{"title":"Huntington's disease clinical trials update: March 2025.","authors":"Mena Farag, Sarah J Tabrizi, Edward J Wild","doi":"10.1177/18796397251337000","DOIUrl":"10.1177/18796397251337000","url":null,"abstract":"<p><p>In this edition of the Huntington's Disease Clinical Trials Update, we expand on the ongoing phase I clinical trial of ALN-HTT02 from Alynlam Pharmaceuticals. We also report on the SAGE-718 (also known as dalzanemdor) program from Sage Therapeutics, with results of the phase II DIMENSION study and the recent termination of the open-label phase III PURVIEW study. Additionally, we discuss recent developments in the regulatory pathway for AMT-130, following discussions between uniQure and the U.S. Food and Drug Administration regarding key aspects of accelerated approval. Finally, we provide a comprehensive listing of all currently registered and ongoing clinical trials in Huntington's disease.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"191-206"},"PeriodicalIF":2.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12231940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988472","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}
Sabrina Maffi, Nicolò Zarotti, Marta Scocchia, Ferdinando Squitieri
{"title":"Childhood trauma and psychological distress during adulthood in children from Huntington's disease families: An exploratory retrospective analysis.","authors":"Sabrina Maffi, Nicolò Zarotti, Marta Scocchia, Ferdinando Squitieri","doi":"10.1177/18796397251348677","DOIUrl":"10.1177/18796397251348677","url":null,"abstract":"<p><p>BackgroundChildren of people with Huntington's disease (HD) often face a wide range of early psychological challenges which may lead to further psychological difficulties later in life.ObjectiveThis exploratory retrospective study aimed to investigate the relationship between childhood traumatic experiences and psychological difficulties during adulthood in individuals raised in HD families compared to matched controls.MethodsThirty-eight adult children of people with HD and 20 matched controls completed a demographic questionnaire, the Childhood Trauma Questionnaire-Short Form (CTQ-SF), and the Symptom Checklist-90-Revised (SCL-90-R). Mann-Whitney U Tests were used to compare groups on all measures. A multiple regression model was developed within the HD Family group to investigate which aspects of childhood trauma best predicted psychological distress in adulthood.ResultsCompared to controls, people raised in an HD family reported significantly more total childhood trauma as well emotional abuse, physical abuse, and emotional and physical neglect. Global psychological distress in adulthood, depression, and psychoticism were also observed to be significantly higher in the HD Family Group. The regression model identified childhood emotional abuse as the only significant predictor of global psychological distress in adulthood.ConclusionsGrowing up in an HD family may be significantly associated with higher levels of self-reported childhood trauma as well as psychological distress in adulthood, with emotional abuse playing a more significant role in shaping long-term mental health outcomes.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"162-170"},"PeriodicalIF":2.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199305","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}
Marja D Sepers, Cameron L Woodard, Daniel Ramandi, Haley A Vecchiarelli, Matthew N Hill, Lynn A Raymond
{"title":"Upregulation of endocannabinoid signaling in vivo restores striatal synaptic plasticity and motor performance in Huntington's disease mice.","authors":"Marja D Sepers, Cameron L Woodard, Daniel Ramandi, Haley A Vecchiarelli, Matthew N Hill, Lynn A Raymond","doi":"10.1177/18796397251337021","DOIUrl":"10.1177/18796397251337021","url":null,"abstract":"<p><p>BackgroundSynaptic dysfunction underlies early sensorimotor and cognitive deficits in Huntington's disease (HD) and precedes the degeneration of striatal spiny projection neurons and cortical pyramidal neurons. Movement selection and motor learning, which are impaired early in HD, are regulated by connections between the motor cortex, basal ganglia and thalamus. In particular, plasticity at corticostriatal synapses, including endocannabinoid-mediated long-term depression (LTD), is critical for motor learning. Previously, we found impaired endocannabinoid-mediated LTD, induced by high frequency stimulation (HFS) at corticostriatal synapses in brain slice recordings from pre-manifest HD mouse models, which was corrected by JZL184, an inhibitor of endocannabinoid 2-arachidonoyl glycerol (2-AG) degradation.ObjectiveDetermine the effects of <i>in vivo</i> JZL184 administration on YAC128 HD model and wild-type (WT) littermate mice.MethodsJZL184 was administered to mice