The human olfactory bulb in Huntington's disease: sex-specific differences in volume and gliosis.

Propagation of gut-injected AAV2/1-Htt171-82Q to the brain induces Huntington's disease-like pathology.

Huntington's disease (HD) is a neurodegenerative autosomal dominant hereditary disease caused by a CAG triplet repeat expansion mutation in the gene encoding the huntingtin (HTT) protein. The main feature of HD is the loss of striatal neurons, accompanied by metabolic and transcriptional alterations in both neural and peripheral tissues. Induced pluripotent stem cells (iPSCs) derived from a transgenic HD (TgHD) minipig model expressing a mutant HTT construct were generated to investigate early metabolic, antioxidant and DNA integrity changes associated with HD development. Gene expression analysis showed increased expression of vascular endothelial growth factor (VEGF), pyruvate dehydrogenase kinase 1 (PDK1) and glutamine-oxaloacetic transaminase 1 (GOT1), implying early metabolic alteration in TgHD iPSCs. Moreover, upregulated FANCD2/FANCI-associated nuclease 1 (FAN1) expression indicated genotoxic stress linked to early HD development. These findings suggest metabolic shifts and putative genotoxic events in the pluripotent stem cell state of the TgHD model and point to early effect of the HD mutation. The model may be suitable for evaluating potential cell therapy and in vitro differentiation of iPSCs to neurons and other cells affected in HD.

Many individuals affected by the hereditary neurological condition Huntington's disease (HD) have reported experiences of stigmatization, yet the extant literature is currently theoretically and methodologically underdeveloped. Therefore, this scoping review aimed to examine the methodological approaches and theoretical conceptualizations of stigma used and to identify areas of underrepresentation given the emerging evidence base. A systematic search of five databases and hand-searches of included papers resulted in 3273 articles. Thirty-two met predefined inclusion criteria, which included primary research reporting experiences of stigma by people with HD or who have an inherited genetic risk. Selected articles represented qualitative (59% of included papers), quantitative (22%), and mixed-methods (19%) designs. Almost half did not provide theoretical definitions of stigma. Theories describing societal unacceptance based upon a discrediting attribute of an individual by the sociologist Erving Goffman, and of discrimination solely based upon real/perceived differences from the typical genome, were most prominent among theories referenced, conceptualizing stigma and genetic discrimination respectively. Findings suggested a limited theoretical grounding of stigma in primary research exploring HD, with a lack of discussion around conceptualizations of stigma applied to people affected by HD. Future research should apply clear definitions to differentiate constructs contributing to different forms of stigma and could explore whether experiences of stigma and support needs might differ across groups affected by HD. Implications for theoretical development and multilevel interventions are also discussed.

Longitudinal and combined assessment of 24(S)-hydroxycholesterol and Neurofilament light chain in the early stages of Huntington's disease.

Extensive transcriptomic changes in cellular and animal models of Huntington's disease depending on the length of CAG repeats in the exon 1 of the HTT gene.

The Huntington's Disease Society of America (HDSA) protocol requires in-person result disclosure for predictive testing due to the increased suicidality risk in the Huntington's disease (HD) population. The 21st Century Cures Act (Cures), a United States law requiring immediate release of all healthcare test results, contradicts this protocol. There is no published literature exploring how Cures has impacted HDSA centers of excellence (CoE). This study used semi-structured interviews with 15 HDSA CoE healthcare professionals (HCPs) to explore the impact of Cures on the HDSA CoE's disclosure of predictive HD test results. Interviews were recorded, transcribed, and coded to identify recurring categories via inductive content analysis. Two-thirds of participants reported changes made due to Cures. Three major categories were identified: changes made, changes wished for, and concerns regarding immediate release of predictive HD test results. There was variability among reported workflow changes. The most requested change was embargoing release of HD results due to concerns about patient result misinterpretation, suicidality, and survivor's guilt. Published guidelines on how to navigate immediate release of HD genetic testing results could provide a standardized approach across HDSA CoE.

Guidance for predictive genetic testing for Huntington disease (HD) has been available for more than four decades and has been applied to other adult-onset hereditary conditions, especially neurogenetic conditions. Yet this protocol has not been updated since 2016 even though there have been significant changes in healthcare delivery and policy/legal issues, including widespread use of telemedicine and new legislation impacting patients' ready access to medical records. There also have been technological advances where HD status can be revealed with genomic sequencing and societal paradigm shifts away from paternalism. Even with the well-established components and content to cover for predictive genetic testing for HD, variability exists in how the guidance has been applied by different institutions across the United States. This variability in clinical practice can be attributed to multiple factors including institutional differences in clinical staffing, whether genetic counselors are licensed, and approaches to care. This article describes the protocol's history and how the above changes affect aspects of this guidance. Given these changes and growing availability of predictive genetic testing, we recommend an update to the 2016 Huntington Disease Society of America's (HDSA) protocol, suggest changes and offer interim practice guidance. In summary, because of changes in technology, laws, and healthcare, the Huntington disease protocol for predictive genetic testing needs to be updated. This paper offers recommendations for these changes.

