Profiling Social Cognition in Premanifest Huntington's Disease.

OBJECTIVE: Discrepancies exist in reports of social cognition deficits in individuals with premanifest Huntington's disease (HD); however, the reason for this variability has not been investigated. The aims of this study were to (1) evaluate group- and individual-level social cognitive performance and (2) examine intra-individual variability (dispersion) across social cognitive domains in individuals with premanifest HD. METHOD: Theory of mind (ToM), social perception, empathy, and social connectedness were evaluated in 35 individuals with premanifest HD and 29 healthy controls. Cut-off values beneath the median and 1.5 × the interquartile range below the 25th percentile (P25 - 1.5 × IQR) of healthy controls for each variable were established for a profiling method. Dispersion between social cognitive domains was also calculated. RESULTS: Compared to healthy controls, individuals with premanifest HD performed worse on all social cognitive domains except empathy. Application of the profiling method revealed a large proportion of people with premanifest HD fell below healthy control median values across ToM (>80%), social perception (>57%), empathy (>54%), and social behaviour (>40%), with a percentage of these individuals displaying more pronounced impairments in empathy (20%) and ToM (22%). Social cognition dispersion did not differ between groups. No significant correlations were found between social cognitive domains and mood, sleep, and neurocognitive outcomes. CONCLUSIONS: Significant group-level social cognition deficits were observed in the premanifest HD cohort. However, our profiling method showed that only a small percentage of these individuals experienced marked difficulties in social cognition, indicating the importance of individual-level assessments, particularly regarding future personalised treatments.

Effects of sleepiness on clinical decision making among paramedic students: a simulated night shift study.

OBJECTIVE: Paramedics are at the forefront of emergency healthcare. Quick and careful decision making is required to effectively care for their patients; however, excessive sleepiness has the potential to impact on clinical decision making. Studies investigating the effects of night shift work on sleepiness, cognitive function and clinical performance in the prehospital setting are limited. Here, we aimed to determine the extent to which sleepiness is experienced over the course of a simulation-based 13-hour night shift and how this impacts on clinical performance and reaction time. METHODS: Twenty-four second year paramedic students undertook a 13-hour night shift simulation study in August 2017. The study consisted of 10 real-to-life clinical scenarios. Sleepiness, perceived workload and motivation were self-reported, and clinical performance graded for each scenario. Reaction time, visual attention and task switching were also evaluated following each block of two scenarios. RESULTS: The accuracy of participants' clinical decision making declined significantly over the 13-hour night shift simulation. This was accompanied by an increase in sleepiness and a steady decline in motivation. Participants performed significantly better on the cognitive flexibility task across the duration of the simulated night shift and no changes were observed on the reaction time task. Perceived workload varied across the course of the night. CONCLUSION: Overall, increased sleepiness and decreased clinical decision making were noted towards the end of the 13-hour simulated night shift. It is unclear the extent to which these results are reflective of practising paramedics who have endured several years of night shift work, however, this could have serious implications for patient outcomes and warrants further investigation.

Exploring the brain-body composition relationship in Huntington's disease.

OBJECTIVE: Changes in body composition are a common feature of Huntington's disease (HD) and are associated with disease progression. However, whether these changes in body composition are associated with degeneration of the striatum is unknown. This study aimed to explore the associations between body composition metrics and striatal brain volume in individuals with premanifest HD and healthy controls. METHODS: Twenty-one individuals with premanifest HD and 22 healthy controls participated in this cross-sectional study. Body composition metrics were measured via dual-energy X-ray absorptiometry. Structural magnetic resonance imaging of subcortical structures of the brain was performed to evaluate striatal volume. RESULTS: There were no significant differences in body composition metrics between the premanifest HD and healthy controls group. Striatal volume was significantly reduced in individuals with premanifest HD compared to healthy controls. A significant association between bone mineral density (BMD) and right putamen volume was also observed in individuals with premanifest HD. CONCLUSION: These findings show striatal degeneration is evident during the premanifest stages of HD and associated with BMD. Additional longitudinal studies are nevertheless needed to confirm these findings.

Virtual Reality Triage Training Can Provide Comparable Simulation Efficacy for Paramedicine Students Compared to Live Simulation-Based Scenarios.

