Performance on adsorption of toluene by ionic liquid-modified AC in high-humidity exhaust gas.

Volatile organic compounds (VOCs) frequently pose a threat to the biosphere, impacting ecosystems, flora, fauna, and the surrounding environment. Industrial emissions of VOCs often include the presence of water vapor, which, in turn, diminishes the adsorption capacity and efficacy of adsorbents. This occurs due to the competitive adsorption of water vapor, which competes with target pollutants for adsorption sites on the adsorbent material. In this study, hydrophobic activated carbons (BMIMPF6-AC (L), BMIMPF6-AC (g), and BMIMPF6-AC-H) were successfully prepared using 1-butyl-3-methylimidazolium hexafluorophosphate (BMIMPF6) to adsorb toluene under humidity environment. The adsorption performance and mechanism of the resulting ionic liquid-modified activated carbon for toluene in a high-humidity environment were evaluated to explore the potential application of ionic liquids as hydrophobic modifiers. The results indicated that BMIMPF6-AC-H exhibited superior hydrophobicity. The toluene adsorption capacity of BMIMPF6-AC-H was 1.53 times higher than that of original activated carbon, while the adsorption capacity for water vapor was only 37.30% of it at 27 °C and 77% RH. The Y-N model well-fitted the dynamic adsorption experiments. To elucidate the microscopic mechanism of hydrophobic modification, the Independent Gradient Model (IGM) method was employed to characterize the intermolecular interactions between BMIMPF6 and toluene. Overall, this study introduces a new modifier for hydrophobic modification of activated carbon, which could enhance the efficiency of activated carbon in treating industrial VOCs.

Associations between gut microbiota and Parkinson disease: A bidirectional Mendelian randomization analysis.

BACKGROUND AND PURPOSE: Parkinson disease (PD)-associated alterations in the gut microbiome have been observed in clinical and animal studies. However, it remains unclear whether this association reflects a causal effect in humans. METHODS: We performed two-sample bidirectional Mendelian randomization using summary statistics from the international consortium MiBioGen (N = 18,340), the Framingham Heart Study (N = 2076), and the International Parkinson's Disease Genomics Consortium for PD (33,674 cases and 449,056 controls) and PD age at onset (17,996 cases). RESULTS: Twelve microbiota features presented suggestive associations with PD risk or age at onset. Genetically increased Bifidobacterium levels correlated with decreased PD risk (odds ratio = 0.77, 95% confidence interval [CI] = 0.60-0.99, p = 0.040). Conversely, high levels of five short-chain fatty acid (SCFA)-producing bacteria (LachnospiraceaeUCG010, RuminococcaceaeUCG002, Clostridium sensustricto1, Eubacterium hallii group, and Bacillales) correlated with increased PD risk, and three SCFA-producing bacteria (Roseburia, RuminococcaceaeUCG002, and Erysipelatoclostridium) correlated with an earlier age at PD onset. Gut production of serotonin was associated with an earlier age at PD onset (beta = -0.64, 95% CI = -1.15 to -0.13, p = 0.013). In the reverse direction, genetic predisposition to PD was related to altered gut microbiota composition. CONCLUSIONS: These results support a bidirectional relationship between gut microbiome dysbiosis and PD, and highlight the role of elevated endogenous SCFAs and serotonin in PD pathogenesis. Future clinical studies and experimental evidence are needed to explain the observed associations and to suggest new therapeutic approaches, such as dietary probiotic supplementation.

Neuroimaging uncovers distinct relationships of glymphatic dysfunction and motor symptoms in Parkinson's disease.

