIA sufferers?

IMPACT OF SLEEP DISORDERED BREATHING Sleep, like diet and exercise, is essential for maintaining good health. During sleep, the body performs many fundamental functions including hormone rebalancing, cell repair

and memory consolidation. It is particularly important for children and adolescents to get adequate sleep, as it is crucial for their physical and intellectual growth and socioemotional development.

Obstructive sleep apnoea in children is a serious public health concern. Its timely diagnosis and treatment is important, as OSA is associated with adverse health outcomes (cardiovascular morbidity, obesity) and increased use of healthcare resources.

OSA is a common sleep disorder, affecting 1–4% of typically developing children, but the prevalence of OSA in JIA is unknown.

Obstruction of the upper airway leads to irregular breathing, hypoxia (reduced blood oxygen levels), snoring and fragmented sleep. The peak time of OSA is between the ages of two and six. During this period the tonsils and adenoids are comparatively large in relation to the airway, and can cause partial blockage.

Poor sleep health secondary to an underlying sleep disorder such as OSA and/or poor sleep habits has negative health consequences, including an inability to concentrate, restlessness, excessive daytime sleepiness, mood disturbances, and behavioural issues (e.g., hyperactivity). In fact, children displaying these symptoms can be misdiagnosed with attention deficit hyperactivity disorder.

JIA AND SLEEP DISORDER COMORBIDITY Research conducted by Dr Ward and her team has shown that 40% to 50% of school-age children with JIA suffer from OSA, in comparison to healthy controls.

Polysomnography, otherwise known as 'sleep study', is the gold standard to diagnose OSA, and this was used in her studies of JIA (involving 221 participants). During sleep, the patient's brain waves, blood oxygen level, carbon dioxide, heart and breathing rate, arousals from sleep, and the number of times a patient stops breathing are recorded and analysed. Importantly, none of these JIA patients had been referred to a sleep clinic for OSA evaluation. This is likely due to sleep not being routinely screened and assessed for in

Although paediatric sleep clinics improve sleep health, waiting lists are long and there is a lack of paediatric providers trained in sleep medicine 23

Child Health

Contrast in polysomnography readings between normal breathing (top) and OSA (bottom)

Actigraphy showing sleep fragmentation

paediatric primary and specialty care clinics.

Additionally, children and their parents may not be aware of their child’s sleep symptoms, thus needing a prompt from healthcare providers during clinic visits.

Dr Ward recently conducted studies to examine how OSA impacts the quality of life and fatigue in JIA. She compared JIA children with OSA to JIA children and typically developing control children without OSA, and found that JIA children with OSA had increased fatigue and impaired quality of life compared to JIA and typically developing controls without OSA. Quality of life and fatigue are important health outcomes for clinicians who manage JIA patients. Dr Ward’s findings highlight that OSA extends beyond sleep to affect children’s physical, emotional, and overall wellbeing. Further, JIA children with OSA also showed a slower mean reaction time and reduced attention span in comparison to JIA and typically developing controls without OSA. WHY ARE JIA PATIENTS MORE VULNERABLE TO OSA? Although there is no definitive answer, Dr Ward's research may help explain why JIA patients are more prone to OSA. JIA children

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have a high prevalence of arthritis in the temporomandibular joint (TMJ), which is a risk factor for OSA. The TMJ (or 'jaw joint') is connected to the temporal bone and mandible (or lower jaw), and TMJ arthritis may impair mandibular growth, restricting breathing and resulting in OSA development.

However, more research is required to confirm this.

POTENTIAL TREATMENTS AND BIOMARKERS JIA and OSA can be treated independently – JIA patients respond to a combination of anti-inflammatory and disease-modifying drugs, whereas OSA patients who are children are treated with surgery (removal of tonsils and/or adenoids) or use of ventilation therapy. However, more research is needed to determine whether or not these therapies resolve OSA in JIA. Dr Ward and her team have conducted a small pilot study on the use of urinary protein biomarkers to examine if urine proteins were expressed differently in JIA children with OSA from JIA children without OSA and typically developing controls without OSA. The preliminary findings suggest that JIA children with OSA excrete different proteins

than JIA and control children without OSA. Additional research is needed with a larger sample to confirm and validate why certain proteins may be more abundant in JIA with OSA relative to JIA and typically developing controls without OSA. The use of biomarkers as a potential diagnostic tool for OSA is novel, and may be more cost effective and less labour intensive than the current method of polysomnography.

Finally, Dr Ward is also exploring the possibility of developing a web-based selfmanagement sleep promotion intervention for children suffering from poor sleep health (e.g., unhealthy sleep habits such as lack of a bedtime routine or media use before bed]) that is not related to an underlying sleep disorder, like OSA. Although paediatric sleep clinics can improve sleep health, waiting lists are long and currently there is a lack of paediatric providers trained in sleep medicine. Therefore, a low-cost, accessible and convenient web-based platform that encourages children and their parents to change certain behaviours and develop self-management skills to improve their sleep health, will be of great benefit, and may also improve disease management and health outcomes in children living with JIA.

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Detail How was the relationship between JIA and sleep disordered breathing discovered?

In 2006, during my two-year post-doctoral fellowship I had an opportunity to examine data on sleep quality in JIA. Our findings showed that JIA children had fragmented sleep secondary to obstructive sleep apnoea, which we did not expect. We hypothesised that sleep fragmentation would be secondary to pain.

Why is poor sleep and sleep disordered breathing common in JIA patients?

Poor sleep is common in JIA likely due to multiple factors including underlying disease mechanisms, pain, poor sleep habits, and sleep disorders (OSA, periodic limb movements). Although poor sleep is common, we do not know the prevalence of OSA in JIA because few studies have used polysomnography, the gold standard technique to diagnose OSA, in JIA. Of the few studies that used polysomnography, OSA and periodic limb movements have been found. Additional research using the gold standard polysomnography is needed to better understand the prevalence of OSA in JIA. What is the long-term impact for JIA patients, whose sleep disorder is undiagnosed?

Unrecognised and untreated sleep disorders, like obstructive sleep apnoea, may contribute to pain, fatigue, and healthrelated quality of life in JIA. The presence of OSA – a treatable condition – with JIA places children at increased risk for poor disease management, increased health care

costs, and poor clinical health outcomes, including health-related quality of life, fatigue, pain, and physical and psychosocial function.

Why might the protein biomarkers be more abundant in JIA with OSA patients compared to JIA and typically developing control children without OSA? Right now we are unsure, but recent findings suggest that systemic inflammation, as reflected in urinary proteins, can be induced by episodes of low oxygen levels, increased carbon dioxide, and arousals from sleep that characterise OSA. The kidney is sensitive to the effects of intermittent low oxygen levels that result in activation of the sympathetic nervous system and the renin-angiotensin system.

Such inflammation represents a mechanistic finding that could lead to additional studies linking how the physiologic perturbations seen in OSA result in alterations in protein expression that distinguish JIA children with OSA from JIA without OSA and healthy control children without OSA. How can these biomarkers be used clinically?

Development of reliable non-invasive clinical biomarkers capable of distinguishing JIA children with OSA, from those with only JIA, to healthy control children without OSA would provide new knowledge about the underlying mechanisms of OSA in children with and without JIA and enable early screening and diagnosis of OSA in JIA children.

Additional research using the gold standard polysomnography is needed to better understand the prevalence of OSA in JIA MORE INFO: • https://cissm.nursing.uw.edu • http://www.bizjournals.com/seattle/blog/ health-care-inc/2016/09/uw-nursing-schoolopens-center-to-improve-sleep.html • www.sleepreviewmag.com/2016/09/school-

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nursing-center-focuses-enhancing-sleep/ • w ww.seattletimes.com/author/teresa-mward-maida-lynn-chen/ • https://nursing.uw.edu/research/programs/ sleep-research/

RESEARCH OBJECTIVES Dr Ward’s research focuses on improving sleep health and health outcomes for children with and without chronic conditions such as arthritis, asthma or chronic pain. Throughout her research, she has been particularly interested in the effect of poor sleep health on caregiver– child dyad interactions, symptoms, health outcomes, and the underlying mechanisms that might predispose some children to develop sleep disordered breathing. Focusing on these, she hopes to determine unique and essential information for clinical practice to detect sleep disorders more quickly and effectively, and improve the sleep health and quality of life of those affected.

FUNDING NIH: National Institute of Nursing Research (P30 NR016585; R01NR01734; P30 NR011400); University of Washington, School of Nursing Research & Intramural Funding Program COLLABORATORS Tonya Palermo PhD; Michelle Garrison PhD; Sarah Ringold, MS, MD; Sina Gharib MD; Maida Chen MD; Dean Beebe, PhD; Ken Pike, PhD; Carol A Landis, DNSc; Carol A Wallace; Ching Hung, CRA; Lucas Reilly BIO Dr Teresa Ward is an Associate Professor at the University of Washington who has dedicated her time to improving the lives of children with chronic conditions affected by sleep disorders and poor sleep health. She works within the Family and Child Nursing department teaching both undergraduate and graduate students in the use of physiologic and behavioural sleep measures.

CONTACT Teresa M Ward, RN, PhD Associate Professor Department of Family & Child Nursing University of Washington, Box 357262, Seattle, WA 98195 USA E: teward@uw.edu T: + 1 206 221 6576 W: www.nursing.uw.edu/person/teresaward/

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Exposing the mechanisms of sexbiased childhood developmental disorders

Neuroscience

Noting that learning disabilities and developmental disorders are more prevalent in boys than girls, Dr Jaclyn Schwarz and her team at the Department of Psychological and Brain Sciences, University of Delaware are investigating the underlying causes. Looking at early-life immune activation and its interaction with intrinsic factors such as sex, they aim to improve our understanding of these problems and identify potential targets for therapeutic interventions.

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evelopmental disorders in children are relatively common, affecting nearly 14% of children in the United States of America.

However, this broad term covers a range of disorders which affect normal childhood development. They may impact on one or several areas of development (including language, motor, social, and learning skills) and males are twice as likely to be affected as females. Learning disabilities, one of the most common forms of developmental disorder, are a case in point. Although these are often diagnosed early in childhood before the age of nine, when children are entering formal education, neuroscientists are only now uncovering how the brain matures during childhood to exhibit specific learning patterns at different ages. Researchers still know very little about how early life events can upset or modify this development; the observation that sex is clearly a factor has led Dr Schwarz and others to consider this a critical element in any investigations into the causes.

PROTECTOR TURNED PRODUCER Dysregulation of the immune system is known to cause cognitive impairments in adults, including anxiety, depression and dementia; an emerging body of work now suggests that it also leads to behavioural and emotional disorders in children, but the precise mechanism is not clear. This is the focus of investigations in the Schwarz lab, with particular emphasis on how the sex of an individual is implicated. They hypothesise that neonatal infection results in significant developmental delays in

learning and memory through its impact on the development of microglia (the cells responsible for immune defence in the central nervous system).

As very little is known about the developing immune systems of juveniles as opposed to adults, it is difficult to examine their impact on neuronal development. However, Dr Schwarz thinks that these subtle disturbances of neuronal development can result in significant changes in behaviour (such as those seen in children with developmental disorders).

Using well-known measures of development and learning, such as spatial learning and memory associated with the hippocampus (a vital component of the brain associated with consolidating short-term memory to long-term memory), Dr Schwarz believes she will be able to test her hypotheses in rodent models with good translation to humans.

THE SHOCKING CONTEXT The thrust of Dr Schwarz’s research is based around a type of contextual fear conditioning. Rats are pre-exposed to a specific context (or not for controls) and allowed to explore freely. On later return to that context they immediately receive a small electric shock. Then, twenty-four hours later they are returned to the same context and their behaviour assessed for evidence of fear, showing they have been able to associate the shock with a specific context. Dr Schwarz's collaborators within the University of Delaware have shown that the ability to identify the context is related to

Through a series of experiments, Dr Schwarz aims to push forward understanding of the interactions between sex, immune activation and neuronal development 27

Neuroscience

Above and right: microglia in the developing brain

hippocampal development at a very early age.

Dr Schwarz and her team will take this a step further by exposing the neonatal rats to a low-grade infection, as well as using both male and female rats. Male neonates are known to produce a more robust response to infection than females, including significant increases in microglial volume and higher levels of cytokines (cell signalling molecules). For these reasons, Dr Schwarz expects to see a delay in contextual fear conditioning in infected males. It is already known that altered

cytokine production in the hippocampus can significantly impact learning and memory, but these experiments will look at juveniles and crucially compare male and female responses.

GETTING UNDER THE SKIN Coupled with these behavioural experiments will be an examination of the structure of microglia in the different groups and through the developmental

What is the impact of early life developmental disorders on those affected?

The impact of developmental disorders is devastating because they are lifelong and many of the disorders (e.g., autism, schizophrenia, or even learning disabilities) have no known causes let alone cures.

immune activation may impact the brain, its development, and ultimately behaviour, dependent upon the timing of the initial insult or even subsequent insults that activate the immune system. This may hold the clue to the variability in outcomes that stem from simple immune activation, the result of possibly numerous insults to the developing foetus or infant.

Why do you believe that such a range of outcomes may have such a simple common cause?

Immune activation can result from a number of different insults (triggers), but importantly, the end result of early-life

How can you be confident that the animal models reflect the human conditions?

We can be confident that animal models reflect the human condition for a number of reasons. Primarily, the immune systems

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process. A range of histological and molecular investigations will be performed to assess whether the morphology (shape) and number of microglia are affected, as well as investigating the presence of molecules known to promote plasticity in hippocampal development. This will assist the team in moving from the discovery of the underlying mechanisms affecting neuronal development (and therefore developmental disorders), to identifying

are relatively conserved across species.

Similarly, the processes that underlie neural development are relatively conserved across species, though the timing of these processes may be different across species.

Finally, animals (including rodents) are quite intelligent and capable of performing a number of learning tasks, they engage in social behaviours, and the neural structures that underlie these behavioural and cognitive processes are similar in humans and rodents.

What is the biggest challenge to the expansion of understanding in this field?

The biggest challenge towards

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They hypothesise that neonatal infection results in significant developmental delays in learning and memory via its impact on the development of microglia

Detail RESEARCH OBJECTIVES Dr Schwarz’s research focuses on the importance of sex factors in developmental disorders. Using rodent models, she is exploring how sex dictates the effect of neonatal immune activation on the brain and neural development.

targets for therapeutics which can rescue this process.

of prime importance in this field generally and minocycline therapies specifically.

DEVELOPING A STRATEGY In the search for potential therapeutic agents against these effects, the team propose minocycline as a promising candidate. This tetracycline antibiotic (a class of antibiotics which inhibit protein synthesis) is known to be lipid soluble and so able to cross the blood–brain barrier. Known to inhibit microglialrelated processes associated with immune activation or infection, clinical trials have been undertaken on the basis that minocycline rescues synaptic abnormalities, inhibits neuroinflammation, and improves behaviours in rodent models. However, Dr Schwarz believes many issues remain unanswered. The rodent studies are often in adults, which the team have shown to have significantly different microglial morphology to juveniles. They also either use one sex exclusively or do not distinguish the data based on sex, another issue that the Schwarz lab have shown to be

Through a series of experiments investigating physiological and behavioural responses to immune activation and minocycline treatment, Dr Schwarz aims to push forward understanding of the interactions between sex, immune activation and neuronal development. She is aiming to increase understanding to the point at which their findings can inform further study of clinical populations and result in drastically improved knowledge of sex differences in brain development.

BIO She received her BA in Psychology at Boston College in 2002. In 2008, she received her PhD in Neuroscience from the University of Maryland, School of Medicine. She was a postdoctoral fellow at Duke University from 2008-2012. She has been an Assistant Professor at the University of Delaware since 2013.

Dr Schwarz is adamant that, ‘it is necessary [to] determine the effect of minocycline on microglia and cognitive function in the juvenile brain of males and females’. By doing this in tandem with consideration of early life immune activation, their studies ‘will help determine whether minocycline is an effective treatment for developmental disorders in both males and females’.

CONTACT Dr Jaclyn M Schwarz, PhD Assistant Professor Department of Psychological and Brain Sciences McKinly Lab 111 University of Delaware Newark, DE 19716 USA

FUNDING National Institute of Mental Health

E: jschwarz@psych.udel.edu T: +1 302 831 4582 W: https://www.psych.udel.edu/labsub-site/jschwarz-sub-site/Pages/JaclynSchwarz.aspx /jaclyn-schwarz-242a186 understanding the causes of many neurodevelopmental disorders lies in our lack of understanding of what causes them. There is just so much that we do not understand about how the healthy “normal” brain works, let alone how neural function can be perturbed.

What led you to focus on this area?

