Efficacy and safety of tibial nerve stimulation using a wearable device for overactive bladder.

OBJECTIVE: To evaluate the efficacy and safety of a wearable, smartphone-controlled, rechargeable transcutaneous tibial nerve stimulation (TTNS) device in patients with overactive bladder (OAB). PATIENTS AND METHODS: This multicentre, prospective, single-blind, randomised clinical trial included eligible patients with OAB symptoms who were randomly assigned to the stimulation group or sham group. The primary efficacy outcome was change from baseline in voiding frequency/24 h after 4 weeks of treatment. The secondary efficacy outcomes included changes in bladder diary outcomes (urgency score/void, nocturia episodes/day, micturition volume/void, and incontinence episodes/day), questionnaires on Overactive Bladder Symptom Score (OABSS), Patient Perception of Bladder Condition (PPBC), and American Urological Association Symptom Index Quality of Life Score (AUA-SI-QoL) at baseline and after 4 weeks of treatment. Device-related adverse events (AEs) were also evaluated. RESULTS: In the full analysis set (FAS), the mean (sd) change of voiding frequency/24 h in the stimulation group and sham group at 4 weeks were -3.5 (2.9) and -0.6 (2.4), respectively (P < 0.01). Similar results were obtained in the per-protocol set (PPS): -3.5 (2.9) vs -0.4 (2.3) (P < 0.01). In the FAS and PPS, micturition volume/void significantly improved at 4 weeks (P = 0.01 and P = 0.02). PPBC improvement almost reached significance in the FAS (P = 0.05), while it was significant in the PPS (P = 0.02). In the FAS and PPS, AUA-SI-QoL significantly improved at 4 weeks in the two groups (P < 0.01 and P < 0.01), whereas there were no significant differences in urgency score/void, nocturia episodes/day or OABSS between the groups. Also, no device-related serious AEs were reported. CONCLUSIONS: The non-invasive neuromodulation technique using the novel ambulatory TTNS device is effective and safe for treating OAB. Its convenience and easy maintenance make it a new potential home-based treatment modality. Future studies are warranted to confirm its longer-term efficacy.

Mechanism of Action of Tibial Nerve Stimulation in the Treatment of Lower Urinary Tract Dysfunction.

BACKGROUND AND OBJECTIVE: Tibial nerve stimulation (TNS) has long been used to effectively treat lower urinary tract dysfunction (LUTD). Although numerous studies have concentrated on TNS, its mechanism of action remains elusive. This review aimed to concentrate on the mechanism of action of TNS against LUTD. MATERIALS AND METHODS: A literature search was performed in PubMed on October 31, 2022. In this study, we introduced the application of TNS for LUTD, summarized different methods used in exploring the mechanism of TNS, and discussed the next direction to investigate the mechanism of TNS. RESULTS AND CONCLUSIONS: In this review, 97 studies, including clinical studies, animal experiments, and reviews, were used. TNS is an effective treatment for LUTD. The study of its mechanisms primarily concentrated on the central nervous system, tibial nerve pathway, receptors, and TNS frequency. More advanced equipment will be used in human experiments to investigate the central mechanism, and diverse animal experiments will be performed to explore the peripheral mechanism and parameters of TNS in the future.

Detrusor relaxing agents for neurogenic detrusor overactivity: a systematic review, meta-analysis and network meta-analysis.

OBJECTIVE: To evaluate the evidence regarding the therapeutic benefits and safety of oral detrusor relaxing agents (DRAs) in treating neurogenic detrusor overactivity (NDO). METHODS: A comprehensive search was performed on 1 September 2022. Two authors independently reviewed the articles to extract data using a pre-designed form. The meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A common-effect or random-effects model was used based on the heterogeneity among studies. Bayesian network meta-analysis (NMA) was further performed to make indirect comparisons of antimuscarinics and mirabegron. RESULTS: A total of 23 randomised controlled trials (RCTs) comprising 1697 patients were included in our analysis. Compared to placebo, the clinical benefits of oral DRAs, along with more adverse events (AEs), were demonstrated in the treatment of NDO. In the subgroup analysis, antimuscarinics significantly improved both urodynamic and bladder diary outcomes (including urinary incontinence episodes, urinary frequency, and residual volume), with a higher rate of AEs, such as xerostomia. Mirabegron improved some of the parameters and had fewer bothersome side-effects in patients with NDO. The NMA showed that none of the antimuscarinics or mirabegron was superior or inferior to the other. CONCLUSIONS: Detrusor relaxing agents are associated with improved outcomes in patients with NDO and our analysis has added new evidence regarding antimuscarinics. Evidence concerning mirabegron as first-line therapy for NDO is still limited. Well-designed RCTs are still required in this specific population.