BACKGROUND: Studies of glymphatic dysfunction in Parkinson's disease (PD) patients have attracted much attention in recent years. However, the relationships between glymphatic dysfunction and clinical symptoms remains unclear. OBJECTIVES: To determine whether the diffusion tensor image analysis along the perivascular space (DTI-ALPS) affect the severity and types of motor and non-motor symptoms in PD patients. METHODS: De novo PD patients and controls who performed both DTI and 123I-DaTscan single photon emission computed tomography (SPECT) scanning were retrieved from the international multicenter Parkinson's Progression Marker Initiative (PPMI) cohort. Glymphatic system was evaluated by the DTI-ALPS. Motor symptoms were assessed by Movement Disorders Society Unified Parkinson's Disease Rating Scale III (MDS-UPDRS-III). The influence of glymphatic activity on motor and non-motor symptoms was explored by multivariate linear regression models. RESULTS: A total of 153 PD patients (mean age 60.97 ± 9.47 years; 99 male) and 67 normal controls (mean age 60.10 ± 10.562 years; 43 male) were included. The DTI-ALPS index of PD patients was significantly lower than normal controls (Z = - 2.160, p = 0.031). MDS-UPDRS III score (r = - 0.213, p = 0.008) and subscore for rigidity (r = - 0.177, p = 0.029) were negatively correlated with DTI-ALPS index. The DTI-ALPS index was significantly associated with MDS-UPDRS-III score (ß = - 0.160, p = 0.048) and subscore for rigidity (ß = - 0.170, p = 0.041) after adjusting for putamen dopamine transporter availability and clinical factors. CONCLUSIONS: Our results showed distinct relationships between glymphatic dysfunction and the severity and types of PD motor symptoms, suggesting the potential of DTI-ALPS index as a biomarker for PD motor symptoms.

[Inhibition of the Wnt signaling pathway contributes to the cardiac protection of exercise training in spontaneously hypertensive rats].

The objective of this study was to investigate the cardiac protective effect of low-to-moderate intensity exercise training and the role of the Wnt signaling pathway in spontaneously hypertensive rats (SHR). SHR and Wistar-Kyoto (WKY) rats were randomly divided into 5 groups, namely hypertensive control (SHR-S), hypertensive plus exercise training (SHR-E), normal blood pressure control (WKY-S), normal blood pressure plus exercise training (WKY-E) and SHR-E plus Wnt agonist (SHR-E-Wnt). The rats in SHR-E and WKY-E groups underwent low-to-moderate intensity swimming for 16 weeks, and the rats in SHR-E-Wnt group were injected with Wnt agonist 1 through tail vein 4 weeks before the end of swimming. The blood pressure of rats was measured every week. After exercise training, the left ventricular wall thickness and ejection function were measured by ultrasound cardiogram, myocardial structure and collagen fiber changes were observed by HE staining and Masson staining, and the expression levels of ß-catenin and Dishevelled-1 (DVL-1) mRNA and protein in left ventricular myocardium were detected by real-time fluorescence quantitative PCR and Western blot, respectively. The results showed that the body weight was decreased (P < 0.05), blood pressure was increased (P < 0.01), heart weight and ventricular wall thickness were increased (P < 0.01), and the left ventricular ejection function was decreased (P < 0.05) in SHR-S group compared with those in WKY-S group. In addition, the heart structure was damaged, collagen fibers were significantly increased, and the mRNA and protein expressions of ß-catenin and DVL-1 in the left ventricle were significantly up-regulated in SHR-S group compared with those in WKY-S group (P < 0.01). Compared with those in SHR-S group, the body weight of SHR-E group did not change significantly (P > 0.05), but the blood pressure was decreased (P < 0.01), heart weight and ventricular wall thickness were diminished, ejection function was increased (P < 0.01), myocardial structure injury was significantly improved, collagen fibers were significantly reduced, and mRNA and protein expression levels of ß-catenin and DVL-1 in the left ventricle were significantly down-regulated (P < 0.01) in SHR-E group. Importantly, exercise-induced antihypertensive and cardioprotective effects in SHR were blunted by Wnt agonist. These results suggest that low-to-moderate intensity exercise training exerts cardioprotective effects in SHR, possibly through inhibiting the Wnt signaling pathway.

Clinical features of NOTCH2NLC-related neuronal intranuclear inclusion disease.

