Journal of Huntington's Disease - Volume 13, issue 3

Authors: Dorsey, E. Ray | Anderson, Karen E.

Article Type: Obituary

DOI: 10.3233/JHD-249002

Citation: Journal of Huntington's Disease, vol. 13, no. 3, pp. 265-266, 2024

Authors: Alshehabi, Yasmeen | Martin, Dale D.O.

Article Type: Review Article

Abstract:  Huntington’s disease (HD) is a devastating neurodegenerative disorder characterized by impaired motor function and cognitive decline, ultimately leading to death. HD is caused by a polyglutamine expansion in the N-terminal region of the huntingtin (HTT) protein, which is linked to decreased HTT turnover, increased HTT proteolysis, increased HTT aggregation, and subsequent neuronal death. In this review, we explore the mechanism of the protective effect of blocking HTT proteolysis at D586, which has been shown to rescue the HD phenotype in HD mouse models. Until recently, the mechanism remained unclear. Herein, we discuss how blocking HTT proteolysis at D586 promotes HTT …turnover by correcting autophagy, and making HTT a better autophagy substrate, through post-translational myristoylation of HTT at G553. Show more

Keywords: Autophagy, huntingtin, myristoylation, neurodegeneration, proteolysis

DOI: 10.3233/JHD-240028

Citation: Journal of Huntington's Disease, vol. 13, no. 3, pp. 267-277, 2024

Authors: Hanrahan, Jenna | Locke, Drew P. | Cahill, Lindsay S.

Article Type: Review Article

Abstract: Structural magnetic resonance imaging (MRI) is a powerful tool to visualize 3D neuroanatomy and assess pathology and disease progression in neurodegenerative disorders such as Huntington’s disease (HD). The development of mouse models of HD that reproduce many of the psychiatric, motor and cognitive impairments observed in human HD has improved our understanding of the disease and provided opportunities for testing novel therapies. Similar to the clinical scenario, MRI of mouse models of HD demonstrates onset and progression of brain pathology. Here, we provided an overview of the articles that used structural MRI in mouse models of HD to date, highlighting …the differences between studies and models and describing gaps in the current state of knowledge and recommendations for future studies. Show more

Keywords: Brain structure, Huntington’s disease, magnetic resonance imaging, mouse models, neuroanatomy

DOI: 10.3233/JHD-240045

Citation: Journal of Huntington's Disease, vol. 13, no. 3, pp. 279-299, 2024

Authors: Yin, Jin-Hui | Liu, Ya-Ou | Li, Hong-Liang | Burgunder, Jean Marc | Huang, Yue

Article Type: Research Article

Abstract: Background: Diffusion magnetic resonance imaging (dMRI) has revealed microstructural changes in white matter (WM) in Huntington’s disease (HD). Objective: To compare the validities of different dMRI, i.e., diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) in HD. Methods: 22 mutant huntingtin (mHTT ) carriers and 14 controls were enrolled. Clinical assessments and dMRI were conducted. Based on CAG-Age Product (CAP) score, mHTT carriers were categorized into high CAP (hCAP) and medium and low CAP (m& lCAP) groups. Spearman analyses were used to explore correlations between imaging parameters in brain regions and clinical assessments. …Receiver operating characteristic (ROC) was used to distinguish mHTT carriers from control, and define the HD patients at advanced stage. Results: Compared to controls, mHTT carriers exhibited WM changes in DKI and DTI. There were 22 more regions showing significant differences in HD detected by MK than FA. Only MK in five brain regions showed significantly difference between any two group, and negatively correlated with the disease burden (r  = –0.80 to –0.71). ROC analysis revealed that MK was more sensitive and FA was more specific, while Youden index showed that the integration of FA and MK gave rise to higher authenticities, in distinguishing m& lCAP from controls (Youden Index = 0.786), and discerning different phase of HD (Youden Index = 0.804). Conclusions: Microstructural changes in WM occur at early stage of HD and deteriorate over the disease progression. Integrating DKI and DTI would provide the best accuracies for differentiating early HD from control and identifying advanced HD. Show more

Keywords: Huntington’s disease, diffusion kurtosis imaging, diffusion tensor imaging, mean kurtosis, fractional anisotropy, CAG-Age product