I have always been fascinated by the developing brain and the plasticity it possesses. I also have a great passion for understanding how peripheral factors (hormones and immune function) can impact the brain. The brain does not function in isolation, but rather is

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influenced by the environment and one’s physiology. I have also been very interested in sex differences in neural function, but especially how they may influence neurodevelopmental and neuropsychiatric disease. Until recently, females have been underrepresented in basic biomedical research and this has hindered our full understanding of the causes and possibly the cures for a number of important diseases and disorders of the nervous system. This has really compelled me to utilise both males and females in my own research given the strong sex-bias in so many neurodevelopmental disorders.

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Thought Leadership

Alzheimer Europe: The importance of awareness in dementia Alzheimer’s disease is a neurodegenerative condition that affects more and more people throughout the world each year. Jean Georges is the Executive Director of Alzheimer Europe, a non-profit organisation aimed at improving care and treatment of patients with the disease. Research Features recently spoke to him about the organisation’s work and how awareness of Alzheimer’s disease has changed throughout his 20 years at the organisation.

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lois Alzheimer identified the first case of Alzheimer’s disease over 116 years ago in a patient called Auguste D. Since then, the disease has become more and more prevalent worldwide and is today recognised as the most common cause of dementia. According to the 2016 Alzheimer’s Disease International report, the condition now affects 47 million people worldwide and that figure is set to treble by 2050.

In light of these growing numbers, Alzheimer Europe wants to make dementia a European public health priority. Research Features recently sat down with their Executive Director, Jean Georges to find out more about the organisation and discuss the way forward towards this goal.

Hi Jean! Could you tell us what your role is at Alzheimer Europe and what kind of responsibilities you have there?

I have been the Executive Director of Alzheimer Europe for the past 20 years and joined the organisation on 1 November 1996.

My duties include overseeing the small, but truly dynamic team of Alzheimer Europe, supporting the board and managing the various projects of the organisation.

Could you tell us some more about Alzheimer Europe’s background and the kind of work that is done there?

Alzheimer Europe was formed in 1990 and operates a common European platform through co-operation among our 39 members of national Alzheimer associations.

Through our work we hope to answer a growing need in society, especially among the community of people affected by dementia. In 2012, we set up a European Working Group of People with Dementia (EWGPWD), comprised of people with different forms of dementia and of different ages and nationalities. The EWGPWD advises and participates, either as a group or as individual members, in all our activities and projects.

We are also a source of information on all aspects of dementia, through our yearbooks and the European Dementia Ethics Network (EDEN) which was established in 2009. The yearbooks focus on different issues linked to dementia, for example the legal rights and protection of people with dementia, social support, care pathways and dementiafriendly environments, and they provide a comparison of national systems allowing for the identification of existing good practices.

In 2017, Alzheimer Europe will continue to develop EDEN and will look at the ethical implications of recognising dementia as a disability. In September 2016, Alzheimer Europe launched its Clinical Trial Watch (CTW), which provides accessible and up-to-date information on clinical trials that are investigating drugs for Alzheimer’s disease and/or dementia. All our activities aim at making dementia a European priority; promoting a rights-based approach to dementia, supporting dementia research and strengthening the European dementia movement.

How big an influence has Alzheimer Europe had on the understanding of Alzheimer’s disease since it was first established?

When I started working for Alzheimer Europe 20 years ago, there was little recognition that dementia constituted a public health challenge. Thanks to the campaigning of national Alzheimer associations and individual people with dementia and their carers this has now completely changed.

The number of countries recognising dementia as a priority and developing national dementia strategies or plans continues to grow. Currently there are such plans in Austria, Belgium, the Czech Republic, Denmark, Finland, France, Greece, Ireland, Italy, Luxembourg, Malta, the Netherlands, Norway, Slovenia and the United Kingdom (with separate plans for England, Northern Ireland, Scotland and Wales). This public recognition needs to go hand in hand with greater awareness campaigns, the promotion of timely diagnosis, the development of postdiagnostic support, the improvement of care services and increased funding of dementia research.

Supporting dementia research and campaigning for increased funding for dementia research at EU and national level continues to be one of the main priorities of Alzheimer Europe 30

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A meeting of existing and new members of the European Working Group of People with Dementia, their carers, and Alzheimer Europe staff (October 2016, Copenhagen)

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Thought Leadership

Alzheimer Europe is involved in several research projects across Europe. Could you tell us about the current projects you are involved in, and what you are hoping to achieve from them?

We are active in many European projects funded by the Innovative Medicines Initiative (IMI) and Horizon 2020, and are a partner in the European Commission's second Joint Action on Dementia, which follows on from ALCOVE, the first Joint Action on Dementia. The aim of the second Joint Action, launched in March 2016, is to provide practical guidance for policy makers when developing and implementing their national dementia plans, policies and strategies. It will focus on four key areas: diagnosis and post-diagnostic support; crisis and care coordination; residential care; dementiafriendly communities. To ensure that the voice of people with dementia in Europe is heard, in relation to research being conducted in these four areas, one of the things we have committed to do for our core funding is to ensure the involvement of the EWGPWD in the work of the Joint Action.

In addition to this governmental collaboration on dementia, we are also partners in a wide range of research projects. We want to ensure that this research addresses relevant issues, is conducted in an ethical manner and involves people with dementia in a meaningful way. It is also important that it promotes the interests and wellbeing of people with dementia across Europe by working towards timely diagnosis or detection, appropriate care and measures to promote independent living and social inclusion.

Why is advancing the debate on Alzheimer’s disease so important and how does Alzheimer Europe go about facilitating this?

Until recently much of the focus has been on the later stages of Alzheimer`s disease.

It is now becoming increasingly recognised that with a timely diagnosis and adequate post-diagnostic support, it is possible to “live well with dementia”. Alzheimer Europe works very closely with people who have been diagnosed with Alzheimer’s disease and other dementias. The input of the EWGPWD into our work has been tremendous and thanks to their contributions we have been able to change perceptions of the disease.

We are also a lobbying organisation, promoting dementia awareness, care and research within the EU institutions. This includes the European Alzheimer’s Alliance, a group of 128 MEPs in the European Parliament from all political parties and 27 member states aiming to make dementia a public health priority at a pan-European level. In addition, research into the stages preceding the dementia phase provides us with hope of identifying treatments which may delay or postpone the appearance of symptoms.

Is Alzheimer’s disease sufficiently recognised within scientific research? Or do you think it should receive more funding and attention?

European-wide research continues to grow.

Several European level initiatives worth mentioning are Horizon 2020, the Innovative Medicines Initiative (IMI) and the Joint Programme – Neurodegenerative Disease Research (JPND), all of which are actively

Executive Director, Jean Georges

supporting key dementia research projects.

This shows that the European Union (EU) has fully understood that dementia cannot be solved by one single country.

However, despite this growing recognition, dementia research is still underdeveloped, compared to research into other diseases.

Supporting dementia research and campaigning for increased funding for dementia research at EU and national level, and for greater collaboration between European countries in the field of research

Until recently much of the focus has been on the later stages of Alzheimer`s disease. It is now becoming recognised that with a timely diagnosis and adequate post-diagnostic support, it is possible to “live well with dementia” 32

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Heike von Lützau-Hohlbein (former Chairperson, Alzheimer Europe) Birgitte Vølund, (Alzheimerforeningen, Denmark), Jean Georges (Alzheimer Europe), Sabine Jansen (Deutsche Alzheimer Gesellschaft Selbsthilfe Demenz, Germany), Iva Holmerová (Chairperson Alzheimer Europe) (October 2016, Copenhagen)

European Union should develop a European Action Plan, promoting a rights-based approach to dementia.

By 2020, Alzheimer Europe hopes to have expanded its membership to all countries of the European Union with a view to reaching all countries belonging to the European region of the World Health Organization.

Do you think we will ever find a cure for Alzheimer’s disease?

Looking at the increased recognition of dementia as a public health and research priority, I am truly hopeful for the future.

We need to continue research efforts in the hope of better treatment and eventually a cure or prevention for Alzheimer’s disease. In the meantime, we need to provide concrete answers and care approaches to the people currently living with the disease and their carers.

“Care today, cure tomorrow” best captures the holistic approach necessary to dementia care and research which, as mentioned before, is the theme of this year’s annual conference. therefore continues to be one of the main priorities of Alzheimer Europe.

Although your name (Alzheimer Europe) has Europe in its title, do you collaborate with other countries internationally? Or are you a mainly European-focused institution?

All our members are from Europe (WHO region) and our main focus and work is within Europe, but we collaborate with Alzheimer’s Disease International (ADI) for the recognition of dementia as a global priority, at G7, G20, OECD and WHO level.

Alzheimer Europe organises an annual conference which brings together all types of people who are affected by, and work within the field of, dementia. What kind of impact do these conferences have, especially in terms of the relationship between researchers and those living with dementia?

Our annual conferences attract people with varied backgrounds in dementia, including people with dementia and their carers, representatives of national Alzheimer

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associations, healthcare professionals, academics and researchers, as well as policy makers. The conference offers participants the opportunity to inform themselves about new findings in the fields of research on, and treatment of, Alzheimer's disease. The 2017 conference will take place in Berlin, Germany, under the theme “Care today, cure tomorrow”. The conference in 2016 was held in Copenhagen, Denmark and its theme was “Excellence in dementia research and care”.

Alzheimer Europe has recently released its strategic plan, outlining the aims they hope to achieve by 2020. Could you tell us what some of your main objectives are?

Making dementia a European priority with people with dementia and their carers as full partners in policy development, research and service design is at the heart of our strategy.

This includes developing closer ties with the Joint Programme – Neurodegenerative Disease Research (JPND) and the Innovative Medicines Initiative (IMI). We would like to see all European countries develop a comprehensive dementia strategy and the

• To find out more information about Alzheimer Europe’s upcoming conference, or to read more about their work, please visit their website at www.alzheimer-europe.org.

Contact Alzheimer Europe, 14, Rue Dicks, L-1417 Luxembourg.

E: info@alzheimer-europe.org W: www.alzheimer-europe.org

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Dr Schneider’s work focuses on identifying the common pathways of neurodegenerative diseases and examining the shared biological mechanisms that cause them

Neuroscience

Newly identified pathways could advance understanding of neurodegenerative diseases and define novel therapeutic strategies Dr Benoit Schneider is a researcher for the National Centre for Scientific Research of France (CNRS), based at Paris Descartes University. He is head of a team that uses stem cells to tackle a variety of clinical challenges, such as neurodegeneration. His current research looks at whether deregulation of the PrPC/ROCK-PDK1/TACE signalling axis contributes to neurodegeneration in several amyloid protein-based neurodegenerative diseases.

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eurodegenerative diseases affect the neurons in the brain, causing their function to be progressively impaired. The reasons for this remain largely unknown, and have been the focus of much research throughout the years. Millions of people worldwide currently live with some form of neurodegenerative disease, and this number is increasing exponentially as the population continues to age.

Neurodegenerative diseases like prion, Alzheimer’s and Parkinson’s diseases are all characterised by the accumulation of abnormal proteins that are toxic for neurons in the brain (‘neurotoxic’). Despite their different aetiologies and clinical manifestations, these neurodegenerative diseases may share common biological causal pathways, known as ‘pathogenic (disease-inducing) cascades’.

This means that there may be a shared explanation, and therefore a shared solution, to these related neurodegenerative diseases.

Starting from studies on prion diseases, Dr Schneider’s work focuses on identifying common pathways and examining the shared biological mechanisms that cause neurodegenerative diseases. The team

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notably uses an inducible neuronal stem cell to investigate the mechanisms sustaining degeneration of neurons in prion and Alzheimer’s diseases. The team’s work paves the way to help the development of effective therapies against these pathologies.

PRION DISEASES Transmissible Spongiform Encephalopathies, commonly known as prion diseases, are caused by tiny infectious particles called pathogenic prions (PrPSc). These are misfolded proteins that transmit disease by causing, in healthy tissue (notably in brain), the conversion of the non-pathological cellular prion protein PrPC into PrPSc, that is, the replication of the PrPSc-associated misfolded structure. This causes infected brain tissue to become spongy and riddled with holes. By provoking PrPC conversion into a diseased form, PrPSc corrupt the physiological function(s) of PrPC in neurons, which is at the heart of prion diseases.

DEMYSTIFYING PrPC FUNCTIONS TO UNRAVEL PATHOGENIC CASCADES IN PRION DISEASES It is thus essential to find the function(s) of PrPC in neurons, so that the mechanisms by which pathogenic prions exert toxic effects

can be elucidated. However, PrPC normal function(s) largely remain(s) a mystery. To challenge PrPC role(s), Schneider’s team has exploited a neuronal stem cell line (1C11) that expresses PrPC. Key to their approach is the identification that PrPC is a critical actor for the differentiation of the stem cell (the process whereby ‘blank slate’ stem cells specialise and develop into specific cells) into neurons and the regulation of neuronal functions through the control of diverse signalling effectors, including the enzymes TACE alpha-secretase and the Rho kinases (ROCK). When pathogenic prions PrPSc alter the regulatory action of PrPC, prion diseases could then form.

Dr Schneider follows this approach: exposure of 1C11 neuronal cells to pathogenic prions PrPSc. Neuronal cells infected by prions, that is, chronically replicating PrPSc, were instrumental in the team's search for the nature and sequence of molecular events leading to neurodegeneration that take place in prion diseases.

From this method, they found that over-activation of the kinase enzyme PDK1 (Phosphoinositide-dependent kinase-1) is important in prion-induced neurodegeneration because it stops TACE alpha-secretase acting. TACE, another enzyme, has neuroprotective qualities, which means it guards against some of the neurodegenerative properties of pathogenic agents like PrPSc. The suppression of TACE alpha-secretase activity preferentially allows the production and accumulation of pathogenic prions, and makes infected neurons sensitive to inflammatory stress.

This is because the suppression of TACE alpha-secretase leads to a build-up of TNF (a critical mediator of inflammation and cell death) receptors, and makes cells vulnerable to TNF-induced inflammation. This finding has been validated in vivo in mice infected by pathogenic prions.

APPLICATION TO OTHER NEURODEGENERATIVE DISEASES Following the discovery that deregulation of the PDK1-TACE cascade in prion diseases leads to increased sensitivity to inflammatory stress and amplifies the production of toxic PrPSc protein, the team next investigated whether this same mechanism was present in other neurodegenerative diseases. Sure enough, they found that deregulation of the PDK1-TACE pathway also occurs in Alzheimer’s disease. The team was the first to show that the PDK1-TACE pathway is

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Neuroscience

Prion and Alzheimers diseases Amyloid proteins PrPSc / Aβ

ROCK PDK1

ROCK/PDK1 inhibition Amyloid proteins PrPSc / Aβ

Drugs

ROCK PDK1

PrPSc / Aβ

PrPSc / Aβ Synapse disconnection

Neurodegeneration

deregulated in Alzheimer’s neurons, where it increases the production of neurotoxic amyloid beta peptides (Aβ peptides). Aβ peptides are short chains of amino acids that are the main component in the Aβ plaques that form in the brains of Alzheimer’s patients.

Lastly, Dr Schneider demonstrated that inhibiting the PDK1 pathway mitigates prion and Alzheimer’s diseases in mice.

This suggests that PDK1 could be a useful therapeutic target for both diseases – a suggestion supported by evidence that shows an increase in PDK1 activity in the postmortem brains of Alzheimer’s patients.

FINDING THE RIGHT TREATMENT Theoretically, a treatment could be developed that minimises the effect of PDK1 pathways. However, the problem is that the inhibitors used to suppress PDK1 pathways are toxic. This led the team to investigate the mechanism by which PDK1 becomes overactivated in diseased neurons.

In the case of prion infection, another kinase (ROCK) was shown to positively regulate PDK1 activity, so Dr Schneider’s team hypothesised that minimising the overactivation of PDK1 by suppressing the activity of ROCK, would indirectly reduce the effects of the PDK1 pathway. This would therefore

Preservation of synapse connectivity and neurotransmission

Neuronal survival

make ROCK-PDK1 a prime target to combat prion diseases, and potentially Alzheimer’s as well.

Finally, how do neurotoxic Aβ peptides (in Alzheimer’s) or PrPSc (in prion diseases) trigger the over-activation of ROCK-PDK1 kinases?

Dr Schneider and his team found that the cellular prion protein PrPC acts as a receptor for pathogenic prions and Aβ peptides at the neuronal surface, relaying their neurotoxicity and promoting ROCK-PDK1 over-activation.

A COMMON CAUSE The interesting thing about PrPC is that it not only interacts with PrPSc but also Aβ peptides.

Dr Schneider and his team suggest that the same principle applies to other amyloid proteins causing neurotoxicity implicated in diverse diseases such as Parkinson’s and Amyotrophic Lateral Sclerosis (ALS).

His team is currently trying to determine if the PrPC-ROCK/PDK1-TACE pathway is also corrupted in these diseases, and hence if they can find a common cause of neurodegeneration more broadly. If so, their next step would be to establish a common solution to amyloid-based neurodegenerative diseases, for which the causes of onset are still unknown.

