The development of disease-modifying therapies for Huntington’s disease (HD) necessitates sensitive, scalable, and objective biomarkers for patient stratification and tracking. Current clinical scales are rater-dependent and time-consuming, while neuroimaging is costly and inaccessible. We aim to develop and validate a novel Speech Index, derived from automated acoustic analysis, to stratify HD stages and predict the severity of disease. We recruited 141 HTT gene carriers (37 premanifest, 104 manifest HD) and 69 healthy controls. Participants read a standardized passage, and the recordings were processed to extract 28 speech features. A composite Speech Index was constructed using Bootstrap LASSO Regression for feature selection. Its performance was validated against the HD stages, clinical scale scores and the volume of the caudate and putamen from MRI. The Speech Index significantly increased across HD stages (p < 0.001). The Index showed strong correlations with clinical measures (cUHDRS: ρ = -0.67; TMS: ρ = 0.57; SDMT: ρ = -0.63; all p < 0.001) and neuroimaging biomarkers (caudate: ρ = -0.55; putamen: ρ = -0.62; all p < 0.001). Generalized additive models confirmed the Index’s high predictive value for these outcomes (pseudo-R2 from 0.430 to 0.596). We developed a fully automated, interpretable Speech Index that serves as a valid digital biomarker for HD severity. It holds promise for remote monitoring, clinical trial enrichment, and objective assessment of therapeutic efficacy.

Objective:To investigate the effects of bone marrow mesenchymal stem cells (BMSCs) on extrapyramidal neural network of Wilson disease (WD). Methods:27 6-month-old toxic milk mice (TX mice, WD animal model) and 15 C57 mice were selected. Corrected phase (CP) value on susceptibility weighted imaging (SWI), fractional anisotropy (FA) on diffusion tensor imaging (DTI) were performed. The volume of fiber connections was determined. BMSCs was transplanted though tail vein injection (1 × 106, 0.5 mL). The myelin basic protein (MBP), amyloid precursor protein (β-APP), nitric oxide (NO), glutathione (GSH) and interleukin (IL-1β) were determined at 1, 2, 4 and 8 weeks after transplantation. Results:The CP value of TX mice increased at 4 (p = 0.029) and 8 weeks (p = 0.037) after transplantation. FA values (p = 0.026, 0.020, 0.037) and the volume of neural fibers (p = 0.016, 0.023, 0.018) increased at 2, 4 and 8 weeks after transplantation. The pathological indexes of demyelination (MBP) and axon injury (β-APP) improved after BMSCs transplantation. The brain copper content decreased at 4 and 8 weeks after transplantation (p = 0.024, 0.038). The indexes of oxidative stress (NO and GSH) and inflammation (IL-1β) of TX mice were improved after transplantation. Conclusion:BMSCs can ameliorate WD extrapyramidal neural network injury. The mechanism may be related to reducing copper deposition and alleviating oxidative stress and inflammatory response.

BackgroundCognitive impairment significantly impacts the quality of life in patients with neurodegenerative disorders, including Huntington's disease (HD), Parkinson's disease (PD), and Alzheimer's disease (AD).ObjectiveThis study aims to assess the utility of MemTrax, a contemporary digital continuous recognition task platform originally developed for AD, as an effective tool for revealing cognitive and clinical motor impairments in HD and PD populations as aligned with respective disease staging.MethodsA total of 135 healthy controls, 131 HD, and 212 PD participants were included in the study. MemTrax metrics, recognition accuracy (MTx-%C), response time (MTx-RT), and a composite score (MTx-Cp) were correlated with clinical motor and cognition scales and disease staging.ResultsMemTrax metrics showed stage-dependent declines in both HD and PD. In HD, both MTx-%C and MTx-Cp decreased significantly from pre-HD stage to stage 2 (p < 0.001), showing negative correlations with motor impairment and cognitive scales. In PD, MTx-Cp declined across Hoehn and Yahr stages (1-4, p < 0.001), with strong negative correlations to Unified Parkinson's Disease Rating Scale Part III (UPDRS III) and positive links to Montreal Cognitive Assessment/Mini-Mental State Examination. Additionally, MTx-RT increased with disease progression and correlated positively with UPDRS III, indicating it could assess psychomotor slowing in PD (p < 0.01).ConclusionsMemTrax effectively captures cognitive-motor decline in HD and PD. The responsivity of MemTrax to the severity of these disorders extends its utility beyond AD, positioning MemTrax performance as a cross-disease digital biomarker for early detection in neurodegenerative diseases.

