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Introduction: Dysarthria, a motor speech disorder caused by muscle weakness or paralysis, severely impacts speech intelligibility and quality of life. The condition is prevalent in motor speech disorders such as Parkinson's disease (PD), atypical parkinsonism such as progressive supranuclear palsy (PSP), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Improving intelligibility is not only an outcome that matters to patients but can also play a critical role as an endpoint in clinical research and drug development. This study validates a digital measure for speech intelligibility, the ki: SB-M intelligibility score, across various motor speech disorders and languages following the Digital Medicine Society (DiMe) V3 framework. Methods: The study used four datasets: healthy controls (HCs) and patients with PD, HD, PSP, and ALS from Czech, Colombian, and German populations. Participants' speech intelligibility was assessed using the ki: SB-M intelligibility score, which is derived from automatic speech recognition (ASR) systems. Verification with inter-ASR reliability and temporal consistency, analytical validation with correlations to gold standard clinical dysarthria scores in each disease, and clinical validation with group comparisons between HCs and patients were performed. Results: Verification showed good to excellent inter-rater reliability between ASR systems and fair to good consistency. Analytical validation revealed significant correlations between the SB-M intelligibility score and established clinical measures for speech impairments across all patient groups and languages. Clinical validation demonstrated significant differences in intelligibility scores between pathological groups and healthy controls, indicating the measure's discriminative capability. Discussion: The ki: SB-M intelligibility score is a reliable, valid, and clinically relevant tool for assessing speech intelligibility in motor speech disorders. It holds promise for improving clinical trials through automated, objective, and scalable assessments. Future studies should explore its utility in monitoring disease progression and therapeutic efficacy as well as add data from further dysarthrias to the validation. [ABSTRACT FROM AUTHOR]

IntroductionDysarthria, a motor speech disorder caused by muscle weakness or paralysis, severely impacts speech intelligibility and quality of life. The condition is prevalent in motor speech disorders such as Parkinson's disease (PD), atypical parkinsonism such as progressive supranuclear palsy (PSP), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Improving intelligibility is not only an outcome that matters to patients but can also play a critical role as an endpoint in clinical research and drug development. This study validates a digital measure for speech intelligibility, the ki: SB-M intelligibility score, across various motor speech disorders and languages following the Digital Medicine Society (DiMe) V3 framework.MethodsThe study used four datasets: healthy controls (HCs) and patients with PD, HD, PSP, and ALS from Czech, Colombian, and German populations. Participants’ speech intelligibility was assessed using the ki: SB-M intelligibility score, which is derived from automatic speech recognition (ASR) systems. Verification with inter-ASR reliability and temporal consistency, analytical validation with correlations to gold standard clinical dysarthria scores in each disease, and clinical validation with group comparisons between HCs and patients were performed.ResultsVerification showed good to excellent inter-rater reliability between ASR systems and fair to good consistency. Analytical validation revealed significant correlations between the SB-M intelligibility score and established clinical measures for speech impairments across all patient groups and languages. Clinical validation demonstrated significant differences in intelligibility scores between pathological groups and healthy controls, indicating the measure's discriminative capability.DiscussionThe ki: SB-M intelligibility score is a reliable, valid, and clinically relevant tool for assessing speech intelligibility in motor speech disorders. It holds promise for improving clinical trials through automated, objective, and scalable assessments. Future studies should explore its utility in monitoring disease progression and therapeutic efficacy as well as add data from further dysarthrias to the validation.

Introduction: 3-NP induction in rodent models has been shown to induce selective neurodegeneration in the striatum followed by the cortex (Brouillet, 2014). However, it remains unclear whether, under such a neurotoxic condition, characterized by neuroinflammation and oxidative stress, the gene expression of the immune resident protein, T-cell receptor beta subunit (TCR-β), α7 nicotinic acetylcholine receptor (α7 nAChRs), the nuclear factor kappa B (NF-κB), inflammatory cytokines (TNF-α and IL-6), and antioxidants (Cat and GpX4) get modulated on Vitamin D3 (VD) supplementation in the central nervous system. Methods: In the present study, real-time polymerase chain reaction (RT-PCR) was performed to study the expression of respective genes. Male C57BL/6 mice (8–12 weeks) were divided into four groups namely, Group I: Control (saline); Group II: 3-NP induction via i.p (HD); Group III: Vitamin D3 (VD) and Group IV: (HD + VD) (Manjari et al., 2022). Results: On administration of 500IU/kg/day of VD, HD mice showed a significant reduction in the gene expression of the immune receptor, TCR-β subunit, nuclear factor kappa B (NF-κB), inflammatory cytokines, and key antioxidants, followed by a decrease in the acetylcholinesterase activity. Conclusion: A novel neuroprotective effect of VD in HD is demonstrated by combating the immune receptor, TCR-β gene expression, antioxidant markers, and inflammatory cytokines. In addition, HD mice on VD administration for 0–15 days showed an enhancement in cholinergic signaling with restoration in α7 nAChRs mRNA and protein expression in the striatum and cortex.

Sleep disturbances are common in various neurological pathologies, including amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), hereditary ataxias, Huntington's disease (HD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). This article reviews the prevalence and characteristics of sleep disorders in these conditions, highlighting their impact on patients' quality of life and disease progression. Sleep-related breathing disorders, insomnia, restless legs syndrome (RLS), periodic limb movement syndrome (PLMS), and rapid eye movement sleep behavior disorder (RBD) are among the common sleep disturbances reported. Both pharmacological and non-pharmacological interventions play crucial roles in managing sleep disturbances and enhancing overall patient care. [ABSTRACT FROM AUTHOR]

• We examined EEG oscillatory power and functional connectivity as potential correlates of non-motor symptoms in Huntington's disease (HD). • The HD group had lower theta power, higher delta power and connectivity, and theta power was correlated with processing speed. • Our findings support the use of quantitative EEG metrics as a potential marker of processing speed for clinical research in HD. To find sensitive neurophysiological correlates of non-motor symptoms in Huntington's disease (HD), which are essential for the development and assessment of novel treatments. We used resting state EEG to examine differences in oscillatory activity (analysing the isolated periodic as well as the complete EEG signal) and functional connectivity in 22 late premanifest and early stage people with HD and 20 neurotypical controls. We then assessed the correlations between these neurophysiological markers and clinical measures of apathy and processing speed. Significantly lower theta and greater delta resting state power was seen in the HD group, as well as significantly greater delta connectivity. There was a significant positive correlation between theta power and processing speed, however there were no associations between the neurophysiological and apathy measures. We speculate that these changes in oscillatory power and connectivity reflect ongoing, frontally concentrated degenerative and compensatory processes associated with HD. Our findings support the potential utility of quantitative EEG as a proximate marker of processing speed, but not apathy in HD. [ABSTRACT FROM AUTHOR]

