Developing The Oxford Study for Biomarkers in Motor Neuron Disease (BioMOx): Capturing pre-symptomatic events and advancing clinical translation

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

Abstract

Motor neuron disease (MND) is a neurodegenerative condition in which the upper and lower motor neurons of the brain and spinal cord die prematurely. Also known as amyotrophic lateral sclerosis (ALS), it leads to progressive muscle weakness and wasting affecting the arms, legs, and speech and swallowing muscles. Involvement of the motor nerves supplying the respiratory muscles leads to death within three years of the onset of symptoms for half of patients. There is no effective treatment despite multiple drug trials over the last 20 years. About 5000 people suffer from MND in the UK, and many more are indirectly affected as their carers. It affects men and women and, although the peak incidence is in the early 60s, there is a wide age range.

Little is understood about why people develop MND. Whilst for most patients there is no clear single genetic reason for developing the disease, in a small number of patients there are multiple family members at risk due to single mutations or expansions in the genetic code. This project will study healthy volunteers who are known to carry genetic abnormalities linked to the development of MND, in order to try and capture the very earliest signs of nerve damage. Such changes might reveal new targets for preventative drug therapy, that then also have value in slowing progress in those with established disease. This part of the project will use one of only two very strong magnetic field (7 Tesla) MRI scanners in the UK in order to detect subtle changes in brain function and structure. Developments in MRI mean that it is now possible to study the spinal cord as well as the brain, and to look non-invasively at chemical substances within the tissue using a technique known as Magnetic Resonance Spectroscopy. This will be coupled to an extremely sensitive magnetoencephalography (MEG) scanner, which can detect patterns of brain motor nerve activity in real-time. This unique combination has the potential to unlock previously unrecognised changes in the brain and spinal cord of individuals long before symptoms appear, with the aim of identifying new targets for therapy, and new ways to monitor future therapeutic agents.

The symptoms of MND may initially not seem serious to the GP. Once referred to a hospital physician, making a diagnosis is not always straightforward without a diagnostic test. Currently diagnosis depends upon the opinion of an experienced neurologist and the exclusion of potential mimic disorders, which often involves lengthy investigations and a distressing period of uncertainty for patients. On average MND patients wait at least one year for a diagnosis. This delays the earlier administration of the only marginally disease-slowing medication, riluzole, and might be one reason that so many other drug trials have failed to show benefit. It is also precious time when individuals wish to maximise the quality of their remaining life. Finding reliable markers of disease activity in MND, called biomarkers, might help to speed up diagnosis, aid care-planning, and the assessment of new candidate drugs.

The Oxford Study for Biomarkers in MND (BioMOx) is a group of more than 60 MND patients, of all sub-types, who volunteered to be followed throughout their disease, undergoing tests every six months to try and identify biomarkers. Advanced MRI brain scans and analysis of spinal fluid and blood have revealed several candidates, and shown that their combination improves accuracy. This project will test these in people whose symptoms make MND a likely diagnosis, and in people with disease mimics, in order to see which biomarkers perform most reliably. It will also allow BioMOx to continue studying new cases of MND at regular intervals in order to understand why the pattern and speed of spread of initially isolated symptoms varies between individuals. This might help with the more efficient organisation of clinical trials, as well as effective care-planning.

Technical Summary

The aims of this project are:

1. To understand the earliest, pre-symptomatic changes in those carrying genetic mutations linked to MND, and how they link to spread of symptoms in affected individuals.

2. The refinement, validation and clinical translation of a multimodal biomarker diagnostic signature for MND.

The objectives of this project are:

1. The longitudinal study of pre-symptomatic individuals at risk of MND, particularly those carrying expansions of the C9ORF72 hexanucleotide repeat, as well as those with pathological SOD1, TARDBP and FUS gene mutations. It will uniquely combine the spatial resolution of very high-field 7 Tesla MRI of the brain and cord (including GABA and glutamate MR Spectroscopy, MRS), with the temporal resolution of cerebral magnetoencephalography (MEG) to explore changes in cortical neurophysiology that pre-date symptom onset, and with the hope of capturing the transition to disease in a small proportion of individuals. Incident MND cases will also be studied longitudinally in comparison.