Regional atrophy and metal deposition are typical manifestations in Wilson's disease, but their relationship has not been systematically investigated. We aim to investigate the association of regional brain atrophy and metal deposition in the deep gray matter nucleus at MRI in Wilson's disease. We acquired the structural and susceptibility mapping and performed a cross-sectional comparison of volume and susceptibility in deep gray matter nucleus. The most extensive and severe atrophy was detected in brain regions in neuro-Wilson's disease, as well as the most widespread and heaviest metal deposits. Metal deposits were significantly negatively correlated with volume in the bilateral thalamus, caudate, and putamen. None of correlation was found between the clinical score with volume or susceptibility in the focused regions. In the 1-year follow-up analysis, the volume of right thalamus, globus pallidus, and brainstem and the susceptibility of the left caudate have decreased significantly as the symptom improvement. In Wilson's disease, phenotypes have varied scope and extend of volumetric atrophy and metal deposits. This study is expected to take the lead in revealing that in neuro-Wilson's disease, greater regional atrophy associated with heavier metal deposits in Wilson's disease. Moreover, after 1-year treatment, the imaging data have changed as the patient's condition improvement.

Huntington’s disease (HD) is a rare progressive neurological disorder, and telemedicine has the potential to improve the quality of care for patients with HD. Deutetrabenazine (DTBZ) can reduce chorea symptoms in HD; however, there is limited experience with this medication in Asian countries. Retrospective and prospective studies were employed to explore the feasibility and reliability of a video-based telemedicine system for HD patient care. Reliability was demonstrated through consistency between selected-item scores (SIS) and total motor scores (TMS) and the agreement of scores obtained from hospital and home videos. Finally, a single-centre real-world DTBZ management study was conducted based on the telemedicine system to explore the efficacy of DTBZ in patients with HD. There were 77 patients included in the retrospective study, and a strong correlation was found between SIS and TMS (r = 0.911, P < 0.0001), indicating good representativeness. There were 32 patients enrolled in the prospective study. The reliability was further confirmed, indicated by correlations between SIS and TMS (r = 0.964, P < 0.0001) and consistency of SIS derived from the in-person and virtual visits (r = 0.969, P < 0.0001). There were 17 patients included in the DTBZ study with a mean 1.41 (95

肢体抖动型短暂性脑缺血发作(limb-shaking transient ischemic attack,LS-TIA)是一种罕见的脑血管病类型,本文报道1例LS-TIA患者在双联抗血小板、调脂等常规治疗下仍反复出现不自主肢体抖动,但通过补液扩容使症状得到了改善.本文结合患者的影像学特点深入探讨脑血流灌注在LS-TIA发病机制中的作用,并对其治疗方式进行文献综述.

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Objectives: None of the previous studies have focused on the genetic effect on neurological worsening in neurological Wilson’s disease (WD) patients following chelator therapy. We aimed to evaluate the clinical and genetic role in the occurrence of neurological worsening. Methods: We retrospectively reviewed the medical records of neurological WD patients who received initial chelator therapy and genetic test. Clinical, laboratory, and genetic data were collected. The genotype was classified into two types: 1) severe mutation genotype: patients who carried at least one of the following three types of mutations: frameshift mutation, splicing mutation, or nonsense mutation; 2) non-severe mutation genotype: patients who only carried missense mutations. Then, the clinical features and genotype of the patients with and without neurological worsening were investigated. Results: Forty-seven neurological WD patients were identified with a median age at onset of 16.17 years (range 7.75–47 years) and 35 (74.5%) males. The mean interval from onset to diagnosis was 0.6 years (range: 0.5 months-6.25 years). Neurological deterioration was observed in 29 patients (61.7%) and the other 18 patients (38.3%) were stable or improved during anti-copper treatment. The neurological worsening was completely irreversible in 6 cases (20.7%) and partially irreversible in 16 cases (55.2%). The common deteriorated symptoms were as follows: rigidity in 20 cases (69%), speech difficulties in 20 cases (69%)), walking difficulties in 13 cases (44.8%), dysphagia in 9 cases (31%), and salivation in 9 cases (31%). The patients with neurological worsening had significantly younger age ( p = 0.028), shorter delayed diagnosis time ( p = 0.011), higher rate of dystonia ( p = 0.003), and severe mutation genotype ( p = 0.036), compared to those without neurological worsening. Conclusion: We found that younger age of onset, the presence of dystonia, and genotype with severe mutations may be predictive of neurological worsening in the neurological WD patients that received chelator therapy. For those patients, chelator therapy should be given with caution and needs closer observation during follow-up.

