Abstract

Advances in new treatments for dementia require a new mechanistic understanding of disease, linking changes in cognitive function to underlying neural systems and their pharmacology. They also require new tools to identify the signatures of nascent pathology in (as yet) asymptomatic patients that can be used to safely and reliably track the emergence of disease in the context of preventive and therapeutic clinical trials. In the first part of this program, we develop new models of cognitive function, based neurophysiological models of decision making circuits. We examine decisions about behavioural control (including response inhibition), volition and the perception of environmental cues that guide actions. Using accumulation-to-threshold models of perception and behaviour, we will determine the processes by which sensory inputs are transformed to motor outputs, and the vulnerability of these processes to two different disorders: Parkinson’s disease and Alzheimer’s disease. In the second part of the program, we will examine the problem that some people have increasingly poor cognitive function with age. This may be the presence of subclinical dementias, and we will compare neural signatures in healthy older adults to those with early dementia. However, unsuccessful cognitive ageing is not necessarily just a matter of early dementia. Even those without emerging dementia will vary in their cognitive ageing profile, for reasons that we will elucidate. This builds on the CamCAN study of healthy ageing, bringing in for the first time those adults who performed poorly on screening tests. We will apply a tailored battery of imaging and psychological assessments, using MRI, fMRI and MEG, and use supervised machine earning methods to identify the neural factors that are associated with poor function. These will be compared with neural factors associated with early AD. This program links directly to the Cambridge Centre for Ageing and Neuroscience (CamCAN) and the Dementias Platform UK, both in terms of the Synaptic Health Theme for Experimental Medicines, and the Deep and Frequent Phenotyping study of prodromal dementia. The MRC “ACA5. Decision making in dementia” provides vital links between normative studies, ageing and neurodegeneration. Through my Wellcome Trust Senior Research Fellowship and the NIHR Biomedical Research Centre’s Neurodegeneration and dementia theme we are developing pharmacological interventions to restore cognition, with direct translation from ACA5 innovations to clinical populations.

Aims

Our research group uses brain scanning and new methods in computer science and psychology to understand how healthy people and those with brain illnesses make decisions about what to do, and what not to do.

These decisions are made possible by the flow of information through brain networks. We use MRI and MEG type brain scanners to study these networks, in health, over the lifespan, and in people with emerging dementia.