BACKGROUND: Abnormal expanded GGC repeats within the NOTCH2HLC gene has been confirmed as the genetic mechanism for most Asian patients with neuronal intranuclear inclusion disease (NIID). This cross-sectional observational study aimed to characterise the clinical features of NOTCH2NLC-related NIID in China. METHODS: Patients with NOTCH2NLC-related NIID underwent an evaluation of clinical symptoms, a neuropsychological assessment, electrophysiological examination, MRI and skin biopsy. RESULTS: In the 247 patients with NOTCH2NLC-related NIID, 149 cases were sporadic, while 98 had a positive family history. The most common manifestations were paroxysmal symptoms (66.8%), autonomic dysfunction (64.0%), movement disorders (50.2%), cognitive impairment (49.4%) and muscle weakness (30.8%). Based on the initial presentation and main symptomology, NIID was divided into four subgroups: dementia dominant (n=94), movement disorder dominant (n=63), paroxysmal symptom dominant (n=61) and muscle weakness dominant (n=29). Clinical (42.7%) and subclinical (49.1%) peripheral neuropathies were common in all types. Typical diffusion-weighted imaging subcortical lace signs were more frequent in patients with dementia (93.9%) and paroxysmal symptoms types (94.9%) than in those with muscle weakness (50.0%) and movement disorders types (86.4%). GGC repeat sizes were negatively correlated with age of onset (r=-0.196, p<0.05), and in the muscle weakness-dominant type (median 155.00), the number of repeats was much higher than in the other three groups (p<0.05). In NIID pedigrees, significant genetic anticipation was observed (p<0.05) without repeat instability (p=0.454) during transmission. CONCLUSIONS: NIID is not rare; however, it is usually misdiagnosed as other diseases. Our results help to extend the known clinical spectrum of NOTCH2NLC-related NIID.

Sensitivity of Sniffer Dogs for a Diagnosis of Parkinson's Disease: A Diagnostic Accuracy Study.

BACKGROUND: The diagnostic criteria for Parkinson's disease (PD) remain complex, which is especially problematic for nonmovement disorder experts. A test is required to establish a diagnosis of PD with improved accuracy and reproducibility. OBJECTIVE: The study aimed to investigate the sensitivity and specificity of tests using sniffer dogs to diagnose PD. METHODS: A prospective, diagnostic case-control study was conducted in four tertiary medical centers in China to evaluate the accuracy of sniffer dogs to distinguish between 109 clinically established medicated patients with PD, 654 subjects without PD, 37 drug-naïve patients with PD, and 185 non-PD controls. The primary outcomes were sensitivity and specificity of sniffer dog's identification. RESULTS: In the study with patients who were medicated, when two or all three sniffer dogs yielded positive detection results in a sample tested, the index test sensitivity, specificity, and positive and negative likelihood ratios were 91% (95% CI: 84%-96%), 95% (95% CI: 93%-97%), and 19.16 (95% CI: 13.52-27.16) and 0.10 (95% CI: 0.05-0.17), respectively. The corresponding sensitivity, specificity, and positive and negative likelihood ratios in patients who were drug-naïve were 89% (95% CI: 75%-96%), 86% (95% CI: 81%-91%), and 6.6 (95% CI: 4.51-9.66) and 0.13 (95% CI: 0.05-0.32), respectively. CONCLUSIONS: Tests using sniffer dogs may be a useful, noninvasive, fast, and cost-effective method to identify patients with PD in community screening and health prevention checkups as well as in neurological practice. © 2022 International Parkinson and Movement Disorder Society.

Associations of multiple visual rating scales based on structural magnetic resonance imaging with disease severity and cerebrospinal fluid biomarkers in patients with Alzheimer's disease.