Background: Mass-casualty incidents (MCIs) are catastrophic. Whether they arise from natural or man-made disasters, the nature of such incidents and the multiple casualties involved can rapidly overwhelm response personnel. Mass-casualty triage training is traditionally taught via either didactic lectures or table top exercises. This training fails to provide an opportunity for practical application or experiential learning in immersive conditions. Further, large-scale simulations are heavily resource-intensive, logistically challenging, require the coordination and time of multiple personnel, and are costly to replicate. This study compared the simulation efficacy of a bespoke virtual-reality (VR) MCI simulation with an equivalent live simulation scenario designed for undergraduate paramedicine students. Methods: Both simulations involved ten injured patients resulting from a police car chase and shooting. Twenty-nine second-year paramedicine students completed the live and VR simulation in a random order. The training efficacy of the VR and live simulation was evaluated with respect to student immersion and task-difficulty, clinical decision-making (i.e. triage card allocation accuracy and timeliness), learning satisfaction, and cost of delivery. Results: While perceived physical demand was higher in the live simulation compared to VR (p < 0.001), no differences were observed across mental demand, temporal demand, performance, effort or frustration domains. No differences were found for participant satisfaction across the two platforms. No differences were observed in the number of triage cards correctly allocated to patients in each platform. However, participants were able to allocate cards far quicker in VR (p < .001). Cost of running the VR came to AUD $712.04 (staff time), compared to the live simulations which came to AUD $9,413.71 (staff time, moulage, actors, director, prop vehicle), approximately 13 times more expensive. Conclusion: The VR simulation provided near identical simulation efficacy for paramedicine students compared to the live simulation. VR MCI training resources represent an exciting new direction for authentic and cost-effective education and training for medical professionals.

Effects of multidisciplinary therapy on physical function in Huntington's disease.

OBJECTIVE: The primary objective of this trial was to evaluate the effects of outpatient multidisciplinary therapy, compared to usual care, on measures of physical function and muscle strength in patients with manifest Huntington's disease (HD). METHODS: Twenty-two patients with clinically verified HD were randomized to receive 36 weeks of outpatient multidisciplinary therapy or usual care. Outpatient multidisciplinary therapy comprised 9 months of supervised exercise, cognitive therapy and self-directed home-based exercise. Usual care consisted of standard medical care. Patients were assessed at 0 and 36 weeks by blinded assessors. The primary outcome was changed in mobility as measured by the 10-m Timed Walk Test. Secondary outcome measures included changes in manual dexterity (Timed Nut and Bolt Test), balance (Berg Balance Scale), cardiorespiratory endurance (6-Minute Walk Test) and upper and lower extremity muscle strength (isokinetic and isometric muscle strength and 10 Repetition Sit-to-Stand Tests). RESULTS: Patients receiving outpatient multidisciplinary therapy demonstrated significantly enhanced manual dexterity (P < 0.05) and lower extremity muscle strength (P < 0.05) than patients receiving usual care. No significant differences in mobility, balance, cardiorespiratory endurance and upper extremity strength outcomes were observed between groups after the intervention period. There were no adverse events associated with multidisciplinary therapy. CONCLUSION: Our findings suggest that outpatient multidisciplinary therapy has positive effects on manual dexterity and muscle strength, but no meaningful effects on mobility, balance, cardiorespiratory endurance and upper extremity muscle strength in patients with HD. Larger randomized controlled trials are needed to confirm these preliminary findings.

The multidimensional sleep health of individuals with multiple sclerosis and Huntington's disease and healthy controls.