DOI: 10.3233/JHD-240018

Citation: Journal of Huntington's Disease, vol. 13, no. 3, pp. 301-313, 2024

Authors: Hinkle, Jared T. | Wildermuth, Erin | Tong, Xiao J. | Ross, Christopher A. | Bang, Jee

Article Type: Research Article

Abstract: Background: Anosognosia, or unawareness of symptoms, is common in Huntington’s disease (HD), but the neuroanatomical basis of this is unknown. Objective: To identify neuroanatomical correlates of HD anosognosia using structural MRI data. Methods: We leveraged a pre-processed dataset of 570 HD participants across the well-characterized PREDICT-HD and TRACK-HD cohort studies. Anosognosia index was operationalized as the score discrepancies between HD participants and their caregivers on the Frontal Systems Behavior Scale (FrSBe). Results: Univariate correlation analyses identified volumes of globus pallidus, putamen, caudate, basal forebrain, substantia nigra, angular gyrus, and cingulate cortex as significant correlates …of anosognosia after correction for multiple comparisons. A multivariable model constructed with stepwise regression that included volumetric data showed globus pallidus volume alone explained more variance in anosognosia severity than motor impairment or CAP score alone. Conclusions: Anosognosia appears to be related to degeneration affecting both cortical and subcortical areas. Globus pallidus neurodegeneration in particular appears to be a key process of importance. Show more

Keywords: Anosognosia, globus pallidus, Huntington’s disease, FrSBe, PREDICT-HD, TRACK-HD

DOI: 10.3233/JHD-240010

Citation: Journal of Huntington's Disease, vol. 13, no. 3, pp. 315-320, 2024

Authors: van Os, Nienke J.H. | Oosterloo, Mayke | Essers, Brigitte A.B. | Grutters, Janneke P.C. | van de Warrenburg, Bart P.C.

Article Type: Research Article

Abstract: Background: For various genetic disorders characterized by expanded cytosine-adenine-guanine (CAG) repeats, such as spinocerebellar ataxia (SCA) subtypes and Huntington’s disease (HD), genetic interventions are currently being tested in different clinical trial phases. The patient’s perspective on such interventions should be included in the further development and implementation of these new treatments. Objective: To obtain insight into the thoughts and perspectives of individuals with SCA and HD on genetic interventions. Methods: In this qualitative study, participants were interviewed using semi-structured interview techniques. Topics discussed were possible risks and benefits, and logistic factors such as timing, location and …expertise. Data were analyzed using a generic thematic analysis. Responses were coded into superordinate themes. Results: Ten participants (five with SCA and five with HD) were interviewed. In general, participants seemed to be willing to undergo genetic interventions. Important motives were the lack of alternative disease-modifying treatment options, the hope for slowing down disease progression, and preservation of current quality of life. Before undergoing genetic interventions, participants wished to be further informed. Logistic factors such as mode and frequency of administration, expertise of the healthcare provider, and timing of treatment are of influence in the decision-making process. Conclusions: This study identified assumptions, motives, and topics that require further attention before these new therapies, if proven effective, can be implemented in clinical practice. The results may help in the design of care pathways for genetic interventions for these and other rare genetic movement disorders. Show more

Keywords: Genetic interventions, Huntington’s disease, spinocerebellar ataxia, antisense oligonucleotides

DOI: 10.3233/JHD-240026

Citation: Journal of Huntington's Disease, vol. 13, no. 3, pp. 321-328, 2024

Authors: Bin Kashif, Muhammad Arham | Mahmood, Samar | Saqib, Tahrim | Waheed, Syeda Tahira | Kumar, Piresh | Javaid, Aima | Riaz, Muhammad Asjad | Fatima, Urooj | Nadeem, Zain Ali | Nasir, Shahbaz Ali | Hassan, Afrah

