Journal of Huntington's Disease - Volume 11, issue 2

Authors: Turner, Emily C. | Gantman, Emily C. | Sampaio, Cristina | Sivakumaran, Sudhir

Article Type: Research Article

Abstract: Huntington’s disease (HD) is a devastating neurodegenerative disorder that urgently needs disease-modifying therapeutics. To this end, collaboration to standardize clinical research practices in the field and drive progress in addressing drug development challenges is paramount. At a meeting in 2017 organized by CHDI Foundation and the Critical Path Institute, stakeholders across the pharmaceutical industry, academia, regulatory agencies, and patient advocacy groups discussed the need for and potential impact of a consortium dedicated to HD regulatory science. Consequently, the Huntington’s Disease Regulatory Science Consortium (HD-RSC) was formed, a precompetitive consortium that is dedicated to building a regulatory strategy to expedite the …approval of HD therapeutics. Show more

Keywords: Huntington’s disease, neurodegenerative, biomarkers, clinical outcome assessment, mutant huntingtin, model-informed drug development, Critical Path Institute (C-Path)

DOI: 10.3233/JHD-220533

Citation: Journal of Huntington's Disease, vol. 11, no. 2, pp. 97-104, 2022

Authors: Estevez-Fraga, Carlos | Rodrigues, Filipe B. | Tabrizi, Sarah J. | Wild, Edward J.

Article Type: Other

Abstract: In this edition of the Huntington’s Disease Clinical Trials Corner we expand on GENERATION HD1, PRECISION-HD1 and PRECISION-HD2, SELECT-HD, and VIBRANT-HD trials, and list all currently registered and ongoing clinical trials in Huntington’s disease.

Keywords: Huntington disease, clinical trials

DOI: 10.3233/JHD-229002

Citation: Journal of Huntington's Disease, vol. 11, no. 2, pp. 105-118, 2022

Authors: Aronin, Neil

Article Type: Editorial

DOI: 10.3233/JHD-229003

Citation: Journal of Huntington's Disease, vol. 11, no. 2, pp. 119-120, 2022

Authors: Petersen, Maria Hvidberg | Willert, Cecilie Wennemoes | Andersen, Jens Velde | Madsen, Mette | Waagepetersen, Helle Sønderby | Skotte, Niels Henning | Nørremølle, Anne

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is a neurodegenerative disorder characterized by synaptic dysfunction and loss of white matter volume especially in the striatum of the basal ganglia and to a lesser extent in the cerebral cortex. Studies investigating heterogeneity between synaptic and non-synaptic mitochondria have revealed a pronounced vulnerability of synaptic mitochondria, which may lead to synaptic dysfunction and loss. Objective: As mitochondrial dysfunction is a hallmark of HD pathogenesis, we investigated synaptic mitochondrial function from striatum and cortex of the transgenic R6/2 mouse model of HD. Methods: We assessed mitochondrial volume, ROS production, and antioxidant levels …as well as mitochondrial respiration at different pathological stages. Results: Our results reveal that striatal synaptic mitochondria are more severely affected by HD pathology than those of the cortex. Striatal synaptosomes of R6/2 mice displayed a reduction in mitochondrial mass coinciding with increased ROS production and antioxidants levels indicating prolonged oxidative stress. Furthermore, synaptosomal oxygen consumption rates were significantly increased during depolarizing conditions, which was accompanied by a marked increase in mitochondrial proton leak of the striatal synaptosomes, indicating synaptic mitochondrial stress. Conclusion: Overall, our study provides new insight into the gradual changes of synaptic mitochondrial function in HD and suggests compensatory mitochondrial actions to maintain energy production in the HD brain, thereby supporting that mitochondrial dysfunction do indeed play a central role in early disease progression of HD. Show more

Keywords: Huntington’s disease, mitochondria, synapses, striatum, cortex, synaptosomes, oxygen consumption

DOI: 10.3233/JHD-210518

Citation: Journal of Huntington's Disease, vol. 11, no. 2, pp. 121-140, 2022

Authors: Xun, Zhiyin | Wipf, Peter | McMurray, Cynthia T.