Evidence shows an increase in PDK1 activity in the post-mortem brains of Alzheimer’s patients. This suggests that PDK1 could be a useful therapeutic target, not only for prion diseases but also Alzheimer’s 36

How significant are your findings for combatting neurodegenerative diseases?

We were the first to show that overactivation of the kinase PDK1 and downstream neutralisation of the protective TACE α-secretase is a critical neurodegenerative event occurring in both prion and Alzheimer’s diseases, and probably in other amyloid protein-based neurodegenerative diseases. Importantly, neutralisation of TACE α-secretase by PDK1 considerably augments the production of neurotoxic proteins (pathogenic prions PrPSc in prion diseases and neurotoxic Aβ peptides in Alzheimer’s) creating a vicious circle of PrPSc/Aβ-induced deregulation of the PDK1-TACE cascade that amplifies PrPSc/Aβ production. Our work permits to posit PDK1 as an attractive, potential therapeutic target for both prion and Alzheimer’s diseases as the inhibition of PDK1 in mouse models with prion or Alzheimer’s diseases breaks down the vicious circle of PrPSc and Aβ productions, decreases PrPSc and Aβ neurotoxicity and thereby mitigates prion and Alzheimer’s pathologies. The therapeutic relevance of our data is supported by the rise of PDK1 activity in the post-mortem brain of Alzheimer’s individuals.

To date, there is no effective medicine to combat these neurodegenerative diseases.

Most therapeutic approaches have failed or do not display significant improvements.

This is notably because of our incapacity to diagnose the pathologies at early stages and thereby stop the neurodegenerative process very early. For example, therapeutic assays performed by different laboratories in prion-infected mice revealed beneficial effects when treatments were done (very) close to the prion infection date. The beneficial effects were, however, lost when the treatment started at later stages along prion pathology. Contrasting with those studies, our work on PDK1 clearly demonstrates that antagonising PDK1 activity in prion-infected mice at late stages (i.e., when the neurodegenerative process is deeply engaged) does exert beneficial effects in terms of locomotor activity and survival of diseased animals. Because of the late time-window of the beneficial action of PDK1 inhibition towards prion diseases, there is a rationale to transpose these results

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Detail to the clinics. It however remains to suppress the toxicity of the PDK1 inhibitors.

How effective will ROCK-targeting therapies be if they only indirectly affect the PDK1-TACE pathway?

Targeting ROCK activity with pharmacological inhibitors permits considerable reduction in PDK1 activity and thereby restores the neuroprotective activity of the TACE α-secretase in prion-infected mice. The inhibition of ROCK reduces the brain level of pathogenic prions to the same extent as the direct inhibition of PDK1. However, the beneficial effect of ROCK inhibition in terms of animal survival was less pronounced with ROCK inhibitors than with PDK1 inhibitors.

Because ROCK is a more upstream signalling effector than PDK1 in the signalling pathways governed by PrPC, ROCK would likely be involved in diverse signalling cascades distinct from the PDK1-TACE axis. Thus, the inhibition of ROCK may interfere with other key cellular functions and thereby minimise the beneficial effects associated with restoration of normal PDK1 activity. That is why we are currently focusing our research on how PDK1 neutralises the activity of TACE α-secretase in diseased neurons to get closer to the systems whose deregulation promotes the accumulation of neurotoxic amyloid proteins.

When do you anticipate you will be able to test your findings in human trials?

We already measured an increase of PDK1 activity in the post-mortem brain of six Alzheimer’s individuals at the five and six Braak stages of the disease. We provided evidence that the rise of PDK1 activity is associated with disturbance of TACE α-secretase protective activity. This indicates there is a therapeutic rationale to target PDK1 in Alzheimer’s patients to stop the production source of Aβ peptides by rescuing TACE α-secretase activity. However, the main unresolved problem still remains the toxicity of PDK1 inhibitors that we have to understand in order to envision safe therapeutic strategies.

What is the value of using 1C11 stem cells?

1C11 cells are neuronal stem cells established

by Prof Odile Kellermann when she was researcher at the Pasteur Institute (Paris) in the lab of Nobel laureate Prof François Jacob.

1C11 stem cells display a stable neuroepithelial

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phenotype and can convert into either serotonergic or noradrenergic neuronal cells upon appropriate induction. The differentiation pathways are mutually exclusive and recruit 100% of cells. At the end of the neuronal programmes, the cells have acquired all the functional properties of brain mature neurons, i.e., serotonergic neurons of the raphe nuclei and noradrenergic neurons of the locus coeruleus. In 1C11-derived neuronal progeny, all neuronal functions can be quantified with accuracy. The creation of pure populations of stable mature neurons in vitro allows to bypass the multiplicity of signals that operate in vivo and to conduct “clean” biochemical and pharmacological experiments to decipher basic mechanisms underlying neuronal differentiation, regulation of neuronal functions or neurodegeneration. 1C11 cells are “testtubes” useful to identify actors and signals involved in several pathophysiological situations that are then validated in primary neuronal cultures and in vivo.

What are the similarities and differences between Aβ peptides and prions?

Pathogenic prions PrPSc and Aβ peptides both derive from endogenous proteins: the cellular prion protein PrPC, whose transconformational conversion gives rise to PrPSc in prion diseases, and the amyloid precursor protein APP, whose abnormal cleavage augments the production of Aβ peptides in Alzheimer’s disease. Biochemically speaking, PrPSc and Aβ peptides are misfolded proteins that are enriched with β-sheets structures. This confers PrPSc and Aβ the capacity to assemble into oligomers and fibrils, to make deposits in the brain, and to resist some degradation processes.

PrPSc and Aβ peptides both spread within the central nervous system along the time course of prion and Alzheimer’s diseases, respectively. The specificity of PrPSc is to be an infectious agent that has transmitted prion disease to humans after food ingestion, neurosurgical interventions (dura mater grafting), blood transfusion or medical treatment (growth hormone). While displaying “prion-like” properties, there is no convincing data supporting Aβ infectivity and transmission between humans.

RESEARCH OBJECTIVES Dr Schneider’s research focuses on understanding the mechanisms behind several neurodegenerative diseases, including prion, Alzheimer’s, and Parkinson’s diseases. His current research has looked at how the deregulation of the PrPC/ROCK-PDK1/TACE axis contributes to neurodegeneration, but he and his team have also been involved in research related to bone mineralisation and dental repair.

FUNDING • Agence Nationale de la Recherche (ANR) • European Joint Program on Neurodegenerative Diseases (JPND) • LECMA-Vaincre Alzheimer • Domaine d’Intérêt Majeur - Région Ile de France - Maladies Infectieuses & Cerveau et Pensée COLLABORATORS Prof Jean-Marie Launay (Lariboisière Hospital, Inserm UMR-S 942, France & Hoffmann-La-Roche Ltd, Switzerland) BIO Dr Benoit Schneider studied for a PhD in Biochemistry at the Pasteur Institute, Paris before becoming a researcher at CNRS in 2003. He later went on to be a Professor at Ecole Polytechnique in 2008. He became Director of Research at CNRS in 2014 and, during the same year, became, with Prof Odile Kellermann, the head of the team “Stem Cells, Signalling and Prions” at Paris Descartes University.

CONTACT Dr Benoit Schneider, PhD, Team leader Université Paris Descartes - Inserm UMR-S 1124 Team “Stem Cells, Signalling and Prions” 45 rue des Saints-Pères 75006 Paris France T: + 33 1 42 86 22 09 E: benoit.schneider@parisdescartes.fr

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Down syndrome accelerates Alzheimer's disease onset Down syndrome and Alzheimer’s disease are two diseases you would not commonly associate. But Dr Elizabeth Head and Dr Frederick Schmitt, of the Sanders-Brown Center on Aging, have dedicated their research to identifying the key physiological and behavioural changes associated with Alzheimer’s disease onset in people with Down syndrome.

They now plan on using this knowledge to support development of dementia-preventative treatments for people with Down syndrome.

We can see the connections between different parts of the brain (colored bundles) in people with Down syndrome using magnetic resonance imaging. Drs Head and Schmitt's study has now shown that these connections are weaker in people with Down syndrome who are demented compared with those who are not.

Neuroscience

Magnetic resonance imaging (MRI) pictures showing the brain of an older person with Down syndrome (left) compared with a person of similar age without Down syndrome (right). Notice that the hippocampus, an area important for Alzheimer disease, is shrunken in Down syndrome.

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own syndrome (DS) impacts approximately 60,000 people in the UK and 400,000 people in the United States. In 94% of cases, DS is a genetic disorder caused by a random triplication of chromosome 21. Intellectual disability, delayed growth, muscular weakness and distinctive facial features are the main characteristics but, with the appropriate education and support, people with DS can develop employable skills and live independent, rewarding lives. Often, people with DS have health problems due to their condition: approximately 50% of children born with DS may have congenital heart disease (CHD), more than 60% are visually impaired and many may also experience hearing loss, immune system deficiency, blood disorders and seizures.

With careful monitoring, most of these conditions can be treated and, as a result, average life expectancy has increased to over 60 years. However, people with DS are at greater risk of developing age-related conditions such as Alzheimer's disease (AD).

ALZHEIMER’S RISK AD results from progressive brain degeneration, due to the formation of harmful 'plaques' and 'neurofibrillary tangles'. These protein abnormalities block neuron connections, eventually leading to neuron death and brain tissue loss.

Ultimately, long-term brain deterioration stimulates dementia onset, which involves symptoms such as memory loss, personality changes, problems with language and confusion. This debilitating condition increases in severity over time and, as it has no cure, people with AD often require constant care.

Interestingly, by the age of 40, virtually all people with DS have AD-associated brain changes. However, dementia symptom onset is often more variable. Clinical AD symptoms generally emerge approximately a decade after their brain tissue changes, generally when people are in their 50s or 60s. By exploring the neuropathological, cognitive and functional decline of people with DS, Drs Head and Schmitt aim to identify potential clinical targets, thus potentially preventing the development of dementia in older people with DS. THE IMPACT OF CHROMOSOME 21 OVER-EXPRESSION Genes on chromosome 21 are overexpressed, due to the chromosome’s triplication. This includes a key gene involved in AD development which encodes beta-amyloid precursor protein (APP). Cleavage of APP by two enzymes, β-secretase and γ-secretase, leads to beta-amyloid (Aβ) formation. Aggregations of these misfolded Aβ peptides become surrounded by fragmented neurons to

By the age of 40, virtually all people with Down syndrome have Alzheimer’s disease-associated brain changes

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Neuroscience

produce senile plaques – an AD diagnostic hallmark. In fact, it has been shown that Aβ accumulation in plaques rapidly increases between the ages of 30 and 40 years in DS adults.

Furthermore, Aβ plaque deposition can indirectly increase brain oxidative stress.

Oxidative damage is greater in people with DS compared to the general population.

This is because in excessive quantities, Aβ peptides can damage mitochondria which can reduce the brain cells’ ability to maintain antioxidant defences. This consequently results in an inadvertent increase in reactive oxygen species (ROS) levels. The consequences of this oxidative stress are severe and include further mitochondrial damage and β-secretase expression.

Ultimately, this creates a degenerative ‘ripple effect’, and DS individuals show an age-related increase in oxidised DNA/RNA.

Alzheimer disease neuropathology in a person with Down syndrome. The green color shows beta-amyloid plaques and neurofibrillary tangles. The blue color shows where blood vessels also have beta-amyloid in their walls.

Neurodegeneration, caused by another chromosome 21-located gene, such as DYRK1a, greatly accelerates AD progression in middle-aged DS adults. 'Dual-specificity tyrosine phosphorylation-regulated kinase' (DYRK1a) is an enzyme that contributes to hyperphosphorylation of the tau protein (a highly abundant neuronal microtubule stabiliser). This is extremely damaging as phosphorylated tau proteins become insoluble and aggregate, causing neurofibrillary tangle formation and neuron death. Previous research also indicates that phosphorylated tau levels greatly increase with age in DS adults.

CURRENT RESEARCH The Down syndrome and Aging research team at the University of Kentucky are currently conducting a 10-year longitudinal study to explore aspects of cognitive decline associated with early-onset AD in people with DS. A range of magnetic resonance imaging (MRI) methods will be used by Drs Powell and Gold at the University of Kentucky to study: i) changes in white matter (WM) connections, ii) cerebrovascular dysfunction and iii) neuroinflammation.

Not only will the team continue to examine a cohort of older adults with DS (who have been volunteers for over six years), but they will also recruit a younger group of people with DS 25 years and older. This should enable the identification of the exact physiological, biochemical and behavioural processes that occur as AD develops.

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Beta-amyloid protein can be found in plaques and along blood vessel walls (arrow) leading to neurodegeneration in older people with Down syndrome.

Past research has shown that these factors are intertwined and are associated with AD onset in DS adults. For example, WM located in the frontal cortex degenerates as Aβ accumulates. Diffuse tensor imaging (DTI) is used to examine changes in WM integrity. DTI is a non-invasive, in vivo technique that measures the rate and direction of water molecule diffusion in the neural tissue. This reveals the architecture of WM and integrity loss in brain circuit connections can be observed over time.

Additionally, Aβ can build up on the blood vessels in the brain and can lead to cerebrovascular damage, and further WM degradation. In fact, Aβ deposition occurs

decades earlier in DS adults, compared to people without DS. To address the hypothesis that cerebrovascular disease increases the risk of dementia onset, MRI technology (arterial spin labelling used by Dr Ai-Ling Lin at the University of Kentucky) is being used to detect blood flow changes, cerebrovascular damage, and their progression in the volunteers with DS. Neuroinflammation is another key characteristic of AD. Aβ plaques bind to cell surface receptors on microglia (brain immune defence cells), triggering chemokine and cytokine release (chemicals which destroy plaques and damaged cells). However, some debatable evidence suggests that this immune response can

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Detail Why are Down syndrome (DS) patients predisposed to age-related conditions such as Alzheimer’s disease (AD)?

Most of this has to do with the genes that are overexpressed in DS (~200 genes) with a subset of these being linked to AD. Extra genes leads to higher levels of protein expression and this may drive pathology at an earlier age.

Most middle-aged people with DS are affected by AD, but tend not to develop dementia until much older, if at all. Why is this?

Indeed, if we can find out how people with DS can “buffer” the AD pathology in the brain and still function at the same level then we can learn some fascinating new potential ways to slow or halt AD dementia.

For example, do they overexpress proteins on chromosome 21 that are protective?

What are the key earliest indicators of AD and dementia onset?

In DS, typically changes in behaviour are noticed in people with DS and sometimes changes in frontal lobe function (e.g.,

lethargy, depression). Some families notice a change in memory. We are still learning more about this in people with DS. By detecting AD early on, what therapies are available to prevent subsequent dementia development?

There are some approved drugs that when started early can help some people, and there is evidence that one or two of these may slow dementia. However, we do not have a treatment that truly changes the course of the disease as of yet. This is why this research is critically important.

Where do you see your research focus in five years’ time?

I hope that we will have identified some of the key changes in cognition that are linked to brain pathology. We also hope that we can learn at what age changes happen (e.g., when does cerebrovascular pathology start, when does inflammation start?) so that in future, when we develop clinical trials we will know not only what to change, but also when to change it.

It is extremely important we recognise Alzheimer’s disease development early on in Down syndrome patients, to predict who is vulnerable to dementia actually accelerate the onset of AD. By studying the relationship between neuroinflammation and age, AD neuropathology and cognitive decline, Drs Head and Schmitt aim to tackle this important question by using blood biomarkers and magnetic resonance spectroscopy (chemical signals from brain).

THE UPSIDE OF DOWN SYNDROME Overall, it is extremely important that we recognise AD development early on in people with DS, to assist patients and families.

This team’s initial research has already shown that as people with DS start to

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develop dementia several key changes occur in brain connectivity– which could act as early indicators. At the same time, clinical dementia diagnosis relies on obvious differences that friends and family can identify – namely changes in personality, behaviour, memory and learning and gait (i.e., slowing or hesitation in movement with age could indicate dementia onset).

Ultimately, the earlier these changes are detected, the easier preventative treatments (once developed) can be implemented to reduce AD dysfunction, drastically improving the quality of life of people with DS.

RESEARCH OBJECTIVES Dr Head’s and Schmitt’s work focuses on the study of ageing and Alzheimer’s disease in people with Down syndrome.

Their latest research seeks to identify the changes in brain inflammation and cerebrovascular dysfunction and how they might contribute to the cognitive and behavioural traits associated with Alzheimer’s disease in Down syndrome.

The aim of their work is to identify the earliest indicators of cognitive decline and develop preventative approaches that reduce Alzheimer’s disease prevalence.