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is an autosomal dominant, progressive neurodegenerative disorder debilitating mainly in adults. Objective: This study aimed to assess the trends in HD-related mortality regarding various demographic factors. Methods: Death certificates from the CDC WONDER were studied from 1999 to 2019, for HD-related mortality in adults aged 25 + years. Age-adjusted Mortality Rate (AAMR) per 100,000 persons and Annual Percentage Change (APC) were calculated and stratified by year, age groups, gender, race/ethnicity, state, census region, urbanization, and place of death. Results: Between 1999 to 2019, 22,595 deaths occurred in adults due to HD. The …AAMR increased from 0.43 to 0.54 during this period (APC = 0.50; 95% CI: 0.18 to 0.84). Old adults (65–85 + years) had the highest overall AAMR, followed by middle-aged adults (45–64 years) and young adults (25–44 years) (AAMR old: 1.01 vs. AAMR middle-age: 0.68 vs. AAMR young: 0.16). Men had slightly greater overall AAMRs than women (AAMR men: 0.54 vs. AAMR women: 0.48). When stratified by race, non-Hispanic (NH) Whites had significantly higher mortality rates than NH African Americans (AAMR NH White: 0.61 vs. NH African American: 0.35), while the AAMR were lowest in Hispanic/Latino (0.28). The AAMRs also showed variation by region (overall AAMR: Midwest: 0.63, Northeast: 0.47, West: 0.48, South: 0.46), and non-metropolitan areas had higher HD-related AAMR (0.66) than metropolitan areas (0.47). Conclusions: HD-related mortality in US adults has increased since 1999. Reflecting on the variations in trends observed, new strategies are required to optimize the quality of care in long-term care facilities. Show more

Keywords: Mortality trends, Huntington’s disease, United States, CDC WONDER database, neurodegenerative, autosomal dominant

DOI: 10.3233/JHD-240037

Citation: Journal of Huntington's Disease, vol. 13, no. 3, pp. 329-338, 2024

Authors: Snow, Abigail L.B. | Ciriegio, Abagail E. | Watson, Kelly H. | Baumann, Mary G. | Pfalzer, Anna C. | Diehl, Spencer | Duncan, Kathleen | McDonell, Katherine E. | Claassen, Daniel O. | Compas, Bruce E.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) presents patients and individuals at risk for HD with significant levels of stress. However, relatively little research has examined how individuals cope with stress related to the disease or the association of specific coping strategies with psychological symptoms. Objective: This study examined the ways in which HD patients and at-risk individuals cope with HD-related stress using a control-based model of coping and the association of coping strategies with symptoms of depression and anxiety. Methods: HD patients (n  = 49) and at-risk individuals (n  = 76) completed the Responses to Stress Questionnaire – Huntington’s Disease …Version to assess coping strategies in response to HD-related stress, as well as standardized measures of depression and anxiety symptoms. Patient health records were accessed to obtain information related to disease characteristics. Results: Patients and at-risk individuals reported using comparable levels of primary control coping, secondary control coping, and disengagement coping strategies. In linear regression analyses, only secondary control coping was significantly associated with lower depression (β = –0.62, p  < 0.001) and anxiety (β = –0.59, p  < 0.001) symptoms in patients and at-risk individuals (β = –0.55, p  < 0.001 and β = –0.50, p  < 0.001, respectively). Conclusions: Secondary control coping may be beneficial for both HD patients and at-risk individuals. Future research using the control-based model of coping in longitudinal studies with the HD population is needed, and future interventions could test the effects of cognitive reframing and acceptance as coping strategies for families affected by HD. Show more

Keywords: Huntington disease, coping, depression, anxiety

DOI: 10.3233/JHD-240027

Citation: Journal of Huntington's Disease, vol. 13, no. 3, pp. 339-347, 2024

Authors: da Silva van der Laan, Andressa | Borges, Vanderci | Saba, Roberta Arb | Ferraz, Henrique Ballalai

