Apathy and Impulsivity Co-Occur in Huntington's Disease.

BACKGROUND: Apathy is a debilitating behavioral change in Huntington's disease (HD), but impulsivity in HD has not been well documented, and the co-occurrence of these behaviors in HD has not been investigated. OBJECTIVE: Our objective was to determine whether apathy and impulsivity co-occur in people with HD and their associations with quality of life. METHODS: Carriers of Huntington's gene expansion (premanifest to mild motor manifest disease; n = 42) along with healthy controls (n = 20) completed measures of apathy (Apathy Evaluation Scale and Apathy Motivation Index) and impulsivity (Barratt Impulsiveness Scale-11 and UPPS-P impulsivity scale), along with mood, cognition, clinical, and quality of life measures. Apathy and impulsivity measures were each reduced to a single metric per patient using principal component analysis. Correlations and multiple linear regression models determined associations between apathy and impulsivity and the potential influence of other covariates. RESULTS: Apathy and impulsivity were significantly correlated (r = 0.6, p < 0.001, 95% CI [0.36, 0.76]) in HD, with this association remaining after controlling for depressive symptoms, motor disease severity, and cognitive function. Furthermore, apathy and depressive symptoms were associated with poorer quality of life. CONCLUSIONS: Apathy and impulsivity co-occur in individuals with premanifest to mild manifest HD and have a significant impact on wellbeing. We add to a growing evidence body that apathy and impulsivity may be intrinsically linked.

Protocol for a randomised controlled unblinded feasibility trial of HD-DRUM: a rhythmic movement training application for cognitive and motor symptoms in people with Huntington's disease.

INTRODUCTION: Huntington's disease (HD) is an inherited neurodegenerative disease causing progressive cognitive and motor decline, largely due to basal ganglia (BG) atrophy. Rhythmic training offers promise as therapy to counteract BG-regulated deficits. We have developed HD-DRUM, a tablet-based app to enhance movement synchronisation skills and improve cognitive and motor abilities in people with HD. This paper outlines a randomised controlled unblinded trial protocol to determine the feasibility of a larger effectiveness trial for HD-DRUM. Additionally, the trial investigates cognitive and motor function measures, along with brain microstructure, aiming to advance our understanding of the neural mechanisms underlying training effects. METHODS, DESIGN AND ANALYSIS: 50 individuals with HD, confirmed by genetic testing, and a Total Functional Capacity (TFC) score of 9-13, will be recruited into a two-arm randomised controlled feasibility trial. Consenting individuals with HD will be randomised to the intervention group, which entails 8 weeks of at-home usage of HD-DRUM or a usual-activity control group. All participants will undergo cognitive and motor assessments, alongside ultra-strong gradient (300 mT/m) brain microstructural MRI before and after the 8-week period. The feasibility assessment will encompass recruitment, retention, adherence and acceptability of HD-DRUM following prespecified criteria. The study will also evaluate variations in cognitive and motor performance and brain microstructure changes resulting from the intervention to determine effect size estimates for future sample size calculations. ETHICS AND DISSEMINATION: The study has received favourable ethical opinion from the Wales Research Ethics Committee 2 (REC reference: 22/WA/0147) and is sponsored by Cardiff University (SPON1895-22) (Research Integrity, Governance and Ethics Team, Research & Innovation Services, Cardiff University, second Floor, Lakeside Building, University Hospital of Wales, Cardiff, CF14 4XW). Findings will be disseminated to researchers and clinicians in peer-reviewed publications and conference presentations, and to participants, carers and the general public via newsletters and public engagement activities. Data will be shared with the research community via the Enroll-HD platform. TRIAL REGISTRATION NUMBER: ISRCTN11906973.

Profiling deutetrabenazine extended-release tablets for tardive dyskinesia and chorea associated with Huntington's disease.

