Sampling, biomarker OPtimization and Harmonization In ALS (SOPHIA)

Lead Research Organisation: University of Oxford
Department Name: Clinical Neurosciences

Abstract

Amyotrophic Lateral Sclerosis (ALS) is one of the most devastating diseases in neurology affecting some 50,000 individuals at any time in Europe, and causing around 10,000 deaths each year. The main clinical features are weakness and wasting of muscles, but dementia may also occur. ALS represents a good model for study of all neurodegenerative conditions, as it has a characteristic phenotype, rapid progression and the correlation between diagnosis during life and autopsy diagnosis is close to 100%. However, validated neurochemical biomarkers for monitoring disease activity, for generating earlier diagnoses and for defining prognosis are lacking. Active European collaborations are in place for harmonizing clinical datasets, neuroimaging and neuropathology protocols. A preliminary strategy for harmonization of biological and tissue samples has been established. Standardized protocols for clinical data and sample collection are now urgently required for optimization and harmonization of biomarker development.
The overall aim of this proposal is to provide a common European strategy for the prioritization and selection of candidate biomarker domains for optimization and harmonization. This will in turn provide a long-term platform by which existing collaborative structures that are relevant to neurodegenerative disease biomarkers (including academic initiatives, co-funding strategies, biobanks, industrial efforts, private-public alliances) are integrated within an inclusive web-based virtual biobank. Samples and clinical/imaging/neurophysiologic and neuropathological datasets provided by participating members can then be optimally utilized to enable state of the art collaborative analyses.
The established platform will also act as an important communication channel between this consortium and the rest of the ALS/Neurodegeneration field to ensure that the optimization efforts are in line with the whole ALS/ND field, to avoid duplication of work, and to ensure better acceptance and utilization of the project results by all stakeholders. Ultimately, the platform will be used to disseminate the results to the whole ALS/Neurodegeneration field, and will act as a permanent Interactive European ALS biomarker platform for researchers to optimize/harmonize novel biomarkers using an established pan-European ALS methodology. The platform will also allow interaction with those of other cognate groups (e.g the NEALS group within the US) and with patient groups and other relevant stakeholders.

Technical Summary

Tasks in the MRI component of SOPHIA:
T1. Registration of participating EU ALS centres to the Jena MRI database.
T2. Establish bidirectional interface to the core clinical data management.
T3. Assessment of acquisition parameters driving variability in T1W and DTI datasets
T4. Comparison of group-level results from different analysis platforms (SPM versus FSL versus TIFT).
T5. Identification of a standardised protocol for T1W and DTI acquisition.
T6. Linkage of core dataset and non-MRI biomarkers to individual MRI datasets to explore the additional value of a multimodal profile.
T7. Implementation of standardised protocol prospectively in ALS and healthy control subjects.
T8. Publication and international challenge of neurodegenerative disease research groups to test protocol against non-ALS neurodegenerative disease cases.
T9. Re-assessment of variability of both pre-processed MRIs and results post-analysis in prospective data, through multi-site data sharing (inter and intra-site variability).
T10. Correlation with post-mortem neuropathology reports in a subset of centers adhering to the standards of established European brain banks.
T11. Application of quality control systems to other MRI modalities i.e. resting state fMRI, MR spectroscopy and advanced fibre track analysis tools of DTI.
T12. Implementation of a continuous quality control framework which feeds back to participating centres.

Planned Impact

This project has benefit for patients with MND and their carers, through the development of much-needed biomarkers of disease progression and phenotype. These can improve care planning and the development of therapeutic agents for a devastating neurological disorder.

The project will deliver standardization and harmonization of candidate biomarkers across multiple EU MND centres so that there is a coherent approach to this vital area of need, avoiding duplication of work and wasted resources. The inherent QC aspect means that valuable biofluid samples and MRI scans are acquired and stored consistently to allow meaningful comparison of results across centres.

