23,635 results on '"Huntington's disease"'
Search Results
2. Safety and Proof-of-Concept (POC) Study With AMT-130 in Adults With Early Manifest Huntington's Disease
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- 2024
3. At-Home Research Study for Patients With Autoimmune, Inflammatory, Genetic, Hematological, Infectious, Neurological, CNS, Oncological, Respiratory, Metabolic Conditions
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- 2024
4. Impacts of H2O2, SARM1 inhibition, and high NAm concentrations on Huntington's disease laser‐induced degeneration
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Barber, Sophia, Gomez‐Godinez, Veronica, Young, Joy, Wei, Abigail, Chen, Sarah, Snissarenko, Anna, Chan, Sze Sze, Wu, Chengbiao, and Shi, Linda
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Analytical Chemistry ,Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Brain Disorders ,Neurosciences ,Neurodegenerative ,Huntington's Disease ,Rare Diseases ,Neurological ,axonal damage ,cell morphology ,dorsal root ganglion cells ,Huntington's disease ,laser cutting ,neurons ,Optical Physics ,Medical Biotechnology ,Optoelectronics & Photonics ,Analytical chemistry ,Medicinal and biomolecular chemistry - Abstract
Axonal degeneration is a key component of neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease, and amyotrophic lateral sclerosis. Nicotinamide, an NAD+ precursor, has long since been implicated in axonal protection and reduction of degeneration. However, studies on nicotinamide (NAm) supplementation in humans indicate that NAm has no protective effect. Sterile alpha and toll/interleukin receptor motif-containing protein 1 (SARM1) regulates several cell responses to axonal damage and has been implicated in promoting neuronal degeneration. SARM1 inhibition seems to result in protection from neuronal degeneration while hydrogen peroxide has been implicated in oxidative stress and axonal degeneration. The effects of laser-induced axonal damage in wild-type and HD dorsal root ganglion cells treated with NAm, hydrogen peroxide (H2 O2 ), and SARM1 inhibitor DSRM-3716 were investigated and the cell body width, axon width, axonal strength, and axon shrinkage post laser-induced injury were measured.
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- 2024
5. Neurodevelopment Is Dependent on Maternal Diet: Placenta and Brain Glucose Transporters GLUT1 and GLUT3
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Daida, Tomoko, Shin, Bo-Chul, Cepeda, Carlos, and Devaskar, Sherin U
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Medical Physiology ,Biomedical and Clinical Sciences ,Intellectual and Developmental Disabilities (IDD) ,Neurosciences ,Mental Health ,Pediatric ,Behavioral and Social Science ,Nutrition ,Brain Disorders ,Autism ,Diabetes ,Complementary and Integrative Health ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Neurological ,Reproductive health and childbirth ,Glucose Transporter Type 3 ,Humans ,Pregnancy ,Brain ,Placenta ,Female ,Glucose Transporter Type 1 ,Neurodevelopmental Disorders ,Animals ,Maternal Nutritional Physiological Phenomena ,Diet ,Ketogenic ,Diet ,High-Fat ,Neurodegenerative Diseases ,Glucose ,glucose transporter ,glucose transporter 3 ,maternal diet ,postnatal diet ,neurodevelopment ,neurodevelopmental disorders ,neurodegenerative disorders ,Huntington's disease ,brain ,placenta ,Huntington’s disease ,Food Sciences ,Nutrition and Dietetics ,Clinical sciences ,Nutrition and dietetics ,Public health - Abstract
Glucose is the primary energy source for most mammalian cells and its transport is affected by a family of facilitative glucose transporters (GLUTs) encoded by the SLC2 gene. GLUT1 and GLUT3, highly expressed isoforms in the blood-brain barrier and neuronal membranes, respectively, are associated with multiple neurodevelopmental disorders including epilepsy, dyslexia, ADHD, and autism spectrum disorder (ASD). Dietary therapies, such as the ketogenic diet, are widely accepted treatments for patients with the GLUT1 deficiency syndrome, while ameliorating certain symptoms associated with GLUT3 deficiency in animal models. A ketogenic diet, high-fat diet, and calorie/energy restriction during prenatal and postnatal stages can also alter the placental and brain GLUTs expression with long-term consequences on neurobehavior. This review focuses primarily on the role of diet/energy perturbations upon GLUT isoform-mediated emergence of neurodevelopmental and neurodegenerative disorders.
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- 2024
6. Enroll -HD: A Prospective Registry Study in a Global Huntington's Disease Cohort
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- 2024
7. A Study to Evaluate the Effect of SAGE-718 on Cognitive Function in Participants With Huntington's Disease (HD)
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- 2024
8. Skin Tau Quantification as a Novel Biomarker in Huntington's Disease.
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Ruiz‐Barrio, Iñigo, Vázquez‐Oliver, Anna, Puig‐Davi, Arnau, Rivas‐Asensio, Elisa, Perez‐Perez, Jesus, Fernandez‐Vizuete, Cristina, Horta‐Barba, Andrea, Olmedo‐Saura, Gonzalo, Salvat‐Rovira, Nil, Sampedro, Frederic, Vacchi, Elena, Melli, Giorgia, Pagonabarraga, Javier, Kulisevsky, Jaime, and Martinez‐Horta, Saul
- Abstract
Background Objective Methods Results Conclusions Emerging research implicates tau protein dysregulation in the pathophysiology of Huntington's disease.This study investigated skin tau quantification as a potential biomarker for Huntington's disease and its correlation with disease burden outcomes.In this cross‐sectional study, we measured skin tau levels using enzyme‐linked immunosorbent assay in 23 Huntington's disease mutations carriers and eight control subjects, examining group discrimination, correlations with genetic markers, clinical assessments, and neuroimaging data. Brain atrophy was quantified by both volumetric measurements from brain segmentation and a voxel‐based morphometry approach.Our findings showed elevated skin tau levels in manifest Huntington's disease compared with premanifest and healthy controls. These levels correlated with CAG repeat length, CAG‐Age‐Product score, composite Unified Huntington's Disease Rating Scale Total Motor Score, cognitive assessments, and disease‐related cortical and subcortical volumes, all independent of age and gender. Using skin tau levels in cluster analysis along with genetic and clinical measures led to improved subject stratification, providing enhanced distinction and validity of clusters.This study not only confirms the feasibility of skin tau quantification in Huntington's disease but also establishes its potential as a biomarker for enhancing group classification and assessing disease severity across the Huntington's disease spectrum, opening new directions in biomarker research. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]
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- 2024
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9. Magnetic Resonance Imaging to Detect Structural Brain Changes in Huntington’s Disease: A Review of Data from Mouse Models.
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Hanrahan, Jenna, Locke, Drew P., and Cahill, Lindsay S.
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Structural magnetic resonance imaging (MRI) is a powerful tool to visualize 3D neuroanatomy and assess pathology and disease progression in neurodegenerative disorders such as Huntington’s disease (HD). The development of mouse models of HD that reproduce many of the psychiatric, motor and cognitive impairments observed in human HD has improved our understanding of the disease and provided opportunities for testing novel therapies. Similar to the clinical scenario, MRI of mouse models of HD demonstrates onset and progression of brain pathology. Here, we provided an overview of the articles that used structural MRI in mouse models of HD to date, highlighting the differences between studies and models and describing gaps in the current state of knowledge and recommendations for future studies. [ABSTRACT FROM AUTHOR]
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- 2024
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10. Pathogenic TDP‐43 accelerates the generation of toxic exon1 HTT in Huntington's disease knock‐in mice.
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Bai, Dazhang, Deng, Fuyu, Jia, Qingqing, Ou, Kaili, Wang, Xiang, Hou, Junqi, Zhu, Longhong, Guo, Mingwei, Yang, Su, Jiang, Guohui, Li, Shihua, Li, Xiao‐Jiang, and Yin, Peng
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Huntington's disease (HD) is caused by a CAG repeat expansion in exon1 of the HTT gene that encodes a polyglutamine tract in huntingtin protein. The formation of HTT exon1 fragments with an expanded polyglutamine repeat has been implicated as a key step in the pathogenesis of HD. It was reported that the CAG repeat length‐dependent aberrant splicing of exon1 HTT results in a short polyadenylated mRNA that is translated into an exon1 HTT protein. Under normal conditions, TDP‐43 is predominantly found in the nucleus, where it regulates gene expression. However, in various pathological conditions, TDP‐43 is mislocalized in the cytoplasm. By investigating HD knock‐in mice, we explore whether the pathogenic TDP‐43 in the cytoplasm contributes to HD pathogenesis, through expressing the cytoplasmic TDP‐43 without nuclear localization signal. We found that the cytoplasmic TDP‐43 is increased in the HD mouse brain and that its mislocalization could deteriorate the motor and gait behavior. Importantly, the cytoplasmic TDP‐43, via its binding to the intron1 sequence (GU/UG)n of the mouse Htt pre‐mRNA, promotes the transport of exon1‐intron1 Htt onto ribosome, resulting in the aberrant generation of exon1 Htt. Our findings suggest that cytoplasmic TDP‐43 contributes to HD pathogenesis via its binding to and transport of nuclear un‐spliced mRNA to the ribosome for the generation of a toxic protein product. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Structural Mapping of Protein Aggregates in Live Cells Modeling Huntington's Disease.