FUNDING NIH: NICHD/Grant #R01HD064993 COLLABORATORS Dr Allison Caban-Holt; Dr Gregory Jicha; Dr Amelia Anderson-Mooney; Dr Carl Mattacola; Dr Phillip Gribble; Roberta Davis; Katie McCarty; Dr David Powell; Dr Ai-Ling Lin; Dr Donna Wilcock; Dr Donita Lightner; Dr William Robertson; Dr Ira Lott; Eric Doran; Down syndrome associations of Louisville, Central Kentucky, Southern Indiana, and Bowling Green; Mrs Lynn Braker; Dr Ira Lott BIO Dr Head received a Master’s in Psychology and a PhD in Neuroscience from the University of Toronto, Canada.

She undertook postdoctoral training at the University of California, Irvine before moving to the University of Kentucky.

She currently works with her colleague Dr Schmitt – a Professor of Neurology with a career in brain pathology-neurocognition associations and dementia therapies.

CONTACT Elizabeth Head, PhD Sanders-Brown Center on Aging Pharmacology & Nutritional Sciences University of Kentucky 203 Sanders-Brown Building 800 South Limestone Street Lexington, KY, 40536-0230 USA E: Elizabeth.Head@uki.edu T: + 1 859-218-3172 W: http://www.uky.edu/DSAging/

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Thought Leadership

CASA: Addiction is a disease, not a choice

According to Dr Samuel Ball of The National Center on Addiction and Substance Abuse, addiction can be a life-threatening, debilitating condition, but the seriousness of it is often overlooked. The CEO and President recently met with Research Features to discuss his organisation's strategies for dealing with what is now the USA’s number one public health problem.

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ddiction – is it a disease or is it a choice? With the United States currently in the grip of an opioid epidemic, this is a distinction of great significance. Dr Samuel Ball, President and CEO at The National Center on Addiction and Substance Abuse believes that improving our collective understanding of addiction as a disease rather than a moral failing is a crucial step in the right direction.

Research Features recently spoke to Dr Ball about this and some of the other major challenges within his field.

Hi Samuel! Can you tell us what The National Center on Addiction and Substance Abuse (CASA) does? What is your role within the centre?

Our interdisciplinary team of experts work closely with academic, government, and service organisations to improve the understanding, prevention, and treatment of substance use and addiction. We accomplish this through the dissemination of knowledge, creation of resources, training of providers, and evaluation of systems of care.

We are best known for our major reports, our evaluation of service systems, and our

education of parents and policymakers about what works to prevent and treat substance use and addiction. I have been President and CEO for the past three years and am also a Professor of Psychiatry at Yale School of Medicine.

Can you tell us about CASA’s background and the aims of the centre?

We were founded 25 years ago by Joseph A Califano, Jr, former Secretary of Health Education and Welfare, as a nonprofit organisation in New York City affiliated with Columbia University. We have a wellestablished reputation as a leading addiction policy and research organisation. Our mission is to connect science with policy and practice to better the lives of all people impacted by substance use and addiction. We do this by conducting and synthesising research; informing and guiding the public; evaluating and improving healthcare, and analysing and recommending policy.

Can you explain how research is conducted at CASA? We engage in various forms of research.

In addition to analysing national surveys and summarising major areas of research, we conduct our own survey research on

Our mission is to connect science with policy and practice to better the lives of all people impacted by substance use and addiction www.researchfeatures.com

attitudes, behaviours and problems related to substance use and other addictive behaviours. Our programme of health services research evaluates evidencedbased practices in the community delivered to people with mental health, HIV, and substance use problems. This involves both innovative and established interventions designed to improve outcomes within a rapidly changing healthcare environment.

Our programme of research on adolescents and families includes randomised clinical trials that test integrative methods of treating patients, and rigorous evaluation of practical methods of training service providers.

What are the organisation’s key research focuses over the next two years?

Major work is underway evaluating the practical assessment and intervention methods in various clinical settings for adults and adolescents who have mental health, HIV, substance use, and criminal justice problems. We are also evaluating the rates and correlates of tobacco and other nicotine product (e-cigarettes) use in college students and studying brain-imaging changes among youth who are addicted to opioids and receiving medication-assisted treatment.

Other research will examine the effects of marijuana legalisation to inform policy decisions that reduce the risk of exposure to children and teens.

Can you tell us about CASA’s collaborative relationship with substance use and addiction researchers at various universities?

The National Center on Addiction and Substance Abuse was founded as an affiliate of Columbia University. We continue to collaborate with their researchers in the evaluation of juvenile justice agency processes for identifying mental health and substance use problems and getting teens into treatment. Another Columbia clinic is helping us evaluate different family-based approaches to treating substance use and attention deficit hyperactivity disorder in adolescents. Our more recent academic collaborations have been with Yale University, New York University, Northwell Health, and City University of New York faculty and staff and include a wide range of studies on substance use, addiction and addictive behaviour. These research projects occur in diverse service settings including community addiction treatment programmes, patientcentered medical homes, primary care centers, emergency rooms, colleges, medical specialty and behavioral health clinics.

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Thought Leadership

Addiction is the USA’s number one public health problem. What are the key considerations when addressing this issue?

The two overarching considerations for promoting effective policies and practices are to reduce access to addictive substances and expand access to effective prevention and treatment. Although our country has effectively reduced cigarette smoking, many other addictive substances have increased accessibility in ways that pose an especially high risk for young people. The greater availability of prescription pain medicine and heroin fuelled our current opioid epidemic.

The greater availability of marijuana is already having a negative health impact in states where it is legalised. The greater availability of e-cigarettes seems to be translating into greater use of other tobacco products.

Stronger regulatory policies and practices are needed to reduce the harms associated with all substances, whether legal or illegal. With regard to increasing access to prevention and treatment, our systems of education, healthcare and justice still do not provide adequate access to the interventions which research shows are effective. Here again, the risks to young people are especially high. If substance use is not prevented, delayed, or stopped at an early age, the risk of it progressing to a chronic addiction in adulthood is magnified. Not enough is being done early enough to keep young people healthy and addiction-free.

What are the greatest addiction challenges at this time? What are CASA’s strategies for addressing these issues?

In my opinion, there are three great challenges to our public health when it comes to addiction and one great threat when it comes to how we prevent and treat the problem. The three great challenges are: 1) implementing a comprehensive, rather than piecemeal, strategy to control and end our current opioid epidemic; 2) voting to legalise marijuana for recreational and medical use while ignoring or distorting the researchproven risks and benefits; 3) limited access to and payment for evidence-based prevention and treatment.

The biggest threat to the ways our society (especially our education, healthcare, and justice system) responds is political leadership that lacks the knowledge, compassion, or courage to act in ways that promote the well-being of our most vulnerable citizens – especially those with mental health and addiction risks or problems. When our education, healthcare, and justice systems

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Dr Ball introduces a research seminar presentation on e-cigarettes.

blame, deprive, or punish people rather than provide services, our entire society suffers the consequences and costs of addiction.

Important national legislation passed in 2016 is at risk of being undone by a careless repeal of the Affordable Care Act. Our Center cannot do anything by itself to change these huge challenges and threats. We join forces and voices with other non-profit organisations committed to helping people with mental health and addiction problems. Together, we have impact.

and marijuana access. The slow federal responsiveness on opioid regulations has contributed to thousands of deaths over recent years. Federal non-response to state marijuana legalisation will result in increased rates of addiction. Our Center released major reports in the past year aimed at educating policymakers about the extent of the problem and offered strong, science-based recommendations to improve the education, healthcare, and justice system response to our addiction crisis.

How responsive is federal policy to changes in addiction behaviour? What involvement does CASA have in the formation of addiction policy?

For the past 10 years, the federal government has been unacceptably slow in its response to the opioid epidemic and unacceptably nonresponsive to the rapid expansion of state legalisation of marijuana. Both forms of nonresponsiveness were powerfully influenced by corporate interests that expanded opioid

On the CASA website, you state that in 2016, 'great progress has been made in improving our collective understanding of addiction as a disease instead of a moral failing'. What is the significance of this change in perception?

What part did CASA play in bringing about this change?

Attempts to change the view of addiction from a moral failing to a disease began 250 years ago, and we still have a long way to go. Continued emphasis on addiction as a

If substance use is not prevented, delayed, or stopped at an early age, the risk of it progressing to a chronic addiction in adulthood is magnified. Not enough is being done early enough to keep young people healthy and addiction-free www.researchfeatures.com

Dr Samuel Ball

disease is necessary to reduce the shame affected people and their families feel, which often prevents them from admitting they have a problem and seeking and accepting help. Understanding addiction as a disease is also necessary for maintaining a public health approach that provides health interventions instead of a criminal justice approach that punishes the sick. Our Center has supported the view of addiction as a disease by promoting awareness of the role of the brain in developing addiction and promoting knowledge about effective medicines and professional therapies to support recovery and prevent relapse.

How do you see the landscape of addiction changing over the next ten years?

Our country has cycled through various addiction crises since its founding. There have been several opioid epidemics and, although the current one is our worst to date, it will likely recede in a few years and another substance will become a crisis. I am concerned that our next major drug crisis will be marijuana fuelled by the unchecked spreading of state legalisation and greater access to higher potency products with greater addiction and mental health risk.

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I am concerned that we are not going to know how to counteract this and undo the damage to individuals and society.

Many people describe themselves as coffee addicts, but you do not think coffee should be described as an addiction. Can you explain why?

I believe the term “addiction” is grossly overused by the general public and by some experts when they are trying to increase interest in their work. Physical withdrawal symptoms can occur when one cuts back or eliminates regular coffee drinking. But there are many other symptoms that are needed before calling something an addictive disease. Addiction is a very serious, potentially life threatening medical condition characterised by a severe loss of control and continued use despite experiencing significant damage to one’s health, relationships, and the ability to learn and contribute to society.

If someone drinking an excessive amount of coffee on a daily basis experiences some value from calling themselves a “coffee addict” and then adopts healthier habits, that may be helpful. But as an addiction expert, I think their use of the

term “addiction” trivialises a serious disease from which people suffer devastating consequences and sometimes die if they do not get help.

Contact The National Center on Addiction and Substance Abuse 633 Third Avenue, 19th Floor New York, NY 10017-6706 USA E: SBall@centeronaddiction.org W: www.centeronaddiction.org /CASAaddiction /centeronaddiction/

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Mental Health

Explaining the unexplained: the link between panic and non-cardiac chest pain Dr Guillaume Foldes-Busque is an assistant professor in the School of psychology at Université Laval (Laval University). His research focuses on the association between panic and non-cardiac chest pain, and is paving the way for effective screening techniques used in clinical environments.

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hest pain is a frequent cause of visits to the accident and emergency departments of hospitals. This is because chest pain is often associated with heart problems, and many people believe they are having a heart attack when they experience it. However, it is not always a sign of cardiac problems – any chest pain that isn’t related to cardiac issues is called noncardiac chest pain (NCCP), or unexplained chest pain.

NCCP is generally not life-threatening, nor particularly medically dangerous, but it can have a significant impact on patients’ quality of life and day-to-day function. Estimates suggest that 41–60% of people who have had NCCP report some kind of constraint on their daily activities, such as exercise, housework or walking, and that 17–35% of sufferers are prevented from going to work by their chest pain. These negative effects can persist for up to 10 years after the symptoms occur.

In the US, the estimated total annual healthcare cost for NCCP is greater than the combined costs associated with myocardial infarction (heart attack) and angina. These patients are also more likely to be frequent

users of healthcare services, and to have a greater fear of developing serious health conditions.

PANIC AND NCCP Often, NCCP is related to panic-like anxiety – a much larger number of patients presenting with NCCP have panic attacks or panic disorder than in the general population. In fact, panic attacks and panic disorder are up to 11 times more prevalent in patients with NCCP. However, despite this impressive statistic, approximately 92% of cases of panic remain undiagnosed when a patient is discharged from hospital.

It is unclear what causes this co-occurrence of panic and NCCP, but it may be because there are shared vulnerabilities, underlying causes, or because patients with panic-like anxiety are more sensitive to anxiety and pain.

WHAT ARE PANIC ATTACKS AND PANIC DISORDER? Panic attacks cause patients to abruptly feel physical symptoms such as chest pain, nausea, or heart palpitations, and mental symptoms such as a fear of dying, ‘going crazy’, or a detachment from reality.

The name ‘panic attack’ comes from the

Dr Foldes-Busque has carried out numerous studies in hospitals, examining the link between non-cardiac chest pain and panic-like anxiety 51

Mental Health

symptoms that generally characterise them: namely an overwhelming sense of fear, apprehension or anxiety. People may experience panic attacks with varying frequency and intensity, and they may occur in a variety of contexts. Some will develop panic disorder which is a condition characterised by recurring panic attacks and persistent concerns about the consequences or the recurrence of these attacks.

CHEST PAIN AND PSYCHIATRIC DISORDERS In the studies conducted by Dr FoldesBusque and his team, patients with panic attacks were more likely to suffer negative impacts of NCCP on their daily lives, and to have suicidal thoughts. Approximately 20–44% of those who present with NCCP have some kind of psychiatric condition including panic attacks and panic disorder, and 15% have what is referred to as ‘suicidal ideation’. Despite this, fewer than 5% of patients receive a referral to a psychiatric specialist.

With these shocking statistics in mind, the importance of identifying panic attacks in emergency departments is evident.

However, panic attacks or panic disorder are rarely diagnosed. Even doctors participating in Dr Foldes-Busque’s studies rarely diagnosed panic in patients with NCCP, even when they were explicitly aware of the purposes and objectives of the study.

This may be partly explained by the fact that physicians often have limited time to make a diagnosis, and are usually focused on physical conditions. On top of this, the somatic symptoms of panic frequently resemble those of other disorders, such as coronary artery disease, therefore making it more difficult to make an accurate diagnosis.

CUTTING EDGE RESEARCH Dr Foldes-Busque has carried out numerous studies in hospitals over the last few years, examining the link between NCCP and panic, to find methods that will allow earlier diagnosis of panic attacks and panic disorder. His team have been at the forefront of research into NCCP and panic, and many of their papers have been the first of their kind.

Early diagnosis improves patients’ prognoses and minimises the strain on the health service caused by repeated visits to emergency departments. Dr Foldes-Busque participated in research showing that

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NCCP patients with panic disorder showed significant improvement in their condition following post-diagnosis treatment with cognitive behavioral therapy.

As well as the connection between panic and NCCP, they have also found a strong link with non-fearful panic attacks, a variation of panic where sufferers do not feel fear or anxiety, but do feel physical symptoms, like chest pain, during panic attacks. While these patients are less likely to have other psychiatric complaints, the condition can still be distressing and cause problems.

Dr Foldes-Busque’s team have developed two assessment methods for diagnosing panic, one of which is called the Panic Screening Score, which was first developed in 2011. This method is designed for patients with NCCP, and has been shown

to be up to eight times more effective at diagnosing panic attacks than a doctor’s clinical evaluation. It involves a short series of questions that can be completed quickly in an A&E situation, making it more likely to be used in a clinical setting. The Panic Screening Score is in the process of further validation and the results from this research will be available this year.

Dr Foldes-Busque’s team have been leading research in this field, identifying the barriers that prevent the diagnosis of panic in NCCP patients. They have established that panic can explain a larger proportion of NCCP than was previously thought, and have devised methods to improve diagnosis. Their most recent work examines in more depth the factors that contribute to a patient’s experience of pain, and consequently how to reduce it.

Dr Foldes-Busque’s recent work examines in more depth the factors that contribute to a patient’s experience of pain, and consequently how to reduce it www.researchfeatures.com

Detail What first prompted you to investigate the link between panic and NCCP? I had the incredible opportunity to work with Drs Fleet and Marchand during my PhD studies in Montreal. They were the ones who introduced me to this topic. I was rapidly struck by the idea that so many patients were seeking care in A&E but presented severe psychological problems that often remained undiagnosed. This also meant that they often did not receive the treatment they needed for this psychological problem in a timely manner.

That is what motivated me then and still motivates me now to pursue this field of research: to improve care for patients with panic and NCCP. Were you surprised that the doctors involved in your studies largely failed to diagnose panic in NCCP patients, despite being aware of the study’s objectives?

The diagnostic rate was certainly lower than expected as there was a lot of attention on the problem of panic in patients with NCCP following the ground-breaking works on the topic that were published in the late 1980s and during the 1990s. Still, we must acknowledge that A&E physicians have to tend to multiple competing demands and have limited time to tend to each patient. Furthermore, A&E physicians are not typically extensively trained in assessing psychological conditions such as panic disorder. In that context, assessing psychological conditions such as panic can be quite challenging. I think this is why a brief and easy to administer screening instrument such as the Panic Screening Score is so important.

Do you see direct improvements in clinical outcomes as a result of the deployment of your diagnostic tools, like the Panic Screening Score?

