Autism is a spectrum of neurodevelopmental conditions. It is heterogeneous, which means that every autistic person is different and has a unique set of strengths and challenges. Some autistic people are able to live and work independently while others may have learning differences and need more or specialist support. Some co-occurring physical and mental health conditions are more common in autism, such as epilepsy, anxiety and depression.
Autism is highly heritable, and its underlying genetic mechanisms are complex and varied. It is clear that both genetics and environmental factors influence the development of autism, but the relative contributions from and interactions between genetic and environmental factors are not yet known.
EU-AIMS – meeting the research challenges head-on
The heterogeneity of autism creates a challenge for the development of effective clinical trials for medicines and non-medical interventions. For a number of reasons, prior clinical trials have been less definitive than researchers would have hoped. To address some of these reasons, EU-AIMS contributed to the development of specific tools and methods and created a European network of specialised and skilled centres for diagnosis and running of clinical studies and trials.
Another complicating factor for clinical trials is that autistic people can be extremely different from one another, so that no single treatment could hope to help all of them. Clinical trials working with subgroups of autistic people who share similar characteristics are more likely to find successful treatments than trials working with large, diverse groups of autistic people. The EU-AIMS project therefore aimed to learn more about the diversity of autism. This work will aid the development of personalised therapies by improving understanding of the mechanisms underpinning core features and differences in individual needs.
EU-AIMS has considerably advanced our knowledge of the variability within the biology and behavioural characteristics of autistic people, identified areas for medical intervention and successfully demonstrated that medicines can modulate biological differences associated with autism. In order to conduct this work, the EU-AIMS project brought together over 150 leading psychiatrists, psychologists, cognitive developmental neuroscientists, basic neuroscientists, neurobiologists, geneticists and others from over 16 academic institutions, 6 industry partners, and 3 small-to-medium size enterprises (SMEs).
Identifying biomarkers for autism on an unprecedented scale
A key focus of EU-AIMS was the identification of biomarkers, short for biological markers. These are any objective measures such as patterns of brain activity, a cognitive test score, or particular genetic variants that may, for example, predict how a person responds to interventions.
Biomarkers could, for example, be used during the diagnostic process to predict whether symptoms will change during development, and/ or to select the best interventions, support or treatment for any given person. Biomarkers have the potential for supporting research into personalised profiles and thereby addressing the challenges of the diversity seen in autism.
To aid in the search for autism biomarkers, EU-AIMS conducted three longitudinal studies with over 1,200 participants across the lifespan, at a scale and complexity that was previously unprecedented anywhere in the world.
Data was collected from the cohorts below using the highest research standards, then analysed with newly developed methods, leading to significant progress in the understanding of the relationship of brain structure and signs of autism:
- Eurosibs: a study of infants with an autistic sibling. These siblings, who have an increased genetic likelihood of developing autism, were followed up from 4 months to 3 years with the aim of better understanding early signs of autism.
- Longitudinal European Autism Project (LEAP): the largest study of its type to identify biological markers for autism from childhood to adulthood, this study included autistic and non-autistic children, adolescents and adults and volunteers with mild intellectual disabilities aged 6-30 years.
- SynaG study: this aimed to better understand the relationship between genes and symptoms in individuals with genetic syndromes associated with autism, such as variations in genes called SHANK3 and NRXN (Neurexin).
Some of the EU-AIMS research findings from these studies include:
- Brain ‘over-connectivity’ at 14 months predicted more repetitive behaviours later in childhood.
- Six-month-old babies that show little interest in faces went on to show more social-communication difficulties later in development.
- Biological sex, whether you are genetically male or female, is associated with significant variation in the brain phenotype of autism (phenotype means a person’s observable characteristics or traits).
- Differences in cortical connectivity and ‘shiftability’ (changes) in brain function following a one-time dose of a serotonergic or glutamatergic medication are associated with aspects of clinical symptomatology.
- Lastly and importantly, researchers identified potential candidate biomarkers that could be further developed for use in clinical trials.