orally over a 3-week period and their motor function was assessed using several behavioral tasks. In addition, brain tissue was collected from mice in order to quantify changes in endocannabinoid levels and measure HFS-induced plasticity at corticostriatal synapses.ResultsOral administration of JZL184 significantly increased levels of 2-AG in striatal tissue. While JZL184 treatment had no impact on open field behavior, the treatment eliminated the difference in motor learning on the rotarod task between YAC128 and WT mice. Moreover, HFS-induced striatal plasticity in YAC128 mice was normalized to WT levels after JZL184 treatment.ConclusionsThese results suggest a novel target for mitigating early symptoms of HD and support the need for clinical trials of therapies that modulate the endocannabinoid system.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"149-161"},"PeriodicalIF":2.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12231859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022453","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}
Muna Abedrabbo, Pardis Kazemian, Colúm Connolly, Blair R Leavitt
{"title":"Emerging roles of microglia and neuroinflammation in Huntington's disease: From pathophysiology to clinical trials.","authors":"Muna Abedrabbo, Pardis Kazemian, Colúm Connolly, Blair R Leavitt","doi":"10.1177/18796397251330144","DOIUrl":"https://doi.org/10.1177/18796397251330144","url":null,"abstract":"<p><p>Microglia, the resident immune cells of the central nervous system, play a pivotal role in the response to Huntington's disease (HD) pathology. Through both cell-autonomous mechanisms and exposure to external pathogenic stimuli, microglia transition from a resting to an activated state, producing pro-inflammatory cytokines and chemokines that mediate inflammation. While this inflammatory response attempts to have a neuroprotective compensatory effect, chronic microglial activation exacerbates neuroinflammation, neurodegeneration and contributes to disease progression. Evidence from postmortem analyses and neuroimaging studies indicates that activated microglia are present in various stages of HD, correlating with neuronal degeneration and clinical symptoms. Enhanced microglial activation has been identified as an early predictor of disease onset, particularly in premanifest HD, highlighting the potential of targeting microglial pathways for therapeutic interventions. This review explores microglia's dual role in HD pathophysiology, exploring their contributions to both neuroinflammation and neuroprotection. It also examines recent advances in clinical trials aimed at modulating microglial activity, paving the way for novel therapeutic strategies to alter disease progression and improve patient outcomes.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"18796397251330144"},"PeriodicalIF":2.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730320","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":"The glymphatic system in Huntington's disease.","authors":"Wenzhen Duan, Yuan Zhou, Hongshuai Liu","doi":"10.1177/18796397251331436","DOIUrl":"10.1177/18796397251331436","url":null,"abstract":"<p><p>The glymphatic system, a macroscopic waste clearance network in the brain, plays a vital role in maintaining neuronal health and brain homeostasis. Functionally analogous to the lymphatic system in other organs, the term \"glymphatic\" combines \"glial\" and \"lymphatic.\" This system facilitates the exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) in the parenchyma, aiding in the removal of soluble proteins and metabolites while distributing essential nutrients and signaling molecules. Its functionality is closely tied to aquaporin 4 (AQP4) water channels, located primarily on astrocytic endfeet, which mediate water movement between the CSF and ISF. Proper glymphatic function relies on the cellular distribution of AQP4 channels and its astroglial endfeet polarization. Emerging evidence links glymphatic dysfunction to several neurodegenerative disorders, including Huntington's disease (HD). Understanding the role of the glymphatic system in HD pathogenesis could provide novel insights into disease pathogenesis and new therapeutic approaches. This review examines the connection between glymphatic dysfunction and HD, highlighting future research directions and therapeutic advancement for HD. It explores pharmacological interventions and lifestyle modifications aimed at optimizing glymphatic function to improve HD management.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"18796397251331436"},"PeriodicalIF":2.