2. To perform multivariate analysis of existing candidate neuroimaging, biofluid and eye-tracking biomarkers acquired through BioMOx, and to test performance in undiagnosed patients with focal weakness referred for electromyography and established mimics of MND ('disease controls') referred to me in the Oxford MND Centre.

The discovery that pre-symptomatic individuals have changes in brain function or structure compared to healthy individuals with no family history of MND profoundly influences the scientific thinking about this condition. As well as raising the possibility of preventative therapies for familial cases, there would be the hope of additional value when similar treatments are applied earlier to apparently sporadic cases. Such cases would be detected at an earlier stage through the development of a robust biomarker signature for MND, and the BioMOx resource offers a unique opportunity to develop this.

Planned Impact

Several groups will benefit from the research proposed:

1. Patients and carers

Biomarker research such as that proposed, aimed at improving the diagnostic pathway and prognostication, will improve patients' and carers' quality of life. MND patients frequently report that the delay in their diagnosis was distressing and deprived them of time to enjoy remaining life before the onset of severe disability. They resent the necessity for lengthy therapeutic trials that rely on survival as the principal outcome measure. This proposal's development of biomarkers sensitive to early response (or lack) would mark a major step in reducing clinical trial length and permit faster rejection of ineffective candidates. There is an enormous desire among MND patients and their carers to take part in clinical research, despite knowing that it may not directly benefit them. They recognise that this is a vital way to develop therapeutic options, and those facing the particular challenge of a family history of MND stand to gain from understanding the earliest changes. There may well be benefits for patients with other neurodegenerative disorders through the discovery of mechanisms translatable across diseases.

2. Commercial sector

With common themes emerging in the pathogenesis of neurodegenerative disorders, such as protein misfolding, pharmaceutical companies are increasingly interested in MND as one that (regrettably) runs its course over a short time frame compared with Alzheimer's and Parkinson's disease. The need for validated biomarkers of disease activity has become the major obstacle which this research addresses. The development of the BioMOx framework for cohort studies in MND also provides valuable knowledge about natural history and stratification of patients for future trials Information on the earliest stages of disease development may help to maximise success of clinical trials in the longer term. Another area of gain for industry is in the 'repositioning' of their abandoned drug libraries, which depends critically on the biomarker development. The biotech industry also benefits through promotion and development of novel biomarker assays and diagnostic kits that may emerge from the work proposed.

3. Policy makers & funding agencies

Both benefit from greater understanding of MND patients' needs and concerns. I will continue to support the MND Association in lobbying Government about the high care burden of MND and the need for rapid access to support. I will continue to highlight the value of non-therapeutic clinical research as vital groundwork to therapeutic translation. The process of research ethics committee approval is currently prohibitive to all but large longitudinal studies, and frequently appears adversarial. This point was highlighted in my contribution to the 'National Strategy for MND' presented to Government, along with bureaucratic barriers around sharing of biofluid samples across international boundaries which is currently holding back wider collaborative possibilities.

4. UK economy and global science platform

In the longer-term the successful prevention or even just delay in the development of disability, for up to 10% of MND patients (the proportion with a genetic mutation identified at present), would substantially reduce loss of productive years for both patients and carers, and reduce the overall burden of long-term disability. The use of advanced brain scanning techniques, including one of only two UK 7 Tesla MRI scanners and MEG, towards the long-term goal of pre-symptomatic therapeutic intervention in this most challenging of diseases, provides a very strong example of the UK leading the way in cutting-edge research. This has the potential to encourage the brightest individuals to work in UK neuroscience, and supports wider efforts to make a scientific career attractive to those in full-time education.

Publications

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Balendra R (2014) Estimating clinical stage of amyotrophic lateral sclerosis from the ALS Functional Rating Scale. in Amyotrophic lateral sclerosis & frontotemporal degeneration

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Balendra R (2015) Use of clinical staging in amyotrophic lateral sclerosis for phase 3 clinical trials. in Journal of neurology, neurosurgery, and psychiatry

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Bäumer D (2014) Advances in motor neurone disease. in Journal of the Royal Society of Medicine

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Chad DA (2013) Peer recommendations on how to improve clinical research, and Conference wrap-up. in Amyotrophic lateral sclerosis & frontotemporal degeneration

 
Description ABN Clinical Research Training Fellowship Chair
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Continued development and leadership of ABN's Clinical Research Training Fellowship scheme in Clinical Neuroscience. Associated workshops at annual ABN meeting for trainees interested in an academic neurology career.
 