Animal and cellular studies – translating findings into humans
Animal models and new non-invasive techniques, such as induced pluripotent stem cells (iPSC), were used to identify causal links from genes and environmental factors to molecular changes and biological pathways. Using iPSC methods, researchers can reprogramme cells from, for example, a human hair root to stem cells so they can be turned (induced) into any cells (pluripotent) that researchers are interested in studying. In this case researchers were interested in brain cells such as neurons.
Various EU-AIMS animal and cellular studies have focused on conditions associated with autism that are caused by changes in a single gene, to identify associated biological and behavioural characteristics.
A key task was to ‘translate’ findings from animal models to humans to identify comparable underlying mechanisms characteristic of autism. This can be achieved by using measures that are safe to use in humans such as high-tech magnetic resonance spectroscopy (MRS), electroencephalogram (EEG), and structural and functional magnetic resonance imaging (sMRI and fMRI). It is important to understand how mechanisms describing certain types of behaviour in animal studies relate and compare to mechanisms described in humans.
For example, researchers tested whether certain medicines or related pharmacological compounds were effective in rodent and cellular models, thereby identifying potential new treatments for humans based on an improved understanding of underlying biological mechanisms across animals and humans at cellular and behavioural levels.
Creating trained networks for future research
EU-AIMS established the first European Clinical Trials Network for autism including over 118 clinical and research sites across 37 European countries. This network provides a platform for training, research, biomarker identification and to facilitate clinical trials for medical and non-medical approaches. This network has so far supported three industry-sponsored clinical trials for autism. It will continue to accelerate information exchange, critical discourse, and collaboration between leaders of the European autism community, having a long-lasting impact on the competitiveness and quality of autism research in Europe as part of AIMS-2-TRIALS, the follow-up project that began in 2018.
EU-AIMS was the first academic/industry group to submit a proposal for potential autism biomarkers and obtain ‘qualification advice’ from the European Medicines Agency (EMA). This is key to clarifying the research standards required for identifying biomarkers for subsequent approval by the EMA. This crucial step improved understanding between regulatory authorities, academics and industry; and helps to ensure that measures used in and developed for research and clinical trials are safe and reliable. This work led to a joint publication between EU-AIMS researchers and the EMA in Nature Reviews Drug Discovery (‘Identification and validation of biomarkers for autism spectrum disorders’). The EMA quoted the work of the project when they developed new EU policies on medicine testing in autism, and as such, EU-AIMS contributed significantly to the progress in regulatory science to support the development of medical/ non-medical interventions.
Creating a secure and sustainable central database
EU-AIMS research efforts were underpinned by a central database to efficiently and safely store the research data collected, conduct quality control steps, pre-process and download data from each study for registered analysis projects. This anonymised and harmonised data has been made available via a custom-built infrastructure called the EU-AIMS DataSharingSystems. Institute Pasteur agreed to host the central database from the project.
Achievements & News
IMI Associated Partner the Simons Foundation Autism Research Initiative (SFARI) is a research programme whose mission is 'to improve the understanding, diagnosis and treatment of autism spectrum disorders by funding innovative research of the highest quality and relevance.' ### The project started working with IMI through the IMI1 project EU-AIMS, and is now an Associated Partner in the IMI2 project AIMS-2-TRIALS.
‘In addition to expanding and sharing our SPARK cohort — which will be a community of over 50 000 individuals with autism, and their families, for a majority of whom we will have genomic data — we have provided supplies of an experimental medication that is being tested in a clinical trial run by AIMS-2-TRIALS,’ says SFARI Deputy Director of Clinical Research, Paul Wang, in an interview with the IMI Programme Office.
‘Autism is enormously complex, and we believe that collaborative efforts spanning academia, industry, and the non-profit sectors, are invaluable for advancing autism science. Indeed, we strive to have representation from all of these sectors in many of our own workshops and other initiatives,’ he says.