INTRODUCTION: Tardive dyskinesia (TD) and Huntington's disease (HD)-associated chorea are persistent and disabling hyperkinetic disorders that can be treated with vesicular monoamine transporter type 2 (VMAT2) inhibitors, including the recently approved once-daily (QD) formulation of deutetrabenazine (DTBZ ER). While its efficacy and safety profile have not been directly investigated, currently available data confirms bioequivalence and similar bioavailability to the twice-daily formulation (DTBZ BID). AREAS COVERED: The authors briefly review the pivotal trials establishing efficacy of DTBZ for TD and HD-associated chorea, the pharmacokinetic data for bioequivalence between QD and BID dosing of DTBZ, as well as dose proportionality evidence, titration recommendations, and safety profile for DTBZ ER. EXPERT OPINION: Long-term data show that DTBZ is efficacious and well tolerated for the treatment of TD and HD-associated chorea. DTBZ ER likely demonstrates therapeutic equivalence with no new safety signals. Due to the lack of comparative clinical trial data, no evidence-based recommendation about choice of VMAT2 inhibitor or switching between VMAT2 inhibitors can be made about best practice. Ultimately, QD dosing may offer the chance of improved medication adherence, an important consideration in patients with complex treatment regimens and/or patients with cognitive decline.

A Case Series of Delusional Infestation in Huntington's Disease.

 Huntington's disease (HD) is an autosomal dominant disorder that affects the basal ganglia, caused by CAG repeats in the huntingtin gene. Delusional infestation (DI) is a rare psychotic manifestation of the disease. This report presents two cases of HD patients with DI, both middle-aged females. The first patient achieved remission of DI with olanzapine, later cross-tapered to risperidone, but had spontaneous relapses. The second experienced gradual resolution of DI with risperidone in the setting of iron repletion and amantadine discontinuation, although her other psychotic symptoms remained. These cases shed light on an uncommon condition and may help guide understanding of the most effective treatment for it.

Deciphering Cognitive Impairments in Huntington's Disease: A Comparative Study of Stroop Test Variations.

Background: Huntington's disease (HD) is a neurodegenerative disorder marked by cognitive impairment, movement abnormalities, and behavioral disturbances. The Stroop Color Word Test (SCWT) is a widely used tool to detect cognitive decline in HD. Variations in SCWT formats-horizontal (original) and vertical (Golden)-may influence performance, given HD's impact on cognitive and oculomotor abilities. Objective: This study aimed to compare the effectiveness of the horizontal and Golden vertical SCWT formats in detecting cognitive decline in HD, and to determine how performance may have been influenced by eye movement abnormalities. Methods: Forty-five participants with genetically confirmed HD were recruited. Both SCWT formats were administered to each participant in a counterbalanced fashion. Individual performance of all three sections on each format was standardized across 2 different norms. Raw and normed scores on each variation were compared and correlated with eye movement ratings on the Unified Huntington's Disease Rating Scale. Results: The Golden variation elicited significantly slower responses, particularly in the Word Reading section, across two benchmark norms. Statistical analysis revealed significant performance differences between the two formats. Correlations between vertical eye movement ratings and performance on the Golden SCWT were highly significant, highlighting the impact of oculomotor coordination on cognitive assessments in HD. Conclusion: This study underscores the importance of considering test format in cognitive assessments for HD. The Golden vertical SCWT demonstrates increased sensitivity in detecting deficits in HD, possibly linked to vertical saccade abnormalities. These insights are important for improving the sensitivity of cognitive assessments and monitoring disease progression in HD research and clinical practice.

Oropharyngeal Dysphagia Phenotypes Across Huntington's Disease Stages: Endoscopic Findings and Tongue Pressure Analysis.