STUDY OBJECTIVES: Sleep issues are common for people with neurodegenerative conditions, yet research has focused on specific aspects of sleep. While important, a more holistic approach to investigating sleep, termed "sleep health," considers sleep's positive and negative aspects. Current studies exploring sleep health have lacked a control group for reference. For the first time, this study investigated the sleep health of people living with multiple sclerosis and Huntington's disease (HD) and compared it with a community sample. METHODS: 111 people, including 43 with multiple sclerosis, 19 with HD, and 49 from a community sample, participated in this study. The data, including actigraphy, Pittsburgh Sleep Quality Index, and Epworth Sleepiness Scale, were collected as part of ongoing research studies. Seven sleep health domains were determined from the collected data, and a composite sleep health score was developed. Analysis of variance and independent t tests were performed to identify population and sex differences. RESULTS: The HD group had higher sleep regularity and lower sleep rhythmicity than the multiple sclerosis and community sample groups. The HD group had significantly less sleep duration than the multiple sclerosis group. No significant differences between the groups were observed in the sleep health composite score. Males had significantly higher sleep regularity within the HD group but significantly lower sleepiness scores in the community sample. CONCLUSIONS: These findings indicate that people with HD may experience greater variance in their wake times, therefore decreasing the consistency of being awake or asleep 24 hours apart. Understanding the mechanisms for this should be explored in people with HD. CITATION: Turner M, Griffiths M, Laws M, Vial S, Bartlett D, Cruickshank T. The multidimensional sleep health of individuals with multiple sclerosis and Huntington's disease and healthy controls. J Clin Sleep Med. 2024;20(6):967-972.

Associations between Sleep Quality and Serum Levels of Neurofilament Light in Individuals with Premanifest Huntington Disease.

Objectives To evaluate the associations between sleep quality and serum levels of neurofilament light (NfL) protein in individuals with premanifest Huntington disease (HD). Materials and Methods We recruited 28 individuals with premanifest HD from a pre-existing database (of the Huntington's Environmental Research Optimisation Scheme, HEROs). The participants filled out the Pittsburgh Sleep Quality Index (PSQI), a subjective measure of sleep quality, and blood was collected via routine venepuncture to measure peripheral NfL levels. Results The PSQI scores (median: 5.0; interquartile range: 4.0-7.5) indicated poor sleep quality. General linear modelling revealed no significant ( p = 0.242) association between PSQI scores and NfL levels. No significant differences were found between individuals with good and poor sleep quality for any demographic variable collected. Discussion Contrary to studies on other neurological conditions, there was no association between sleep quality and NfL levels in individuals with premanifest HD. This was unexpected, given the influence of environmental factors (such as social network size) on neurodegeneration in individuals with premanifest HD.

Sleep health of Australian community tennis players during the COVID-19 lockdown.

Background: Poorer sleep health outcomes have been documented in the general population during the COVID-19 outbreak. However, the impact of the COVID-19 outbreak on sleep health outcomes in specific population groups, including the sporting community, has not been extensively investigated. This study evaluated sleep health outcomes and their relationship with lifestyle behaviours during the initial COVID-19 lockdown period in Australian community tennis players. Methods: This cross-sectional study evaluated sleep health outcomes and lifestyle behaviours using an online survey. The survey was disseminated online between the 24th of April and the 6th of June 2020 and comprised the Sleep Health Index, Sleep Satisfaction Tool and questions regarding weekly hours of tennis play, general physical activity, training location and alcohol consumption. Two-hundred and eighty-five individuals completed the survey. Results: Compared to normative data, respondents displayed positive sleep health values during the initial COVID-19 lockdown period, with median values (IQR) of 85.3 (73.4, 91.7) and 64.8 (54.4, 73.4) for the Sleep Health Index and Sleep Satisfaction Tool, respectively. Sleep health outcomes were not significantly correlated (p > 0.05) with tennis play (Tb = 0.054-0.077), physical activity (Tb = -0.008 to 0.036), training location (Tb = -0.012 to -0.005) or alcohol consumption (Tb = -0.079 to -0.018). Conclusion: Positive sleep health values were observed in Australian community-level tennis players during the initial COVID-19 pandemic. Sleep health values were not associated with lifestyle behaviours. Other unexplored factors may have influenced sleep health outcomes, including personal finances and socialisation, however these factors need to be investigated in future studies.

Hair and salivary cortisol and their relationship with lifestyle, mood and cognitive outcomes in premanifest Huntington's disease.