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Guo, Zhongyue, Chiesa, Giulio, Yin, Jiaze, Sanford, Adam, Meier, Stefan, Khalil, Ahmad S., and Cheng, Ji‐Xin
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While protein aggregation is a hallmark of many neurodegenerative diseases, acquiring structural information on protein aggregates inside live cells remains challenging. Traditional microscopy does not provide structural information on protein systems. Routinely used fluorescent protein tags, such as Green Fluorescent Protein (GFP), might perturb native structures. Here, we report a counter‐propagating mid‐infrared photothermal imaging approach enabling mapping of secondary structure of protein aggregates in live cells modeling Huntington's disease. By comparing mid‐infrared photothermal spectra of label‐free and GFP‐tagged huntingtin inclusions, we demonstrate that GFP fusions indeed perturb the secondary structure of aggregates. By implementing spectra with small spatial step for dissecting spectral features within sub‐micrometer distances, we reveal that huntingtin inclusions partition into a β‐sheet‐rich core and a ɑ‐helix‐rich shell. We further demonstrate that this structural partition exists only in cells with the [RNQ+] prion state, while [rnq−] cells only carry smaller β‐rich non‐toxic aggregates. Collectively, our methodology has the potential to unveil detailed structural information on protein assemblies in live cells, enabling high‐throughput structural screenings of macromolecular assemblies. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Rasch Measurement Theory (RMT) Analyses of the Huntington’s Disease Everyday Functioning (Hi-DEF) to Evaluate Item Fit and Performance.
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Petrillo, Jennifer, Sawant, Ruta, Elliott, Emma, Cleanthous, Sophie, Rogers, Rebecca, Cano, Stefan, Baradaran, Sarah, and Johannesen, Jason
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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.To assess the measurement properties and finalize item content of the Hi-DEF.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.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.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. [ABSTRACT FROM AUTHOR]
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- 2024
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13. Beneficial effects of miR-132/212 deficiency in the zQ175 mouse model of Huntington's disease.
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Nateghi, Behnaz, Keraudren, Remi, Boulay, Gabriel, Bazin, Marc, Goupil, Claudia, Canet, Geoffrey, Loiselle, Andréanne, St-Amour, Isabelle, Planel, Emmanuel, Soulet, Denis, and Hébert, Sébastien S.
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Huntington's disease (HD) is a rare genetic neurodegenerative disorder caused by an expansion of CAG repeats in the Huntingtin (HTT) gene. One hypothesis suggests that the mutant HTT gene contributes to HD neuropathology through transcriptional dysregulation involving microRNAs (miRNAs). In particular, the miR-132/212 cluster is strongly diminished in the HD brain. This study explores the effects of miR-132/212 deficiency specifically in adult HD zQ175 mice. The absence of miR-132/212 did not impact body weight, body temperature, or survival rates. Surprisingly, miR-132/212 loss seemed to alleviate, in part, the effects on endogenous Htt expression, HTT inclusions, and neuronal integrity in HD zQ175 mice. Additionally, miR-132/212 depletion led to age-dependent improvements in certain motor functions. Transcriptomic analysis revealed alterations in HD-related networks in WT- and HD zQ175-miR-132/212-deficient mice, including significant overlap in BDNF and Creb1 signaling pathways. Interestingly, however, a higher number of miR-132/212 gene targets was observed in HD zQ175 mice lacking the miR-132/212 cluster, especially in the striatum. These findings suggest a nuanced interplay between miR-132/212 expression and HD pathogenesis, providing potential insights into therapeutic interventions. Further investigation is needed to fully understand the underlying mechanisms and therapeutic potential of modulating miR-132/212 expression during HD progression. [ABSTRACT FROM AUTHOR]
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- 2024
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14. Scheduled feeding improves sleep in a mouse model of Huntington's disease.
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Chiem, Emily, Zhao, Kevin, Dell'Angelica, Derek, Ghiani, Cristina A., Paul, Ketema N., and Colwell, Christopher S.
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SLEEP interruptions ,BACTERIAL artificial chromosomes ,HUNTINGTON disease ,SLEEP ,DISEASE risk factors - Abstract
Sleep disturbances are common features of neurodegenerative disorders including Huntington's disease (HD). Sleep and circadian disruptions are recapitulated in animal models, providing the opportunity to evaluate the effectiveness of circadian interventions as countermeasures for neurodegenerative disease. For instance, time restricted feeding (TRF) successfully improved activity rhythms, sleep behavior and motor performance in mouse models of HD. Seeking to determine if these benefits extend to physiological measures of sleep, electroencephalography (EEG) was used to measure sleep/wake states and polysomnographic patterns in male and female wild-type (WT) and bacterial artificial chromosome transgenic (BACHD) adult mice, under TRF and ad lib feeding (ALF). Our findings show that male, but not female, BACHD mice exhibited significant changes in the temporal patterning of wake and non-rapid eye movement (NREM) sleep. The TRF intervention reduced the inappropriate early morning activity by increasing NREM sleep in the male BACHD mice. In addition, the scheduled feeding reduced sleep fragmentation (# bouts) in the male BACHD mice. The phase of the rhythm in rapid-eye movement (REM) sleep was significantly altered by the scheduled feeding in a sex-dependent manner. The treatment did impact the power spectral curves during the day in male but not female mice regardless of the genotype. Sleep homeostasis, as measured by the response to six hours of gentle handling, was not altered by the diet. Thus, TRF improves the temporal patterning and fragmentation of NREM sleep without impacting sleep homeostasis. This work adds critical support to the view that sleep is a modifiable risk factor in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]
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- 2024
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15. Economic Burden of Huntington’s Disease: Analysis from a Brazilian Tertiary Care Perspective.
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da Silva van der Laan, Andressa, Borges, Vanderci, Saba, Roberta Arb, and Ferraz, Henrique Ballalai
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MEDICAL economics , *MEDICAL care costs , *ECONOMIC impact , *CAREGIVERS , *ECONOMIC statistics - Abstract
Huntington’s disease (HD) exerts significant impacts on individuals and families worldwide. Nevertheless, data on its economic burden in Brazil are scarce, revealing a critical gap in understanding the associated healthcare costs.This study was conducted at a tertiary neurology outpatient clinic in Brazil with the aim of assessing annual healthcare service utilization and associated costs for HD patients.We conducted a cross-sectional observational study involving 34 HD patients. A structured questionnaire was applied to collect data on direct medical costs (outpatient services, medications), non-medical direct costs (complementary therapies, mobility aids, home adaptations), and indirect costs (lost productivity, caregiver costs, government benefits) over one year.Significant economic impacts were observed, with average annual direct medical costs of $4686.82 per HD patient. Non-medical direct and indirect costs increased the financial burden, highlighting extensive resource utilization beyond healthcare services. Thirty-three out of 34 HD patients were unemployed or retired, and 16 relied on government benefits, reflecting broader socioeconomic implications. Despite the dataset’s limitations, it provides crucial insights into the economic impact of HD on patients and the Brazilian public health system.The findings underscore the urgent need for a more comprehensive evaluation of the costs to inform governmental policies related to HD. Future research is needed to expand the data pool and develop a nuanced understanding of the economic burdens of HD to help formulate effective healthcare strategies for patients. [ABSTRACT FROM AUTHOR]
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- 2024
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16. Dysregulation of choline metabolism and therapeutic potential of citicoline in Huntington's disease.
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Chang, Kuo‐Hsuan, Cheng, Mei‐Ling, Tang, Hsiang‐Yu, Lin, Chung‐Yin, and Chen, Chiung‐Mei
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HUNTINGTON disease , *CYTIDINE diphosphate choline , *ENZYME metabolism , *CHOLINE , *OXIDATIVE stress - Abstract
Huntington's disease (HD) is associated with dysregulated choline metabolism, but the underlying mechanisms remain unclear. This study investigated the expression of key enzymes in this pathway in R6/2 HD mice and human HD postmortem brain tissues. We further explored the therapeutic potential of modulating choline metabolism for HD. Both R6/2 mice and HD patients exhibited reduced expression of glycerophosphocholine phosphodiesterase 1 (GPCPD1), a key enzyme in choline metabolism, in the striatum and cortex. The striatum of R6/2 mice also showed decreased choline and phosphorylcholine, and increased glycerophosphocholine, suggesting disruption in choline metabolism due to GPCPD1 deficiency. Treatment with citicoline significantly improved motor performance, upregulated anti‐apoptotic Bcl2 expression, and reduced oxidative stress marker malondialdehyde in both brain regions. Metabolomic analysis revealed partial restoration of disrupted metabolic patterns in the striatum and cortex following citicoline treatment. These findings strongly suggest the role of GPCPD1 deficiency in choline metabolism dysregulation in HD. The therapeutic potential of citicoline in R6/2 mice highlights the choline metabolic pathway as a promising target for future HD therapies. [ABSTRACT FROM AUTHOR]
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- 2024
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17. Linking coronary artery disease to neurodegenerative diseases through systems genetics.
