Abstract Background Recently, PCDHGB1 has been identified as a novel causative gene of dystonia predominantly affecting the cervical muscles. However, no large cohort study has been conducted to confirm the association. Objectives The objective of the study was to systematically evaluate the genetic associations of PCDHGB1 with dystonia in a large Chinese dystonia cohort. Methods We analyzed rare variants of PCDHGB1 in a discovery cohort, including 878 dystonia patients, and a validation cohort, including 509 dystonia patients, using whole‐exome sequencing. The overrepresentation of rare variants in patients was examined using Fisher's exact test at allele and gene levels. Results Twenty‐seven rare variants of PCDHGB1 were identified in 55 individuals in the discovery cohort, including 3 frameshift variants (p.Leu177Valfs*7, p.Arg635Profs*24, p.Asp797Glufs*51) and 24 missense variants. Another 10 rare variants were detected in 12 patients in the validation cohort, including 1 frameshift variant (p.Leu709Argfs*13) and 9 missense variants. Fourteen patients carried the frameshift variant p.Leu177Valfs*7. Thirteen patients carried the p.Met111Val variant, including 3 patients from one family. At variant level, p.Pro773Ser and p.Arg408Gln were significantly associated with a higher risk of dystonia, whereas 15 variants (including p.Arg635Profs*24, p.Asp797Glufs*51, p.Leu709Argfs*13, and 12 missense variants) were nominally associated with a higher risk of dystonia. Gene‐based burden analysis detected the enrichment of ultra‐rare variants of PCDHGB1 in dystonia. Western blot experiments revealed that these four frameshift variants (p.Leu177Valfs*7, p.Arg635Profs*24, p.Asp797Glufs*51, p.Leu709Argfs*13) induced a truncated PCDHGB1 protein. Conclusions Our study supplemented the evidence on the role of PCDHGB1 in dystonia and expanded the genotypic and phenotypic spectrum of PCDHGB1 . © 2026 International Parkinson and Movement Disorder Society.

BACKGROUND:Symptom-based indicators suggestive of autonomic dysfunction are common but underrecognized in Parkinson's disease (PD), with potential implications as a biomarker of aging for early detection and prognosis. We aimed to examine the associations between autonomic dysfunction and PD in a large, population-based cohort. METHODS:We analyzed 374 657 UK Biobank participants who were free of PD at baseline. Autonomic symptoms-including orthostatic hypotension, constipation, urinary and sexual dysfunction, hyperhidrosis, and other autonomic disorders-were identified via hospital records. Incident PD and subsequent outcomes, including dementia and all-cause mortality, were tracked through June 2023. Cox models estimated hazard ratios for PD and adverse outcomes, and conditional logistic regression assessed the temporal trajectory of autonomic dysfunction relative to PD diagnosis. RESULTS:Over a median 14.1-year follow-up, 2568 participants developed PD. Orthostatic hypotension (HR: 2.91; 95% CI: 1.39-6.13), constipation (HR: 1.63; 95% CI: 1.19-2.24), urinary dysfunction (HR: 1.45; 95% CI: 1.04-2.02), and sexual dysfunction (HR: 3.56; 95% CI: 1.60-7.95) independently predicted PD risk. Prediagnostic and postdiagnostic autonomic dysfunction was associated with a higher risk of PD dementia and mortality. Autonomic dysfunction was detectable over 10 years before PD diagnosis (OR: 4.46; 95% CI: 3.76-5.29), with the strongest association observed within 5 years after PD onset (OR: 8.59; 95% CI: 7.58-9.74). CONCLUSIONS:Symptom-based indicators suggestive of autonomic dysfunction serve as early clinical signals and robust prognostic markers in PD, highlighting their potential utility for early risk stratification and long-term patient management in large population-based settings.