Background: Oropharyngeal dysphagia (OD) is a common symptom in Huntington's disease (HD) and is associated with severe health and psychosocial consequences. Different OD phenotypes are defined on the basis of characteristic patterns at fiberoptic endoscopic evaluation of swallowing (FEES), and they may vary during disease progression. Objective: To describe OD phenotypes in different HD stages and to analyze their association with neurological data and tongue pressure measurements. Methods: Twenty-four patients with HD at different stages of disease progression underwent a FEES. Data on penetration/aspiration, pharyngeal residue, and OD phenotypes were gained. Neurological examination was performed with the Unified Huntington's Disease Rating Scale (UHDRS). Patient Maximum tongue pressure (MTP) and tongue endurance were measured. Results: We confirmed that the occurrence of penetration/aspiration increased with disease duration and pharyngeal residue increased from 16.7% to 100%, respectively. The most common OD phenotypes were oropharyngeal dyspraxia (91.7%), posterior oral incontinence (87.5%), and delayed pharyngeal phase (87.5%). These types of dysfunctions are already detectable in >80% of patients in the early disease stages. In more advanced stages, we also observed propulsion deficit (66.7%), resistive issue (54.2%), and protective deficit (37.5%). Propulsion deficit was associated with higher disease stage, greater motor dysfunction (UHDRS-I), and lower MTP and tongue endurance (p < 0.05). Conclusions: OD in HD results from a combination of different swallowing phenotypes. Early assessment of swallowing and periodical follow-ups are necessary to monitor OD severity and phenotypes and to revise diet recommendations.

Intensification of Diurnal Abnormal Movements During Sleep in Huntington's Disease.

Huntington's disease (HD) is a rare neurodegenerative disorder with a distinct phenotype, including involuntary movements, cognitive decline, and behavioral disturbances. Sleep disorder include insomnia, increased sleep onset latency, decrease in total sleep time with frequent nocturnal awakenings and excessive daytime sleepiness. Increased sleep motor activities and abnormal nocturnal agitation have been increasingly recognized as an important component affecting negatively the sleep quality. Here, we report a case of an intensification of diurnal choreic movement during the night, notably during REM-sleep in a patient with manifest HD. This case highlights the diversity of nocturnal sleep motor disorders encountered in HD.

Influence of anosognosia on patient-reported outcomes for psychiatric symptoms and quality of life in Huntington's disease.

INTRODUCTION: Anosognosia, defined as reduced awareness of one's deficit or symptom, is common in Huntington's disease (HD) and detectable at each disease stage. The impact of anosognosia on self-reporting in HD populations is critical to understand given growing use of patient-reported outcomes in HD clinical care and research. We aimed to determine the influence of anosognosia on patient-reported outcome measures assessing psychiatric symptoms and quality of life in HD. METHODS: We enrolled HD patients to complete a battery of patient-reported and rater-administered measures, including the Anosognosia Scale, at baseline and 6 months later. Patient-reported outcome measures included NeuroQoL short forms for depression, anxiety, satisfaction with social roles and activities, and positive affect and well-being and Patient-Reported Outcomes Measurement Information System short forms for emotional distress-anger and sleep-related impairment. Anosognosia Scale-Difference Score indexed patient-clinician agreement on patient motor, cognitive, and behavioral abilities. We conducted multivariable linear regression analyses to quantify the association of baseline anosognosia with 6-month patient-reported outcomes. RESULTS: Of 79 patients with complete Anosognosia Scale data at baseline, 25 (31.6 %) met the scale's criterion for anosognosia. In the regression analyses, baseline Difference Score improved prediction of 6-month patient-reported outcomes for depression, anxiety, anger, and positive affect and well-being (χ2(1) value range for likelihood ratio tests contrasting models with and without Difference Score: 13.1-20.9, p-values <0.001). Patients with more anosognosia self-reported less severe psychiatric symptoms and more positive affect and well-being. CONCLUSION: Study results suggest that anosognosia influences patient-reported outcomes for psychiatric symptoms and quality of life in HD populations.

The utility of the irritability scale in Huntington's disease patients with evidence of irritability or aggression.

