Journal of Huntington's Disease - Volume 10, issue 2

Authors: The SC4HD Consortium

Article Type: Short Communication

Abstract: Huntington’s disease (HD) research is entering an exciting phase, with new approaches such as huntingtin lowering strategies and cell therapies on the horizon. Technological advances to direct the differentiation of stem cells to desired neural types have opened new strategies for restoring damaged neuronal circuits in HD. However, challenges remain in the implementation of cell therapy approaches for patients suffering from HD. Cell therapies, together with other invasive approaches including allele specific oligonucleotides (ASOs) and viral delivery of huntingtin-lowering agents, require direct delivery of the therapeutic agents locally into the brain or cerebrospinal fluid. Delivering substances directly into the brain …is complex and presents multiple challenges, including those related to regulatory requirements, safety and efficacy, surgical instrumentation, trial design, patient profiles, and selection of suitable and sensitive primary and secondary outcomes. In addition, production of clinical grade cell-based medicinal products also requires adherence to regulatory standards with extensive quality control of the protocols and cell products across different laboratories and production centers. Currently, there is no consensus on how best to address these challenges. Here we describe the formation of Stem Cells For Huntington ’s Disease (SC4HD: https://www.sc4hd.org/ ), a network of researchers and clinicians working to develop guidance and greater standardization for the HD field for stem cell based transplantation therapy for HD with a mission to work to develop criteria and guidance for development of a neural intra-cerebral stem cell-based therapy for HD. Show more

Keywords: Neuroscience, Huntington’s disease, stem cells, transplantation

DOI: 10.3233/JHD-210473

Citation: Journal of Huntington's Disease, vol. 10, no. 2, pp. 221-226, 2021

Authors: Grosso Jasutkar, Hilary | Yamamoto, Ai

Article Type: Review Article

Abstract: Although Huntington’s disease (HD) is classically considered from the perspective of the motor syndrome, the cognitive changes in HD are prominent and often an early manifestation of disease. As such, investigating the underlying pathophysiology of cognitive changes may give insight into important and early neurodegenerative events. In this review, we first discuss evidence from both HD patients and animal models that cognitive changes correlate with early pathological changes at the synapse, an observation that is similarly made in other neurodegenerative conditions that primarily affect cognition. We then describe how autophagy plays a critical role supporting synaptic maintenance in the healthy …brain, and how autophagy dysfunction in HD may thereby lead to impaired synaptic maintenance and thus early manifestations of disease. Show more

Keywords: Huntington’s disease, cognition, autophagy, synapse, synaptic dysfunction

DOI: 10.3233/JHD-200466

Citation: Journal of Huntington's Disease, vol. 10, no. 2, pp. 227-238, 2021

Authors: Seeley, Connor | Kegel-Gleason, Kimberly B.

Article Type: Review Article

Abstract: Mass spectrometry (MS) is a physical technique used to identify specific chemicals and molecules by precise analysis of their mass and charge; this technology has been adapted for biological sciences applications. Investigators have used MS to identify differential expressions of proteins in Huntington’s disease (HD), to discover Huntingtin (HTT) interacting proteins and to analyze HTT proteoforms. Using systems biology and computational approaches, data from MS screens have been leveraged to find differentially expressed pathways. This review summarizes the data from most of the MS studies done in the HD field in the last 20 years and compares it to the …protein data reported before the use of MS technology. The MS results validate early findings in the field such as differential expression of PDE10a and DARPP-32 and identify new changes. We offer a perspective on the MS approach in HD, particularly for identification of disease pathways, the challenges in interpreting data across different studies, and its application to protein studies moving forward. Show more

Keywords: Huntingtin, Huntington’s disease, HTT, mass spectrometry, proteomics, proteome, interactome

DOI: 10.3233/JHD-200465

Citation: Journal of Huntington's Disease, vol. 10, no. 2, pp. 239-257, 2021

Authors: Lang, Christina | Gries, Christopher | Lindenberg, Katrin S. | Lewerenz, Jan | Uhl, Stefanie | Olsson, Christian | Samzelius, Jan | Landwehrmeyer, G. Bernhard

