Cognitive impairment: quantification and possibilities for pharmacological treatment

Cognitive impairments are a common feature of neurological and neuropsychiatric disorders, as well as of substance-abuse disorders. The impairments seen in these disorders can be caused by disruptions to common neural substrates, and therefore pharmacological agents can be repositioned from use in neuropsychiatric to neurological disorders, and vice versa. Together, these disorders have been estimated to comprise 13% of the global burden of disease. Indeed, an individual’s ability to successfully perform everyday activities can be limited by deficits in crucial cognitive functions such as attention, response inhibition, planning and working memory. Frontal-striatal networks in the brain have been shown to underlie these vital functions, which are modulated by neurotransmitters including acetylcholine, dopamine, and noradrenaline. Importantly, these functions are susceptible to pharmacological intervention with drugs such as physostigmine, modafinil, and atomoxetine. In order to explore the nature of a variety of forms of cognitive impairment, which were diverse in severity from mild to more severe, studies were carried out on amateur boxers and sleep-deprived doctors, as well as on patients with subarachnoid haemorrhage (SAH) and on patients with Parkinson’s disease (PD). Quantification of cognitive impairment is the crucial first step in determining which neural networks are involved, and thus which pharmacological agents would be suitable candidates for treatment. A longitudinal study was carried out using a comprehensive battery of well-validated cognitive tasks, in order to quantify the change in cognitive ability in healthy individuals who participated in amateur boxing. Subtle cognitive impairments, which were related to structural changes, were documented. Using existing understanding of pharmacological agents, novel treatments for cognitive impairments were explored in relation to sleep-deprived doctors, as well as to PD and SAH patients. A novel treatment for specific cognitive problems in PD was investigated: atomoxetine, a noradrenaline reuptake inhibitor. A double-blind placebo-controlled study revealed that atomoxetine may be a candidate for treatment of response inhibition impairments seen in PD. This finding is important as noradrenergic treatments are not currently used in PD, despite degeneration in the locus coeruleus, the main cortical source of noradrenaline. Another novel treatment explored was modafinil, a drug that has also been shown to modulate the noradrenergic system, as well as the dopaminergic system. Modafinil is currently licensed for use in narcolepsy and shift work sleep disorder. It was found that modafinil remediates task set-switching impairments and reduces impulsivity in sleep-deprived doctors. Furthermore, it was shown that modafinil might be a potential treatment for cognitive impairments found in neurological patients with SAH. In contrast to this, physostigmine, a cholinesterase inhibitor, did not seem to alter the cognitive symptoms investigated. To summarise, this thesis aims to quantify cognitive impairment in a range of groups, and to explore the potential use of existing pharmacological agents that could be repurposed to treat cognitive impairments in novel ways