Objective: Apathy, a frequent neuropsychiatric symptom in aging neurocognitive disorders, has been associated with cognitive decline and functional disability. Therefore, timely provision of pharmacological interventions for apathy is greatly needed. Design: A systematical literature review of existing studies was conducted up to 30 May 2023 in several databases (PubMed, PsychInfo, Cochrane, Google Scholar, etc.) that included randomized controlled trials (RCTs) and meta-analyses assessing pharmacological treatments for apathy in aging neurocognitive disorders. The quality of the studies was appraised. Results: In patients with Alzheimer's Disease (AD), donepezil, galantamine, rivastigmine, methylphenidate, and gingko biloba were proven efficacious for apathy, while rivastigmine, cognitive enhancer IRL752 and piribedil were found to be beneficial in patients with Parkinson's Disease (PD) and agomelatine in patients with Frontotemporal Dementia (FD). The extensive proportion of RCTs in which apathy was used as a secondary outcome measure, along with the considerable methodological heterogeneity, did not allow the evaluation of group effects. Conclusions: Pharmacological interventions for apathy in aging neurocognitive disorders are complex and under-investigated. The continuation of systematic research efforts and the provision of individualized treatment for patients suffering from these disorders is vital. [ABSTRACT FROM AUTHOR]

The G-protein-coupled estrogen receptor-1 (GPER) is an extranuclear estrogen receptor that regulates the expression of several downstream signaling pathways with a variety of biological actions including cell migration, proliferation, and apoptosis in different parts of the brain area. It is endogenously activated by estrogen, a steroidal hormone that binds to GPER receptors which help in maintaining cellular homeostasis and neuronal integrity as well as influences neurogenesis. In contrast, neurodegenerative disorders are a big problem for society, and still many people suffer from motor and cognitive impairments. Research to date reported that GPER has the potential to whittle down motor abnormalities and cognitive dysfunction by limiting the progression of neurodegenerative disorders. Although several findings suggest that GPER activation accelerated transcription of the PI3K/Akt/Gsk-3β and ERK1/2 signaling pathway that halt disease progression by decreasing oxidative stress, neuroinflammation, and apoptosis. Accordingly, the goal of this review is to highlight the basic mechanism of GPER signaling pathway-mediated neuroprotection in various neurodegenerative disorders including Parkinson's disease (PD), Huntington's disease (HD), Tardive dyskinesia (TD), and Epilepsy. This review also discusses the role of the GPER activators which might be a promising therapeutic target option to treat neurodegenerative disorders. All the data were obtained from published articles in PubMed (353), Web of Science (788), and Scopus (770) databases using the search terms: GPER, PD, HD, TD, epilepsy, and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Abstract Introduction Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in development for the treatment of Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). Pridopidine’s activation of S1R enhances cellular processes that are crucial for neuronal function and survival but are impaired in neurodegenerative diseases. Human brain positron emission tomography (PET) imaging studies show that at the therapeutic dose of 45 mg twice daily (bid), pridopidine selectively and robustly occupies the S1R. We conducted concentration-QTc (C-QTc) analyses to assess pridopidine’s effect on the QT interval and investigated its cardiac safety profile. Methods C-QTc analysis was conducted using data from PRIDE-HD, a phase 2, placebo-controlled trial evaluating four pridopidine doses (45, 67.5, 90, 112.5 mg bid) or placebo over 52 weeks in HD patients. Triplicate electrocardiograms (ECGs) with simultaneous plasma drug concentrations were determined in 402 patients with HD. The effect of pridopidine on the Fridericia-corrected QT interval (QTcF) was evaluated. Cardiac-related adverse events (AEs) were analyzed from PRIDE-HD alone and from pooled safety data of three double-blind, placebo-controlled trials with pridopidine in HD (HART, MermaiHD, and PRIDE-HD). Results A concentration-dependent effect of pridopidine on the change from baseline in the Fridericia-corrected QT interval (ΔQTcF) was observed, with a slope of 0.012 ms (ms) per ng/mL (90% confidence interval (CI), 0.0109–0.0127). At the therapeutic dose of 45 mg bid, the predicted placebo-corrected ΔQTcF (ΔΔQTcF) was 6.6 ms (upper bound 90% CI, 8.0 ms), which is below the level of concern and not clinically relevant. Analysis of pooled safety data from three HD trials demonstrates that at 45 mg bid, pridopidine cardiac-related AE frequencies are similar to those with placebo. No patients reached a QTcF of 500 ms and no patients experienced torsade de pointes (TdP) at any pridopidine dose. Conclusions At the 45 mg bid therapeutic dose, pridopidine demonstrates a favorable cardiac safety profile, with an effect on the QTc interval that is below the level of concern and not clinically relevant. Trial Registration PRIDE-HD (TV7820-CNS-20002) trial registration: ClinicalTrials.gov identifier, NCT02006472, EudraCT 2013-001888-23; HART (ACR16C009) trial registration: ClinicalTrials.gov identifier, NCT00724048; MermaiHD (ACR16C008) trial registration: ClinicalTrials.gov identifier, NCT00665223, EudraCT No. 2007-004988-22.

Introduction: Huntington’s disease (HD) is a neurodegenerative disease that primarily affects the striatum, a brain region that controls movement and some forms of cognition. Neuronal dysfunction and loss in HD is accompanied by increased astrocyte density and astrocyte pathology. Astrocytes are a heterogeneous population classified into multiple subtypes depending on the expression of different gene markers. Studying whether mutant Huntingtin (HTT) alters specific subtypes of astrocytes is necessary to understand their relative contribution to HD. Methods: Here, we studied whether astrocytes expressing two different markers; glial fibrillary acidic protein (GFAP), associated with astrocyte activation, and S100 calcium-binding protein B (S100B), a marker of matured astrocytes and inflammation, were differentially altered in HD. Results: First, we found three distinct populations in the striatum of WT and symptomatic zQ175 mice: GFAP+, S100B+, and dual GFAP+S100B+. The number of GFAP+ and S100B+ astrocytes throughout the striatum was increased in HD mice compared to WT, coinciding with an increase in HTT aggregation. Overlap between GFAP and S100B staining was expected, but dual GFAP+S100B+ astrocytes only accounted for less than 10% of all tested astrocytes and the number of GFAP+S100B+ astrocytes did not differ between WT and HD, suggesting that GFAP+ astrocytes and S100B+ astrocytes are distinct types of astrocytes. Interestingly, a spatial characterization of these astrocyte subtypes in HD mice showed that while S100B+ were homogeneously distributed throughout the striatum, GFAP+ preferentially accumulated in “patches” in the dorsomedial (dm) striatum, a region associated with goal directed behaviors. In addition, GFAP+ astrocytes in the dm striatum of zQ175 mice showed increased clustering and association with white matter fascicles and were preferentially located in areas with low HTT aggregate load. Discussion: In summary, we showed that GFAP+ and S100B+ astrocyte subtypes are distinctly affected in HD and exist in distinct spatial arrangements that may offer new insights to the function of these specific astrocytes subtypes and their potential implications in HD pathology. [ABSTRACT FROM AUTHOR]