Description MRC Clinical Research Training Fellows Day
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Presentation on career pathways in clinical academia.
 
Description MRC Training and Careers Group
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact Senior Clinical Fellow representative for committee concerned with all aspects of medical research funding and career development.
 
Description NHS Direct patient information on MND
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
Impact Re-wrote and updated the NHS Direct patient information on MND.
URL http://www.nhs.uk/conditions/Motor-neurone-disease/Pages/Introduction.aspx
 
Description NIV withdrawal UK guidelines
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact Audit and guideline development for the withdrawal of NIV in ALS patients.
 
Description Sheffield BMedSci presentation
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Presentation to medical students undertaking intercalated BMedSci on benefits of a research career.
 
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 BRC Biomarker Theme
Amount £106,000 (GBP)
Funding ID Biomarker theme 
Organisation Oxford University Hospitals NHS Foundation Trust 
Department NIHR Oxford Biomedical Research Centre
Sector Public
Country United Kingdom
Start 03/2012 
End 03/2017
 
Description Brain PhD Entry Fellowship Malcolm Proudfoot
Amount £53,000 (GBP)
Organisation Guarantors of Brain 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2013 
End 08/2014
 
Description Emily Feneberg CRTF
Amount £132,933 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2017 
End 09/2019
 
Description Families for the Treatment of Hereditary MND (FaTHoM) study day
Amount £4,000 (GBP)
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2017 
End 04/2017
 
Description Ice Bucket Challenge
Amount £800,000 (GBP)
Funding ID AMBRoSIA 
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2016 
End 04/2021
 
Description John Fell Fund
Amount £54,976 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 05/2015 
End 04/2016
 
Description MNDA small grants
Amount £10,000 (GBP)
Funding ID MSD Reader 
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2015 
End 06/2015
 
Description MNDA small grants
Amount £3,000 (GBP)
Funding ID PLS Day 
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 10/2015
 
Description MNDA small grants
Amount £1,500 (GBP)
Funding ID Athleticism in ALS meeting 
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2014 
End 03/2014
 
Description Malcolm Proudfoot CRTF
Amount £134,391 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2014 
End 07/2016
 
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 EV extraction from CSF 
Description UFLC method offers greater yield than conventional UC from CSF. 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? No  
Impact Methods paper in submission 
 
Title AMBRoSIA 
Description A Multi-centre Biomarker Resource Strategy in ALS. Oxford, QMUL and Sheffield collecting and storing biofluid samples from 300 patients and 450 controls over 5 years (MNDA-funded). 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Infrastructure and governance nearing completion prior to first recruitment April 2017. 
 
Title NiSALS MRI repository 
Description Neuroimaging Society in ALS (NiSALS). Founded by me in 2010 to bring together academic centres involved in MND imaging. Development of a secure repository for anonymised MRI scans in Jena, Germany to facilitate multi-centre studies. 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact Multi-centre study of DTI in MND (PMID 26746186) 
 
Title Oxford Biomarker Bank 
Description Ethical approval to seek consent 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 AMBRoSIA grant bid 
Organisation Queen Mary University of London
Department School of Engineering and Materials Science
Country United Kingdom 
Sector Academic/University 
PI Contribution Application writing and expertise. Collection of ALS neurochemical samples for biomarker discovery.
Collaborator Contribution Harmonisation of, and multi-site collection of ALS neurochemical samples for biomarker discovery.
Impact SOPs for sample collection
Start Year 2015
 
Description AMBRoSIA grant bid 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution Application writing and expertise. Collection of ALS neurochemical samples for biomarker discovery.
Collaborator Contribution Harmonisation of, and multi-site collection of ALS neurochemical samples for biomarker discovery.
Impact SOPs for sample collection
Start Year 2015
 