Article Type: Research Article

Abstract: Background: Mitochondria (MT) are energy “powerhouses” of the cell and the decline in their function from oxidative damage is strongly correlated in many diseases. To suppress oxygen damage, we have developed and applied XJB-5-131 as a targeted platform for neutralizing reactive oxygen species (ROS) directly in MT. Although the beneficial activity of XJB-5-131 is well documented, the mechanism of its protective effects is not yet fully understood. Objective: Here, we elucidate the mechanism of protection for XJB-5-131, a mitochondrial targeted antioxidant and electron scavenger. Methods: The Seahorse Flux Analyzer was used to probe the respiratory states …of isolated mouse brain mitochondria treated with XJB-5-131 compared to controls. Results: Surprisingly, there is no direct impact of XJB-5-131 radical scavenger on the electron flow through the electron transport chain. Rather, XJB-5-131 is a mild uncoupler of oxidative phosphorylation. The nitroxide moiety in XJB-5-131 acts as a superoxide dismutase mimic, which both extracts or donates electrons during redox reactions. The electron scavenging activity of XJB-5-131 prevents the leakage of electrons and reduces formation of superoxide anion, thereby reducing ROS. Conclusion: We show here that XJB-5-131 is a mild uncoupler of oxidative phosphorylation in MT. The mild uncoupling property of XJB-5-131 arises from its redox properties, which exert a protective effect by reducing ROS-induced damage without sacrificing energy production. Because mitochondrial decline is a common and central feature of toxicity, the favorable properties of XJB-5-131 are likely to be useful in treating Huntington’s disease and a wide spectrum of neurodegenerative diseases for which oxidative damage is a key component. The mild uncoupling properties of XJB-5-131 suggest a valuable mechanism of action for the design of clinically effective antioxidants. Show more

Keywords: Antioxidant, metabolism, mitochondrial, oxidative stress, reactive oxygen species

DOI: 10.3233/JHD-220539

Citation: Journal of Huntington's Disease, vol. 11, no. 2, pp. 141-151, 2022

Authors: Warner, John H. | Long, Jeffrey D. | Mills, James A. | Langbehn, Douglas R. | Ware, Jennifer | Mohan, Amrita | Sampaio, Cristina

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is an autosomal dominant, neurological disease caused by an expanded CAG repeat near the N-terminus of the huntingtin (HTT) gene. A leading theory concerning the etiology of HD is that both onset and progression are driven by cumulative exposure to the effects of mutant (or CAG expanded) huntingtin (mHTT). The CAG-Age-Product (CAP) score (i.e., the product of excess CAG length and age) is a commonly used measure of this cumulative exposure. CAP score has been widely used as a predictor of a variety of disease state variables in HD. The utility of the CAP score has …been somewhat diminished, however, by a lack of agreement on its precise definition. The most commonly used forms of the CAP score are highly correlated so that, for purposes of prediction, it makes little difference which is used. However, reported values of CAP scores, based on commonly used definitions, differ substantially in magnitude when applied to the same data. This complicates the process of inter-study comparison. Objective: In this paper, we propose a standardized definition for the CAP score which will resolve this difficulty. Our standardization is chosen so that CAP = 100 at the expected age of diagnosis. Methods: Statistical methods include novel survival analysis methodology applied to the 13 disease landmarks taken from the Enroll-HD database (PDS 5) and comparisons with the existing, gold standard, onset model. Results: Useful by-products of our work include up-to-date, age-at-onset (AO) results and a refined AO model suitable for use in other contexts, a discussion of several useful properties of the CAP score that have not previously been noted in the literature and the introduction of the concept of a toxicity onset model. Conclusion: We suggest that taking L  = 30 and K  = 6.49 provides a useful standardization of the CAP score, suitable for use in the routine modeling of clinical data in HD. Show more

Keywords: Huntington’s disease, CAP Score, age-at-onset, time-to-event models

DOI: 10.3233/JHD-210475

Citation: Journal of Huntington's Disease, vol. 11, no. 2, pp. 153-171, 2022

Authors: Reasoner, Erin E. | van der Plas, Ellen | Langbehn, Douglas R. | Conrad, Amy L. | Koscik, Timothy R. | Epping, Eric A. | Magnotta, Vincent A. | Nopoulos, Peggy C.