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Vescio, Martina and Pattini, Linda
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HUNTINGTON disease ,AMYLOID beta-protein precursor ,CORONARY artery disease ,ALZHEIMER'S disease ,GENETIC variation - Abstract
Coronary artery disease (CAD) is still a leading cause of death worldwide despite the extensive research and the considerable progresses made through the years. As other cardiovascular diseases, CAD is the result of the complex interaction between genetic variants and environmental factors. Currently identified genetic loci associated to CAD revealed the contribution of multiple molecular pathways to its pathogenesis, suggesting the need for a systemic approach to understand the role of genetic determinants. In this study we wanted to investigate how GWAS variants associated to CAD interact with each other and with nearby genes in the context of the coronary artery molecular interactome. GWAS variants associated to CAD were selected from GWAS Catalog, then, a tissue-specific interactome was constructed integrating protein-protein interactions (PPI) from multiple public repositories and computationally inferred co-expression relationships. To focus on the part of the network most relevant for CAD, we selected the interactions connecting the genes carrying a variant associated to the disease. A functional enrichment analysis conducted on the subnetwork revealed that genes carrying genetic variants associated to CAD closely interact with genes related to relevant biological processes, such as extracellular matrix organization, lipoprotein clearance, arterial morphology and inflammatory response. These results confirm that the identified subnetwork reflects the molecular pathways altered in CAD and intercepted by the selected variants. Interestingly, the most connected nodes of the network included amyloid beta precursor protein (APP) and huntingtin (HTT), both implicated in neurodegenerative disorders. In recent years the interest in investigating the common processes between cardiovascular diseases and neurodegenerative disorders is increasing, with growing evidence of a link between CAD and Alzheimer's disease. The results obtained in this work support the association between such apparently unrelated diseases and highlight the necessity of a systems biology approach to better elucidate shared pathological mechanisms. [ABSTRACT FROM AUTHOR]
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- 2024
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18. The meaning of apathy in Huntington's disease: A qualitative study of caregiver perspectives.
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Mason, Sarah Louise, Barker, Roger Alistair, Andresen, Katie, Gracey, Fergus, and Ford, Catherine
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HUNTINGTON disease , *CAREGIVERS , *THEMATIC analysis , *APATHY , *JUDGMENT (Psychology) - Abstract
Although one of the most prevalent and impactful features of Huntington’s disease (HD), little is known about the impact of apathy on HD caregivers, although there is evidence it affects perceptions of distress and burden. Given the importance of the caregivers, we aimed to explore the lived experience of people supporting someone with HD and associated apathy. Semi-structured interviews were conducted with 11 caregivers and analysed using reflective thematic analysis, informed by a phenomenological framework. Five overarching themes were produced: (1) What even is apathy? (2) It makes my life harder: the practical impact of apathy, (3) They haven’t forgotten me, but they have forgotten that they ever loved me, (4) I’m grieving for someone who hasn’t died yet, and (5) I need a safe space to say what I really feel without fear of judgement. Inter-woven between these themes were complex narratives about the unspoken nature of HD, the invisibility of caregivers who felt trapped and unheard, and the one-sided nature of loving someone with the disease. Findings are discussed in relation to theoretical frameworks of anticipatory grief and ambiguous loss, and situated within the wider literature on caregiving for people with a neurodegenerative condition. [ABSTRACT FROM AUTHOR]
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- 2024
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19. Time to Functional Loss as an Endpoint in Huntington's Disease Trials: Enrichment and Sample Size.
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Mills, James A., Long, Jeffrey D., Vaidya, Jatin G., Gantman, Emily C., Sathe, Swati, Tabrizi, Sarah J., and Sampaio, Cristina
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HUNTINGTON disease , *SAMPLE size (Statistics) , *MOVEMENT disorders , *INFORMATION design , *PERIODICAL publishing - Abstract
Background Objective Methods Results Conclusions Clinical trial scenarios can be modeled using data from observational studies, providing critical information for design of real‐world trials. The Huntington's Disease Integrated Staging System (HD‐ISS) characterizes disease progression over an individual's lifespan and allows for flexibility in the design of trials with the goal of delaying progression. Enrichment methods can be applied to the HD‐ISS to identify subgroups requiring smaller estimated sample sizes.Investigate time to the event of functional decline (HD‐ISS Stage 3) as an endpoint for trials in HD and present sample size estimates after enrichment.We classified individuals from observational studies according to the HD‐ISS. We assessed the ability of the prognostic index normed (PIN) and its components to predict time to HD‐ISS Stage 3. For enrichment, we formed groups from deciles of the baseline PIN distribution for HD‐ISS Stage 2 participants. We selected enrichment subgroups closer to Stage 3 transition and estimated sample sizes, using delay in the transition time as the effect size.In predicting time to HD‐ISS Stage 3, PIN outperforms its components. Survival curves for each PIN decile show that groups with PIN from 1.48 to 2.74 have median time to Stage 3 of approximately 2 years and these are combined to create enrichment subgroups. Sample size estimates are presented by enrichment subgroup.PIN is predictive of functional decline. A delay of 9 months or more in the transition to Stage 3 for an enriched sample yields feasible sample size estimates, demonstrating that this approach can aid in planning future trials. © 2024 The Author(s).
Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]- Published
- 2024
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20. Outcomes of Percutaneous Endoscopic Gastrostomy in Huntington's Disease at a Tertiary Center.
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Farag, Mena, Coleman, Annabelle, Knights, Harry, Murphy, Michael J., Rajagopal, Sangeerthana, Touzé, Alexiane, Shoai, Maryam, Hearst, Cara, Salanio, Desiree M., Wild, Edward J., and Tabrizi, Sarah J.
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HUNTINGTON disease , *SKIN infections , *PUBLIC hospitals , *POLYETHYLENE glycol , *SURVIVAL rate , *PERCUTANEOUS endoscopic gastrostomy - Abstract
Background: Clinically assisted nutrition and hydration via percutaneous endoscopic gastrostomy (PEG) is a therapeutic option to ameliorate the difficulties associated with enhanced catabolism, weight loss, and dysphagia in Huntington's disease (HD). Objectives: The objective is to provide insights into demographics, staging (Shoulson‐Fahn), complications, weight trajectories, and survival rates in people with HD (pwHD) who underwent PEG. Methods: This retrospective study included 705 consecutive pwHD who attended our HD clinic between July 2006 and March 2024, of whom 52 underwent PEG. A control group (n = 52), comprising pwHD without PEG, were closely matched for sex, stage, age, CAG length, and disease burden score at PEG. The study was registered as a service evaluation at the National Hospital for Neurology and Neurosurgery. Results: PEG prevalence was 15.0% (n = 52/347) among manifest pwHD: 4.8% (n = 3/62) for Stage 3; 33.3% (n = 16/48) for stage 4; and 44.1% (n = 30/68) for stage 5. Commonest indications were dysphagia, weight loss, and inadequate oral intake. Complications included chest infection, tube dislodgement, and peristomal and skin infections. Modeling of weight trajectories after PEG found no difference between PEG and non‐PEG groups. Mortality rate was 34.6% (n = 18/52) in the PEG and 36.5% (n = 19/52) in the non‐PEG groups (P = 0.84). Treatment duration (until study endpoint or death) was 3.48 years (interquartile range = 1.71–6.02; range = 0.23–18.8), with 65.4% (n = 34/52) alive at the study endpoint. Conclusion: PEG in pwHD at‐risk for weight loss may help slow weight loss. Prospective studies are required to strengthen PEG decision‐making in pwHD. PEG survival was much longer than other dementias, highlighting the need to consider PEG independently in pwHD. [ABSTRACT FROM AUTHOR]
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- 2024
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21. Stress-Related Roles of Exosomes and Exosomal miRNAs in Common Neuropsychiatric Disorders.
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Chamakioti, Myrsini, Chrousos, George P., Kassi, Eva, Vlachakis, Dimitrios, and Yapijakis, Christos
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Exosomes, natural nanovesicles that contain a cargo of biologically active molecules such as lipids, proteins, and nucleic acids, are released from cells to the extracellular environment. They then act as autocrine, paracrine, or endocrine mediators of communication between cells by delivering their cargo into recipient cells and causing downstream effects. Exosomes are greatly enriched in miRNAs, which are small non-coding RNAs that act both as cytoplasmic post-transcriptional repression agents, modulating the translation of mRNAs into proteins, as well as nuclear transcriptional gene activators. Neuronal exosomal miRNAs have important physiologic functions in the central nervous system (CNS), including cell-to-cell communication, synaptic plasticity, and neurogenesis, as well as modulating stress and inflammatory responses. Stress-induced changes in exosomal functions include effects on neurogenesis and neuroinflammation, which can lead to the appearance of various neuropsychiatric disorders such as schizophrenia, major depression, bipolar disorder, and Alzheimer's and Huntington's diseases. The current knowledge regarding the roles of exosomes in the pathophysiology of common mental disorders is discussed in this review. [ABSTRACT FROM AUTHOR]
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- 2024
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22. Gastrointestinale Störungen bei hyperkinetischen Bewegungsstörungen und Ataxien.
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Claus, Inga and Warnecke, Tobias
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RESTLESS legs syndrome , *HUNTINGTON disease , *SYMPTOMS , *GENETIC disorders , *PARKINSON'S disease , *MOVEMENT disorders - Abstract
Disorders of the gastrointestinal tract in patients suffering from hypokinetic movement disorders, and in particular Parkinson's disease, have increasingly been the subject of more intensive neuromedical research. So far, few data are available for patients with hyperkinetic movement disorders and ataxias. This review article summarizes the currently available and relevant publications on this topic. The particular focus is on essential tremor, restless legs syndrome, Huntington's disease and the group of hereditary ataxias. Further intensive research will be necessary in the future to collect detailed information also for these disease symptoms about specific disturbance patterns, in order to understand the underlying pathological pathways and to derive specific treatment approaches. [ABSTRACT FROM AUTHOR]
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- 2024
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23. Circadian rhythm alterations affecting the pathology of neurodegenerative diseases.
