Journal of Huntington's Disease - Volume 13, issue 2

Authors: Sampaio, Cristina | Kostyk, Sandra K. | Tabrizi, Sarah J. | Rosser, Anne E.

Article Type: Editorial

DOI: 10.3233/JHD-240043

Citation: Journal of Huntington's Disease, vol. 13, no. 2, pp. 115-118, 2024

Authors: DiFiglia, Marian | Leavitt, Blair R. | Macdonald, Douglas | Thompson, Leslie M. | Bates, Gillian P. | Cha, Jang-Ho | Faull, Richard | Feigin, Andrew | Gantman, Emily C. | Gusella, James F. | Hayden, Michael | Housman, David | Howland, David | Langbehn, Doug | Landwehrmeyer, Bernhard G. | Long, Jeffrey D. | MacDonald, Marcy | Noble, Simon | Rosser, Anne E. | Sampaio, Cristina | Tabrizi, Sarah | Vonsattel, Jean P. | Wanker, Erich E. | Yang, X. William | Yohrling, George | Zeitlin, Scott

Article Type: Review Article

Abstract: The field of Huntington’s disease research covers many different scientific disciplines, from molecular biology all the way through to clinical practice, and as our understanding of the disease has progressed over the decades, a great deal of different terminology has accrued. The field is also renowned for its collaborative spirit and use of standardized reagents, assays, datasets, models, and clinical measures, so the use of standardized terms is especially important. We have set out to determine, through a consensus exercise involving basic and clinical scientists working in the field, the most appropriate language to use across disciplines. Nominally, this article …will serve as the style guide for the Journal of Huntington ’s Disease (JHD) , the only journal devoted exclusively to HD, and we lay out the preferred and standardized terminology and nomenclature for use in JHD publications. However, we hope that this article will also serve as a useful resource to the HD research community at large and that these recommended naming conventions will be adopted widely. Show more

Keywords: Nomenclature, Huntington’s disease, HTT, mHTT, preclinical models, neuropathology, neuroanatomy

DOI: 10.3233/JHD-240044

Citation: Journal of Huntington's Disease, vol. 13, no. 2, pp. 119-131, 2024

Authors: Khoshnan, Ali

Article Type: Review Article

Abstract: Huntingtin (HTT) protein is expressed in most cell lineages, and the toxicity of mutant HTT in multiple organs may contribute to the neurological and psychiatric symptoms observed in Huntington’s disease (HD). The proteostasis and neurotoxicity of mutant HTT are influenced by the intracellular milieu and responses to environmental signals. Recent research has highlighted a prominent role of gut microbiota in brain and immune system development, aging, and the progression of neurological disorders. Several studies suggest that mutant HTT might disrupt the homeostasis of gut microbiota (known as dysbiosis) and impact the pathogenesis of HD. Dysbiosis has been observed in HD …patients, and in animal models of the disease it coincides with mutant HTT aggregation, abnormal behaviors, and reduced lifespan. This review article aims to highlight the potential toxicity of mutant HTT in organs and pathways within the microbiota-gut-immune-central nervous system (CNS) axis. Understanding the functions of Wild-Type (WT) HTT and the toxicity of mutant HTT in these organs and the associated networks may elucidate novel pathogenic pathways, identify biomarkers and peripheral therapeutic targets for HD. Show more

Keywords: Huntington’s disease, microbiota, innate immunity, gut-brain, gene-environment

DOI: 10.3233/JHD-240012

Citation: Journal of Huntington's Disease, vol. 13, no. 2, pp. 133-147, 2024

Authors: Oosterloo, Mayke | Touze, Alexiane | Byrne, Lauren M. | Achenbach, Jannis | Aksoy, Hande | Coleman, Annabelle | Lammert, Dawn | Nance, Martha | Nopoulos, Peggy | Reilmann, Ralf | Saft, Carsten | Santini, Helen | Squitieri, Ferdinando | Tabrizi, Sarah | Burgunder, Jean-Marc | Quarrell, Oliver

Article Type: Review Article

Abstract:  Juvenile Huntington’s disease (JHD) is rare. In the first decade of life speech difficulties, rigidity, and dystonia are common clinical motor symptoms, whereas onset in the second decade motor symptoms may sometimes resemble adult-onset Huntington’s disease (AOHD). Cognitive decline is mostly detected by declining school performances. Behavioral symptoms in general do not differ from AOHD but may be confused with autism spectrum disorder or attention deficit hyperactivity disorder and lead to misdiagnosis and/or diagnostic delay. JHD specific features are epilepsy, ataxia, spasticity, pain, itching, and possibly liver steatosis. Disease progression of JHD is faster compared to AOHD and the disease …duration is shorter, particularly in case of higher CAG repeat lengths. The diagnosis is based on clinical judgement in combination with a positive family history and/or DNA analysis after careful consideration. Repeat length in JHD is usually > 55 and caused by anticipation, usually via paternal transmission. There are no pharmacological and multidisciplinary guidelines for JHD treatment. Future perspectives for earlier diagnosis are better diagnostic markers such as qualitative MRI and neurofilament light in serum. Show more