BackgroundHuman parvovirus B19 (B19V) infection is usually symptomless and occurs in the childhood. While in immunocompromised adults, B19V infection also presents various clinical symptoms due to the host's immune status. The classic symptoms include erythema, anemia, arthropathy, and edema, but neurological involvement is rare. Case PresentationIn this report, we present a case of B19V infection caused multiple organ dysfunction in a non-immunosuppressed adult. Metagenomic next-generation sequencing (mNGS) was used and successfully detected the pathogen in multiple types of samples, including blood, cerebrospinal fluid (CSF), and bronchoalveolar lavage fluid (BALF). The diagnosis was subsequently confirmed by polymerase chain reaction (PCR). He was treated with intravenous gamma globulin, resulting in a significant resolution of symptoms after 1 month. ConclusionMultisystem involvement induced by B19V infection was found in this case report. mNGS performed great advantages in rapidly and accurately diagnosing B19V infection in multiple types of samples, which helps the timely adjustment of treatment and improves the prognosis.

Objective: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. Neurofilament light protein (NfL) is correlated with clinical severity of HD but relative data are the lack in the Chinese population. Reactive astrocytes are related to HD pathology, which predicts their potential to be a biomarker in HD progression. Our aim was to discuss the role of blood glial fibrillary acidic protein (GFAP) to evaluate clinical severity in patients with HD. Methods: Fifty-seven HD mutation carriers (15 premanifest HD, preHD, and 42 manifest HD) and 26 healthy controls were recruited. Demographic data and clinical severity assessed with the internationally Unified Huntington's Disease Rating Scale (UHDRS) were retrospectively analyzed. Plasma NfL and GFAP were quantified with an ultra-sensitive single-molecule (Simoa, Norcross, GA, USA) technology. We explored their consistency and their correlation with clinical severity. Results: Compared with healthy controls, plasma NfL (p < 0.0001) and GFAP (p < 0.001) were increased in Chinese HD mutation carriers, and they were linearly correlated with each other (r = 0.612, p < 0.001). They were also significantly correlated with disease burden, Total Motor Score (TMS) and Total Functional Capacity (TFC). The scores of Stroop word reading, symbol digit modalities tests, and short version of the Problem Behaviors Assessments (PBAs) for HD were correlated with plasma NfL but not GFAP. Compared with healthy controls, plasma NfL has been increased since stage 1 but plasma GFAP began to increase statistically in stage 2. Conclusions: Plasma GFAP was correlated with plasma NfL, disease burden, TMS, and TFC in HD mutation carriers. Plasma GFAP may have potential to be a sensitive biomarker for evaluating HD progression.

Huntington's disease is an autosomal-dominant neurodegenerative disease caused by CAG expansion in exon 1 of the huntingtin (HTT) gene. Since mutant huntingtin (mHTT) protein is the root cause of Huntington's disease, oligonucleotide-based therapeutic approaches using small interfering RNAs (siRNAs) and antisense oligonucleotides designed to specifically silence mHTT may be novel therapeutic strategies for Huntington's disease. Unfortunately, the lack of an effective in vivo delivery system remains a major obstacle to realizing the full potential of oligonucleotide therapeutics, especially regarding the delivery of oligonucleotides to the cortex and striatum, the most severely affected brain regions in Huntington's disease. In this study, we present a synthetic biology strategy that integrates the naturally existing exosome-circulating system with artificial genetic circuits for self-assembly and delivery of mHTT-silencing siRNA to the cortex and striatum. We designed a cytomegalovirus promoter-directed genetic circuit encoding both a neuron-targeting rabies virus glycoprotein tag and an mHTT siRNA. After being taken up by mouse livers after intravenous injection, this circuit was able to reprogramme hepatocytes to transcribe and self-assemble mHTT siRNA into rabies virus glycoprotein-tagged exosomes. The mHTT siRNA was further delivered through the exosome-circulating system and guided by a rabies virus glycoprotein tag to the cortex and striatum. Consequently, in three mouse models of Huntington's disease treated with this circuit, the levels of mHTT protein and toxic aggregates were successfully reduced in the cortex and striatum, therefore ameliorating behavioural deficits and striatal and cortical neuropathologies. Overall, our findings establish a convenient, effective and safe strategy for self-assembly of siRNAs in vivo that may provide a significant therapeutic benefit for Huntington's disease.