Description Brazilian ALS Associations 
Organisation Brazilian Association of Amyotrophic Lateral Sclerosis (ABRELA)
Country Brazil 
Sector Public 
PI Contribution Visit to share ideas about ALS care and research
Collaborator Contribution Sharing of ideas. Platform for discussions. Plans for future joint grants.
Impact None to date
Start Year 2014
 
Description Brazilian ALS Associations 
Organisation Instituto Paulo Gontijo
Country Brazil 
Sector Charity/Non Profit 
PI Contribution Visit to share ideas about ALS care and research
Collaborator Contribution Sharing of ideas. Platform for discussions. Plans for future joint grants.
Impact None to date
Start Year 2014
 
Description CSF DPR assay 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of CSF for assay testing
Collaborator Contribution Provision of antibody to allow us to set up local electrochemiluminescence assay.
Impact Initial advice on assay set-up and timetable for antibody delivery
Start Year 2018
 
Description Cholesterol metabolomics 
Organisation Swansea University
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of serum and CSF from ALS patients and healthy controls.
Collaborator Contribution Cholesterol metabolite analysis as potential biomarkers.
Impact Paper published 2016.
Start Year 2013
 
Description EPISWITCH 
Organisation Innovate UK
Country United Kingdom 
Sector Public 
PI Contribution Provision of clinically-characterised blood samples from ALS patients and controls.
Collaborator Contribution Clinical research fellow funding
Impact Ongoing
Start Year 2015
 
Description Extracellular vesicles - Wood Lab 
Organisation University of Oxford
Department Department of Physiology, Anatomy and Genetics
Country United Kingdom 
Sector Academic/University 
PI Contribution Contribution of samples and post-doctoral time to develop exosomal assay for future ALS biomarker discovery;
Collaborator Contribution Techincal knowledge and expertise
Impact Paper on exosome analysis in ALS and PD; DPhil student taken on to work on project; High-impact review of EV biomarker field (Nature Reviews Neurology 2016); Methods paper in UFLC method for extraction (Proteomics 2018).
Start Year 2013
 
Description Eye-tracking 
Organisation University of Oxford
Department Nuffield Department of Clinical Neurosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution DPhil student supervision. Expertise in ALS. Patients with ALS.
Collaborator Contribution Expertise and equipment
Impact Data presented at international and patient-based meetings. Review of field published in JAMA Neurology 2011. Paper in PLoS ONE on novel TMT using eye-tracker 2014. Paper in ALS-FTD on longitudinal analysis in ALS 2015.
Start Year 2009
 
Description GENFI 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of MRI and clinical data on FTD patients.
Collaborator Contribution Multi-centre pooling of FTD data.
Impact Harmonisation of data-collection
Start Year 2015
 
Description Hospital record linkage studies 
Organisation University of Oxford
Department Nuffield Department of Primary Care Health Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Knowledge and hypothesis relating to ALS and neurological disease more widely
Collaborator Contribution Access to and statistical interrogation of Oxford and England Hospital Record Databases
Impact Published studies in ALS relating to cancer 2010, head injury 2010 and cardiovascular fitness 2011, autoimmune disorders 2014, cerebrovascular injury 2015, psychiatric disorders 2016. Published study in Huntington's relating to cancer 2013.
Start Year 2009
 
Description MEG 
Organisation University of Oxford
Department Oxford Centre for Human Brain Activity (OHBA)
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of DPhil student and supervision. Integration with BioMOx ALS biomarker programme.
Collaborator Contribution Expertise and equipment, co-supervision of student.
Impact Review paper on MEG 2014. First-in-ALS paper on beta band changes (HBM 2016).
Start Year 2012
 
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 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 Post mortem MRI 
Organisation University of Oxford
Department Oxford Centre for Functional MRI of the Brain (FMRIB)
Country United Kingdom 
Sector Academic/University 
PI Contribution Grant application and provision of clinically-characterised MRIs and post mortem tissue from BioMOx cohort.
Collaborator Contribution PM MRI sequence development and histological correlation
Impact Development of tools for the cross-correlation of MRI and histopathological material.
Start Year 2013
 
