Associative role of HLA-DRB1 as a protective factor for susceptibility and progression of Parkinson's disease: a Chinese cross-sectional and longitudinal study.

Background: Previous genome-wide association studies investigating the relationship between the HLA-DRB1 and the risk of Parkinson's disease (PD) have shown limited racial diversity and have not explored clinical heterogeneity extensively. Methods: The study consisted of three parts: a case-control study, a cross-sectional study, and a longitudinal cohort study. The case-control study included 477 PD patients and 477 healthy controls to explore the relationship between rs660895 and PD susceptibility. The cross-sectional study utilized baseline data from 429 PD patients to examine the correlation between rs660895 and PD features. The longitudinal study included 388 PD patients who completed a 3-year follow-up to investigate the effects of rs660895 on PD progression. Results: In the case-control study, HLA-DRB1 rs660895-G allele was associated with a decreased risk of PD in allele model (adjusted OR=0.72, p = 0.003) and dominant model (AG + GG vs. AA: adjusted OR = 0.67, p = 0.003). In the cross-sectional analysis, there was no association between rs660895 and the onset age, motor phenotype, or initial motor symptoms. In the longitudinal analysis, PD patients with the G allele exhibited a slower progression of motor symptoms (MDS-UPDRS-III total score: ß = -5.42, p < 0.001, interaction ptime × genotype < 0.001) and non-motor symptoms (NMSS score: ß = -4.78, p = 0.030, interaction ptime × genotype < 0.001). Conclusion: Our findings support HLA-DRB1 rs660895-G allele is a protective genetic factor for PD risk in Chinese population. Furthermore, we also provide new evidence for the protective effect of rs660895-G allele in PD progression.

Pyruvate is modified by tea/coffee metabolites and reversely correlated with multiple system atrophy and Parkinson's disease.

Introduction: Multiple system atrophy (MSA) is a rapidly progressing neurodegenerative disorder. Although diverse biomarkers have been established for Parkinson's disease (PD), no widely accepted markers have been identified in MSA. Pyruvate and lactate are the end-product of glycolysis and crucial for brain metabolism. However, their correlation with MSA remains unclear. Moreover, it is elusive how lifestyles modify these metabolites. Methods: To investigate the correlation and diagnostic value of plasma pyruvate and lactate levels in MSA and PD. Moreover, we explored how lifestyle-related metabolites interact with these metabolites in determining the disease risk. We assayed the 3 metabolites in pyruvate/lactate and 6 in the tea/coffee metabolic pathways by targeted mass spectrometry and evaluate their interactions and performance in diagnosis and differentiation between MSA and PD. Results: We found that 7 metabolites were significantly different between MSA, PD and healthy controls (HCs). Particularly, pyruvate was increased in PD while significantly decreased in MSA patients. Moreover, the tea/coffee metabolites were negatively associated with the pyruvate level in HCs, but not in MSA and PD patients. Using machine-learning models, we showed that the combination of pyruvate and tea/coffee metabolites diagnosed MSA (AUC = 0.878) and PD (AUC = 0.833) with good performance. Additionally, pyruvate had good performance in distinguishing MSA from PD (AUC = 0.860), and the differentiation increased (AUC = 0.922) when combined with theanine and 1,3-dimethyluric acid. Conclusions: This study demonstrates that pyruvate correlates reversely with MSA and PD, and may play distinct roles in their pathogenesis, which can be modified by lifestyle-related tea/coffee metabolites.

Novel mutations in the ABCD1 gene caused adrenomyeloneuropathy in the Chinese population.

Background: As a rare genetic disease, adrenomyeloneuropathy (AMN) is the most common adult phenotype of X-linked adrenoleukodystrophy (X-ALD). Mutations in the ABCD1 gene have been identified to cause AMN. Methods: We applied clinical evaluation, laboratory tests, and neuroimaging on three patients with progressive spastic paraparesis. In genetic analysis, we investigated ABCD1 gene mutations by whole-exome sequencing and Sanger sequencing. Bioinformatics tools were used to predict the effects of identified ABCD1 mutations on the protein. Results: All three patients were men with adult-onset disease, mainly characterized by progressive spastic paraparesis. Among them, two patients had peripheral neuropathy and one patient had signs of adrenal insufficiency. All three patients showed cerebral involvement on brain MRI, while two patients were found with diffuse cord atrophy on spinal MRI. High-VLCFA levels in plasma, as well as C24:0/C22:0 and C26:0/C22:0 ratios, were found in all three patients. In addition, three different ABCD1 mutations were identified in three unrelated Chinese families, including one known mutation (c.1415_1416delAG) and two novel mutations (c.217C>T and c.160_170delACGCAGGAGGC). Based on the clinical assessment, radiographic, biochemical, and genetic testing, the final diagnosis was AMN in these patients with spastic paraparesis. Conclusion: This study reported three patients with AMN and identified two novel mutations in the ABCD1 in the Chinese population. Our finding emphasized that X-ALD is an important cause of adult-onset spastic paraplegia. Thus, neuroimaging, VLCFA testing, and especially the detection of the ABCD1 gene have important implications for the etiological diagnosis of adult patients with spastic paraplegia.

