The role of the Locus Coeruleus-Noradrenergic system integrity in the main Dementia modifiable risk factors: a comparative approach linking neuropsychological measures to biological and lifestyle indices

Abstract

Dementia etiopathogenesis is characterised by a plethora of heterogeneous and diverse factors, which contribute to delay the definition of effective treatments and preventing strategies. Growing evidence identifies in the degeneration of the subcortical neuromodulatory nuclei (Cholinergic, Dopaminergic, Serotoninergic and Noradrenergic) the cause of the early signs of cognitive decline, which ultimately lead to dementia. Cognitive and brain maintenance are key aspects which depend on the integrity of such neuromodulatory seeds, and their extended efficiency counter-acts against normal and pathological neurodegeneration. The variables contributing to brain health and cognitive maintenance are together unified under the comprehensive construct of cognitive reserve. Cognitive reserve comprises different lifestyle and individual aspects that can offer resistance against neurodegeneration by preserving overall brain and cognitive functioning. Increasing the expression of cognitive reserve variables is currently the most efficient approach to reduce dementia risk while delaying dementia onset. Among the main neuromodulatory nuclei, the degeneration of Locus Coeruleus Noradrenergic system (LC-NA) appears to be predominant over the others, being both the earliest system to show signs of neurodegeneration and associated with high-order cognitive functioning. Robertson proposed a model suggesting that the activation of the LC-NA system through attention, learning, and cognitive stimulation, by up-regulating noradrenergic tone, would lead to more preserved brain health contributing to cognitive reserve in the face of neurodegeneration. In Robertson’s model, the neuroprotective properties of noradrenaline, including its ability to reduce inflammation and promote neurogenesis and synaptogenesis, are the proposed neurobiological substrates that may act preserving brain health when the LC-NA system is stimulated. Within this framework, the stimulation of the LC-NA system would reduce vulnerability to neurodegenerative diseases. On the basis of this model, the current PhD project investigated how the integrity of the LC-NA system related to the attentional domain and the degree of biological brain maintenance. These aspects were also examined in their interrelation with the main dementia modifiable risk factors, namely: personological, sociodemographic and lifestyle indices, such as dietary behaviour and physical fitness level. The overarching purpose of the thesis was to test Robertson’s model while aiming to better understand the role of the noradrenergic system in cognition and brain health. This project’s ultimate goal was to extend the knowledge of healthy and pathological aging providing further neurobiological explanation of the construct of Reserve, and to understand how this knowledge can be clinically useful both for preventing strategies and rehabilitation approaches. All in all, the observed PhD findings provide further understanding of the neuromodulatory subcortical system in relationship to neuropsychological indices and lifestyle factors, and they hold important information for the design of future interventions aiming to ameliorate cognitive and brain health in the face of neurodegeneration.