Patient-Reported Outcome Measure of Ataxia Correlates with Canonical Clinical Assessments in Chinese Spinocerebellar Ataxias.

Spinocerebellar ataxia (SCA) patients' reports of their own experiences are essential to the outcome evaluation in clinical trials. To better understand the health condition and well-being of ataxia population, Patient-Reported Outcome Measure of Ataxia (PROM-Ataxia) was developed. The aim of our study was to culturally adapt the PROM-Ataxia into Chinese version and assess its correlation with canonical clinical assessments. We translated the PROM-Ataxia into Chinese following the ISPOR TCA Task Force guidelines and evaluated its correlation with measures of motor ataxia, non-ataxia signs, quality of life, and mental health in 92 Chinese SCA participants. Nearly all the participants found this questionnaire complete and intelligible but some items were found repetitive or ambiguous. The total score of PROM-Ataxia from stage 0 to stage 3 was 23.24 ± 18.53, 79.11 ± 40.45, 144.30 ± 41.30, and 176.20 ± 31.74, respectively (p < 0.0001). It was strongly correlated with the Scale for the Assessment and Rating of Ataxia (SARA) (r = 0.832, p < 0.0001). Physical and activities domain of PROM-Ataxia were correlated with measures of motor ataxia, quality of life, and psychological health while mental health domain was correlated with all the clinical assessments including inventory of non-ataxia signs and cognitive assessment. We translated the PROM-Ataxia into Chinese for the first time, which allows transnational comparability in future studies. Our study validated the responsiveness of PROM-Ataxia to established clinical measures in Chinese SCA patients and implied its potential to evaluate the therapeutic effect and optimize the sensitivity of changes in clinical outcome assessments.

Corrigendum: A bibliometric profile of optogenetics: quantitative and qualitative analyses.

[This corrects the article DOI: 10.3389/fnins.2023.1221316.].

A bibliometric profile of optogenetics: quantitative and qualitative analyses.

Introduction: Optogenetics is a rapidly developing field combining optics and genetics, with promising applications in neuroscience and beyond. However, there is currently a lack of bibliometric analyses examining publications in this area. Method: Publications on optogenetics were gathered from the Web of Science Core Collection Database. A quantitative analysis was conducted to gain insights into the annual scientific output, and distribution of authors, journals, subject categories, countries, and institutions. Additionally, qualitative analysis, such as co-occurrence network analysis, thematic analysis, and theme evolution, were performed to identify the main areas and trends of optogenetics articles. Results: A total of 6,824 publications were included for analysis. The number of articles has rapidly grown since 2010, with an annual growth rate of 52.82%. Deisseroth K, Boyden ES, and Hegemann P were the most prolific contributors to the field. The United States contributed the most articles (3,051 articles), followed by China (623 articles). A majority of optogenetics-related articles are published in high-quality journals, including NATURE, SCIENCE, and CELL. These articles mainly belong to four subjects: neurosciences, biochemistry and molecular biology, neuroimaging, and materials science. Co-occurrence keyword network analysis identified three clusters: optogenetic components and techniques, optogenetics and neural circuitry, optogenetics and disease. Conclusion: The results suggest that optogenetics research is flourishing, focusing on optogenetic techniques and their applications in neural circuitry exploration and disease intervention. Optogenetics is expected to remain a hot topic in various fields in the future.

Transdermal tibial nerve optogenetic stimulation targeting C-fibers.

Purpose: To explore whether stimulation of C-fibers in tibial nerves can induce bladder inhibition by optogenetic transdermal illumination. Methods: Ten rats were injected with AAV2/6-hSyn-ChR2(H134R)-EYFP into the tibial nerves. Transurethral cystometry was performed 4 weeks after the virus injection. Illumination (473-nm blue light at 100 mW) was performed with the fiber positioned above the right hind paw near the ankle. The light transmission efficiency was examined with a laser power meter. The effects on cystometry were compared before and after illumination with the bladder infused with normal saline and acetic acid, respectively. Result: Upon transdermal delivery of 473-nm light at a peak power of 100 mW, the irradiance value of 0.653 mW/mm2 at the target region was detected, which is sufficient to activate opsins. The photothermal effect of 473-nm light is unremarkable. Acute inhibitory responses were not observed during stimulation regarding any of the bladder parameters; whereas, after laser illumination for 30 min, a statistically significant increase in bladder capacity with the bladder infused with normal saline (from 0.53 ± 0.04 mL to 0.72 ± 0.05 mL, p < 0.001) and acetic acid (from 0.25 ± 0.02 mL to 0.37 ± 0.04 mL, p < 0.001) was detected. A similar inhibitory response was observed with pulsed illumination at both 10Hz and 50Hz. However, illumination did not significantly influence base pressure, threshold pressure, or peak pressure. Conclusion: In this preliminary study, it can be inferred that the prolonged bladder inhibition is mediated by the stimulation of C-fibers in the tibial nerves, with no frequency-dependent characteristics. Although the 473-nm blue light has limited penetration efficacy, it is sufficient to modulate bladder functions through transdermal illumination on the superficial peripheral nervous system.

