Journal of Huntington's Disease - Volume 12, issue 1

Authors: Mees, Isaline | Nisbet, Rebecca M. | Hannan, Anthony J. | Renoir, Thibault

Article Type: Review Article

Abstract: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. The disease, characterized by motor, cognitive, and psychiatric impairments, is caused by the expansion of a CAG repeat in the huntingtin gene. Despite the discovery of the mutation in 1993, no disease-modifying treatments are yet available. Understanding the molecular and cellular mechanisms involved in HD is therefore crucial for the development of novel treatments. Emerging research has found that HD might be classified as a secondary tauopathy, with the presence of tau insoluble aggregates in late HD. Increased total tau protein levels have been observed in both HD patients and animal …models of HD. Tau hyperphosphorylation, the main feature of tau pathology, has also been investigated and our own published results suggest that the protein phosphorylation machinery is dysregulated in the early stages of HD in R6/1 transgenic mice, primarily in the cortex and striatum. Protein phosphorylation, catalysed by kinases, regulates numerous cellular mechanisms and has been shown to be dysregulated in other neurodegenerative disorders, including Alzheimer’s disease. While it is still unclear how the mutation in the huntingtin gene leads to tau dysregulation in HD, several hypotheses have been explored. Evidence suggests that the mutant huntingtin does not directly interact with tau, but instead interacts with tau kinases, phosphatases, and proteins involved in tau alternative splicing, which could result in tau dysregulation as observed in HD. Altogether, there is increasing evidence that tau is undergoing pathological changes in HD and may be a good therapeutic target. Show more

Keywords: Huntington’s disease, tauopathy, tau, phosphorylation, aggregates

DOI: 10.3233/JHD-230569

Citation: Journal of Huntington's Disease, vol. 12, no. 1, pp. 1-13, 2023

Authors: Salem, Shireen | Cicchetti, Francesca

Article Type: Review Article

Abstract: There is increasing evidence for the presence of pathological forms of tau in tissues of both Huntington’s disease (HD) patients and animal models of this condition. While cumulative studies of the past decade have led to the proposition that this disorder could also be considered a tauopathy, the implications of tau in cellular toxicity and consequent behavioral impairments are largely unknown. In fact, recent animal work has challenged the contributory role of tau in HD pathogenesis/pathophysiology. This review presents the supporting and opposing arguments for the involvement of tau in HD, highlighting the discrepancies that have emerged. Reflecting on what …is known in other tauopathies, the putative mechanisms through which tau could initiate and/or contribute to pathology are discussed, shedding light on the future research directions that could be considered to confirm, or rule out, the clinical relevance of tau in HD. Show more

Keywords: Huntington’s disease, mutant huntingtin, tau, neurofibrillary tangles, hyperphosphorylated tau, therapeutics, biomarkers

DOI: 10.3233/JHD-220557

Citation: Journal of Huntington's Disease, vol. 12, no. 1, pp. 15-29, 2023

Authors: Spick, Matt | Hancox, Thomas P.M. | Chowdhury, Namrata R. | Middleton, Benita | Skene, Debra J. | Morton, A. Jennifer

Article Type: Research Article

Abstract: Background: Metabolic abnormalities have long been predicted in Huntington’s disease (HD) but remain poorly characterized. Chronobiological dysregulation has been described in HD and may include abnormalities in circadian-driven metabolism. Objective: Here we investigated metabolite profiles in the transgenic sheep model of HD (OVT73) at presymptomatic ages. Our goal was to understand changes to the metabolome as well as potential metabolite rhythm changes associated with HD. Methods: We used targeted liquid chromatography mass spectrometry (LC-MS) metabolomics to analyze metabolites in plasma samples taken from female HD transgenic and normal (control) sheep aged 5 and 7 years. Samples …were taken hourly across a 27-h period. The resulting dataset was investigated by machine learning and chronobiological analysis. Results: The metabolic profiles of HD and control sheep were separable by machine learning at both ages. We found both absolute and rhythmic differences in metabolites in HD compared to control sheep at 5 years of age. An increase in both the number of disturbed metabolites and the magnitude of change of acrophase (the time at which the rhythms peak) was seen in samples from 7-year-old HD compared to control sheep. There were striking similarities between the dysregulated metabolites identified in HD sheep and human patients (notably of phosphatidylcholines, amino acids, urea, and threonine). Conclusion: This work provides the first integrated analysis of changes in metabolism and circadian rhythmicity of metabolites in a large animal model of presymptomatic HD. Show more

Keywords: Huntington’s disease, chronobiology, metabolomics, circadian rhythms, mass spectrometry, machine learning

DOI: 10.3233/JHD-220552

Citation: Journal of Huntington's Disease, vol. 12, no. 1, pp. 31-42, 2023

Authors: Wasser, Cory I. | Mercieca, Emily-Clare | Kong, Geraldine | Hannan, Anthony J. | Allford, Brianna | McKeown, Sonja J. | Stout, Julie C. | Glikmann-Johnston, Yifat