Salivary cortisol dysrhythmias have been reported in some, but not all studies assessing hypothalamic-pituitary-adrenal (HPA) axis function in Huntington's disease (HD). These differences are presumed to be due to environmental influences on temporal salivary cortisol measurement. Further exploration of HPA-axis function using a more stable and longer-term measure, such as hair cortisol, is needed to confirm earlier findings. This study aimed to evaluate hair and salivary cortisol concentrations and their associations with clinical and lifestyle outcomes in individuals with premanifest HD (n = 26) compared to healthy controls (n = 14). Participants provided saliva and hair samples and data were collected on clinical disease outcomes, mood, cognition, physical activity, cognitive reserve, sleep quality and social network size to investigate relationships between clinical and lifestyle outcomes and cortisol concentrations. Hair and salivary cortisol concentrations did not significantly differ between the premanifest HD and control groups. No significant associations were observed between hair or salivary cortisol concentrations and cognitive, mood or lifestyle outcomes. However, hair cortisol concentrations were significantly associated with disease outcomes in individuals with premanifest HD. Significant associations between hair cortisol concentrations and measures of disease burden and onset may suggest a potential disease marker and should be explored longitudinally in a larger sample of individuals with HD.

Torque variability of the plantar flexors in people with Huntington's disease.

BACKGROUND: Torque steadiness can be impaired in people with Huntington's disease (HD) and worsen with disease advancement. However, existing studies have several methodological oversights. Studies have used absolute torque targets, which do not account for differences in maximal torque capacity between people. Furthermore, despite its known influence on torque steadiness, previous studies in HD have not controlled for visual feedback. This study evaluated torque variability at relative intensities with and without visual feedback between people with prodromal HD and healthy controls. METHODS: Twenty-four people with prodromal HD and twenty-seven age- and sex-matched healthy controls were recruited for this study. Torque variability was evaluated, with and without visual feedback, in the right plantar flexors at 10% and 30% of each participant's maximum voluntary isometric contraction (MVIC). Measures of disease burden included the CAG age product, diagnostic confidence level and Unified Huntington's Disease Rating Scale - Total Motor Score. RESULTS: Significant differences in torque variability were observed, though not in overall MVIC, between people with prodromal HD and healthy controls. Significantly higher torque fluctuations were observed for both groups when visual feedback was removed. No associations were observed between torque variability and disease burden in people with prodromal HD. Torque variability measurements showed higher reliability in healthy controls. CONCLUSIONS: People with prodromal HD exhibited greater torque variability than healthy controls. Torque variability worsened for both groups when visual feedback was removed. These findings support further investigation into the utilisation of torque variability measurements as markers of disease progression in people with prodromal HD.

Clinical Determinants of Dual Tasking in People With Premanifest Huntington Disease.

OBJECTIVE: Dual-tasking deficiencies are common in people with Huntington disease (HD) and contribute to reduced functional independence. To date, few studies have investigated the determinants of dual-tasking deficiencies in this population. The reliability of dual-tasking measures has also been poorly investigated in HD. The purpose of this study was to investigate the influence of clinical determinants on dual-tasking performance and to determine the association of disease burden outcomes on dual-tasking performance in individuals with premanifest HD. METHODS: Thirty-six individuals with premanifest HD and 28 age- and sex-matched healthy controls were recruited for this study. Participants performed 3 single-task (2 cognitive and 1 motor) and 2 dual-task assessments, comprising motor (postural stability) and cognitive (simple or complex mental arithmetic) components. In addition, participants performed a comprehensive clinical battery comprising motor, cognitive, mood, and sleep assessments as well as lifestyle and disease burden measures. RESULTS: Poorer sleep quality was associated with greater cognitive dual-task cost in individuals with premanifest HD. Compared with healthy controls, people with premanifest HD demonstrated an impaired capacity to dual task. Dual-task measures exhibited acceptable test-retest reliability in premanifest HD and healthy control groups. CONCLUSION: These results show that dual-tasking measures are sensitive and reliable in individuals with premanifest HD. Furthermore, poor sleep quality is associated with worse cognitive performance on dual tasks, which should be considered by rehabilitation specialists when examining and therapeutically managing dual-tasking problems in individuals with HD and other neurodegenerative populations in the future. IMPACT: This study adds important knowledge to the sparse literature on dual-tasking deficiencies in people with HD. When examining and therapeutically managing dual-tasking problems in this and other neurodegenerative populations, rehabilitation specialists should consider that people with premanifest HD may have an impaired capacity to dual task. Clinicians also should assess sleep quality, as poorer sleep quality is associated with worse cognitive performance on dual tasks in these individuals. LAY SUMMARY: If you have premanifest HD and poor quality of sleep, you may pay more attention to maintaining postural stability rather than performing arithmetic calculations to reduce the risk of falling.

