Huntington's Disease Research Articles

Neuroprotective Effect of Boswellia serrata against 3-NP Induced Experimental Huntington’s Disease

Objectives:: The study aimed to assess the neuroprotective effect of Boswellia serrata against 3-NP-induced experimental Huntington’s disease. Background:: Previous studies have shown Boswellia to have sedative, analgesic, and anti-tumour effects. Boswellia serrata yields four pentacyclic triterpene acids and boswellic acid, a bioactive substance that prevents leukotriene biogenesis. Methods:: The potential neuroprotective effect of Boswellia serrata against 3-nitro propionic acid (3-NP)-induced Huntington's disease (HD) was examined at oral doses of 45 mg/kg, 90 mg/kg, and 180 mg/kg. In this study, HD was induced by 3-NP at a dose of 10 mg/kg in Wistar rats. The study used 56 Wistar rats (8 per group) for biochemical (inflammatory markers, acetylcholinesterase activity) and behavioural (elevated plus maze, Y-maze, open-field, tail suspension tests, etc.) assessments. Additionally, a histological examination of the brain was carried out. In addition, the analysis of Boswellia serrata extract was performed by different analytical techniques, like UV spectrophotometer, FTIR, and HPLC methods. Results:: In the brain, succinate dehydrogenase is a mitochondrial enzyme irreversibly inhibited by 3-NP. Administration of 3-NP resulted in HD with altered behavioural and motor changes in rats. Treatment with Boswellia serrata resulted in remarkable protection of rats against 3-NP-induced behaviour and motor deficits in a dose-dependent manner. Moreover, in rats administered with 3-NP, Boswellia serrata improved memory performance and lowered levels of inflammatory biomarkers. These results have also been supported by histopathological analysis. Acetyl-11-keto-p-boswellic acid was found to be the main active component of Boswellia serrata extract. Conclusion:: Boswellia serrata at a dose of 180 mg/kg exhibited better protection compared to the other doses against HD induced by 3-NP. More detailed studies based on molecular targets are needed for the Boswellia serrata to transition from the bench to the bedside for use as an adjuvant in HD patients.

Advances in iPSC Technology in Neural Disease Modeling, Drug Screening, and Therapy.

Neurodegenerative disorders (NDs) including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease are all incurable and can only be managed with drugs for the associated symptoms. Animal models of human illnesses help to advance our understanding of the pathogenic processes of diseases. Understanding the pathogenesis as well as drug screening using appropriate disease models of neurodegenerative diseases (NDs) are vital for identifying novel therapies. Human-derived induced pluripotent stem cell (iPSC) models can be an efficient model to create disease in a dish and thereby can proceed with drug screening and identifying appropriate drugs. This technology has many benefits, including efficient reprogramming and regeneration potential, multidirectional differentiation, and the lack of ethical concerns, which open up new avenues for studying neurological illnesses in greater depth. The review mainly focuses on the use of iPSC technology in neuronal disease modeling, drug screening, and cell therapy.

New insights into sodium phenylbutyrate as a pharmacotherapeutic option for neurological disorders.

Neurological disorders (NDs) are diseases of the central and peripheral nervous systems that affect more than one billion people worldwide. The risk of developing an ND increases with age due to the vulnerability of the different organs and systems to genetic, environmental, and social changes that consequently cause motor and cognitive deficits that disable the person from their daily activities and individual and social productivity. Intrinsic factors (genetic factors, age, gender) and extrinsic factors (addictions, infections, or lifestyle) favor the persistence of systemic inflammatory processes that contribute to the evolution of NDs. Neuroinflammation is recognized as a common etiopathogenic factor of ND. The study of new pharmacological options for the treatment of ND should focus on improving the characteristic symptoms and attacking specific molecular targets that allow the delay of damage processes such as neuroinflammation, oxidative stress, cellular metabolic dysfunction, and deregulation of transcriptional processes. In this review, we describe the possible role of sodium phenylbutyrate (NaPB) in the pathogenesis of Alzheimer's disease, hepatic encephalopathy, aging, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis; in addition, we describe the mechanism of action of NaPB and its beneficial effects that have been shown in various in vivo and in vitro studies to delay the evolution of any ND.

Prevalence and burden of pain across the entire spectrum of Huntington’s disease

BackgroundPain is an important symptom in Huntington’s disease (HD), however, not systematically studied and understood. The objective of the current study is to assess the prevalence of pain, pain interference...

Base editing strategies to convert CAG to CAA diminish the disease-causing mutation in Huntington's disease.