BACKGROUND:Plasma neurofilament light chain (NfL) is a promising biomarker in multiple system atrophy (MSA). This study aimed to evaluate the prognostic utility of both baseline and longitudinal plasma NfL for predicting motor progression, disease milestones, and survival. METHODS:This prospective cohort study enrolled 93 patients with clinically established MSA, and participants were monitored annually for 4 years. Baseline plasma NfL concentrations were quantified using ultrasensitive single molecule array (Simoa™) technology. Disease progression and milestones were systematically assessed at each follow-up using the Unified Multiple System Atrophy Rating Scale (UMSARS). Linear mixed-effects models analyzed the association between NfL and UMSARS progression. Cox proportional hazards models and Kaplan-Meier analyses assessed the relationship between NfL levels, disease milestones, and mortality. RESULTS:Higher baseline plasma NfL predicted faster progression of UMSARS-I (β = 2.285), UMSARS-II (β = 1.811), and UMSARS-IV (β = 0.267). Patients in the high-risk group (baseline plasma NfL higher than 46.3 pg/mL) had an increased risk of attaining critical milestones, including severe dysarthria (hazard ratio [HR] = 3.85), global disability (HR = 4.54), and mortality (2.28). However, longitudinal NfL trajectories did not correlate with disease progression and prognosis; instead there was a decline in mid-to-late disease course. CONCLUSIONS:Baseline plasma NfL, rather than NfL dynamics, represents a promising biomarker for monitoring and predicting poor prognosis in early-stage MSA. Plasma NfL is anticipated to be a biomarker for prognostic stratification of early-stage MSA patients in future clinical trials. © 2026 International Parkinson and Movement Disorder Society.

BACKGROUND:Magnetic resonance imaging (MRI) markers are identified as important indicators for the diagnosis of multiple system atrophy (MSA). However, whether these MRI markers can predict the disease progression of MSA remain undefined. We aimed to investigate the relationship between MRI markers and disease progression in patients with early MSA. METHODS:The patients were divided into MRI-positive and MRI-negative groups based on MSA-specific MRI markers. Disease progression was evaluated using the Unified MSA Rating Scale (UMSARS), Montreal Cognitive Assessment and Frontal Assessment Battery. A repeated measures ANCOVA was used to compare the rate of disease progression between the two groups. A multiple linear regression model was used to assess the association between MRI subtype and disease progression. RESULTS:A total of 144 patients with early MSA were enrolled and 73 patients completed the 2-year follow-up. Patients with MSA and MSA of the parkinsonian subtype (MSA-P) in the MRI-positive group exhibited significantly faster disease progression on the total UMSARS score over a 2-year follow-up compared to those in the MRI-negative group (p = 0.002 and p = 0.020, respectively). Multiple linear regression analysis revealed that MRI-positive status was a significant predictor of more severe disease progression on the UMSARS total score in patients with MSA and MSA-P at the 1- and 2-year follow-up after adjusting for age, sex, and baseline disease duration (all p < 0.05). CONCLUSIONS:This study highlights that MRI markers are valuable imaging predictors of disease progression in early MSA, in addition to their diagnostic role.

There is a lack of large sample-size studies on the prevalence and outcome of Dopamine dysregulation syndrome (DDS) in Chinese Parkinson’s disease (PD) patients. A total of 706 patients with PD were included in the study. Patients were divided into DDS and non-DDS groups according to whether they met the diagnostic criteria for DDS. The outcome of DDS in patients with DDS was followed up by telephone. DDS was diagnosed in 29 of 706 (4.1

Demyelination and remyelination play key roles in spinal cord injury (SCI), affecting the recovery of motor and sensory functions. Research in rodent models is extensive, but the study of these processes in non-human primates is limited. Therefore, our goal was to thoroughly study the histological features of demyelination and remyelination after contusion injury of the cervical spinal cord in Macaca fascicularis. In a previous study, we created an SCI model in M. fascicularis by controlling the contusion displacement. We used Eriochrome Cyanine staining, immunohistochemical analysis, and toluidine blue staining to evaluate demyelination and remyelination. The results showed demyelination ipsilateral to the injury epicenter both rostrally and caudally, the former mainly impacting sensory pathways, while the latter primarily affected motor pathways. Toluidine blue staining showed myelin loss and axonal distension at the injury site. Schwann cell-derived myelin sheaths were only found at the center, while thinner myelin sheaths from oligodendrocytes were seen at the center and surrounding areas. Our study showed that long-lasting demyelination occurs in the spinal cord of M. fascicularis after SCI, with oligodendrocytes and Schwann cells playing a significant role in myelin sheath formation at the injury site.