Introduction: Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in development for the treatment of Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Pridopidine's activation of S1R enhances cellular processes that are crucial for neuronal function and survival but are impaired in neurodegenerative diseases. Human brain positron emission tomography (PET) imaging studies show that at the therapeutic dose of 45 mg twice daily (bid), pridopidine selectively and robustly occupies the S1R. We conducted concentration-QTc (C-QTc) analyses to assess pridopidine's effect on the QT interval and investigated its cardiac safety profile. Methods: C-QTc analysis was conducted using data from PRIDE-HD, a phase 2, placebo-controlled trial evaluating four pridopidine doses (45, 67.5, 90, 112.5 mg bid) or placebo over 52 weeks in HD patients. Triplicate electrocardiograms (ECGs) with simultaneous plasma drug concentrations were determined in 402 patients with HD. The effect of pridopidine on the Fridericia-corrected QT interval (QTcF) was evaluated. Cardiac-related adverse events (AEs) were analyzed from PRIDE-HD alone and from pooled safety data of three double-blind, placebo-controlled trials with pridopidine in HD (HART, MermaiHD, and PRIDE-HD). Results: A concentration-dependent effect of pridopidine on the change from baseline in the Fridericia-corrected QT interval (ΔQTcF) was observed, with a slope of 0.012 ms (ms) per ng/mL (90% confidence interval (CI), 0.0109–0.0127). At the therapeutic dose of 45 mg bid, the predicted placebo-corrected ΔQTcF (ΔΔQTcF) was 6.6 ms (upper bound 90% CI, 8.0 ms), which is below the level of concern and not clinically relevant. Analysis of pooled safety data from three HD trials demonstrates that at 45 mg bid, pridopidine cardiac-related AE frequencies are similar to those with placebo. No patients reached a QTcF of 500 ms and no patients experienced torsade de pointes (TdP) at any pridopidine dose. Conclusions: At the 45 mg bid therapeutic dose, pridopidine demonstrates a favorable cardiac safety profile, with an effect on the QTc interval that is below the level of concern and not clinically relevant. Trial Registration: PRIDE-HD (TV7820-CNS-20002) trial registration: ClinicalTrials.gov identifier, NCT02006472, EudraCT 2013-001888-23; HART (ACR16C009) trial registration: ClinicalTrials.gov identifier, NCT00724048; MermaiHD (ACR16C008) trial registration: ClinicalTrials.gov identifier, NCT00665223, EudraCT No. 2007-004988-22. [ABSTRACT FROM AUTHOR]

Introduction: Huntington’s disease (HD) remains an incurable and fatal neurodegenerative disease long after CAG-expansion mutation in the huntingtin gene (HTT) was identified as the cause. The underlying pathological mechanism, whether HTT loss of function or gain of toxicity results from mutation, remains a matter of debate.Methods: In this study, we genetically modulated wild-type or mutant HTT expression levels in isogenic human embryonic stem cells to systematically investigate their contribution to HD-specific phenotypes.Results: Using highly reproducible and quantifiable in vitro micropattern-based assays, we observed comparable phenotypes with HD mutation and HTT depletion. However, halving endogenous wild-type HTT levels did not strongly recapitulate the HD phenotypes, arguing against a classical loss of function mechanism. Remarkably, expression of CAG-expanded HTT in non-HD cells induced HD like phenotypes akin to HTT depletion.Discussion: By corollary, these results indicate a dominant negative effect of mutated HTT on its wild-type counterpart. Complementation with additional copies of wild-type HTT ameliorated the HD-associated phenotypes, strongly supporting a classical dominant negative mechanism. Understanding the molecular basis of this dominant negative effect will guide the development of efficient clinical strategies to counteract the deleterious impact of mutant HTT on the wild-type HTT function.

IntroductionHuntington’s disease (HD) is a neurodegenerative disease that primarily affects the striatum, a brain region that controls movement and some forms of cognition. Neuronal dysfunction and loss in HD is accompanied by increased astrocyte density and astrocyte pathology. Astrocytes are a heterogeneous population classified into multiple subtypes depending on the expression of different gene markers. Studying whether mutant Huntingtin (HTT) alters specific subtypes of astrocytes is necessary to understand their relative contribution to HD.MethodsHere, we studied whether astrocytes expressing two different markers; glial fibrillary acidic protein (GFAP), associated with astrocyte activation, and S100 calcium-binding protein B (S100B), a marker of matured astrocytes and inflammation, were differentially altered in HD.ResultsFirst, we found three distinct populations in the striatum of WT and symptomatic zQ175 mice: GFAP+, S100B+, and dual GFAP+S100B+. The number of GFAP+ and S100B+ astrocytes throughout the striatum was increased in HD mice compared to WT, coinciding with an increase in HTT aggregation. Overlap between GFAP and S100B staining was expected, but dual GFAP+S100B+ astrocytes only accounted for less than 10% of all tested astrocytes and the number of GFAP+S100B+ astrocytes did not differ between WT and HD, suggesting that GFAP+ astrocytes and S100B+ astrocytes are distinct types of astrocytes. Interestingly, a spatial characterization of these astrocyte subtypes in HD mice showed that while S100B+ were homogeneously distributed throughout the striatum, GFAP+ preferentially accumulated in “patches” in the dorsomedial (dm) striatum, a region associated with goal-directed behaviors. In addition, GFAP+ astrocytes in the dm striatum of zQ175 mice showed increased clustering and association with white matter fascicles and were preferentially located in areas with low HTT aggregate load.DiscussionIn summary, we showed that GFAP+ and S100B+ astrocyte subtypes are distinctly affected in HD and exist in distinct spatial arrangements that may offer new insights to the function of these specific astrocytes subtypes and their potential implications in HD pathology.