An expanded CAG repeat in the huntingtin gene (HTT) causes Huntington's disease (HD). Since the length of uninterrupted CAG repeat, not polyglutamine, determines the age-at-onset in HD, base editing strategies to convert CAG to CAA are anticipated to delay onset by shortening the uninterrupted CAG repeat. Here, we developed base editing strategies to convert CAG in the repeat to CAA and determined their molecular outcomes and effects on relevant disease phenotypes. Base editing strategies employing combinations of cytosine base editors and guide RNAs (gRNAs) efficiently converted CAG to CAA at various sites in the CAG repeat without generating significant indels, off-target edits, or transcriptome alterations, demonstrating their feasibility and specificity. Candidate BE strategies converted CAG to CAA on both expanded and non-expanded CAG repeats without altering HTT mRNA and protein levels. In addition, somatic CAG repeat expansion, which is the major disease driver in HD, was significantly decreased in the liver by a candidate BE strategy treatment in HD knock-in mice carrying canonical CAG repeats. Notably, CAG repeat expansion was abolished entirely in HD knock-in mice carrying CAA-interrupted repeats, supporting the therapeutic potential of CAG-to-CAA conversion strategies in HD and potentially other repeat expansion disorders.

Cholesterol Metabolism in Neurodegenerative Diseases.

Cholesterol plays a crucial role in brain, where it is highly concentrated and tightly regulated to support normal brain functions. It serves as a vital component of cell membranes, ensuring their integrity, and acts as a key regulator of various brain processes. Dysregulation of cholesterol metabolism in the brain has been linked to impaired brain function and the onset of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). A significant advancement has been the identification of astrocyte-derived ApoE as a key regulator of de novo cholesterol biosynthesis in neurons, providing insights into how extracellular signals influence neuronal cholesterol levels. Additionally, the development of antibody-based therapies, particularly for AD, presents promising opportunities for therapeutic interventions. Despite significant research, the association between cholesterol and neurodegenerative diseases remains inconclusive. It is crucial to distinguish between plasma cholesterol and brain cholesterol, as these pools are relatively independent. This differentiation should be considered when evaluating statin-based treatment approaches. Assessing not only the total cholesterol content in the brain but also its distribution among different types of brain cells is essential. Establishing a causal link between changes in brain/plasma cholesterol levels and the onset of brain dysfunction/neurodegenerative diseases remains a key objective. Additionally, conducting cell-specific analyses of cholesterol homeostasis in various types of brain cells under pathological conditions will enhance our understanding of cholesterol metabolism in neurodegenerative diseases. Manipulating cholesterol levels to restore homeostasis may represent a novel approach for alleviating neurological symptom.

Disruption of the mitochondrial network in a mouse model of Huntington's disease visualized by in-tissue multiscale 3D electron microscopy

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.

Evaluation of walking activity and gait to identify physical and mental fatigue in neurodegenerative and immune disorders: preliminary insights from the IDEA-FAST feasibility study

BackgroundMany individuals with neurodegenerative (NDD) and immune-mediated inflammatory disorders (IMID) experience debilitating fatigue. Currently, assessments of fatigue rely on patient reported outcomes (PROs), which are subjective and prone to recall biases. Wearable devices, however, provide objective and reliable estimates of gait, an essential component of health, and may present objective evidence of fatigue. This study explored the relationships between gait characteristics derived from an inertial measurement unit (IMU) and patient-reported fatigue in the IDEA-FAST feasibility study.MethodsParticipants with IMIDs and NDDs (Parkinson's disease (PD), Huntington's disease (HD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (PSS), and inflammatory bowel disease (IBD)) wore a lower-back IMU continuously for up to 10 days at home. Concurrently, participants completed PROs (physical fatigue (PF) and mental fatigue (MF)) up to four times a day. Macro (volume, variability, pattern, and acceleration vector magnitude) and micro (pace, rhythm, variability, asymmetry, and postural control) gait characteristics were extracted from the accelerometer data. The associations of these measures with the PROs were evaluated using a generalised linear mixed-effects model (GLMM) and binary classification with machine learning.ResultsData were recorded from 72 participants: PD = 13, HD = 9, RA = 12, SLE = 9, PSS = 14, IBD = 15. For the GLMM, the variability of the non-walking bouts length (in seconds) with PF returned the highest conditional R2, 0.165, and with MF the highest marginal R2, 0.0018. For the machine learning classifiers, the highest accuracy of the current analysis was returned by the micro gait characteristics with an intrasubject cross validation method and MF as 56.90% (precision = 43.9%, recall = 51.4%). Overall, the acceleration vector magnitude, bout length variation, postural control, and gait rhythm were the most interesting characteristics for future analysis.ConclusionsCounterintuitively, the outcomes indicate that there is a weak relationship between typical gait measures and abnormal fatigue. However, factors such as the COVID-19 pandemic may have impacted gait behaviours. Therefore, further investigations with a larger cohort are required to fully understand the relationship between gait and abnormal fatigue.