N7-methylguanosine (m7G) modification of transfer RNA (tRNA) is essential for the biological functions of tRNAs and has been found to play a regulatory role in a variety of human cancers. However, the biological function of METTL1-mediated m7G tRNA modification in papillary thyroid cancer (PTC) is unclear. Here, we found that METTL1 is significantly upregulated in PTC tissues compared to normal control tissues and is associated with poor PTC prognosis. Functional analysis confirmed that METTL1 promotes the proliferation and metastasis of PTC cells in a manner dependent on its tRNA methyltransferase activity. Mechanistically, METTL1 knockdown leads to a decrease in the abundance of certain m7G-modified tRNAs, which suppresses the m7G tRNA modification-mediated codon-specific translation of TNF-α. Furthermore, exogenous supplementation with TNF-α partially reversed the decrease in the proliferation and metastasis of PTC cells induced by METTL1 deletion. Positive correlations between METTL1, WDR4, and TNF-α expression, which affect the proliferation and metastasis of PTC, were confirmed via analysis of microarrays containing PTC tissues. These results demonstrate the oncogenic role of METTL1-mediated m7G tRNA modification in regulating codon-specific translation efficiency in PTC and suggest that targeting METTL1 may be a promising therapeutic approach for overcoming PTC progression by inhibiting PTC cell proliferation and metastasis.

BackgroundConsiderable heterogeneity in genotypes and phenotypes has been observed among patients with amyotrophic lateral sclerosis (ALS) harbouring optineurin gene (OPTN) mutations, as reported in prior studies. The study aimed to elucidate the correlation betweenOPTNgenotypes and phenotypes.MethodsOPTNgene variants were screened within a substantial Chinese cohort of patients with ALS, encompassing LoF and rare missense variants. Additionally, a systematic literature review was conducted to compile the spectrum ofOPTNmutations and explore the relationship between the genotype and phenotype of patients with ALS withOPTN.ResultsA total of 33 unrelated patients with ALS with 24 rareOPTNvariants, including 17 novel variants, were identified in 2279 patients with ALS. Among 24 variants in our cohort and 106 variants in previous studies, only 33.3% and 35.8% were pathogenic/likely pathogenic variants. Moreover, the frequency ofOPTNvariants in the Asian ALS population was higher (1.08%) than that of the Caucasian population (0.55%). For the phenotype of patients with ALS carrying OPTN variants, we found that patients with pathogenic/likely pathogenic variants had the highest baseline progression rate and the shortest survival time among groups in our cohort.ConclusionOur study contributed to a broader understanding of the genotype and phenotype spectrum of patients with ALS carryingOPTNvariants. Further investigations are warranted to definitively establish the genotype-phenotype associations.

Amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) is a fatal neurodegenerative condition, and identifying its modifiable risk factors is a critical public health issue. This large-scale prospective cohort study investigated the role of sleep-related factors in ALS-FTSD risk using data from 396,918 UK Biobank participants. Eight sleep-related exposures were assessed, and Cox proportional hazards regression was employed to evaluate their associations with ALS-FTSD incidence. Subgroup and sensitivity analyses were conducted to validate the robustness of our findings. At baseline, participants had a mean age of 56.31 ± 8.12 years, with 47.5% being male. In the fully adjusted Cox model, organic sleep disorders (G47) (HR: 1.81, 95% CI: 1.21, 2.72, P = 0.004), hypersomnia (G47.1) (HR: 36.53, 95% CI: 9.04, 147.55, P < 0.001), and extreme short sleep (<5 h per day) (HR: 2.09, 95% CI: 1.09, 3.99, P = 0.046) were significantly associated with increased ALS-FTSD risk. In conclusions, these findings revealed the relationship between sleep and the risk of ALS-FTSD, identifying new modifiable risk factors and potential preventive possibilities for ALS-FTSD. Further research is warranted to elucidate the mechanistic links between sleep disturbances and ALS-FTSD pathogenesis.