Description Target Discovery Institute - Kessler Lab 
Organisation University of Oxford
Department Target Discovery Institute (TDI)
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of deep-phenotyped biofluid samples in MND.
Collaborator Contribution Proteomics expertise.
Impact CSF chitinases in ALS (Annals of Neurology 2018). CSF EV proteome paper (Proteomics 2018).
Start Year 2014
 
Description University of Sydney Visiting Post-doctoral Fellows 
Organisation University of Sydney
Department Brain and Mind Research Institute
Country Australia 
Sector Academic/University 
PI Contribution Help with writing applications to Australian funders for visiting post-doctoral fellows in ALS neuroimaging.
Collaborator Contribution Selection of candidates and initiation of applications to Australian funders for visiting post-doctoral fellows in ALS neuroimaging.
Impact Publications on research led by the visiting fellow; Training of fellow in neuroimaging analysis skills.
Start Year 2015
 
Description miRNAs in ALS 
Organisation University of Sussex
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual contribution to grant application. Provision of clinically-characterised CSF and blood samples for miRNA biomarker discovery.
Collaborator Contribution Technical expertise in miRNA analysis; Contribution to post-doctoral salary through grant ward from MNDA 2018.
Impact Ongoing
Start Year 2015
 
Description pre-FALS 
Organisation University of Miami
Department Department of Neurology
Country United States 
Sector Academic/University 
PI Contribution MEG and MRI study of pre-symptomatic carriers of ALS genetic mutations.
Collaborator Contribution Provision of pre-counselled and pre-tested pre-symptomatic ALS genetic mutation carriers.
Impact Paper on DTI and R-FMRI 2016. MEG beta band changes paper (HBM) 2016.
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 ABN Clinical Research Advisory Committee 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Discussion of ABN strategy and funding for clinical research in neurology.

Raised personal profile and chance to shape future research agenda.
Year(s) Of Engagement Activity 2013,2014
 
Description ACE Symposium 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Organised workshop to consider Athleticism, Cardiovascular risk and Exercise in ALS patients.

Planned studies by attendees
Year(s) Of Engagement Activity 2014
 
Description ALS Canada 
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 Advice to major ALS/MND research-awarding body.
Year(s) Of Engagement Activity 2018
 
Description ALS Canada webinar 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact ALS Canada live broadcast presentation on ALS/MND biomarkers.
Year(s) Of Engagement Activity 2018
 
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 ANZAN meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited speaker on MND care and management, biomarker and therapy development and incidental findings in MRI research.
Year(s) Of Engagement Activity 2017
 
Description Asia-Pacific FTD-MND 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talks on the cerebral lesion in ALS and how I manage ALS.
Year(s) Of Engagement Activity 2015
 
Description BBC Radio 5 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Contribution to discussion and debate on unproven treatment use in MND.
Year(s) Of Engagement Activity 2017
 
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 British Geriatrics Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Update on MND care and research
Year(s) Of Engagement Activity 2016
 
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 Chancellors Court of Benefactors meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Showcasing departmental research activity, in my case MND developments, with view to major funding donations.
Year(s) Of Engagement Activity 2017
 
Description Cytokinetics Tirasemtiv trial 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Enrollment of participants in Phase IIb study.

Enhancement of Oxford's status as clinical trials centre in ALS.
Increased recruitment to clinical research more widely.
Year(s) Of Engagement Activity 2013
 
Description Edinburgh Advanced Neurology Course 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Health professionals
Results and Impact Invited discussant for clinicopathological conference concerning rare case of ALS.
Other talks on clinical neurological topics more widely.

Increased profile as ALS opinion leader.
CPD in general neurology
Year(s) Of Engagement Activity 2013
 
Description European Academy of Neurology ALS Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Co-organiser of workshop on ALS diagnostics, including neuroimaging.
Year(s) Of Engagement Activity 2018
 
Description FTD UK 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation on CSF biomarkers in ALS.
Year(s) Of Engagement Activity 2015
URL http://www.ftduk.org
 
Description FTD UK meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Update on latest research and overlap with MND. 2017: led debate on genetic testing of all new diagnoses
Year(s) Of Engagement Activity 2016,2017
 
