Brain imaging and cognitive ageing in the Lothian Birth Cohort 1936: IV

As older people form an increasingly large proportion of human populations across the planet, greater resources will be needed for their management and care. Cognitive ageing, the process by which some cognitive abilities decline in older age, is of particular concern, leading as it does to reduced quality of life, loss of independence, and, in its later stages, increased risk of dementia. Characterising the biological causes of cognitive ageing is therefore important if we are to reduce the burden of ageing at both the individual and societal level. Those over 80 years old are more likely to require assistance to live independently, and are at almost double the risk of dementia, yet we understand little about the brain and cognitive changes that come about at this age, and which factors might be most important to ameliorate this in future.

The Medical Research Council has highlighted the importance of understanding how, and to what degree, ageing of the circulatory (vascular) system is related to brain ageing. In this proposal we request funds to collect and analyse brain magnetic resonance imaging (MRI) data from participants of the Lothian Birth Cohort 1936. They are a large group of relatively healthy community-dwelling subjects who are unique in having cognitive data from youth (a well-validated measure of IQ obtained at age 11 years), ongoing linkage to their health records, and repeat cognitive testing, brain, retinal and carotid imaging, genetic, epigenetic, lifestyle, psychological, social and other important information obtained from ages 70, 73, 76, 79 years. Age UK has funded a new wave of testing to begin shortly, in which we will collect much of these data again at age 82 years. Having brain imaging and vascular information collected at the same time is vital, since the both systems can change rapidly at this age; data collection at this age is also vital because we will have a large enough number of people to detect the subtle changes and links that are likely to exist among these different types of measure, which we will be well-situated to examine in detail. As such, we judge that this is an important chance - for which we request funds - to add brain imaging data to this upcoming wave. We also plan to make the scan shorter and more tolerable for these participants in future, and so will conduct a pilot to test comparability of the current scanner with a newer machine (which reduces scan times and can collect other potentially informative data).

A fourth wave of brain MRI will be highly valuable - it is extremely rare to have rich longitudinal data over a preceding decade for individuals in their eighties. This longer period of follow up will enable more precise detection of different aspects of brain structural decline (e.g. brain shrinkage, damage to the brain's connections), and its relation to the factors most responsible (e.g. genetics, diet, exercise) and their impact on thinking skills. Understanding these relationships is an important step in helping to develop strategies to slow age-related cognitive decline, and in characterising what role cognitive ageing plays in heralding dementia.

Importantly, this grant would also support staff crucial for conducting these investigations. The present application is for minority funding for a project whose principal funder is Age UK, which supports 9 staff, and the collection of the cognitive, medical, biomarker, and psychosocial data, their collation and analyses.

Studying brain structural changes that accompany older age is useful for understanding the biological underpinnings of cognitive ageing, and for reducing the dementia risk in the elderly. We seek funds to acquire a 4th wave of brain MRI from the Lothian Birth Cohort 1936, a large group of relatively healthy subjects in their early eighties, all of whom were born in 1936 (N=1,091 at recruitment). The cohort has a wide range of phenotypic data from older age (at 70, 73, 76, 79) including cognitive, genetic, epigenetic, lifestyle, physical and medical, with MRI data at ages 73, 76 and 79. Uniquely, they also have a measure of childhood intelligence from age 11. A fourth brain MRI scan (at 82) confers important benefits - multi-wave, multi-modal MRI data is lacking for people in their 9th decade. The longer duration and extra sampling point gives greater statistical power to detect small associations with determinants, and with which to characterise patterns of brain ageing more precisely. The availability of longitudinal retinal imaging, carotid ultrasound, blood pressure, medical history, blood assays (e.g. S100B, inflammation) can be combined with longitudinal MRI markers of vascular pathology to give key information about neurovascular ageing at age 82, and to identify the preceding brain hallmarks, determinants and consequences using multivariate latent growth curve models.

This 4th brain MRI will be undertaken on the same GE 1.5T clinical scanner as in previous waves. We will derive measures of brain atrophy, cortical thickness, surface area, volume, and perivascular, subcortical and white matter hyperintensity volume, and diffusion parameters (including peak width of skeletonized MD) for a range of major white matter tracts from the structural, diffusion tensor (DT), magnetization transfer (MT) and quantitative T1-mapping sequences. We also aim to conduct a 1.5T-3T scanner comparison on a subsample to allow backwards-comparable 3T scanning in future waves.

Key beneficiaries from this project will be older people and older people's groups, carers, health and social care practitioners and policymakers, academics and the wider public. A knowledge exchange (KE) strategy is already in place and has an excellent track record of engagement with these diverse groups. CCACE has a dedicated KE Officer (funded by the University of Edinburgh) and one of her main foci is the Lothian Birth Cohort 1936. This is an unusual resource and ensures regular and effective public engagement and KE activity. We have also co-developed a formal Joint Impact Plan with our primary funders, Age UK. This is a detailed framework for current and future KE activities which reflects our mutual ambitions to realise the potential for impact beyond academia throughout the lifetime of the project period. We are committed to maintaining our successful KE strategy to improve understanding of cognitive and brain ageing and identifying which potentially preventable factors affect brain health and cognitive function.

For older people, carers and public health providers, our research has the potential to lead to interventions to prevent or ameliorate age-related cognitive decline and provides clinical benefits through the development of methods for more accurate diagnosis of dementia. For third sector organisations, our research will provide benefits in terms of advice and support they can offer to older people who are concerned about cognitive ageing and brain health. It is hoped that our findings will ultimately contribute to future healthcare policy, which will ideally serve to prolong the amount of time in old age during which individuals remain cognitively healthy and independent.

We will continue to proactively engage directly with policy makers at a national and local government level and indirectly through our 3rd sector close partners such as Age UK, Age Scotland and Alzheimer Scotland and public sector organisations such as NHS Health Scotland and Edinburgh City Council. Age UK's direct engagement with older people is critical to successful exchange of Disconnected Mind-generated knowledge with the public. This is particularly pertinent for medium and short-term impact. Research findings so far signal that in the future, people will be able to take informed decisions to influence their own brain and cognitive health and that there are significant messages for public health (e.g. physical fitness and brain white matter integrity, smoking and the thickness of the brain's cortex). Lifestyle factors, controllable physical factors and social factors are most likely to be the focus of Age UK's KE activity. Regular contact between Age UK and the research team allows Age UK to disseminate new findings to the wider Age UK family through audience-appropriate Insight and Evidence briefings. These, in turn, allow various parts of Age UK to use this knowledge for the benefit of older people in the form of services, products and influencing activities. These include publications such as overview articles for the general public and for policy makers and through co-produced key stakeholder workshops which aim to raise awareness of brain and cognitive ageing and their determinants.

As well as our joint work with charities, we will continue to engage with policy makers through Cross-party Groups, committees, policy-focussed meetings, networking events and consultations. We will also seek to engage policy makers through our programme of stakeholder workshops. We will continue to engage with schools, families and the media using presentations, workshops, museums, science festivals, our presence on policy committees, art collaborations (previous examples include theatre, portraits, short films and a CCACE-published book of short stories) and via our established online following. CCACE has been particularly successful in engaging individuals and groups through integrated online content.