Metabolic abnormalities play a pivotal role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Metabolic syndrome (MetS), a cluster of metabolic disorders, is highly prevalent among the elderly. However, the association between MetS and clinical characteristics, disease progression, and survival in ALS remains unclear. We included 529 ALS patients and collected demographic, clinical, and hematological data, including blood glucose, HbA1c, and lipid profiles. Patients were followed longitudinally. MetS was defined according to the criteria of the Chinese Diabetes Society. Multivariate logistic regression, Kaplan–Meier survival analysis, and Cox proportional hazards models were used to analyze. Compared to ALS patients without MetS, those with MetS had higher proportion of lower limb onset (44.3

Background:Serum total cholesterol (TC) is associated with the risk of multiple system atrophy (MSA). However, the potential impact of the serum TC levels on the mortality of patients with MSA remains to be elucidated. The study aims to clarify the association between baseline level of serum TC and survival of patients with early MSA. Methods:A total of 364 patients with MSA were recruited and assessed at baseline and follow-up. Patients with MSA were stratified into three groups based on the serum TC tertiles. The role of serum TC on survival was analyzed using Kaplan-Meier survival analysis and Cox regression models. Restricted Cubic Spline regression was employed to investigate the non-linear relationship between serum TC levels and survival. Results:During a median follow-up period of 4.75 years, the survival duration of patients with MSA was shorter in the lowest serum TC group compared to the other two groups (Log-rank p = 0.004). In the multivariable Cox regression model, individuals in the intermediate serum TC group demonstrated a reduced mortality compared to those in the lowest group (HR: 0.47; 95% CIs: 0.23-0.96). There was a non-linear relationship between serum TC level and survival with the lowest risk of death at the value of 4.38 mmol/L. Conclusion:Serum TC level at baseline negatively correlated with survival of patients with MSA. Serum TC emerges as a significant predictor of mortality in patients with early-stage MSA.

In multiple system atrophy with parkinsonian type (MSA-P), the dual-task cost and the underlying neurological mechanisms remain under-researched. We included 20 early-stage MSA-P patients and 10 matched healthy controls (HC). Using a video-based gait analysis machine, we explored gait characteristics under three conditions: single-task gait (STG), dual-task gait with backward counting (DTG-BC), and dual-task gait with spontaneous animal naming (DTG-SAN). Neuroimaging scans were collected to analyze the gray matter and white matter structures related to the dual-task cost in MSA-P. Our neuroimaging analysis focused on the infratentorial structures, as previous studies have indicated that these regions are closely related to dual-task cost. There were no differences in gait metrics between MSA-P and HC in STG. In the DTG-BC, patients with MSA-P exhibited a higher dual-task cost burden, as indicated by longer turning durations and shorter swing cycles compared to HC. MSA-P patients had decreased gray matter volume in the right culmen and increased radial diffusivity in the left declive compared to HC. Diffusion tensor imaging analysis showed that the higher dual-task cost of the right swing cycle in DTG-BC was related to the higher mean diffusivity of the left mesencephalic locomotor region (MLR). Additionally, a higher dual-task cost of turning duration in DTG-BC was related to increased axial diffusivity and radial diffusivity in the white matter of the bilateral culmen. Patients with MSA-P exhibited a higher dual-task burden compared to HC, and WM deficit in MLR and culmen were related to the disease’s specific dual-task cost in MSA-P.