Insights into AlphaFold's breakthrough in neurodegenerative diseases.

Neurodegenerative diseases (ND) are disorders of the central nervous system (CNS) characterized by impairment in neurons' functions, and complete loss, leading to memory loss, and difficulty in learning, language, and movement processes. The most common among these NDs are Alzheimer's disease (AD) and Parkinson's disease (PD), although several other disorders also exist. These are frontotemporal dementia (FTD), amyotrophic lateral syndrome (ALS), Huntington's disease (HD), and others; the major pathological hallmark of NDs is the proteinopathies, either of amyloid-β (Aβ), tauopathies, or synucleinopathies. Aggregation of proteins that do not undergo normal configuration, either due to mutations or through some disturbance in cellular pathway contributes to the diseases. Artificial Intelligence (AI) and deep learning (DL) have proven to be successful in the diagnosis and treatment of various congenital diseases. DL approaches like AlphaFold (AF) are a major leap towards success in CNS disorders. This 3D protein geometry modeling algorithm developed by DeepMind has the potential to revolutionize biology. AF has the potential to predict 3D-protein confirmation at an accuracy level comparable to experimentally predicted one, with the additional advantage of precisely estimating protein interactions. This breakthrough will be beneficial to identify diseases' advancement and the disturbance of signaling pathways stimulating impaired functions of proteins. Though AlphaFold has solved a major problem in structural biology, it cannot predict membrane proteins-a beneficial approach for drug designing.

Using Wearable Sensors and Machine Learning to Assess Upper Limb Function in Huntington's Disease.

Huntington's disease (HD), like many other neurological disorders, affects both lower and upper limb function that is typically assessed in the clinic - providing a snapshot of disease symptoms. Wearable sensors enable the collection of real-world data that can complement such clinical assessments and provide a more comprehensive insight into disease symptoms. In this context, almost all studies are focused on assessing lower limb function via monitoring of gait, physical activity and ambulation. In this study, we monitor upper limb function during activities of daily living in individuals with HD (n = 16), prodromal HD (pHD, n = 7), and controls (CTR, n = 16) using a wrist-worn wearable sensor, called PAMSys ULM, over seven days. The participants were highly compliant in wearing the sensor with an average daily compliance of 99% (100% for HD, 98% for pHD, and 99% for CTR). Goal-directed movements (GDM) of the hand were detected using a deep learning model, and kinematic features of each GDM were estimated. The collected data was used to predict disease groups (i.e., HD, pHD, and CTR) and clinical scores using a combination of statistical and machine learning-based models. Significant differences in GDM features were observed between the groups. HD participants performed fewer GDMs with long duration (> 7.5 seconds) compared to CTR (p-val = 0.021, d = -0.86). In velocity and acceleration metrics, the highest effect size feature was the entropy of the velocity zero-crossing length segments (HD vs CTR p-val <0.001, d = -1.67; HD vs pHD p-val = 0.043, d=-0.98; CTR vs pHD p-val = 0.046, d=0.96). In addition, this same variable showed a strongest correlation with clinical scores. Classification models achieved good performance in distinguishing HD, pHD and CTR individuals with a balanced accuracy of 67% and a 0.72 recall for the HD group, while regression models accurately predicted clinical scores. Notably the explained variance for the upper extremity function subdomain scale of Unified Huntington's Disease Rating Scale (UHDRS) was the highest, with the model capturing 60% of the variance. Our findings suggest the potential of wearables and machine learning for early identification of phenoconversion, remote monitoring in HD, and evaluating new treatments efficacy in clinical trials and medicine.

Stick-slip unfolding favors self-association of expanded HTT mRNA.

