Imaging in large populations: better defining later life brain disease risks in terms of development,exposure and aging
Paul M. Matthews, OBE, MD, DPhil, FRCP, FMedSci
Edmond and Lily Safra Chair, Head, Division of Brain Sciences, Department of Medicine Imperial College
London and Centre for Neurotechnology
p.matthews@imperial.ac.uk
Imaging, family history, genetics, lifestyle and exposure data promise new opportunities for understanding
disease risk as an integrated outcome of developmental factors and environment. New capabilities appliedat large scale are offering an unprecedented opportunity to address this challenge.
One of the most recent of these studies is the most ambitious to date. It is being developed within the UK
Biobank (www.ukbiobank.ac.uk/), a large prospective cohort that was established by the UK Medical
Research Council and Wellcome Trust as a resource for the investigation of risk factors for major diseases
and morbidities of middle and older age. 500,000 men and women aged 40-69 years were recruitednationwide between 2006 and 2010. The baseline assessment was extensive, with detailed information
gathered on prevalent disease, diet, lifestyle, socioeconomic factors, education, medications/ supplements
and specific measurements such as blood pressure, weight, height, bio-impedance, grip strength andultrasound measures of heel bone density and cognitive testing. Biomarker and genetic data also areavalaible. Longitudinal follow up to death will continue with linkage to medical records.
The UK Biobank thus combines great size, breadth and depth for a prospective longitudinal cohort study.
As incident cases accrue, it allows a broad range of health outcomes- particularly including those for latelife brain diseases to be related to a uniquely broad range of risk factors through case-control studies“nested” within the overall cohort.
Last year, the UK Biobank Imaging Enhancement was initiated with funding from the UK Medical ResearchCouncil and the Wellcome Trust. The objective of the Imaging Enhancement is to provide acomprehensive imaging assessment that will include 3T MRI of the brain including advanced DTI andresting state fMRI for connectivity analysis; 1.5T MRI of the heart and upper abdomen; carotid doppler andDEXA of whole body, on a total of 100,000 participants across England. During the first year, processes
have been optimised ethical issues explored and the feasibility of this complex, high throughput imaging
demonstrated.
For my group, this resource will enable investigations of brain disease based on genetic and observationsof longitudinal changes in probands, along with observations of forme fruste of disease across clinically
healthy individuals sharing risk factors. One area of focus will be further testing of the hypothesis that
healthy age-related brain degeneration mirrors development, with the areas of the brain thought to develop
later also degenerating earlier. To illustrate how such large imaging datasets can be used, I will review apilot study of 484 healthy subjects that revealed a transmodal network, the lifespan pattern of age-relatedchanges in which highlighted ways in aging is related to the patterns of development of the brain. This work
provided evidence that the network of brain regions which develops relatively late during adolescenceshows accelerated degeneration in old age compared with the rest of the brain and is characterized byareas of heightened vulnerability to unhealthy developmental and aging processes. This link between
development, processes of aging and cognitive outcomes provides a broad framework for consideration ofmany diseases of the brain. Availability of large imaging datasets from UK Biobank and similar initiatives in
the near future should enable powerful explorations of this to be undertaken.
References
C Sudlow et al. 2015. UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Rangeof Complex Diseases of Middle and Old Age. PLoS Med. 12(3):e1001779
Douaud G et al. 2015. A common brain network links development, aging, and vulnerability to disease.
Proc Natl Acad Sci U.S.A. 111(49):17648-53