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.

Detection and prognostic role of heterogeneous populations of melanoma circulating tumour cells.

BACKGROUND: Circulating tumour cells (CTCs) can be assessed through a minimally invasive blood sample with potential utility as a predictive, prognostic and pharmacodynamic biomarker. The large heterogeneity of melanoma CTCs has hindered their detection and clinical application. METHODS: Here we compared two microfluidic devices for the recovery of circulating melanoma cells. The presence of CTCs in 43 blood samples from patients with metastatic melanoma was evaluated using a combination of immunocytochemistry and transcript analyses of five genes by RT-PCR and 19 genes by droplet digital PCR (ddPCR), whereby a CTC score was calculated. Circulating tumour DNA (ctDNA) from the same patient blood sample, was assessed by ddPCR targeting tumour-specific mutations. RESULTS: Our analysis revealed an extraordinary heterogeneity amongst melanoma CTCs, with multiple non-overlapping subpopulations. CTC detection using our multimarker approach was associated with shorter overall and progression-free survival. Finally, we found that CTC scores correlated with plasma ctDNA concentrations and had similar pharmacodynamic changes upon treatment initiation. CONCLUSIONS: Despite the high phenotypic and molecular heterogeneity of melanoma CTCs, multimarker derived CTC scores could serve as viable tools for prognostication and treatment response monitoring in patients with metastatic melanoma.

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.

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.

SIRT1 activation mediates heat-induced survival of UVB damaged Keratinocytes.

BACKGROUND: Exposure to heat stress after UVB irradiation induces a reduction of apoptosis, resulting in survival of DNA damaged human keratinocytes. This heat-mediated evasion of apoptosis appears to be mediated by activation of SIRT1 and inactivation of p53 signalling. In this study, we assessed the role of SIRT1 in the inactivation of p53 signalling and impairment of DNA damage response in UVB plus heat exposed keratinocytes. RESULTS: Activation of SIRT1 after multiple UVB plus heat exposures resulted in increased p53 deacetylation at K382, which is known to affect its binding to specific target genes. Accordingly, we noted decreased apoptosis and down regulation of the p53 targeted pro-apoptotic gene BAX and the DNA repair genes ERCC1 and XPC after UVB plus heat treatments. In addition, UVB plus heat induced increased expression of the cell survival gene Survivin and the proliferation marker Ki67. Notably, keratinocytes exposed to UVB plus heat in the presence of the SIRT1 inhibitor, Ex-527, showed a similar phenotype to those exposed to UV alone; i.e. an increase in p53 acetylation, increased apoptosis and low levels of Survivin. CONCLUSION: This study demonstrate that heat-induced SIRT1 activation mediates survival of DNA damaged keratinocytes through deacetylation of p53 after exposure to UVB plus heat.

Heat-mediated reduction of apoptosis in UVB-damaged keratinocytes in vitro and in human skin ex vivo.

BACKGROUND: UV radiation induces significant DNA damage in keratinocytes and is a known risk factor for skin carcinogenesis. However, it has been reported previously that repeated and simultaneous exposure to UV and heat stress increases the rate of cutaneous tumour formation in mice. Since constant exposure to high temperatures and UV are often experienced in the environment, the effects of exposure to UV and heat needs to be clearly addressed in human epidermal cells. METHODS: In this study, we determined the effects of repeated UVB exposure 1 kJ/m(2) followed by heat (39 °C) to human keratinocytes. Normal human ex vivo skin models and primary keratinocytes (NHEK) were exposed once a day to UVB and/or heat stress for four consecutive days. Cells were then assessed for changes in proliferation, apoptosis and gene expression at 2 days post-exposure, to determine the cumulative and persistent effects of UV and/or heat in skin keratinocytes. RESULTS: Using ex vivo skin models and primary keratinocytes in vitro, we showed that UVB plus heat treated keratinocytes exhibit persistent DNA damage, as observed with UVB alone. However, we found that apoptosis was significantly reduced in UVB plus heat treated samples. Immunohistochemical and whole genome transcription analysis showed that multiple UVB plus heat exposures induced inactivation of the p53-mediated stress response. Furthermore, we demonstrated that repeated exposure to UV plus heat induced SIRT1 expression and a decrease in acetylated p53 in keratinocytes, which is consistent with the significant downregulation of p53-regulated pro-apoptotic and DNA damage repair genes in these cells. CONCLUSION: Our results suggest that UVB-induced p53-mediated cell cycle arrest and apoptosis are reduced in the presence of heat stress, leading to increased survival of DNA damaged cells. Thus, exposure to UVB and heat stress may act synergistically to allow survival of damaged cells, which could have implications for initiation skin carcinogenesis.