Monitoring the activity of mice within their home cage is proving to be a powerful tool for revealing subtle and early-onset phenotypes in mouse models. Video-tracking, in particular, lends itself to automated machine-learning technologies that have the potential to improve the manual annotations carried out by humans. This type of recording and analysis is particularly powerful in objective phenotyping, monitoring behaviors with no experimenter intervention. Automated home-cage testing allows the recording of non-evoked voluntary behaviors, which do not require any contact with the animal or exposure to specialist equipment. By avoiding stress deriving from handling, this approach, on the one hand, increases the welfare of experimental animals and, on the other hand, increases the reliability of results excluding confounding effects of stress on behavior. In this study, we show that the monitoring of climbing on the wire cage lid of a standard individually ventilated cage (IVC) yields reproducible data reflecting complex phenotypes of individual mouse inbred strains and of a widely used model of neurodegeneration, the N171-82Q mouse model of Huntington's disease (HD). Measurements in the home-cage environment allowed for the collection of comprehensive motor activity data, which revealed sexual dimorphism, daily biphasic changes, and aging-related decrease in healthy C57BL/6J mice. Furthermore, home-cage recording of climbing allowed early detection of motor impairment in the N171-82Q HD mouse model. Integrating cage-floor activity with cage-lid activity (climbing) has the potential to greatly enhance the characterization of mouse strains, detecting early and subtle signs of disease and increasing reproducibility in preclinical studies. [ABSTRACT FROM AUTHOR]

Epidemiological studies and clinical observations show evidence of sexual dimorphism in brain responses to several neurological conditions. It is suggested that sex-related differences between men and women may have profound effects on disease susceptibility, pathophysiology, and progression. Sexual differences of the brain are achieved through the complex interplay of several factors contributing to this phenomenon, such as sex hormones, as well as genetic and epigenetic differences. Despite recent advances, the precise link between these factors and brain disorders is incompletely understood. This review aims to briefly outline the most relevant aspects that differ between men and women in ischemia and neurodegenerative disorders (AD, PD, HD, ALS, and SM). Recognition of disparities between both sexes could aid the development of individual approaches to ameliorate or slow the progression of intractable disorders. [ABSTRACT FROM AUTHOR]

Abstract Background Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of the CAG repeat in the huntingtin (HTT) gene. When the number of CAG repeats exceeds 36, the translated expanded polyglutamine-containing HTT protein (mutant HTT [mHTT]) interferes with the normal functions of many cellular proteins and subsequently jeopardizes important cellular machineries in major types of brain cells, including neurons, astrocytes, and microglia. The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome, which comprises NLRP3, ASC, and caspase-1, is involved in the activation of IL-1β and IL-18 and has been implicated in various biological functions. Although the existence of the NLRP3 inflammasome in the brain has been documented, the roles of the NLRP3 inflammasome in HD remain largely uncharacterized. MCC950 is a highly selective and potent small-molecule inhibitor of NLRP3 that has been used for the treatment of several diseases such as Alzheimer’s disease. However, whether MCC950 is also beneficial in HD remains unknown. Therefore, we hypothesized that MCC950 exerts beneficial effects in a transgenic mouse model of HD. Methods To evaluate the effects of MCC950 in HD, we used the R6/2 (B6CBA-Tg[HDexon1]62Gpb/1J) transgenic mouse model of HD, which expresses exon 1 of the human HTT gene carrying 120 ± 5 CAG repeats. Male transgenic R6/2 mice were treated daily with MCC950 (10 mg/kg of body weight; oral administration) or water for 5 weeks from the age of 7 weeks. We examined neuronal density, neuroinflammation, and mHTT aggregation in the striatum of R6/2 mice vs. their wild-type littermates. We also evaluated the motor function, body weight, and lifespan of R6/2 mice. Results Systematic administration of MCC950 to R6/2 mice suppressed the NLRP3 inflammasome, decreased IL-1β and reactive oxygen species production, and reduced neuronal toxicity, as assessed based on increased neuronal density and upregulation of the NeuN and PSD-95 proteins. Most importantly, oral administration of MCC950 increased neuronal survival, reduced neuroinflammation, extended lifespan, and improved motor dysfunction in R6/2 mice. Conclusions Collectively, our findings indicate that MCC950 exerts beneficial effects in a transgenic mouse model of HD and has therapeutic potential for treatment of this devastating neurodegenerative disease.

Monitoring the activity of mice within their home cage is proving to be a powerful tool for revealing subtle and early-onset phenotypes in mouse models. Video-tracking, in particular, lends itself to automated machine-learning technologies that have the potential to improve the manual annotations carried out by humans. This type of recording and analysis is particularly powerful in objective phenotyping, monitoring behaviors with no experimenter intervention. Automated home-cage testing allows the recording of non-evoked voluntary behaviors, which do not require any contact with the animal or exposure to specialist equipment. By avoiding stress deriving from handling, this approach, on the one hand, increases the welfare of experimental animals and, on the other hand, increases the reliability of results excluding confounding effects of stress on behavior. In this study, we show that the monitoring of climbing on the wire cage lid of a standard individually ventilated cage (IVC) yields reproducible data reflecting complex phenotypes of individual mouse inbred strains and of a widely used model of neurodegeneration, the N171-82Q mouse model of Huntington’s disease (HD). Measurements in the home-cage environment allowed for the collection of comprehensive motor activity data, which revealed sexual dimorphism, daily biphasic changes, and aging-related decrease in healthy C57BL/6J mice. Furthermore, home-cage recording of climbing allowed early detection of motor impairment in the N171-82Q HD mouse model. Integrating cage-floor activity with cage-lid activity (climbing) has the potential to greatly enhance the characterization of mouse strains, detecting early and subtle signs of disease and increasing reproducibility in preclinical studies.

Quantitative susceptibility mapping (QSM) is a promising tool for investigating iron dysregulation in neurodegenerative diseases, including Huntington's disease (HD). Many diverse methods have been proposed to generate accurate and robust QSM images. In this study, we evaluated the performance of different dipole inversion algorithms for iron-sensitive susceptibility imaging at 7T on healthy subjects of a large age range and patients with HD. We compared an iterative least-squares-based method (iLSQR), iterative methods that use regularization, single-step approaches, and deep learning-based techniques. Their performance was evaluated by comparing: (1) deviations from a multiple-orientation QSM reference; (2) visual appearance of QSM maps and the presence of artifacts; (3) susceptibility in subcortical brain regions with age; (4) regional brain susceptibility with published postmortem brain iron quantification; and (5) susceptibility in HD-affected basal ganglia regions between HD subjects and healthy controls. We found that single-step QSM methods with either total variation or total generalized variation constraints (SSTV/SSTGV) and the single-step deep learning method iQSM generally provided the best performance in terms of correlation with iron deposition and were better at differentiating between healthy controls and premanifest HD individuals, while deep learning QSM methods trained with multiple-orientation susceptibility data created QSM maps that were most similar to the multiple orientation reference and with the best visual scores.