DOI: 10.3233/JHD-231523

Citation: Journal of Huntington's Disease, vol. 13, no. 2, pp. 149-161, 2024

Authors: Hobbs, Nicola Z. | Papoutsi, Marina | Delva, Aline | Kinnunen, Kirsi M. | Nakajima, Mitsuko | Van Laere, Koen | Vandenberghe, Wim | Herath, Priyantha | Scahill, Rachael I.

Article Type: Research Article

Abstract:  Neuroimaging is increasingly being included in clinical trials of Huntington’s disease (HD) for a wide range of purposes from participant selection and safety monitoring, through to demonstration of disease modification. Selection of the appropriate modality and associated analysis tools requires careful consideration. On behalf of the EHDN Imaging Working Group, we present current opinion on the utility and future prospects for inclusion of neuroimaging in HD trials. Covering the key imaging modalities of structural-, functional- and diffusion- MRI, perfusion imaging, positron emission tomography, magnetic resonance spectroscopy, and magnetoencephalography, we address how neuroimaging can be used in HD trials to: 1) …Aid patient selection, enrichment, stratification, and safety monitoring; 2) Demonstrate biodistribution, target engagement, and pharmacodynamics; 3) Provide evidence for disease modification; and 4) Understand brain re-organization following therapy. We also present the challenges of translating research methodology into clinical trial settings, including equipment requirements and cost, standardization of acquisition and analysis, patient burden and invasiveness, and interpretation of results. We conclude, that with appropriate consideration of modality, study design and analysis, imaging has huge potential to facilitate effective clinical trials in HD. Show more

Keywords: Neuroimaging, Huntington’s disease, clinical trial, magnetic resonance imaging, positron-emission tomography, magnetoencephalography

DOI: 10.3233/JHD-240016

Citation: Journal of Huntington's Disease, vol. 13, no. 2, pp. 163-199, 2024

Authors: Geijtenbeek, Karlijne W. | Aranda, Angela Santiago | Sanz, Alicia Sanz | Janzen, Jolien | Bury, Aleksandra E. | Kors, Suzan | Al Amery, Nur | Schmitz, Nina C.M. | Reits, Eric A.J. | Schipper-Krom, Sabine

Article Type: Research Article

Abstract: Background: Huntington’s disease is an inheritable autosomal dominant disorder caused by an expanded CAG trinucleotide repeat within the Huntingtin gene, leading to a polyglutamine (polyQ) expansion in the mutant protein. Objective: A potential therapeutic approach for delaying or preventing the onset of the disease involves enhancing the degradation of the aggregation-prone polyQ-expanded N-terminal mutant huntingtin (mHTT) exon1 fragment. A few proteases and peptidases have been identified that are able to cleave polyQ fragments with low efficiency. This study aims to identify a potent polyQ-degrading endopeptidase. Methods: Here we used quenched polyQ peptides to identify a polyQ-degrading …endopeptidase. Next we investigated its role on HTT turnover, using purified polyQ-expanded HTT fragments and striatal cells expressing mHTT exon1 peptides. Results: We identified insulin-degrading enzyme (IDE) as a novel endopeptidase for degrading polyQ peptides. IDE was, however, ineffective in reducing purified polyQ-expanded HTT fragments. Similarly, in striatal cells expressing mHTT exon1 peptides, IDE did not enhance mHTT turnover. Conclusions: This study shows that despite IDE’s efficiency in degrading polyQ peptides, it does not contribute to the direct degradation of polyQ-expanded mHTT fragments. Show more

Keywords: Huntington’s disease, huntingtin protein, insulysin, IDE protein, protein aggregates

