Systems Cognitive Neuroscience of Healthy Ageing: Population-Representative Studies of Functional Plasticity and Neural Change

As greater numbers of us are living longer, it is increasingly important to understand how we can age healthily. Growing older involves dramatic changes to all aspects of our lives, but one of the most important concerns is our mental or 'cognitive' health. This research focuses on the cognitive abilities that enable us to function in the world, including memory, attention, emotion, language, action. We aim to understand how individuals can best retain these abilities into old age. Addressing this issue requires us to understand how brain structure and function support cognitive performance. Recent developments in neuroimaging technology show that as we age there is widespread loss of brain tissue in regions important for everyday cognition. Much research has focused on this tissue loss, and its role in cognitive decline in later life. However, other findings paint a more positive picture. While some cognitive abilities decline with normal ageing, many are spared. Moreover, cognitive decline doesn't occur abruptly at a pensionable age: cognitive abilities follow different trajectories across the lifespan, some remaining stable into our 80s, and some beginning to decline even in our 30s. Underpinning this complex pattern of spared and impaired cognition are complex interactions between neural structure and activity. A growing number of studies show that the brain responds flexibly to tissue loss, recruiting other brain regions to support neural function. This functional plasticity is possible because cognitive abilities, like memory or attention, are not underpinned by single brain regions, but by networks of regions. Successful ageing is therefore characterised by successful functional plasticity. Although ageing is often stereotyped as a time of mental restriction and inflexibility, cognitive neuroscience reveals that across the adult lifespan individuals make flexible use of available resources, including recruiting other regions and cognitive processes when necessary. Research Aims and Objectives Our aim is to identify what determines successful flexibility. This requires us to sample across the adult lifespan, measuring different aspects of neural structure and activity, and of cognitive performance. We will study a cohort of 700 participants aged 18 to 88, who will have a structural brain scan and perform key cognitive tests. Some members of this cohort will also participate in functional neuroimaging experiments to measure brain activity during cognitive tasks. We will ask (1) Is functional plasticity maintained across the lifespan and does it vary across cognitive abilities? (2) Are the distributed neural networks that support different cognitive abilities preserved in ageing? (3) Does the preservation of different cognitive functions vary, given the variability of neural change in different brain regions? Potential applications and benefits Our research will generate a unique resource of neuroimaging and cognitive measures about change across the adult lifespan, generating important benefits for academic researchers, the older community, and wider society. It will provide major contributions to ageing research, and provide a 'virtual brain and behaviour bank' acting as a continuing international resource for future research. Our focus on healthy ageing will be educationally important for all older adults. Few studies of ageing focus on healthy ageing, and the prevalent view of ageing is of deficit and ill-health. Our focus is on what characterizes older adults with preserved performance, a perspective with huge implications for how society views the ageing process. Moreover, our detailed analysis of neural and cognitive flexibility will help identify the conditions under which older adults may be aided by interventions. Finally, because our findings will help specify normal age-related deficits, they will show how normal ageing differs from pathological ageing in conditions such as Alzheimer's Disease.

A population-based cohort of 3000 adults will be recruited with demographic and basic cognitive assessments (LoLa3000 cohort). Of these, 700 will be selected for the Virtual Brain and Behaviour Bank (LoLa700 cohort) comprising structural and functional neuroimaging (MRI & MEG), standardised neuropsychological tests, and specialised cognitive tests. From the multi-faceted neuroimaging data, several measures of neural structure and function will be derived, using a broad array of analysis tools, techniques and expertise. Structural MRI data will be analysed using SPM8 and the Dartel toolbox; FMRI using SPM8; DTI using FSLs probabilistic tractography; connectivity with PPI & DCM; and custom Matlab. MEG data will be analysed using tools from Elekta Neuromag, SPM8 (including DCM), Fieldtrip; and custom Matlab. Our 'automatic analysis' parallel processing tools will be used to facilitate rapid processing of the large quantities of MRI and MEG data. We will measure both local neural integrity and neural integration across cortical regions taking care to control for factors that are not related to neural function but which influence neuroimaging, such as changes in neuro-vascular coupling. The derived neural measures will be related to age and performance, and to current models from cognitive neuroscience. On a subset of 280 adults (LoLa280 cohort) further investigations of neuro-cognitive functions will use FMRI, MEG/EEG and further behavioural testing. These will allow investigation of the effect of ageing on the specific cognitive domains of Attention, Language, Motor & Learning, Memory, Emotion, and the relationship between these different domains. Formal statistical models will be used to examine the changes that occur with healthy ageing, and the reorganisation in terms of strategies and structures invoked to compensate for them. This approach offers hypothesis-driven insights into healthy ageing that are relevant to the general population.