At this point in time, the Panic Screening Score has only been implemented in the context of research. The results are very promising and we are really looking forward to presenting the research to the clinical community in the next few months. In the course of our recent research, we observed that awareness of panic and its association with NCCP increased in some of the A&E

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physicians. However, we also recognised that there are multiples barriers to panic screening in A&E patients with NCCP. While a screening instrument such as the Panic Screening Score is an important part of the puzzle, educational intervention as well as systemic changes, such as improved access to mental health professionals, are also very important factors that need to be addressed to improve care of A&E patients with NCCP. Has awareness of the link between panic and chest pain increased in the time that you have been working in the area?

From my many exchanges with A&E physicians, they really seem more aware of this link than they were when I began working in this field. In the last five years, we can also see that more and more research is being conducted on this topic.

This is all very encouraging as there is a lot of work to be done.

Do you have any explanation of the mechanisms underlying the connection between panic and chest pain?

As yet, there is no scientific or clinical consensus on this topic. The most likely answer is that there are multiple and overlapping mechanisms. One of these is that the rapid and significant increase in respiratory rhythm that occurs during panic attacks can cause benign intercostal muscular spasms that may cause chest pain. Another possibility is that some minor medical condition or benign physiological change, such as chest muscle soreness or minor injury, provokes the NCCP symptoms.

Then patients with panic disorder, being more attentive and fearful of somatic symptoms, may be more likely than other patients to perceive these symptoms as potentially dangerous and to visit the A&E for medical assessment. Still, it is always possible that patients present a yet undiagnosed medical condition such as gastro oesophageal reflux or some form of cardiac condition, and just happen to also suffer from panic attacks. This is why we recommend that screening of NCCP for panic be made part of medical assessment

by A&E physicians.

RESEARCH OBJECTIVES Dr Foldes-Busque’s research and clinical interests generally focus on anxiety disorders and health psychology.

More specifically, he is interested in the relationship between anxiety and medically unexplained symptoms. He is also very active in student supervision and in clinical training, using the cognitive and behavioural approach.

FUNDING Fonds de recherche du Québec – Santé Canadian Institute for Health Research Hôtel-Dieu de Lévis Hospital Foundation COLLABORATORS Dr Patrick Archambault, Dr Fleet and Dr Poitras. All three are ED physicians and researcher who contributed to the research project. Dr Isabelle Denis, a fellow psychologist, researcher and professor at Université Laval. Dr Clermont Dionne, clinical epidemiologist, researcher and professor at Université Laval. Dr André Marchand, psychologist, researcher and professor at the Université du Québec à Montréal.

BIO Dr Guillaume Foldes-Busque has been a psychologist since 2009, specialising in cognitivebehaviourally oriented interventions. He obtained his PhD in psychology from the Université du Québec à Montréal before completing a postdoctoral fellowship in clinical epidemiology at both the Research Centre of the Québec University Hospital, and the Centre de recherche du Centre hospitalier affilié universitaire de Lévisin Quebec, Canada.

CONTACT Dr Guillaume Foldes-Busque PsyD, PhD Université Laval School of Psychology Pavillon Félix-Antoine-Savard 2325, rue des Libraries Quebec City, Quebec G1V 0A6 CANADA T: +1 (418) 656-2131 ext. 2592 E: Guillaume.foldes-busque@psy.ulaval.ca

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The complex web of addiction, disease and mental health

Neuroscience

Investigations into the relationships between substance abuse and infection, until recently, have focused primarily on socio-economic factors. Dr Jennifer Loftis of VA Portland Health Care System (VAPORHCS) and Oregon Health & Science University (OHSU), has gone a step further, uncovering the tangled web of co-morbidity associated with chronic infection, inflammation and substance use. This opens new avenues of treatment for those suffering from disease and/or recovering from addiction.

S

ubstance use disorders (SUD), including excessive alcohol consumption and dependency, pose a major problem to health services around the world.

Methamphetamine (known colloquially as meth), a potent psychoactive stimulant used as a recreational drug, is known to have long-lasting effects on the immune system of the brain. It is common in SUD for these substances to be used concurrently.

Similarly, substance abuse is known to be associated with increased prevalence of infections such as hepatitis C (HCV) and human immunodeficiency virus (HIV), as well as cognitive and psychological problems such as depression and anxiety. Dr Loftis has shown that the links between these different aspects of the physical and mental health of individuals with a substance use disorder are not as simple as first thought.

ALCOHOL FUELS THE FIRE Looking first at the impact of alcohol consumption on HCV infection, Dr Loftis saw that HCV is associated not just with liver damage, but also central nervous system (CNS) damage and neuropsychiatric impairments. Alcohol abuse is known to exacerbate these effects, so Dr Loftis and her colleagues set out to investigate the role of alcohol in regulating viral persistence and CNS immunopathology (damage to the immune system of the brain and spinal cord).

Using a mouse model and HCV-like virus, the team showed that mice given ad libitum access to alcohol entered into a vicious cycle.

Infection with the virus prompted increased

alcohol consumption, and increased alcohol consumption raised viral titres (the measure of viral particles in circulation) and increased viral persistence in the brain. Like others in her field, Dr Loftis came to the conclusion that, ’Alcohol use may exacerbate the adverse effects of chronic viral infections, such as HCV, on brain and behaviour’.

METH ADDS TO THE DAMAGE Evidence suggests that it is immune factors such as cytokines and chemokines (immune system signalling molecules), as well as dysregulation of the cell adhesion molecules which support the blood–brain barrier, which contribute to the cognitive and psychiatric impairments associated with meth use. Using a cross-species translational approach, Dr Loftis demonstrated that both mice and humans experienced changes to the mix of immune factors on exposure to meth, with humans in remission shown to have an associated reduction in cognitive abilities. The fact that at least some cognitive difficulties only appear in remission, suggests that the neuronal damage caused by these inflammatory processes may contribute to the long-lasting neuropsychiatric symptoms that are experienced by some individuals in recovery. Recent research by the team has found that adults in early recovery can experience attention, memory and executive function problems.

THE DISEASE STRAND Patterns of behaviour in substance abuse, such as injection drug use, are known to increase the prevalence of blood-borne

Individuals with a substance use disorder may be more likely to suffer from infection and psychiatric symptoms, and those infections may be prolonged and more severe 47

Neuroscience

infections such as HCV and HIV among persons with SUD. These can contribute to poor disease management and abstinence relapse either directly, through neural injury, or indirectly through the effects of neuropsychiatric symptoms of cognitive dysfunction, depression and anxiety. Dr Loftis and her colleagues have shown that this means that individuals with a SUD may be more likely to suffer from infection and psychiatric symptoms, and those infections may be prolonged and more severe.

Highlighting research which shows that even mild cognitive impairments can have significant effects on real-world outcomes such as employment, treatment adherence and quality of life, Dr Loftis has suggested there is a need for neuropsychological screening for those with both severe infections and SUD. INTERFERING INTERFERONS This is particularly important considering her research on HCV treatment using interferons. Interferon-alpha therapy aims to assist the body in eliminating the virus by provoking a sustained virological response (patients continuing to be clear of the virus after treatment has stopped), preventing the virus from replicating so the natural immune system can cope. However, Dr Loftis has shown that during the therapy patients experience significantly increased psychiatric symptoms such as depression. Although these are usually short term and improve on completion of the therapy, particularly if it is successful, it gives another example of how immune system changes impact on neuropsychiatric indicators.

Thankfully, new HCV treatment options such as direct acting antiviral therapies (DAA) are set to overturn the problems associated with interferon therapy such as long treatment time, poor viral clearance rates and the side effects mentioned above. Current DAA regimens of just eight to 12 weeks have shown a 90–95% sustained viral response rate. However, research is needed to assess the impact of HCV on CNS function and

Meth Use

Neuropsychiatric Disorders

Interferon Treatment

HCV Infection

A diagram to illustrate the complex web of possible interactions between SUD, viral disease, treatment strategies and neuropsychiatric symptoms. Dr Loftis has uncovered many of the mechanisms underlying these interactions, as detailed in the article.

mental health outcomes following the newer antiviral agents.

A NEW THERAPEUTIC TARGET FOR SUBSTANCE USE DISORDERS This complex interplay between the immune system and the CNS, mediated by substance abuse and resulting in cognitive and emotional dysfunction, is where Dr Loftis and her colleagues have targeted their investigations. They believe that, in untangling these relationships, new therapies

Recent research by the team has shown that adults in early recovery from some substances of abuse can experience more attention, memory and executive problems than adults actively using 48

Alcohol Abuse

may be uncovered which treat the root causes of the CNS pathology. This would in turn result in psychiatric recoveries and drive improved health outcomes for both the prevalent infections and the SUD. Current pharmacological therapies for SUD such as meth addiction focus on the neurotransmitters (brain signalling molecules) involved in the drug’s effects, blocking or changing their action to combat the effects of the drug. The research team at VAPORHCS and OHSU believe that this approach fails to combat the full range of drug actions in the CNS. “One key limitation of neurotransmitterbased therapies is that, alone, they do not offer a mechanism for repairing stimulantinduced neuronal injury,” says Dr Loftis, “which might be vital for successful recovery”.

By failing to include an element of brain repair in the therapy, cognitive dysfunction continues in abstinence and results in increased likelihood of relapse.

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Detail Why does chronic infection cause cognitive impairment?

Clinical studies indicate that neuropsychiatric impairments may be present in up to 50% of patients with chronic HCV infection, and these symptoms may be independent of the HCV viral load. Chronic infection likely contributes to cognitive problems and other neuropsychiatric symptoms through multiple mechanisms, including altered immune signalling, neuronal impairment, reduced cortical thickness, and disintegrity within white matter tracts of the brain.

How does substance abuse impact on neuropsychiatric disorders?

Like HCV infection, chronic exposure to alcohol and other drugs of abuse induces inflammatory responses that contribute to the drug’s adverse CNS and neuropsychiatric effects. This growing body of research shows, for example, that neuroinflammation is evident in the brains of adults with a history of alcohol abuse, with increased activation of microglia and elevated expression of central and peripheral inflammatory factors.

Animal studies also show that alcohol induces gliosis, and specifically, activation of immune receptors that stimulate microglia and the induction of pro-inflammatory factors that putatively contribute to alcohol-induced BBB permeability and neuropsychiatric symptoms.

The team are currently testing and evaluating a range of potential immunotherapy agents with the aim of repairing the damage caused by chronic inflammation of the CNS and promoting functional recovery. Unique ligands which bind to receptors on immune cells, originally shown to reduce inflammation in models of multiple sclerosis and stroke, have the potential to effectively address the neuropsychiatric effects of meth use. Dr Loftis identifies this as part of a combination

How will your work address the underlying issues in substance use disorders?

I have had the privilege of conducting research on substance abuse for more than 15 years. My translational research programme investigates the neurochemical mechanisms contributing to psychiatric symptoms and cognitive impairments in the context of substance abuse and chronic viral infection, with a particular focus on pharmacotherapeutic treatment development for substance use disorders. These pre-clinical and clinical studies have identified molecular targets (e.g., glutamatergic receptors and inflammatory signalling pathways) and specific brain regions involved in druginduced neurotoxicity and the adverse behavioural effects that contribute to addiction. Through collaborations with clinicians and other scientists, this work has led to the testing of hypotheses regarding how genetic risk factors and circulating inflammatory cytokines affect central nervous system and psychiatric functioning and how immunotherapeutic strategies may help to treat these conditions – with the ultimate goal of moving collective research findings closer to clinical application and improving treatment outcomes.

therapy which may include behavioural therapies (for example, cognitive therapy or psychotherapy) and potentially vaccines developed to suppress the action of drugs of abuse. This approach has the potential to finally break the complex web of interplay between drug and alcohol abuse, infectious diseases and psychiatric disorders which impacts so heavily on sufferers.

CONFLICT OF INTEREST STATEMENT: OHSU and Dr Loftis have a significant financial interest in Artielle Immunotherapeutics, a company that may have a commercial interest in the results of this research and technology.

This potential individual and institutional conflict of interest has been reviewed and managed by OHSU.

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RESEARCH OBJECTIVES Dr Loftis’ work explores the complex relationship between substance abuse and viral infection and the effect of these on the cognitive health of sufferers.

She has a particular interest in chronic hepatitis C viral infection, alcohol abuse and methamphetamine abuse.

FUNDING This work was supported in part by the United States (US) Department of Veterans Affairs (Biomedical Laboratory Research and Development) and National Institutes of Health (NIH) (NIDA and NIAAA).

The contents do not represent the views of the US Department of Veterans Affairs or the US Government.

COLLABORATORS Marilyn Huckans, PhD; Arthur Vandenbark, PhD; Methamphetamine Abuse Research Center (NIDA-funded; PI: Aaron Janowsky, PhD) BIO Dr Loftis completed a BA in Psychology and in Business Economics at University of California at Santa Barbara and an MA in Clinical Psychology from Fairleigh Dickinson University in New Jersey before completing her PhD in Behavioral Neuroscience at OHSU. She is currently a Research Scientist at VAPORHCS and Professor in the Department of Psychiatry at OHSU. In addition to her research work, she makes time to mentor students and provide community outreach.

CONTACT Jennifer Loftis, PhD VA Portland Health Care System 3710 SW US Veterans Hospital Rd. Mail code R&D 16, Portland, OR 97239 USA E: loftisj@ohsu.edu T: +1 503 220 8262 (ext. 57155) W: http://www.ohsu.edu/xd/education/ schools/school-of-medicine/departments/ clinical-departments/psychiatry/faculty/ loftis.cfm http://www.ohsu.edu/pniresearch http://www.ohsu.edu/marc/

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Mental Health

A technologybased future for psychotherapy Despite suffering from high rates of depression, homebound older adults often have limited access to clinic-based psychotherapy. Professor Namkee Choi from the University of Texas has been investigating how videoconferencing can be used to deliver cost-effective mental health care for low-income homebound older adults suffering from depression.

H

omebound older adults suffering from chronic medical conditions, mobility impairments and financial stress are particularly susceptible to social isolation and often experience depression. Recent studies have found that these older adults suffer from clinically significant depressive symptoms at rates two to three times higher than their mobile peers. Despite their high rates of depression, these older adults face significant barriers to accessing effective, evidence-based psychotherapy or other psychosocial interventions due to their homebound state, financial hardship and lack of transportation.

THE BARRIERS TO TREATMENT Psychotherapy treatments available at present are largely clinic-based. This limits low-income homebound older adults’ access given their mobility impairment and transport limitations. Other systemic access barriers include difficulties in scheduling appointments around existing primary care commitments, a notable shortage of licensed psychotherapists for older patients, and treatment cost. Personal barriers include the perceived stigma of mental health issues, denial of depression, lack of motivation and reliance on religious faith as the primary means of coping.

Depression is commonly treated with pharmacotherapy (i.e., antidepressants).

However, pharmacotherapy has shown

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limited effect on tackling depression in low-income homebound older adults: antidepressants can provide a short-term relief but do not provide a framework of how to cope with the many daily stressors that these older adults experience.

With rapidly increasing numbers of older adults, there is a growing need for accessible, affordable and effective psychotherapy or other psychosocial interventions to treat depression in this population group. Since 2009, Dr Choi has been exploring how technology can be capitalised on to address this need and improve access and patient healthcare outcomes.

IN-HOME VIDEOCONFERENCED PROBLEM-SOLVING THERAPY Dr Choi’s research between 2009 and 2012 tested videoconferenced problem-solving therapy (tele-PST). Originating from the cognitive-behavioural theory, PST is a shortterm, structured treatment based on the idea that people who struggle with problemsolving skills are less able to cope with high levels of stress and are therefore more susceptible to depression. PST is focused on providing practical, ‘here and now’ problem solving skills and behavioural activation and is therefore particularly well suited to helping older disadvantaged sufferers of depression to cope with daily stressors. Dr Choi’s research, funded by the US National Institute of Mental Health, investigated

whether five–six sessions of PST could be tele-delivered for homebound older adults in their own homes.

Although tele-therapy has been growing in popularity over the last decade, it has generally been confined to office-/clinicbased videoconferencing or telephoneadministered care. Dr Choi’s research took this approach one step further, implementing home-based tele-therapy.

In a randomised controlled trial, Dr Choi compared the acceptance and efficacy of home-based tele-PST to those of in-person PST (i.e., therapists conducted PST sessions

An absolute majority of tele-PST participants were highly satisfied with tele-sessions’ convenience achievement at mastering a new, previously unknown technology and took pride in ‘joining the technical age’. Secondly, patients enjoyed the comfort and convenience of in-home tele-sessions. Thirdly, therapists reported that patients were often more focused during tele-sessions than in-person sessions. Distractions that commonly occur during in-person, in-home therapy, such as answering the phone, getting a drink etc. were rare during tele-PST sessions, suggesting that the use of technology facilitated higher engagement in the therapy while allowing the same benefits of face-toface therapy sessions.