【目的】探讨中国南方地区亨廷顿病患者不同运动分型的临床特征,便于个体化精准治疗。【方法】纳入自2014年3月至2021年5月在中国亨廷顿病协作网广州中心登记的亨廷顿病患者58例,利用亨廷顿舞蹈症整体评估量表对患者进行运动分型,精神状态、认知功能以及全面生活能力测试,最后利用Kruskal-Wallis H检验方法对不同分型患者各组临床特征进行分析。【结果】中国南方地区亨廷顿患者运动分型以混合型为主,共42例,占比72.41%。不同分型临床特征不同,运动机能减退-僵硬为主型患者全面生活能力低于舞蹈症状为主型患者[8.00（4.00～11.00）vs 13.00（11.00～13.00）;P=0.037]。【结论】中国南方地区亨廷顿患者运动症状复杂。精准的运动分型,对药物治疗与预后评估有一定的意义。

We report a case of late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) with recurrent abdominal pain, vomiting, and impaired consciousness as the initial symptoms in Yemen; the case showed distinctive characteristics from those of Asian or Caucasian patients. Initially, he was misdiagnosed with pancreatitis, acute disseminated encephalomyelitis(ADEM), and fatty liver. Final diagnosis was further confirmed by electromyography, muscle biopsy, uric organic acid analysis, and a novel missense mutation in exon 7 (c.807A>C) of ETFDH was identified by next-generation sequencing. To our knowledge, we report this mutation in an adult MADD patient as well as late-onset MADD in a Middle East country for the first time. MADD is characterised by varied genotypes and broad spectrum of clinical manifestations among different populations and ages, which requires more attention and awareness in the clinic.

Background and aimsFew studies have focused on the treatment failure of zinc monotherapy for oligosymptomatic Wilson disease (WD) patients. Therefore, we aimed to evaluate the long-term efficacy of zinc monotherapy in oligosymptomatic patients and to analyze the possible factors that may influence the outcome of this treatment.MethodsWe retrospectively reviewed the medical records of oligosymptomatic WD patients who received zinc monotherapy from the time of diagnosis. Then, the characteristics of patients who were treated with zinc monotherapy successfully and those who experienced treatment failure were investigated.ResultsForty oligosymptomatic WD patients were identified that have received zinc monotherapy as initial treatment, with a median age of 3.83 years at the time of diagnosis. 36 (90%) patients had abnormal alanine transaminase/aspartate transaminase levels at baseline. None of the patients became symptomatic during zinc monotherapy. 28 (70%, Group 1) patients were treated with zinc monotherapy successfully for a median period of 2.4 years. In Group 1, serum aminotransferase levels significantly decreased 6 and 12 months after zinc therapy compared to the baseline levels (P <  0.05). 12 (30%, Group 2) patients experienced treatment failure with zinc monotherapy due to uncontrolled serum liver enzyme levels, and d-penicillamine was combined. The baseline 24-hour urine copper levels before treatment were significantly higher in Group 2 compared to that in Group 1 (182.5 vs 90.92 μg /day, P = 0.018). Comparing the age at onset; ceruloplasmin, serum copper, ALT, and AST levels; and proportions of abdominal ultrasonography abnormality at baseline between Group 1 and 2 revealed no statistically significant differences.ConclusionsWe found that high initial 24 -h urinary copper levels may lead to treatment failure of zinc monotherapy in oligosymptomatic WD patients. It might be reasonable to follow up liver function tests more closely during zinc monotherapy and to begin combination treatment with chelators early in patients with high level of 24 -h urinary copper.