Discriminant validity of the Hospital Anxiety and Depression Scale, Beck Depression Inventory (II) and Beck Anxiety Inventory to confirmed clinical diagnosis of depression and anxiety in patients with chronic obstructive pulmonary disease.

The objective of this study was to investigate the discriminant validity of commonly used depression and anxiety screening tools in order to determine the most suitable tool for patients with chronic obstructive pulmonary disease (COPD). COPD patients (n = 56) completed the Hospital Anxiety and Depression Scale (HADS), Beck Depression Inventory (BDI-II) and Beck Anxiety Inventory (BAI). These scores were compared to confirmed clinical diagnoses of depression and anxiety using the Mini Neuropsychiatric Interview. HADS depression subscale (HADS-D) sensitivity/specificity was 78/81%; BDI-II 89/77%; HADS anxiety subscale (HADS-A) 71/81%; and BAI 89/62%. HADS-D sensitivity/specificity was improved (100/83%) with the removal of Q4 'I feel as if I am slowed down' and adjusted cut-off (≥5). Removal of BDI-II Q21 'Loss of interest in sex' with adjusted cut-off ≥12 resulted in similar improvement (100/79%). No problematic items were identified for HADS-A or BAI. Previously reported low sensitivity/specificity of the HADS for COPD patients was not replicated. Furthermore, simple modifications of the HADS-D markedly improved sensitivity/specificity for depression.BDI-II, HADS-A and BAI produced acceptable sensitivity/specificity unmodified. Pending further research for COPD patients we recommend continued use of the HADS-A with standard cut-off (≥8) and removal of Q4 of the HADS-D with lower cut-off ≥5.

Respiratory muscle training on pulmonary and swallowing function in patients with Huntington's disease: a pilot randomised controlled trial.

OBJECTIVE: To examine the effects of 4-month of respiratory muscle training on pulmonary and swallowing function, exercise capacity and dyspnoea in manifest patients with Huntington's disease. DESIGN: A pilot randomised controlled trial. SETTING: Home based training program. PARTICIPANTS: Eighteen manifest Huntington's disease patients with a positive genetic test and clinically verified disease expression, were randomly assigned to control group (n=9) and training group (n=9). INTERVENTION: Both groups received home-based inspiratory (5 sets of 5 repetitions) and expiratory (5 sets of 5 repetitions) muscle training 6 times a week for 4 months. The control group used a fixed resistance of 9 centimeters of water, and the training group used a progressively increased resistance from 30% to 75% of each patient's maximum respiratory pressure. MAIN MEASURES: Spirometric indices, maximum inspiratory pressure, maximum expiratory pressure, six minutes walk test, dyspnoea, water-swallowing test and swallow quality of life questionnaire were assessed before, at 2 and 4 months after training. RESULTS: The magnitude of increases in maximum inspiratory (d=2.9) and expiratory pressures (d=1.5), forced vital capacity (d=0.8), forced expiratory volume in 1 second (d=0.9) and peak expiratory flow (d=0.8) was substantially greater for the training group in comparison to the control group. Changes in swallowing function, dyspnoea and exercise capacity were small (d ≤ 0.5) for both groups without substantial differences between groups. CONCLUSIONS: A home-based respiratory muscle training program appeared to be beneficial to improve pulmonary function in manifest Huntington's disease patients but provided small effects on swallowing function, dyspnoea and exercise capacity.

Pulmonary function in patients with Huntington's disease.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive motor, cognitive and psychiatric disturbances. Chest muscle rigidity, respiratory muscle weakness, difficulty in clearing airway secretions and swallowing abnormalities have been described in patients with neurodegenerative disorders including HD. However limited information is available regarding respiratory function in HD patients. The purpose of this study was to investigate pulmonary function of patients with HD in comparison to healthy volunteers, and its association with motor severity. METHODS: Pulmonary function measures were taken from 18 (11 male, 7 female) manifest HD patients (53 ± 10 years), and 18 (10 male, 8 female) healthy volunteers (52 ± 11 years) with similar anthropometric and life-style characteristics to the recruited HD patients. Motor severity was quantified by the Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS). Maximum respiratory pressure was measured on 3 separate days with a week interval to assess test-retest reliability. RESULTS: The test-retest reliability of maximum inspiratory and expiratory pressure measurements was acceptable for both HD patient and control groups (ICC ≥0.92), but the values over 3 days were more variable in the HD group (CV < 11.1%) than in the control group (CV < 7.6%). The HD group showed lower respiratory pressure, forced vital capacity, peak expiratory flow and maximum voluntary ventilation than the control group (p < 0.05). Forced vital capacity, maximum voluntary ventilation and maximum respiratory pressures were negatively (r = -0.57; -0.71) correlated with the UHDRS-TMS (p < 0.05). CONCLUSION: Pulmonary function is decreased in manifest HD patients, and the magnitude of the decrease is associated with motor severity.