Alongside enhanced patient outcomes, Dr Choi also stresses the additional benefits of tele-delivery that eliminates the need for older adults to travel to see a therapist or the need for a therapist to travel to see homebound older adults. Savings from travel time and costs mean reduced treatment costs and also allow one therapist to see more patients. Thus, tele-therapy offers a sustainable, economic and effective alternative to in-person therapy.

face-to-face at older adults’ homes) and care call (regular telephone calls providing support and monitoring of depressive symptoms). The participants in this study were referred by case managers of ageing service agencies that served low-income disabled/homebound older adults.

The study found that tele-PST was more acceptable than in-person PST. An absolute majority of tele-PST participants were highly satisfied with tele-sessions’ convenience.

12-week follow-up assessments showed that compared to care calls, both tele-PST and in-person PST were more effective in reducing depressive symptoms. However,

at 36 weeks, compared to both in-person PST participants and care call participants, tele-PST participants had significantly lower levels of depressive symptoms (measured with the 24-item Hamilton Rating Scale for Depression) and disability (day-to-day difficulties due to health conditions, either mental or medical, measured with the 12item World Health Organization Disability Assessment Schedule).

According to Dr Choi, tele-PST’s higher long-term effectiveness can be attributed to a combination of factors. Firstly, patients were found to experience a high sense of

TRAINING THE WORKFORCE FOR A SUSTAINABLE MENTAL HEALTH CARE DELIVERY MODEL While Dr Choi’s research clearly indicates the acceptance and efficacy of tele-PST for underserved older adults, the access to this mode of psychotherapy is still ultimately limited in real-world settings due to the current and projected shortage of licensed geriatric mental health clinicians.

In the United States, most states have strict licensing laws allowing only licensed master’s- or PhD-level clinicians to practise psychotherapy. However, in other countries, lay mental health workers have been proven to deliver effective interventions for underserved population groups.

With funding from the US National Institute on Minority Health and Health Disparities,

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Mental Health

Dr Choi demonstrates a mental health care delivery model that can improve access to evidence-based treatment for underserved population groups Dr Choi is currently testing comparative clinical and cost effectiveness of teledelivered self-care management support (tele-SCM) for homebound older adults by lay (i.e., bachelor’s-level) mental health providers versus tele-PST by master’s-level psychotherapists. Like PST, SCM is a shortterm (five weekly sessions and two monthly booster calls), structured treatment focusing on behavioural activation, an evidencebased depression treatment. Participants learn systematic steps to engage in healthy behaviours and better self-care and maintain social connections. The study shows that after 40–50 hours of training in the manualised tele-SCM treatment modality, lay providers can effectively deliver the intervention. Preliminary outcomes also show that tele-SCM is likely to be as acceptable and effective as tele-PST. The current study also aims at testing if teledelivered, short-term depression treatment (i.e., tele-SCM or tele-PST) that is integrated in an ageing service agency (Meals on Wheels Central Texas in this case) will increase older

adults’ willingness to seek treatment. In Dr Choi’s earlier tele-PST efficacy study, case managers reported very low levels of consent (10–20%) from those older adults who met the referral criteria. Case managers cited multiple reasons for this lack of uptake: fear and pessimism of a new treatment and mistrust of mental health providers; religious coping; denial of depression; lack of time, energy or motivation; and stigma and discomfort associated with seeking treatment for depression.

In the current tele-SCM and tele-PST study, SCM and PST providers are co-located in the agency and coordinate care with the participants’ case managers. Given lowincome homebound older adults’ needs for both social and mental health services, care coordination is an important strategy.

Preliminary results show that older adults tend to be more receptive to depression treatment when they are told that it is part of the agency services; however, to date, the consent rate has been still at about 50%, while treatment dropout is rare once they engage in treatment.

FUTURE DIRECTIONS Dr Choi’s work sets the stage for a different future for depression treatment for rapidly growing numbers of disabled/homebound older adults. By taking advantage of easily available technology and both licensed professional and lay mental health providers, she demonstrates a mental health care delivery model that can improve access to evidence-based treatment for underserved population groups.

Tele-PST has been shown to be an effective and economic treatment modality. While tele-SCM is still in its testing stage, it also appears to be effective and economic and is likely to be more sustainable than tele-PST given its use of lay mental health providers. Depression treatment integrated in ageing service agencies may also increase older adults’ willingness to seek treatment.

However, further research needs to address overall low treatment-consent rates among depressed older adults.

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Your research focuses on low-income homebound older adults. Why is this group particularly susceptible to depression?

Low-income homebound older adults contend with multiple life stressors on a daily basis, which increases their vulnerability to depression. They have to deal with physical, functional and psychological effects of chronic medical conditions and disability. Their homebound state caused by disability also means that they are more socially isolated than their mobile peers. Most low-income homebound older adults lack means of transportation and have to rely on formal and informal support systems to get around. Financial strain is also a significant stressor contributing to these older adults’ depression.

Why is problem solving therapy (PST) particularly effective for treating depression in low-income homebound older adults?

PST is a short-term (i.e., five to six sessions in our studies), structured talk therapy.

It focuses on “here and now” stressors/ problems and teaches patients systematic problem-solving coping skills. It aims at behavioural activation through this problem-solving skills training and daily pleasant activity scheduling. Most older adults who have participated in our study like PST’s structured and practical approach to solving problems and its immediate positive effect on their daily lives. As they learn how to better deal with daily stressors, they feel more empowered. Sense of self-efficacy is a powerful antidote to depression.

Your recent studies have been investigating the use of Skype and other videoconferencing platforms to deliver PST to homebound older adults. What sort of feedback have you received?

In our earlier tele-PST study, we used Skype because it is a free programme used by millions of people. In our current study, we are using a videoconferencing platform that is compliant with HIPAA (Health Insurance Portability and Accountability Act of 1996: US legislation that provides data privacy and security provisions for safeguarding

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Detail medical information). With technological advances, most tele-therapy platforms are low-cost and the cost is likely to go down further.

Many older adults initially expressed reluctance towards videoconferenced sessions, because they had never done them. However, after their first sessions, almost all of them felt comfortable with their tele-sessions and accepted tele-delivery as a great way to engage in treatment.

Because a large proportion of low-income older adults, especially those in their 70s and 80s, do not have their own computers and Internet connection (due mostly to the cost of Internet subscription), we have been providing a laptop and wireless card for tele-sessions. The laptops were set up in ways that are easy to use even for those without any prior experience. The problem that we have encountered with videoconferencing is not because of older adults’ lack of technological savvy but because of faulty Internet transmissions. When audio and/ or video transmissions are not optimal, we have to reschedule tele-sessions and in some cases have to switch to telephone sessions. With continued advancement in telecommunication technology, transmission problems are expected to become fewer in the future. However, wider dissemination and implementation of tele-therapy in the real world requires universal access to an Internet connection as a right, not a privilege, regardless of economic status.

Many case managers have reported low patient uptake. What, in your opinion, are the main steps required to increase patient engagement in tele-therapy?

Older adults in their 70s and 80s have had very limited experience of discussing their mental health issues and treatment other than pharmacotherapy. Many in these age cohorts often feel stigmatised about their depression.

They also often misperceive psychotherapy solely as a long-term psychoanalytic psychotherapy and do not want to “dig up the past” especially with a stranger (therapist). Thus, we need to do more work to normalise depression as a treatable medical condition that is no different from other health conditions. We also need to provide more education about short-term, evidence-based

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psychosocial interventions that focus on “here and now” stressors and behavioural activation.

Also because of our history of institutional racism and mistreatment of mentally ill people, racial/ethnic minority older adults often mistrust mental health providers.

Integration of mental health services into ageing service agencies is an important step to reduce their mistrust, as older adults tend to trust their ageing service providers more than mental health providers.

Younger cohorts of older adults in their 50s and 60s are more open to evidencebased psychotherapy; however, low-income individuals are often concerned about treatment cost. Even those with health insurance often cannot afford co-pay given their already high out-of-pocket medical spending. To improve access to mental health care in the real world, we need more funding for mental health services.

Throughout your trials you have received positive feedback from both case managers and patients. What needs to be done to encourage more healthcare providers to use tele-therapy?

I believe most healthcare providers accept tele-therapy as a resource- and timesaving alternative to in-person therapy.

However, both public and private health insurance programmes currently have some restrictions about the types of tele-therapy that can be reimbursed. Reimbursement policies for in-home tele-therapy for homebound older adults need to be instituted for wider implementation.

The Older Americans Act (OAA) has some funding available for OAA-funded agencies to directly provide or purchase mental health services (screening, diagnosis, and treatment) for their clients. Ageing service agencies should utilise this funding to integrate mental health services into their existing ageing services. However, the shortage of geriatric mental health service providers is a major challenge especially in health-/mental health- professional shortage areas. That is why I set out to test tele-SCM by lay mental health workers.

RESEARCH OBJECTIVES Professor Choi’s work focuses on the development and testing of effective treatment delivery models for late-life depression, with a particular focus on the use of technology.

FUNDING US National Institute on Minority Health and Health Disparities (2016-2020) and National Institute of Mental Health (20092012) COLLABORATORS KEY PARTNERS: C Nathan Marti, PhD, University of Texas at Austin; Mark M. Kunik, MD, MPH, Baylor College of Medicine; Nancy Wilson, LCSW, Baylor College of Medicine; Guoqing "John" Chen, MD, PhD, University of Kansas Medical School COMMUNITY PARTNER/ COLLABORATOR: Meals on Wheels Central Texas: www.mealsonwheelscentraltexas.org/ CONSULTANTS: Martha L Bruce, PhD, MPH, and Mark T Hegel, PhD, both Giesel School of Medicine, Dartmouth University; Leslie Sirrianni, LCSW, University of Texas at Austin BIO Namkee G Choi, PhD, MSW, is Professor and Louis and Ann Wolens Centennial Chair in Gerontology in the School of Social Work at the University of Texas at Austin. She received her PhD from the University of California at Berkeley and her training through the Advanced Research Institute in Geriatric Mental Health.

CONTACT Professor Namkee Choi University of Texas at Austin Austin Texas USA E: nchoi@austin.utexas.edu T: +1 512 232 9590 W: http://socialwork.utexas.edu/directory/ choi/ /choi-namkee-286bbb98

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Thought Leadership

Wings for Life: The backbone of spinal cord research

R

ed Bull gives you wings is the catchy slogan we have all come to associate with the caffeinated drinks company. Not many will know about the company’s background charity work though, where it provides the financial backbone for Wings for Life – a spinal research charity founded

by Heinz Kinigadner and Red Bull’s founder, Dietrich Mateschitz.

Hello Anita! What does your role involve as CEO of Wings for Life?

In general, this role is no different to a similar position in the business world, including, as it does, building and leading a team, setting strategies or shaping our foundation's culture and behaviour. Basically, I am responsible for making sure that we as a team raise as much money as possible and spend it responsibly, wisely and effectively on research.

Following an accident to Kinigadner’s son which left him paralysed, the two realised that spinal cord injury research was hugely underfunded, so they set up the charity to bridge the funding gap and find a cure. Since that time, Wings for Life has established itself as a significant force in spinal cord research and its fundraising events, such as the Wings for Life World Run, have garnered huge support and done much to raise awareness.

Research Features recently sat down with Anita Gerhardter, CEO of Wings for Life, to discuss the charity’s history in more detail, and find out where science currently stands on finding a potential cure.

Can you explain the background and aims of Wings for Life?

Wings for Life is committed to finding a cure for spinal cord injuries. The driving forces behind it are two-time motocross world champion Heinz Kinigadner and the founder of Red Bull, Dietrich Mateschitz.

In 2003, Kinigadner's son Hannes suffered a tragic accident that left him tetraplegic.

Reeling from shock, but determined to find a way forward, Kinigadner and Mateschitz invited leading scientists from across the world to Salzburg. All these experts reported that contrary to common opinion, there is

Finding a cure is a matter very close to my heart.

I know so many people who are affected and I admire their mental and physical strength and the way that they cope with a daily life so full of obstacles, difficulties and deprivations 58

© Andreas Langreiter

Think of energy drinks company Red Bull and by association some of the most exhilarating sports probably spring to mind. Sponsoring over 500 extreme sports, from base jumping to downhill skating, has done much to get the brand noticed. But its sponsorship does not end there. Red Bull founder, Dietrich Mateschitz, set up the charity Wings for Life with Heinz Kinigadner back in 2003 after noticing a gap in funding for spinal cord research. We spoke to Anita Gerhardter, Wings for Life’s CEO, to find out more about the charity’s background, heritage and philosophy.

Wings for Life World Run participants in the UK

legitimate reason to hope that traumatic spinal cord injury can be cured.

Kinigadner and Mateschitz soon realised that research into spinal cord injury was underfunded. Paralysis is not considered a widespread condition so investing millions in research to help a small number of people was generally thought to be an unprofitable endeavour for the medical industry.

This realisation prompted Kinigadner and Mateschitz to set up the Wings for Life research foundation – with the goal of finding ways to cure everyone affected.

What impact do you think Wings for Life has had on spinal cord injury research since it was first established in 2004?

Without question, Wings for Life has contributed to pushing the whole field of neuroscience forward. We have grown from a small entity to a renowned and well-positioned foundation in spinal cord

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research. Nowadays, we receive more than 250 applications from scientists out of 30+ countries every year. Over the years more than 400 reviewers helped us to evaluate these proposals. In total, we have funded 142 research projects, resulting in 256 publications, which have also appeared in scientific journals such as Nature and Science.

Wings for Life clinical director Professor Armin Curt together with a patient

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During that time, what have been the foundation’s most notable research breakthroughs?

This is a tough question to answer, as there is no common agreement as to what constitutes a breakthrough, or a method by which to measure it. Personally, I tend to speak of a breakthrough when a successful treatment has passed the clinical tests and is available for a larger group of patients. This is something we and the whole field are still working towards.

To get there sooner, we have established a programme called the Accelerated Translational Program (ATP), which aims to bring basic research projects into the clinics.

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Thought Leadership

Wings for Life funds spinal cord research projects all over the world. How does the foundation go about centralising and sharing the research findings?

Centralising and sharing findings is very important to make significant progress. We work on several levels to achieve this. First of all, we ensure that funded scientists publish their findings, whether positive or negative – this is stipulated by contract. Then, we are part of the AllTrials campaign, an initiative advocating that all clinical trials should be listed in a registry, and their results should always be shared as open data. We also fund bioinformatic projects for datasharing and harnessing big data to accelerate translation.

And we supported a FAIR-share (FAIR is a set of guiding principles for scientific data management) workshop together with preclinical researchers, industry and NGOs to look deeper into the potential opportunities and challenges of big data.

What are the key considerations when seeking to identify potential research projects?

The goal of Wings for Life is to find biological repair strategies. To do so, we support all approaches, in various stages of development, anything from molecularpharmacological approaches to stem cells,

Wings for Life is committed to finding a cure for spinal cord injuries. The driving forces behind it are two-time motocross world champion Heinz Kinigadner and the founder of Red Bull, Dietrich Mateschitz which could result in a promotion of axon growth – axons are extensions of neurons which transmit information to different neurons, or directly to effector organs. There is even a clinical study that investigates how low oxygen levels can stimulate walking function recovery in people with chronic spinal cord injury.

from neuroprotection to neuroregeneration, and from basic research to clinical studies. A key requirement for us is that the proposals from scientists have the potential to provide real benefits for patients and a view to translate from the laboratory to the clinical setting.

Can you tell us about some of the exciting research projects currently underway?

There are so many exciting projects underway that it is hard to home in on just a few. One example is a very promising study which uses electrical stimulation to improve locomotion. Another example is a study with an antibody which works against Nogo-A – a protein that prevents nerves from growing.

Repurposing of existing drugs is also a very exciting field. One example of that is a current study into the pain killer Ibuprofen,

Wings for Life organises international conferences every year to bring together leaders in research and medicine. Can you tell us more about these conferences?

Our annual scientific meeting is definitely a highlight in our yearly event calendar.

All scientists who are funded by Wings for Life come together in Austria to present their projects, and to discuss and exchange their knowledge. The who’s who of spinal cord research attend and I think that the conference is highly effective, due in no small part to its intimate format.

Wings for Life fund world-class scientific research and clinical trials around the globe

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Left © Richi Hopson. Right © Chris Garrison

While on a layover at Moscow airport in 2012, the idea of the Wings for Life World Run was born. The premise was simple - a race run simultaneously at multiple sites

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© Joerg Mitter

Wings for Life CEO Anita Gerhardter with World Run International Director, Colin Jackson at the World Run control centre

across the world, in support of spinal cord injury research. How did a passing idea in an airport go on to become a global fundraising event?