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) exerts significant impacts on individuals and families worldwide. Nevertheless, data on its economic burden in Brazil are scarce, revealing a critical gap in understanding the associated healthcare costs. Objective: This study was conducted at a tertiary neurology outpatient clinic in Brazil with the aim of assessing annual healthcare service utilization and associated costs for HD patients. Methods: We conducted a cross-sectional observational study involving 34 HD patients. A structured questionnaire was applied to collect data on direct medical costs (outpatient services, medications), non-medical direct costs (complementary therapies, mobility aids, home adaptations), and …indirect costs (lost productivity, caregiver costs, government benefits) over one year. Results: Significant economic impacts were observed, with average annual direct medical costs of $4686.82 per HD patient. Non-medical direct and indirect costs increased the financial burden, highlighting extensive resource utilization beyond healthcare services. Thirty-three out of 34 HD patients were unemployed or retired, and 16 relied on government benefits, reflecting broader socioeconomic implications. Despite the dataset’s limitations, it provides crucial insights into the economic impact of HD on patients and the Brazilian public health system. Conclusions: The findings underscore the urgent need for a more comprehensive evaluation of the costs to inform governmental policies related to HD. Future research is needed to expand the data pool and develop a nuanced understanding of the economic burdens of HD to help formulate effective healthcare strategies for patients. Show more

Keywords: Huntington’s disease, health care costs, Brazil, health expenditures, socioeconomic factors, neurodegenerative diseases, health economics

DOI: 10.3233/JHD-240025

Citation: Journal of Huntington's Disease, vol. 13, no. 3, pp. 349-356, 2024

Authors: Bakels, Hannah S. | Feleus, Stephanie | Rodríguez-Girondo, Mar | Losekoot, Monique | Bijlsma, Emilia K. | Roos, Raymund A.C. | de Bot, Susanne T.

Article Type: Research Article

Abstract: Background: Juvenile-onset Huntington’s disease (JHD) represents 1–5% of Huntington’s disease (HD) patients, with onset before the age of 21. Pediatric HD (PHD) relates to a proportion of JHD patients that is still under 18 years of age. So far, both populations have been excluded from interventional trials. Objective: Describe the prevalence and incidence of JHD and PHD in the Netherlands and explore their ability to participate in interventional trials. Methods: The prevalence and incidence of PHD and JHD patients in the Netherlands were analyzed. In addition, we explored proportions of JHD patients diagnosed at pediatric versus …adult age, their diagnostic delay, and functional and modelled (CAP100 ) disease stage in JHD and adult-onset HD patients at diagnosis. Results: The prevalence of JHD and PHD relative to the total manifest HD population in January 2024 was between 0.84–1.25% and 0.09–0.14% respectively. The mean incidence of JHD patients being diagnosed was between 0.85–1.28 per 1000 patient years and of PHD 0.14 per 1.000.000 under-aged person years. 55% of JHD cases received a clinical diagnosis on adult age. At diagnosis, the majority of JHD patients was functionally compromised and adolescent-onset JHD patients were significantly less independent compared to adult-onset HD patients. Conclusions: In the Netherlands, the epidemiology of JHD and PHD is lower than previously suggested. More than half of JHD cases are not eligible for trials in the PHD population. Furthermore, higher functional dependency in JHD patients influences their ability to participate in trials. Lastly, certain UHDRS functional assessments and the CAP100 score do not seem appropriate for this particular group. Show more

Keywords: Juvenile-onset Huntington’s disease, pediatric Huntington’s disease, prevalence, incidence, trial eligibility, disease stage

DOI: 10.3233/JHD-240034

Citation: Journal of Huntington's Disease, vol. 13, no. 3, pp. 357-368, 2024

Authors: Saft, Carsten | Jessen, Julia | Hoffmann, Rainer | Lukas, Carsten | Skodda, Sabine

Article Type: Short Communication

Abstract: Speech alterations have been reported in manifest Huntington’s disease (HD) and premanifest mutation carriers (preHD). The aim of our study was to explore these alterations in preHD and whether they can be used as biomarkers. 13 preHD mutation carriers performed reading task, sustained phonation task and syllable repetition tasks at baseline and after 21 months, as well as clinical examination and MRI. Syllable repetition capacity and self-chosen velocity of single syllable repetition differed significantly between time points. There were no changes in clinical ratings or MRI volumetry. Measurements of speech might be sensitive tools for monitoring subclinical changes in preHD.