Find out more
- Read the interview in full
The value of IMI projects goes beyond their immediate scientific discoveries. Outputs often include large databases which are a goldmine of data for future research. IMI’s EU-AIMS project is an excellent example. The project has developed a large autism database, one of the richest of its kind in the world, which has the potential to drastically change the knowledge base for autism. ###The database contains comprehensive medical information on 450 people with an existing diagnosis of autism spectrum disorders (ASD) and 300 babies with a high risk of developing autism. This data is further combined and compared to 450 individuals with either typical development or various forms of intellectual disabilities. All this data was gathered through two big clinical studies within the EU-AIMS project: the Longitudinal European Autism Project (LEAPS) and Eurosibs. All the study participants were very comprehensively characterised in terms of their clinical profile, behaviour, family history, medical history, cognitive profile, electroencephalography (EEG), various brains scans, and genomics. ‘The scale and level of phenotyping of LEAPS is unprecedented in the world,’ said the project coordinators. ‘Conducting a study of this scope would most likely not be possible without the IMI funding.’
The database is already being used by EU-AIMS researchers to identify biological clues which could help stratify autism patients in order to improve future clinical trials and develop more personalised treatments. Additionally, EU-AIMS is already sharing the database with five large international organisations with which it has signed data sharing agreements. The database will open to the entire scientific community in 2020. Preregistration will be required to access the data in order to increase transparency and reproducibility of findings. The building of the database fits perfectly within the overall goal of the EU-AIMS project, which is to generate tools that will enhance our understanding of ASD and ultimately pave the way for the development of new, safe and effective treatments for use in both children and adults.
The approach of the EU-AIMS project to carrying out clinical studies on autism and assessing the effectiveness of new treatments has gained the support of the European Medicines Agency. This development, announced in an article in Nature Reviews Drug Discovery, will facilitate the development of new treatments for autism spectrum disorders (ASD).### EU-AIMS is running a Europe-wide study of people with autism, in which participants undergo genetic tests, brain scans, cognitive tests and clinical assessments to identify biological markers that could be associated with different subtypes of autism. The project has been working with regulators for some time to ensure the results of their studies will be accepted as reliable by regulators. ‘It’s critical for researchers to engage with the drug regulators early on, to figure out exactly what will be required to prove that a treatment is safe and effective for persons with autism,’ said Paul Wang of project partner Autism Speaks. ‘The new publication shows how the EU-AIMS group has succeeded in starting this dialogue, and it represents a key step toward translating autism science into autism treatment.’
Dutch IT company Noldus Information Technology has developed a new set of tools to make it easier to study and analyse the behaviour of rodent ‘models’ of autism.### The tools, which are now available for purchase, were developed and validated through the EU-AIMS project, which is working to speed up the development of new treatments for autism spectrum disorders (ASD).
Mice and rats that display ASD-like symptoms are used in research to study the causes of autism, how it progresses, and how it is affected by potential drugs. The suite of tools developed by Noldus comprises three elements. The video tracking system EthoVision XT automatically tracks and records movements of animals, while UltraVox XT captures and analyses animals’ calls. Finally, a software package called The Observer XT enables the coding and analysis of behaviours. Users can also hook up an EEG (electroencephalography) system to include brain activity in the analysis.
EU-AIMS has an entire work package dedicated to improving animal models of ASD. The 12 partners in the work package, who come from academia and industry, defined the requirements for the tools. In addition, partners from academia and industry gave feedback to Noldus throughout the design process and tested and validated the tools.
The creation of the tools is a welcome development for the project. ‘We are pleased to see new tools becoming available for behavioural testing of animal models of ASD,’ said EU-AIMS Scientific Director Professor Declan Murphy of King’s College London in the UK. ‘This is what EU-AIMS is about: to advance our research methods in order to accelerate drug discovery and development.’
Babies who move their eyes more often when looking at a picture are more likely to go on to develop autism spectrum disorder (ASD) as children, according to new research supported by IMI’s EU-AIMS project.### Although the research is in the early stages, the findings could help to identify babies at risk of ASD. In the study, scientists used eye tracking technology to assess how often babies aged six to eight months moved their eyes when looking at a (still) picture. Around half the babies in the study had an older sibling with ASD and so were at a higher risk of developing ASD themselves. The research revealed that while typical babies move their eyes on average twice a second, babies that went on to develop autism moved their eyes more often – around three times a second. Furthermore, typical babies assessed the picture in a similar way to adults, with an initial quick scan of the picture (with frequent eye movements) followed by a phase characterised by less frequent movements. In contrast, the babies at a higher risk of developing ASD did not change the way they looked at the picture over time.