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730393","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":"Economic burden of Huntington's disease: A systematic review.","authors":"Pooja Gokhale, Lorenzo Villa Zapata","doi":"10.1177/18796397251319209","DOIUrl":"10.1177/18796397251319209","url":null,"abstract":"<p><p>BackgroundHuntington's disease (HD) is an autosomal dominant neurodegenerative disease, characterized by progressive motor, cognitive, and psychiatric symptoms. The disease poses a significant social and economic burden.ObjectiveThis systematic review aims to characterize the global economic burden by analyzing the direct, indirect, and total costs associated with HD.MethodsA comprehensive literature search was conducted across PubMed/MEDLINE, Web of Science, and Cochrane Library from inception to June 2024. The titles and abstracts were screened independently by two reviewers and full-text, English-language articles assessing direct, indirect, and/or total costs of HD were included. The costs were converted to annual costs in 2024 United States Dollars (USD).ResultsOut of the initial 608 de-duplicated articles, 19 full-text articles were included. The articles spanned 44 years, from 1980 to 2024. The studies covered a total of 15 countries. Annual costs in 2024 USD ranged significantly by region: Americas ($2542-$90,515), Europe ($40,000-$215,020), Asia ($1915-$7132), and Oceania ($3678-$8721). The highest costs were reported in Norway ($171,842) and the UK ($215,020), while Asian countries reported substantially lower costs (China: $6469; South Korea: $6305; Taiwan: $1915-$7132).ConclusionsThe global economic burden of HD varies substantially across regions, influenced by prevalence rates, healthcare systems, and reporting methodologies. Study limitations include heterogeneous cost reporting methods, potential underestimation in cost conversions, and lack of disease severity stratification. Standardizing cost-of-illness study methodologies and developing specific quality assessment tools would enhance cross-study comparability and improve resource allocation globally.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"30-42"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458217","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}
Maud Mj Daemen, Annelien A Duits, Lucienne B van der Meer, Ruben L Andriessen, Ruth B Veenhuizen, Renske Wassenberg, Tanja Peeters, Lia de Jager, Mayke Oosterloo
{"title":"Through their eyes: A retrospective mixed-methods study on the experiences and support needs of children growing up with a parent with Huntington's disease.","authors":"Maud Mj Daemen, Annelien A Duits, Lucienne B van der Meer, Ruben L Andriessen, Ruth B Veenhuizen, Renske Wassenberg, Tanja Peeters, Lia de Jager, Mayke Oosterloo","doi":"10.1177/18796397241304333","DOIUrl":"10.1177/18796397241304333","url":null,"abstract":"<p><p>BackgroundGrowing up with a parent with Huntington's disease (HD) profoundly impacts children. However, this impact and children's needs are often misunderstood, even by professional services. Even when resources are available, children often feel that their needs are unmet, raising concerns about the adequacy of available guidance and support.ObjectiveThis study aims to offer an in-depth understanding of the multifaceted impact of growing up with a parent with HD, examining the needs for professional guidance on emotional and social aspects, and identifying specific areas where support can be improved to better aid them.MethodsThis retrospective study utilized an exploratory sequential mixed methods design, combining qualitative focus groups (<i>n </i>= 13) and a quantitative survey (<i>n </i>= 23). Qualitative data were analyzed using an inductive thematic analysis with a descriptive phenomenological approach. Quantitative data were analyzed using descriptive statistics.ResultsThe impact of HD on children extends across various domains, affecting self-development, social interactions, and family dynamics. Support received at home varied, with limited access to professional help. Support needs primarily revolved around emotional support and access to comprehensive information. Key support providers, such as parents, peers, mentors, healthcare providers and coaches with expertise in HD, play crucial roles in addressing these needs.ConclusionsThe study underscores challenges faced by children in HD families. By centering our efforts on the emotional well-being of these children, offering tailored information, involving their social network, providing community-based support, and strengthening parental support systems, we can improve the support required by children in these families.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"93-102"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12231935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458145","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":"Upcoming meetings related to Huntington's disease.","authors":"","doi":"10.1177/18796397251323357","DOIUrl":"10.1177/18796397251323357","url":null,"abstract":"","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"109"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515567","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}