INTRODUCTION: Irritability, a common neuropsychiatric symptom in Huntington's disease (HD), lacks a standardized measurement. The Irritability Scale (IS), tailored for HD, has patient and informant versions, but variable interrater agreement has been reported frequently in previous studies. To enhance the clinical utility of the IS, this study aimed to identify the most reliable components estimating the underlying construct and develop a shortened version for time-limited contexts. METHODS: Participant and informant/observer concordance and the relationship of individual items to the complete IS scale were assessed. The short-form (SF) items were selected based on interrater agreement, exploratory factor analysis (EFA), and Item Response Theory (IRT) analysis results. Pair-wise correlation and covariance models were used to examine how SF predicted total IS score in 106 participants from the STAIR (Safety, Tolerability, and Activity of SRX246 in Irritable Subjects with Huntington's Disease) trial. Item Response Theory (IRT) analysis was used to evaluate the range and function of the selected items. RESULTS: IS interrater agreement was statistically significant (r = 0.33, p = .001). In combination with EFA factors and IRT analyses, five items were identified that showed good reliability and performance in differentiating levels of irritability. CONCLUSION: The proposed 5-item SF IS provided a reliable measure of the full scale and may be less burdensome for use in a clinical setting.

Assessment of Perivascular Space Morphometry Across the White Matter in Huntington's Disease Using MRI.

Background: Perivascular spaces (PVS) are fluid-filled cavities surrounding small cerebral blood vessels. There are limited reports of enlarged PVS across the grey matter in manifest Huntington's disease (HD). Little is known about how PVS morphometry in the white matter may contribute to HD. Enlarged PVS have the potential to both contribute to HD pathology and affect the distribution and success of intraparenchymal and intrathecally administered huntingtin-lowering therapies. Objective: To investigate PVS morphometry in the global white matter across the spectrum of HD. Relationships between PVS morphometry and disease burden and severity measures were examined. Methods: White matter PVS were segmented on 3T T2 W MRI brain scans of 33 healthy controls, 30 premanifest HD (pre-HD), and 32 early manifest HD (early-HD) participants from the Vancouver site of the TRACK-HD study. PVS count and total PVS volume were measured. Results: PVS total count slightly increased in pre-HD (p = 0.004), and early-HD groups (p = 0.005), compared to healthy controls. PVS volume, as a percentage of white matter volume, increased subtly in pre-HD compared to healthy controls (p = 0.044), but not in early-HD. No associations between PVS measures and HD disease burden or severity were found. Conclusions: This study reveals relatively preserved PVS morphometry across the global white matter of pre-HD and early-HD. Subtle morphometric abnormalities are implied but require confirmation in a larger cohort. However, in conjunction with previous publications, further investigation of PVS in HD and its potential impact on future treatments, with a focus on subcortical grey matter, is warranted.

Assessment of Fitbit Charge 4 for sleep stage and heart rate monitoring against polysomnography and during home monitoring in Huntington's disease.

STUDY OBJECTIVES: Wearable devices that monitor sleep stages and heart rate offer the potential for longitudinal sleep monitoring in patients with neurodegenerative diseases. Sleep quality reduces with disease progression in Huntington's disease (HD). However, the involuntary movements characteristic of HD may affect the accuracy of wrist-worn devices. This study compares sleep stage and heart rate data from the Fitbit Charge 4 (FB) against polysomnography (PSG) in participants with HD. METHODS: Ten participants with manifest HD wore an FB during overnight hospital-based PSG, and 9 of these participants continued to wear the FB for 7 nights at home. Sleep stages (30-second epochs) and minute-by-minute heart rate were extracted and compared against PSG data. RESULTS: FB-estimated total sleep and wake times and sleep stage times were in good agreement with PSG, with intraclass correlations of 0.79-0.96. However, poor agreement was observed for wake after sleep onset and the number of awakenings. FB detected waking with 68.6 ± 15.5% sensitivity and 93.7 ± 2.5% specificity, rapid eye movement sleep with high sensitivity and specificity (78.7 ± 31.9%, 95.6 ± 2.3%), and deep sleep with lower sensitivity but high specificity (56.4 ± 28.8%, 95.0 ± 4.8%). FB heart rate was strongly correlated with PSG, and the mean absolute error between FB and PSG heart rate data was 1.16 ± 0.42 beats/min. At home, longer sleep and shorter wake times were observed compared with hospital data, whereas percentage sleep stage times were consistent with hospital data. CONCLUSIONS: Results suggest the potential for long-term monitoring of sleep patterns using wrist-worn wearable devices as part of symptom management in HD. CITATION: Doheny EP, Renerts K, Braun A, et al. Assessment of Fitbit Charge 4 for sleep stage and heart rate monitoring against polysomnography and during home monitoring in Huntington's disease. J Clin Sleep Med. 2024;20(7):1163-1171.

