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HD InsightsSleep disturbances are among the earliest non-motor symptoms in HD

By: Alpar S. Lazar, PhD and Roger A. Barker, MRCP, PhD, FMedSci

We spend approximately one-third of our lives asleep. Sleep quality is central to brain health,1,2 and problems with sleep are commonly seen in most neurodegenerative disorders,3-5 including HD.3,6 Several studies convincingly show abnormal sleep quality in manifest HD patients,7-12 and indicate that this happens early in the course of the disease.13 Exactly what the first sleep problems are in HD, and whether they emerge in the premanifest stage, when other non-motor symptoms including cognitive abnormalities are already present, is unknown. Patients with HD have metabolic alterations characterized by weight loss and increased energy expenditure,14,15 which may also relate to sleep problems, given that both are controlled by similar CNS structures, such as the hypothalamus.

We therefore aimed to investigate whether sleep problems are found in premanifest patients, and if so, to characterize these problems, and evaluate whether they are associated with cognitive and/or metabolic deficits. We designed a comprehensive cognitive, sleep, and metabolic study, performed both in the field and in the laboratory, with 38 individuals with premanifest HD and 36 age- and sex-matched controls. This consisted of two weeks of actigraphy at home, allowing assessment of habitual rest-activity rhythmicity using a small, wrist-worn movement sensor; two nights of sleep study (polysomnography) and multiple sleep latency tests in the laboratory, allowing objective assessment of sleep quality, brain electric activity (EEG) and daytime sleepiness; and a body composition assessment using dual energy X-ray absorptiometry scanning. Energy expenditure was measured over 10 days at home using doubly labelled water (DLW), and for 36 hours in the laboratory by indirect calorimetry (IC). DLW is water containing a stable isotope which is administered to the patients and its elimination tracked by daily urine samples to enable estimation of metabolic rate. IC determines metabolic rate based on oxygen consumption and carbon dioxide production during rest and exercise performed in an isolated respiratory chamber. We also performed detailed cognitive and clinical assessments.

Figure: Representative sleep profiles of a premanifest participant and an age- and sex-matched control showing more awakenings and time spent awake during the sleep period with less REM sleep, and an overall more fragmented sleep profile in the premanifest participant.
Figure: Representative sleep profiles of a premanifest participant and an age- and sex-matched control showing more awakenings and time spent awake during the sleep period with less REM sleep, and an overall more fragmented sleep profile in the premanifest participant.

We found that premanifest HD gene carriers had more disrupted sleep, characterized by a fragmented sleep profile, meaning more time spent awake during the night (see Figure); increased objective daytime sleepiness; and alterations in sleep-dependent brain activity as measured by EEG, with a clear association with increasing disease burden. In addition, the development of these abnormalities coincided with the development of cognitive, affective, and subtle motor deficits, and preceded any metabolic alterations.16 In spite of the presence of these objectively measured sleep deficits, premanifest HD gene carriers did not complain of poorer sleep quality compared to controls, which fits with an earlier study we had done in a small group of early manifest patients who also denied any sleep problems, despite objective measures to the contrary.13 This suggests that subjective measures of sleep quality are not necessarily helpful for research or clinical use in HD.

These new sleep results in patients are in line with reports from transgenic rodent models of HD that report gradually worsening sleep quality from a very early stage, and together raise many interesting questions. What causes these early sleep disturbances? What is their significance in the early cognitive deficits and the onset and progression of the disease? These questions remain to be investigated. Finally, it remains to be established whether therapeutic sleep quality improvement could help premanifest and manifest patients with HD to reduce the cognitive symptoms or even slow down the disease process, as suggested by earlier studies performed in transgenic animal models of HD.17,18

This study was supported by the CHDI Foundation (CHDI-RG50786).

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16Lazar AS, Panin F, Goodman AO, et al. Sleep deficits but no metabolic deficits in premanifest Huntington’s disease. Ann Neurol. 2015;78(4):630-648.

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18Pallier PN, Morton AJ. Management of sleep/wake cycles improves cognitive function in a transgenic mouse model of Huntington’s disease. Brain Res. 2009;1279:90-98.

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