Cortisol as a biological marker of depression and memory difficulties in the early stages of Huntington's disease

Abstract

Huntington’s disease (HD) is a genetic neurodegenerative condition which manifests a motor disorder, psychiatric disturbance, and a decline in cognitive functioning. Cortisol dysregulation in HD has been reported in a limited number of human and mouse model studies, but no published research has focussed on investigating the relationship between cortisol levels and the clinical signs of HD. Cortisol is a stress hormone produced by the hypothalamic-pituitary-adrenal (HPA) axis, and it is involved in a broad range of physical, behavioural, and cognitive functions. The concentration of circulating cortisol is a marker of HPA axis integrity and the ability of the HPA axis negative feedback loop to regulate itself. HPA axis dysfunction is associated with psychiatric and cognitive signs in a number of medical conditions, neuropsychiatric disorders, and neurodegenerative diseases. There is strong evidence of relationships between high cortisol, particularly around the time of morning awakening, and depression as well as between high cortisol and poor memory ability. In HD, however, these relationships have not been studied despite the fact that depression and memory decline are prominent early psychiatric and cognitive signs of this disease. A link between a neurobiological marker of HD progression and the first clinical signs of depression and memory decline may provide an objective indication of early pathophysiological changes in HD. Such a relationship may also make it possible to clinically assess the therapeutic benefit of an early intervention. The aim of the current research project was to extend on previous HD research by examining the relationship between cortisol levels and cognitive and psychiatric signs and symptoms in the early stages of HD. This thesis comprises two studies that have been written up as manuscripts and submitted for publication. Individually, the papers aim to examine the relationship between cortisol levels and signs of depression (Study 1) and memory performance (Study 2) in pre-diagnosed participants (pre-HD) and patients who had received a diagnosis of HD in the past 5 years (early-HD). Salivary cortisol was collected at four time points over a 24-hour period in 57 participants (17 early-HD, 20 pre-HD, 20 gene-normal healthy controls). To place this research project in the context of previous HPA axis studies of HD, cortisol levels within the subject sample of this project were first analysed at four time points across a 24-hour period, without taking into account clinical signs. The results indicated a trend for higher cortisol levels in pre-HD at all four time points. Study 1 of the thesis reports depression symptoms as measured by the Inventory of Depressive Symptomatology – Self-Report (IDS–SR), and Study 2 reports verbal learning and memory ability as measured using the California Verbal Learning Test – Second Edition (CVLT–II). Results from Study 1 indicated that the morning cortisol concentration in early-HD was dependent on the severity of depression, such that higher levels of depression were associated with higher morning cortisol than in non-depressed early-HD. This pattern was not observed in control and pre-HD. Study 2 reports an association between poorer memory encoding and retrieval, and higher evening cortisol in participants with more severe HD motor signs. This association was also not evident in control and pre-HD. Overall, these results indicate that cortisol dysregulation appears to begin well in advance of an HD diagnosis, perhaps resulting in chronic hypercortisolism through the pre-HD phase. Once HD is diagnosed, cortisol may be differentially influenced depending on the presence or absence of depression. Cortisol also appears to be related to memory decline in HD, but only once motor signs have become pronounced. Neuropathological changes related to HPA axis function, which worsen with disease progression, could account for these findings. Cortisol, and therefore HPA axis function, could thus be considered as a candidate biomarker of HD progression which is meaningfully associated with early neuropsychiatric and cognitive signs of HD.