A next-generation MRI brain imaging platform for dementia research: from microstructure to function

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

Dementia is arguably the most urgent public health challenge confronting the developed world. Recent progress in the molecular biology of neurodegeneration has been matched by rapid developments in neuroimaging technology that can capture disease effects and mechanisms with unprecedented sensitivity, yet the clinical value of these technologies remains largely unrealised. At the same time imaging, most commonly MRI, has become a requisite part of the investigation of cognitive disorders; together these factors contribute to the need for fundamental and translational imaging research in dementia. This proposal will establish cutting edge next-generation MRI technology in the dedicated Dementia Research Scanner Centre at Queen Square, UCL, to maintain and enhance our institution's position as a leader in translational dementia imaging research and maximise our contribution to the UK Dementia Platform. We propose seven Key Innovations that will enable us to deliver major insights into the microstructural (KI1-3), functional (KI4), perfusion (KI5) and inflammatory changes (KI6) in the dementias, along with advances in motion correction (KI7) that will make these innovations feasible in the populations we need to study - together these technological advances will allow us to address critical translational challenges in imaging in dementia. The proposed innovations depend crucially on access to the latest MRI scanner hardware, providing maximal gradient power (80mT/m), massively parallel radio-frequency (RF) head receive coils (64 channels), parallel RF transmit technology and the latest ultra-fast MRI pulse sequences. To most effectively translate this enhanced hardware performance into improved image quality in patients, it will be complemented by ultra-fast prospective motion correction (PMC) to minimise motion artifacts. Thus, we propose an upgrade of our 3T scanning facilities to a Siemens 3T Prisma MRI scanner with multinuclear capability, complemented by the installation of a Kineticor PMC system. The upgrade will not only enhance the imaging capabilities locally but the related innovations will help direct the way for major multi-centre clinical trials in dementia, which are increasingly reliant on 3T infrastructure.

Technical Summary

Magnetic resonance imaging (MRI) will be crucial in early detection, diagnosis, and treatment trials in dementia. We will establish next-generation MRI technology in the UCL 3T Dementia Research Scanner. The upgrade including multi-nuclear, parallel transmit, multi band excitation, 64 channel RF head-coil, and stronger gradients will yield the spatial resolution, diffusion sensitivity, and scan-time efficiency essential for delivery and rapid translation of MRI innovation in 7 key areas:
Diffusion microstructure imaging: Neurite orientation dispersion and density imaging (NODDI), ActiveAx to map average axon diameter, and oscillating gradient spin-echo (OGSE) methods.
Multi-contrast quantitative MRI: Multi-parameter mapping reflecting microstructure; in vivo histology MRI quantifying cortical microanatomy, myelin, iron and amyloid plaque distribution.
Advanced tractography and tractometry: Probing tracts important in dementia, but too small to investigate reliably to date, and structural connectivity as a whole, illuminating network changes and offering connectivity-based biomarkers.
Clinical Functional MRI: Functional connectivity metrics may be sensitive markers of neural network dysfunction prior to irreversible structural brain damage.
Arterial spin labelling (ASL) perfusion mapping: ASL has begun to impact in dementia research and perfusion may be key in the multi-parametric MRI signature differentiating neurodegenerative diseases.
Sodium Imaging: Provides indices sensitive to inflammation and neuroaxonal loss. The role of neuroinflammation in dementia, long recognised is still poorly understood.
Ultra-Fast Prospective Motion Correction (PMC): Optical tracking PMC completely compensates for head motion, a major limitation in clinical high resolution imaging.
The work aligns completely with the UKDP priorities of establishing cohorts and methods to expedite trials of interventions effective before widespread, irreversible neuronal damage occurs.

Planned Impact

Who will benefit from this research?

Patients with neurodegenerative diseases and their families and caregivers will benefit most directly. These diseases exact a devastating human and socioeconomic cost. Diagnosis, prognosis and care all present major unresolved problems for which there is an urgent need for improved, effective diagnostic algorithms and disease markers that might ultimately guide therapy and facilitate its development. The substantial disease burden implications and the genetic component of these diseases raises many specific, difficult and cascading issues for caregivers and families. As the dementias collectively present such a huge public health and social challenge the potential research beneficiaries are much wider and include health policy makers (including those involved in drawing up consensus guidelines for dementia diagnosis and management) and the allied health services and government agencies involved in managing and mobilising services for people with dementia. The commercial sector is also a potential beneficiary in future large-scale drug trials informed by the research.


How will they benefit?