INTRODUCTION:Parkinson's disease (PD) is the second most common neurodegenerative disease with largely unknown etiology. Evaluating the association between a healthy lifestyle with PD and genetic risk is necessary. METHODS:The study included 438,241 participants from the UK Biobank, with lifestyle information collected via baseline questionnaires. Polygenic risk scores (PRS) were divided into quartiles. The healthy lifestyle, including alcohol consumption, body mass index, physical activity, sleep duration, sedentary time, social connections, and diet, was categorized into favorable (scoring 6-7), intermediate (scoring 4-5), and unfavorable (scoring ≤3) lifestyles. RESULTS:During an average follow-up of 9.34 years, 2,996 cases were diagnosed with PD. Compared to participants with an unfavorable lifestyle, those with a favorable lifestyle had a significantly lower risk (hazard ratio [HR] 0.862, 95% CI: 0.753-0.986), whereas those with an intermediate lifestyle had no difference in PD risk. Regular physical activity, adequate sleep, and appropriate social connection were protective factors for the risk of PD (HR 0.839, 95% CI: 0.779-0.905; HR 0.921, 95% CI: 0.851-0.997; HR 0.790, 95% CI: 0.698-0.893). Subgroup analysis by PRS showed that adhering to a healthy lifestyle reduced the risk of PD in all subgroups except the low genetic risk (HR 0.673, 95% CI: 0.510-0.889; HR 0.774, 95% CI: 0.611-0.982; HR 0.769, 95% CI: 0.633-0.935). There was an interaction between high genetic risk and lifestyle scores and sleep duration (p = 0.015 and p = 0.024, respectively) and also between sex and sedentary time (p = 0.002). CONCLUSION:A healthy lifestyle was associated with a lower risk of PD, and it is important to identify the effect of genetic risk and sex on PD significantly influenced by lifestyle.

Corneal refractive laser surgery is widely used to correct myopia and astigmatism due to its safety and effectiveness. However, postoperative changes in corneal biomechanics, such as corneal ectasia, can occur, necessitating a deeper understanding of these changes. Finite Element Analysis has shown promise in predicting surgical outcomes based on corneal biomechanics. Devices like the Ocular Response Analyser (ORA) and Corvis ST provide noninvasive ways to measure corneal biomechanics, aiding in the assessment of corneal behavior post-surgery. Young's modulus and tangent modulus are crucial parameters for describing corneal elasticity, but there is limited data on the changes in tangent modulus following Femtosecond Laser-Assisted LASIK (FS-LASIK) in humans. This study aimed to investigate the effect of FS-LASIK on the corneal tangent modulus using a novel corneal indentation device (CID). The study sought to explore changes in corneal tangent modulus after FS-LASIK, taking into account central corneal thickness (CCT) and corneal radius, to enhance our understanding of the biomechanical changes induced by this surgical procedure. Sixty-six patients (66 eyes) underwent FS-LASIK, resulting in significant changes in CCT, corneal radius, and Goldmann intraocular pressure (GAT IOP) 6 months post-surgery (△CCT = − 88 ± 31 µm, △corneal radius = 0.81 ± 0.30 mm, △GAT IOP = − 3.2 ± 2.4 mmHg, p < 0.001) 6 months after surgery. However, corneal stiffness did not significantly change (△ = − 0.002 ± 0.011, p < 0.2). The corneal tangent modulus showed a significant increase post-surgery (△ = 0.263 ± 0.146, p < 0.001), exhibiting a negative correlation with CCT (r = − 0.68, P < 0.001) and a positive correlation with corneal radius (r = 0.71, P < 0.001). For each 1 mm increase in corneal radius, there was a 0.23 MPa increase in corneal modulus, and for every 100 µm reduction in corneal thickness, there was a 0.14 MPa increase in corneal modulus. The corneal tangent modulus, influenced by corneal radius and CCT, increased significantly following FS-LASIK. This study highlights the biomechanical changes induced by FS-LASIK, with implications for understanding corneal behavior post-surgery and its potential impact on patient outcomes.