The relationships between multiple visual rating scales based on structural magnetic resonance imaging (sMRI) with disease severity and cerebrospinal fluid (CSF) biomarkers in patients with Alzheimer's disease (AD) were ambiguous. In this study, a total of 438 patients with clinically diagnosed AD were recruited. All participants underwent brain sMRI scan, and medial temporal lobe atrophy (MTA), posterior atrophy (PA), global cerebral atrophy-frontal sub-scale (GCA-F), and Fazekas rating scores were visually evaluated. Meanwhile, disease severity was assessed by neuropsychological tests such as the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating (CDR). Among them, 95 patients were tested for CSF core biomarkers, including Aß1-42, Aß1-40, Aß1-42/Aß1-40, p-tau, and t-tau. As a result, the GCA-F and Fazekas scales showed positively significant correlations with onset age (r = 0.181, p < 0.001; r = 0.411, p < 0.001, respectively). Patients with late-onset AD (LOAD) showed higher GCA-F and Fazekas scores (p < 0.001, p < 0.001). With regard to the disease duration, the MTA and GCA-F were positively correlated (r = 0.137, p < 0.05; r = 0.106, p < 0.05, respectively). In terms of disease severity, a positively significant association emerged between disease severity and the MTA, PA GCA-F, and Fazekas scores (p < 0.001, p < 0.001, p < 0.001, p < 0.05, respectively). Moreover, after adjusting for age, gender, and APOE alleles, the MTA scale contributed to moderate to severe AD in statistical significance independently by multivariate logistic regression analysis (p < 0.05). The model combining visual rating scales, age, gender, and APOE alleles showed the best performance for the prediction of moderate to severe AD significantly (AUC = 0.712, sensitivity = 51.5%, specificity = 84.6%). In addition, we observed that the MTA and Fazekas scores were associated with a lower concentration of Aß1-42 (p < 0.031, p < 0.022, respectively). In summary, we systematically analyzed the benefits of multiple visual rating scales in predicting the clinical status of AD. The visual rating scales combined with age, gender, and APOE alleles showed best performance in predicting the severity of AD. MRI biomarkers in combination with CSF biomarkers can be used in clinical practice.

Lack of bidirectional association between age-related macular degeneration and Alzheimer's disease: A Mendelian randomization study.

INTRODUCTION: Observational studies have reported inconsistent results on the relationship between age-related macular degeneration (AMD) and Alzheimer's disease (AD). Therefore, we aimed to determine whether there is a causal association between AMD and AD. METHODS: This two-sample bidirectional Mendelian randomization (MR) study evaluated causal associations between advanced AMD and AD using summary data from large genome-wide association studies. RESULTS: Genetic liability for advanced AMD showed no statistical causal association with AD risk (odds ratio [OR] = 0.999, 95% confidence interval [CI]: 0.955-1.044, P = .948). Reverse MR analysis provided little support for a causal effect of AD on advanced AMD (OR = 0.973, 95%CI: 0.938-1.008, P = .133). DISCUSSION: This MR study found no evidence to support a bidirectional causality between advanced AMD and AD. HIGHLIGHTS: We evaluated the bidirectional causal relationship between advanced AMD and AD. Advanced AMD showed no statistical causal association with risk of AD. We found no evidence to support a causal effect of AD on advanced AMD risk. The associations observed in epidemiological studies should not be considered causal.

Association of rare PPARGC1A variants with Parkinson's disease risk.

BACKGROUND: Recent researches on Parkinson's disease (PD) pathogenesis discovered the correlation between PD and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) dysfunction and reduction of PPARGC1A gene expression. Hence, we detected PPARGC1A rare variants to clarify their effect on PD risk in a large population of PD patients in mainland China. METHODS: We applied whole-exome sequencing (WES) to 1917 patients with early-onset or familial PD and 1652 controls (WES cohort), and whole-genome sequencing (WGS) to 1962 patients with sporadic late-onset PD and 1279 controls (WGS cohort). To identify PPARGC1A rare variants, we used burden analysis to assess the relationship between PPARGC1A rare variants and PD susceptibility. RESULTS: 30 rare missense variants in the cohort WES and 21 missense variants in the cohort WGS have been detected in the study and PPARGC1A missense variants are significantly associated with early-onset and familial PD susceptibility in our study (P = 0.012), which supports evidence that PPARGC1A rare variants are involved in the onset of early-onset and familial PD. CONCLUSIONS: The study suggested that PPARGC1A rare variants may contribute to the risk of early-onset and familial PD.

Efficacy of repetitive transcranial magnetic stimulation in Parkinson's disease: A systematic review and meta-analysis of randomised controlled trials.