The relationship between lifestyle and serum neurofilament light protein in Huntington's disease.

OBJECTIVES: Serum neurofilament light protein (NfL) is a promising marker of disease onset and progression in Huntington's disease (HD). This study investigated associations between lifestyle factors and NfL levels in HD mutation carriers compared to healthy age- and sex-matched controls. MATERIALS AND METHODS: Participants included 29 HD mutation carriers and 15 healthy controls. Associations between serum NfL concentrations and lifestyle factors, including cardiorespiratory fitness, social network size and diversity, physical activity, cognitive reserve, smoking status, and alcohol consumption, were examined using a stepwise multivariable linear regression model. RESULTS: Higher NfL levels were associated with lower cognitive reserve, social network size and diversity and cardiorespiratory fitness in HD mutation carriers. Group × lifestyle factor effects were observed between lower serum NfL levels and a greater social network diversity. CONCLUSION: These findings highlight a relationship between lifestyle factors and NfL levels in HD mutations carriers; however, longitudinal studies are required to confirm if these observed relationships persist over time.

Rate of torque development and striatal shape in individuals with prodromal Huntington's disease.

The aim of the present study was to quantify explosive joint torque or the ability to develop joint torque rapidly, typically measured as the rate of torque development, in individuals with prodromal Huntington's disease and healthy controls and its associations with measures of disease burden and striatal pathology. Twenty prodromal Huntington's disease and 19 healthy control individuals volunteered for this study. Plantar flexor isometric rate of torque development values were evaluated using isokinetic dynamometry. Pathological changes in striatal shape were evaluated using magnetic resonance imaging. Disease burden was evaluated using the disease burden score and cytosine-adenine-guanine age product score. No statistical differences in the rate of torque development were observed between individuals with prodromal Huntington's disease and healthy controls. However, significant associations were observed between the rate of torque development values and measures of disease burden (r = -0.42 to -0.69) and striatal pathology (r = 0.71-0.60) in individuals with prodromal Huntington's disease. We found significant associations between lower rate of torque development values and greater striatal shape deflation and disease burden and striatal pathology in individuals with prodromal Huntington's disease. While no significant differences in the rate of torque development were found between prodromal Huntington's disease and healthy controls, the noted associations suggest that differences may emerge as the disease advances, which should be investigated longitudinally in future studies.

Dual tasking impairments are associated with striatal pathology in Huntington's disease.

BACKGROUND: Recent findings suggest that individuals with Huntington's disease (HD) have an impaired capacity to execute cognitive and motor tasks simultaneously, or dual task, which gradually worsens as the disease advances. The onset and neuropathological changes mediating impairments in dual tasking in individuals with HD are unclear. The reliability of dual tasking assessments for individuals with HD is also unclear. OBJECTIVES: To evaluate differences in dual tasking performance between individuals with HD (presymptomatic and prodromal) and matched controls, to investigate associations between striatal volume and dual tasking performance, and to determine the reliability of dual tasking assessments. METHODS: Twenty individuals with HD (10 presymptomatic and 10 prodromal) and 20 healthy controls were recruited for the study. Individuals undertook four single and dual task assessments, comprising motor (postural stability or force steadiness) and cognitive (simple or complex mental arithmetic) components, with single and dual tasks performed three times each. Participants also undertook a magnetic resonance imaging assessment. RESULTS: Compared to healthy controls, individuals with presymptomatic and prodromal HD displayed significant deficits in dual tasking, particularly cognitive task performance when concurrently undertaking motor tasks (P < 0.05). The observed deficits in dual tasking were associated with reduced volume in caudate and putamen structures (P < 0.05),however, not with clinical measures of disease burden. An analysis of the reliability of dual tasking assessments revealed moderate to high test-retest reliability [ICC: 0.61-0.99] for individuals with presymptomatic and prodromal HD and healthy controls. CONCLUSIONS: Individuals with presymptomatic and prodromal HD have significant deficits in dual tasking that are associated with striatal degeneration. Findings also indicate that dual tasking assessments are reliable in individuals presymptomatic and prodromal HD and healthy controls.