Cardiac autonomic involvement in Huntington's disease.

INTRODUCTION: Huntington's disease (HD) is known as a neurodegenerative disease with movement disorder and cognitive impairment; autonomic involvement is also becoming common in some recent studies. The aim of this study is to demonstrate the presence of cardiac autonomic involvement in HD patients. METHOD: Time and frequency domain parameters obtained from the 24-h Holter ECG(hECG) were compared between 20 HD patients and 20 healthy control subjects. RESULTS: Fourteen HD patients had tachycardia, bradycardia, and extra beats. Interval between two heartbeats, normal-to-normal (NN), standard deviation of all normal-to-normal (SDNN), square root of the mean of the sum of the squares of the differences between consecutive N-N intervals in ms (rMSSD), and the ratio of the number of consecutive pairs of N-N intervals that differ by more than 50 ms to the total number of N-N intervals (pNN50) were all significantly higher in the patient group than in the control group during 24-h hECG monitoring. However, hECG monitoring showed that the patient group had significantly higher values of the frequency-domain metrics high frequency (HF) than the control group did (P = 0.003). Very low frequency (VLF) was lower in the patient group (P = 0.009). There was no difference in low frequency (LF) in both groups. In comparison to the control group, LF/HF was much reduced in the patient group (P = 0.001). CONCLUSION: Cardiac disfunction increases, and autonomic functions change in HD, but more comprehensive studies are needed to distinguish sympathetic and parasympathetic involvement.

Language-Independent Acoustic Biomarkers for Quantifying Speech Impairment in Huntington's Disease.

PURPOSE: Changes in voice and speech are characteristic symptoms of Huntington's disease (HD). Objective methods for quantifying speech impairment that can be used across languages could facilitate assessment of disease progression and intervention strategies. The aim of this study was to analyze acoustic features to identify language-independent features that could be used to quantify speech dysfunction in English-, Spanish-, and Polish-speaking participants with HD. METHOD: Ninety participants with HD and 83 control participants performed sustained vowel, syllable repetition, and reading passage tasks recorded with previously validated methods using mobile devices. Language-independent features that differed between HD and controls were identified. Principal component analysis (PCA) and unsupervised clustering were applied to the language-independent features of the HD data set to identify subgroups within the HD data. RESULTS: Forty-six language-independent acoustic features that were significantly different between control participants and participants with HD were identified. Following dimensionality reduction using PCA, four speech clusters were identified in the HD data set. Unified Huntington's Disease Rating Scale (UHDRS) total motor score, total functional capacity, and composite UHDRS were significantly different for pairwise comparisons of subgroups. The percentage of HD participants with higher dysarthria score and disease stage also increased across clusters. CONCLUSION: The results support the application of acoustic features to objectively quantify speech impairment and disease severity in HD in multilanguage studies. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.25447171.

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.

Prevalence and burden of pain across the entire spectrum of Huntington's disease.