Description Families for the Treatment of Hereditary MND (FaTHoM) initiative 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Workshops to educate families linked to genetic forms of MND and FTD in relation to local research initiatives and future therapies.
Year(s) Of Engagement Activity 2017,2019
 
Description Fighting For Life 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Performance of play 'Fighting For Life' at Sue Ryder Hospice after which I took part in expert Q&A on MND with audience.
Year(s) Of Engagement Activity 2018
 
Description Forefront ALS Research Programme Review 
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 Expert external review panel member for University of Sydney flagship research programme in neurodegenerative disorders.
Year(s) Of Engagement Activity 2018
 
Description GP Study Day 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Educational day for GPs on neurology including MND
Year(s) Of Engagement Activity 2016
 
Description Gastprofessorship Ulm University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Invited professorship to share ideas around MND research and biomarker development.
Year(s) Of Engagement Activity 2017
 
Description Genetech consultancy 
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 Consultancy around biomarker choice for future trials in MND, in particular the use of imaging.
Year(s) Of Engagement Activity 2017
 
Description Gloucester Branch MNDA talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Research update
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 Incidental findings in MRI research 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Benchmarking workshop around management and ethical issues with IFs in imaging research. Held jointly with WT Centre for Ethics & Humanities.
Year(s) Of Engagement Activity 2017
 
Description International Conference on FTD 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact Presentation and live webinar to FTD carers and patients on the overlap of ALS and FTD.
Year(s) Of Engagement Activity 2018
 
Description JNNP Editorial Board 
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 Commissioning Editor and Editorial Board member for JNNP.
Year(s) Of Engagement Activity 2015,2016,2017
URL http://www.jnnp.com
 
Description King's MSc Neuroscience 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Reviewed marking scheme and course material.

Educational value in understanding how MSc courses run in other institutions
Year(s) Of Engagement Activity 2013
 
Description Kings Neuroscience / MND seminar 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Invited talk on 'New frontiers in ALS research'.
Invited debate on role of tracheostomy in ALS.

Raised personal research profile.
Year(s) Of Engagement Activity 2013,2014
 
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 MA Healthcare MND Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation on MND biomarker and therapy development.
Year(s) Of Engagement Activity 2018
 
Description MND Association AGM 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Invited Keynote presentation on MND biomarker progress.
Year(s) Of Engagement Activity 2018
 
Description MND presentation to University Hospital Birmingham neurologists 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Presentation on the evolving needs of the MND clinic and progress in biomarker development
Year(s) Of Engagement Activity 2017
 
Description MND professionals study day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Day course for allied health professionals: 'New Horizons in MND care and management' from Oxford clinic perspective, including genetics and difficult case discussions.
Year(s) Of Engagement Activity 2017
 
Description MNDA Biomedical Research Advisory Panel 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Discussion and scoring of grant applications

Helping to shape national MND research
Year(s) Of Engagement Activity 2012,2013,2014,2015
URL http://www.mndassociation.org
 
Description MNDA Care Centre Meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Annual meeting of care centre directors, co-directors and coordinators to review best practice and future intiatives.
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014
 
Description MNDA Donor dinner 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Research presentations and discussion with patients and MNDA donors
Year(s) Of Engagement Activity 2016,2017
 
Description MNDA Legacy Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Outline of Oxford MND Centre care and research
Year(s) Of Engagement Activity 2016
 
Description MNDA Legacy Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Overview of Oxford MND Clinic and research activities
Year(s) Of Engagement Activity 2016
 
Description MNDA Major donor presentations 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Annual MND Association-organised Royal Society presentation of my ALS research to major donors.
Visits to Oxford MND Care & Research Centre - tour of labs 2012, 2013.
Lady Edith Wolfson Day at Sheffield 2013.

Interest in continued funding of ALS research.
Year(s) Of Engagement Activity 2010,2011,2012,2013
 
Description MNDA PRISM event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Annual meeting of philanthropic group interested in supporting MND research.
Year(s) Of Engagement Activity 2017
 
Description MNDA regional patient meetings 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Annual regional branch meetings to 25-50 patient and carer attendees. Presented biomarker research progress.