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Canever, Jaquelini Betta, Queiroz, Letícia Yoshitome, Soares, Ericks Sousa, de Avelar, Núbia Carelli Pereira, and Cimarosti, Helena Iturvides
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ALZHEIMER'S disease , *HUNTINGTON disease , *MULTIPLE sclerosis , *AMYOTROPHIC lateral sclerosis , *CHRONOBIOLOGY disorders - Abstract
The circadian rhythm is a nearly 24‐h oscillation found in various physiological processes in the human brain and body that is regulated by environmental and genetic factors. It is responsible for maintaining body homeostasis and it is critical for essential functions, such as metabolic regulation and memory consolidation. Dysregulation in the circadian rhythm can negatively impact human health, resulting in cardiovascular and metabolic diseases, psychiatric disorders, and premature death. Emerging evidence points to a relationship between the dysregulation circadian rhythm and neurodegenerative diseases, suggesting that the alterations in circadian function might play crucial roles in the pathogenesis and progression of neurodegenerative diseases. Better understanding this association is of paramount importance to expand the knowledge on the pathophysiology of neurodegenerative diseases, as well as, to provide potential targets for the development of new interventions based on the dysregulation of circadian rhythm. Here we review the latest findings on dysregulation of circadian rhythm alterations in Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, spinocerebellar ataxia and multiple‐system atrophy, focusing on research published in the last 3 years. [ABSTRACT FROM AUTHOR]
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- 2024
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24. Cardiac autonomic involvement in Huntington's disease.
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İşcan, Dilek and Çetinkaya, Yakup
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HUNTINGTON disease , *ROOT-mean-squares , *MOVEMENT disorders , *HEART beat , *NEURODEGENERATION - Abstract
Introduction: Huntington's disease (HD) is known as a neurodegenerative disease with movement disorder and cognitive impairment; autonomic involvement is also becoming common in some recent studies. The aim of this study is to demonstrate the presence of cardiac autonomic involvement in HD patients. Method: Time and frequency domain parameters obtained from the 24-h Holter ECG(hECG) were compared between 20 HD patients and 20 healthy control subjects. Results: Fourteen HD patients had tachycardia, bradycardia, and extra beats. Interval between two heartbeats, normal-to-normal (NN), standard deviation of all normal-to-normal (SDNN), square root of the mean of the sum of the squares of the differences between consecutive N-N intervals in ms (rMSSD), and the ratio of the number of consecutive pairs of N-N intervals that differ by more than 50 ms to the total number of N-N intervals (pNN50) were all significantly higher in the patient group than in the control group during 24-h hECG monitoring. However, hECG monitoring showed that the patient group had significantly higher values of the frequency-domain metrics high frequency (HF) than the control group did (P = 0.003). Very low frequency (VLF) was lower in the patient group (P = 0.009). There was no difference in low frequency (LF) in both groups. In comparison to the control group, LF/HF was much reduced in the patient group (P = 0.001). Conclusion: Cardiac disfunction increases, and autonomic functions change in HD, but more comprehensive studies are needed to distinguish sympathetic and parasympathetic involvement. [ABSTRACT FROM AUTHOR]
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- 2024
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25. Effect of Capsaicin on 3-NP-Induced Neurotoxicity: A Pre-Clinical Study.
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Tyagi, Sakshi and Thakur, Ajit Kumar
- Subjects
- *
POISONS , *HUNTINGTON disease , *CAPSAICIN , *HOT peppers , *NEUROTOXICOLOGY , *MULTIENZYME complexes - Abstract
The study objectives are to investigate the ability of capsaicin to revert the toxic effects in glutamate and lipopolysaccharide (LPS)-induced neurotoxicity in Neuro2a (N2a) cells as well as thwarting cognitive impairments, mitochondrial deficits, and oxidative insults induced by 3-nitropropanoic acid (3-NP) in a rodent model of Huntington's disease. In-vitro study with N2a cells was performed through MTT and LDH assay and their biochemical examinations were also performed. 3-NP-administered mice (n = 6) were treated with capsaicin (5, 10, and 20 mg/kg) through the per-oral (p.o.) route for 7 consecutive days. Physiological and behavioral studies were performed in drug-treated mice. After behavioral studies, biochemical parameters were performed for cytokines levels, various oxidative stress parameters, and mitochondrial enzyme complex activities with mitochondrial permeability. N2a cells treated with capsaicin demonstrated neuroprotective effects and reduced neurotoxicity. Based on experimental observation, in an in-vitro study, the effective dose of CAP was 50 µM. Moreover, a 100 µM dose of capsaicin had toxic effects on neuronal cells (N2a cells). On the other hand, the effective dose of 3-NP was 20 mg/kg, (p.o.) in animals (in-vivo). All tested doses of capsaicin upturned the cognitive impairment and motor in-coordination effects induced by 3-NP. 3-NP-injected mice demonstrated substantially increased pro-inflammatory cytokine concentrations, defective mitochondrial complex activity, and augmented oxidative insult. However, capsaicin at different doses reduced oxidative damage and cytokines levels and improved mitochondrial complex activity along with mitochondrial permeability. Furthermore, capsaicin (10 and 20 mg/kg) improved the TNF-α concentration. These findings suggested because of the anti-inflammatory and antioxidant effect, capsaicin can be considered a novel treatment for the management of neurodegenerative disorders by reverting the antioxidant enzyme activity, pro-inflammatory cytokines concentration, and mitochondrial functions. [ABSTRACT FROM AUTHOR]
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- 2024
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26. "Man, This Isn't Easy": Exploring the Manifestation of Parentification Among Young Carers of a Parent with Huntington's Disease.
- Author
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Hendricks, Bailey A., Bakitas, Marie A., Odom, J. Nicholas, Johnston, Emily E., Childs, Gwendolyn, and Kavanaugh, Melinda S.
- Subjects
- *
HEALTH services accessibility , *QUALITATIVE research , *DEATH , *SECONDARY analysis , *RESEARCH funding , *CONTENT analysis , *SCHOOLS , *PARENT-child relationships , *HEALTH policy , *INTERVIEWING , *PARENTING , *SOCIAL responsibility , *PSYCHOLOGICAL adaptation , *DESCRIPTIVE statistics , *THEMATIC analysis , *BURDEN of care , *EXPERIENCE , *CONCEPTUAL structures , *PSYCHOLOGY of caregivers , *NEEDS assessment , *PSYCHOLOGY of parents , *SOCIAL support , *INDIVIDUAL development , *HUNTINGTON disease , *CAREGIVER attitudes , *FRIENDSHIP , *SOCIAL stigma , *SOCIAL isolation , *GENETICS , *ADULTS - Abstract
Background: Due to the progressive deterioration of motor, cognitive, and psychological function, individuals with Huntington's disease (HD) rely heavily on family caregivers, including children in the home. This "young carer" role can result in responsibilities that are inappropriate for the child's age and abilities. Also referred to as parentification, this experience can result in both positive and negative outcomes for the child, spanning multiple domains of health and well-being. Objective: To explore the manifestation of parentification among young carers of a parent with HD. Method: Directed content analysis, guided by a literature-derived framework of parentification, was utilized for this qualitative study. Participants included 28 young carers (mean age of 16.6 (± 2.6)) who self-identified as engaging in caregiving activities related to HD with the majority providing care for 1–3 years (53.6%)- averaging 25.4 h of care per week. Results: Three main themes with subthemes emerged: (1) being a young carer [perceptions of caregiving, learning to be a caregiver, caregiver burden, coping], (2) living with a new normal (school and friends, feeling unheard/alone, support system, personal growth), and (3) facing HD as a young carer (stigma and isolation, parent/child relationship, end of life, genetic risk). Conclusions: Young carers in the context of HD experience many attributes and consequences of parentification generally present among young carers of ill parents. However, HD specific findings emerged from this study that can be used to inform clinicians and direct future research aimed at guiding policy and developing tailored support services. [ABSTRACT FROM AUTHOR]
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- 2024
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27. Neuroprotective effects of levothyroxine on cognition deficits and memory in an experimental model of Huntingtonʼs disease in rats: An electrophysiological study.
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Badini, Fereshteh, Mirshekar, Mohammad Ali, Shahraki, Samira, Fanaei, Hamed, and Bayrami, Abolfazl
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HUNTINGTON disease ,BRAIN-derived neurotrophic factor ,OXIDANT status ,ACTION potentials ,SPATIAL memory - Abstract
Huntington's disease (HD) is a neurodegenerative disorder characterized by cognitive deficits and motor function. Levothyroxine (L-T4) is a synthetic form of Thyroxine (T4), which can improve cognitive ability. The aim of the present study was to determine the neuroprotective effect of L-T4 administration in rats with 3-nitropropionic acid (3-NP)-induced Huntingtonʼs disease. Forty-eight Wistar male rats were divided into six groups (n = 8): Group 1 control group that received physiological saline, Group 2 and 3: which received L-T4 (30 and 100 μg/kg), Group 4: HD group that received 3-NP and Groups 5 and 6: The treatment of the HD rats with L-T4 (30 and 100 μg/kg). Spatial memory, locomotor activity, and frequency of neuronal firing were assessed. After decapitation, the Brain-Derived Neurotrophic Factor (BDNF) and Total antioxidant capacity (TAC) levels in the striatum was measured. The results showed that the indices of spatial memory (mean path length and latency time) and motor dysfunction (immobility time) significantly increased, while time spent in the goal quadrant, swimming speed, spike rate, and striatum levels of BDNF significantly decreased in the HD group compared to the control group. L-T4 treatment significantly enhanced time spent in the goal quadrant, swimming speed, motor activity (number of line crossing and rearing), spike rate and striatal BDNF level. This research showed that L-T4 prevented the disruption of motor activity and cognitive deficiencies induced by 3-NP. The beneficial effects of L-T4 may be due to an increase in the concentration of BDNF and enhancement of the spike rate in the striatum. [ABSTRACT FROM AUTHOR]
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- 2024
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28. Epidemiology of Huntington's Disease in Latin America: A Systematic Review and Meta‐Analysis.