There are at least 4 broad areas of benefit from the new imaging environment and research platform, for both those affected by the target diseases directly, and other clinical, lay and policy-shaping stakeholders.

i) Improved diagnosis and management
within the lifetime of the project, new imaging techniques and protocols and new information about disease biology and evolution and characterisation of imaging signatures associated with pathogenic processes could translate to earlier and more accurate disease diagnosis (e.g., via the medium of consensus guideline working parties).

ii) Improved understanding of disease mechanisms
It has recently been recognised that the common forms of neurodegeneration share the key theme of specific brain network disintegration: more accurate characterisation of this process would generate testable biomarker strategies that could then be evaluated in a range of diseases and inform trial design and management strategies.

iii) Design and evaluation of clinical trials
In the longer term (next five to ten years), new biomarkers of neurodegenerative brain damage would inform trial design and assist in evaluating the impact of new therapies. In addition, improved characterisation of brain imaging changes in terms of underlying molecular abnormalities could suggest new disease mechanisms that might be targeted by disease-modifying therapies.

iv) Improved awareness, dissemination and health policy shaping
This research will fill an important ongoing role in improving public awareness of these diseases. Recent high profile cases of unusual dementias in the public eye and the Prime Minister's recent Dementia Challenge initiative have demonstrated the potential importance of public awareness in shaping health policy. There is considerable and growing public interest in new imaging technologies and their accessibility to key stakeholders. The techniques and protocols developed and the research supported by this programme will be actively promulgated in public engagement activities extending those already in place at the host Centre including lay lectures, media releases and support group out-reach activities, and engagement with expert health policy committees and working parties. These activities engage a range of nonmedical groups as well as lay patient support organisations.
Senior coapplicants on the programme sit regularly on national and international advisory boards and steering groups and played a key consultative role to the recent G8 Dementia Research Summit (Fox Lancet 2013). These are practical mechanisms for allowing the research findings to help shape health policy in the longer term, with implications extending to the much wider burden of dementia in the UK and international communities and well beyond the lifetime of this programme.

Publications

10 25 50
 
Description Alzheimer Society - clinical fellowship awarded to Antoinette O Connor
Amount £206,040 (GBP)
Funding ID 439 
Organisation Alzheimer’s Society 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2018 
End 04/2022
 
Description BRC Funding for Software Platform for Longitudinal Qunatitative Neuroradiology
Amount £112,728 (GBP)
Funding ID BRC612/HEI/JT/110410 
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Public
Country United Kingdom
Start 02/2019 
End 01/2021
 
Description BRC Funding for validating biomarkers for clinical trials of genetic therapies in Charcot Marie Tooth Disease type 1A project
Amount £77,407 (GBP)
Funding ID BRC574/NS/AR/101410 
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Public
Country United Kingdom
Start 08/2018 
End 07/2020
 
Description BRC award to UCL/H (Dementia Theme)
Amount £5,000,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 04/2022
 
Description Does the Gut Microbiome Determine Microgli Function In Amyotrophic Lateral Sclerosis?
Amount £1,200,000 (GBP)
Organisation Reta Lila Weston Trust For Medical Research 
Sector Charity/Non Profit
Country Unknown
Start 06/2017 
End 05/2021
 
Description EC Horizon 2020 PHC 11
Amount € 6,454,612 (EUR)
Funding ID Grant agreement 667510 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2016 
End 12/2019
 
Description Enabling clinical decisions from low-power MRI in developing nations through image quality transfer
Amount £1,020,000 (GBP)
Funding ID EP/R014019/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 02/2018 
End 01/2021
 
Description MRC UK Dementia Research Institute Award - Dementia Bench to Bedside
Amount £6,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2017 
End 10/2022
 
Description Muscle MRI in Charcot Marie Tooth disease
Amount $1,001,314 (USD)
Funding ID MDA510281 
Organisation Muscular Dystrophy Association 
Sector Charity/Non Profit
Country United States
Start 12/2017 
End 12/2020
 
Description Network Accelerate Scheme
Amount £249,807 (GBP)
Funding ID ARUK-NAS2016B-2 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2017 
End 12/2019
 
Description New MRI markers for detecting and defining frontotemporal dementias
Amount £221,380 (GBP)
Funding ID 319 
Organisation Alzheimer’s Society 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2017 
End 12/2020
 
Description Research Capability Funding
Amount £100,000 (GBP)
Funding ID BRC345/NS/SB/101410 
Organisation National Institute for Health Research 
Department NIHR Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 03/2018
 
Description Rosetrees: Detecting and tracking brain changes in early Alzheimer's Disease
Amount £248,130 (GBP)
Funding ID M668-CD1 
Organisation Rosetrees Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2017 
End 08/2020
 
