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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. INTERPRETATION: 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.

Asymptomatic sleep abnormalities are a common early feature in patients with Huntington's disease.

Huntington's disease (HD) is a fatal neurodegenerative disease characterized by motor, cognitive, and psychiatric disturbance. In this article, we used polysomnography, actigraphy and a variety of validated questionnaires to ascertain the extent to which sleep changes are identifiable and measurable in mild stage HD, and importantly, to see whether patients are negatively impacted by the changes in their sleep. We found significant differences in sleep architecture and sleep efficiency in patients compared with controls using polysomnography. However, patient scores on the Functional Outcomes of Sleep Questionnaire, Medical Outcomes of Sleep Scale, and Epworth Sleepiness Scale were not significantly different to controls. These results suggest that although marked changes in sleep architecture are present in early HD and can be detected using polysomnography, patients do not necessarily recognize or report these abnormalities.

Body composition in premanifest Huntington's disease reveals lower bone density compared to controls.

Huntington's disease (HD) is a debilitating autosomal dominant, neurodegenerative disease with a fatal prognosis. Classical features include motor disturbances, dementia and psychiatric problems but are not restricted to this triad as patients often experience other abnormalities such as unintended weight loss, the exact cause of which is unknown. We studied the body composition of 25 premanifest HD and compared it to 25 control subjects using a dual energy x-ray absorptiometer (DEXA) scan. Like the R6/2 transgenic mouse model, we identified significantly lower bone mineral density z-scores in premanifest individuals, that was not related to any difference in testosterone, cortisol, leptin or Vitamin D levels. These results identify an early gene-related change that occurs in HD which not only could lead to a potential biomarker for the disease, but given it is also seen in other manifest neurodegenerative diseases, could also reveal a common disease related process.

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

Sleep disturbances have been shown to affect patients with various neurological diseases, including Huntington's disease (HD). We therefore aimed to develop a sleep questionnaire that could be used by clinicians to help identify sleep disturbances in patients with the disease.Design A detailed questionnaire was used that was modelled on recent sleep questionnaires used for Parkinson's disease patients, and developed after consultation with sleep specialists. This questionnaire contained 45 questions that focused on different sleep-related issues such as duration, quality of sleep, abnormal nocturnal behaviour and quality of life. Setting Questionnaires were either completed in the home environment or in clinic.Participants 66 patients, 38 carers and 60 non-carers were recruited.Measurements & Results Various sleep-related difficulties were identified in a significantly greater proportion of HD patients compared to control subjects, with both quality and quantity of sleep being affected. Conclusions Disturbed sleep in HD may contribute towards the deterioration of the patient's ability to do activities of daily living and have a significantly deleterious effect on the quality of life of both patients and carers. This simple questionnaire should aid the clinician by providing subjective insight into the patient's sleep patterns that could enable more effective, individual-specific treatment to be instigated and ultimately improve quality of life.

How vital is sleep in Huntington's disease?

Huntington's disease (HD) is a fatal neurodegenerative disease caused by an abnormal expansion of a CAG repeat in exon 1 of the HD gene on chromosome 4. The disease runs a debilitating and progressive course with an average survival of 15-25 years after disease onset. HD patients classically develop involuntary movements including chorea, as well as progressive cognitive and psychiatric disturbances, although a number of other features have also been reported, including changes in sleep and circadian rhythms; it is this latter area that forms the focus of this review.

Increased thirst and drinking in Huntington's disease and the R6/2 mouse.

While Huntington's disease (HD) is a condition that primarily involves the basal ganglia, there is evidence to suggest that the hypothalamus is also affected. Because the osmoreceptors regulating thirst are situated in the circumventricular region of the hypothalamus, we were interested in whether altered thirst is a part of the HD phenotype. We used the LABORAS behavioural monitoring system and water consumption to show that drinking behaviour was abnormal in R6/2 mice. By 10 weeks of age, R6/2 mice spent significantly more time drinking and drank a greater volume than their wild-type (WT) littermates. The numbers of immunoreactive vasopressin neurons in the paraventricular nucleus (PVN) of the hypothalamus in R6/2 mice were significantly decreased from 8 weeks of age, suggesting that the change in drinking behaviour may be the result of hypothalamic dysfunction. We gave a xerostomia (dry mouth) questionnaire to HD patients and control subjects, and also measured their urine osmolality and serum vasopressin. The mean total xerostomia score was significantly higher in HD patients than in controls, indicating greater thirst in HD patients. Urine osmolality was unaffected in HD patients up to clinical stage III, and none of the patients had diabetes. However, serum vasopressin was increased, suggesting a dysregulation in the control of hypothalamic vasopressin release. A dry mouth can affect taste, mastication and swallowing, all of which may contribute to the significant weight loss seen in both HD patients and R6/2 mice, as can dehydration. We suggest that increased thirst may be an important and clinically relevant biomarker for the study of disease progression in HD.

The metabolic profile of early Huntington's disease--a combined human and transgenic mouse study.

Huntington's disease (HD) is a debilitating autosomal dominant, neurodegenerative disease with a fatal prognosis. Classical symptoms include motor disturbances, subcortical dementia and psychiatric symptoms but are not restricted to this triad. Patients often experience other problems such as weight loss, although why and when this occurs in the disease course is not known. We studied metabolism using whole body indirect calorimetry in both early stage HD patients and in the R6/2 transgenic mouse model of HD, at times before and after they displayed signs of disease. Using this combined approach we found that patients with early HD tended to be in negative energy balance for reasons not related to their movement disorder, which was paralleled in the transgenic R6/2 mice. These mice had significantly elevated total energy expenditure as they developed overt disease with weight loss due primarily to a loss of muscle bulk. This study has shown for the first time that in HD there is the development of early negative energy balance, which in turn may cause weight loss with loss of muscle bulk in particular. The reason for this is not known but may reflect a catabolic state secondary to hypothalamic pathology, as abnormalities have been reported in the hypothalamus early in the disease course.

Olfactory abnormalities in Huntington's disease: decreased plasticity in the primary olfactory cortex of R6/1 transgenic mice and reduced olfactory discrimination in patients.

Reduced neuronal plasticity in the striatum, hippocampus, and neocortex is a common feature of transgenic mouse models of Huntington's disease (HD). Doublecortin (DCX) and polysialylated neural cell adhesion molecule (PSA-NCAM) are associated with structural plasticity in the adult mammalian brain, are markers of newly formed neurons in the dentate gyrus of the adult hippocampus, and are highly expressed in primary olfactory (piriform) cortex. Animal studies have demonstrated that a reduction in plasticity in the piriform cortex is associated with a selective impairment in odour discrimination. Therefore, the number of DCX and PSA-NCAM immunoreactive cells in the piriform cortex were quantified as measures of plasticity in early stage (fifteen week old) R6/1 transgenic HD mice. The transgenic mice had a large reduction in the number of DCX and PSA-NCAM immunoreactive cells in the piriform cortex, similar to that previously reported in the R6/2 mice. We also tested whether odour discrimination, as well as identification and detection, were impaired in HD patients and found that patients (at a similar disease stage as the mice) had an impairment in odour discrimination and identification, but not odour detection. These results suggest that olfactory impairments observed in HD patients may be the result of reduced plasticity in the primary olfactory cortex.