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Medina Escobar, Alex, Pringsheim, Tamara, Gautreau, Sylvia, Rivera‐Duarte, Jose D., Amorelli, Gabriel, Cornejo‐Olivas, Mario, and Rossi, Malco
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HUNTINGTON disease , *MOVEMENT disorders , *EPIDEMIOLOGY , *SEARCH engines , *DATABASE searching - Abstract
Background Methods Results Conclusion Latin America has played a crucial role in advancing our understanding of Huntington's disease (HD). However, previous global reviews include limited data from Latin America. It is possible that English‐based medical search engines may not capture all the relevant studies.We searched databases in Spanish, Portuguese, and English. The names of every country in Latin America in English‐based search engines were used to ensure we found any study that had molecular ascertainment and provided general epidemiological information or subpopulation data. Additionally, we contacted experts across the region.The search strategy yielded 791 citations; 24 studies met inclusion criteria, representing 12 of 36 countries. The overall pooled prevalence was 0.64 per 100,000 (prediction interval, 0.06–7.22); for cluster regions, it was 54 per 100,000 (95% CI, 34.79–84.92); for juvenile HD, it was 8.7% (prediction interval, 5.12–14.35), and 5.9% (prediction interval, 2.72–13.42) for late‐onset HD. The prevalence was higher for Mexico, Peru, and Brazil. However, there were no significant differences between Central America and the Caribbean versus South America.The prevalence of HD appears to be similar across Latin America. However, we infer that our findings are underestimates, in part because of limited research and underdiagnosis of HD because of limited access to molecular testing and the availability of neurologists and movement disorders specialists. Future research should focus on identifying pathways to improve access to molecular testing and education and understanding differences among different ancestral groups in Latin America. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]
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- 2024
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29. Differential microRNA expression in the SH-SY5Y human cell model as potential biomarkers for Huntington's disease.
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Belkozhayev, Ayaz, Niyazova, Raigul, Kamal, Mohammad Amjad, Ivashchenko, Anatoliy, Sharipov, Kamalidin, and Wilson, Cornelia M.
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HUNTINGTIN protein ,HUNTINGTON disease ,GENE expression ,BIOMARKERS ,TRINUCLEOTIDE repeats ,MICRORNA ,PROTEIN microarrays - Abstract
Huntington's disease (HD) is caused by an expansion of CAG trinucleotide repeat in the HTT gene; the exact pathogenesis of HD currently remains unclear. One of the promising directions in the study of HDs is to determine the molecular mechanism underlying the development and role of microRNAs (miRNAs). This study aimed to identify the profile of miRNAs in an HD human cell line model as diagnostic biomarkers for HD. To study HD, the human SH-SY5Y HD cell model is based on the expression of two different forms: pEGFP-Q23 and pEGFP-Q74 of HTT. The expression of Htt protein was confirmed using aggregation assays combined with immunofluorescence and Western blotting methods. miRNA levels were measured in SH-SY5Y neuronal cell model samples stably expressing Q23 and Q74 using the extraction-free HTG EdgeSeq protocol. A total of 2083 miRNAs were detected, and 354 (top 18 miRNAs) miRNAs were significantly differentially expressed (DE) (p < 0.05) in Q23 and Q74 cell lines. A majority of the miRNAs were downregulated in the HD cell model. Moreover, we revealed that six DE miRNAs target seven genes (ATN1, GEMIN4, EFNA5, CSMD2, CREBBP, ATXN1, and B3GNT) that play important roles in neurodegenerative disorders and showed significant expression differences in mutant Htt (Q74) when compared to wild-type Htt (Q23) using RT-qPCR (p < 0.05 and 0.01). We demonstrated the most important DE miRNA-mRNA profiles, interaction binding sites, and their related pathways in HD using experimental and bioinformatics methods. This will allow the development of novel diagnostic strategies and provide alternative therapeutic routes for treating HD. [ABSTRACT FROM AUTHOR]
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- 2024
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30. Promoting Physical Activity in Huntington’s Disease: Co-Design of a Care Partner Resource.
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Jones, Una, Hamana, Katy, and Busse, Monica
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PHYSICAL activity , *SCHEDULING , *BURDEN of care , *PARTICIPATORY design , *CARE of people - Abstract
Clinical guidelines recommend that people with Huntington’s disease (HD) should exercise to maintain/improve fitness and motor function, yet physical activity levels remain low in this group. Promotion of physical activity is often via care partners with little evidence that they are supported in this role.The aim was to co-design a resource for care partners of people with HD to support promotion of physical activity.A four-step co-design approach was used to develop a care partner resource. Five care partners took part in an online workshop exploring experiences and the knowledge, support and skills needed by care partners to promote physical activity. A co-design team (
n = 7) developed a prototype that was user tested by three people who had attended the workshop. Findings from user testing were used to develop the final resource.An easy to read, image-based prototype was developed that contained tips on planning activity, safety and activity examples. User testing identified the need for grouping of activities suitable for 10, 20, and 30 minutes of available time, information on maintaining and improving activity and re-organization of information to support engagement of activity.A resource for care partners that has been translated into seven languages was developed to promote physical activity. User testing indicated confidence in using the resource and appreciation of the autonomy provided to the person with HD to plan activities. Further work is needed to evaluate the impact of the resource in promotion of physical activity and the impact on care partner burden. [ABSTRACT FROM AUTHOR]- Published
- 2024
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31. NfL concentration in CSF is a quantitative marker of the rate of neurodegeneration in aging and Huntington's disease: a semi-mechanistic model-based analysis.
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Machacek, Matthias, Garcia-Montoya, Elena, McColgan, Peter, Sanwald-Ducray, Patricia, and Mazer, Norman Alan
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HUNTINGTON disease ,NEURODEGENERATION ,PRESBYCUSIS ,CEREBROSPINAL fluid shunts ,AGING ,ALZHEIMER'S disease ,SPINAL muscular atrophy - Abstract
The article discusses the development of a semi-mechanistic model that relates the concentration of neurofilament light chain (NfL) in cerebrospinal fluid (CSF) to neurodegeneration in aging and Huntington's disease (HD). The model successfully predicts NfL concentration in CSF and suggests that it reflects the rate of neurodegeneration. The text also discusses the potential application of the model to other neurodegenerative diseases. The document is a list of references that cover various studies and papers related to NfL and its role in neurological disorders, providing a comprehensive source for further research. [Extracted from the article]
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- 2024
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32. Perillaldehyde alleviates polyQ‐induced neurodegeneration through the induction of autophagy and mitochondrial UPR in Caenorhabditis elegans.
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Fang, Minglv, Liu, Ying, Gao, Xiaoyan, Yu, Jing, Tu, Xiaohui, Mo, Xueying, Zhu, Huanhu, Zou, Yan, Huang, Cheng, and Fan, Shengjie
- Subjects
- *
HUNTINGTIN protein , *CAENORHABDITIS , *HUNTINGTON disease , *CAENORHABDITIS elegans , *AUTOPHAGY , *MITOCHONDRIA , *PERILLA frutescens , *MITOCHONDRIAL pathology - Abstract
Huntington's disease (HD) is a fatal neurodegenerative disease associated with autophagy disorder and mitochondrial dysfunction. Here, we identified therapeutic potential of perillaldehyde (PAE), a monoterpene compound obtained from Perilla frutescens (L.) Britt., in the Caenorhabditis elegans (C. elegans) model of HD, which included lifespan extension, healthspan improvement, decrease in polyglutamine (polyQ) aggregation, and preservation of mitochondrial network. Further analyses indicated that PAE was able to induce autophagy and mitochondrial unfolded protein reaction (UPRmt) activation and positively regulated expression of associated genes. In lgg‐1 RNAi C. elegans or C. elegans with UPRmt‐related genes knockdown, the effects of PAE treatment on polyQ aggregation or rescue polyQ‐induced toxicity were attenuated, suggesting that its neuroprotective activity depended on autophagy and UPRmt. Moreover, we found that pharmacological and genetic activation of UPRmt generally protected C. elegans from polyQ‐induced cytotoxicity. Finally, PAE promoted serotonin synthesis by upregulating expression of TPH‐1, and serotonin synthesis and neurosecretion were required for PAE‐mediated UPRmt activation and its neuroprotective activity. In conclusion, PAE is a potential therapy for polyQ‐related diseases including HD, which is dependent on autophagy and cell‐non‐autonomous UPRmt activation. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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33. Speech Biomarkers in Huntington’s Disease: A Longitudinal Follow-Up Study in Premanifest Mutation Carriers.
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Saft, Carsten, Jessen, Julia, Hoffmann, Rainer, Lukas, Carsten, and Skodda, Sabine
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HUNTINGTON disease , *BIOMARKERS , *LONGITUDINAL method , *GENETIC mutation - Abstract
Speech alterations have been reported in manifest Huntington’s disease (HD) and premanifest mutation carriers (preHD). The aim of our study was to explore these alterations in preHD and whether they can be used as biomarkers. 13 preHD mutation carriers performed reading task, sustained phonation task and syllable repetition tasks at baseline and after 21 months, as well as clinical examination and MRI. Syllable repetition capacity and self-chosen velocity of single syllable repetition differed significantly between time points. There were no changes in clinical ratings or MRI volumetry. Measurements of speech might be sensitive tools for monitoring subclinical changes in preHD. [ABSTRACT FROM AUTHOR]
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- 2024
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34. How does the age of control individuals hinder the identification of target genes for Huntington's disease?