The variety of drugs available to treat neurodegenerative diseases is limited. Most of these drug's efficacy is restricted by individual genetics and disease stages and usually do not prevent neurodegeneration acting long after irreversible damage has already occurred. Thus, drugs targeting the molecular mechanisms underlying subsequent neurodegeneration have the potential to negate symptom manifestation and subsequent neurodegeneration. Neuroinflammation is a common feature of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis, and is associated with the activation of the NLRP3 inflammasome, which in turn leads to neurodegeneration. Inflammasome activation and oligomerisation is suggested to be a major driver of disease progression occurring in microglia. With several natural products and natural product derivatives currently in clinical trials, mushrooms have been highlighted as a rich and largely untapped source of biologically active compounds in both in vitro and in vivo neurodegenerative disease models, partially supported by successful clinical trial evaluations. Additionally, novel high-throughput methods for the screening of natural product compound libraries are being developed to help accelerate the neurodegenerative disease drug discovery process, targeting neuroinflammation. However, the breadth of research relating to mushroom natural product high-throughput screening is limited, providing an exciting opportunity for further detailed investigations. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an autosomal-dominant inherited progressive neurodegenerative disorder. It is caused by a CAG repeat expansion in the Huntingtin gene that is translated to an expanded polyglutamine (PolyQ) repeat in huntingtin protein. HD is characterized by mood swings, involuntary movement, and cognitive decline in the late disease stage. HD patients often die 15–20 years after disease onset. Currently, there is no cure for HD. Due to the striking neuronal loss in HD, most studies focused on the investigation of the predominantly neuronal degeneration in specific brain regions. However, the pathology of the white matter area in the brains of HD patients was also reported by clinical imaging studies, which showed white matter abnormalities even before the clinical onset of HD. Since oligodendrocytes form myelin sheaths around the axons in the brain, white matter lesions are likely attributed to alterations in myelin and oligodendrocyte-associated changes in HD. In this review, we summarized the evidence for white matter, myelin, and oligodendrocytes alterations that were previously observed in HD patients and animal models. We also discussed potential mechanisms for white matter changes and possible treatment to prevent glial dysfunction in HD. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is distinguished by a triple repeat of CAG in exon 1, an increase in poly Q in the Htt gene, and a loss of GABAergic medium spiny neurons (MSN) in the striatum and white matter of the cortex. Mitochondrial ETC-complex dysfunctions are involved in the pathogenesis of HD, including neuronal energy loss, synaptic neurotrophic decline, neuronal inflammation, apoptosis, and grey and white matter destruction. A previous study has demonstrated that beta Boswellic acid (β-BA), a naturally occurring phytochemical, has several neuroprotective properties that can reduce pathogenic factors associated with various neurological disorders. The current investigation aimed to investigate the neuroprotective potential of β-BA at oral doses of 5, 10, and 15 mg/kg alone, as well as in conjunction with the potent antioxidant vitamin E (8 mg/kg, orally) in 3-NP-induced experimental HD rats. Adult Wistar rats were separated into seven groups, and 3-NP, at a dose of 10 mg/kg, was orally administered to each group of adult Wistar rats beginning on day 1 and continuing through day 14. The neurotoxin 3-NP induces neurodegenerative, g, neurochemical, and pathological alterations in experimental animals. Continuous injection of 3-NP, according to our results, aggravated HD symptoms by suppressing ETC-complex-II, succinate dehydrogenase activity, and neurochemical alterations. β-BA, when taken with vitamin E, improved behavioural dysfunctions such as neuromuscular and motor impairments, as well as memory and cognitive abnormalities. Pharmacological treatments with β-BA improved and restored ETC complexes enzymes I, II, and V levels in brain homogenates. β-BA treatment also restored neurotransmitter levels in the brain while lowering inflammatory cytokines and oxidative stress biomarkers. β-BA's neuroprotective potential in reducing neuronal death was supported by histopathological findings in the striatum and cortex. As a result, the findings of this research contributed to a better understanding of the potential role of natural phytochemicals β-BA in preventing neurological illnesses such as HD. [ABSTRACT FROM AUTHOR]

The zebrafish is increasingly recognized as a model organism for translational research into human neuropathology. The zebrafish brain exhibits fundamental resemblance with human neuroanatomical and neurochemical pathways, and hallmarks of human brain pathology such as protein aggregation, neuronal degeneration and activation of glial cells, for example, can be modeled and recapitulated in the fish central nervous system. Genetic manipulation, imaging, and drug screening are areas where zebrafish excel with the ease of introducing mutations and transgenes, the expression of fluorescent markers that can be detected in vivo in the transparent larval stages overtime, and simple treatment of large numbers of fish larvae at once followed by automated screening and imaging. In this review, we summarize how zebrafish have successfully been employed to model human neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. We discuss advantages and disadvantages of choosing zebrafish as a model for these neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease is an inherited autosomal dominant trait neuro-degenerative disorder caused by changes (mutations) of a gene called huntingtin (htt) that is located on the short arm (p) of chromosome 4, CAG expansion mutation. It is characterized by unusual movements, cognitive and psychiatric disorders. Objective: This review was undertaken to apprehend biological pathways of Huntington's disease (HD) pathogenesis and its management by nature-derived products. Natural products can be lucrative for the management of HD as it shows protection against HD in pre-clinical trials. Advanced research is still required to assess the therapeutic effectiveness of the known organic products and their isolated compounds in HD experimental models. Summary: Degeneration of neurons in Huntington's disease is distinguished by progressive loss of motor coordination and muscle function. This is due to the expansion of CAG trinucleotide in the first exon of the htt gene responsible for neuronal death and neuronal network degeneration in the brain. It is believed that the factors such as molecular genetics, oxidative stress, excitotoxicity, mitochondrial dysfunction, neuroglia dysfunction, protein aggregation, and altered UPS leads to HD. The defensive effect of the natural product provides therapeutic efficacy against HD. Recent reports on natural drugs have enlightened the protective role against HD via antioxidant, anti-inflammatory, antiapoptotic, and neurofunctional regulation. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease disease (HD) is characterized by motor, cognitive, and neuropsychiatric symptoms. Oculomotor impairments and gait variability have been independently considered as potential markers in HD. But there lacks an integration analysis of eye movement and gait., Objective: We assessed multiple examinations of eye movement and gait variability in HTT mutation carriers, analyzed the consistency between these parameters and clinical severity, then examined the association between oculomotor impairments and gait deficits., Methods: Seven pre-HD, 30 HD patients and 30 age-matched controls were included. We collected demographics and assessed the Unified Huntington's Disease Rating Scale (UHDRS). Examinations including saccade, smooth pursuit and optokinetic (OPK) test were performed to evaluate eye movement function. The parameters of gait include stride length, walking velocity, step deviation, step length and gait phase., Results: There are significant impairments in HD patients in the latency and velocity of saccades, the gain of smooth pursuit as well as the gain and slow phase velocities (SPV) of OPK tests. Only the speed of saccades has significant difference between pre-HD and controls. There are significant impairments of stride length, walking velocity, step length and gait phase in HD patients. Parameters of eye movement and gait variability in HD patients showed consistency with the scores of UHDRS. There were significant correlations between eye movement and gait parameters., Conclusions: Our results show that eye movement and gait are impaired in HD patients, and speed of saccades is early impaired in pre-HD. Eye movement and gait abnormalities in HD are significantly correlated with clinical disease severities.