Article Type: Research Article

Abstract: Background: Besides cognitive and psychiatric abnormalities, motor symptoms are the most prominent in Huntington’s disease. The manifest disease is preceded by a prodromal phase with subtle changes such as fine motor disturbances or concentration problems. Objective: Movement disorders show a high variation in their clinical manifestation depending on condition and external influences. Therefore, devices for continuous measurements, which patients use in their daily life and which can monitor motor abnormalities, in addition to the medical examination, might be useful. The aim of current scientific efforts is to find markers that reflect the prodromal phase in gene carriers. …This is important for future interventional studies, as future therapies should be applied at the stage of neuronal dysfunction, i.e., before the clinical manifestation. Methods: We performed a software-supported, continuous monitoring of keyboard typing on the participants’ own computer to evaluate this method as a tool to assess the motor phenotype in HD. We included 40 participants and obtained sufficient data from 25 participants, 12 of whom were manifest HD patients, 7 HD gene expansion carriers (HDGEC) and 6 healthy controls. Results: In a cross-sectional analysis we found statistically significant higher typing inconsistency in HD patients compared to controls. Typing inconsistency compared between HDGEC and healthy controls showed a trend to higher inconsistency levels in HDGEC. We found correlations between typing cadence and clinical scores: the UHDRS finger tapping item, the composite UHDRS and the CAP score. Conclusion: The typing cadence inconsistency is an appropriate marker to evaluate fine motor skills of HD patients and HDGEC and is correlated to established clinical measurements. Show more

Keywords: Huntington’s disease, digital biomarker, keyboard typing, fine motor skills, prodromal phase

DOI: 10.3233/JHD-200451

Citation: Journal of Huntington's Disease, vol. 10, no. 2, pp. 259-268, 2021

Authors: van der Zwaan, Kasper F. | Jacobs, Milou | van Zwet, Erik W. | Roos, Raymund A.C. | de Bot, Susanne T.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is an inherited neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric symptoms. Although 65%of HD expanded gene carriers report changes in employment as the first functional loss, little is known about the predictors leading to changes of working capacity. Given the impact on quality of life, understanding of these factors is of great clinical value. Objective: This study evaluates disease specific characteristics and their predictive value in loss of working capacity in HD. Methods: Longitudinal data was collected through the worldwide observational study (Enroll-HD), with 15,301 participants in total and …2,791 HD and healthy control participants meeting the inclusion criteria. Changes in working capacity were analyzed by means of a survival analysis. Predictive values of demographic factors and clinical characteristics were assessed for premanifest and manifest HD through Cox regressions. Results: HD expanded gene carriers, manifest and premanifest combined, had a 31%chance of experiencing changes in employment after three years, compared to 4%in healthy controls. Apathy was found to be the most crucial determinant of working capacity changes in premanifest HD, while executive and motor dysfunction play an important role in manifest HD. Conclusion: HD expanded gene carriers are more likely to lose working capacity compared to healthy controls. Disease progression, altered motor function, cognitive decline, and in an early stage of the disease apathetic symptoms are indicative of negative changes in working capacity. Clinicians should recognize that early disease related changes, especially apathy, can affect working capacity. Show more

Keywords: Huntington’s disease, employment, occupation, survival analysis, work status

DOI: 10.3233/JHD-200446

Citation: Journal of Huntington's Disease, vol. 10, no. 2, pp. 269-276, 2021

Authors: Eccles, Fiona J.R. | Craufurd, David | Smith, Alistair | Davies, Rhys | Glenny, Kristian | Homberger, Max | Rose, Leona | Theed, Rachael | Peeren, Siofra | Rogers, Dawn | Skitt, Zara | Zarotti, Nicolò | Simpson, Jane

