What is EU-AIMS?
EU-AIMS was a previous project that aimed to identify biomarkers of autism. EU-AIMS was also funded by the Innovative Medicines Initiative (IMI) and ran from 2012 to 2018. Below we provide an overview of some of the main goals and achievements of the EU-AIMS project.
EU-AIMS – meeting the research challenges head-on
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.
The heterogeneity of autism creates a challenge for the development of effective therapies, including both medical and non-medical interventions. In addition, as a field we do not yet fully understand the causes and mechanisms that bring about autistic features. These factors have contributed to less definite results of prior clinical trials than researchers would have hoped. The EU-AIMS project therefore aimed to learn more about the diversity of 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).
Together, 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. 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.
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 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. In comparison the majority of individual research studies in autism research over the past 30 years included 20-30 autistic individuals, which is often too small a sample size to meaningfully understand individual differences. EU-AIMS also included groups of autistic people that had been previously underrepresented in research studies including autistic women and girls, individuals with co-occurring mental health conditions, intellectual disability and rare genetic conditions.
Declan Murphy, Project Lead and Professor at Kings College London (KCL) said about EU-AIMS: “We started by improving knowledge of the biological diversity of autism, translated results of rodent studies to make them relevant to humans, demonstrated that certain compounds could affect the biological differences seen in autism – including in autistic adults – and searched for biomarkers that could enhance clinical trials.”
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.
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 showed 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.
- 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 involved in synapse development (which is the way nerve cells are connected and communicate) and symptoms in individuals with genetic syndromes associated with autism, such as variations in genes called SHANK3.
Animal and cellular studies – identifying the mechanisms underlying autistic features
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. These techniques allow us to study the brain at a level of precision and detail that is currently just not possible with human neuroimaging techniques. Using iPSC methods, researchers can reprogram adult 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 particular EU-AIMS animal and cellular studies have focused on conditions associated with autism that are caused by changes in genes that impact how neurons (brain cells) develop and communicate. The human brain has about one hundred billion neurons, which form about 100 trillion connections or synapses. These processes depend on our experiences in early childhood and throughout life and in turn impact on our understanding of other people, emotions, cognition etc.
Clearly, as animals are not the same as people, 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 a secure and sustainable central database
EU-AIMS created a central database to efficiently and safely store the research data collected (ensuring participant confidentiality), 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 and its follow-on project AIMS-2-TRIALS.
EU-AIMS was the first academic/industry group to submit a proposal for potential autism biomarkers and obtain ‘qualification advice’ from a major regulatory authority; 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 helps to ensure that measures used in and developed for research and clinical trials are safe and reliable and that clinicians, pharmaceutical companies and regulatory authorities agree on key criteria and standards. 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. The EU-AIMS team worked with a North American network (ABC-CT) to discover the first biomarker in autism accepted into the FDA development programme (U.S. Food and Drug administration – U.S equivalent of EMA), with potential to reduce the size of clinical trials by ~38%. AIMS-2-TRIALS will take this work even further.
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.
What came next?
Members of the EU-AIMS consortium have joined forces with more partners across Europe and the world to successfully launch AIMS-2-TRIALS in 2018. You can read more about the aims and progress of this project across this website.
Overall the project has over 250 publications (2010-2017) in high impact journals. Information about the project has been presented at academic conferences, and public engagement events.
Some of our key publications are outlined below with links to the full article. For more details visit www.eu-aims.eu/.
Change in processing of facial expressions when given serotonin differs in autistic people.
Serotonin and the Neural Processing of Facial Emotions in Adults with Autism: An fMRI Study Using Acute Tryptophan Depletion.
Daly, E. M., et al (2012) Archives of General Psychiatry.
Clinical characteristics of individuals in the Longitudinal European Autism Project (LEAP).
The EU-AIMS Longitudinal European Autism Project (LEAP): clinical characterization.
Charman T, et al (2017) Molecular autism.
Outlining the methods used in the Longitudinal European Autism Project (LEAP).
The EU-AIMS Longitudinal European Autism Project (LEAP): design and methodologies to identify and validate stratification biomarkers for autism spectrum disorders.
Loth et al. (2017) Molecular autism.
Mice with a mutation to gene linked to fragile X syndrome show brain differences and these differences can be altered by making changes to the gene later in development.
Shared synaptic pathophyisiology in syndromic and nonsyndromic rodent models of autism.
Baudouin S et al. (2012) Science
Differences in communication within the brain in autistic people which is linked to social development.
Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [1H]MRS study.
Horder et al. (2013) Translational Psychiatry.
Connections in the brain measured by electrical activity at 14 months was linked to repetitive behaviours.
EEG hyper-connectivity in high-risk infants is associated with later autism.
Orekhova EV, et al. (2014) J Neurodev Disord.
Engagement with faces at 6 months is linked to social-communication difficulties seen in autism.
Cortical responses before 6 months of life associate with later autism.
Lloyd-Fox S, et al (2018) Eur J Neurosci.
Differences in brain connectivity and changes in brain function following neurochemical administration are associated with variation in autistic traits.
Shifting brain inhibitory balance and connectivity of the prefrontal cortex of adults with autism spectrum disorder. Ajram LA, et al. (2017) Transl Psychiatry.
Identifying differences between autism, ADHD, and comorbid autism and ADHD.
Disorder-specific functional abnormalities during temporal discounting in youth with Attention Deficit Hyperactivity Disorder (ADHD), Autism and comorbid ADHD and Autism.
Chantiluke, K et al. (2014) Psychiatry research.
No differences in neurotransmitter GABAA receptor in autistic adults and in mice models of autism, contradicting excitatory/ inhibitory theory of autism.
GABAA receptor availability is not altered in adults with autism spectrum disorder or in mouse models.
Horder, J et al (2018) Science Translational Medicine.
Evaluating brain connectivity in four independent groups of autistic people and the relationship to autistic symptoms.ere
Patients with autism spectrum disorders display reproducible functional connectivity alterations.
Holiga, S et al. (2019) Science Translational Medicine.