Journal of Huntington's disease最新文献

BackgroundRecent evidence suggests that accumulation of mutant exon 1 protein (HTT1a) may be critical to HD pathogenesis, but the relation of this to differential regional and cellular vulnerability in HD is unknown.ObjectiveWe assessed the contribution of the accumulation of the mutant huntingtin HTT1a to the regional and cellular variation in HD brain pathology by determining if more vulnerable regions and neuron types were relatively enriched.MethodsWe performed immunolabeling using the novel monoclonal antibodies 11G2 and 1B12 against the C-terminal proline 90 (P90) neoepitope of huntingtin HTT1a, which detect accumulation of monomeric, oligomeric and aggregated mutant HTT1a, on forebrain of Q175 and R6/2 mice and human HD cases.ResultsDiffuse nuclear and aggregate immunolabeling increased in abundance in Q175 with age, with striatal projection neurons showing immunolabeling earlier than cortical neurons, and only neuropil immunolabeling prominent in pallidal regions. Nonetheless, some regions less affected in HD, such as hippocampus, were rich in mutant HTT1a as well. In humans, striatal immunolabeling was sparser than in mouse, and mainly in the neuropil, but sparser in striatal target areas. In human HD cortex, the P90 antibodies detected predominantly neuropil aggregates, which appeared to, in part, localize to dendrites. Immunostaining in mouse and human could be blocked with HTT1a target peptide, demonstrating antibody specificity.ConclusionsOur results indicate that mutant HTT1a burden appears to partly account for overall differential forebrain regional vulnerability in HD, but additional factors may contribute to vulnerability differences among forebrain regions and between specific neuron types.

BackgroundComputerized cognitive training (CCT) has been found to improve cognition by altering functional activity and functional connectivity of brain networks in people with and without cognitive impairment. The effects of CCT on functional brain networks in Huntington's disease (HD) have not been comprehensively examined.ObjectiveIn our pilot trial of CCT, we aimed to explore effects of CCT on functional activity and connectivity of fronto-striatal regions during processing speed and cognitive flexibility tasks, and functional connectivity of resting-state networks in HD.MethodsSixteen participants in pre-manifest and early stages of HD were randomised to either a 12-week multi-domain CCT intervention (n = 6) or lifestyle education (n = 10). Participants completed a 1-h magnetic resonance imaging (MRI) scan at baseline and follow-up, which included task-based and resting-state functional MRI. Analyses examined changes in functional activity and connectivity of fronto-striatal regions during processing speed and cognitive flexibility task performance, as well as functional connectivity within default mode and frontoparietal resting-state networks.ResultsWhile there was evidence of benefits to in-scanner task performance, there were no significant effects on functional activity or functional connectivity of fronto-striatal regions during task performance, or resting-state functional connectivity.ConclusionCCT did not generate significant effects on functional activity or connectivity of fronto-striatal networks associated with processing speed or cognitive flexibility, or resting-state networks in HD. A larger study is required to further examine the effects of CCT on functional brain outcomes and potential moderating factors.

BackgroundGene silencing is widely recognized as a promising therapeutic approach for dominant monogenic disorders. Current silencing strategies, many of which are transient, utilize RNA interference. Gene silencing may also be achieved through directed epigenetic editing using a CRISPR/dCas9 effector fused to DNA methyltransferase 3A (dCas9-DNMT3A). We used this system to direct DNA methylation to HTT, the causal gene underlying the autosomal dominant neurodegenerative disorder Huntington's disease, to assess the translational potential of this strategy for treating a genetic neurological disease.ObjectiveTo characterize the regulatory effect of targeted dCas9-DNMT3A-mediated DNA methylation at HTT.MethodsWe exploited DNA methylation profiles of high and low HTT-expressing tissues and targeted hypomethylated regions of HTT associated with high levels of HTT expression.ResultsDe novo DNA methylation of loci within defined upstream, promoter, intragenic and downstream regions of HTT resulted in robust, acute silencing of HTT. The best long-term silencing of HTT, which persisted up to 30 days, was observed when targeted DNA methylation was directed to the 5'UTR and promoter regions of HTT.ConclusionsHTT gene silencing may be achieved via targeted de novo DNA methylation within hypomethylated regulatory regions at the HTT locus. DNA methylation editing may be an attractive therapeutic approach for Huntington disease due to its potential for long-term silencing and reversibility.