Find out more in this Medical Research Council Press Release.
Professor Peter Scheiffele of the Biozentrum at the University of Basel in Switzerland, a participant in IMI’s autism project EU-AIMS, has been awarded the prestigious Robert Bing Prize by the Swiss Academy of Medical Sciences.### The prize is awarded biannually to young scientists who have done ‘outstanding work which has helped in the recognition, treatment and cure of neurological diseases’ and who will be encouraged by the prize to do further research in this area. The CHF 60 000 (approx. EUR 60 000) prize money comes from a fund set up by Swiss neurologist Robert Bing (1878-1956). The Biozentrum contributes to EU-AIMS with research on animal models of autism-spectrum disorders using advanced genetics, physiology and imaging approaches, among others.
An analysis of a combination of children’s life experiences, personalities and brain structures at age 14 can predict which youngsters will be binge drinking by the age of 16, according to research published in the journal Nature and supported in part by IMI’s EU-AIMS project.### The findings are now being transformed into simple tests to ensure that children at risk of alcohol abuse can be identified early and offered targeted help. The EU-AIMS project focuses on paving the way for new treatments for autism spectrum disorders. Professor Gunter Schumann of King’s College London explains why this new research is relevant for the project. ‘Our work is a paradigmatic model for the identification and development of prediction models for different mental health conditions, included autism-related disorders, as it takes into account all possible risk factors for disease in a systematic way,’ he said.
Autism affects different parts of the brain in males and females, reveals new research from IMI project EU-AIMS published in the journal Brain. The findings suggest that researchers should stratify their results by gender and avoid assuming that results found in males also apply to females.###
The team used magnetic resonance imaging (MRI) scans of both healthy adults and adults with high-functioning autism to determine whether the condition affects male and female brains in the same way or differently. They found that the brain areas that were atypical in women with autism are similar to the areas that usually differ between males and females, lending support to the idea that females with autism show neuroanatomical ‘masculinisation’. In the men with autism, different brain areas were affected.
‘This is one of the largest brain imaging studies of sex/gender differences yet conducted in autism. Females with autism have long been under-recognised and probably misunderstood,’ commented Dr Meng-Chuan Lai of the University of Cambridge, who led the research. ‘The findings suggest that we should not blindly assume that everything found in males with autism applies to females. This is an important example of the diversity within the ‘spectrum’.
Emily Jones, a Birkbeck College researcher working on IMI’s autism project EU-AIMS has won a prestigious L’Oréal-UNESCO UK & Ireland For Women In Science (FWIS) Fellowship.### Dr Jones is particularly interested in the early development of basic skills in children with autism spectrum disorder (ASD), as this contributes to our understanding of the underlying causes of autism and could pinpoint targets for intervention. In EU-AIMS, Dr Jones coordinates a large cross-European study of infants at high familial risk for autism.
The FWIS award is worth GBP 15 000 (approx. EUR 17 500), and winners can spend it on whatever they need to further their career, including equipment, travel, and childcare costs. ‘The fellowship will allow me to buy crucial equipment that I require to investigate the link between attention and arousal in the development of autism,’ says Dr Jones. ‘Combining a research career with family responsibilities can be challenging, and the flexible support provided by the fellowship will help me achieve the right balance.’
Now in their seventh year, the FWIS awards were established with the goal of promoting the greater participation of women in science by offering awards to outstanding female postdoctoral researchers.
Babies aged 4-6 months that are at risk of autism show a reduced response to social cues compared to other babies, according to new research from IMI’s EU-AIMS project published in the Proceedings of the Royal Society B.### The symptoms of autism, which include difficulties in social interactions and communication, emerge gradually during early childhood, and firm diagnoses are only made in children aged two and up. Until now, little research has focused on what happens in children below that age. In this study, the team studied brain activity in babies that are known to be at risk of autism as they have an older brother or sister with autism (autism being a highly heritable condition) and infants with no family history of the condition. Wearing caps bearing sensors, the babies watched videos of human actions (such as the game of ‘peek-a-boo’) or listened to human sounds (laughter, yawning) and non-human sounds (e.g. running water). The results showed that the high-risk babies responded less to the social cues than the low-risk babies, and furthermore the brain activity patterns seen closely resemble those of children and adults with autism. The researchers point out that the next step would be to assess the children when they are older to see which youngsters, if any, actually develop autism symptoms. In a press release by Birkbeck College (which is not an EU-AIMS partner), a mother of one of the babies involved in the study said: ‘Having been through this myself, I felt it was my duty to ensure I helped in any way I could by involving [my son] in the Babylab research. I feel very strongly that this is a very important start towards improving the lives of many families with children on the autistic spectrum.’
