Neurotransmitter Systems and their role in Cognitive and Metabolic Reserve in Ageing

During healthy ageing, network structure and function deteriorates but individual differences appear to moderate cognitive decline to some extent. Previous work has concluded that variations in cholinergic basal forebrain (ChBF) atrophy influences the degree of cognitive reserve, (i.e. the magnitude of a buffer from a critical point, beyond which competence diminishes). Similarly, environmental factors contribute to the level of metabolic reserve, which is the extent of cell functioning compared to its maximum metabolic capacity. This leads to further individual differences in resisting cell dysfunction, which can ultimately engender retention of cognitive faculties.

This work aims to investigate the mechanisms allowing cholinergic projections to promote alternative white matter connections, in order to preserve cognitive network function. It will also explore individual differences in metabolic and cognitive reserve in ageing, and how they relate to cholinergic and other transmitter systems, with the intention of gaining insight into their mechanisms and illuminating potential therapy targets. This work will include analysis of human MRI scans and cognitive testing to determine how ChBF atrophy, functional connectivity, and cognition are related. As new techniques emerge, this work can be extended to other transmitter systems; for instance, neuromelanin-weighted MRI utilises magnetisation transfer principles to quantify atrophy of dopaminergic and noradrenergic nuclei in humans. Furthermore, this project will examine underlying reserve mechanisms by using rat models to study the relationship between the cholinergic system and metabolic reserve, employing MRI before and after injections of metabolism-boosting methylene blue, and histological techniques.