Background: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive form of brain stimulation that positively regulates the motor and non-motor symptoms of Parkinson's disease (PD). Although, most reviews and meta-analysis have shown that rTMS intervention is effective in treating motor symptoms and depression, very few have used randomised controlled trials (RCTs) to analyse the efficacy of this intervention in PD. We aimed to review RCTs of rTMS in patients with PD to assess the efficacy of rTMS on motor and non-motor function in patients with PD. Methods: In this systematic review and meta-analysis, we searched PubMed, MEDLINE and Web of Science databases for RCTs on rTMS in PD published between January 1, 1988 to January 1, 2022. Eligible studies included sham-controlled RCTs that used rTMS stimulation for motor or non-motor symptoms in PD. RCTs not focusing on the efficacy of rTMS in PD were excluded. Summary data were extracting from those RCTs by two investigators independently. We then calculated standardised mean difference with random-effect models. The main outcome included motor and non-motor examination of scales that were used in PD motor or non-motor assessment. This study was registered with PROSPERO, CRD42022329633. Findings: Fourteen studies with 469 patients met the criteria for our meta-analysis. Twelve eligible studies with 381 patients were pooled to analyse the efficacy of rTMS on motor function improvement. The effect size on motor scale scores was 0.51 (P < 0.0001) and were not distinctly heterogeneous (I2 = 29%). Five eligible studies with 202 patients were collected to evaluate antidepressant-like effects. The effect size on depression scale scores was 0.42 (P = 0.004), and were not distinctly heterogeneous (I2 = 25%), indicating a significant anti-depressive effect (P = 0.004). The results suggest that high-frequency of rTMS on primary motor cortex (M1) is effective in improving motor symptoms; while the dorsolateral prefrontal cortex (DLPFC) may be a potentially effective area in alleviating depressive symptom. Interpretation: The findings suggest that rTMS could be used as a possible adjuvant therapy for PD mainly to improve motor symptoms, but could have potential efficacy on depressive symptoms of PD. However, further investigation is needed. Funding: The National Natural Science Foundation of China (NO: 81873777, 82071414), Initiated Foundation of Zhujiang Hospital (NO: 02020318005), Scientific Research Foundation of Guangzhou (NO: 202206010005), and Science and Technology Program of Guangdong of China (NO: 2020A0505100037).

Telomere Length and COVID-19 Outcomes: A Two-Sample Bidirectional Mendelian Randomization Study.

Observational studies have found a relationship between directly measured short leukocyte telomere length (LTL) and severe coronavirus disease 19 (COVID-19). We investigated the causal association between genetically predicted LTL and COVID-19 susceptibility or severity. A previous genome-wide association study (GWAS) of 78,592 European-ancestry participants identified single nucleotidepolymorphisms (SNPs) that can be utilized to genetically predict LTL. Summary-level data for COVID-19 outcomes were analyzed from the COVID-19 Host Genetics Initiative. A two-sample bidirectional Mendelian randomization (MR) study was designed to evaluate these causal relationships. Using an inverse-weighted MR analysis and population-based controls, genetically predicted LTL did not reveal any significant association with COVID-19 susceptibility (odds ratio (OR): 0.94; 95% CI: 0.85-1.04; p = 0.202) or severity (OR: 0.85; 95% CI: 0.70-1.03; p = 0.099). Similar results were found for five other definitions of cases/controls and/or COVID-19 outcomes. Six additional MR methods and sensitivity analyses were conducted after removing variants with potential horizontal pleiotropy and including variants at a liberal significance level, which produced similar results. Using SNPs identified for the prediction of LTL from another GWAS study, we found a non-significant association for COVID-19 susceptibility or severity with narrower CIs toward the null hypothesis. No proof of genetically predicted COVID-19 phenotypes remained causally associated with genetically predicted LTL, and the null association was consistent with a lack of significant genetic correlation. Genetic evidence does not support shorter LTL as a causal risk factor for COVID-19 susceptibility or severity.

PSEN1 G417S mutation in a Chinese pedigree causing early-onset parkinsonism with cognitive impairment.

Presenilin 1 (PSEN1) mutations are a major cause of familial Alzheimer's disease. The pathogenic variant, PSEN1 p.G417S, has been reported to be associated with spastic paraparesis and cotton wool plaques in Japan. Here, we report a 3 generation Chinese pedigree that included 10 patients presenting with early-onset and rapid progression of parkinsonism with cognitive impairment in their third or fourth decade of life. Three additional living patients developed different degrees of cognitive impairment, without movement disorders. Magnetic resonance imaging of the brain showed white matter hyperintensities, multiple microbleeds, and enlarged perivascular spaces. Whole exome sequencing analysis of the proband detected the mutation, p.G417S, in PSEN1, which was completely co-segregated with the disease phenotype within the family by Sanger sequencing. 3D protein structures predicted that the mutation might influence contact with the lipid membrane and the interaction with beta-catenin. Our study provides insights into the heterogeneity in clinical presentation and imaging associated with mutations in PSEN1.