Background: Huntington's disease (HD) is a neurodegenerative disease resulting in devastating motor, cognitive, and psychiatric deficits. The striatum is a brain region that controls movement and some forms of cognition and is most significantly impacted in HD. However, despite well-documented deficits in learning and memory in HD, knowledge of the potential implication of other brain regions such as the hippocampus remains limited., Objective: Here, we study the comparative impact of enhanced mHTT aggregation and neuropathology in the striatum and hippocampus of two HD mouse models., Methods: We utilized the zQ175 as a control HD mouse model and the Q175DN mice lacking the PGK-Neomycin cassette generated in house. We performed a comparative characterization of the neuropathology between zQ175 and Q175DN mice in the striatum and the hippocampus by assessing HTT aggregation, neuronal and glial pathology, chaperone expression, and synaptic density., Results: We showed that Q175DN mice presented enhanced mHTT aggregation in both striatum and hippocampus compared to zQ175. Striatal neurons showed a greater susceptibility to enhanced accumulation of mHTT than hippocampal neurons in Q175DN despite high levels of mHTT in both regions. Contrary to the pathology seen in the striatum, Q175DN hippocampus presented enhanced spare capacity showing increased synaptic density, decreased Iba1 + microglia density and enhanced HSF1 levels in specific subregions of the hippocampus compared to zQ175., Conclusions: Q175DN mice are a valuable tool to understand the fundamental susceptibility differences to mHTT toxicity between striatal neurons and other neuronal subtypes. Furthermore, our findings also suggest that cognitive deficits observed in HD animals might arise from either striatum dysfunction or other regions involved in cognitive processes but not from hippocampal degeneration., Competing Interests: Conflict of Interest: The authors have no conflict of interest to report.

The zebrafish is increasingly recognized as a model organism for translational research into human neuropathology. The zebrafish brain exhibits fundamental resemblance with human neuroanatomical and neurochemical pathways, and hallmarks of human brain pathology such as protein aggregation, neuronal degeneration and activation of glial cells, for example, can be modeled and recapitulated in the fish central nervous system. Genetic manipulation, imaging, and drug screening are areas where zebrafish excel with the ease of introducing mutations and transgenes, the expression of fluorescent markers that can be detected in vivo in the transparent larval stages overtime, and simple treatment of large numbers of fish larvae at once followed by automated screening and imaging. In this review, we summarize how zebrafish have successfully been employed to model human neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. We discuss advantages and disadvantages of choosing zebrafish as a model for these neurodegenerative conditions.

Sleep disturbances are common in various neurological pathologies, including amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), hereditary ataxias, Huntington’s disease (HD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). This article reviews the prevalence and characteristics of sleep disorders in these conditions, highlighting their impact on patients’ quality of life and disease progression. Sleep-related breathing disorders, insomnia, restless legs syndrome (RLS), periodic limb movement syndrome (PLMS), and rapid eye movement sleep behavior disorder (RBD) are among the common sleep disturbances reported. Both pharmacological and non-pharmacological interventions play crucial roles in managing sleep disturbances and enhancing overall patient care.

Objective: Apathy, a frequent neuropsychiatric symptom in aging neurocognitive disorders, has been associated with cognitive decline and functional disability. Therefore, timely provision of pharmacological interventions for apathy is greatly needed. Design: A systematical literature review of existing studies was conducted up to 30 May 2023 in several databases (PubMed, PsychInfo, Cochrane, Google Scholar, etc.) that included randomized controlled trials (RCTs) and meta-analyses assessing pharmacological treatments for apathy in aging neurocognitive disorders. The quality of the studies was appraised. Results: In patients with Alzheimer’s Disease (AD), donepezil, galantamine, rivastigmine, methylphenidate, and gingko biloba were proven efficacious for apathy, while rivastigmine, cognitive enhancer IRL752 and piribedil were found to be beneficial in patients with Parkinson’s Disease (PD) and agomelatine in patients with Frontotemporal Dementia (FD). The extensive proportion of RCTs in which apathy was used as a secondary outcome measure, along with the considerable methodological heterogeneity, did not allow the evaluation of group effects. Conclusions: Pharmacological interventions for apathy in aging neurocognitive disorders are complex and under-investigated. The continuation of systematic research efforts and the provision of individualized treatment for patients suffering from these disorders is vital.

Dysregulated endocannabinoid (eCB) signaling and the loss of cannabinoid receptors (CB1Rs) are important phenotypes of Huntington’s disease (HD) but the precise contribution that eCB signaling has at the circuit level is unknown. Using a computational model of spiking neurons, synapses, and eCB signaling, we demonstrate that eCB signaling functions as a homeostatic control mechanism, minimizing excess glutamate. Furthermore, our model demonstrates that metabolic risk, quantified by excess glutamate, increases with cortico-striatal long-term depression (LTD) and/or increased cortico-striatal activity, and replicates a progressive loss of cannabinoid receptors on inhibitory terminals as a function of the excitatory/inhibitory ratio. [ABSTRACT FROM AUTHOR]

