Stuck in place: the cognitive and neural bases of inflexibility in ageing and dementia

Abstract

Flexible thinking and behaviour are critical for navigating the uncertainties of daily life, enabling individuals to adapt, problem-solve, and respond to dynamic challenges. The capacity for flexible thinking and behaviour is diminished in ageing and dementia; however, the neurocognitive mechanisms underlying these changes remain poorly delineated. This thesis explores changes in flexibility in healthy ageing and dementia syndromes across cognitive, behavioural, and neural levels, leveraging machine learning approaches to predict rigid behaviours in dementia. Across four experimental chapters, the thesis aims to provide a comprehensive understanding of the multidimensional nature of inflexibility in healthy and pathological ageing, with a view to informing strategies to manage these symptoms. Chapter 2 examines cognitive flexibility in healthy ageing and reveals associations with reduced neural flexibility within specific functional brain networks. Chapter 3 investigates cognitive and behavioural inflexibility across dementia syndromes, identifying marked cognitive rigidity in semantic dementia (SD) and pronounced behavioural rigidity in behavioural-variant frontotemporal dementia (bvFTD). Chapter 4 applies connectome-based predictive modelling to assess whether structural connectivity in the frontoparietal, salience, default mode, and limbic networks predicts behavioural rigidity in dementia. Chapter 5 explores alterations in neurotransmitter systems in FTD using a novel approach, demonstrating that reduced serotonin transporter density is associated with behavioural rigidity in bvFTD. Collectively, the work presented in this thesis offers an integrated framework for understanding inflexible thoughts and behaviours in ageing and dementia. By combining cognitive, neural, and behavioural insights, it informs predictive and management strategies to improve patient care and quality of life.