Motor disturbances, cognitive decline and psychiatric symptoms are considered as the key symptoms of Huntington__s disease (HD). Yet, other prevalent features include unintended weight loss, sleep... Show moreMotor disturbances, cognitive decline and psychiatric symptoms are considered as the key symptoms of Huntington__s disease (HD). Yet, other prevalent features include unintended weight loss, sleep and circadian disturbances and autonomic nervous system dysfunction. The nature of these features supports a pivotal role of the hypothalamus in the HD disease process. In this thesis data is presented from immunocytochemical and in situ hybridization studies demonstrating substantial pathology in hypothalamic neuropeptide expression in HD patients. Main findings include neuropeptide changes in the suprachiasmatic nucleus, the body__s master clock, that will likely be responsible for disruption of 24h circadian rhythmicity. Secondly, the neuronal histaminergic system is hyperactive at both the level of the hypothalamic tuberomamillary nucleus as well as in the cerebral neocortex. These changes could partly explain weight loss and cognitive decline in patients. The expression of neuropeptides in the hypothalamic paraventricular and infundibular nuclei, however, seems to be relatively unaffected by the HD disease process. Finally, a discrepancy between mRNA expression and protein expression of many hypothalamic neuropeptides was observed that can be partly explained by a decrease of prohormone convertase expression. Interestingly, hypothalamic changes in existing HD transgenic rodent models are largely non-representative of hypothalamic changes in HD patients. Show less
The nuclear symptoms and signs of Huntington__s disease (HD) consist of motor, cognitive and behavioural disturbances. Other less well-known, but prevalent and debilitating features of HD include... Show moreThe nuclear symptoms and signs of Huntington__s disease (HD) consist of motor, cognitive and behavioural disturbances. Other less well-known, but prevalent and debilitating features of HD include unintended weight loss, sleep and circadian rhythm disturbances, as well as autonomic nervous system dysfunction. However, the pathogenesis of these less well-known features of HD is poorly understood and currently no effective treatment options are available. It is thus of paramount importance to elucidate the pathological basis of these symptoms and signs in order to design and apply more effective therapeutic interventions. Recently, substantial dysfunction of the hypothalamus was reported in both human studies and various knock-in and transgenic animal models of HD. The hypothalamus consists of groups of interconnected neuronal nuclei located at the base of the brain that regulate a broad array of physiologic, homeostatic and behavioural activities. Therefore, in this thesis we attempt to substantiate the premise that hypothalamic dysfunction per se, as well as secondary (neuro)endocrine and metabolic alterations could contribute to the pathogenesis of several non-motor symptoms and signs of HD. Show less
The first part deals with the hypothalamic hypocretin system in disorders that are accompanied by narcolepsy-like sleep disturbances, i.e. Prader-Willi Syndrome, Parkinson__s Disease and Huntington... Show moreThe first part deals with the hypothalamic hypocretin system in disorders that are accompanied by narcolepsy-like sleep disturbances, i.e. Prader-Willi Syndrome, Parkinson__s Disease and Huntington__s Disease. To determine whether the hypocretin system is affected in these disorders, the total number of hypocretin neurons was determined using quantitative techniques in post-mortem human hypothalami. The reason why hypocretin neurons disappear in narcolepsy is still a mystery. A putative autoimmune aetiology has been hypothesized, but a screening for autoantibodies and a n=1 trial with intravenous immunoglobulins yielded no unequivocal results in favor of this hypothesis. In the second part, the consequences of hypocretin deficiency in narcoleptic patients are explored, focussing on vigilance, metabolism and the autonomic nervous system and skin temperature regulation. The ability of a specific neuropsychological test to measure vigilance as a severity indicator for narcolepsy is explored. Two possible causes for the obesity commonly seen in narcolepsy are a decreased basal metabolic rate and a changed autonomic tone. To assess the influence of hypocretin deficiency on skin temperature regulation, thermoregulatory profiles of the proximal and distal skin of narcoleptic subjects were compared to profiles of healthy controls during a daytime sleep registration. Show less