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.

Differential PAX3 functions in normal skin melanocytes and melanoma cells.

The PAX3 transcription factor is the key regulator of melanocyte development during embryogenesis and is also frequently found in melanoma cells. While PAX3 is known to regulate melanocyte differentiation, survival, proliferation and migration during development, it is not clear if its function is maintained in adult melanocytes and melanoma cells. To clarify this we have assessed which genes are targeted by PAX3 in these cells. We show here that similar to its roles in development, PAX3 regulates complex differentiation networks in both melanoma cells and melanocytes, in order to maintain cells as "stem" cell-like (via NES and SOX9). We show also that mediators of migration (MCAM and CSPG4) are common to both cell types but more so in melanoma cells. By contrast, PAX3-mediated regulation of melanoma cell proliferation (through TPD52) and survival (via BCL2L1 and PTEN) differs from that in melanocytes. These results suggest that by controlling cell proliferation, survival and migration as well as maintaining a less differentiated "stem" cell like phenotype, PAX3 may contribute to melanoma development and progression.

Inhaled methoxyflurane and intranasal fentanyl for prehospital management of visceral pain in an Australian ambulance service.

OBJECTIVE: This study analysed the analgesic effect and changes in vital signs associated with administration of inhaled Methoxyflurane (MTX) and/or intranasal Fentanyl (INF) for prehospital management of visceral pain. METHOD: A retrospective, observational study reviewing 1024 randomly selected records of patients with presumed visceral pain administered MTX (465), INF (397) or both (162) by the Western Australian Ambulance Service between January 2004 and February 2006. Clinical variables assessed included systolic blood pressure, pulse rate, respiration rate and Glasgow Coma Scale score. Pain was assessed utilising Visual/Verbal Analogue Scale pain scores. RESULTS: Overall effects on vital signs appeared favourable 5 min after use and at hospital arrival with either agent alone or in combination. As sole agents, MTX produced the greatest initial pain scores reduction (2.0 (1.7 to 2.2) vs 1.6 (1.4 to 1.8)) (mean (95% CI), and INF provided greater pain reduction by hospital arrival (3.2 (2.9 to 3.5) vs 2.5 (2.1 to 2.9)). While both agents were effective, INF provided a greater pain score reduction for cardiac (3.0 (2.6 to 3.4) vs 2.3 (1.8 to 2.8)), female (3.4 (2.9 to 4.0) v 2.5 (2.0 to 3.0)) and age 75+ patients (3.2 (2.5 to 3.8) vs 1.8 (1.0 to 2.5)). Combined use of agents was not advantageous. CONCLUSIONS: MTX and INF are effective agents for providing visceral pain analgesia in the prehospital setting. While MTX provided a more rapid onset of pain relief, INF provided superior analgesia after subsequent doses and in female, cardiac and older patients.

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.

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.

Circulating Tumour DNA in Advanced Melanoma Patients Ceasing PD1 Inhibition in the Absence of Disease Progression.

Immunotherapy is an important and established treatment option for patients with advanced melanoma. Initial anti-PD1 trials arbitrarily defined a two-year treatment duration, but a shorter treatment duration may be appropriate. In this study, we retrospectively assessed 70 patients who stopped anti-PD1 therapy in the absence of progressive disease (PD) to determine clinical outcomes. In our cohort, the median time on treatment was 11.8 months. Complete response was attained at time of anti-PD1 discontinuation in 61 (87%). After a median follow up of 34.2 months (range: 2-70.8) post discontinuation, 81% remained disease free. Using ddPCR, we determine the utility of circulating tumour DNA (ctDNA) to predict progressive disease after cessation (n = 38). There was a significant association between presence of ctDNA at cessation and disease progression (p = 0.012, Fisher's exact test) and this conferred a negative and positive predictive value of 0.82 (95% CI: 0.645-0.930) and 0.80 (95% CI 0.284-0.995), respectively. Additionally, dichotomised treatment-free survival in patients with or without ctDNA at cessation was significantly longer in the latter group (p < 0.001, HR: 0.008, 95% CI: 0.001-0.079). Overall, our study confirms that durable disease control can be achieved with cessation of therapy in the absence of disease progression and undetectable ctDNA at cessation was associated with longer treatment-free survival.

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.

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.

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.

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.