Subjective sleep problems in Huntington's disease: A pilot investigation of the relationship to brain structure, neurocognitive, and neuropsychiatric function
Introduction
Sleep disturbance is an early and pervasive feature of the neurodegenerative Huntington's disease (HD) [1], caused by an expanded CAG repeat in the huntingtin gene (HD Collaborative Research Group, 1993) [2]. Common sleep problems include insomnia, lower sleep efficacy, longer sleep latency, more frequent night-time waking and less slow-wave sleep [3], [4]. Disturbed sleep can severely affect the quality of life of both patients and carers and can also exasperate neurocognitive and neuropsychiatric problems. In HD, there is ample evidence for robust structural brain changes, cognitive decline and psychiatric problems (see for example refs. [5], [6], [7]). However, how reports of sleep problems in HD may be associated with structural brain changes and neurocognitive and neuropsychiatric deficits remains unclear.
Neurodegenerative changes can be observed up to 20 years prior to clinical diagnosis of HD [5], [7]. A number of studies have shown significant alterations in primary sleep regulating structures, including hypothalamus and thalamus [8], [9], and secondary structures such as the striatum (caudate and putamen) in HD [5], [6], [7], [8]. It is possible that structural brain changes might be influencing the sleep problems reported by HD individuals. Evidence for such a relationship can be found in studies that have shown narcolepsy-like episodes in transgenic mice models of HD with depleted orexin/hypocretin neurons in hypothalamus [10]. Importantly, orexin loss has also been reported in post-mortem hypothalamic tissue from HD patients [11], [12]. Atrophy in secondary sleep regulating structure, such as caudate, is also associated with sleep disruption and reduced amount of slow-wave-sleep in HD [13], suggesting the important role of these brain structures in regulating sleep behaviour in HD.
Neurocognitive decline and neuropsychiatric symptoms in HD appear to run in parallel with the reported sleep problems. For example, the transgenic R6/2 HD mouse model showed cognitive decline that correlated with sleep and circadian disturbances [14]. In a study with both pre-HD and symp-HD individuals, a delayed sleep phase in symp-HD correlated with reduced cognitive performance [15]. Although sleep problems have been implicated in the development of psychiatric symptoms in healthy controls [16], there is no evidence to support an association with the neuropsychiatric profile of HD.
This study sought to investigate whether structural brain atrophy, neurocognitive and neuropsychiatric dysfunction was associated with subjective reports of sleep problems in pre-HD and symp-HD individuals. We predicted that individuals with the mutant HD gene (both pre-HD and symp-HD) with reported sleep problems would show increased atrophy in sleep-critical brain structures, greater neurocognitive decline and neuropsychiatric symptoms compared with individuals who reported no sleep problems.
Section snippets
Participants
This study used retrospective data from the IMAGE-HD project, a longitudinal neuroimaging study in HD based in Melbourne, Australia [5], [6], [17], [18], [19], [20]. The present study used cross-sectional data collected at study baseline (2008–2009) from participants in the pre-HD and symp-HD groups only [6], [21]. One pre-HD and 4 symp-HD participants were excluded due to missing data and segmentation errors, leaving a total of 35 pre-HD and 32 symp-HD participants. All participants underwent
Neurocognitive measures
In the both pre-HD (see Table 2) and symp-HD (see Table 3) groups, no significant differences were found between those with reported sleep problems and those without reported sleep problems on any neurocognitive measures.
Neuropsychiatric measures
In pre-HD (see Table 2), there was a significant difference between groups on total FrSBe, FrSBe disinhibition and HADS. Mean scores were higher in the reported sleep problems group compared to the no reported sleep problems group for each of these conditions with a medium
Discussion
In the present study we report structural brain, neurocognitive, and neuropsychiatric differences in pre-HD and symp-HD individuals reporting sleep problems. Our analyses suggest greater neuropsychiatric problems in the pre-HD and symp-HD individuals reporting sleep problems compared to those without the sleep problems. There was a greater loss of thalamic volume in symp-HD with sleep problems compared with symp-HD without sleep problems. Although, it is not possible from these data to
Conclusion
This study has provided pilot evidence that sleep problems is related to thalamic atrophy and psychiatric decline in HD individuals. In particular, there was a significant difference between HD individuals not reporting sleep problems and HD individuals reporting sleep problems in thalamic atrophy, as well as on a variety of neuropsychiatric measures. No significant differences were found in the volume of the hypothalamus or caudate, or in neurocognitive measures. Given the exploratory nature
Conflict of interest
There is no conflict of interest.
Acknowledgements
We would like to acknowledge the contribution of the participants who took part in this study. We are also grateful to the CHDI Foundation Inc. (grant number A – 3433), New York (USA), and to the National Health and Medical Research Council (NHMRC) (grant number 606650) for their support in funding this research. We also thank the Royal Children's Hospital for the use of their 3T MR scanner. GFE is a Principal NHMRC Research Fellow. GP is supported by the Postdoctoral Fellowship from the
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