The project establishes a platform that will be accessible to global research communities involved in neurodegenerative biomarker development, many of whom use similar biofluid and advanced MRI technology within other diseases. Information about variability of measures across sites, and issues of QC have great potential to save time and resources.

Publications

10 25 50
 
Description ENMC Workshop on EU Consensus in Amyotrophic lateral sclerosis (ALS)
Geographic Reach Asia 
Policy Influence Type Participation in advisory committee
Impact Led to formation of ENCALS - The European Network for the Cure of ALS which has led on to numerous research grants, meetings, and clinical trials.
URL http://www.encals.eu
 
Description Roadmap for wet biomarker development in amyotrophic lateral sclerosis (ALS)
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Produced international consensus statement (with me as co-first author) on future development and validation of 'wet' biomarkers in ALS, Published in ALS journal.
 
Description The Neuroimaging Symposium in Amyotrophic lateral sclerosis (ALS) (NISALS)
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact I convened the first meeting in 2010, now annual, of global researchers studying ALS using neuroimaging. Guidelines were developed and published in Lancet Neurology PMID:21511189. Second meeting in Jena Germany 2011 has laid foundation for standardization and harmonization of MRI data across centres. Meeting in Miami developing multi-centre collaborative MRI study. Meetings in Milan, Leuven, Orlando and Dublin have developed multi-centre projects and Governance framework.
URL http://europepmc.org/abstract/MED/21511189
 
Description Neurofilament round robin
Amount £200,000 (GBP)
Organisation ALS Association 
Sector Charity/Non Profit
Country United States
Start 12/2017 
End 11/2018
 
Description Thierry Latran Foundation 4th Project Call
Amount £100,100 (GBP)
Funding ID PROMISES 
Organisation Thierry Latran Foundation 
Sector Charity/Non Profit
Country France
Start 12/2012 
End 12/2014
 
Title ALS biomarkers 
Description Longitudinal MRI, CSF and blood from large group of ALS patients 
Type Of Material Biological samples 
Year Produced 2012 
Provided To Others? Yes  
Impact Candidate MRI and biofluid biomarkers. Major finding of NfL as a prognostic biomarker through sample sharing with QMUL 
 
Title Jena MRI repository 
Description Repository for multi-centre MRI data in MND. 
Type Of Material Improvements to research infrastructure 
Year Produced 2012 
Provided To Others? Yes  
Impact Quality control process for T1-weighted MRIs for VBM analysis. Platform for future multi-centre meta-analyses. 
URL http://www.nisals.org
 
Title Oxford Biomarker Bank 
Description Ethical approval for extra sample of CSF and blood from patients having routine investigations, to use as disease controls in biomarker studies. 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact Access to disease controls for ALS biomarker development, including contribution to standardisation efforts. New collaborations with local groups increases sample collecting infrastructure. 
 
Description NISALS 
Organisation Friedrich Schiller University Jena (FSU)
Country Germany 
Sector Academic/University 
PI Contribution Establishment of an international consortium of neuroscientists focused on neuroimaging in ALS. Organise annual meetings.
Collaborator Contribution Online repository for multi-site MRI data for multi-site analyses.
Impact Consensus statementas on neuroimaging in ALS (Lancet Neurology 2011 and 2015). Multi-site analysis of T1 and DTI data (paper on DTI 2016). Paper on clinical correlations 2016
Start Year 2010
 
Description Neurofilaments 
Organisation Euroimmun
Country Germany 
Sector Private 
PI Contribution Provision of longitudinal serum and CSF samples from ALS patients and controls
Collaborator Contribution ELISA-based assay for neurofilaments as potential biomarker
Impact Papers on CSF and serum NfL as prognostic marker, and link to DTI metrics 2015. Multi-centre validation studies (papers 2016). Planned commercial assay study with IHD.
Start Year 2013
 