BackgroundHuntington's Disease-like 2 (HDL2) presents complexities in diagnosis due to its similarity to Huntington's Disease (HD). Limited research highlights gaps in knowledge about management and genetic counselling for the condition. HDL2 is rare but an important differential diagnosis for individuals with HD-like symptoms who have tested negative for HD.ObjectiveThis review aimed to synthesise published clinical and genetic data on HDL2, identify knowledge gaps, and serve as a resource for healthcare professionals supporting individuals affected by or at risk of HDL2.MethodsA mixed method integrative systematic review of four databases (Medline, Embase, Scopus, and PsycINFO) generated 323 peer-reviewed articles, of which 36 were included. Data about clinical features, genetic testing and counselling, and patient experiences were interpreted via narrative synthesis.ResultsThe majority of included studies explored the clinical features, genetic testing results and medical histories of individuals with HDL2. A total of 109 people with HDL2 were reported. Limited data was obtained about genetic counselling, management and support, and experiences of those with HDL2 and their families. Findings related to seven categories: DNA repeat length and impact on phenotype, age of onset and disease duration, family history, African ancestry, neurological characteristics, clinical characteristics, and experiences and support.ConclusionsThis review highlights the importance of understanding the reduced penetrance range and early psychiatric symptoms in HDL2 for accurate genetic counselling and interpretation of test results. Adapting existing protocols for HD and qualitatively collecting patient experiences can inform the development of a HDL2 genetic testing and counselling protocol.

This piece recounts the deeply personal journey of the author (Alex) in supporting families affected by Huntington's Disease (HD) in Barranquitas, Venezuela. The author draws a parallel between her childhood fascination with small spaces and the overlooked potential for innovation within small communities, especially Barranquitas, which played a pivotal part in the HD genetics research led by Dr Nancy Wexler in the 1980s and 1990s. The narrative details Alex's involvement with Factor-H and Habitat Luz, NGOs dedicated to aiding HD families in Latin America by providing essential resources, health support, and caregiver assistance amidst political and economic turmoil. The story highlights the challenges faced by the communities, and the emotional impact for Alex of witnessing extreme neglect. It describes Alex's leadership in establishing the Caregivers' Programme and pursuing imaginative solutions, such as a roving caregiving team, an innovation that was recognized by the prestigious Amgen Prize for Rare Diseases. The author underscores the ongoing commitment of Factor-H and Habitat Luz to improving lives in a community where state support is minimal and caregiving often remains an invisible but vital responsibility that we all have in the era of therapeutic advancement.

BackgroundHuntington's disease (HD) is a neurodegenerative disorder caused by CAG expansions in the Huntingtin (HTT) gene. Due to its non-specific and variable phenotype, diagnosis requires clinical assessments and genetic testing. In the Caribbean, the genetic etiology of HD is underexplored due to the unavailability of genetic testing.ObjectiveWe investigated whether 32 participants from four multigenerational families from Trinidad and Tobago (T&T) presenting with Huntington-like symptoms carried HTT CAG expansions, and whether CAG length was related to decreasing age of onset with each generation.MethodsParticipants were genotyped using triplet repeat primed PCR followed by previously-established fragment analysis and a nanopore sequencing based method with a custom bioinformatics workflow.ResultsAll symptomatic participants carried HTT CAG expansions (42-57 CAGs), confirming HD. Among participants aged 20-65 years (n = 24), clinical and genetic diagnoses were concordant for 22 participants (13 symptomatic with 42-57 CAGs, and nine asymptomatic with 13-27 CAGs). Two asymptomatic participants aged 22 and 43 years carried 46-47 and 37-39 CAGs, respectively. Among eight participants <18 years, one symptomatic 16-year-old carried 49-50 CAGs, and seven are currently asymptomatic (three with 50-52 CAGs, and four with 14-17 CAGs). In three families, decreasing age of onset and increasing CAG length were observed in each successive generation. Methods were highly correlated (R² = 0.998).ConclusionsWe demonstrated the application of nanopore sequencing with a custom bioinformatics workflow to estimate the size of HTT CAG repeats. This is the first genetic report of HD in T&T, among limited records in the Caribbean.

BackgroundHuntington's disease (HD) is a hereditary neurodegenerative disorder, with pathological changes detectable by MRI before symptom onset. Quantitative MRI (qMRI) provides tissue-specific parameters and holds potential for capturing disease-related biomarkers. However, conventional analysis methods often rely on single-modality imaging or mean features, constraining their ability to capture HD's complex microstructural evolution.PurposeTo assess the feasibility of multi-modal MRI combined with the MOLED sequence in HD patients and explore its value in early disease detection and staging.Methods22 HD patients (14 Pre-HD and 8 M-HD) and 27 healthy controls were enrolled. MOLED-derived T2 and T2* maps, along with structural MRI, were acquired using two 3.0 T scanners to assess inter-scanner consistency. The MOLED sequence incorporates ultrafast acquisition techniques to minimize motion artifacts and improve image quality. Histogram-based features (e.g., variance, skewness, and maximum) and volumes were extracted from eight deep brain regions. Multiple machine learning models were employed for classification analysis.ResultsThe MOLED demonstrated good image consistency and reproducibility across scanners. Significant group differences were observed in the volumes of several basal ganglia regions and in variance-based features across multiple modalities. Machine learning models combining clinical and mapping features achieved the highest classification performance (maximum F1-macro = 0.846, Sensitivity-macro = 0.838).ConclusionMOLED provides stable and complementary quantitative information for multi-modal MRI. Integrating multimodal multi-feature with machine learning enables a more comprehensive depiction of HD-related microstructural heterogeneity and disease progression.