In Huntington's Disease (HD) and related disorders, expansion of CAG trinucleotide repeats produces a toxic gain of function in affected neurons. Expanded huntingtin (expHTT) mRNA forms aggregates that sequester essential RNA binding proteins, dysregulating mRNA processing and translation. The physical basis of RNA aggregation has been difficult to disentangle owing to the heterogeneous structure of the CAG repeats. Here, we probe the folding and unfolding pathways of expHTT mRNA using single-molecule force spectroscopy. Whereas normal HTT mRNAs unfold reversibly and cooperatively, expHTT mRNAs with 20 or 40 CAG repeats slip and unravel non-cooperatively at low tension. Slippage of CAG base pairs is punctuated by concerted rearrangement of adjacent CCG trinucleotides, trapping partially folded structures that readily base pair with another RNA strand. We suggest that the conformational entropy of the CAG repeats, combined with stable CCG base pairs, creates a stick-slip behavior that explains the aggregation propensity of expHTT mRNA.

CircHTT(2,3,4,5,6)— co-evolving with the HTT CAG-repeat tract — modulates Huntington's disease phenotypes

Circular RNA (circRNA) molecules have critical functions during brain development and in brain related disorders. Here, we identified and validated a circRNA, circHTT(2,3,4,5,6), stemming from the Huntington's disease (HD) gene locus that is most abundant in the CNS. We uncovered its evolutionary conservation in diverse mammalian species, and a correlation between circHTT(2,3,4,5,6) levels and the length of the CAG-repeat tract in exon-1 of HTT in human and mouse HD model systems. The mouse orthologue, circHtt(2,3,4,5,6), is expressed during embryogenesis, increases during nervous system development, and is aberrantly up-regulated in presence of the expanded CAG-tract. While an IRES-like motif was predicted in circHtt(2,3,4,5,6), the circRNA does not appear to be translated in adult mouse brain tissue. Nonetheless, a modest, but consistent fraction of circHtt(2,3,4,5,6) associates with the 40S ribosomal subunit, suggesting a possible role in the regulation of protein translation. Finally, circHtt(2,3,4,5,6) over-expression experiments in HD-relevant STHdh striatal cells revealed its ability to modulate CAG-expansion driven cellular defects in cell-to-substrate adhesion, thus uncovering an unconventional modifier of HD pathology.

Presymptomatic Testing for Huntington's Disease in Mexico: 28 Years of Experience

IntroductionHuntington's disease (HD) is a genetic neurodegenerative disorder with dominant inheritance. Our center in Mexico City has offered presymptomatic testing (PT) since 1995. ObjectiveTo describe the main clinical and demographic characteristics of at-risk HD individuals who applied to the PT program, the reasons for seeking it, and the molecular results. MethodsA cross-sectional study was conducted with sociodemographic and clinical data of all PT applicants from 1995–2023. Reasons for seeking PT were assessed using a modified questionnaire. In addition, anxiety, and depressive symptoms before and after PT were evaluated with Beck's instruments; cognitive impairment (CI) was assessed with the Mini-Mental State Examination (MMSE) and molecular results. Results214 people applied for PT (2.1% of the at-risk population identified in our center); 63% were women (mean age of 37.11 years). 204 (95.3%) were accepted and 190 received results. 70% indicated that the main reason for applying for PT was to inform their offspring about the risk of inheriting HD. Significant differences were observed in the reasons for seeking PT by age group. Although some subjects received treatment, Beck's instrument scores did not indicate special attention or pharmacological treatment. The MMSE showed probable CI in 20 subjects. Of those who received results, 37% were carriers of a full penetrance allele. ConclusionOur center has the only formal PT program for HD in Mexico. The reasons for seeking PT are varied and age-related. Although PT is offered to all subjects at risk for HD, uptake remains low.

An Update on the Application of Nano Phytomedicine as an Emerging Therapeutic Tool for Neurodegenerative Diseases

Abstract: The existence of the blood-brain barrier (BBB), a densely woven network of blood vessels and endothelial cells designed to prevent the infiltration of foreign substances into the brain, the methods employed in developing treatments for neurodegenerative disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Multiple sclerosis, Amyotrophic lateral sclerosis, and others, pose significant challenges and complexities. These illnesses have had a terrible impact on the human population's health. Because early detection of these problems is poor and no good therapy has been established, they have emerged as the biggest lifethreatening healthcare burden worldwide compared to other significant illnesses. Traditional drug delivery techniques do not offer efficient treatment for NDs due to constraints in the BBB design, efflux pumps, and metabolic enzyme expression. Nanotechnology has the potential to significantly enhance ND therapy by utilizing systems that have been bioengineered to engage with living organisms at the cellular range. Compared to traditional techniques, nanotechnological technologies have several potential ways for crossing the BBB and increasing therapeutic efficacy in the brain. The introduction and growth of nanotechnology indicate promising potential for overcoming this issue. Engineered nanoparticles coupled with therapeutic moieties and imaging agents with dimensions ranging from 1-100 nm can improve effectiveness, cellular uptake, selective transport, and drug delivery to the brain due to their changed physicochemical properties. Conjugates of nanoparticles and medicinal plants, or their constituents known as nano phytomedicine, have recently gained importance in developing cutting-edge neuro-therapeutics due to their abundant natural supply, promising targeted delivery to the brain, and lower potential for adverse effects. This study summarizes the common NDs, their prevalence and pathogenesis, and potential herbal nanoformulation for treating NDs.