The Phenotypes and Mechanisms of NOTCH2NLC-Related GGC Repeat Expansion Disorders: a Comprehensive Review.

The human-specific gene NOTCH2NLC is primarily expressed in radial glial cells and plays an important role in neuronal differentiation and cortical neurogenesis. Increasing studies were conducted to verify the relationship between NOTCH2NLC gene and many neurological diseases, such as neuronal intranuclear inclusion disease, essential tremor, multiple system atrophy, Parkinson's disease, Alzheimer's disease, and even oculopharyngodistal myopathy. Thus, we support the concept, NOTCH2NLC-related GGC repeat expansion disorders (NRED), to summarize all diseases with the GGC repeat expansion in the 5'UTR of NOTCH2NLC gene, regardless of their various clinical phenotypes. Here, we discuss the reported cases to analyze the clinical features of NOTCH2NLC-related GGC repeat expansion disorders, including dementia, parkinsonism, peripheral neuropathy and myopathy, leukoencephalopathy, and essential tremor. In addition, we outline radiological and pathological manifestations of NOTCH2NLC-related GGC repeat expansion disorders, and then present possible mechanisms, such as toxic polyG protein, toxic repeat RNA, the GGC repeat size, and the size and types of trinucleotide interruption. Therefore, this review provides a systematic description of NOTCH2NLC-related GGC repeat expansion disorders and emphasizes the significance for understanding this type of repeat expansion disease.

Evaluating the role of ARSA in Chinese patients with Parkinson's disease.

Recent studies have suggested ARSA, a gene responsible for metachromatic leukodystrophy, could be a genetic modifier of Parkinson's disease (PD) pathogenesis, acting as a molecular chaperone for α-synuclein. To elucidate the role of ARSA variants in PD, we did a comprehensive analysis of ARSA variants by performing next-generation sequencing on 477 PD families, 1440 sporadic early-onset PD patients and 1962 sporadic late-onset PD patients and 2636 controls from Chinese mainland, as well as the association between ARSA variants and cognitive function of PD patients. We identified 2 familial PD following autosomal dominant inherence carrying rare variants of ARSA, but they had limited clinical significance. We detected a total of 81 coding variants of ARSA in our subjects but none of the identified variants were associated with either susceptibility or cognitive performance of PD, while loss-of-function variants showed slightly increased burden in late-onset PD (0.25% vs. 0%, p = 0.08). Our results suggested ARSA may not play important roles in PD of Chinese population.

Low-frequency and rare coding variants of NUS1 contribute to susceptibility and phenotype of Parkinson's disease.

NUS1 has been recently identified as a candidate gene for Parkinson's disease (PD). Few studies have examined the association of NUS1 variants with PD susceptibility and phenotypes. In the first cohort, whole-exome sequencing was performed to identify variants in NUS1 exon-coding and exon-intron regions in 1542 cases and 1625 controls. 13 variants were totally detected, of which 10 rare variants and 3 low-frequency variants. Burden analysis showed that rare NUS1 variants significantly enriched in PD (p=0.016). We also performed a meta-analysis based on previous and our studies to correlate NUS1 mutations with PD susceptibility. Integrating our previous cohort (3210 cases and 2807 controls) and the first cohort identified the significant association of rs539668656 with PD risk (odds ratio (OR) = 2.82, p = 0.016). The genotype-phenotype association analysis showed that patients carrying rare variants, or rs539668656 were significantly associated with earlier onset age, depression, emotional impairment and severe disease condition. Our results support the role of NUS1 rare variants and rs539668656 towards PD susceptibility and phenotype.

Constructing Prediction Models for Freezing of Gait by Nomogram and Machine Learning: A Longitudinal Study.

