Subjective sleep problems in Huntington's disease: A pilot investigation of the relationship to brain structure, neurocognitive, and neuropsychiatric function

https://doi.org/10.1016/j.jns.2016.03.021Get rights and content

Highlights

  • Sleep disturbances may accelerate neurodegeneration in Huntington's disease.

  • Neuropsychiatric symptoms are more severe in Huntington's disease individuals with sleep problems.

  • Symptomatic Huntington's disease individuals with sleep problems have reduced thalamic volume.

Abstract

Subjective reports of sleep disturbance are a common feature of Huntington's disease (HD); however, there is limited research investigating the relationship between sleep problems with changes in brain and behaviour. This study aimed to investigate whether subjective reports of sleep problems in HD are associated with brain volume, neurocognitive decline, and neuropsychiatric symptoms. This retrospective pilot study used brain volume, neurocognitive and neuropsychiatric data from premanifest (pre-HD) and symptomatic HD (symp-HD). Subjective sleep problem was measured using the sleep item of the Beck's Depression Inventory-II (BDI-II). Pre-HD individuals reporting sleep problems had significantly poorer neuropsychiatric outcomes compared to those not reporting sleep problems. In the symp-HD group, those with sleep problems had significantly accelerated thalamic degeneration and poorer neuropsychiatric outcomes compared to those without sleep problems. There was no relationship between subjective sleep problems and neurocognitive measures. These findings suggest an association between subjective sleep disturbance, neuropathology, and development of neuropsychiatric symptoms in HD. Further studies using quantitative EEG-based monitoring of sleep in HD and changes in the brain and behaviour will be necessary to establish the causal nature of this relationship.

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

References (42)

  • A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group

    Cell

    (1993)
  • A.O. Goodman et al.

    Identifying sleep disturbances in Huntington's disease using a simple disease-focused questionnaire

    PLoS Curr.

    (2010)
  • D.J. Dominguez et al.

    Multi-modal neuroimaging in premanifest and early Huntington's disease: 18 month longitudinal data from the IMAGE-HD study

    PLoS One

    (2013)
  • H.P. Kremer et al.

    Atrophy of the hypothalamic lateral tuberal nucleus in Huntington's disease

    J. Neuropathol. Exp. Neurol.

    (1990)
  • A.J. Morton et al.

    Disintegration of the sleep-wake cycle and circadian timing in Huntington's disease

    J. Neurosci. Off. J. Soc. Neurosci.

    (2005)
  • S. Gabery et al.

    Changes in key hypothalamic neuropeptide populations in Huntington disease revealed by neuropathological analyses

    Acta Neuropathol.

    (2010)
  • A. Petersen et al.

    Orexin loss in Huntington's disease

    Hum. Mol. Genet.

    (2005)
  • M. Wiegand et al.

    Nocturnal sleep in Huntington's disease

    J. Neurol.

    (1991)
  • P.N. Pallier et al.

    Pharmacological imposition of sleep slows cognitive decline and reverses dysregulation of circadian gene expression in a transgenic mouse model of Huntington's disease

    J. Neurosci.

    (2007)
  • G.R. Poudel et al.

    Abnormal synchrony of resting state networks in premanifest and symptomatic Huntington disease: the IMAGE-HD study

    J. Psychiatry Neurosci. JPN.

    (2014)
  • G.R. Poudel et al.

    Functional changes during working memory in Huntington's disease: 30-month longitudinal data from the IMAGE-HD study

    Brain Struct. Funct.

    (2015)
  • Cited by (27)

    • Sleep disturbances by disease type and stage in Huntington's disease

      2021, Parkinsonism and Related Disorders
      Citation Excerpt :

      Other hypothesized causes of sleep abnormalities in HD include involuntary movements [27] or the presence of psychiatric conditions, such as depression and anxiety [28]. Greater severity of depressive symptoms have been shown to be associated with sleep disturbances in both preHD patients and those with motor symptoms [29]; Medication used to treat common early symptoms of HD also have the potential to alter sleep structure which could lead to sleep abnormalities. While this study provides evidence of the point in time during which sleep disturbances are most common in HD patients, there are limitations.

    • Huntington disease: A quarter century of progress since the gene discovery

      2019, Journal of the Neurological Sciences
      Citation Excerpt :

      Changes in sleep and circadian rhythms are also common in HD [84,131]. Sleep disturbances can be associated with mood disturbances and impaired cognition [132,133], although in one study subjective sleep complaints did not correlate with cognitive measures [133]. Restless sleep, frequent and too-early awakening, and insomnia are all reported.

    View all citing articles on Scopus
    View full text