Article Type: Research Article

Abstract: Background: Gastrointestinal symptoms are clinical features of Huntington’s disease (HD), which adversely affect people’s quality of life. We recently reported the first evidence of gut dysbiosis in HD gene expansion carriers (HDGECs). Here, we report on a randomized controlled clinical trial of a 6-week probiotic intervention in HDGECs. Objective: The primary objective was to determine whether probiotics improved gut microbiome composition in terms of richness, evenness, structure, and diversity of functional pathways and enzymes. Exploratory objectives were to determine whether probiotic supplementation improved cognition, mood, and gastrointestinal symptoms. Methods: Forty-one HDGECs, including 19 early manifest and …22 premanifest HDGECs were compared with 36 matched-healthy controls (HCs). Participants were randomly assigned probiotics or placebo and provided fecal samples at baseline and 6-week follow-up, which were sequenced using 16S-V3-V4 rRNA to characterize the gut microbiome. Participants completed a battery of cognitive tests and self-report questionnaires measuring mood and gastrointestinal symptoms. Results: HDGECs had altered gut microbiome diversity when compared to HCs, indicating gut dysbiosis. Probiotic intervention did not ameliorate gut dysbiosis or have any effect on cognition, mood, or gastrointestinal symptoms. Gut microbiome differences between HDGECs and HCs were unchanged across time points, suggesting consistency of gut microbiome differences within groups. Conclusion: Despite the lack of probiotic effects in this trial, the potential utility of the gut as a therapeutic target in HD should continue to be explored given the clinical symptomology, gut dysbiosis, and positive results from probiotics and other gut interventions in similar neurodegenerative diseases. Show more

Keywords: Huntington’s disease, randomized controlled trial, neurodegenerative disease, gut microbiome, cognitive impairment, gut–brain axis

DOI: 10.3233/JHD-220556

Citation: Journal of Huntington's Disease, vol. 12, no. 1, pp. 43-55, 2023

Authors: Long, Jeffrey D. | Gantman, Emily C. | Mills, James A. | Vaidya, Jatin G. | Mansbach, Alexandra | Tabrizi, Sarah J. | Sampaio, Cristina

Article Type: Research Article

Abstract: Background: The Huntington’s Disease Integrated Staging System (HD-ISS) has four stages that characterize disease progression. Classification is based on CAG length as a marker of Huntington’s disease (Stage 0), striatum atrophy as a biomarker of pathogenesis (Stage 1), motor or cognitive deficits as HD signs and symptoms (Stage 2), and functional decline (Stage 3). One issue for implementation is the possibility that not all variables are measured in every study, and another issue is that the stages are broad and may benefit from progression subgrouping. Objective: Impute stages of the HD-ISS for observational studies in which missing data …precludes direct stage classification, and then define progression subgroups within stages. Methods: A machine learning algorithm was used to impute stages. Agreement of the imputed stages with the observed stages was evaluated using graphical methods and propensity score matching. Subgroups were defined based on descriptive statistics and optimal cut-point analysis. Results: There was good overall agreement between the observed stages and the imputed stages, but the algorithm tended to over-assign Stage 0 and under-assign Stage 1 for individuals who were early in progression. Conclusion: There is evidence that the imputed stages can be treated similarly to the observed stages for large-scale analyses. When imaging data are not available, imputation can be avoided by collapsing the first two stages using the categories of Stage≤1, Stage 2, and Stage 3. Progression subgroups defined within a stage can help to identify groups of more homogeneous individuals. Show more

Keywords: Huntington’s disease, integrated staging system, missing data imputation, disease progression, Enroll-HD

DOI: 10.3233/JHD-220555

Citation: Journal of Huntington's Disease, vol. 12, no. 1, pp. 57-69, 2023

Authors: Andrew, Kelly M. | Fox, Leora M.

Article Type: Article Commentary

Abstract: Recent years have been turbulent ones for the Huntington’s disease (HD) community. Three clinical trials for HD, including the first Phase 3 trial of a potentially disease modifying genetic therapy for HD, were all brought to a halt in March of 2021. 2022 brought more study roadblocks and an additional trial termination. As HD science progresses and larger scale trials become more frequent in the community, HD families are faced with the difficult reality that clinical research rarely results in a new drug hitting the market. To better understand how the HD community can be prepared for the ups and …downs that accompany an expanding clinical research pipeline, the Huntington’s Disease Society of America (HDSA) spoke with members of the Huntington’s Disease Coalition for Patient Engagement (HD-COPE). This group of global advocates led by HDSA and the Huntington’s Society of Canada (HSC) collaborates with pharmaceutical companies to ensure that HD voices are represented in the planning of clinical trials. These conversations allowed HDSA to summarize how the HD community can be best supported through the clinical research process in three key areas: engagement, support, and education. Show more

Keywords: Huntington’s disease, clinical trials, HD-COPE, community engagement, trial recruitment, community support

DOI: 10.3233/JHD-230565

Citation: Journal of Huntington's Disease, vol. 12, no. 1, pp. 71-76, 2023

Authors: Farag, Mena | Salanio, Desiree M. | Hearst, Cara | Rae, Daniela | Tabrizi, Sarah J.

Article Type: Article Commentary

Abstract: Advance care planning (ACP) is a useful tool that benefits adult patients, care providers, and surrogate decision makers, through providing opportunities for patients to consider, express, and formalize their beliefs, preferences, and wishes pertaining to decisions regarding future medical care at a time when they retain decision-making capacity. Early and timely consideration of ACP discussions is paramount in Huntington’s disease (HD) given the potential challenges in ascertaining decision-making capacity in the advanced stages of the disease. ACP helps to empower and extend patient autonomy, providing clinicians and surrogate decision makers with reassurance that management is consistent with a patient’s expressed …wishes. Regular follow up is vital to establish consistency of decisions and wishes. We outline the framework of the dedicated ACP clinic integrated within our HD service to highlight the importance of a patient-centred and tailored care plan that fulfils the patient’s expressed goals, preferences, and values. Show more

Keywords: Advance care planning, Huntington’s disease

DOI: 10.3233/JHD-220559

Citation: Journal of Huntington's Disease, vol. 12, no. 1, pp. 77-82, 2023

Article Type: Meeting Report

DOI: 10.3233/JHD-239000

Citation: Journal of Huntington's Disease, vol. 12, no. 1, pp. 83-83, 2023