27850
Cross-Domain Cognitive Subgroups of Autism Spectrum Disorder Show Differences Both in Terms of Their Clinical Symptom Profile and Neurofunctional Characteristics: Evidence from the EU-AIMS LEAP Cohort
Oral Presentation
Saturday, May 12, 2018: 3:04 PM
Willem Burger Zaal (de Doelen ICC Rotterdam)
E. Loth1, C. Moessnang2, J. Ahmad1, S. Baumeister3, L. Mason4, D. V. Crawley1, C. H. Chatham5, H. L. Hayward6, A. San Jose Caceres1, B. Oakley1, T. Charman7, J. Tillmann8, E. J. Jones4, R. Holt9, C. Bours10, M. C. Lai11, M. V. Lombardo9, C. B. Beckmann12, M. J. Brammer13, W. Spooren14, S. Baron-Cohen15, M. H. Johnson16, H. Tost2, A. Meyer-Lindenberg2, J. K. Buitelaar17, D. G. Murphy18 and G. Dumas19, (1)Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom, (2)Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany, (3)Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany, (4)Centre for Brain and Cognitive Development, Birkbeck, University of London, London, United Kingdom, (5)Neuroscience, Ophthalmology, and Rare Diseases (NORD) Roche Pharma Research and Early Development. Roche Innovation Center Basel, Hoffmann La Roche, Basel, Switzerland, (6)Institute of Psychiatry, Psychology and Neuroscience, King’s College London, King's College London, London, United Kingdom, (7)Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom, (8)Institute of Psychiatry Psychology & Neuroscience, London, United Kingdom, (9)University of Cambridge, Cambridge, United Kingdom, (10)Nigmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands, (11)Centre for Addiction & Mental Health, University of Toronto, Toronto, ON, Canada, (12)Radboud University Medical Center Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, Nijmegen, Netherlands, (13)Centre for Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom, (14)Behavioural Pharmacology and Preclinical Imaging at Hoffmann-La Roche, Basel, Switzerland, (15)Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom, (16)Centre of Brain and Cognitive Development, Birkbeck College, University of London, London, United Kingdom, (17)Radboud University Medical Center Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands, (18)Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom, (19)Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, France
Background: The immense clinical and etiological diversity among people with Autism Spectrum Disorder (ASD) is now well established. This has shifted the research focus from identifying
diagnostic markers to the discovery of
stratification markers to parse the umbrella condition into more homogeneous subgroups. For example, at the cognitive level, no single marker has been found that characterizes all individuals with ASD. We recently highlighted this by contrasting case-control comparisons with normative modeling approaches on a set of cognitive tasks tapping theory of mind (ToM), executive function (EF), and weak central coherence (WCC). Akin to growth curves, normative modeling allows one to define each individual in terms of their deviation from age-expected means. Despite significant mean-group differences on each of these tasks, the majority of people with ASD in fact performed within 1 Standard Deviation of their age-expected TD group means (Fig 1 a,b). Next, we used hierarchical clustering to identify cognitive subgroups based on individual performance profiles across cognitive domains. This yielded three clusters, which can be characterized as Subgroup 1: EF impairments, Subgroup 2: intact cognition across-the-board, and Subgroup 3: impaired ToM+EF (Fig 1c). We then demonstrated significant differences in the clinical symptom profile between the three groups, such that Subgroup 3 had significantly more severe ASD core symptoms than the two other groups (Fig 1d) while Subgroup 2 had significantly fewer associated ADHD symptoms and higher levels of adaptive behavior than the two other groups. (Fig 1f). However, one important question remained: do these subgroups also differ in their neurobiological underpinnings?
Objectives: To investigate neurofunctional differences between cognitive subgroups on 1) an fMRI ToM “Animated Shapes Task”, and 2) an fMRI executive function “Flanker/NoGo Task”.
Methods: The present analyses focused only on individuals with a clinical diagnosis of ASD. Participants were assessed as part of the multi-site EU-AIMS LEAP cohort and included in this project if data on the cognitive subgrouping analyses as well as fMRI data on the ToM task (N=139) and/ or Flanker task (N=123) were available. fMRI data from all study centres were preprocessed in a common pipeline using SPM12. To investigate differences in functional activation between the three subgroups we used both region-of-interest approaches (comprising areas involved in the ToM and EF networks, respectively) and exploratory whole-brain voxel-wise analyses. Site was included as covariate throughout.
Results: On the Animated Shapes task (contrast “ToM> random”) we found a significant activation difference between subgroups 3 and 1 (whole brain p<corr>=.01; ROI pcorr=.01) in the right middle temporal gyrus; a region previously implicated in ToM processing (Fig 1e). On the Flanker Task (contrast “[NoGo+incongruent] >[neutral+congruent]”) whole-brain analyses showed a significant effect of cluster (pFWE=.017) on right superior frontal gyrus- with subgroup 2 showing significant deactivation compared to subgroup 1 (Fig 1g).
Conclusions: We herein report first evidence for cognitive subgroups that differ on average in both clinical symptom profile and neurofunctional characteristics. To validate these cross-domain cognitive subgroups as stratification marker for ASD, replication of findings will be essential.
