Journal of Huntington's disease最新文献

{"title":"Genetic Interventions for Spinocerebellar Ataxia and Huntington's Disease: A Qualitative Study of the Patient Perspective.","authors":"Nienke J H van Os, Mayke Oosterloo, Brigitte A B Essers, Janneke P C Grutters, Bart P C van de Warrenburg","doi":"10.3233/JHD-240026","DOIUrl":"10.3233/JHD-240026","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>To obtain insight into the thoughts and perspectives of individuals with SCA and HD on genetic interventions.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"321-328"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards Standardizing Nomenclature in Huntington's Disease Research.","authors":"Marian DiFiglia, Blair R Leavitt, Douglas Macdonald, Leslie M Thompson","doi":"10.3233/JHD-240044","DOIUrl":"10.3233/JHD-240044","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"13 2","pages":"119-131"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11307060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats.","authors":"Russell G Wells, Azzam F Azzam, Amie L Hiller, Michael F Sardinia","doi":"10.3233/JHD-231507","DOIUrl":"10.3233/JHD-231507","url":null,"abstract":"<p><strong>Background: </strong>Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric dysfunction caused by a mutant huntingtin protein. Compromised metabolic activity resulting from systemic administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), is known to mimic the pathology of HD and induce HD-like symptoms in rats. N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408), also known as Dihexa, has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer's and Parkinson's diseases. Given the mechanism of action and success in other neurodegenerative diseases, we felt it an appropriate compound to investigate further for HD.</p><p><strong>Objective: </strong>The present study was designed to test if PNB-0408, an angiotensin IV analog, could attenuate 3-NP-induced HD-like symptoms in rats and serve as a potential therapeutic agent.</p><p><strong>Methods: </strong>Forty male Wistar rats were randomized into three groups consisting of a \"vehicle\" group, a \"3-NP\" group, and a \"3-NP + PNB-0408\" group. PNB-0408 was administered along with chronic exposure to 3-NP. Animal body weight, motor function, and cognitive abilities were measured for five weeks, before euthanasia and histopathological analysis.</p><p><strong>Results: </strong>Exposure to 3-NP decreased the amount of weight rats gained, impaired spatial learning and memory consolidation, and led to marked motor dysfunction. From our observations and analysis, PNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity.</p><p><strong>Conclusions: </strong>Our findings suggest that PNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model. These data highlight the need for further research of this compound in alternate models and/or alternative approaches to managing this disorder.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"55-66"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140136908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroimaging to Facilitate Clinical Trials in Huntington's Disease: Current Opinion from the EHDN Imaging Working Group.","authors":"Nicola Z Hobbs, Marina Papoutsi, Aline Delva, Kirsi M Kinnunen, Mitsuko Nakajima, Koen Van Laere, Wim Vandenberghe, Priyantha Herath, Rachael I Scahill","doi":"10.3233/JHD-240016","DOIUrl":"10.3233/JHD-240016","url":null,"abstract":"<p><p> 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.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"163-199"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11307036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Review of Juvenile Huntington's Disease.","authors":"Mayke Oosterloo, Alexiane Touze, Lauren M Byrne, Jannis Achenbach, Hande Aksoy, Annabelle Coleman, Dawn Lammert, Martha Nance, Peggy Nopoulos, Ralf Reilmann, Carsten Saft, Helen Santini, Ferdinando Squitieri, Sarah Tabrizi, Jean-Marc Burgunder, Oliver Quarrell","doi":"10.3233/JHD-231523","DOIUrl":"10.3233/JHD-231523","url":null,"abstract":"<p><p> 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.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"149-161"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11307030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140856129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Freesurfer Software Update Significantly Impacts Striatal Volumes in the Huntington's Disease Young Adult Study and Will Influence HD-ISS Staging.","authors":"Harry Knights, Annabelle Coleman, Nicola Z Hobbs, Sarah J Tabrizi, Rachael I Scahill","doi":"10.3233/JHD-231512","DOIUrl":"10.3233/JHD-231512","url":null,"abstract":"<p><strong>Background: </strong>The Huntington's Disease Integrated Staging System (HD-ISS) defined disease onset using volumetric cut-offs for caudate and putamen derived from FreeSurfer 6 (FS6). The impact of the latest software update (FS7) on volumes remains unknown. The Huntington's Disease Young Adult Study (HD-YAS) is appropriately positioned to explore differences in FS bias when detecting early atrophy.</p><p><strong>Objective: </strong>Explore the relationships and differences between raw caudate and putamen volumes, calculated total intracranial volumes (cTICV), and adjusted caudate and putamen volumes, derived from FS6 and FS7, in HD-YAS.</p><p><strong>Methods: </strong>Images from 123 participants were segmented and quality controlled. Relationships and differences between volumes were explored using intraclass correlation (ICC) and Bland-Altman analysis.