Article Type: Research Article

Abstract: Background: Psychological difficulties such as anxiety, depression, and irritability are common in Huntington’s disease, even for premanifest individuals. However, very little evidence exists of psychological approaches to manage this distress. We have conducted a feasibility study with an embedded qualitative component to investigate the possibility of using mindfulness-based cognitive therapy (MBCT) and present here the findings from the qualitative data. Objective: To investigate the experience of premanifest individuals learning and practising mindfulness through completing a course of MBCT. Methods: Twelve premanifest individuals completed a course of MBCT and attended three follow up reunion meetings over the …following year. Eleven participants agreed to be interviewed post-course and ten participants one year post-course about their experience of the course and any impact on their lives. Seven participants nominated a friend or relative (supporter) to be involved in the research, of whom six agreed to be interviewed post-course and two at one year about the impact of the course on the participants. Data were analysed using reflexive thematic analysis. Results: Four themes were constructed from the data: 1) A meeting of minds: the group facilitating learning and support; 2) Mindfulness is hard, but enables more effective emotional management; 3) Mindfulness can change the relationship with self and others; and 4) Benefiting from mindfulness: the importance of persistence. Conclusion: The participants who completed the course found it beneficial. Some participants reported reductions in psychological distress, a greater sense of calm and better emotion regulation, with some of these positive changes also noticed by supporters. MBCT is worthy of further investigation for this population. Show more

Keywords: Huntington’s disease, mindfulness, depression, anxiety, irritability, emotion regulation, premanifest, presymptomatic

DOI: 10.3233/JHD-210471

Citation: Journal of Huntington's Disease, vol. 10, no. 2, pp. 277-291, 2021

Authors: Waddell, Emma M. | Dinesh, Karthik | Spear, Kelsey L. | Elson, Molly J. | Wagner, Ellen | Curtis, Michael J. | Mitten, David J. | Tarolli, Christopher G. | Sharma, Gaurav | Dorsey, E. Ray | Adams, Jamie L.

Article Type: Research Article

Abstract: Background: Current Huntington’s disease (HD) measures are limited to subjective, episodic assessments conducted in clinic. Smartphones can enable the collection of objective, real-world data but their use has not been extensively evaluated in HD. Objective: Develop and evaluate a smartphone application to assess feasibility of use and key features of HD in clinic and at home. Methods: We developed GEORGE® , an Android smartphone application for HD which assesses voice, chorea, balance, gait, and finger tapping speed. We then conducted an observational pilot study of individuals with manifest HD, prodromal HD, and without a movement disorder. …In clinic, participants performed standard clinical assessments and a battery of active tasks in GEORGE. At home, participants were instructed to complete the activities thrice daily for one month. Sensor data were used to measure chorea, tap rate, and step count. Audio data was not analyzed. Results: Twenty-three participants (8 manifest HD, 5 prodromal HD, 10 controls) enrolled, and all but one completed the study. On average, participants used the application 2.1 times daily. We observed a significant difference in chorea score (HD: 19.5; prodromal HD: 4.5, p  = 0.007; controls: 4.3, p  = 0.001) and tap rate (HD: 2.5 taps/s; prodromal HD: 8.9 taps/s, p  = 0.001; controls: 8.1 taps/s, p  = 0.001) between individuals with and without manifest HD. Tap rate correlated strongly with the traditional UHDRS finger tapping score (left hand: r  = –0.82, p  = 0.022; right hand: r  = –0.79, p  = 0.03). Conclusion: GEORGE is an acceptable and effective tool to differentiate individuals with and without manifest HD and measure key disease features. Refinement of the application’s interface and activities will improve its usability and sensitivity and, ideally, make it useful for clinical care and research. Show more

Keywords: Huntington’s disease, chorea, motor function, gait, smartphone, technology

DOI: 10.3233/JHD-200452

Citation: Journal of Huntington's Disease, vol. 10, no. 2, pp. 293-301, 2021

Authors: Guttman, Mark | Pedrazzoli, Marco | Ponomareva, Marina | Pelletier, Marsha | Townson, Louisa | Mukelabai, Kopano | Levine, Aaron | Nordström, Anna-Lena | Reilmann, Ralf | Burgunder, Jean-Marc

