Research Challenges

 

The term “dementia” is used to describe a syndrome that results, initially, in cognitive function impairment and in many cases, a descending staircase of psychological dysfunction, leading eventually to death

Our hypothesis is that these differential early and late functional and structural changes can be assessed using MR GSI, which leverages and unifies the complementary strengths of both dMRI and IVIM MRI.

It is known that vascular lesions in VCI (or in combined AD/VCI) produce early and distinctive fluid transport alterations and subsequent microstructural WM damage; predominantly in the central hemispheric WM and subcortical structures. These changes hamper the precision and fidelity of information transfer underlying brain function and impact on cognitive health.

Our overall aim is tocharacterise and quantify early differential alterations in brain blood transport and subsequent microstructural tissue damage using one-stop-shop perfusion/diffusion MR GSI incorporating novel MR signal models and optimal MR sequence design based on new human brain histomorphometric data in health and disease.

Novelty and Timeliness.

The proposed research is novel as previous work on p/d MRI has a) largely treated these as two independent problems; and b) interpreted microstructure loosely (dMRI) or ignored it completely (IVIM). MR GSI will be developed as a one-stop-shop approach that sees p/d as two extremes of the same phenomenon. This is exploited in the context of VCI where we propose the novel concept of associating the two regimes to different stages of the condition. In terms of dMRI, we will develop ultra-detailed models of myelinated axon fibres and neuroglia, and of WM microcirculation in normal and VCI-affected brains, based on high-res electron and light microscopy and through open data repositories. This approach contrasts with prior efforts in dMRI that, although claiming to link MR signals with microstructure, in fact, relied on idealised axonal models. Finally, we will progress the state of the art in IVIM not only by developing an integrated approach with dMRI, but also by a substantial leap forward in the way that IVIM is analysed. Despite its potential, IVIM remains at the very early stages of development compared with dMRI.

The proposed project is timely as interest in MRI for in vivo virtual histology is rapidly growing; more principled and microstructurally-rooted MR signal models will enable a new generation of imaging biomarkers that match current and future knowledge of underlying pathological processes. Until recently, analysis and interpretation of MRI data have been largely divorced from knowledge of the structural changes that WM undergoes in both normal and dementia-related ageing. Consequently, discovery of novel imaging biomarker identification has followed a path of trial and error based on establishing statistical associations between markers and clinical end points. This approach is poor and ineffective at elucidating causal relationships. Despite impressive recent progress, e.g. in dMRI, linking biophysics, pathology, and imaging physics, further work is required to gain mechanistic insights. OCEAN will deliver MRI sequences and analysis tools to link neuropathology, neuroimaging, and biophysics, thus being optimally positioned to discover novel biomarkers of disease onset and progression, and to understand the effects of novel drugs and treatments.

Why is Dementia Research Important?

In 2012, the WHO declared dementia a global health priority, highlighting the urgent need for improvements in this area. The disease is a major socio-economic challenge with care costs approaching 1% of global GDP (WHO Report 2012). Several conditions that lead to serious loss of cognitive ability are grouped under this syndrome, including Alzheimer’s disease (AD), Vascular Dementia (VaD), Frontotemporal Dementia, etc.  A high publicity announcement was made in 2012, by the UK Prime Minister, emphasising the high priority that should be given to dementia-related research and that funding will more than double in the immediate future (Guardian, 26/3/12).

In Dec 2013, the G8 Summit hosted in London brought together G8 ministers, researchers, pharmaceutical companies, and charities to develop co-ordinated global action on dementia. As part of the response to agreements to boost research against dementia, EPSRC launched the first £5M call, which was informed by the EPSRC Dementia Scoping Workshop and Report.

Dementia has marked adverse effects on the quality of life of tens of millions of people (both patients and carers) and exerts tremendous pressure on healthcare systems, especially when clear trends towards an ageing population, changing environmental influences, and contemporary lifestyle choices are considered altogether. Ca. 35M people suffer from dementia worldwide, a figure to quadruple by 2050. Europe and North America share a disproportionally high burden: the effects of ageing are particularly stark for these regions, exacerbating the healthcare provision implications.