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Dias Pinto, João Rafael, Faustinoni Neto, Benedito, Sanches Fernandes, Joyce Macedo, Kerkis, Irina, and Araldi, Rodrigo Pinheiro
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HUNTINGTON disease ,GENE expression ,PROPENSITY score matching ,AGE distribution ,IDENTIFICATION ,FALSE positive error - Abstract
Several studies have compared the transcriptome across various brain regions in Huntington's disease (HD) gene-positive and neurologically normal individuals to identify potential differentially expressed genes (DEGs) that could be pharmaceutical or prognostic targets for HD. Despite adhering to technical recommendations for optimal RNA-Seq analysis, none of the genes identified as upregulated in these studies have yet demonstrated success as prognostic or therapeutic targets for HD. Earlier studies included samples from neurologically normal individuals older than the HD gene-positive group. Considering the gradual transcriptional changes induced by aging in the brain, we posited that utilizing samples from older controls could result in the misidentification of DEGs. To validate our hypothesis, we reanalyzed 146 samples from this study, accessible on the SRA database, and employed Propensity Score Matching (PSM) to create a "virtual" control group with a statistically comparable age distribution to the HD gene-positive group. Our study underscores the adverse impact of using neurologically normal individuals over 75 as controls in gene differential expression analysis, resulting in false positives and negatives. We conclusively demonstrate that using such old controls leads to the misidentification of DEGs, detrimentally affecting the discovery of potential pharmaceutical and prognostic markers. This underscores the pivotal role of considering the age of control samples in RNA-Seq analysis and emphasizes its inclusion in evaluating best practices for such investigations. Although our primary focus is HD, our findings suggest that judiciously selecting age-appropriate control samples can significantly improve best practices in differential expression analysis. [ABSTRACT FROM AUTHOR]
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- 2024
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35. Dermal Fibroblast Cell Line from a Patient with the Huntington's Disease as a Promising Model for Studying Disease Pathogenesis: Production and Characterization.
- Author
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Kraskovskaya, Nina, Koltsova, Anna, Parfenova, Polina, Shatrova, Alla, Yartseva, Natalya, Nazarov, Vladimir, Devyatkina, Ekaterina, Khotin, Mikhail, and Mikhailova, Natalia
- Subjects
- *
HUNTINGTON disease , *HUNTINGTIN protein , *GENETIC disorders , *MUTANT proteins , *FIBROBLASTS - Abstract
Huntington's disease (HD) is an incurable hereditary disease caused by expansion of the CAG repeats in the HTT gene encoding the mutant huntingtin protein (mHTT). Despite numerous studies in cellular and animal models, the mechanisms underlying the biological role of mHTT and its toxicity to striatal neurons have not yet been established and no effective therapy for HD patients has been developed so far. We produced and characterized a new line of dermal fibroblasts (HDDF, Huntington's disease dermal fibroblasts) from a patient with a confirmed HD diagnosis. We also studied the growth characteristics of HDDF cells, stained them for canonical markers, karyotyped these cells, and investigated their phenotype. HDDF cells was successfully reprogrammed into induced striatal neurons via transdifferentiation. The new fibroblast line can be used as a cell model to study the biological role of mHTT and manifestations of HD pathogenesis in both fibroblasts and induced neuronal cells obtained from them by reprogramming techniques. [ABSTRACT FROM AUTHOR]
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- 2024
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36. Heavy Metal Interactions with Neuroglia and Gut Microbiota: Implications for Huntington's Disease.
- Author
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Tizabi, Yousef, Bennani, Samia, El Kouhen, Nacer, Getachew, Bruk, and Aschner, Michael
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HUNTINGTON disease , *COPPER , *HEAVY metals , *GUT microbiome , *COGNITION disorders - Abstract
Huntington's disease (HD) is a rare but progressive and devastating neurodegenerative disease characterized by involuntary movements, cognitive decline, executive dysfunction, and neuropsychiatric conditions such as anxiety and depression. It follows an autosomal dominant inheritance pattern. Thus, a child who has a parent with the mutated huntingtin (mHTT) gene has a 50% chance of developing the disease. Since the HTT protein is involved in many critical cellular processes, including neurogenesis, brain development, energy metabolism, transcriptional regulation, synaptic activity, vesicle trafficking, cell signaling, and autophagy, its aberrant aggregates lead to the disruption of numerous cellular pathways and neurodegeneration. Essential heavy metals are vital at low concentrations; however, at higher concentrations, they can exacerbate HD by disrupting glial–neuronal communication and/or causing dysbiosis (disturbance in the gut microbiota, GM), both of which can lead to neuroinflammation and further neurodegeneration. Here, we discuss in detail the interactions of iron, manganese, and copper with glial–neuron communication and GM and indicate how this knowledge may pave the way for the development of a new generation of disease-modifying therapies in HD. [ABSTRACT FROM AUTHOR]
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- 2024
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37. The Role of miR-137 in Neurodegenerative Disorders.
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Bodai, László, Borosta, Roberta, Ferencz, Ágnes, Kovács, Mercédesz, and Zsindely, Nóra
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- *
NEURODEGENERATION , *ALZHEIMER'S disease , *HUNTINGTON disease , *AMYOTROPHIC lateral sclerosis , *NON-coding RNA , *HUNTINGTIN protein , *PROTEIN stability - Abstract
Neurodegenerative diseases affect an increasing part of the population of modern societies, burdening healthcare systems and causing immense suffering at the personal level. The pathogenesis of several of these disorders involves dysregulation of gene expression, which depends on several molecular processes ranging from transcription to protein stability. microRNAs (miRNAs) are short non-coding RNA molecules that modulate gene expression by suppressing the translation of partially complementary mRNAs. miR-137 is a conserved, neuronally enriched miRNA that is implicated in neurodegeneration. Here, we review the current body of knowledge about the role that miR-137 plays in five prominent neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The presented data indicate that, rather than having a general neuroprotective role, miR-137 modulates the pathology of distinct disorders differently. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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38. The effect of Huntington's disease on cognitive and physical motivation.
- Author
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Atkins, Kelly J, Andrews, Sophie C, Stout, Julie C, and Chong, Trevor T J
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HUNTINGTON disease , *APATHY , *MOTIVATION (Psychology) , *TASK performance - Abstract
Apathy is one of the most common neuropsychiatric features of Huntington's disease. A hallmark of apathy is diminished goal-directed behaviour, which is characterized by a lower motivation to engage in cognitively or physically effortful actions. However, it remains unclear whether this reduction in goal-directed behaviour is driven primarily by a motivational deficit and/or is secondary to the progressive cognitive and physical deficits that accompany more advanced disease. We addressed this question by testing 17 individuals with manifest Huntington's disease and 22 age-matched controls on an effort-based decision-making paradigm. Participants were first trained on separate cognitively and physically effortful tasks and provided explicit feedback about their performance. Next, they chose on separate trials how much effort they were willing to exert in each domain in return for varying reward. At the conclusion of the experiment, participants were asked to rate their subjective perception of task load. In the cognitive task, the Huntington's disease group were more averse to cognitive effort than controls. Although the Huntington's disease group were more impaired than controls on the task itself, their greater aversion to cognitive effort persisted even after controlling for task performance. This suggests that the lower levels of cognitive motivation in the Huntington's disease group relative to controls was most likely driven by a primary motivational deficit. In contrast, both groups expressed a similar preference for physical effort. Importantly, the similar levels of physical motivation across both groups occurred even though participants with Huntington's disease performed objectively worse than controls on the physical effort task, and were aware of their performance through explicit feedback on each trial. This indicates that the seemingly preserved level of physical motivation in Huntington's disease was driven by a willingness to engage in physically effortful actions despite a reduced capacity to do so. Finally, the Huntington's disease group provided higher ratings of subjective task demand than controls for the cognitive (but not physical) effort task and when assessing the mental (but not the physical) load of each task. Together, these results revealed a dissociation in cognitive and physical motivation deficits between Huntington's disease and controls, which were accompanied by differences in how effort was subjectively perceived by the two groups. This highlights that motivation is the final manifestation of a complex set of mechanisms involved in effort processing, which are separable across different domains of behaviour. These findings have important clinical implications for the day-to-day management of apathy in Huntington's disease. [ABSTRACT FROM AUTHOR]
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- 2024
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39. Comparison of the calcium signaling alterations in GABA-ergic medium spiny neurons produced from iPSCs of different origins.
- Author
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Oshkolova, Arina A., Grekhnev, Dmitriy A., Kruchinina, Anna A., Belikova, Lilia D., Volovikov, Egor A., Lebedeva, Olga S., Bogomazova, Alexandra N., Vigont, Vladimir A., Lagarkova, Maria A., and Kaznacheyeva, Elena V.