Background: Health information-seeking is a coping strategy used globally by individuals with a personal or family history of a medical condition, including Huntington's disease (HD). Objective: We sought to ascertain information-seeking practices of young people who grew up at-risk for HD. Methods: Participants ages 18–25 were recruited from HD support organizations. An online 96-item survey assessed information-seeking motivations and timing as well as information topics accessed, sources, and needs. Results: Fifty young adults (mean age 22.2 years) who grew up at-risk for HD responded. HD had been generally kept a secret (35.4%) or talked about but difficult to bring up (43.8%) in many families. Most (78.0%) became aware of HD in their family before age 15. Few (7.1%) received information resources at the time of disclosure. Most (68.1%) first sought information independently online, half within a week of disclosure. Respondents were motivated to understand the potential impact of HD on their personal lives and family members, obtain general information about the condition, and learn about treatments and research. Most sought information on clinical features and inheritance with > 80% interested in information on symptoms and personal risk and > 70% about having children. Conclusion: Limited information is provided to young people when first informed about HD in their families leading to independent, mostly online information-seeking. Information is used to build knowledge about HD to facilitate coping and life planning. Healthcare providers can direct young people to reliable resources and guide parents in talking with children to ensure that information needs are met. [ABSTRACT FROM AUTHOR]

Abstract Huntington’s disease (HD) is one of neurodegenerative diseases, and is defined as a monogenetic disease due to the mutation of Huntingtin gene. This disease affects several cellular functions in neurons, and further influences motor and cognitive ability, leading to the suffering of devastating symptoms in HD patients. MicroRNA (miRNA) is a non-coding RNA, and is responsible for gene regulation at post-transcriptional levels in cells. Since one miRNA targets to several downstream genes, it may regulate different pathways simultaneously. As a result, it raises a potential therapy for different diseases using miRNAs, especially for inherited diseases. In this review, we will not only introduce the update information of HD and miRNA, but also discuss the development of potential miRNA-based therapy in HD. With the understanding toward the progression of miRNA studies in HD, we anticipate it may provide an insight to treat this devastating disease, even applying to other genetic diseases.

Dysregulated endocannabinoid (eCB) signaling and the loss of cannabinoid receptors (CB1Rs) are important phenotypes of Huntington's disease (HD) but the precise contribution that eCB signaling has at the circuit level is unknown. Using a computational model of spiking neurons, synapses, and eCB signaling, we demonstrate that eCB signaling functions as a homeostatic control mechanism, minimizing excess glutamate. Furthermore, our model demonstrates that metabolic risk, quantified by excess glutamate, increases with cortico-striatal long-term depression (LTD) and/or increased cortico-striatal activity, and replicates a progressive loss of cannabinoid receptors on inhibitory terminals as a function of the excitatory/inhibitory ratio.

Background: Neuroacanthocytosis (NA) and Huntington's disease (HD) are neurodegenerative conditions that share clinical symptoms and imaging findings, despite their distinct genetic etiologies. Usually, the presence of acanthocytes can help narrow the differential diagnosis of a familial choreiform disorder, as the diagnosis of NA syndrome is supported by the presence of acanthocytes in peripheral blood. In this study, we demonstrate four patients who present with HD and acanthocytosis. Methods: We retrieved the data of 40 HD patients with fresh peripheral blood screened for erythrocytes in our hospital from 2014 to 2022. Of these 40 patients, four patients with acanthocytes were recruited for this study. Patients' investigations included clinical and laboratory studies, HTT gene sequencing, and whole-exome sequencing. Fresh peripheral blood was screened for erythrocytes by scanning electron microscopy. Results: The four adult patients were Han Chinese and unrelated. The age ranged from 45 to 61 years, with a disease duration of 4–10 years. The main neurological features at diagnosis included progressive involuntary movements, psychiatric changes, and dementia. Genetic analysis showed an expansion at the HTT gene. The mean proportion of acanthocytes was mild (6–10%) elevated in patient one and high (>20%) elevated in patients 2–4 by scanning electron microscopy examination. Conclusion: Our study illustrates that HD can combine with acanthocytosis, which may expand the clinical phenotype. Even though the primary gene defect appears to be predominately directed at the brain, a peripheral defect can be seen in HD. Our study highlights the complexity and diversity of HD. [ABSTRACT FROM AUTHOR]

[Display omitted] • VD administration reversed motor impairment and locomotor dysfunction in HD. • VD supplementation enhances the mRNA expression of BDNF, NGF and VDR in the striatum of HD mice. • VD alleviates anti-oxidative markers (catalase and GpX4) in the striatal brain tissue of HD mice. A number of studies has explored a positive correlation between low levels of serum Vitamin D 3 (VD; cholecalciferol) and development of neurodegenerative diseases including Huntington's disease (HD). In the present study, the prophylactic effect of VD on motor dysfunction was studied in an experimental model of HD. An HD-like syndrome was induced in male C57BL/6 mice through an intraperitoneal injection (i.p) of 3-NP for 3 consecutive doses at 12 h interval of time as described previously (Amende et al. 2005). This study investigated the in-vivo therapeutic potential of VD (500 IU/kg/day) supplementation on movement, motor coordination, motor activity and biochemical changes in this HD model. Mice were divided into four groups: Group I: Control (saline); Group II: 3-NP induced HD (HD); Group III : Vitamin D 3 (VD) and Group IV: 3-NP induced + post Vitamin D 3 injection (HD + VD). All groups of mice were tested for locomotion, gait analysis and rotarod performances over a span of 30-days. VD administration rescued locomotor dysfunction and neuromuscular impairment in HD mice with no change in gait dynamics. In addition, administration of VD to 3-NP treated mice led to a significant enhancement in the expression of key neurotrophic factors including brain-derived neurotrophic factor (BDNF) and nerve-growth factor (NGF), the Vitamin D receptor (VDR), and antioxidant markers (catalases [Cat] and glutathione peroxidase [GpX4]) in the striatum, suggesting a detoxification effect of VD. Altogether, our results show that VD supplementation induces survival signals, diminishes oxidative stress, and reduces movement and motor dysfunction in HD. [ABSTRACT FROM AUTHOR]

