Multimodal longitudinal prediction of cerebrovascular disease

1) Brief description of the context of the research including potential impact

Cerebral small vessel disease (CsVD) is a chronic intracranial vascular disease that affects the small vessels and blood blow in the brain. The disease is prevalent in 28% of people aged over 80 and may lead to brain damage and cognitive impairment. The progression of CsVD is multi-factorial and multi-pathological. One important type of lesion in CsVD are white matter hyperintensities (WMHs).

Multiple etiologies have been proposed to explain the progression in WMHs. The Rotterdam Scan Study has found age, blood pressure, current smoking and the presence of lacunar infarcts as predictors of WMH progression after three years' of follow-up. APOE4 is another a potential marker. Interestingly, baseline WMH lesion load was found to be associated with WMH progression in the LADIS study, indicating the condition's accelerating progression rate. While WMHs are positively associated with age, the histopathology of WMH is heterogeneous. A prospective study found WMH regression in 37% of minor ischemic stroke patients after 1 year. As the load and locations of WMHs could determine their clinical relevance, those factors should be incorporated in future research. This could be enabled by an automated regional-zonal WMH burden quantification method that was previously proposed to describe the spatial distribution of WMHs over 4 layers and 9 lobar zones.

2) Aims and Objectives

The aim of the four-year project is to predict the evolution of cerebral small vessel damage based on multiple types of data and support early intervention. It is hypothesised that such multimodal approaches could provide a better indication of how WMHs may progress over time. The baseline work should include MRI only, and other sources of information should be added incrementally. These sources include other neuroimaging modalities, cardiac imaging,
and clinical data. The deliverables should provide uncertainty estimation alongside the regional predictions, and should evaluate the impact of additional sources of information on the prediction performance.

As a logical first step, the first-year project will focus on the prediction of WMH load at the regional level. In addition to the regional WMH volumetric measures, experiments could include an ablation study of different markers from other sources (eg. blood pressure). The study should be rigorously conducted, and exploit both internal validation and external validation using an independent dataset if time permits. As the regional progression is provided, effort should be taken to identify patterns of how the lesions shrink, grow or remain stable at different locations of the brain. In terms of the modelling approaches, references could be made to studies on other brain or heart conditions.

1. Data: We have identified the publicly available Alzheimer's Disease Neuroimaging Initiative 3 (ADNI3) cohort as the primary dataset. The two-centred data was collected between 2017 and 2023 (data collection still ongoing). In addition to the MRI scans, demographic information (eg. age, sex), medical history (eg. blood pressure) and biomarkers (eg. APOE4) are also available.
2. Model input: While the 4-year project is aimed at making longitudinal predictions based on MRI scans in 3D, the input to the MRes project is primarily regional WMH volumes from the ADNI3 cohort. As mentioned above, demographics such as age and sex, medical history such as blood pressure could be added as part of the experiments.
3. Expected outcomes: The anticipated outcomes are longitudinal predictions of WMH volumes at different locations of the brain.

3) Novelty of Research Methodology

The student will develop image-based multi-modal longitudinal prediction of white matter hyperintensities where research is currently lacking. Further work will extend to other types of CsVD.

The critical mass of scientists and engineers that i4health will produce will ensure the UK's continued standing as a world-leader in medical imaging and healthcare technology research. In addition to continued academic excellence, they will further support a future culture of industry and entrepreneurship in healthcare technologies driven by highly trained engineers with deep understanding of the key factors involved in delivering effective translatable and marketable technology. They will achieve this through high quality engineering and imaging science, a broad view of other relevant technological areas, the ability to pinpoint clinical gaps and needs, consideration of clinical user requirements, and patient considerations. Our graduates will provide the drive, determination and enthusiasm to build future UK industry in this vital area via start-ups and spin-outs adding to the burgeoning community of healthcare-related SMEs in London and the rest of the UK. The training in entrepreneurship, coupled with the vibrant environment we are developing for this topic via unique linkage of Engineering and Medicine at UCL, is specifically designed to foster such outcomes. These same innovative leaders will bolster the UK's presence in medical multinationals - pharmaceutical companies, scanner manufacturers, etc. - and ensure the UK's competitiveness as a location for future R&D and medical engineering. They will also provide an invaluable source of expertise for the future NHS and other healthcare-delivery services enabling rapid translation and uptake of the latest imaging and healthcare technologies at the clinical front line. The ultimate impact will be on people and patients, both in the UK and internationally, who will benefit from the increased knowledge of health and disease, as well as better treatment and healthcare management provided by the future technologies our trainees will produce.

In addition to impact in healthcare research, development, and capability, the CDT will have major impact on the students we will attract and train. We will provide our talented cohorts of students with the skills required to lead academic research in this area, to lead industrial development and to make a significant impact as advocates of the science and engineering of their discipline. The i4health CDT's combination of the highest academic standards of research with excellent in-depth training in core skills will mean that our cohorts of students will be in great demand placing them in a powerful position to sculpt their own careers, have major impact within our discipline, while influencing the international mindset and direction. Strong evidence demonstrates this in our existing cohorts of students through high levels of conference podium talks in the most prestigious venues in our field, conference prizes, high impact publications in both engineering, clinical, and general science journals, as well as post-PhD fellowships and career progression. The content and training innovations we propose in i4health will ensure this continues and expands over the next decade.