- Subjects
- *
MEDIUM spiny neurons , *CALCIUM channels , *INDUCED pluripotent stem cells , *CALCIUM , *NUCLEUS accumbens , *SENDAI virus , *SOMATIC cells - Abstract
Disease models based on induced pluripotent stem cells (iPSCs) are in high demand because of their physiological adequacy and well-reproducibility of the pathological phenotype. Nowadays, the most common approach to generate iPSCs is the reprogramming of somatic cells using vectors based on lentivirus or Sendai virus. We have previously shown impairments of calcium signaling including store-operated calcium entry in Huntington's disease-specific iPSCs-based GABA-ergic medium spiny neurons. However, different approaches for iPSCs generation make it difficult to compare the models since the mechanism of reprogramming may influence the electrophysiological properties of the terminally differentiated neurons. Here, we have studied the features of calcium homeostasis in GABA-ergic medium spiny neurons differentiated from iPSCs obtained from fibroblasts of the same donor using different methods. Our data demonstrated that there were no significant differences neither in calcium influx through the store-operated channels, nor in the levels of proteins activating this type of calcium entry in neurons differentiated from iPSCs generated with lenti- and Sendai viruses-based approaches. We also found no differences in voltage-gated calcium entry for these neurons. Thus, we clearly showed that various methods of cell reprogramming result in similar deregulations in neuronal calcium signaling which substantiates the ability to combine the experimental data on functional studies of ion channels in models based on iPSCs obtained by different methods and expands the prospects for the use of biobanking. • Different methods of iPSCs generation result in similar neuronal calcium signaling. • Data obtained with different iPSCs-based models can be combined. • Calcium alterations in HD-specific neurons do not depend on iPSCs generation method. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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40. Glutamine stimulates the S6K/4E-BP branch of insulin signalling pathway to mitigate human poly(Q) disorders in Drosophila disease models.
- Author
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Tandon, Shweta and Sarkar, Surajit
- Subjects
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CELLULAR signal transduction , *GLUTAMINE , *DROSOPHILA , *HUNTINGTON disease , *INSULIN - Abstract
Human polyglutamine [poly(Q)] disorders such as Huntington's disease, different types of ataxias, etc. are devastating brain illnesses which are characterised by the presence of neurotoxic protein aggregates in the affected neurons. We have recently reported that S6K/4E-BP mediated growth promoting branch of insulin signalling pathway alleviates human poly(Q) induced neurotoxicity in Drosophila disease models. Since, the S6K/4E-BP sub-pathway can be stimulated by various amino acids; we extended our investigation to examine if oral feeding of amino acids delivers rescue against human poly(Q) toxicity in Drosophila. We utilised Drosophila models of two different poly(Q) disorders to test our hypothesis. Glutamine was fed to the test flies orally mixed in the food. Control and treated flies were then tested for different parameters, such as formation of poly(Q) aggregates and neurodegeneration, to evaluate glutamine's proficiency in mitigating poly(Q) neurotoxicity. Our study, for the first time, reports that glutamine feeding stimulates the growth promoting S6K/4E-BP branch of insulin signalling pathway and restricts pathogenesis of poly(Q) disorders in Drosophila disease models. We noted that glutamine treatment restricts the formation of neurotoxic poly(Q) aggregates and minimises neuronal deaths. Further, glutamine treatment re-establishes the chromatin architecture by improving the histone acetylation which is otherwise compromised in poly(Q) expressing neuronal cells. Since, the insulin signalling pathway as well as mechanism of action of glutamine are fairly conserved between human and Drosophila, our finding strongly suggests that glutamine holds immense potential to be developed as an intervention therapy against the incurable human poly(Q) disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
41. Graph methods to infer spatial disturbances: Application to Huntington's Disease's speech.
- Author
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Chenain, Lucie, Riad, Rachid, Fraisse, Nicolas, Jubin, Cécilia, Morgado, Graça, Youssov, Katia, Lunven, Marine, and Bachoud-Levi, Anne-Catherine
- Subjects
HUNTINGTON disease ,COGNITION disorders ,LANGUAGE ability ,ALZHEIMER'S disease ,SHORT-term memory - Published
- 2024
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42. Diagnostic Potential of Alternations of Bile Acid Profiles in the Plasma of Patients with Huntington's Disease.
- Author
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Chiang, Ping-I, Chang, Kuo-Hsuan, Tang, Hsiang-Yu, Wu, Yih-Ru, Cheng, Mei-Ling, and Chen, Chiung-Mei
- Subjects
HUNTINGTON disease ,BILE acids ,CHOLESTEROL metabolism ,URSODEOXYCHOLIC acid ,METABOLIC disorders - Abstract
Huntington's disease (HD) is characterized by progressive involuntary chorea movements and cognitive decline. Recent research indicates that metabolic disturbance may play a role in its pathogenesis. Bile acids, produced during cholesterol metabolism in the liver, have been linked to neurodegenerative conditions. This study investigated variations in plasma bile acid profiles among individuals with HD. Plasma levels of 16 primary and secondary bile acids and their conjugates were analyzed in 20 healthy controls and 33 HD patients, including 24 with symptoms (symHD) and 9 carriers in the presymptomatic stage (preHD). HD patients exhibited significantly higher levels of glycochenodeoxycholic acid (GCDCA) and glycoursodeoxycholic acid (GUDCA) compared to healthy controls. Conversely, isolithocholic acid levels were notably lower in the HD group. Neurotoxic bile acids (glycocholic acid (GCA) + glycodeoxycholic acid (GDCA) + GCDCA) were elevated in symHD patients, while levels of neuroprotective bile acids (ursodeoxycholic acid (UDCA) + GUDCA + tauroursodeoxycholic acid (TUDCA)) were higher in preHD carriers, indicating a compensatory response to early neuronal damage. These results underscore the importance of changes in plasma bile acid profiles in HD and their potential involvement in disease mechanisms. The identified bile acids (GCDCA, GUDCA, and isolithocholic acid) could potentially serve as markers to distinguish between HD stages and healthy individuals. Nonetheless, further research is warranted to fully understand the clinical implications of these findings and their potential as diagnostic or therapeutic tools for HD. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
43. Emerging phosphodiesterase inhibitors for treatment of neurodegenerative diseases.
- Author
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Xiang, Yu, Naik, Swapna, Zhao, Liyun, Shi, Jianyou, and Ke, Hengming
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NEURODEGENERATION ,PHOSPHODIESTERASE inhibitors ,ADENOSINES ,THERAPEUTICS ,HUNTINGTON disease ,CYCLIC-AMP-dependent protein kinase ,ALZHEIMER'S disease - Abstract
Neurodegenerative diseases (NDs) cause progressive loss of neuron structure and ultimately lead to neuronal cell death. Since the available drugs show only limited symptomatic relief, NDs are currently considered as incurable. This review will illustrate the principal roles of the signaling systems of cyclic adenosine and guanosine 3′,5′‐monophosphates (cAMP and cGMP) in the neuronal functions, and summarize expression/activity changes of the associated enzymes in the ND patients, including cyclases, protein kinases, and phosphodiesterases (PDEs). As the sole enzymes hydrolyzing cAMP and cGMP, PDEs are logical targets for modification of neurodegeneration. We will focus on PDE inhibitors and their potentials as disease‐modifying therapeutics for the treatment of Alzheimer's disease, Parkinson's disease, and Huntington's disease. For the overlapped but distinct contributions of cAMP and cGMP to NDs, we hypothesize that dual PDE inhibitors, which simultaneously regulate both cAMP and cGMP signaling pathways, may have complementary and synergistic effects on modifying neurodegeneration and thus represent a new direction on the discovery of ND drugs. [ABSTRACT FROM AUTHOR]
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- 2024
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44. Genetic Interventions for Spinocerebellar Ataxia and Huntington’s Disease: A Qualitative Study of the Patient Perspective.
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van Os, Nienke J.H., Oosterloo, Mayke, Essers, Brigitte A.B., Grutters, Janneke P.C., and van de Warrenburg, Bart P.C.
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HUNTINGTON disease , *GENETIC engineering , *SPINOCEREBELLAR ataxia , *PATIENTS' attitudes , *MOVEMENT disorders , *GENETIC disorders - Abstract
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.To obtain insight into the thoughts and perspectives of individuals with SCA and HD on genetic interventions.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.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.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. [ABSTRACT FROM AUTHOR]
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- 2024
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45. Uncovering the ferroptosis related mechanism of laduviglusib in the cell-type-specific targets of the striatum in Huntington's disease.
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Liu, Mei, Zhao, Jinlan, Xue, Chengcheng, Yang, Jun, and Ying, Li
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HUNTINGTON disease , *GENE expression , *NEUROTROPHIN receptors , *T helper cells , *RNA sequencing , *CELL death - Abstract
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder featured by abnormal movements, arising from the extensive neuronal loss and glial dysfunction in the striatum. Although the causes and pathogenetic mechanisms of HD are well established, the development of disease-modifying pharmacological therapies for HD remains a formidable challenge. Laduviglusib has demonstrated neuroprotective effects through the enhancement of mitochondrial function in the striatum of HD animal models. Ferroptosis is a nonapoptotic form of cell death that occurs as a consequence of lethal iron-dependent lipid peroxidation and mitochondrial dysfunction. However, the ferroptosis-related mechanisms underlying the neuroprotective effects of laduviglusib in the striatum of HD patients remain largely uncharted. In this study, we leveraged single-nucleus RNA sequencing data obtained from the striatum of HD patients in stages 2–4 to identify differentially expressed genes within distinct cell-type. We subsequently integrated these differentially expressed genes of HD, laduviglusib target genes and ferroptosis-related genes to predict the ferroptosis-related mechanisms underpinning the neuroprotective effects of laduviglusib in HD patients. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses unveiled that the effects of laduviglusib on direct pathway striatal projection neurons (dSPNs) is mainly associated with Th17 cell differentiation pathways. Conversely, its impact on indirect pathway striatal projection neurons (iSPNs) extends to the Neurotrophin signaling pathway, FoxO signaling pathway, and reactive oxygen species pathway. In microglia, laduviglusib appears to contribute to HD pathology via mechanisms related to Th17 cell differentiation and the FoxO signaling pathway. Further, molecular docking results indicated favorable binding of laduviglusib with PARP1 (associated with dSPNs and iSPNs), SCD (associated with astrocytes), ALOX5 (associated with microglia), and HIF1A (associated with dSPNs, iSPNs, and microglia). In addition, the KEGG results suggest that laduviglusib may enhance mitochondrial function and protect against neuronal loss by targeting ferroptosis-related signaling pathways, particularly mediated by ALOX5 in microglia. These findings provide valuable insights into the potential mechanisms through which laduviglusib exerts its effects on distinct cell-types within the HD striatum. [ABSTRACT FROM AUTHOR]
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- 2024
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46. Preserved VPS13A distribution and expression in Huntington's disease: divergent mechanisms of action for similar movement disorders?
