Three EU funded Multi-Centre Studies focused on

Child & Adolescent Psychiatry

• TACTICS – Compulsivity in ASD & OCD• EU-AIMS – European Autism Interventions

A Multicentre Study for Developing New Medications

• MATRICS – Multidisciplinary Approaches to Translational Research In Conduct Syndromes

The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n°278948

TACTICS

EU FP7 consortium focused on compulsivity in:

• Obsessive Compulsive Disorder• Autism Spectrum Disorders• Matched Controls

• Coordinatoring team: • Prof. Jan Buitelaar / Dr. Jeffrey Glennon• Donders Institute, Radboud University Medical Centre,

Nijmegen, The Netherlands.

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The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n°278948

11 partners across 8 countries

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Radboud University Nijmegen (Medical Center)

King’s College London

Zentralinstitut fur seelische Gesundheit

University Medical Center Utrecht

Tel Aviv University

University College Cork

Massachusetts General Hospital

GenOway S.A.

University of Cambridge

Concentris research management GmbH

H. Lundbeck A/S

1H PRESS MRS Results from Anterior Cingulate Cortex

• Voxel Dimensions = 2 cm x 2 cm x 2cm• Prescribed from a “classic” ADNI-2/GO volume scan• Also used to determine WM/GM/CSF contribution• TE = 30 ms• TR = 3000 ms• NEX = 96• Total Acquisition Time ~ 6 mins• No of successful spectra from ACCASD = 51 (out of 68); OCD = 29 (out of 34); HC= 53 (out of 61)

Voxel Positions

Superposition on the MNI152 template of: (A) all ACC and (B) left dorsal striatum voxelsLondon(blue), Mannheim (red), Nijmegen (yellow), and Utrecht (green)

Marcel Zwiers (Donders)

“Typical” example from Anterior Cingulate

NAA

ChomI

Cr

Cr

glnglu

Dave Lythgoe (King’s College London)

Voxel composition and glutamate concentrations

ASD OCD HC F statistic p-value

Mean SD Mean SD Mean SD

ACC

% grey matter 67.8 8.6 68 10 67 11 0.98 0.91

% white matter 11.6 2.9 11.23 4.5 12.5 4.2 1.17 0.32

% CSF 20.5 9.0 20.9 10.5 20.5 9.9 0.20 0.98

Glutamate (i.u.) 12.4 3.1 11.5 3.2 11.3 2.4 3.62 0.019*

Striatum

% grey matter 56.0 7.7 57.3 10.5 58.0 9.0 0.54 0.59

% white matter 43.3 8.1 42.3 10.8 41.0 9.1 0.70 0.50

% CSF 0.66 0.97 0.44 0.52 0.99 1.8 1.51 0.22

Glutamate (i.u.) 7.3 1.7 7.1 1.3 7.1 1.3 1.26 0.310

Sig at p < 0.05 corrected for multiple comparisons and co-varying for 4 sites, 3 scanner manufactures

Jill Naaijen (Donders)

Forward – translation

Clinical Trial of Memantine

Well tolerated NMDA antagonist Reduces cerebral glutamate

Correlation between ACC glutamate and compulsivity(r=0.24, p=0.03 - derived from the Repetitive Behaviours Scale)

Back - translation

Rodent models linking a tangible psychiatric symptom/behaviour to brain chemistry

Ralf Dittmann (Donders)

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SVM - training

Input Output

Volumes from group 1

Volumes from group 2

…

… Map: Discriminating regions between group 1 and group 2

Pattern recognition approach: Multivariate Analysis

SVM - test Prediction: group 1 or group 2New example

Applying Machine Learning Methods to Brain Images

Automated “Diagnosis” of Adult Autism

90% Accuracy

Ecker C et al, Describing the brain in autism in five dimensions, The Journal of Neuroscience 2010 30(32),: 10612-10623.

EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)

The Consortium

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Eva Loth

EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)

Project Structure

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EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI) 14

http://www.eu-aims.eu/

EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)

Primary Study Objectives

● To identify biomarkers and methodologies that can be used to stratify individuals with ASD into more (biologically) homogeneous subgroups and that predict clinical outcome

● To examine how the clinical ASD phenotype and biomarker profile develop over time

EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)

Why we need biomarkers?**Objective measure of a quantifiable process

● Risk/ diagnostic biomarker: predicts which child will develop ASD, detect ASD as early as possible

● Stratification biomarker: groups patients into biologically (more homogeneous) subtypes

● Prognostic biomarker: predicts the progression of symptoms and ‘outcome’ in adulthood

● Predictive biomarker: Estimates a patient’s treatment response ● Biomarker as surrogate outcome measure: predicts clinical

outcome and can be used as a substitute for a clinical end-point

EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)

Multi-modal assessment

• King’s College London• Cambridge• Nijmegen• Utrecht• Mannheim• Rome• Karolinska Institute

EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)

Qualification Advice from EMA

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Priorities to be considered in the core analysis plan:• Define cut-offs for clinically

meaningful changes in primary outcome measures and surrogate outcome measures

• Cut-offs for stratification biomarkers

• Establishing sensitivity and specificity of any biomarker

• Independent replication, in particular to validate a biomarker as a surrogate outcome measure

• Test-retest reliabilityLoth, Spooren et al., Nature Reviews Drug Discovery, 2015

EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)

EU-AIMS LEAP Study Recruitment

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Apr-

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Aug-

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Sep-

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Nov

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Jan-

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End of March 2016

Target

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Original recruitment completion deadline for all sites except KI.

Target: 600: 350 ASD, 250 TD

Caroline Wooldridge

EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)

Data Cleaning

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Banksy

EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)

Stratification by participant characteristics

• Age• Sex • Comorbidities• IQ

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Loth, Spooren et al., 2015, Nat Rev Drug Discovery

EU-AIMS – the work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI)

II. Stratification by …

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Brain anatomy, function, cognitive profile: Cluster analysis, functional data analysis, Multivariate pattern recognition

Genetic-molecular profile:Network-based stratification

The research leading to these results has received funding from the European Community’sSeventh Framework Programme (FP7/2007– 2013) under grant agreement n° 603016

Aggression!

Reactive Aggression (Frustration)

Proactive aggression (Planned act)

Hot blooded

Coldblooded