Article Type: Research Article

Abstract: Background: Molecular studies provide evidence that mutant huntingtin (mHTT ) affects early cortical development; however, cortical development has not been evaluated in child and adolescent carriers of mHTT . Objective: To evaluate the impact of mHTT on the developmental trajectories of cortical thickness and surface area. Methods: Children and adolescents (6–18 years) participated in the KidsHD study. mHTT carrier status was determined for research purposes only to classify participants as gene expanded (GE) and gene non-expanded (GNE). Cortical features were extracted from 3T neuroimaging using FreeSurfer. Nonlinear mixed effects models were conducted to determine …if age, group, and CAG repeat were associated with cortical morphometry. Results: Age-related changes in cortical morphometry were similar across groups. Expanded CAG repeat was not significantly associated with cortical features. Conclusion: While striatal development is markedly different in GE and GNE, developmental change of the cortex appears grossly normal among child and adolescent carrier of mHTT. Show more

Keywords: Huntington’s disease, cortical development, children at risk for HD, magnetic resonance imaging, trinucleotide repeat disorder

DOI: 10.3233/JHD-210512

Citation: Journal of Huntington's Disease, vol. 11, no. 2, pp. 173-178, 2022

Authors: Shaw, Eileen | Mayer, Michelle | Ekwaru, Paul | McMullen, Suzanne | Graves, Erin | Wu, Jennifer W. | Budd, Nathalie | Maturi, Bridget | Cowling, Tara | Mestre, Tiago A.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) has been shown to reduce health-related quality of life (HRQoL) and affect healthcare resource utilization (HRU) among patients and care partners internationally but has not been studied specifically in the Canadian context. Objective: To characterize the burden of HD on individuals with HD and care partners of individuals with HD in Canada. Methods: An online survey was distributed (September 14–November 23, 2020) through patient organizations to collect data on demographic and clinical characteristics, as well as: HRQoL, measured using the 36-Item Short-Form Health Survey (SF-36v1); HRU, measured using the Client Service Receipt …Inventory (CSRI); and care partner burden, measured using the Caregiver Strain Index (CSI) and Huntington’s Disease Quality of Life Battery for Carers (HDQoL-C). Descriptive statistics were used to report data and compare subgroups. Results: A total of 62 adult individuals with HD (or their proxies) and 48 care partners met defined eligibility criteria. The mean [standard deviation] age was 51.2 [13.8 ] and 58.1 [13.9 ] years for individuals with HD and care partner respondents, respectively. For individuals with HD, the greatest HRQoL burden (i.e., lowest score) was for the SF-36v1 Role –Physical scale (46.8 [42.9 ]). HRU was higher for some services (e.g., general practitioner visits) for respondents who had experienced motor onset transition. Among care partners, 55.3% experienced high strain, as indicated by the CSI. The HDQoL-C showed the greatest HRQoL burden in feelings about life (45.1 [17.9 ]). Conclusion: This study quantified the substantial burden on individuals with HD and care partners in Canada, addressing a critical knowledge gap that can affect the availability of and access to healthcare services. Show more

Keywords: Huntington’s disease, health-related quality of life, care giving burden, burden of illness, chronic disease, neurodegenerative diseases

DOI: 10.3233/JHD-210505

Citation: Journal of Huntington's Disease, vol. 11, no. 2, pp. 179-193, 2022

Authors: Bocoum, Abdoulaye | Coulibaly, Toumany | Ouologuem, Madani | Cissé, Lassana | Diallo, Seybou H. | Maiga, Boubacar B. | Dembélé, Kékouta | Diallo, Salimata | Coulibaly, Souleymane dit Papa | Kané, Fousseyni | Coulibaly, Thomas | Coulibaly, Dramane | Taméga, Abdoulaye | Yalcouyé, Abdoulaye | Diarra, Salimata | Dembélé, Mohamed E. | Maiga, Alassane B. | Cissé, Cheick A.K. | Traoré, Oumou | Fischbeck, Kenneth H. | Guinto, Cheick O. | Maiga, Youssoufa | Landouré, Guida | from The H3Africa consortium

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by mutation in the HTT gene and characterized by involuntary movements as well as cognitive and behavioral impairment. Since its first description 150 years ago, studies have been reported worldwide. However, genetically confirmed cases have been scarce in Africa. Objective: To describe the clinical and genetic aspects of HD in the Malian population. Methods: Patients with HD phenotype and their relatives were enrolled after obtaining consent. Symptoms were assessed using the Total Motor Scale (TMS) of the United Huntington’s Disease Rating Scale (UHDRS) and …the Mini-Mental State Examination (MMSE). Brain imaging and blood tests were performed to exclude other causes. DNA was extracted for HTT sequencing. Results: Eighteen patients (13 families) with a HD phenotype were evaluated. A familial history of the disease was found in 84.6% with 55.5% of maternal transmission. The average length of the HTT CAG repeat was 43.6±11.5 (39–56) CAGs. The mean age at onset was 43.1±9.7years. Choreic movements were the predominant symptoms (100% of the cases) with an average TMS of 49.4±30.8, followed by cognitive impairment (average MMSE score: 23.0±12.0) and psychiatric symptoms with 22.2% and 44.4%, respectively. Conclusion: This is one of the largest HD cohorts reported in Africa. Increasing access to genetic testing could uncover many other HD cases and disease-modifying genetic variants. Future haplotype and psychosocial studies may inform the origin of the Malian mutation and the impact of the disease on patients and their relatives. Show more

