OCEAN: One-stop-shop microstructure-sensitive perfusion/diffusion MRI: Application to vascular cognitive impairment

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.
It is a major socio-economic challenge with care costs approaching 1% of global GDP. 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 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, to partially remedy the fact that the overwhelming impact of the syndrome has been over-looked (Guardian, 26/3/12). On 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.

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. 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.

The Clinical Relevance: Vascular Cognitive Impairment (VCI). VCI defines alterations in cognition attributable to cerebrovascular causes, ranging from subtle or fixed deficits to full-blown dementia. VCI is a wide and accepted term referring to the "syndrome with evidence of clinical stroke or subclinical vascular brain injury and cognitive impairment affecting at least one cognitive domain", with resulting VaD being its most severe form. VaD is responsible for at least 20% of dementias, second only to AD, with a prevalence doubling every 5. 3 years. Several trials examined cholinesterase inhibitors for the treatment of vascular dementia, but the benefits are very modest, except in the individuals with a combination of AD and VaD. Vascular changes result in white matter (WM) damage (leukoaraiosis), which profoundly affect the fidelity of the information transfer underlying brain function and cognitive health8.

Cerebral Magnetic Resonance Imaging (MRI) of Diffusion and Perfusion. MRI is a medical imaging technique affording non-invasive investigation of anatomy and tissue function, which is particularly suited to studying cognitive disorders due to its sensitivity and reliability. Our main interest is to characterise vascular and non-vascular tissues using quantitative diffusion and perfusion MR. Our overall aim is to characterise 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.

Dementia already is one of society's biggest medical challenges. No cures are so far available. Yet, research is intense and strong candidate therapies are on the horizon. Given the variety of causes and aetiologies of dementia, reliable identification of the underlying pathologies is a requisite for therapy effectiveness. Differential diagnosis is therefore key. Effectiveness, also, is greatly modulated by the level of disease progression in individuals. Even where outright cure is unrealistic, evidence already suggests that lifestyle changes and other treatments can delay the progression of symptoms, provided these are identified sufficiently early. This is of enormous significance to sufferers and their families. Societal economic implications aside, the quality of life benefits for sufferers from prolonged independence, and the emotional and financial alleviation for families and carers are substantial. Early diagnosis is therefore key. It is in the provision of differential and early diagnosis that the technologies developed within OCEAN can have a serious impact.

Knowledge management and exchange with other key EU-, RCUK- and NIHR-funded initiatives. To maximise synergies with other relevant initiatives and ensure knowledge cross-fertilisation, we set up a Scientific Advisory Board (SAB) experienced in relevant engineering and physical sciences and with a track record of clinical translation of research results. This cadre of academics includes world class scientists in the areas of MR diffusion imaging, medical image computing, and computational modelling.

Industrial engagement and commercial take-up. Several companies are committed to OCEAN thus incorporating a technological and exploitation dimension from the outset of the project. Companies were selected to cover all key areas and technologies in OCEAN where exploitable outcomes or collaborations are anticipated; previous or ongoing research collaborations were also accounted. Statements of support are appended.
Microscopy data will be made available to community. OCEAN is committed to making the multimodal image database of light and electron microscopy and 7T MRI brain tissue data available online by the end of the project. We shall also make available the quantitative statistics of microstructural composition and properties. Access to this unique resource will be made online via a project portal built and
managed jointly by SITraN and CISTIB-INSIGNEO.

MR GSI Image Analysis & Visualisation Tool. Once validation of the modelling methodologies has taken place, these tools will be made available to the wider clinical and research community. We plan to prototype an MR GSI Image Analysis & Visualisation Tool based on GIMIAS (www.gimias.org), an open-source platform developed at CISTIB.

From proof of principle and feasibility to demonstration of clinical impact. Once we have established the feasibility of MR GSI and evaluated it in simulation, phantom studies and short series of volunteers, we will seek follow-up funding streams to conduct a clinical proof-of-concept in a large cohort. This will be designed to assess the effectiveness of MR GSI for early detection of VCI-related disorders and, importantly, the differentiation of pathological mechanisms that is essential for therapy formulation.

Engaging patient and public in research through the Dementia Public and Patient Involvement (PPI) group. We have partnered with the Alzheimer's Society, which will contribute two volunteers in our Scientific and Clinical Advisory Boards, respectively. Funds have been set apart according to the INVOLVE guidance to facilitate the participation of these volunteers.