Real-time changes in brain activity during tibial nerve stimulation for overactive bladder: Evidence from functional near-infrared spectroscopy hype scanning.

Purpose: To use functional near-infrared spectroscopy (fNIRS) to identify changes in brain activity during tibial nerve stimulation (TNS) in patients with overactive bladder (OAB) responsive to therapy. Methods: Eighteen patients with refractory idiopathic OAB patients were recruited consecutively for this pilot study. At baseline, all patients completed 3 days voiding diary, Quality-of-Life score, Perception-of-Bladder-Condition, and Overactive-Bladder-Symptom score. Then 4 region-of-interest (ROI) fNIRS scans with 3 blocks were conducted for each patient. The block design was used: 60 s each for the task and rest periods and 3 to 5 repetitions of each period. A total of 360 s of data were collected. During the task period, patients used transcutaneous tibial nerve stimulation (TTNS) of 20-Hz frequency and a 0.2-millisecond pulse width and 30-milliamp stimulatory current to complete the experiment. The initial scan was obtained with a sham stimulation with an empty bladder, and a second was obtained with a verum stimulation with an empty bladder. Patients were given water till strong desire to void, and the third fNIRS scan with a verum stimulation was performed. The patients then needed to urinate since they could not tolerate the SDV condition for a long time. After a period of rest, the patients then were given water until they exhibited SDV state. The fourth scan with sham fNIRS scan in the SDV state was performed. NIRS_KIT software was used to analyze prefrontal activity, corrected by false discovery rate (FDR, p < 0.05). Statistical analyses were performed using GraphPad Prism software; p < 0.05 was considered significant. Results: TTNS treatment was successful in 16 OAB patients and unsuccessful in 2. The 3 days voiding diary, Quality-of-Life score, Perception-of-Bladder-Condition, and Overactive-Bladder-Symptom score were significantly improved after TNS in the successfully treated group but not in the unsuccessfully treated group. The dorsolateral prefrontal cortex (DLPFC) (BA 9, Chapters 25 and 26) and the frontopolar area (FA) (BA 10, Chapters 35, 45, and 46) were significantly activated during TNS treatment with an empty bladder rather than with an SDV. Compared with the successfully treated group, the unsuccessfully treated group did not achieve statistical significance with an empty bladder and an SDV state. Conclusion: fNIRS confirms that TNS influences brain activity in patients with OAB who respond to therapy. That may be the central mechanism of action of TNS.

Typical value ranges and signal patterns in patients with neurogenic bladder: Quality control in urodynamics using an air-charged catheter system.

PURPOSE: To establish typical value ranges (TVRs) of the air-charged catheter (ACC) system, and analyze the typical signal patterns (TSPs) of cough under different bladder volumes for quality control of a urodynamic study using the ACC system. MATERIALS AND METHODS: The urodynamic traces of 1977 patients with neurogenic bladder (NB) were analyzed for intravesical pressure (pves ), abdominal pressure (pabd ), and detrusor pressure (pdet ) in the cough test at our center from July 2017 to December 2021. The pdet cough signals were described and classified. The pdet cough signal patterns in different bladder volumes and postures were analyzed. RESULTS: The 50% range of the initial resting pves , pabd , and pdet in the supine and sitting positions were 7-15, 7-14, and 0-0 cmH2 O, and 24-33, 24-33, and 0-0 cmH2 O, respectively. The cough amplitudes for pves and pabd were similar in the 50% range, as follows: 10-27 and 8-25 cmH2 O in the supine position, respectively; and 18-43 and 17-40 cmH2 O in the sitting position, respectively. The cough amplitude of pves and pabd was not related to bladder volume (p > 0.05). The cough spikes of pdet were divided into three types: type I, in which pdet has a minimal change (<5 cmH2 O); type II, a monophasic cough spike, in which could be a positive (IIa, ≥5 cmH2 O) or negative spike (IIb, ≥5 cmH2 O); and type III, a biphasic spike, in which could be a positive-to-negative biphasic (IIIa) or negative-to-positive spike (IIIb). Under different bladder volumes, the cough signals of pdet were all expressed as type I, II, or III, and the cough signals were unrelated to bladder volume (p > 0.05). CONCLUSIONS: TVRs of the initial resting state in patients with NB were established to provide guidance for quantitative quality control of the ACC system. The TSPs of the pdet cough signal under different bladder volume and posture were described, which could be used for qualitative quality control of the ACC system.