Autism project EU-AIMS held an IMI networking event at the annual meeting of the Society for Neuroscience (SfN) in New Orleans, US, on 16 October.### The SfN annual meeting is the world’s biggest gathering of neuroscientists, attracting 30 000 attendees from around the world. The networking event was therefore an excellent opportunity for EU-AIMS to promote its work to the neuroscience community.
Andreas Meyer-Lindenberg of the Central Institute of Mental Health in Mannheim, Germany and a participant in IMI’s NEWMEDS and EU-AIMS projects has been awarded the prestigious ECNP Neuropsychopharmacology Award 2012### for his groundbreaking work linking genetic variation associated with risk of mental illness to brain structure and function. The award, handed out at the annual congress of the ECNP (European College of Neuropsychopharmacology), recognises innovative and distinguished research achievements in neuropsychopharmacology and related fields. Dr Meyer-Lindenberg’s work focuses on the genetic and environmental risk factors associated with psychiatric diseases such as schizophrenia. ‘Especially our recent work on rare, high-risk genetic variants associated with schizophrenia and autism would not have been possible without the cooperative science funded in IMI,’ Dr Meyer-Lindenberg said.
Autism Spectrum Disorders (ASD) refers to a complex of different conditions. In some cases autism is present together with other conditions (e.g. epilepsy) as part of a syndrome caused by a single, specific gene mutation (e.g. Fragile X)###, but in the majority of patients its causes are largely unknown and could include different genetic and environmental factors. Certain brain changes in syndromes with autism appear to be reversible, and new research from the IMI-funded EU-AIMS project suggests that this may also be the case for the broader autism population. The study, published in Science, looked at the effects of the loss of the neuroligin-3 gene in mice. Neuroligin-3 is involved in the transmission of nerve signals and has been linked to heritable forms of autism. In this study, researchers found that mice lacking neuroligin-3 produced unusually high levels of a specific glutamate receptor. Glutamate receptors are proteins that are known to be involved in memory and learning; the high levels of glutamate receptor production in the mice in this study impaired the learning process, thereby disrupting brain development in the long term. However, the researchers did not stop there – they reactivated neurligin-3 production in the mice and found that this effectively returned glutamate receptor production levels to normal. Furthermore, the structural, autism-like defects in the brains of the mice disappeared. The findings suggest that there may be common deficits in the brains of individuals affected by many different forms of autism, and that drugs designed to target these glutamate receptors could halt the development of autism or even reverse it. The work was widely covered in the press, including in the Wall Street Journal and on Swiss TV (in French).
Elsewhere in the EU-AIMS project, researchers have shed new light on the workings of proteins called neuroligins that are involved in the transmission of nerve signals and have been linked to a heritable form of autism.### Nerve signals are transmitted from one nerve cell to another at junctions called synapses. Neuroligins are found on the receiving side of synapses; if they malfunction or are absent, nerve signals are not transmitted correctly. The research, published in the Biochemical Journal, focuses on the functioning of neuroligins in mice. Mice have four kinds of neuroligin (dubbed neuroligins 1-4), and this study reveals that these neuroligins form pairs (‘dimers’) featuring either the same kind of neuroligin or different kinds of neuroligin. This is important because if neuroligin 3 pairs up with neuroligin 1, a mutation affecting neuroligin 3 will also indirectly impact neuroligin 1’s functioning. As neuroligin 3 is linked with heritable autism, many scientists use mice with mutated neuroligin genes as a mouse ‘model’ of autism in their work. These new findings will help to determine how well these mouse models work. Looking to the future, the team now plans to study the physiological and functional consequences of the loss of neuroligin 3.