Background: Fatigue is a prevalent non-motor symptom that often appears in the early stages of Parkinson’s disease (PD). Plasma neurofilament light chain (NfL) was elevated in PD patients and may be considered a potential biomarker for both motor and cognitive progression. Objectives: In this study, we explored the association between plasma NfL levels and various fatigue subtypes and the prediction of baseline plasma NfL levels for fatigue subtype conversion. Methods: Patients with PD were classified into four categories: persistent fatigue, never fatigue, non-persistent fatigue, and new-onset fatigue. They underwent detailed neurological evaluations at baseline and a 2-year follow-up. Plasma NfL, glial fibrillary acidic protein, phosphorylated tau181, amyloid beta 42, and Aβ40 levels in both PD patients and control subjects were measured using an ultrasensitive single molecule array. Results: The study enrolled 174 PD patients and 95 control subjects. Plasma NfL levels were significantly higher in the persistent fatigue group compared to the never fatigue group at the 2-year follow-up ( p < 0.05). Longitudinally, 45.16% of baseline fatigue patients converted to non-fatigue at the 2-year follow-up. Additionally, 22.12% of patients initially without-figure patients converted to fatigue patients at the 2-year follow-up. Baseline plasma NfL levels were significantly higher in both the persistent fatigue and new-onset fatigue groups compared to the never fatigue group ( p < 0.05). Higher baseline NfL levels were significantly associated with new-onset fatigue (odds ratio = 1.127, p = 0.034) after adjusting for confounders. Conclusion: Baseline plasma NfL levels may serve as a biomarker for predicting fatigue subtype conversion and the progression of fatigue in PD.

BACKGROUND:Biallelic PLA2G6 mutations are associated with early onset autosomal recessive parkinsonism, exhibiting a broad spectrum of clinical heterogeneity. OBJECTIVE:To comprehensively characterise the clinical, imaging and genetic features of PLA2G6-related parkinsonism. METHODS:We report 14 new cases of PLA2G6-related parkinsonism in Southwest China and conduct a systematic literature review. RESULTS:Among the 14 patients in our cohort, 16 PLA2G6 variants were identified, including seven novel and nine previously reported variants. The mean age at symptom onset was 26.50±6.57 years. The most common initial presentation was parkinsonism (9/14, 64.3%), followed by gait disturbance (6/14, 42.9%) and psychiatric symptoms (1/14, 7.1%). A literature review identified 118 patients with PLA2G6-related parkinsonism, with a mean age at onset of 24.53±8.84 years. The most common initial clinical features included parkinsonism (61/117, 52.1%), cerebellar signs (46/85, 54.1%), cognitive impairment (65/92, 70.7%) and psychiatric symptoms (80/93, 86.0%). Subgroup analysis showed that the mean age at symptom onset was older in Chinese patients (26.65±7.08 years) compared with those of European ancestry (20.83±9.79 years) (p=0.016). Additionally, patients of European ancestry showed delayed parkinsonism 5.35±8.14 years after onset. Iron deposition was reported more frequently in patients of European ancestry (10/16, 62.5%) than that in Chinese patients (6/37, 16.2%) (p=0.0002). CONCLUSION:Our study provides new insights on the diverse clinical spectrum of PLA2G6-related parkinsonism, encompassing parkinsonian features, psychiatric symptoms, cognitive impairment and early levodopa-induced motor complications.

Aberrant DNA methylation alterations are implicated in amyotrophic lateral sclerosis (ALS). Nevertheless, the influence of genetic variants in genes regulating DNA methylation on ALS patients is not well understood. Therefore, we aim to provide a comprehensive variant profile of genes related to DNA methylation (DNMT1, DNMT3A, DNMT3B, DNMT3L) and demethylation (TET1, TET2, TET3, TDG) and to investigate the association of these variants with ALS. Variants were screened in a cohort of 2240 ALS patients from Southwest China, using controls from the Genome Aggregation Database (n = 9976) and the China Metabolic Analytics Project (n = 10,588). The over-representation of rare variants and their association with ALS risk were evaluated using Fisher’s exact test with Bonferroni correction at both allele and gene levels. Kaplan–Meier analysis and Cox regression analysis were employed to explore the relationship between variants and survival. A total of 210 variants meeting the criteria were identified. Gene-based burden analysis identified a significant increase in ALS risk associated with rare variants in the TET2 gene (OR = 1.95, 95