Description Wellcome Institutional Strategic Support Fund: "Computational platform for longitudinal quantitative neuroradiology"
Amount £36,822 (GBP)
Funding ID ISSF3/H17RCO/005 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2019 
End 12/2019
 
Description A joint collaborative project, based on the H2020 funded GLINT project will lead us to collaborate on a 2-site clinical trial using the PRISMA scanner 
Organisation Max Planck Society
Department Max Planck Institute for Biological Cybernetics
Country Germany 
Sector Academic/University 
PI Contribution The partner will provide a pulse sequence to be used on the MRI scanner to establish a 2-site clinical trial. The whole project is explained in details in the H2020 project.
Collaborator Contribution See above
Impact This collaboration has just started
Start Year 2016
 
Description ARUK MRI protocol harmonisation for dementia 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution PI on this project, aiming to define and harmonise optimised MRI acquisition protocols across 9 different major research sites in the UK
Collaborator Contribution This is a collaborative project involving active input from all collaborators
Impact Project just started in Oct 2017 so no outputs yet
Start Year 2017
 
Description ARUK MRI protocol harmonisation for dementia 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution PI on this project, aiming to define and harmonise optimised MRI acquisition protocols across 9 different major research sites in the UK
Collaborator Contribution This is a collaborative project involving active input from all collaborators
Impact Project just started in Oct 2017 so no outputs yet
Start Year 2017
 
Description ARUK MRI protocol harmonisation for dementia 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution PI on this project, aiming to define and harmonise optimised MRI acquisition protocols across 9 different major research sites in the UK
Collaborator Contribution This is a collaborative project involving active input from all collaborators
Impact Project just started in Oct 2017 so no outputs yet
Start Year 2017
 
Description ARUK MRI protocol harmonisation for dementia 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution PI on this project, aiming to define and harmonise optimised MRI acquisition protocols across 9 different major research sites in the UK
Collaborator Contribution This is a collaborative project involving active input from all collaborators
Impact Project just started in Oct 2017 so no outputs yet
Start Year 2017
 
Description ARUK MRI protocol harmonisation for dementia 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution PI on this project, aiming to define and harmonise optimised MRI acquisition protocols across 9 different major research sites in the UK
Collaborator Contribution This is a collaborative project involving active input from all collaborators
Impact Project just started in Oct 2017 so no outputs yet
Start Year 2017
 
Description ARUK MRI protocol harmonisation for dementia 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution PI on this project, aiming to define and harmonise optimised MRI acquisition protocols across 9 different major research sites in the UK
Collaborator Contribution This is a collaborative project involving active input from all collaborators
Impact Project just started in Oct 2017 so no outputs yet
Start Year 2017
 
Description ARUK MRI protocol harmonisation for dementia 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution PI on this project, aiming to define and harmonise optimised MRI acquisition protocols across 9 different major research sites in the UK
Collaborator Contribution This is a collaborative project involving active input from all collaborators
Impact Project just started in Oct 2017 so no outputs yet
Start Year 2017
 
Description ARUK MRI protocol harmonisation for dementia 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution PI on this project, aiming to define and harmonise optimised MRI acquisition protocols across 9 different major research sites in the UK
Collaborator Contribution This is a collaborative project involving active input from all collaborators
Impact Project just started in Oct 2017 so no outputs yet
Start Year 2017
 
Description Collaboration with Gold Standard Phantoms Ltd 
Organisation Gold Standard Phantoms Limited
Country United Kingdom 
Sector Private 
PI Contribution We are working together with GSP for establishment of ASL as a recognised biomarker. We are scanning their phantoms on the PRISMA scanner.
Collaborator Contribution GSP Ltd (https://www.goldstandardphantoms.com/) has developed an ASL phantom, and need it to be scanned repetitively on MRI scanners in hospitals. As its CEO, I am therefore collaborating with Prof Yoursy and his team to scan GSP product on the PRISMA system.
Impact Ongoing.
Start Year 2017
 
Description Towards End-To-End Calibration of Clinical MRI: NHS England Chief Scientific Officer Knowledge Transfer Programme Associateship 
Organisation National Physical Laboratory
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise in imaging physics, specifically quantitative MRI biomarkers for clinical service and treatment trial applications Design and delivery of a study evaluating accuracy, precision and reproducibility of in vivo T2 relaxation time mapping as a potential clinical biomarker, in a test-object and human participants.
Collaborator Contribution Hosting a national workshop Co-authorship of review paper (in preparation) Expertise in measurement science and test objects calibrated to secondary and primary standards
Impact National workshop May 2019 Multidisciplinary linking NHS Healthcare Scientists specialist in imaging physics with measurement scientists at the NPL.
Start Year 2018