Life expectancy in the UK has increased by over 30 years in the last century. This reflects a wider international trend with major implications for the development of economic, social and health policy at local, national, and international levels. Cognitive change through the healthy lifespan is a topic of urgent scientific and social concern. Our team brings together highly experienced groups from Cambridge University Departments of Experimental Psychology, Psychiatry and Clinical Neurosciences, the Institute of Public Health and MRC Units in Cognition and Brain Sciences and Biostatistics, with a strong track record in top rank research publication and dissemination, and a common interest in understanding neurocognitive changes in healthy ageing. Beneficiaries of the research: Data derived from the three cohorts (LoLa3000, LoLa700, and LoLa280) and the Virtual Brain Bank will provide unique and rich resources. LoLa3000 will constitute a large, population-representative data sample on health and basic cognition; LoLa700 will include a uniquely detailed sample representing development across the adult human lifespan, relating major domains of cognitive function to structural and functional measures of brain function. LoLa280 offers a set of targeted intensive investigations of specific cognitive changes. The project's novel outcomes, methods, and database resources, will impact at multiple levels of a large and widely varied international community. These include academic research concerned with the epidemiology of neuro-cognitive change across the lifespan change; the development of pharmacological interventions for age-related disorders of cognitive function within both academic and private sectors; the formation of government policy, such as long-term care modelling and pensions; and the preparation of third-sector organisation reports, such as Dementia-UK, commissioned by the Alzheimer's Society. The project will also provide a world class training environment for members of the research support team to acquire specific skills in epidemiological and cognitive neuroscience research, including state-of-the-art neuroimaging analysis, and more general skills in time management, written and oral presentations and working as a team. Lay persons of all ages will benefit from the public dissemination of knowledge about the positive aspects of lifelong development of brain and cognition. Ensuring the benefits of this research?: The project's success is not only ensured by the track record of the applicants, but also by the substantial expertise of the collaborators who consist of highly respected researchers in cognitive ageing (Prof Patrick Rabbitt, University of Oxford), uni- and multi-variate statistics (Dr Ian Nimmo-Smith, MRC CBSU), functional connectivity analysis of neuroimaging data (Prof Paul Fletcher, University of Cambridge), MR physics (Dr Christian Schwarzbauer. MRC CBSU), human motor control (Prof Daniel Wolpert, University of Cambridge), emotional regulation (Dr Tim Dalgleish, MRC CBSU), and psychiatry (Prof Ian Goodyer, University of Cambridge). Behavioural and neuroimaging data from the LoLa 3000, LoLa700, and LoLa280 will be made into publicly available web-based, data resources for the international research community (see Data sharing and preservation) which we expect to form a significant, lasting international resource. In addition to dissemination of results through open-access peer-reviewed journals and conference presentations, where appropriate, the media will be informed of novel findings, through the University Press Office. Members of the LoLa cohorts will be kept informed of the research through a dedicated website and annual newsletter, highlighting the progress of the project and its results. The website will also be accessible by the wider public. Our work will be promoted at public events such as The Cambridge Science Festival and British Science Festival.