Flavonoids as Potential Therapeutics Against Neurodegenerative Disorders: Unlocking the Prospects.

Neurodegeneration, the decline of nerve cells in the brain, is a common feature of neurodegenerative disorders (NDDs). Oxidative stress, a key factor in NDDs such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease can lead to neuronal cell death, mitochondria impairment, excitotoxicity, and Ca2+ stress. Environmental factors compromising stress response lead to cell damage, necessitating novel therapeutics for preventing or treating brain disorders in older individuals and an aging population. Synthetic medications offer symptomatic benefits but can have adverse effects. This research explores the potential of flavonoids derived from plants in treating NDDs. Flavonoids compounds, have been studied for their potential to enter the brain and treat NDDs. These compounds have diverse biological effects and are currently being explored for their potential in the treatment of central nervous system disorders. Flavonoids have various beneficial effects, including antiviral, anti-allergic, antiplatelet, anti-inflammatory, anti-tumor, anti-apoptotic, and antioxidant properties. Their potential to alleviate symptoms of NDDs is significant.

An Update on Parkinson's Disease and its Neurodegenerative Counterparts.

Neurodegenerative disorders are a group of diseases that cause nerve cell degeneration in the brain, resulting in a variety of symptoms and are not treatable with drugs. Parkinson's disease (PD), prion disease, motor neuron disease (MND), Huntington's disease (HD), spinal cerebral dyskinesia (SCA), spinal muscle atrophy (SMA), multiple system atrophy, Alzheimer's disease (AD), spinocerebellar ataxia (SCA) (ALS), pantothenate kinase-related neurodegeneration, and TDP-43 protein disorder are examples of neurodegenerative diseases. Dementia is caused by the loss of brain and spinal cord nerve cells in neurodegenerative diseases. Even though environmental and genetic predispositions have also been involved in the process, redox metal abuse plays a crucial role in neurodegeneration since the preponderance of symptoms originates from abnormal metal metabolism. Hence, this review investigates several neurodegenerative diseases that may occur symptoms similar to Parkinson's disease to understand the differences and similarities between Parkinson's disease and other neurodegenerative disorders based on reviewing previously published papers. Based on the findings, the aggregation of alpha-synuclein occurs in Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. Other neurodegenerative diseases occur with different protein aggregation or mutations. We can conclude that Parkinson's disease, Multiple system atrophy, and Dementia with Lewy bodies are closely related. Therefore, researchers must distinguish among the three diseases to avoid misdiagnosis of Multiple System Atrophy and Dementia with Lewy bodies with Parkinson's disease symptoms.

Cross-Sectional Analysis of Exome Sequencing Diagnosis in Patients With Neurologic Phenotypes Facing Barriers to Clinical Testing.

