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Ann Neurol. 2015 Oct;78(4):630-48. doi: 10.1002/ana.24495. Epub 2015 Aug 21.

Sleep deficits but no metabolic deficits in premanifest Huntington's disease.

Author information

John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
Faculty of Medical Science, Anglia Ruskin University, Cambridge, United Kingdom.
In Silico Lead Discovery, Novartis Institutes for Biomedical Research, Basel, Switzerland.
Department of Physics, Babes-Bolyai University, Cluj-Napoca, Romania.
Respiratory Support and Sleep Centre, Papworth Hospital, Cambridge, United Kingdom.
National Institute for Health Research/Wellcome Trust Clinical Research Facility, Addenbrooke's Hospital, Cambridge, United Kingdom.
University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrookes Hospital, Cambridge, United Kingdom.
Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, United Kingdom.
CHDI Management/CHDI Foundation, Princeton, NJ, United States of America.



Huntington disease (HD) is a fatal autosomal dominant, neurodegenerative condition characterized by progressively worsening motor and nonmotor problems including cognitive and neuropsychiatric disturbances, along with sleep abnormalities and weight loss. However, it is not known whether sleep disturbances and metabolic abnormalities underlying the weight loss are present at a premanifest stage.


We performed a comprehensive sleep and metabolic study in 38 premanifest gene carrier individuals and 36 age- and sex-matched controls. The study consisted of 2 weeks of actigraphy at home, 2 nights of polysomnography and multiple sleep latency tests in the laboratory, and body composition assessment using dual energy x-ray absorptiometry scanning with energy expenditure measured over 10 days at home by doubly labeled water and for 36 hours in the laboratory by indirect calorimetry along with detailed cognitive and clinical assessments. We performed a principal component analyses across all measures within each studied domain.


Compared to controls, premanifest gene carriers had more disrupted sleep, which was best characterized by a fragmented sleep profile. These abnormalities, as well as a theta power (4-7Hz) decrease in rapid eye movement sleep, were associated with disease burden score. Objectively measured sleep problems coincided with the development of cognitive, affective, and subtle motor deficits and were not associated with any metabolic alterations.


The results show that among the earliest abnormalities in premanifest HD is sleep disturbances. This raises questions as to where the pathology in HD begins and also whether it could drive some of the early features and even possibly the pathology.

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