The effects of multidisciplinary rehabilitation on neuroimaging, biological, cognitive and motor outcomes in individuals with premanifest Huntington's disease.

BACKGROUND: Huntington's disease (HD) is a chronic, progressive neurodegenerative condition for which there are currently no proven disease-modifying therapies. Lifestyle factors have been shown to impact on the age of disease onset and progression of disease features. We therefore investigated the effects of a nine-month multidisciplinary rehabilitation intervention on neuroimaging, biological and clinical disease outcomes in individuals with premanifest HD. METHODS: 31 individuals with premanifest HD participated in the study. Eighteen participants underwent a nine-month multidisciplinary rehabilitation intervention comprising aerobic and resistance exercise, computerised cognitive training, dual-task training and sleep hygiene and nutritional guidance. The remaining 13 participants were allocated to a standard care control group. Neuroimaging, biological, cognitive, motor and cardiorespiratory fitness data was collected. RESULTS: Participants displayed good adherence (87%) and compliance (85%) to the intervention. Maintenance of the shape of the right putamen was observed in the intervention group when compared to the control group. The intervention group displayed significant improvements in verbal learning and memory, attention, cognitive flexibility and processing speed following the intervention when compared to the control group. Performance on the mini-social cognition and emotional assessment (mini-SEA) was maintained in the intervention group, but decreased in the control group. No changes were observed in serum neurofilament light protein levels, postural stability outcomes or cardiorespiratory fitness. CONCLUSION: This study adds to the accumulating body of literature to suggest that multidisciplinary rehabilitation is of clinical benefit for individuals with HD. Large randomised controlled trials are necessary to determine the extent to which benefits occur across the spectrum of the disease.

Multidisciplinary rehabilitation reduces hypothalamic grey matter volume loss in individuals with preclinical Huntington's disease: A nine-month pilot study.

BACKGROUND: Hypothalamic pathology is a well-documented feature of Huntington's disease (HD) and is believed to contribute to circadian rhythm and habitual sleep disturbances. Currently, no therapies exist to combat hypothalamic changes, nor circadian rhythm and habitual sleep disturbances in HD. OBJECTIVE: To evaluate the effects of multidisciplinary rehabilitation on hypothalamic volume, brain-derived neurotrophic factor (BDNF), circadian rhythm and habitual sleep in individuals with preclinical HD. METHODS: Eighteen individuals with HD (ten premanifest and eight prodromal) undertook a nine-month multidisciplinary rehabilitation intervention (intervention group), which included exercise, cognitive and dual task training and social events, and were compared to a community sample of eleven individuals with premanifest HD receiving no intervention (control group). Hypothalamic volume, serum BDNF, salivary cortisol and melatonin concentrations, subjective sleep quality, daytime somnolence, habitual sleep-wake patterns, stress and anxiety and depression symptomatology were evaluated. RESULTS: Hypothalamus grey matter volume loss was significantly attenuated in the intervention group compared to the control group after controlling for age, gender, Unified Huntington's Disease Rating Scale-Total Motor Score and number of cytosine-adenine-guanine repeats. Serum BDNF levels were maintained in the intervention group, but decreased in the control group following the study period. Both groups exhibited decreases in cortisol and melatonin concentrations. No changes were observed in sleep or mood outcomes. CONCLUSIONS: This exploratory study provides evidence that multidisciplinary rehabilitation can reduce hypothalamic volume loss and maintain peripheral BDNF levels in individuals with preclinical HD but may not impact on circadian rhythm. Larger, randomised controlled trials are required to confirm these findings.

Investigating the relationships between hypothalamic volume and measures of circadian rhythm and habitual sleep in premanifest Huntington's disease.