2011 Oxfordshire branch
2011 National Spring Conference (Cambridge)
2012 Cambridgeshire branch
2013 Oxford, Gloucester & Reading West branches
2013 Reading
2015 Oxfordshire

Improved awareness and hope for patients and carers.
Offers to participate in research.
Year(s) Of Engagement Activity 2011,2012,2013,2015
 
Description Motor system workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Inter-disciplinary workshop to look at collaboration in study of motor system in health and disease
Year(s) Of Engagement Activity 2016
 
Description My Name'5 Doddie 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Third sector organisations
Results and Impact Became regular part of expert review panel for Doddie Weir MND Fund to advise on grant calls.
Year(s) Of Engagement Activity 2018
 
Description Neuraltus Pharmaceuticals 
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 Expert advice on unmet clinical needs of ALS patients.
Year(s) Of Engagement Activity 2015
 
Description Neurology Today 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Interview on pre-symptomatic MND study, and wider use of neurofilament assays.
Year(s) Of Engagement Activity 2018
 
Description Omnia-Med Study Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk on MND diagnosis and management.
Year(s) Of Engagement Activity 2015
 
Description Ontario Brain Institute 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited to review 5-year programme and make recommendations for improvement.

Increased awareness of other international studies and personal profile-raising as opinion leader in field.
Year(s) Of Engagement Activity 2013,2014,2015,2016,2017
URL http://www.ondri.ca
 
Description Oxford Neuroscience Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Talk on Biomarkers in ALS
Year(s) Of Engagement Activity 2015
 
Description Oxford University Brain Diaries event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Presentation on MND and local research initiatives.
Year(s) Of Engagement Activity 2017
 
Description Oxfordshire Branch MNDA meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Post-doctoral scientists Liz Gary presented our CSF biomarker work.
Year(s) Of Engagement Activity 2018
 
Description P-CNS 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Day workshop to educate GPs about neurological symptoms
Year(s) Of Engagement Activity 2015
URL http://www.p-cns.org.uk
 
Description PLS Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact 1st UK event for sufferers with Primary Lateral Sclerosis, a rare form of MND. Opportunity for patients and carers to hear latest understanding of this condition and research.
Year(s) Of Engagement Activity 2015
 
Description Palliative Care Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited lecture on 'Palliative Care issues in MND' to 150 Palliative Care professionals.

Interest and awareness of MND-related issues.
Year(s) Of Engagement Activity 2009,2016
 
Description Pre-NI 
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 Workshop on pre-symptomatic studies in neurodegeneration.
Year(s) Of Engagement Activity 2015
 
Description Primary Lateral Sclerosis Study Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Organiser of 1st UK PLS day for carers and practitioners.
Year(s) Of Engagement Activity 2016
 
Description RCN 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Royal College of Nursing presentation on History of MND.
Year(s) Of Engagement Activity 2015
 
Description RCP Advanced Medicine Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Goulstonian Lecture on ALS biomarkers.
Year(s) Of Engagement Activity 2015
 
Description RSM Regional Study Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Update on MND diagnosis.
Year(s) Of Engagement Activity 2015
 
Description Richard Doll Society talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Presentation on MND: understanding of pathogenesis and biomarker development
Year(s) Of Engagement Activity 2017
 
Description SENA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Presentation on latest research and management in ALS to neurologists
Year(s) Of Engagement Activity 2015
 
Description School in Cognitive Neuroscience 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Talk on brain in ALS and FTD.
Year(s) Of Engagement Activity 2015
 
Description Spanish Society of Neurology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation of biomarker work

Advice sought from me on setting up similar research
Year(s) Of Engagement Activity 2013
 
Description TRC-D PET 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Workshop on application of new PET tracers to neurodegenerative disorders
Year(s) Of Engagement Activity 2015
 
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
 
Description Ulm Neuroscience Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation on ALS biomarkers.
Year(s) Of Engagement Activity 2014
 
Description University of Sussex MND mini-symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Invited presentation on imaging in MND research, with wider topic coverage and debate.
Year(s) Of Engagement Activity 2017
 
Description www.oxfordmnd.net 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Development and maintenance of website for Oxford MND Centre.

Increased awareness of Centre's activity, information for patients about Care & Research.
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012
URL http://www.oxfordmnd.net