BACKGROUND: Pain is an important symptom in Huntington's disease (HD), however, not systematically studied and understood. The objective of the current study is to assess the prevalence of pain, pain interference in daily activities, painful conditions, analgesic use and the severity of the pain burden across different disease stages and 'Age at symptom Onset' groups. Additionally, the association between pain and disease burden was investigated. METHODS: A cross-sectional analysis was conducted within two large data sets, which included different types of pain scales. Multivariable logistic regression analyses and analyses of variance were performed to compare the pain levels with those in the general population. The analyses were adjusted for sex and age. Locally Estimated Scatterplot Smoothing was used to test the association between pain and the HD pathology score: a measure of disease burden. RESULTS: The mean prevalence of pain in the HD population was 40% and for pain interference around 35% in both data sets. Patients in the early, middle and late stage of HD experience more pain burden compared with what is reported in patients with chronic pain (p<0.01). A positive and significant association was demonstrated between pain and disease burden. Patients in late stage HD with pain use significantly less analgesics compared with the general population (5% vs 13%, respectively (p<0.01)). CONCLUSIONS: Pain is a prevalent and important symptom in HD. Severe pain burden in the HD population is present and positively associated with disease burden. Risk for undertreatment with analgesics is nevertheless present. Awareness of pain in HD needs to be increased, both clinically and scientifically.

Mild cognitive impairment in Huntington's disease: challenges and outlooks.

Although Huntington's disease (HD) has classically been viewed as an autosomal-dominant inherited neurodegenerative motor disorder, cognitive and/or behavioral changes are predominant and often an early manifestation of disease. About 40% of individuals in the presymptomatic period of HD meet the criteria for mild cognitive impairment, later progressing to dementia. The heterogenous spectrum of cognitive decline is characterized by deficits across multiple domains, particularly executive dysfunctions, but the underlying pathogenic mechanisms are still poorly understood. Investigating the pathophysiology of cognitive changes may give insight into important and early neurodegenerative events. Multimodal imaging revealed circuit-wide gray and white matter degenerative processes in several key brain regions, affecting prefronto-striatal/cortico-basal ganglia circuits and many other functional brain networks. Studies in transgenic animal models indicated early synaptic dysfunction, deficient neurotrophic transport and other molecular changes contributing to neuronal death. Synaptopathy within the cerebral cortex, striatum and hippocampus may be particularly important in mediating cognitive and neuropsychiatric manifestations of HD, although many other neuronal systems are involved. The interaction of mutant huntingtin protein (mHTT) with tau and its implication for cognitive impairment in HD is a matter of discussion. Further neuroimaging and neuropathological studies are warranted to better elucidate early pathophysiological mechanisms and to develop validated biomarkers to detect patients' cognitive status during the early stages of the condition significantly to implement effective preventing or management strategies.

Glucocorticoid receptor antagonist CORT113176 attenuates motor and neuropathological symptoms of Huntington's disease in R6/2 mice.

Huntington's Disease (HD) is a progressive neurodegenerative disease caused by a mutation in the huntingtin gene. The mutation leads to a toxic gain of function of the mutant huntingtin (mHtt) protein resulting in cellular malfunction, aberrant huntingtin aggregation and eventually neuronal cell death. Patients with HD show impaired motor functions and cognitive decline. Elevated levels of glucocorticoids have been found in HD patients and in HD mouse models, and there is a positive correlation between increased glucocorticoid levels and the progression of HD. Therefore, antagonism of the glucocorticoid receptor (GR) may be an interesting strategy for the treatment of HD. In this study, we evaluated the efficacy of the selective GR antagonist CORT113176 in the commonly used R6/2 mouse model. In male mice, CORT113176 treatment significantly delayed the loss of grip strength, the development of hindlimb clasping, gait abnormalities, and the occurrence of epileptic seizures. CORT113176 treatment delayed loss of DARPP-32 immunoreactivity in the dorsolateral striatum. It also restored HD-related parameters including astrocyte markers in both the dorsolateral striatum and the hippocampus, and microglia markers in the hippocampus. This suggests that CORT113176 has both cell-type and brain region-specific effects. CORT113176 delayed the formation of mHtt aggregates in the striatum and the hippocampus. In female mice, we did not observe major effects of CORT113176 treatment on HD-related symptoms, with the exception of the anti-epileptic effects. We conclude that CORT113176 effectively delays several key symptoms related to the HD phenotype in male R6/2 mice and believe that GR antagonism may be a possible treatment option.