Introduction: Neurofilament light chain (NfL) was recently proposed as a promising blood biomarker for nervous system diseases, including Wilson's disease (WD). In this study, we investigated plasma NfL concentrations in patients with different types of WD and their correlations with clinical manifestations and brain atrophy. Methods: Seventy-five WD cases (54 neurological type, 21 hepatic type) and 27 age-matched healthy controls were included in this study. We compared plasma NfL concentrations between the different types and correlated them with Unified Wilson's Disease Rating Scale (UWDRS) scores. Patients were allocated to stable and unstable groups according to changes in UWDRS scores and clinical assessment. We compared the differences in plasma NfL concentrations between groups. Voxel-based morphometry (VBM) and FreeSurfer software were used to analyze MRI images. We investigated the correlation between plasma NfL concentrations and volume of gray matter, white matter, and several areas of interest in the brain MRI of 24 patients. Results: Plasma NfL concentrations were significantly higher in neurological type WD than in hepatic type WD (8.16 vs. 3.19 pg/mL, p < 0.001). Plasma NfL concentrations were positively correlated with UWDRS scores (r = 0.291, p = 0.035) in patients with neurological type WD. Plasma NfL was significantly higher in unstable patients than in stable patients (10.74 vs. 7.23 pg/mL, p = 0.004). Significant negative associations were found between plasma NfL level and the volumes of total gray matter, bilateral caudate nucleus, putamen, and nucleus accumbens. Conclusion: Plasma NfL is valuable as a biomarker for neurological damage in patients with WD.

1 临床资料 患者女,63 岁,因"肢体近端和咀嚼肌乏力4 个月,加重并吞咽困难1 周"于2019 年12 月4 日入住中山大学附属第一医院神经科. 患者子女代诉,患者于2019 年8 月始出现步行 20～30 min 后出现双下肢乏力,蹲下起立困难;双上肢近端乏力,上臂难以抬起过肩,无法梳头.咀嚼易疲劳,喜食流质.伴胸闷、全身冒汗,休息后好转,无胸痛,无肢体疼痛,无明显晨轻暮重.说话声音变小,不愿说话,休息后稍改善.10月起抬头困难,休息后好转.11 月起步行10 余步后即感行走无力,步行时低头、弯腰,并出现声音嘶哑、说话不清.11 月 26 日因受凉、失眠后,突发全身无力,不能站立行走,卧位时无法自行翻身,全身多处肌肉疼痛,不能发声,吞咽困难.

Using non-integrative reprogramming method, a human induced pluripotent stem cell (iPSC) line, ZZUNEUi005-A, was generated from a 36-year-old male patient with Wilson’s disease, carrying a homozygous Pro992Leu mutation in the ATP7B gene. This cell line shows pluripotency both in vitro and in vivo and has a normal karyotype. Furthermore, we showed that this iPSC line could be differentiated into neural and hepatocyte-like cells.

Human IPSC Line, ZZUNEUi004-A, was generated from a 34-year-old male patient with Wilson's Disease carrying a homozygous Pro992Leu mutation in ATP7B gene, using non-integrative reprogramming method. This cell line shows pluripotency both in vitro and vivo, and has a normal karyotype.

A randomized-controlled trial comparing study of the changes in brain sensitive-weighted imaging (SWI) of Wilson disease (WD) patients during the treatment with metal chelator was done. 100 untreated WD patients (80 cases of cerebral type, 20 cases of hepatic type, age 20.13 ± 9.12 years old) and 20 normal controls were selected. Neurological symptoms were scored using the modified Young scale. Liver function tests and copper indices were collected. All study objects received SWI test of the brain. The values of corrected phase (CP) were calculated on SWI. Cerebral-type WD patients were treated with D-penicillamine (DPA) (group 1) or Dimercaptopropane Sulfonate (DMPS) + Dimercaptosuccinic Acid (DMSA) (group 2). Hepatic-type WD patients were treated with DPA (group 3). All patients received annual neurological symptom score, liver function, copper indices, and SWI examination. At the first year of treatment, score of the modified Young scale in group 2 was lower than that in group 1 (P = 0.023) and lower than that before treatment (P = 0.040). After 2 years of treatment, the score of the modified Young scale in group 1 was lower than that before treatment (P = 0.012). At the second year after treatment, the urinary copper in group 2 was higher than that in group 1 (P = 0.014). Urinary copper was maintained at 200 µg/day in group 1 and 300 µg/day in group 2 after 3 years of treatment. At the first year of treatment, serum copper in group 1 was lower than that in group 2 (P = 0.032). At the first year of treatment, CP values of the pallidum and substantia nigra in group 2 were higher than those in group 1 (P = 0.026, 0.040). At the second year of treatment, CP value of substantia nigra in group 2 was higher than that in group 1 (P = 0.037). After 3 years of treatment, there was no difference in CP values between WD patients and normal controls. Therapy with DMPS and DMSA improves neurological symptoms of WD patients more quickly and leads to less aggravation, compared with therapy with DPA. The metal content in the brain of WD patients was at a low level after 3 years of treatment. DMPS and DMSA can remove metal from brain tissue faster than DPA.