OBJECTIVE: Pathological changes within the hypothalamus have been proposed to mediate circadian rhythm and habitual sleep disturbances in individuals with Huntington's disease (HD). However, investigations examining the relationships between hypothalamic volume and circadian rhythm and habitual sleep in individuals with HD are sparse. This study aimed to comprehensively evaluate the relationships between hypothalamic pathology and circadian rhythm and habitual sleep disturbances in individuals with premanifest HD. METHODS: Thirty-two individuals with premanifest HD and twenty-nine healthy age- and gender-matched controls participated in this dual-site, cross-sectional study. Magnetic resonance imaging scans were performed to evaluate hypothalamic volume. Circadian rhythm and habitual sleep were assessed via measurement of morning and evening cortisol and melatonin levels, wrist-worn actigraphy, the Consensus Sleep Diary and sleep questionnaires. Information on mood, physical activity levels and body composition were also collected. RESULTS: Compared to healthy controls, individuals with premanifest HD displayed significantly reduced grey matter volume in the hypothalamus, decreased habitual sleep efficiency and increased awakenings; however, no alterations in morning cortisol or evening melatonin release were noted in individuals with premanifest HD. While differences in the associations between hypothalamic volume and cortisol and melatonin output existed in individuals with premanifest HD compared to healthy controls, no consistent associations were observed between hypothalamic volume and circadian rhythm or habitual sleep outcomes. CONCLUSION: While significant differences in associations between hypothalamic volume and cortisol and melatonin existed between individuals with premanifest HD and healthy controls, no differences in circadian markers were observed between the groups. This suggests that circadian regulation is maintained despite hypothalamic pathology, perhaps via neural compensation. Longitudinal studies are required to further understand the relationships between the hypothalamus and circadian rhythm and habitual sleep disturbances in HD as the disease course lengthens.

Computerised Dynamic Posturography in Premanifest and Manifest individuals with Huntington's Disease.

Evidence from small-scale studies indicates that impairments in postural stability are an early and disabling feature of Huntington's disease (HD) and may be a useful clinical endpoint for disease modifying trials. Larger studies are needed to confirm these preliminary findings and the suitability of postural stability outcomes as clinical endpoints. Static and dynamic postural stability were evaluated in 54 premanifest HD, 36 manifest HD and 45 healthy individuals using the Sensory Organization Test (SOT) and Limits of Stability (LOS) test. Manifest HD displayed significantly lower scores on all SOT conditions and on the SOT composite score and had more falls than healthy and premanifest HD (p < 0.05). Premanifest and manifest HD demonstrated significantly lower endpoint excursion (p < 0.001), maximum excursion (p ≤ 0.001), and directional control (p ≤ 0.004) values than healthy individuals on the LOS test. Deficits in LOS were found to manifest on the left side of premanifest HD. Significant but low associations were observed between UHDRS-TMS, disease burden score, diagnostic confidence level, SOT conditions and SOT composite score. We confirm here that individuals with premanifest and manifest HD display significant impairments in static and dynamic postural stability. Dynamic posturography assessments should be considered as clinical endpoints for future disease modifying trials.

Neuroendocrine and neurotrophic signaling in Huntington's disease: Implications for pathogenic mechanisms and treatment strategies.

Huntington's disease (HD) is a fatal neurodegenerative disease caused by an extended polyglutamine tract in the huntingtin protein. Circadian, sleep and hypothalamic-pituitary-adrenal (HPA) axis disturbances are observed in HD as early as 15 years before clinical disease onset. Disturbances in these key processes result in increased cortisol and altered melatonin release which may negatively impact on brain-derived neurotrophic factor (BDNF) expression and contribute to documented neuropathological and clinical disease features. This review describes the normal interactions between neurotrophic factors, the HPA-axis and circadian rhythm, as indicated by levels of BDNF, cortisol and melatonin, and the alterations in these intricately balanced networks in HD. We also discuss the implications of these alterations on the neurobiology of HD and the potential to result in hypothalamic, circadian, and sleep pathologies. Measurable alterations in these pathways provide targets that, if treated early, may reduce degeneration of brain structures. We therefore focus here on the means by which multidisciplinary therapy could be utilised as a non-pharmaceutical approach to restore the balance of these pathways.