Elsewhere, the EU-AIMS team has had a paper published in Molecular Psychiatry setting out some of the latest findings in autism research and highlighting their potential importance.
IMI autism project EU-AIMS starred as Nature’s cover story with its research revealing that the father’s age when a child is conceived is the biggest single contributor to the number of new mutations passed on to a child.### The findings suggest that the increase in the number of autism cases may be due in part to the fact that the average age of fathers at the time of conception is on the rise. The researchers arrived at their results after studying the genomes of around 2 000 Icelanders, including some with a diagnosis of autism or schizophrenia. On average, for every one-year increase in the father’s age, an additional two mutations were passed on to the offspring. ‘Our results all point to the possibility that as a man ages, the number of hereditary mutations in his sperm increases, and the chance that a child would carry a deleterious mutation that could lead to diseases such as autism and schizophrenia increases proportionally,’ said lead author Kari Stefansson of Iceland’s deCODE Genetics. ‘It is of interest here that conventional wisdom has been to blame developmental disorders of children on the age of mothers, whereas the only problems that come with advancing age of mothers is a risk of Down syndrome and other rare chromosomal abnormalities. It is the age of fathers that appears to be the real culprit.’
ParticipantsShow participants on map
- Eli Lilly And Company LTD, Basingstoke, United Kingdom
- F. Hoffmann-La Roche AG, Basel, Switzerland
- Institut De Recherches Servier, Suresnes, France
- Islensk Erfdagreining Ehf, Reykjavik, Iceland
- Janssen Pharmaceutica Nv, Beerse, Belgium
- Pfizer Limited, Sandwich, Kent , United Kingdom
- Vifor SA, Villars-sur-Glâne, Switzerland
Universities, research organisations, public bodies, non-profit groups
- Birkbeck College - University Of London, London, United Kingdom
- Commissariat A L Energie Atomique Et Aux Energies Alternatives, Paris, France
- European Molecular Biology Laboratory, Heidelberg, Germany
- Institut Pasteur, Paris, France
- Karolinska Institutet, Stockholm, Sweden
- King'S College London, London, United Kingdom
- Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften Ev, Munich, Germany
- Stichting Radboud Universiteit, Nijmegen, Netherlands
- Universita Campus Bio Medico Di Roma, Rome, Italy
- Universitaet Ulm, Ulm, Germany
- Universitair Medisch Centrum Utrecht, Utrecht, Netherlands
- Universitat Basel, Basel, Switzerland
- University of Cambridge, Cambridge, United Kingdom
- Zentralinstitut Fuer Seelische Gesundheit, Mannheim, Germany
Small and medium-sized enterprises (SMEs)
- Arttic, Paris, France
- Laeknisfraedileg myndgreining ltd, Reykjavik, Iceland
- Noldus Information Technology BV, Wageningen, Netherlands
- Autism Speaks Inc. Non Profit Corporation, Princeton, NJ, United States
- Koninklijke Nederlandse Akademie Van Wetenschappen - Knaw, Utrecht, Netherlands
|Name||EU funding in €|
|Birkbeck College - University Of London||835 258|
|Commissariat A L Energie Atomique Et Aux Energies Alternatives||1 067 084|
|European Molecular Biology Laboratory||236 722|
|Gabo:Mi Gesellschaft Fur Ablauforganisation:Milliarium mbH & Co. KG (left the project)||311 536|
|Institut Pasteur||627 246|
|Islensk Erfdagreining Ehf (left the project)||163 473|
|Karolinska Institutet||1 474 097|
|King'S College London||5 492 667|
|Laeknisfraedileg myndgreining ltd||599 760|
|Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften Ev||901 286|
|Noldus Information Technology BV||106 590|
|Stichting Radboud Universiteit||2 262 122|
|Universita Campus Bio Medico Di Roma||120 682|
|Universitaet Ulm||196 800|
|Universitair Medisch Centrum Utrecht||1 734 703|
|Universitat Basel||1 643 340|
|University of Cambridge||672 362|
|Zentralinstitut Fuer Seelische Gesundheit||1 597 042|
|Name||Funding in €|
|Koninklijke Nederlandse Akademie Van Wetenschappen - Knaw||263 727|
|Total Cost||20 490 981|