Description Neurofilaments 
Organisation Iron Horse Diagnostics, Inc.
Country United States 
Sector Private 
PI Contribution Provision of longitudinal serum and CSF samples from ALS patients and controls
Collaborator Contribution ELISA-based assay for neurofilaments as potential biomarker
Impact Papers on CSF and serum NfL as prognostic marker, and link to DTI metrics 2015. Multi-centre validation studies (papers 2016). Planned commercial assay study with IHD.
Start Year 2013
 
Description Neurofilaments 
Organisation Queen Mary University of London
Department Clinical Research Facilities
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of longitudinal serum and CSF samples from ALS patients and controls
Collaborator Contribution ELISA-based assay for neurofilaments as potential biomarker
Impact Papers on CSF and serum NfL as prognostic marker, and link to DTI metrics 2015. Multi-centre validation studies (papers 2016). Planned commercial assay study with IHD.
Start Year 2013
 
Description Neurofilaments 
Organisation University of Ulm
Country Germany 
Sector Academic/University 
PI Contribution Provision of longitudinal serum and CSF samples from ALS patients and controls
Collaborator Contribution ELISA-based assay for neurofilaments as potential biomarker
Impact Papers on CSF and serum NfL as prognostic marker, and link to DTI metrics 2015. Multi-centre validation studies (papers 2016). Planned commercial assay study with IHD.
Start Year 2013
 
Description SOPHIA 
Organisation EU Joint Programme - Neurodegenerative Disease Research (JPND)
Country European Union (EU) 
Sector Public 
PI Contribution This consortium of ~20 EEA countries responded to a call from the JPND to address standardization and optimization of biomarker candidates in ALS. I wrote the MRI-based part of this bid, and am coordinating the implementation.
Collaborator Contribution Other centres have contributed MRI and neurochemical data for cross-site comparison studies.
Impact Initial analysis of multisite variability in MRI (T1 and DTI). DTI paper 2016. Initial multisite comparison of neurochemical markers in CSF and serum. Round robin papers 2014 and 2016. Initial multisite comparison of MUNIX neuropysiology data.
Start Year 2012
 
Title Neurofilaments 
Description Neurofilament (CSF and serum) as a diagnostic, predictive and pharmacodynamic biomarker in MND. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2017
Development Status Under active development/distribution
Impact International workshops for harmonisation of efforts. ALS Association grant for round robin standardisation activity. 
 
Description ALSRG 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Discussions around clinical trials and funding for ALS research

Planned meeting to redesign clinical trials in ALS
Year(s) Of Engagement Activity 2014
 
Description Biogen Idec Imaging Advisory Panel 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Expert view on use of neuroimaging for ALS biomarkers

Company keen to pursue
Year(s) Of Engagement Activity 2014
 
Description Brazilian ALS Outreach 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Invited presentations to ALS neurologists and researchers in Brazil (Sao Paulo and Curitiba)

New collaborations planned, and advice on setting up infrastructure for ALS care and research in Brazil.
Year(s) Of Engagement Activity 2014
 
Description CSF Society 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Collaboration and standardisation on all aspects of CSF analysis
Year(s) Of Engagement Activity 2016
 
Description ICCN meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited presentation on neuroimaging biomarkers in ALS

Increased awareness and profile-raising
Year(s) Of Engagement Activity 2014
 
Description Lady Edith Wolfson Programme Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Third sector organisations
Results and Impact Presentation of achievements and ongoing work in MND biomarker research to major donor to MND Association who have part funded my Fellowships.
Year(s) Of Engagement Activity 2018
 
Description SOPHIA meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Joint meeting to discuss progress and strategy in SOPHIA project.

Advancement of project goals and wider multi-site collaborative work.
Year(s) Of Engagement Activity 2012,2013,2014,2015
URL http://www.sophiaproject.eu
 
Description Taubman Institute Lectureship 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited presentation on ALS biomarkers

Stimulate local research and advice on logistics.
Year(s) Of Engagement Activity 2014