Tetrabenazine has been shown to improve gating of abnormal visual stimuli and improve postural stability in Huntington's disease (HD) patients as measured by computerized dynamic posturography testing. This open label pilot study aims to elucidate whether partial dopaminergic depletion via low dose tetrabenazine has a similar effect on masking out of abnormal visual stimuli on the Stroop interference test in HD patients. The study endpoint is the Golden formula calculated from off and on tetrabenazine Stroop test raw scores. The study will be performed as a single arm medication de novo or withdrawal trial. Informed consent to participate will be obtained from all participants and the next of kin. The data collection instrument is the standard Stroop color naming, word reading, and interference test.Stroop test will be administered in the morning to patients who are off tetrabenazine (de novo or three-day withdrawal). 12.5 mg of TBZ will be administered just after the first Stroop test and also 3 h later. On Stroop test will to be administered 6 h after the off Stroop test.The raw Stroop word reading, color naming, and interference scores will be recorded and used for further analysis using Golden's formula.

Glucose transporter 3 gene deficiency modifies Huntington's disease progression in zQ175 model mice.

The pathological expansion of the polyglutamine (polyQ) repeat within the first exon of huntingtin (Httex1) protein is a defining hallmark of Huntington's disease (HD). Multiple evidence supports that the membrane recruitment of Httex1 is critical for its self-assembly and related toxicity in HD. In this work, we quantitatively examined the early steps of monomeric Httex1(23Q) association with lipid membranes and its impact on the conformational dynamics of the adjacent polyQ regions-the N-terminal N17 segment and C-terminal proline-rich region (PRR). A broad range of membrane physical properties was explored, including zwitterionic and anionic lipids, and also co-existing liquid-ordered and liquid-disordered phases. Two single cysteine mutants were engineered at the N- and C-termini of Httex1(23Q) and fluorescently labeled with acrylodan or Atto 488 to probe their local polarity and flexibility, respectively. Our results indicate that Httex1(23Q) preferentially binds to negatively charged lipid vesicles, and to a lower extent to liquid ordered/disordered phases. The N-terminal N17 segment interacts with anionic membranes, adopting a less flexible state than in aqueous solution. At variance, the C-terminal PRR remains highly dynamic and solvent exposed in the Httex1(23Q) membrane-bound state, preserving its intrinsic disordered features across all lipid compositions used. Altogether, our work provides quantitative insight into the distinct roles of each flanking polyQ region in mediating Httex1-lipid binding, and how distinct lipid compositions further modulate these early interaction steps.

Amyloid fibrils are involved in devastating conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and systemic amyloidosis. They exhibit polymorphism, meaning that a single protein sequence can adopt different amyloid folds that vary with time and self-assembly conditions. Polymorphism confounds structure-based drug design and raises fundamental questions regarding why particular fibril structures form and how they cause disease. Here, we highlight the latest advances in our understanding of amyloid polymorphism, including its structural basis, thermodynamic origins, kinetic influences, and significance for disease. The next frontier will be to predict fibril structures, disentangle the dynamic mechanisms that guide the progression of fibril polymorphs, and illuminate how cofactors and the physiological milieu select for particular polymorphs in disease.

Molecular insights into SEN177 binding to human glutaminyl cyclase: a combined MD and DFT study.

Agmatine interaction with imidazoline receptor inhibits manifestation of depression-like behavior in 3-Nitropropionic acid-induced Huntington's disease-like phenotype in rats.

Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) cause progressive loss of specific neuronal populations and currently lack curative therapies. Animal models and immortalized cell lines incompletely recapitulate human pathology and genetic heterogeneity, limiting drug discovery. Human induced pluripotent stem cells (iPSCs) provide a patient‑specific platform for disease modelling, drug screening and studying individual responses. Translational research (TR) uses iPSC models to identify candidate therapies that are subsequently tested in clinical trials, while reverse translational research (rTR) feeds clinical observations back to the bench by analyzing iPSCs derived from trial participants and integrating molecular data with patient phenotypes. This review summarizes recent advances in iPSC‑based TR and rTR for ALS and extends the discussion to other neurodegenerative diseases. Key clinical trials launched from iPSC screens-ropinirole, retigabine and bosutinib-are reviewed alongside emerging rTR efforts that use patient‑derived iPSCs to identify biomarkers and therapeutic mechanisms. We also survey iPSC models for AD, PD and HD, highlighting applications of three‑dimensional (3D) brain organoids and gene‑editing technologies. Finally, we discuss future directions for precision medicine, multimodal integration and technological challenges, with particular attention to how imaging biomarkers may complement iPSC-based TR/rTR frameworks in neurodegenerative diseases.

Assessment and monitoring of Huntington's disease (HD) symptoms remain limited to infrequent, clinic-based evaluations. We evaluated whether fully automated linguistic analysis of speech tasks recorded via smartphone can remotely capture core clinical markers of HD severity. In this cross-sectional multicenter study across Czech and German sites, 53 participants, including 30 HD (9 pre-symptomatic, 3 prodromal, and 18 manifest) and 23 healthy controls, completed a smartphone-based speech assessment, including spontaneous monologue and fairy tale retelling for 7 consecutive days. Recordings were automatically transcribed and analyzed using natural language processing to derive 3 lexical and 3 syntactic features. Predictive models for clinical outcomes based on the Unified Huntington's Disease Rating Scale and cognitive scales were built using multivariate linear regression with cross-validation. Linguistic features predicted HD severity across multiple domains with high predictive performance, explaining up to 57% of the variance in cognitive performance, 63% in motor impairment, and 59% in functional capacity. A median of 6 days for monologue and 3 for retelling was sufficient to reach 90% of maximal predictive performance. Compared to controls, HD participants showed reduced vocabulary range and increased phrase repetition in both tasks (p < 0.05), with additional monologue-specific deficits in sentence length (p = 0.018) and syntactic complexity (p = 0.004). Fully automated analysis of smartphone-based language assessment can remotely quantify cognitive, motor, and functional impairment in HD, offering a scalable, low-burden digital biomarker for clinical trials and decentralized monitoring.

Sleep in Huntington's disease gene expansion carriers: A systematic review.

Extracellular Vesicles as Paradigm Shifters: Transformative Roles in Diagnosis and Therapy for Brain Disorders.

The long-term averaged spectrum (LTAS) may provide a universal method for capturing distinct patterns of dysarthria. This study aimed to evaluate the sensitivity of LTAS descriptors in a broad range of neurological diseases and various types and severities of dysarthria. Four spectral moments of spectral mean, spectral standard deviation, spectral skewness and spectral kurtosis based on LTAS were computed for reading passage collected from 461 speakers, including 306 healthy controls and 155 neurological patients secondary to Parkinson's disease (PD), progressive supranuclear palsy, multiple system atrophy (MSA), Huntington's disease, essential tremor, cerebellar ataxia (CA), multiple sclerosis (MS), and amyotrophic lateral sclerosis. Compared to controls, the spectral mean was significantly lower in PD and MS while elevated in CA. Significantly changed LTAS features were observed only in hypokinetic dysarthria and in mixed dysarthrias manifesting hypokinetic elements. Although LTAS features differed between controls and patients with varying degrees of dysarthria, there was no progressive increase in dysarthria severity. Our findings suggest that LTAS-based speech analysis may provide valuable cues to aid differential diagnosis among neurological diseases with overlapping clinical features. LTAS appears more informative when applied to specific diseases than to pooled dysarthria types arising from diverse neurological etiologies.

With growing insights into brain networks and neurodegenerative diseases (NDDs), it has become evident that alterations in gene expression often arise from epigenetic regulation rather than changes in DNA sequence. Consequently, extensive research has centered on understanding the epigenetic role in the pathophysiology of Alzheimer's, Parkinson's, and Huntington's disease. Epigenetic modifications are essential for maintaining cellular homeostasis by dynamically controlling gene expression, and their characterization may provide greater understanding into disease mechanisms and potential therapeutic targets. A deeper understanding of these regulatory processes may offer valuable insights into disease mechanisms and reveal new therapeutic avenues. Despite significant progress, the influence of epigenetic modifiers on intracellular signaling pathways governing neuronal survival and degeneration remains poorly understood. Notably, the interaction between DOT1L-mediated histone methylation and RIPK1 signalling is still insufficiently explored, representing an important gap in current knowledge. This review emphasizes the emerging interplay between DOT1L and RIPK1 in the regulation of the cell-death pathway, underscoring their potential role in modulating neuronal survival in NDDs.