Huntington's disease (HD) has traditionally been viewed as a late-onset neurodegenerative disorder. However, emerging evidence suggests that differences in the stoichiometry of wild-type huntingtin (HTT) and mutant huntingtin (mHTT) exert a complex spectrum of pathogenic effects during early brain development, preceding the onset of overt clinical signs by several decades. In this review, we examine how various HD mouse models have revealed distinct yet frequently converging developmental abnormalities through the dynamic interplay of novel early pathogenic and homeostatic processes. Full-length transgenic models like BACHD demonstrate early glial dysmaturation, corticostriatal synaptic deficits, and behavioral phenotypes emerging during infancy. Truncated fragment models such as R6/2 exhibit aggressive phenotypes resembling juvenile HD, with early neuronal and myelination defects. Knock-in models, including HdhQ111, HdhQ140, and zQ175, highlight CAG-length-dependent disruptions in neural progenitor cell dynamics, synaptic formation, and cortical plasticity. Loss-of-function models further implicate wild-type HTT in neural patterning and germ layer specification, recapitulating HD-like features in the absence of mHTT overexpression. Together, these models underscore a developmental dimension to HD pathogenesis and suggest that early-life circuit miswiring, glial dysfunction, and impaired integrity of the specification, maturation, and maintenance of neural cell identity and functions may prime the brain for later neurodegeneration. Understanding these early disruptions is essential for identifying novel early therapeutic windows, biomarkers, and molecular targets essential for devising true disease-modifying paradigms aimed at delaying, reversing, or even preventing the onset of disease hallmarks.

BackgroundHuntington's disease (HD) is a neurodegenerative disorder caused characterized by motor, cognitive, and psychiatric/behavioral impairments. Among these symptoms, irritability is particularly burdensome due to its frequency and significant impact on the daily lives of both patients and caregivers. Currently, no FDA-approved medication specifically targets this symptom.ObjectiveTo assess the efficacy of dextromethorphan/quinidine (DM/Q) 20/10 mg (NUEDEXTA^®) in managing irritability in HD.MethodsDouble-blind, placebo-controlled, randomized, crossover clinical trial. Participants underwent a 13-week study: six weeks of DM/Q treatment, one-week washout, and six weeks of placebo. The DM/Q 20/10 mg regimen started with a once-daily dose, increased to twice daily after the first week, and tapered back to once daily in the sixth week. Participants were evaluated during three in-person visits: at baseline and at the end of each treatment phase. Assessments included motor and cognitive exams, the Irritability Scale, and the Problem Behavior Assessment-short version (PBA-s) (ClinicalTrials.gov NCT03854019).ResultsTwenty participants were enrolled, with 18 completing the study (mean age = 43.94 ± 10.70 years, 11 females and 7 males). Both DM/Q and placebo reduced mean Irritability Scale scores (32% and 27.5%, respectively) and the irritability subscale of the PBA-s (42% and 33%, respectively), with no statistically significant differences between groups. Additionally, DM/Q showed no significant advantage over placebo in motor, behavioral, or cognitive outcomes.ConclusionDM/Q did not demonstrate significant benefits in managing irritability compared to placebo. Further research with larger sample sizes and alternative therapeutic strategies is needed to effectively address this symptom in HD.

Two- and three-dimensional (2D and 3D) cell models derived from human stem cells have shed light on a wide range of molecular and cellular features of Huntington's disease (HD). Here we review the use of human stem cell-derived models to explore neurodevelopmental contributions to HD. We provide a timeline of key advances made in 2D and 3D model systems, ranging from differentiated monocultures to brain-like organoids and assembloids. Models along this spectrum have advanced our understanding of various disease-associated characteristics including disease protein (huntingtin) aggregation, somatic repeat instability, transcriptional dysregulation, perturbations in neurodevelopmental staging, and neural circuitry. We highlight recent findings in brain-like organoids which, despite being a relatively recent innovation, are proving to be a promising tool with which to study aberrant neurodevelopmental features of HD. All models have their limitations, and we compare and contrast the utility and limitations of various stem cell-based methods to study HD. Finally, we speculate on future advances employing advanced computational and transcriptomic methods that will expand the power of 3D model systems for the study of HD and related neurodegenerative disorders.