</p><p><strong>Results: </strong>Across the whole cohort, ICC for raw caudate and putamen was 0.99, cTICV 0.93, adjusted caudate 0.87, and adjusted putamen 0.86 (all p < 0.0005). Compared to FS6, FS7 calculated: i) larger raw caudate (+0.8%, p < 0.00005) and putamen (+1.9%, p < 0.00005), with greater difference for larger volumes; and ii) smaller cTICV (-5.1%, p < 0.00005), with greater difference for smaller volumes. The systematic and proportional difference in cTICV was greater than raw volumes. When raw volumes were adjusted for cTICV, these effects compounded (adjusted caudate +7.0%, p < 0.00005; adjusted putamen +8.2%, p < 0.00005), with greater difference for larger volumes.</p><p><strong>Conclusions: </strong>As new software is released, it is critical that biases are explored since differences have the potential to significantly alter the findings of HD trials. Until conversion factors are defined, the HD-ISS must be applied using FS6. This should be incorporated into the HD-ISS online calculator.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"77-90"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140136909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mono- and Biallelic Inactivation of Huntingtin Gene in Patient-Specific Induced Pluripotent Stem Cells Reveal HTT Roles in Striatal Development and Neuronal Functions.","authors":"Morgane Louessard, Michel Cailleret, Margot Jarrige, Julie Bigarreau, Sophie Lenoir, Noëlle Dufour, Maria Rey, Frédéric Saudou, Nicole Deglon, Anselme L Perrier","doi":"10.3233/JHD-231509","DOIUrl":"10.3233/JHD-231509","url":null,"abstract":"<p><strong>Background: </strong>Mutations in the Huntingtin (HTT) gene cause Huntington's disease (HD), a neurodegenerative disorder. As a scaffold protein, HTT is involved in numerous cellular functions, but its normal and pathogenic functions during human forebrain development are poorly understood.</p><p><strong>Objective: </strong>To investigate the developmental component of HD, with a specific emphasis on understanding the functions of wild-type and mutant HTT alleles during forebrain neuron development in individuals carrying HD mutations.</p><p><strong>Methods: </strong>We used CRISPR/Cas9 gene-editing technology to disrupt the ATG region of the HTT gene via non-homologous end joining to produce mono- or biallelic HTT knock-out human induced pluripotent stem cell (iPSC) clones.</p><p><strong>Results: </strong>We showed that the loss of wild-type, mutant, or both HTT isoforms does not affect the pluripotency of iPSCs or their transition into neural cells. However, we observed that HTT loss causes division impairments in forebrain neuro-epithelial cells and alters maturation of striatal projection neurons (SPNs) particularly in the acquisition of DARPP32 expression, a key functional marker of SPNs. Finally, young post-mitotic neurons derived from HTT-/- human iPSCs display cellular dysfunctions observed in adult HD neurons.</p><p><strong>Conclusions: </strong>We described a novel collection of isogenic clones with mono- and biallelic HTT inactivation that complement existing HD-hiPSC isogenic series to explore HTT functions and test therapeutic strategies in particular HTT-lowering drugs. Characterizing neural and neuronal derivatives from human iPSCs of this collection, we show evidence that HTT loss or mutation has impacts on neuro-epithelial and striatal neurons maturation, and on basal DNA damage and BDNF axonal transport in post-mitotic neurons.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"41-53"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11091579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140012734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intensification of Diurnal Abnormal Movements During Sleep in Huntington's Disease.","authors":"Louis Salaun, Thomas Bonduelle, Imad Ghorayeb, Umberto Spampinato, Sabrina Debruxelles, Dominique Guehl, Cyril Goizet","doi":"10.3233/JHD-231518","DOIUrl":"10.3233/JHD-231518","url":null,"abstract":"<p><p>Huntington's disease (HD) is a rare neurodegenerative disorder with a distinct phenotype, including involuntary movements, cognitive decline, and behavioral disturbances. Sleep disorder include insomnia, increased sleep onset latency, decrease in total sleep time with frequent nocturnal awakenings and excessive daytime sleepiness. Increased sleep motor activities and abnormal nocturnal agitation have been increasingly recognized as an important component affecting negatively the sleep quality. Here, we report a case of an intensification of diurnal choreic movement during the night, notably during REM-sleep in a patient with manifest HD. This case highlights the diversity of nocturnal sleep motor disorders encountered in HD.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"259-262"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective Proteolysis in Huntington's Disease: Unraveling the Role of Post-Translational Myristoylation of Huntingtin in Autophagy.","authors":"Yasmeen Alshehabi, Dale D O Martin","doi":"10.3233/JHD-240028","DOIUrl":"10.3233/JHD-240028","url":null,"abstract":"<p><p> 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.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"267-277"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141600248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rasch Measurement Theory (RMT) Analyses of the Huntington's Disease Everyday Functioning (Hi-DEF) to Evaluate Item Fit and Performance.","authors":"Jennifer Petrillo, Ruta Sawant, Emma Elliott, Sophie Cleanthous, Rebecca Rogers, Stefan Cano, Sarah Baradaran, Jason Johannesen","doi":"10.3233/JHD-240001","DOIUrl":"10.3233/JHD-240001","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>To assess the measurement properties and finalize item content of the Hi-DEF.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"385-397"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}