Efficacy of a novel wearable transcutaneous tibial nerve stimulation device on bladder reflex compared to implantable tibial nerve stimulation in cats.

OBJECTIVE: To determine the efficacy of novel wearable transcutaneous tibial nerve stimulation (TTNS) device on bladder reflex in cats compared to implantable tibial nerve stimulation (ITNS). MATERIALS AND METHODS: Two self-adhesive electrodes of the TTNS device were placed at the left leg, and ITNS was applied to stimulate the tibial nerve of the right leg, respectively. The intensity threshold (T) was defined as inducing observable toe movement. Multiple cystometrograms (CMGs) with normal saline (NS) infusion were performed to determine the inhibitory effects of TTNS and ITNS on the micturition reflex. RESULTS: TTNS at 4 times T (4 T), 6 times T (6 T), and the maximum output current intensity 24 mA significantly increased the bladder capacity (BC) compared to the control level (8.70 ± 2.46 ml) (all p < 0.05); however, there was no statistical significance among the three intensities. At the same time, ITNS at 2 times T (2 T), 4 T, 6 T, and the current intension 24 mA could significantly increase the BC compared to the control level (all p < 0.05). Likewise, no significant difference was observed among the four intensities (p > 0.05). The T values of TTNS were higher than those of ITNS (p = 0.02). The inhibitory effects of TTNS and ITNS revealed no significant difference at their respective 2 T, 4 T, 6 T, and 24 mA. Neither TTNS nor ITNS changed the contraction duration and amplitude (all p > 0.05). CONCLUSIONS: TTNS was effective in increasing BC. The non-invasive neuromodulation technique could achieve a similar effect as ITNS.

Reliability assessment of the upper urinary tract dilation grading system based on magnetic resonance urography in patients with neurogenic bladder.

BACKGROUND: To assess the inter-observer and intra-observer reliability of the magnetic resonance urography (MRU)-upper urinary tract dilation (UUTD) grading system. METHODS: A total of 40 patients with a diagnosis of NB were enrolled in this study. The images were assembled in an electronic presentation randomly. The presentations were reviewed and graded by 4 junior and 4 senior urologists. One week later, the images were randomized again and reassessed. The inter-observer reliability was estimated by Kendall's coefficient of concordance and intra-class correlation coefficient (ICC), and the intra-observer reliability was estimated by weighted Cohen's kappa. RESULTS: The inter-observer reliability strength was excellent for all urologists, with the ICC value of 0.939 (0.908-0.963) and Kendall's W value of 0.967. The highest agreement was shown in Grade 4 at 92.50%, and the lowest in Grade 2 at 82.14%. All disagreements were within one grade of difference. Moreover, the Intra-observer reliability was excellent, with the weighted kappa value ranging from 0.904 to 0.954. CONCLUSIONS: The inter-observer and intra-observer reliability of this novel MRU-UUTD grading system is confirmed, providing adequate evidence for broader clinical application.

Feasibility of a Transcutaneous Tibial Nerve Stimulation Device Use in Overactive Bladder Patients: A Pilot Study From a Single Tertiary Care Center.

