Sleep and circadian rhythm alterations correlate with depression and cognitive impairment in Huntington's disease☆
Introduction
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat sequence in the gene encoding the protein huntingtin [1]. The disease is characterized by motor impairment, cognitive deterioration and behavioral problems [1]. However, disturbed sleep is also a prominent feature of the disease, substantially impairing the quality of life of both patients and caregivers [2]. Polysomnographic and actigraphic findings in small groups of HD patients have documented an increased sleep onset latency, sleep fragmentation and frequent nocturnal awakenings, reduced sleep efficiency, delayed and shortened rapid eye movement (REM) sleep, increased periodic leg movements, as well as circadian rhythm disturbances [3], [4], [5], [6], [7], [8], [9]. However, the exact nature of sleep complaints as well as their association with other symptoms and signs of the disease have not yet been studied in large groups of HD patients or premanifest mutation carriers.
Recently, it was shown that the sleep-wake disturbances in HD patients are partly reproduced in the transgenic R6/2 mouse model of the disease [8]. Importantly, cognitive decline and decay of learning in R6/2 mice were alleviated by pharmacological imposition of sleep, suggesting that a similar strategy might be of benefit to HD patients [9], [10]. Moreover, apart from affecting alertness, attention, memory and executive control, lack of sleep may also be considered as a risk factor for developing depression [11]. Conversely, recent clinical findings indicate that treatment of depressive symptoms may reduce sleep disruption in a number of neurodegenerative and extrapyramidal conditions, especially Alzheimer's and Parkinson's disease [12], [13]. However, in order to provide rationale for the evaluation of comparable approaches in HD, it is first necessary to assess the association between sleep disruption and both cognitive impairment and depressive symptoms in HD patients.
Characterization of sleep problems in HD patients as well as the identification of contributing factors are of paramount importance for the design and implementation of novel therapeutic strategies. Therefore, in this exploratory study, we aimed to (1) delineate the nature of subjective sleep disturbances in HD patients and premanifest mutation carriers in comparison with non-mutation carrying control subjects, and (2) to assess the relation between sleep and various clinical characteristics, including cognitive impairment and depressive symptoms, in order to identify important correlates of sleep disturbances in HD patients. In addition, we evaluated the usefulness of the SCOPA-SLEEP questionnaire, a very short instrument that can assess both daytime sleepiness and night-time sleep [14], in patients with HD.
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Design and participants
HD patients and premanifest mutation carriers were recruited from the outpatient clinic of the department of Neurology of the Leiden University Medical Center (LUMC) between June 2007 and December 2008. Control subjects were recruited over the same period and were randomly selected non-mutation carrying family members, partners or acquaintances of participating patients, employees at our department or their acquaintances. Exclusion criteria for both groups were the diagnosis of a preexistent
Participants
In total, 168 subjects participated in this study (Table 1). Of these 84 were mutation carriers (63 had manifest HD and 21 were premanifest), and 84 were non-mutation carrying subjects. As sleep problems of the mutation carriers may affect the sleep quality of their partners, non-mutation carriers were further divided into a partner group and a group consisting of other controls (Table 1); in the remainder of this paper we will refer to these two groups as partners and controls, respectively.
Discussion
To our knowledge, this is the largest cohort of HD patients and premanifest mutation carriers whose subjective sleep quality and daytime somnolence have been systematically assessed in relation to clinical symptoms and signs. Our findings indicate that while night-time sleep impairment is indeed more prevalent in HD patients, daytime sleepiness appears unlikely to be a major issue in HD. We also show that depression is the most important clinical correlate of sleep impairment in HD patients.
Conflict of interest
There are no conflicts of interest to be disclosed.
Acknowledgments
We would like to cordially thank E.M. Dumas, S.J.A. van den Bogaard, C.K. Jurgens, R. Bos and M.N. Witjes-Ané for collecting parts of the data, as well as all of the participants for their time and efforts. N.A.Aziz is supported by The Netherlands Organisation for Scientific Research (grant #017.003.098).
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The review of this paper was entirely handled by an Associate Editor, Vincenzo Bonifati.