Article Type: Research Article

Abstract: Background: The most advanced disease-modifying therapies (DMTs) in development for Huntington’s disease (HD) require intrathecal (IT) administration, which may create or exacerbate bottlenecks in resource capacity. Objective: To understand the readiness of healthcare systems for intrathecally administered HD DMTs in terms of resource capacity dynamics and implications for patients’ access to treatment. Methods: Forty HD centres across 12 countries were included. Qualitative and quantitative data on current capacity in HD centres and anticipated capacity needs following availability of a DMT were gathered via interviews with healthcare professionals (HCPs). Data modelling was used to estimate the current …capacity gap in HD centres. Results: From interviews with 218 HCPs, 25% of HD centres are estimated to have the three components required for IT administration (proceduralists, nurses and facilities). On average, 114 patients per centre per year are anticipated to receive intrathecally administered DMTs in the future. At current capacity, six of the sampled centres are estimated to be able to deliver DMTs to all the anticipated patients based on current resources. The estimated waiting time for IT administration at current capacity will average 60 months (5 years) by the second year after DMT availability. Conclusion: Additional resources are needed in HD centres for future DMTs to be accessible to all anticipated patients. Timely collaboration by the HD community will be needed to address capacity gaps. Healthcare policymakers and payers will need to address costs and navigate challenges arising from country- or region-specific healthcare delivery schemes. Show more

Keywords: Huntington’s disease, intrathecal injection, spinal puncture, capacity building, health care facilities, manpower, and services, health resources, health services accessibility

DOI: 10.3233/JHD-200462

Citation: Journal of Huntington's Disease, vol. 10, no. 2, pp. 303-311, 2021

Authors: Pfalzer, Anna C. | Hale, Lisa M. | Huitz, Elizabeth | Buchanan, Danielle A. | Brown, Brittany K. | Moroz, Sarah | Rouleau, Renee M. | Hay, Kaitlyn R. | Hoadley, Jennifer | Laird, Amy | Ciriegio, Abagail E. | Watson, Kelly H. | Jones, Maile T. | Lin, Ya-Chen | Kang, Hakmook | Riordan, Heather | Isaacs, David A. | McDonell, Katherine E. | Compas, Bruce E. | Claassen, Daniel O.

Article Type: Research Article

Abstract: Background: Safer-at-home orders during the COVID-19 pandemic altered the structure of clinical care for Huntington’s disease (HD) patients. This shift provided an opportunity to identify limitations in the current healthcare infrastructure and how these may impact the health and well-being of persons with HD. Objective: The study objectives were to assess the feasibility of remote healthcare delivery in HD patients, to identify socioeconomic factors which may explain differences in feasibility and to evaluate the impact of safer-at-home orders on HD patient stress levels. Methods: This observational study of a clinical HD population during the ‘safer-at-home’ orders …asked patients or caregivers about their current access to healthcare resources and patient stress levels. A chart review allowed for an assessment of socioeconomic status and characterization of HD severity. Results: Two-hundred and twelve HD patients were contacted with 156 completing the survey. During safer-at-home orders, the majority of HD patients were able to obtain medications and see a physician; however, 25% of patients would not commit to regular telehealth visits, and less than 50% utilized an online healthcare platform. We found that 37% of participants were divorced/single, 39% had less than a high school diploma, and nearly 20% were uninsured or on low-income health insurance. Patient stress levels correlated with disease burden. Conclusion: A significant portion of HD participants were not willing to participate in telehealth services. Potential explanations for these limitations may include socioeconomic barriers and caregiving structure. These observations illustrate areas for clinical care improvement to address healthcare disparities in the HD community. Show more

Keywords: Huntington’s disease, telehealth, socioeconomic status, health disparities, stress

DOI: 10.3233/JHD-200460

Citation: Journal of Huntington's Disease, vol. 10, no. 2, pp. 313-322, 2021