DOI: 10.3233/JHD-230583

Citation: Journal of Huntington's Disease, vol. 13, no. 2, pp. 201-214, 2024

Authors: Snow, Abigail L.B. | Ciriegio, Abagail E. | Watson, Kelly H. | Pfalzer, Anna C. | Diehl, Spencer | Hale, Lisa | McDonell, Katherine E. | Claassen, Daniel O. | Compas, Bruce E.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is a neurodegenerative disease that presents families with significant numbers of stressful events. However, relatively little empirical research has characterized the stressors encountered by members of HD-affected families and their correlations with psychological symptoms. Objective: This study examined frequencies of specific stressors in HD patients and at-risk individuals and the correlates of these stressors with demographics, disease characteristics, and symptoms of depression and anxiety. Methods: HD patients (n  = 57) and at-risk individuals (n  = 81) completed the Responses to Stress Questionnaire –Huntington’s Disease Version to assess HD-related stressors. Participants completed measures of depression …and anxiety symptoms. Patient health records were accessed to obtain information related to disease characteristics. Results: Patients endorsed a mean number of 5.05 stressors (SD  = 2.74) out of the 10-item list. Demographics were not related to total stressors, but disease characteristics were significantly related to specific stressors. At-risk individuals endorsed a mean number of 3.20 stressors (SD  = 2.65) out of the 11-item list. Age and sex were significantly related to specific stressors. Total number of stressors was significantly related to depression (β=0.67, p  < 0.001) and anxiety symptoms (β=0.58, p  < 0.001) in patients and at-risk individuals (β=0.35, p  = 0.003 and β=0.32, p  = 0.006, respectively). Conclusions: hese findings emphasize the significant burden of stress experienced by HD patients and at-risk individuals. We highlight a need for more specific stress-based measures and psychosocial support interventions for HD-affected families. Show more

Keywords: Huntington’s disease, stress, depression, anxiety

DOI: 10.3233/JHD-231515

Citation: Journal of Huntington's Disease, vol. 13, no. 2, pp. 215-224, 2024

Authors: Pizzorni, Nicole | Ciammola, Andrea | Pirola, Chiara | Nanetti, Lorenzo | Castaldo, Anna | Poletti, Barbara | Mariotti, Caterina | Schindler, Antonio

Article Type: Research Article

Abstract: 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. Show more

Keywords: Huntington’s disease, deglutition disorders, disease progression, tongue

DOI: 10.3233/JHD-231519

Citation: Journal of Huntington's Disease, vol. 13, no. 2, pp. 225-235, 2024

Authors: Anderson, Karen E. | Arbatti, Lakshmi | Hosamath, Abhishek | Feigin, Andrew | Goldstein, Jody | Kayson, Elise | Kinsler, Brett L. | Falanga, Lauren | Denise, Lynn | Carlozzi, Noelle E. | Frank, Samuel | Jackson, Katie | Kostyk, Sandra | Purks, Jennifer L. | Serbin, Kenneth P. | Kinel, Shari | Beck, Christopher A. | Shoulson, Ira

Article Type: Research Article

Abstract: Background: Direct-to-participant online reporting facilitates the conduct of clinical research by increasing access and clinically meaningful patient engagement. Objective: We assessed feasibility of online data collection from adults with diagnosed Huntington’s disease (HD) who directly reported their problems and impact in their own words. Methods: Data were collected online from consenting United States residents who self-identified as 1) having been diagnosed with Huntington’s disease, 2) able to ambulate independently, and 3) self-sufficient for most daily needs. Data for this pilot study were collected using the Huntington Study Group myHDstory online research platform. The Huntington Disease Patient …Report of Problems (HD-PROP), an open-ended questionnaire, was used to capture verbatim bothersome problems and functional impact. Natural language processing, human-in-the-loop curation of verbatim reports involving clinical and experience experts, and machine learning classified verbatim-reports into clinically meaningful symptoms. Results: All 8 questionnaires in the online pilot study were completed by 345 participants who were 60.9% men, 34.5±9.9 (mean±SD) years old, and 9.5±8.4 years since HD diagnosis. Racial self-identification was 46.4% Caucasian, 28.7% African American, 15.4% American Indian/Alaska Native, and 9.5% other. Accuracy of verbatim classification was 99%. Non-motor problems were the most frequently reported symptoms; depression and cognitive impairment were the most common. Conclusions: Online research participation was feasible for a diverse cohort of adults who self-reported an HD diagnosis and predominantly non-motor symptoms related to mood and cognition. Online research tools can help inform what bothers HD patients, identify clinically meaningful outcomes, and facilitate participation by diverse and under-represented populations. Show more

Keywords: Patient-reported outcomes, Huntington’s disease, machine learning, self-report

DOI: 10.3233/JHD-231520

Citation: Journal of Huntington's Disease, vol. 13, no. 2, pp. 237-248, 2024

Authors: Sierra, Luis A. | Wynn, Amy | Lanzaro, Ella | Dzekon, Katya | Russell, Aine | Halko, Mark | Claassen, Daniel O. | Frank, Samuel | Considine, Ciaran M. | Laganiere, Simon

Article Type: Research Article

Abstract: 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. Show more

Keywords: Huntington’s disease, Stroop Color Word Test, cognition, UHDRStrademark

DOI: 10.3233/JHD-231528

Citation: Journal of Huntington's Disease, vol. 13, no. 2, pp. 249-257, 2024