Andrew M Tan, Michal Geva, Y Paul Goldberg, Henk Schuring, Bernd-Jan Sanson, Anne Rosser, Lynn Raymond, Ralf Reilmann, Michael R Hayden, Karen Anderson
{"title":"Antidopaminergic medications in Huntington's disease.","authors":"Andrew M Tan, Michal Geva, Y Paul Goldberg, Henk Schuring, Bernd-Jan Sanson, Anne Rosser, Lynn Raymond, Ralf Reilmann, Michael R Hayden, Karen Anderson","doi":"10.1177/18796397241304312","DOIUrl":"10.1177/18796397241304312","url":null,"abstract":"<p><p>Huntington's disease (HD) is a progressive neurodegenerative disorder marked by motor, cognitive, and behavioral impairments. Antidopaminergic medications (ADMs), such as VMAT2 inhibitors and antipsychotics, are commonly used to manage HD motor disturbances and behavioral disorders. For patients and caregivers, ADMs are an important tool for managing symptoms that negatively affect daily life. However, the impact of ADM use in HD is not firmly understood due to a lack of robust, systematic studies that assessed their overall effect on HD disease. A mounting body of evidence suggests these medications may be associated with worse clinical measures of cognitive function and functional impairment. While regulatory guidelines highlight adverse effects like sedation, cognitive dysfunction, and extrapyramidal symptoms, it is unclear whether ADMs directly impact disease progression or if the side effects mimic or exacerbate measures of HD symptoms in clinical trials. Given ADM effects on the central nervous system and biological uncertainty within HD outcomes, clinical trial designs should recognize the impact of ADMs on key outcomes, as measured by acceptable scales including Total Functional Capacity, Stoop Word Reading, Symbol Digit Modality Test, and the composite Unified Huntington's Disease Rating Scale. The development of novel HD interventions requires consideration of concomitant ADM use that may influence measures of disease presentation. In this review, we highlight the role of ADMs in HD management, their symptomatic benefits and potential risks, especially with high dose associated side effects, interactions with CYP2D6 inhibitors, and the individualized need for careful dose monitoring for clinical care and trial design.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"16-29"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458285","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}
Shayan Abdollah Zadegan, Frank Ramirez, Jung Woo Park, Natalia Pessoa Rocha, Erin Furr Stimming, Antonio L Teixeira
{"title":"Frequency of depression in Huntington's disease: A systematic review and meta-analysis.","authors":"Shayan Abdollah Zadegan, Frank Ramirez, Jung Woo Park, Natalia Pessoa Rocha, Erin Furr Stimming, Antonio L Teixeira","doi":"10.1177/18796397241301774","DOIUrl":"10.1177/18796397241301774","url":null,"abstract":"<p><p>BackgroundHuntington's disease (HD) is a hereditary neurodegenerative disease characterized by a combination of motor, cognitive, and mental health issues, with depression being the most common. Despite its importance, the relationship between depression and disease progression is still debatable.ObjectiveThe primary objective of this study was to examine the frequency of depression across different disease stages in individuals with HD. We also explored the associations between depression and other HD-related factors.MethodsThis systematic review comprehensively searched MEDLINE, APA PsycINFO, and Embase databases for studies on depression in individuals with HD. Pooled depression frequencies were calculated for premanifest and manifest HD. Depression was analyzed based on HD functional stages and diagnostic tools, alongside reviewing its association with various HD factors.ResultsWe assessed 6523 records and included 104 studies. Our meta-analyses revealed that the overall frequency of depression was higher in manifest HD compared to premanifest HD (0.38 vs. 0.23). However, the progression of depression did not follow a consistent pattern, with peaks occurring in earlier rather than later stages. Additionally, the frequency of depression was lower in studies using diagnostic criteria compared to those using clinical scales (0.25 vs. 0.42).ConclusionsOur findings showed that the rate of depression is high in HD and varies depending on the disease stage and the criteria used. This emphasizes the necessity for tailored and unified diagnostic criteria for depression in HD.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"43-58"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458213","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}