The cerebral expression of the A2A adenosine receptor (A2AAR) is altered in neurodegenerative diseases such as Parkinson's (PD) and Huntington's (HD) diseases, making these receptors an attractive diagnostic and therapeutic target. We aimed to further investigate the pharmacokinetic properties in the brain of our recently developed A2AAR–specific antagonist radiotracer [18F]FLUDA. For this purpose, we retrospectively analysed dynamic PET studies of healthy mice and rotenone–treated mice, and conducted dynamic PET studies with healthy pigs. We performed analysis of mouse brain time–activity curves to calculate the mean residence time (MRT) by non–compartmental analysis, and the binding potential (BPND) of [18F]FLUDA using the simplified reference tissue model (SRTM). For the pig studies, we performed a Logan graphical analysis to calculate the radiotracer distribution volume (VT) at baseline and under blocking conditions with tozadenant. The MRT of [18F]FLUDA in the striatum of mice was decreased by 30% after treatment with the A2AAR antagonist istradefylline. Mouse results showed the highest BPND (3.9 to 5.9) in the striatum. SRTM analysis showed a 20% lower A2AAR availability in the rotenone–treated mice compared to the control–aged group. Tozadenant treatment significantly decreased the VT (14.6 vs. 8.5 mL · g−1) and BPND values (1.3 vs. 0.3) in pig striatum. This study confirms the target specificity and a high BPND of [18F]FLUDA in the striatum. We conclude that [18F]FLUDA is a suitable tool for the non–invasive quantitation of altered A2AAR expression in neurodegenerative diseases such as PD and HD, by PET. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are essential post-transcriptional gene regulators involved in various neuronal and non-neuronal cell functions and play a key role in pathological conditions. Numerous studies have demonstrated that miRNAs are dysregulated in major neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease. Hence, in the present work, we constructed a comprehensive overview of individual microRNA alterations in various models of the above neurodegenerative diseases. We also provided evidence of miRNAs as promising biomarkers for prognostic and diagnostic approaches. In addition, we summarized data from the literature about miRNA-based therapeutic applications via inhibiting or promoting miRNA expression. We finally identified the overlapping miRNA signature across the diseases, including miR-128, miR-140-5p, miR-206, miR-326, and miR-155, associated with multiple etiological cellular mechanisms. However, it remains to be established whether and to what extent miRNA-based therapies could be safely exploited in the future as effective symptomatic or disease-modifying approaches in the different human neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

BackgroundNeuroacanthocytosis (NA) and Huntington’s disease (HD) are neurodegenerative conditions that share clinical symptoms and imaging findings, despite their distinct genetic etiologies. Usually, the presence of acanthocytes can help narrow the differential diagnosis of a familial choreiform disorder, as the diagnosis of NA syndrome is supported by the presence of acanthocytes in peripheral blood. In this study, we demonstrate four patients who present with HD and acanthocytosis.MethodsWe retrieved the data of 40 HD patients with fresh peripheral blood screened for erythrocytes in our hospital from 2014 to 2022. Of these 40 patients, four patients with acanthocytes were recruited for this study. Patients’ investigations included clinical and laboratory studies, HTT gene sequencing, and whole-exome sequencing. Fresh peripheral blood was screened for erythrocytes by scanning electron microscopy.ResultsThe four adult patients were Han Chinese and unrelated. The age ranged from 45 to 61 years, with a disease duration of 4–10 years. The main neurological features at diagnosis included progressive involuntary movements, psychiatric changes, and dementia. Genetic analysis showed an expansion at the HTT gene. The mean proportion of acanthocytes was mild (6–10%) elevated in patient one and high (>20%) elevated in patients 2–4 by scanning electron microscopy examination.ConclusionOur study illustrates that HD can combine with acanthocytosis, which may expand the clinical phenotype. Even though the primary gene defect appears to be predominately directed at the brain, a peripheral defect can be seen in HD. Our study highlights the complexity and diversity of HD.

The Unified Huntington's Disease Rating Scale (UHDRS) is the primary clinical assessment tool for rating motor function in patients with Huntington's disease (HD). However, the UHDRS and similar rating scales (e.g., UPDRS) are both subjective and limited to in-office assessments that must be administered by a trained and experienced rater. An objective, automated method of quantifying disease severity would facilitate superior patient care and could be used to better track severity over time. We conducted the present study to evaluate the feasibility of using wearable sensors, coupled with machine learning algorithms, to rate motor function in patients with HD. Fourteen participants with symptomatic HD and 14 healthy controls participated in the study. Each participant wore five adhesive biometric sensors applied to the trunk and each limb while completing brief walking, sitting, and standing tasks during a single office visit. A two-stage machine learning method was employed to classify participants by HD status and to predict UHDRS motor subscores. Linear discriminant analysis correctly classified all participants' HD status except for one control subject with abnormal gait (96.4% accuracy, 92.9% sensitivity, and 100% specificity in leave-one-out cross-validation). Two regression models accurately predicted individual UHDRS subscores for gait, and dystonia within a 10% margin of error. Our regression models also predicted a composite UHDRS score–a sum of left and right arm rigidity, total chorea, total dystonia, bradykinesia, gait, and tandem gait subscores–with an average error below 15%. Machine learning classifiers trained on brief in-office datasets discriminated between controls and participants with HD, and could accurately predict selected motor UHDRS subscores. Our results could enable the future use of biosensors for objective HD assessment in the clinic or remotely and could inform future studies for the use of this technology as a potential endpoint in clinical trials.

Background: Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of the CAG repeat in the huntingtin (HTT) gene. When the number of CAG repeats exceeds 36, the translated expanded polyglutamine-containing HTT protein (mutant HTT [mHTT]) interferes with the normal functions of many cellular proteins and subsequently jeopardizes important cellular machineries in major types of brain cells, including neurons, astrocytes, and microglia. The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome, which comprises NLRP3, ASC, and caspase-1, is involved in the activation of IL-1β and IL-18 and has been implicated in various biological functions. Although the existence of the NLRP3 inflammasome in the brain has been documented, the roles of the NLRP3 inflammasome in HD remain largely uncharacterized. MCC950 is a highly selective and potent small-molecule inhibitor of NLRP3 that has been used for the treatment of several diseases such as Alzheimer's disease. However, whether MCC950 is also beneficial in HD remains unknown. Therefore, we hypothesized that MCC950 exerts beneficial effects in a transgenic mouse model of HD.Methods: To evaluate the effects of MCC950 in HD, we used the R6/2 (B6CBA-Tg[HDexon1]62Gpb/1J) transgenic mouse model of HD, which expresses exon 1 of the human HTT gene carrying 120 ± 5 CAG repeats. Male transgenic R6/2 mice were treated daily with MCC950 (10 mg/kg of body weight; oral administration) or water for 5 weeks from the age of 7 weeks. We examined neuronal density, neuroinflammation, and mHTT aggregation in the striatum of R6/2 mice vs. their wild-type littermates. We also evaluated the motor function, body weight, and lifespan of R6/2 mice.Results: Systematic administration of MCC950 to R6/2 mice suppressed the NLRP3 inflammasome, decreased IL-1β and reactive oxygen species production, and reduced neuronal toxicity, as assessed based on increased neuronal density and upregulation of the NeuN and PSD-95 proteins. Most importantly, oral administration of MCC950 increased neuronal survival, reduced neuroinflammation, extended lifespan, and improved motor dysfunction in R6/2 mice.Conclusions: Collectively, our findings indicate that MCC950 exerts beneficial effects in a transgenic mouse model of HD and has therapeutic potential for treatment of this devastating neurodegenerative disease. [ABSTRACT FROM AUTHOR]