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García-García, Esther, Carreras-Caballé, Maria, Coll-Manzano, Albert, Ramón-Lainez, Alba, Besa-Selva, Gisela, Pérez-Navarro, Esther, Malagelada, Cristina, Alberch, Jordi, Masana, Mercè, and Rodríguez, Manuel J.
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HUNTINGTON disease ,GENE expression ,SPINOCEREBELLAR ataxia ,MEDIUM spiny neurons ,MOVEMENT disorders ,BASAL ganglia diseases ,BASAL ganglia - Abstract
VPS13A disease and Huntington's disease (HD) are two basal ganglia disorders that may be difficult to distinguish clinically because they have similar symptoms, neuropathological features, and cellular dysfunctions with selective degeneration of the medium spiny neurons of the striatum. However, their etiology is different. VPS13A disease is caused by a mutation in the VPS13A gene leading to a lack of protein in the cells, while HD is due to an expansion of CAG repeat in the huntingtin (Htt) gene, leading to aberrant accumulation of mutant Htt. Considering the similarities of both diseases regarding the selective degeneration of striatal medium spiny neurons, the involvement of VPS13A in the molecular mechanisms of HD pathophysiology cannot be discarded. We analyzed the VPS13A distribution in the striatum, cortex, hippocampus, and cerebellum of a transgenic mouse model of HD. We also quantified the VPS13A levels in the human cortex and putamen nucleus; and compared data on mutant Htt-induced changes in VPS13A expression from differential expression datasets. We found that VPS13A brain distribution or expression was unaltered in most situations with a decrease in the putamen of HD patients and small mRNA changes in the striatum and cerebellum of HD mice. We concluded that the selective susceptibility of the striatum in VPS13A disease and HD may be a consequence of disturbances in different cellular processes with convergent molecular mechanisms already to be elucidated. [ABSTRACT FROM AUTHOR]
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- 2024
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47. Risk Factors and Interventions for Suicide in Huntington's Disease—A Systematic Review.
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Grimaldi, Alessandro, Veneziani, Isabella, Culicetto, Laura, Quartarone, Angelo, and Lo Buono, Viviana
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HUNTINGTON disease , *SUICIDE risk factors , *ATTEMPTED suicide , *PSYCHOTHERAPY , *SUICIDAL ideation , *FIBRODYSPLASIA ossificans progressiva - Abstract
Background/Objectives: Huntington's disease (HD) is an autosomal dominant genetic disorder causing progressive neurodegeneration which, aside from symptomatic therapies for controlling psychological and motor problems, currently has no effective treatment. People who receive this diagnosis often feel disoriented and lost without guidance. Furthermore, HD patients are estimated to have a two to seven times greater risk of suicide death compared to the general population. The current review investigates the complex relationship between HD and suicide, seeking to identify key risk factors influencing suicidal ideation and behaviour in affected individuals. Methods: We conducted a systematic review following the PRISMA guidelines. Studies were searched for on the PubMed, Cochrane, and Web of Science databases, and 17 articles met the inclusion criteria. Results: The findings reveal that emotional strain, neuropsychiatric symptoms, and the absence of a cure contribute to heightened suicidal tendencies in HD patients. Critical periods for suicide risk coincide with early symptomatic stages of disease or the successive phase, with the loss of independence impacting on daily functioning. Risk factors associated with HD include a depressive mood, cognitive impairments, and a history of suicide attempts. Conclusions: From a prevention perspective, a comprehensive multidisciplinary and multidimensional approach could enhance the overall well-being of people with HD. In particular, screening for suicidal thoughts in people with HD could mitigate suicide risk. [ABSTRACT FROM AUTHOR]
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- 2024
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48. White Matter Microstructure Changes Revealed by Diffusion Kurtosis and Diffusion Tensor Imaging in Mutant Huntingtin Gene Carriers.
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Yin, Jin-Hui, Liu, Ya-Ou, Li, Hong-Liang, Burgunder, Jean Marc, and Huang, Yue
- Abstract
Diffusion magnetic resonance imaging (dMRI) has revealed microstructural changes in white matter (WM) in Huntington’s disease (HD).To compare the validities of different dMRI, i.e., diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) in HD.22 mutant
huntingtin (mHTT ) carriers and 14 controls were enrolled. Clinical assessments and dMRI were conducted. Based on CAG-Age Product (CAP) score, mHTT carriers were categorized into high CAP (hCAP) and medium and low CAP (m& lCAP) groups. Spearman analyses were used to explore correlations between imaging parameters in brain regions and clinical assessments. Receiver operating characteristic (ROC) was used to distinguish mHTT carriers from control, and define the HD patients at advanced stage.Compared to controls, mHTT carriers exhibited WM changes in DKI and DTI. There were 22 more regions showing significant differences in HD detected by MK than FA. Only MK in five brain regions showed significantly difference between any two group, and negatively correlated with the disease burden (r = –0.80 to –0.71). ROC analysis revealed that MK was more sensitive and FA was more specific, while Youden index showed that the integration of FA and MK gave rise to higher authenticities, in distinguishing m& lCAP from controls (Youden Index = 0.786), and discerning different phase of HD (Youden Index = 0.804).Microstructural changes in WM occur at early stage of HD and deteriorate over the disease progression. Integrating DKI and DTI would provide the best accuracies for differentiating early HD from control and identifying advanced HD. [ABSTRACT FROM AUTHOR]- Published
- 2024
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49. Motor skill learning modulates striatal extracellular vesicles' content in a mouse model of Huntington's disease.
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Solana-Balaguer, Júlia, Garcia-Segura, Pol, Campoy-Campos, Genís, Chicote-González, Almudena, Fernández-Irigoyen, Joaquín, Santamaría, Enrique, Pérez-Navarro, Esther, Masana, Mercè, Alberch, Jordi, and Malagelada, Cristina
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MOTOR learning , *HUNTINGTON disease , *EXTRACELLULAR vesicles , *MEDIUM spiny neurons , *LABORATORY mice , *ANIMAL disease models - Abstract
Huntington's disease (HD) is a neurological disorder caused by a CAG expansion in the Huntingtin gene (HTT). HD pathology mostly affects striatal medium-sized spiny neurons and results in an altered cortico-striatal function. Recent studies report that motor skill learning, and cortico-striatal stimulation attenuate the neuropathology in HD, resulting in an amelioration of some motor and cognitive functions. During physical training, extracellular vesicles (EVs) are released in many tissues, including the brain, as a potential means for inter-tissue communication. To investigate how motor skill learning, involving acute physical training, modulates EVs crosstalk between cells in the striatum, we trained wild-type (WT) and R6/1 mice, the latter with motor and cognitive deficits, on the accelerating rotarod test, and we isolated their striatal EVs. EVs from R6/1 mice presented alterations in the small exosome population when compared to WT. Proteomic analyses revealed that striatal R6/1 EVs recapitulated signaling and energy deficiencies present in HD. Motor skill learning in R6/1 mice restored the amount of EVs and their protein content in comparison to naïve R6/1 mice. Furthermore, motor skill learning modulated crucial pathways in metabolism and neurodegeneration. All these data provide new insights into the pathogenesis of HD and put striatal EVs in the spotlight to understand the signaling and metabolic alterations in neurodegenerative diseases. Moreover, our results suggest that motor learning is a crucial modulator of cell-to-cell communication in the striatum. [ABSTRACT FROM AUTHOR]
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- 2024
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50. Disruption of the mitochondrial network in a mouse model of Huntington's disease visualized by in-tissue multiscale 3D electron microscopy.
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Martin-Solana, Eva, Casado-Zueras, Laura, Torres, Teobaldo E., Goya, Gerardo F., Fernandez-Fernandez, Maria-Rosario, and Fernandez, Jose-Jesus
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HUNTINGTON disease , *LABORATORY mice , *CORPUS striatum , *ANIMAL disease models , *MITOCHONDRIA , *ELECTRON microscopy - Abstract
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the coding sequence of huntingtin protein. Initially, it predominantly affects medium-sized spiny neurons (MSSNs) of the corpus striatum. No effective treatment is still available, thus urging the identification of potential therapeutic targets. While evidence of mitochondrial structural alterations in HD exists, previous studies mainly employed 2D approaches and were performed outside the strictly native brain context. In this study, we adopted a novel multiscale approach to conduct a comprehensive 3D in situ structural analysis of mitochondrial disturbances in a mouse model of HD. We investigated MSSNs within brain tissue under optimal structural conditions utilizing state-of-the-art 3D imaging technologies, specifically FIB/SEM for the complete imaging of neuronal somas and Electron Tomography for detailed morphological examination, and image processing-based quantitative analysis. Our findings suggest a disruption of the mitochondrial network towards fragmentation in HD. The network of interlaced, slim and long mitochondria observed in healthy conditions transforms into isolated, swollen and short entities, with internal cristae disorganization, cavities and abnormally large matrix granules. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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