The idea for the Wings for Life World Run was presented to us by an event specialist who had some time to kill at Moscow airport.

It sounds like a cliché but he drew the

concept on a napkin. We loved the project from the very beginning because we saw the incredible potential to make people aware of spinal cord injuries, win many new supporters around the world, raise money for research and do something fun together – all at the very same time!

The event is logistically, technically and, in terms of communication, a huge challenge.

Without the help of Red Bull we would never have been able to pull off this global event.

Wings for Life’s mission is to make spinal cord injury curable. How close are researchers to finding a cure?

There is no telling when a cure will be found.

Scientists agree that in the next five to 10 years we will see significant progress so Wings for Life is pushing as hard as possible, with all our energy, to bring that day around as soon as possible.

Why is finding a cure for spinal cord injury important to you personally?

Finding a cure is a matter very close to my heart. I know so many people who are affected by this dreadful injury and I admire their mental and physical strength and the way that they cope with a daily life so full of obstacles, difficulties and deprivations. It

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would be wonderful to give these people their bodily functions back - things like being able to breathe on their own, or move their fingers – that would massively change their lives for the better.

• If you would like to donate, get involved with Wings for Life’s World Run, or find out any more information related to Wings for Life’s exciting work, please visit their website at www.wingsforlife.com.

Contact Wings for Life – International Fürstenallee 4 5020 Salzburg Austria W: www.wingsforlife.com F: /wingsforlife T: @WingsforLifeUK

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Treating the wounded: neuroprotection strategies in spinal cord injury Much of the nerve damage associated with spinal cord injury (SCI) is secondary to the initial trauma. Dr Michael Fehlings and his team at the Toronto Western Hospital, University Health Network have been successful in developing strategies to limit these effects.

Spinal Cord Injury

T

raumatic SCI affects millions of people each year, with a disproportionate number coming from the under-30 age group. This means that lifetime treatment costs can run to millions of dollars per patient. Dr Fehlings’ initial work in the 1990s identified that secondary degeneration of neurons occurs around the initial injury, prompting him to further investigate how this might be prevented as well as developing strategies to promote regeneration of the damaged tissue.

Cellular damage in SCI is not limited to the neurons, but also affects the blood supply by damage to the microvasculature. This potent mix of damaged cells, decreased blood flow and disruption of the endothelial barrier between blood and spinal cord, means the injury site becomes a mass of chemicals with the potential to initiate damaging inflammatory signalling cascades. Cell debris promotes microglia (the protective cells of the nervous system) to release cytokines that activate other elements of the body’s response to cell damage. Although intended to assist with clearing cell debris and fighting infection, in any such process collateral damage is inevitable and further cell death results. On top of this, glutamate (a fundamental neurotransmitter) released as part of normal signalling, is not effectively cleared, leading to damage to neurons through over-excitation. There are also systemic and local autoregulation deficits, as the damage affects normal nerve impulses, which further contribute to secondary degeneration. Dr Fehlings has identified each of these elements as potential targets for therapeutic intervention.

PREVENTION IS BETTER THAN CURE One such promising target is the toxicity associated with excessive glutamate signalling at the injury site. Dr Fehlings and colleagues have identified a complex process by which increased activation of sodium channels during ischemia (low oxygen related to reduced blood flow) results in more uptake of calcium ions, which promotes glutamate release into the extracellular space. This is toxic to nearby cells, but has the benefit of being able to be addressed by drugs targeting the mechanisms associated with these signalling molecules.

Glutamate in particular, has long been a target for drug-based therapies, as dysregulation is implicated in a range of

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Neuroregenerative Strategies

Mobilisation/Induction of Endogenous Stem Cells Remyelination of Denuded Axons

Biomaterials as Structural Frameworks and Drug Delivery Vehicles Regeneration of Neurons Degradation of Glial Scar Molecular Signalling for Axon Pathfinding

Enhancement of Synaptic Plasticity and Formation of New Connections

neurological conditions such as amyotrophic lateral sclerosis (ALS, of ice bucket fame), Huntington’s Disease and type 1 spinal muscle atrophy. Dr Fehlings therefore turned to established therapies for these conditions in his search for novel neuroprotective agents that could be utilised in SCI. THE RISE OF RILUZOLE Riluzole was conceived in the 1980s as an anti-epileptic for its properties as a sodium channel blocker. Although never particularly successful at improving outcomes for those patients, it has been found to improve outcomes significantly for ALS patients in a number of large and well-controlled clinical trials. Based on its safety profile and

Transplanted Cells (Green)

Genetically Tranduced Factor Expression

approval for use in humans for this purpose, Dr Fehlings’ team started to investigate its neuroprotective properties in animal models of cervical spondylotic myelopathy (CSM), an age-related compression of the spinal cord which has similarities to traumatic SCI. Decompression surgery is routinely used to alleviate the stress on the damaged tissue. Dr Fehlings’ group coupled this with administration of riluzole in one group while the other had the surgical treatment alone. These studies demonstrated superior neurobehavioral outcomes and preservation of spinal tissue in the riluzole treatment group, strongly indicating a glutamaterelated mechanism underlying the condition’s effects. An ongoing clinical trial

Just as SCI is not limited to a single injury factor, so treatments need to be directed at diverse elements of the condition 63

Spinal Cord Injury

Presynaptic neuron Na+

Postsynaptic neuron Non NMDA receptor

Riluzole

Na+

Cellular edema

Ca2+

Cellular death

Ca2+

Credit: Michael G. Fehlings, Hiroaki Nakashima, Narihito Nagoshi, Diana S.L. Chow, Robert G. Grossman, Branko Kopjar

is investigating if this is mirrored in humans with CSM. The success of the CSM projects encouraged movement to clinical cases of SCI, and Dr Fehlings’ team began a Phase I trial which provided safety and pharmacokinetic data as well as indicating neuroprotective benefits. A Phase IIb/ III trial (the most rigorous test of efficacy on patients with the condition requiring treatment), known as the RISCIS trial, is currently underway. This double-blind, randomised, controlled trial enrols a large cohort of patients from eleven different medical centres. Riluzole is being administered to acute SCI patients for two weeks and its effects examined through motor and sensory scoring criteria after six months. Dr Fehlings’ hypothesis is that, ‘subjects with acute SCI treated with riluzole will experience superior neurological, functional and quality-of-life outcomes’, paving the way for its use in routine clinical management of SCI. A NEW FRONTLINE Not satisfied with progressing treatments on just one front, Dr Fehlings and his team have also been investigating possible interventions to further promote recovery

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NMDA receptor Glutamate

Dr Fehlings’ hypothesis is that, ‘subjects with acute SCI treated with riluzole will experience superior neurological, functional and quality-of-life outcomes’ of damaged neurons. Stem cell therapy, though showing promise in this area, has been plagued by poor knowledge of the mechanisms of action, difficulty in reproducing results and problems associated with correct differentiation.

To remedy this, Dr Fehlings and his colleagues have developed a combination approach using neural precursor cells (stem cells already destined to be neurons or their supporting glial cells) harvested from and transplanted into rats with SCI. Using multiple imaging and functional assessment techniques, they have identified that axon remyelination (repair of the insulating sheath around nerve fibres) is important in recovering motor function. Although more work is needed to ensure these effects are seen in other models, Dr Fehlings is convinced that, ‘strategies to augment remyelination may lead to important

functional improvements for patients with spinal cord injury’.

BRINGING IT ALL TOGETHER These two different strands of Dr Fehlings’ work are a good example of his belief that a combinatorial approach needs to be taken if advances in research are to be translated into significant functional gains for patients.

Just as SCI is not limited to a single injury factor, so treatments need to be directed at diverse elements of the condition. Similarly, while treatments such as riluzole will have benefits for acute injury patients, there are already those living with severe disability who require neuroregenerative treatments such as stem cells if there is any hope of regaining functionality. Dr Fehlings, working in Toronto Western Hospital, has the sort of access to both clinicians and patients that is necessary to make this move from ‘bench to bedside’.

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Detail How important do you consider the issue of secondary injury to be in the treatment of acute SCI? Secondary injury, which is a constellation of biomolecular factors initiated by ischemia, contributes in a substantial manner to the amplification of the primary mechanical trauma to the injured spinal cord. While the initial mechanical trauma is a rate-limiting determinant of the ultimate outcome following injury, the secondary injury is critically important as this is potentially modifiable by therapeutic strategies. This becomes particularly critical when one considers that preservation of only 10–20% of axons in the spinal cord can result in substantial recovery of neurologic function.

What possibilities does this create for developing neuroprotective strategies?

Targeting specific critical pathways which mediate the secondary injury provides unique opportunities to attenuate the severity of the secondary injury. The discovery that ischemia promotes the influx of sodium and calcium as well as glutamatergic excitotoxicity following acute spinal cord injury directly led to the discovery that riluzole could have an important potential clinical benefit for acute traumatic spinal cord injury.

Ultimately, however, spinal cord injury is a heterogeneous phenomenon and it is likely that a number of complementary neuroprotective strategies will be required to optimise clinical outcomes. Some of the key pathways to target include programmed cell death, or apoptosis, as well as the inflammatory cascade which is initiated as part of the secondary injury mechanisms.

Riluzole has great promise, how do you expect it to progress into treatment?

Currently riluzole is being examined in two phase III randomised controlled trials – one for acute traumatic cervical spinal cord injury (RISCIS trial) and the other for a form of non-traumatic cervical spinal cord injury termed degenerative cervical myelopathy (CMS-Protect trial).

Should riluzole show a positive impact in

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one or the other of these conditions, it is anticipated that the clinical uptake of riluzole for cervical spinal cord injury will be rapid. Riluzole is a safe drug which is readily accepted for use in ALS and thus, the application of this therapeutic strategy for cervical spinal cord injury should be rather straightforward.

Stem cell therapy has long been vaunted as the future of SCI treatment, how does your work build into that?

Our work is principally focused on neural stem cells which represent the developmental building blocks of the central nervous system. Spinal cord injury results in a significant loss of neural tissue and hence it is logical to conceive that the regeneration of lost neural tissue will require the use of neural stem cells. It is anticipated that, despite effective treatments targeting secondary injury, many patients will be left with substantial neurologic deficits following acute traumatic spinal cord injury. It is in these patients that complementary regenerative strategies could have a potential impact. It is anticipated that stem cell approaches, and in particular neural stem cells, could have a major role in optimising neurological recovery in these patients.

How does your position in Toronto assist with transferring your research to clinical practice?

My work in the Krembil Neuroscience Centre, at the Toronto Western Hospital and in the University of Toronto Spine Program combines a multi-disciplinary basic science and translational approach with the translation into clinical populations. In Toronto, we have the benefit of a strong linkage between basic pre-clinical science and clinicians who are adept at translating these discoveries. My role as the Vice Chair of Research in the department of Surgery at the University of Toronto and as the co-chairman of the University of Toronto Spine Program has enabled me to harness some of the remarkable translational scientific opportunities that exist in Toronto.

RESEARCH OBJECTIVES Dr Fehlings’ research on spinal cord injury has helped increase understanding of what happens after trauma to the spinal cord. He also focuses on ways to prevent further, secondary damage following spinal cord injury.

FUNDING Gerald and Tootsie Halbert Chair in Neural Repair and Regeneration; Krembil Foundation; DeZwirek Foundation; Honey and Barry Sherman; AO Foundation; Christopher and Dana Reeve Foundation; Ontario Neurotrauma Foundation; Rick Hansen Institute; De Gasperis Family; Canadian Institutes of Health; Wings for Life – Spinal Cord Research Foundation; PSI Foundation BIO Michael Fehlings is internationally recognized as one of the world's leading translational and clinical researchers in the field of spinal cord injury. His pioneering research has been critical in defining the mechanisms of secondary injury after spinal cord injury and the role of demyelination in post-traumatic neurological deficits.

CONTACT Prof Michael G. Fehlings, MD, PhD, FRCSC, FACS Professor of Neurosurgery Krembil Chair in Neural Repair & Regeneration Toronto Western Hospital, University Health Network R. Fraser Elliott Building, 1st Floor 190 Elizabeth St. Toronto, ON M5G 2C4 Canada E: michael.fehlings@uhn.ca T: +1 416 603 5627 W: http://drfehlings.ca/the-team/drmichael-fehlings/

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Learning from the best Dr Jeffrey Kieft, from the Department of Biochemistry and Molecular Genetics at the University of Colorado School of Medicine, is using studies of viral RNA to discover not just how viruses cause illness, but also to develop our understanding of fundamental cellular processes.

Molecular Genetics

R

NA stands for ribonucleic acid – it is a vital molecule involved in turning the information stored in DNA into useful proteins, as well as in many other critical biological processes. With a similar construction to DNA of long chains of nucleotides (a nitrogenous base coupled with a ribose sugar and phosphate), it is created, translated and degraded by cellular ‘machinery’ as necessary to maintain cellular functions. Viruses exploit this system by inserting their own RNA into a cell to hijack the cell and turn it into a factory for viral replication, usually with the result that the cell ruptures and releases new viral particles to infect others.

The Kieft lab are interested in how this versatile molecule, which can encode information like DNA as well as forming complex and compactly-folded bioactive structures like a protein, is able to exert its effects. They are able to draw on a rich diversity of available RNA for their studies; it is thought there may be more than one billion species of virus with only a small proportion so far identified by science.

Those discovered exhibit myriad functional characteristics, fine-tuned through evolution for subtlety and elegance. The team has a dual strategy, to examine the virus in search of therapeutic targets at the same time as using viral RNA as a tool to probe fundamental elements of RNA-based cellular processes.

The first is important enough by itself, viral diseases place a huge burden on healthcare systems around the world. The flavivirus (FV) family, which includes Yellow Fever (flavus is Latin for yellow), West Nile Virus and Dengue Fever (DENV), is a major focus of their work.

In 2010 these viruses caused over 100 million symptomatic human infections. These are often severe and debilitating, and in some cases fatal. They are also widespread, with the World Health Organization estimating that over 40% of the global population were at risk in 2014. International trade and

climate change threaten to further extend the range of the mosquito vector which transmits the disease, and with no effective therapies or vaccines against the majority of FVs, further research is urgently needed.

TEACHING US A LESSON FVs gain entry to the cell by receptormediated endocytosis (essentially piggybacking onto cell signalling mechanisms).

This releases their genomic RNA (gRNA) into the cell where it is translated as if it were part of the cell’s own RNA. This makes a single protein which is further divided to make all the necessary elements for viral replication and transmission. In order to regulate the way that proteins are created within a cell, it has to be possible for normal cellular RNA to be switched off. Cells do this by degrading the RNA once its job is done, but this poses a problem for FVs which need to replicate and protect their RNA to make more copies of themselves.

Dr Kieft and his team have shown how DENV uses a unique RNA structure in a particularly elegant way of overcoming this problem.

The exoribonuclease Xrn1 (a cellular enzyme which degrades RNA) chews its way through the gRNA in a specific direction known as 5’–3’. However it stops short of degrading the entire strand, leaving a section dubbed a subgenomic flaviviral RNA (sfRNA). This remaining section is associated with many of the cytotoxic (cell damaging) effects of the virus, in part by inhibiting the cell’s anti-viral defences.

LEARNING THE HARD WAY The team developed an assay to confirm that specific folding patterns in the RNA, related to nucleotide sequences in the untranslated region which remains after degradation, are responsible for stopping Xrn1 in its tracks. They identified a complex threedimensional fold, created by the pairing of complementary nucleotides on a single strand, which creates a remarkable barrier to Xrn1. Because Xrn1 moves from the 5’ to the 3’ end of the strand (each end is named

The team has a dual strategy, to examine the virus in search of therapeutic targets at the same time as using viral RNA as a tool to probe fundamental elements of RNA-based cellular processes 67

Molecular Genetics

Above: Two views of an exonuclease-resistant RNA from the Zika Virus; the blue end is the 5’ end where the enzyme stops.

Right: Evidence suggests that the Xrn1-resistant structure in mosquito-borne flaviviruses may be linked to their ability to infect both human and mosquito hosts.

after the exposed carbons on the ribose ring which confer directionality to nucleic acids), the barrier it finds when degrading the RNA is not encountered by the virus’ own polymerase which makes copies from the other direction.

Further work by Dr Kieft and his collaborators has shown that this is not restricted to DENV: the sequences necessary to create the interfering structures are conserved across the mosquito-borne flaviviruses. They have shown that a very similar structure is present in the Zika virus RNA, which has recently been the subject of significant media attention for its effects, and that this also results in production of sfRNA. KNOWLEDGE IS POWER For RNA viruses, hijacking of the host’s translational machinery is essential for viral replication and packaging for release. Over millennia the biological arms race between the pathogen and the host has resulted in a range of measures on each side to combat each other. For example, there are very

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It is thought there may be more than one billion species of virus with only a small proportion so far identified by science specific conditions normally required for RNA to be translated into proteins: each RNA should have a special cap, added by an enzyme, to mark it as ready for translation; it then needs to use over a dozen initiation factor proteins to get the small ribosomal unit (first part of the translation machinery) in position and to scan for the start sequence; only then is it able to assemble the full ribosome and proceed to protein synthesis.