Exome sequencing (ES) demonstrates a 20-50 percent diagnostic yield for patients with a suspected monogenic neurologic disease. Despite the proven efficacy in achieving a diagnosis for such patients, multiple barriers for obtaining exome sequencing remain. This study set out to assess the efficacy of ES in patients with primary neurologic phenotypes who were appropriate candidates for testing but had been unable to pursue clinical testing. A total of 297 patients were identified from the UCLA Clinical Neurogenomics Research Center Biobank, and ES was performed, including bioinformatic assessment of copy number variation and repeat expansions. Information regarding demographics, clinical indication for ES, and reason for not pursuing ES clinically were recorded. To assess diagnostic efficacy, variants were interpreted by a multidisciplinary team of clinicians, bioinformaticians, and genetic counselors in accordance with the American College of Medical Genetics and Genomics variant classification guidelines. We next examined the specific barriers to testing for these patients, including how frequently insurance-related barriers such as coverage denials and inadequate coverage of cost were obstacles to pursuing exome sequencing. The cohort primarily consisted of patients with sporadic conditions (n = 126, 42.4%) of adult-onset (n = 239, 80.5%). Cerebellar ataxia (n = 225, 75.8%) was the most common presenting neurologic phenotype. Our study found that in this population of mostly adult patients with primary neurologic phenotypes that were unable to pursue exome sequencing clinically, 47 (15.8%) had diagnostic results while an additional 24 patients (8.1%) had uncertain results. Of the 297 patients, 206 were initially recommended for clinical exome but 88 (42.7%) could not pursue ES because of insurance barriers, of whom 14 (15.9%) had diagnostic findings, representing 29.8% of all patients with diagnostic findings. In addition, the incorporation of bioinformatic repeat expansion testing was valuable, identifying a total of 8 pathogenic repeat expansions (17.0% of all diagnostic findings) including 3 of the common spinocerebellar ataxias and 2 patients with Huntington disease. These findings underscore the importance and value of clinical ES as a diagnostic tool for neurogenetic disease and highlight key barriers that prevent patients from receiving important clinical information with potential treatment and psychosocial implications for patients and family members.

Sex-Specific Differences in the Progression of Huntington’s Disease Symptoms – A National Study in China

Introduction: Huntington’s disease (HD) is a rare, inherited neurodegenerative disorder. Despite extensive research on symptom progression and sex differences in Western populations, little is known about these aspects within the Chinese context. The objective of this study was to investigate the temporal trends of symptoms in individuals with HD in China. Methods: A nationwide cross-sectional study was conducted in Chinese individuals diagnosed with HD. Symptom progression over time, encompassing physical, psychiatric, and cognitive symptoms, was self-reported. We calculated the proportions of individuals who currently had each symptom by disease duration, and tested corresponding temporal trends by linear regression analyses. Results: A total of 269 individuals diagnosed with HD were included. Specific symptoms were found to progress more significantly in males compared to females over time, including psychotic symptoms (p = 0.007), urinary incontinence (p = 0.013), reduced concentration (p = 0.005), font alteration (p = 0.029), atypical facial expression (p = 0.037), and suicidal ideation (p = 0.047). In terms of cognitive and psychiatric symptoms, no significant temporal trends were identified in females, while males demonstrated significant increasing trends, with reduced concentration (p = 0.005) and psychotic symptoms (p = 0.007) standing out. Conclusions: This study emphasizes the existence of sex-specific symptom progression in HD within the Chinese population, underscoring the importance of considering sex in clinical practice. Further research should investigate the mechanisms behind these differences and explore tailored treatment options.

Effect of Capsaicin on 3-NP-Induced Neurotoxicity: A Pre-Clinical Study.

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 20mg/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 20mg/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 20mg/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.

Oropharyngeal Dysphagia Phenotypes Across Huntington’s Disease Stages: Endoscopic Findings and Tongue Pressure Analysis

Background: Oropharyngeal dysphagia (OD) is a common symptom in Huntington’s disease (HD) and is associated with severe health and psychosocial consequences. Different OD phenotypes are defined on the basis of characteristic patterns at fiberoptic endoscopic evaluation of swallowing (FEES), and they may vary during disease progression. Objective: To describe OD phenotypes in different HD stages and to analyze their association with neurological data and tongue pressure measurements. Methods: Twenty-four patients with HD at different stages of disease progression underwent a FEES. Data on penetration/aspiration, pharyngeal residue, and OD phenotypes were gained. Neurological examination was performed with the Unified Huntington’s Disease Rating Scale (UHDRS). Patient Maximum tongue pressure (MTP) and tongue endurance were measured. Results: We confirmed that the occurrence of penetration/aspiration increased with disease duration and pharyngeal residue increased from 16.7% to 100% , respectively. The most common OD phenotypes were oropharyngeal dyspraxia (91.7% ), posterior oral incontinence (87.5% ), and delayed pharyngeal phase (87.5% ). These types of dysfunctions are already detectable in &gt;80% of patients in the early disease stages. In more advanced stages, we also observed propulsion deficit (66.7% ), resistive issue (54.2% ), and protective deficit (37.5% ). Propulsion deficit was associated with higher disease stage, greater motor dysfunction (UHDRS-I), and lower MTP and tongue endurance (p &lt; 0.05). Conclusions: OD in HD results from a combination of different swallowing phenotypes. Early assessment of swallowing and periodical follow-ups are necessary to monitor OD severity and phenotypes and to revise diet recommendations.