Keywords: Huntington’s disease, HTT, Mali, Sub-Saharan Africa

DOI: 10.3233/JHD-220529

Citation: Journal of Huntington's Disease, vol. 11, no. 2, pp. 195-201, 2022

Authors: Petzke, Tara M. | Rodriguez-Girondo, Mar | van der Meer, Lucienne B.

Article Type: Research Article

Abstract: Background: A positive predictive genetic test for Huntington’s disease (HD) can be a life-changing event for both carriers and their partners, leading to lower wellbeing and increasing the risk for separation and divorce. The ‘Hold me Tight’ program (HmT), based on emotionally focused couples’ therapy, aims at strengthening the couple bond by targeting attachment needs. Objective: This study investigates whether the HmT program helps couples strengthen their relationship, as an investment in a future where the disease will affect life in many ways. Methods: In a multiple baseline design using three baselines of varying length, 15 …couples of presymptomatic HD-carriers and their partners were included. In three consecutive groups, couples underwent the intervention (an adapted version of the 8-session HmT program) in four weekly sessions and completed self-report questionnaires throughout the study period of 19 weeks (17 measurements). Attachment style was assessed at baseline, resilience at baseline and at the end of the follow-up, while relationship satisfaction and wellbeing were measured weekly. A multi-level model was applied to the data. Results: Over the course of the study, wellbeing and relationship satisfaction significantly improved; resilience, however, did not. Furthermore, all three outcome measures were moderated by attachment style, with more securely attached individuals showing better outcomes. Conclusion: HmT improved wellbeing and relationship satisfaction of couples facing HD. Due to these improvements and high patient acceptability rates, this program could become a standardized procedure in HD care. The program could be adapted for other populations, e.g., couples facing other genetic neurological disorders. Show more

Keywords: Huntington’s disease, hold me tight, resilience, psychological, couples

DOI: 10.3233/JHD-210516

Citation: Journal of Huntington's Disease, vol. 11, no. 2, pp. 203-215, 2022

Authors: Brumfield, Olivia S. | Zizzi, Christine E. | Dilek, Nuran | Alexandrou, Danae G. | Glidden, Alistair M. | Rosero, Spencer | Weinstein, Jennifer | Seabury, Jamison | Kaat, Aaron | McDermott, Michael P. | Dorsey, E. Ray | Heatwole, Chad R.

Article Type: Research Article

Abstract: Background: When developed properly, disease-specific patient reported outcome measures have the potential to measure relevant changes in how a patient feels and functions in the context of a therapeutic trial. The Huntington’s Disease Health Index (HD-HI) is a multifaceted disease-specific patient reported outcome measure (PROM) designed specifically to satisfy previously published FDA guidance for developing PROMs for product development and labeling claims. Objective: In preparation for clinical trials, we examine the validity, reliability, clinical relevance, and patient understanding of the Huntington’s Disease Health Index (HD-HI). Methods: We partnered with 389 people with Huntington’s disease (HD) and …caregivers to identify the most relevant questions for the HD-HI. We subsequently utilized two rounds of factor analysis, cognitive interviews with fifteen individuals with HD, and test-retest reliability assessments with 25 individuals with HD to refine, evaluate, and optimize the HD-HI. Lastly, we determined the capability of the HD-HI to differentiate between groups of HD participants with high versus low total functional capacity score, prodromal versus manifest HD, and normal ambulation versus mobility impairment. Results: HD participants identified 13 relevant and unique symptomatic domains to be included as subscales in the HD-HI. All HD-HI subscales had a high level of internal consistency and reliability and were found by participants to have acceptable content, relevance, and usability. The total HD-HI score and each subscale score statistically differentiated between groups of HD participants with high versus low disease burden. Conclusion: Initial evaluation of the HD-HI supports its validity and reliability as a PROM for assessing how individuals with HD feel and function. Show more

Keywords: Huntington’s disease, patient reported outcome measure, therapeutic trial, quality of life, neurodegenerative disorder

DOI: 10.3233/JHD-210506

Citation: Journal of Huntington's Disease, vol. 11, no. 2, pp. 217-226, 2022