Keywords: Huntington’s disease, dysarthria, speech, phonation, prodromal biomarker

DOI: 10.3233/JHD-240021

Citation: Journal of Huntington's Disease, vol. 13, no. 3, pp. 369-373, 2024

Authors: Jones, Una | Hamana, Katy | Busse, Monica

Article Type: Research Article

Abstract: Background: Clinical guidelines recommend that people with Huntington’s disease (HD) should exercise to maintain/improve fitness and motor function, yet physical activity levels remain low in this group. Promotion of physical activity is often via care partners with little evidence that they are supported in this role. Objective: The aim was to co-design a resource for care partners of people with HD to support promotion of physical activity. Methods: A four-step co-design approach was used to develop a care partner resource. Five care partners took part in an online workshop exploring experiences and the knowledge, support and …skills needed by care partners to promote physical activity. A co-design team (n  = 7) developed a prototype that was user tested by three people who had attended the workshop. Findings from user testing were used to develop the final resource. Results: An easy to read, image-based prototype was developed that contained tips on planning activity, safety and activity examples. User testing identified the need for grouping of activities suitable for 10, 20, and 30 minutes of available time, information on maintaining and improving activity and re-organization of information to support engagement of activity. Conclusions: A resource for care partners that has been translated into seven languages was developed to promote physical activity. User testing indicated confidence in using the resource and appreciation of the autonomy provided to the person with HD to plan activities. Further work is needed to evaluate the impact of the resource in promotion of physical activity and the impact on care partner burden. Show more

Keywords: Co-design, physical activity, exercise, care partner, Huntington’s disease

DOI: 10.3233/JHD-240014

Citation: Journal of Huntington's Disease, vol. 13, no. 3, pp. 375-383, 2024

Authors: Petrillo, Jennifer | Sawant, Ruta | Elliott, Emma | Cleanthous, Sophie | Rogers, Rebecca | Cano, Stefan | Baradaran, Sarah | Johannesen, Jason

Article Type: Research Article

Abstract: Background: The Huntington’s Disease (HD) Everyday Functioning (Hi-DEF) is a new patient-reported outcome (PRO) instrument designed to measure the impact of cognitive impairment on daily functioning in the early stages of HD. Objective: To assess the measurement properties and finalize item content of the Hi-DEF. Methods: A cross-sectional, observational psychometric validation study was conducted among individuals with early stages of HD at 9 US centers of excellence. Rasch Measurement Theory (RMT) analysis of the initial draft version of the Hi-DEF (47 items) and subscales (i.e., ‘Home’, ‘At work’, ‘Driving’, and ‘Communication’) was conducted to examine measurement …properties including sample-to-scale targeting, suitability of response scale (ordering of response thresholds), scale cohesiveness (item fit), local independence, and person fit. Results: 151 participants (mean age 47 years (SD 12), 59% female) were included. Seven items were removed based on dependency and item fit. The remaining 40-item version of the Hi-DEF demonstrated good measurement properties. Across the four subscales, targeting ranged from 49–70% (72% full scale), reliability ascertained by person separation index ranged from 0.53–0.87 (0.92 full scale), response scales were ordered for 25–100% of items (75% full scale), 0–12% items displayed misfit (2% full scale), and 0–1% (2% full scale) item pairs displayed dependency. Conclusions: Our study supports the psychometric integrity of the Hi-DEF as a reliable and valid new PRO instrument designed to assess the impact of cognitive impairment on daily functioning in the early stages of HD. Future work will evaluate the external validity and utility in clinical trial applications. Show more

Keywords: Huntington’s disease, executive function, activities of daily living, psychometrics, Hi-DEF, patient-reported outcomes

DOI: 10.3233/JHD-240001

Citation: Journal of Huntington's Disease, vol. 13, no. 3, pp. 385-397, 2024

Authors: Song, Wenxin | Daneman, Lauren | Cohen-Oram, Alexis | Aradi, Stephen

Article Type: Letter

Abstract:  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. Show more

Keywords: Huntington’s disease, delusion, infestation, parasitosis, psychiatry, neurology

DOI: 10.3233/JHD-240013

Citation: Journal of Huntington's Disease, vol. 13, no. 3, pp. 399-401, 2024

Article Type: Meeting Report

DOI: 10.3233/JHD-249003

Citation: Journal of Huntington's Disease, vol. 13, no. 3, pp. 403-403, 2024