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

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.

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.

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.