Objectives: Although risk factors for freezing of gait (FOG) have been reported, there are still few prediction models based on cohorts that predict FOG. This 1-year longitudinal study was aimed to identify the clinical measurements closely linked with FOG in Chinese patients with Parkinson's disease (PD) and construct prediction models based on those clinical measurements using Cox regression and machine learning. Methods: The study enrolled 967 PD patients without FOG in the Hoehn and Yahr (H&Y) stage 1-3 at baseline. The development of FOG during follow-up was the end-point. Neurologists trained in movement disorders collected information from the patients on a PD medication regimen and their clinical characteristics. The cohort was assessed on the same clinical scales, and the baseline characteristics were recorded and compared. After the patients were divided into the training set and test set by the stratified random sampling method, prediction models were constructed using Cox regression and random forests (RF). Results: At the end of the study, 26.4% (255/967) of the patients suffered from FOG. Patients with FOG had significantly longer disease duration, greater age at baseline and H&Y stage, lower proportion in Tremor Dominant (TD) subtype, a higher proportion in wearing-off, levodopa equivalent daily dosage (LEDD), usage of L-Dopa and catechol-O-methyltransferase (COMT) inhibitors, a higher score in scales of Unified Parkinson's Disease Rate Scale (UPDRS), 39-item Parkinson's Disease Questionnaire (PDQ-39), Non-Motor Symptoms Scale (NMSS), Hamilton Depression Rating Scale (HDRS)-17, Parkinson's Fatigue Scale (PFS), rapid eye movement sleep behavior disorder questionnaire-Hong Kong (RBDQ-HK), Epworth Sleepiness Scale (ESS), and a lower score in scales of Parkinson's Disease Sleep Scale (PDSS) (P < 0.05). The risk factors associated with FOG included PD onset not being under the age of 50 years, a lower degree of tremor symptom, impaired activities of daily living (ADL), UPDRS item 30 posture instability, unexplained weight loss, and a higher degree of fatigue. The concordance index (C-index) was 0.68 for the training set (for internal validation) and 0.71 for the test set (for external validation) of the nomogram prediction model, which showed a good predictive ability for patients in different survival times. The RF model also performed well, the C-index was 0.74 for the test set, and the AUC was 0.74. Conclusions: The study found some new risk factors associated with the FOG including a lower degree of tremor symptom, unexplained weight loss, and a higher degree of fatigue through a longitudinal study, and constructed relatively acceptable prediction models.

The Association Between Lysosomal Storage Disorder Genes and Parkinson's Disease: A Large Cohort Study in Chinese Mainland Population.

Background: Recent years have witnessed an increasing number of studies indicating an essential role of the lysosomal dysfunction in Parkinson's disease (PD) at the genetic, biochemical, and cellular pathway levels. In this study, we investigated the association between rare variants in lysosomal storage disorder (LSD) genes and Chinese mainland PD. Methods: We explored the association between rare variants of 69 LSD genes and PD in 3,879 patients and 2,931 controls from Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC) using next-generation sequencing, which were analyzed by using the optimized sequence kernel association test. Results: We identified the significant burden of rare putative LSD gene variants in Chinese mainland patients with PD. This association was robust in familial or sporadic early-onset patients after excluding the GBA variants but not in sporadic late-onset patients. The burden analysis of variant sets in genes of LSD subgroups revealed a suggestive significant association between variant sets in genes of sphingolipidosis deficiency disorders and familial or sporadic early-onset patients. In contrast, variant sets in genes of sphingolipidoses, mucopolysaccharidoses, and post-translational modification defect disorders were suggestively associated with sporadic late-onset patients. Then, SMPD1 and other four novel genes (i.e., GUSB, CLN6, PPT1, and SCARB2) were suggestively associated with sporadic early-onset or familial patients, whereas GALNS and NAGA were suggestively associated with late-onset patients. Conclusion: Our findings supported the association between LSD genes and PD and revealed several novel risk genes in Chinese mainland patients with PD, which confirmed the importance of lysosomal mechanisms in PD pathogenesis. Moreover, we identified the genetic heterogeneity in early-onset and late-onset of patients with PD, which may provide valuable suggestions for the treatment.