Dr Kieft’s group have shown how some viruses use RNA structures as a way around this process, and can instead attach directly to the ribosome and initiate translation without many of the normally necessary signals. Hepatitis C virus (HCV) has been shown to do this through what is known as an internal ribosome entry site (IRES).

Structural elements of the RNA interact with

the ribosome to correctly align the coding section independently of many protein factors. The team have then shown that even these structures can undergo conformational changes as part of the process to start elongation. This expands on our knowledge of the processes that underlie the central dogma of gene expression and shows that ribosome activity, fundamental to all living organisms, can be altered by bound RNA, even that originating from outside the cell.

Dr Kieft and his team are therefore bringing to light previously poorly understood processes and mechanisms. This gives invaluable insights – not just for novel therapeutics, but for our understanding of some of the most important cellular processes shared across all life.

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Detail What makes RNA viruses such useful tools for studying cellular processes?

Viruses lack the basic machinery needed to make more copies of themselves, so they depend entirely on their ability to co-opt the machinery of infected cells. Many viruses have evolved ways to use their RNA to manipulate the processes that the cell has in place and that the virus requires to replicate. By understanding how the virus uses its RNA to manipulate specific cellular processes, we learn a lot about those processes and how they can be altered.

Biology has had billions of years to evolve these RNA structures, so by exploring them we really are looking at highly tuned molecules that can teach us basic rules of how RNA structure relates to its activity.

How can this knowledge be used to create synthetic RNA with bioactive properties other than transient regulation of gene expression?

I think one of the most interesting things about structured viral RNAs is how the structure confers remarkable and unexpected properties and functions to the RNA. Understanding how some RNAs fold into complex and compact structures, what those structures look like, and how this drives function could potentially allow us to exploit these structures or design new ones. Part of my lab is working on applying the lessons that we learn from studying naturally-occurring viral RNAs to engineering new synthetic RNAs that do what we want.

Why is it important to expand our basic understanding of the biochemical processes inside cells?

Any hope of using science to improve human health or cure diseases requires that we fundamentally understand how biology works. We must always strive to

answer the question: What are the basic molecular processes that govern biology (or the natural world in general!)? Basic science, motivated by pure curiosity and the desire to understand how things work at their most fundamental level, has always been (and will remain) the foundation upon which progress and innovation depends.

How might this help in the fight against devastating viruses such as Dengue Fever and HCV? Understanding how these viruses interact with the cells they infect, and how this drives processes necessary for viral infection, is critical to find new targets for therapies. For example, if we find that a certain interaction or structure is playing a key role in a virus’ ability to hijack the cellular machinery, then we can start to think about how we might block that interaction or disrupt that structure. If we lack this knowledge, then we are essentially flying blind in terms of finding new therapies.

Your latest work has found that certain RNA can be active in wildly different cell types, such as bacteria and animals, how is this possible?

Bacteria and animals are separated from one another by more than a billion years of evolution, but at their core, many of the processes and molecular machines remain very similar across all of life. Thus, in some cases a molecule that can alter a process in one species can also do so in very different species. Importantly, this means that scientists can use organisms like bacteria, yeast, fruit flies, nematode worms, zebrafish, and many others to explore the basic rules of biology and learn things that can be used to improve human health.

RESEARCH OBJECTIVES Dr Kieft’s work focuses on viral RNA, aiming to understand as much about it as possible. His work is helping to elucidate not only the structure and function of RNA but also fundamental aspects of basic biological processes.

FUNDING National Institutes of Health, Howard Hughes Medical Institute, American Cancer Society, Cancer League of Colorado, American Heart Association BIO Jeffrey Kieft graduated in 1990 from the US Military Academy at West Point, then served as an Army Officer in Germany.

Upon leaving active duty, Dr Kieft earned his PhD from the University of California, Berkeley and did postdoctoral research at Yale University. In 2001 he was awarded the Roger Revelle/AAAS Fellowship in Global Stewardship, working as a member of the White House Office of Science and Technology Policy for one year before joining the faculty at the University of Colorado School of Medicine. He was an Early Career Scientist of the Howard Hughes Medical Institute and is currently a full professor with tenure.

CONTACT Jeffrey Kieft Dept. of BMG, Mail Stop 8101 12801 East 17th Avenue, Room L18-9110 Aurora, CO 80045 E: jeffrey.kieft@ucdenver.edu T: +1 303 724 3257 W: http ://www.medschool.ucdenver.edu/ KieftLab

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Generating novel insights into the consequences of diabetes by integrating clinical, biomarker and genetic data in large cohorts Dr Hertzel Gerstein is a Professor at McMaster University, Ontario, and at Hamilton Health Sciences. Dr Guillaume ParÊ is an Associate Professor in the department of Pathology and Molecular Medicine at McMaster. They are currently collaborating to generate novel insights into the consequences of diabetes by integrating clinical, biomarker and genetic data in large cohorts – with an aim to help clinicians prevent and treat heart disease, kidney disease, cognitive decline and other long-term consequences.

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Epidemiology

People with diabetes are twice as likely to develop heart disease or stroke compared to those who do not suffer from diabetes

abnormalities that are associated with the elevated glucose levels remains the focus of much research worldwide.

M

ore than 750 million people worldwide have either impaired fasting glucose, impaired glucose tolerance or diabetes, and it is estimated that this number will continue to rise progressively in the foreseeable future. Compared to unaffected people, these dysglycaemic individuals suffer from premature cardiovascular disease, kidney disease, cognitive decline, premature mortality and a variety of other long-term health consequences. The subset with diabetes also experience impaired quality of life from the symptoms of high blood sugar levels as well as a higher risk of blindness, kidney failure, amputations and nerve damage than unaffected individuals.

WHY IS DYSGLYCAEMIA LINKED TO LONG-TERM SERIOUS HEALTH PROBLEMS? There are several explanations for the adverse health consequences of dysglycaemia. Whereas most scientists agree that the prolonged exposure of tissue beds to elevated glucose levels is an important part of the explanation, the exact mechanism through which glucose causes damage and the role of the many metabolic

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THE ORIGIN OF GERSTEIN AND PARÉ’S COLLABORATION Gerstein and Paré are currently analysing blood and genetic material obtained from a subset of participants in a recently completed international clinical trial called “ORIGIN” that was led by Gerstein and conducted between 2002 and 2012 in 12,537 people with dysglycaemia located in 40 countries. Published in 2012, the ORIGIN trial demonstrated that insulin has a neutral effect on serious health outcomes during more than six years of treatment. Their current collaboration focuses on the analyses of blood that was stored from a subset of 8,401 of these participants and the genetic material from a further subset of 5,000.

Analysis of the data has been for the following purposes: 1) to find biomarkers that can be used to identify and predict serious health outcomes – these need to be suitable for addition into routine medical data collection, and provide greater insight than current routinely collected data; 2) to find novel genetic variants that have been shown to cause cardiovascular problems (using a technique known as Mendelian randomisation); 3) to find novel biomarkers for already widely used medicines; and 4) to identify genetic and metabolic pathways that can lead to serious health problems and that may account for the benefit of some medications.

Analyses of this sort were made possible by the storage of samples in a large biobank located at the Clinical Research Laboratory in the Population Health Research Institute in Hamilton, Ontario, Canada, which contains samples from more than 250,000 participants who have participated in a large variety of studies over the last two decades. They are also made possible by new technologies that allow rapid and economical measurement of up to 1,500 different biomarkers in just 100 microlitres of blood and other technologies that facilitate comprehensive genetic analysis.

BIOMARKERS A biomarker is any biological measurement or image that potentially contains information pertinent to the development, diagnosis, course or cause of a disease.

Within diabetes, as in other diseases, the value of any one or set of biomarkers depends on how the data are acquired and analysed. For example, Gerstein, Paré and colleagues analysed a dataset of 237 biomarker levels that were measured in stored blood from each of the 8,401 ORIGIN participants. As this analysis was done prior to establishing the biomarker platform at the Population Health Research Institute, the measurement was done commercially (Myriad RBM Inc.). After conducting extensive statistical analyses of these data, Gerstein, Paré and colleagues were able to identify 15 unique biomarkers that individually and independently predicted death, and ten that individually and independently predicted cardiovascular

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Epidemiology

Genetic variants associated with diabetes

Known genetic associations with diabetes

Diabetes

Figure 1: Schematic representaion of the Mendelian randomisation design

outcomes over a six- to seven-year period of time. The predictive ability of the identified panel of biomarkers was then confirmed in blood stored from other studies conducted by the Population Health Research Institute.

Using a similar approach Gerstein and Paré further identified a related but somewhat different set of biomarkers that predicted eye or kidney disease (sometimes referred to as “microvascular outcomes”) in the same individuals.

NEW BIOMARKERS FOR COMMON DRUGS Biomarkers can also be used to test the mechanisms through which current drugs and treatments work. Metformin is a drug that is commonly used to lower blood

Mendelian randomisation analysis

Causal effect estimate Observational studies

Coronary artery disease

Confounders Reverse causation

glucose levels in people with diabetes, and that may also reduce mortality and cardiovascular diseases. The aim of Gerstein and Paré’s research was to identify unrecognised biomarkers for this drug and to use these biomarkers to explore novel pathways for the drug’s effect on serious health consequences.

26 biomarkers were independently associated with metformin use, but one of these jumped out as being up to four times more strongly linked than any of the others.

This biomarker was Growth Differentiation Factor 15 (GDF15), which had also been strongly linked to cardiovascular outcomes in Gerstein and Paré’s previous work. Using publicly available databases, they also found

The identification of novel biomarkers can lead to new prognostic, diagnostic and therapeutic insights in people with dysglycaemia 72

Testing diabetes genetic variants for association with CAD

that genes that control the secretion of this biomarker may be linked to lower risks of cardiovascular outcomes.

Regulation of GDF15 expression and secretion remains unclear, but the strong link observed between metformin use and GDF15 suggests that metformin either enhances the secretion of GDF15 or reduces inhibitory pathways associated with it. The link between GDF15 and both metformin use and cardiovascular outcomes is of particular interest to them.

GENETIC VARIANTS Gerstein and Paré have also used a technique called Mendelian randomisation to determine whether the well-documented statistical link between dysglycaemia and cardiovascular disease represents a causal relationship.

Mendelian randomisation is an analytic approach to genetics that is based on the fact that at the time of conception an individual randomly does or does not inherit genetic variants that increase the propensity to develop risk factors (e.g., high blood

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Detail What are the implications of your findings for the long-term treatment of dysglycaemia and diabetes?

By demonstrating a causal link between dysglycaemia and cardiovascular diseases, our findings suggest that early, long-term, intensive glucose lowering can reduce cardiovascular consequences and strongly support further clinical trials of the effect of safe glucose-lowering therapies.

The identification of novel biomarkers for serious health consequences will enable better discrimination of higher versus lower risk individuals so that clinicians can more precisely focus their therapies on people most likely to benefit.

What has been the most surprising result from your findings so far?

The identification of GDF15 as a very strong biomarker for metformin was surprising, and has opened up a new research focus in collaboration with Dr Gregory Steinberg.

What are the advantages of analysing genetic variants as cardiovascular risk factors versus other cardiovascular risk factors?

Genetic variants have the unique characteristic of being randomly distributed at conception among individuals (Mendel's second law). They

pressure or cholesterol) for a particular disease (e.g., heart disease). When done carefully, if the genetic variant that increases the level of risk factors for a disease is found to also increase the likelihood of developing the disease, it is strong evidence that the risk factor is in fact somehow causing the disease.

When they applied this approach to dysglycaemia, they found that glucose and HbA1c are both causally related to cardiovascular disease. They are currently applying this same approach to the 237 biomarkers identified in ORIGIN and together with publicly available genetic databases are discovering new causal biomarkers for cardiovascular disease.

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are also fixed throughout our lives. These features make it easy to separate the effect of genetic variants from other risk factors, and is one of the main advantages of including genetic information in biomarker studies.

What novelty does your method of combining genetic, clinical and biomarker data represent for research into diabetes and cardiovascular outcomes?

The unique analytic approach that we have developed and refined allows us to carefully separate genetic and/or biomarker associations with disease from those that are causally or mechanistically involved in the development of the disease, to those that are confounded with measured or unmeasured causal factors.

What opportunities do you see presented by the age of ‘big data’?

The phrase "Big Data" means different things to different people. From our perspective, it is both the development of careful, methodical analytic approaches and the application of these approaches to the large biomarker and genetic databases that are available, that yields robust, important findings that are relevant for both patients and health care providers.

THE DANGER OF JUMPING TO CONCLUSIONS Gerstein and Paré only use very large datasets to conduct their analyses, to minimise the likelihood of anomalous or “chance” irreproducible results which are commonly seen when smaller datasets are used for biomarker discovery and related genetic analyses. Their collaborative work clearly demonstrates the prognostic and potentially therapeutic insights that can be gleaned from methodically analysing stored biologic material from large cohorts of people who have been carefully assessed and followed for the development of disease.

RESEARCH OBJECTIVES Dr Gerstein and Paré’s collaborative research focuses on identifying novel serum and genetic biomarkers for cardiovascular and other serious longterm consequences of diabetes to both understand and reduce the likelihood of these consequences in people suffering from type 2 diabetes.

FUNDING This research is funded by Sanofi and the Canadian Institutes of Health Research.

COLLABORATORS Population Health Research Institute and McMaster University in Hamilton Canada: Dr Matthew McQueen, Dr Shun Fu Lee, Dr Janice Pogue (deceased), Dr Gregory Steinberg, and Dr Salim Yusuf. Sanofi: Drs Heinz Haenel and Sibylle Hess BIO Dr Hertzel C Gerstein is an Endocrinologist and Professor at McMaster University and Hamilton Health Sciences, where he holds the Population Health Research Institute Chair in Diabetes. He is also Director of the Division of Endocrinology & Metabolism, Director of the Diabetes Care and Research Program and Deputy Director of the Population Health Research Institute and has had research published in over 300 papers.

Guillaume Paré is an Associate Professor at McMaster University and Director of the Genetic and Molecular Epidemiology Laboratory. He holds the Canada Research Chair in Genetic and Molecular Epidemiology as well as the CISCO Professorship in Integrated Health Biosystems.

His research has been published in over 140 papers.

CONTACT Dr Hertzel C Gerstein MD MSc FRCPC McMaster University Dept. of Medicine 1280 Main Street West HSC 3V38-50 Hamilton, Ontario, L8S 4K1, Canada T: 905-521-2100 (ext. 73371) F: 905-521-4967 E: gerstein@mcmaster.ca E: pareg@mcmaster.ca

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RESEARCH SOCIAL MEDIA NEWS

Animation vs Textbooks: The Facts Walt Disney was once famously quoted as saying: “I would rather entertain and hope that people learned something, than educate people and hope they were entertained.”

This has never been more true today, with many people constantly on the lookout for new methods that break down complex areas of study and condense learning into a simple yet informative format, to seemingly do the impossible: make learning fun.

Many people struggle to get their heads around the complex processes involved within science especially, and often resort to hours of reading numerous textbooks to try and make sense of certain scientific areas. For anyone seeking to share their work with a wider audience, I have some good news for you.

Animation > Textbooks Research is now showing that watching animation as an educative material is one of the most effective methods for learning and retaining information, particularly within scientific subjects. Check out the findings below: • In 2004, Stith reviewed the ability of computer programs and animations to teach cell biology to students. He found that using animations was an effective alternative to using textbooks and concluded his review by encouraging the widespread use of animations in biology teaching.

• In 2006, Thatcher compared the use of a textbook to a computer animation in teaching a group of medical students about DNA replication. Using the computer animation was found to be substantially more effective than the textbook, with significantly higher test results achieved. Even using the textbook after watching the animation did not raise test scores any higher, therefore indicating that using the animation by itself was enough to get the highest score possible for each candidate.

• Similar findings were found in a study

by Soika et al in 2010. During this, they compared two teaching methods – traditional paper teaching and teaching via computer animation. The differences seen were significant and education via animation was found to be more effective than the alternative paper format.

recognised the importance of interactive animations in conceptualising scientific processes, particularly related to cellular structures. They developed and released several freely available multimedia materials to support the learning of upcoming scientists who were struggling to understand particular areas of science.

So, there you have it. Animation is a powerful tool for effectively communicating complex information and, more importantly, ensuring it is successfully retained.

• In 2015, the Virtual Cell Productions team at North Dakota State University studied and

Many people are constantly on the lookout for new methods that break down complex areas of study, to seemingly do the impossible: make learning fun

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