Purpose: To evaluate the preliminary efficacy, safety, and acceptability of a transcutaneous tibial nerve stimulation (TTNS) device in overactive bladder (OAB) patients. Methods: Twenty OAB patients who failed with conservative treatments were recruited consecutively. All patients received 60 min of daily unilateral stimulation for 4 weeks using a smart wearable transcutaneous tibial nerve stimulation device and the stimulations were at 20 Hz frequency, 200 µs pulse width. OAB symptoms were observed at baseline and week 4, using a 3-days voiding diary, the overactive bladder symptom score (OABSS), the perception of bladder condition (PPBC), and the American Urological Association Symptom Index Quality of Life Score (AUA-SI-QoL). Urodynamic characteristics were measured to determine the pilot efficacy of the device during the treatment comparing the baseline parameters to the post-treatment parameters. Results: Among the patients, 15 cases were OAB-dry and five cases were OAB-wet. All patients were evaluated at the end of the study and no significant side effects were found during the treatment. The daily micturition frequency and the number of incontinence episodes per day were reduced from 15.10 ± 1.61 to 12.00 ± 4.56, and 3.20 ± 0.80 to 0.47 ± 0.38, respectively. The mean voiding volume was increased from 130.10 ± 53.07 to 157.30 ± 66.95 mL. The OABSS, AUA-SI-QoL, and PPBC were reduced from 9.35 ± 1.39 to 5.9 ± 2.36, 5.70 ± 0.47 to 3.85 ± 1.04, and 5.70 ± 0.47 to 4.35 ± 0.86, respectively. The first sensation of bladder filling (1st SBF), maximal bladder capacity (MBC), and mean compliance were increased from 87.50 (60.00-167.50) to 150.00 (104.00-211.30) mL, 175.00 (120.30-354.00) to 255.00 (151.50-491.50) mL, and 36.67 (12.44-39.69) to 40.00 (20.00-52.50) mL/cmH2O, respectively. The maximum detrusor pressure (Pdet. max) was reduced from 14.50 (5.00-35.25) to 11.00 (6.00-20.00) cmH2O. Conclusion: The preliminary results demonstrated that the TTNS device was safe, effective, and acceptable to use in OAB patients, but the results need to be substantiated by conducting more randomized controlled studies further.

Clinical and Genetic Analysis in Neurological Wilson's Disease Patients With Neurological Worsening Following Chelator Therapy.

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.

Inhibitory effects of a smartphone-controlled wearable transcutaneous tibial nerve stimulation device on bladder reflexes in anesthetized cats.

OBJECTIVES: To explore the inhibitory effects of a novel, smartphone-controlled, and wearable tibial nerve stimulation device on nonnociceptive and nociceptive bladder reflexes in anesthetized cats and to compare the stimulus results of two current waveforms outputted by this new stimulator. MATERIALS AND METHODS: A novel, intelligent tibial nerve stimulator was put on the ankles of 14 cats and controlled by a mobile application. Cystometrograms (CMGs) were performed repeatedly by infusing 0.9% normal saline (NS) and 0.5% acetic acid (AA) through a urethral catheter. Inhibitory effects were explored by measuring the bladder capacity (BC) in two areas: (1) on nonnociceptive bladder reflex (infused with NS) and on nociceptive bladder reflex (filled with AA to induce overactive bladder [OAB] model); and (2) under the stimulation of two different current waveforms (waveforms A and B). RESULTS: In Group 1, the BC of AA-induced OAB (41.48 ± 8.40%) was significantly different compared with the capacity of a NS-infused bladder (104.89 ± 1.32%, p < 0.05). Both NS-filled (151.35 ± 5.71%, p < 0.05) and AA-instilled (71.41 ± 9.34%, p < 0.05) bladder volumes significantly increased after tibial nerve stimulation (TNS). In Group 2, the BC increased to 166.18 ± 15.17% (p = 0.026) and 127.64 ± 13.00% (p = 0.239), respectively, after TNS with waveforms A and B current. CONCLUSIONS: Results revealed that this novel, smartphone-based, wearable, and wireless tibial nerve stimulation system could inhibit the micturition reflex on physiological condition, serving as a potential option for OAB treatment. In addition, the waveforms of stimulation current had an important influence on the effects of TNS.

Plasma neurofilament light chain as a biomarker in Wilson's disease.

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.

TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large-Sample Study.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one-third of PKD patients are attributed to proline-rich transmembrane protein 2 (PRRT2) mutations. OBJECTIVE: We aimed to explore the potential causative gene for PKD. METHODS: A cohort of 196 PRRT2-negative PKD probands were enrolled for whole-exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case-control analysis, was applied to identify the candidate genes. Another 325 PRRT2-negative PKD probands were subsequently screened with Sanger sequencing. RESULTS: Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A-related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A-positive and PRRT2-positive groups. CONCLUSIONS: We consolidated mutations in TMEM151A causing PKD with the aid of case-control analysis of a large-scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A-related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A-related PKD. © 2021 International Parkinson and Movement Disorder Society.

Evaluation of Blood Glial Fibrillary Acidic Protein as a Potential Marker in Huntington's Disease.

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.

Zinc monotherapy for young patients with oligosymptomatic Wilson disease: A single center, retrospective study.

BACKGROUND AND AIMS: Few 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. METHODS: We 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. RESULTS: Forty 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. CONCLUSIONS: We 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.