Development and Validation of a Predictive Nomogram for Possible REM Sleep Behavior Disorders.

Objectives: To develop and validate a predictive nomogram for idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) in a community population in Beijing, China. Methods: Based on the validated RBD questionnaire-Hong Kong (RBDQ-HK), we identified 78 individuals with possible RBD (pRBD) in 1,030 community residents from two communities in Beijing. The least absolute shrinkage and selection operator (LASSO) regression was applied to identify candidate features and develop the nomogram. Internal validation was performed using bootstrap resampling. The discrimination of the nomogram was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve, and the predictive accuracy was assessed via a calibration curve. Decision curve analysis (DCA) was performed to evaluate the clinical value of the model. Results: From 31 potential predictors, 7 variables were identified as the independent predictive factors and assembled into the nomogram: family history of Parkinson's disease (PD) or dementia [odds ratio (OR), 4.59; 95% confidence interval (CI), 1.35-14.45; p = 0.011], smoking (OR, 3.24; 95% CI, 1.84-5.81; p < 0.001), physical activity (≥4 times/week) (OR, 0.23; 95% CI, 0.12-0.42; p < 0.001), exposure to pesticides (OR, 3.73; 95%CI, 2.08-6.65; p < 0.001), constipation (OR, 6.25; 95% CI, 3.58-11.07; p < 0.001), depression (OR, 3.66; 95% CI, 1.96-6.75; p < 0.001), and daytime somnolence (OR, 3.28; 95% CI, 1.65-6.38; p = 0.001). The nomogram displayed good discrimination, with original AUC of 0.885 (95% CI, 0.845-0.925), while the bias-corrected concordance index (C-index) with 1,000 bootstraps was 0.876. The calibration curve and DCA indicated the high accuracy and clinical usefulness of the nomogram. Conclusions: This study proposed an effective nomogram with potential application in the individualized prediction for pRBD.

Intravenous Thrombolysis Before Mechanical Thrombectomy for Acute Ischemic Stroke: A Meta-Analysis.

Background Whether intravenous thrombolysis before mechanical thrombectomy provides additional benefit for functional outcome in acute ischemic stroke remains uncertain. We performed a meta-analysis to compare the outcomes of direct mechanical thrombectomy (dMT) to mechanical thrombectomy with bridging using intravenous thrombolysis (bridging therapy [BT]) in patients with acute ischemic stroke. Methods and Results We performed a literature search in the PubMed, Excerpta Medica database, and Cochrane Central Register of Controlled Trials from January 1, 2003, to April 26, 2021. We included randomized clinical trials and observational studies that reported the 90-day functional outcome in patients with acute ischemic stroke undergoing dMT compared with BT. The 12 included studies (3 randomized controlled trials and 9 observational studies) yielded 3924 participants (mean age, 68.0 years [SD, 13.1 years]; women, 44.2%; 1887 participants who received dMT and 2037 participants who received BT). A meta-analysis of randomized controlled trial and observational data revealed similar 90-day functional independence (odds ratio [OR], 1.04; 95% CI, 0.90-1.19), mortality (OR, 1.03; 95% CI, 0.78-1.36), and successful recanalization (OR, 0.93; 95% CI, 0.76-1.14) for patients treated with dMT or BT. Compared with those in the BT group, patients in the dMT group were less likely to experience symptomatic intracranial hemorrhage (OR, 0.68; 95% CI, 0.51-0.91; P=0.008) or any intracranial hemorrhage (OR, 0.71; 95% CI, 0.61-0.84; P<0.001). Conclusions In this meta-analysis of patients with acute ischemic stroke, we found no significant differences in 90-day functional outcome or mortality between dMT and BT, but a lower rate of symptomatic intracranial hemorrhage for dMT. These findings support the use of dMT without intravenous thrombolysis bridging therapy. Registration URL: https://www.crd.york.ac.uk/prospero/; Unique identifier: 42021234664.

A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer's dementia.

BACKGROUND: New therapies are urgently needed for Alzheimer's disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide with a novel proposed mechanism of action. The first phase 3 clinical trial of GV-971 has been completed in China. METHODS: We conducted a phase 3, double-blind, placebo-controlled trial in participants with mild-to-moderate AD to assess GV-971 efficacy and safety. Participants were randomized to placebo or GV-971 (900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI). Safety and tolerability were monitored. RESULTS: A total of 818 participants were randomized: 408 to GV-971 and 410 to placebo. A significant drug-placebo difference on the ADAS-Cog12 favoring GV-971 was present at each measurement time point, measurable at the week 4 visit and continuing throughout the trial. The difference between the groups in change from baseline was - 2.15 points (95% confidence interval, - 3.07 to - 1.23; p < 0.0001; effect size 0.531) after 36 weeks of treatment. Treatment-emergent adverse event incidence was comparable between active treatment and placebo (73.9%, 75.4%). Two deaths determined to be unrelated to drug effects occurred in the GV-971 group. CONCLUSIONS: GV-971 demonstrated significant efficacy in improving cognition with sustained improvement across all observation periods of a 36-week trial. GV-971 was safe and well-tolerated. TRIAL REGISTRATION: ClinicalTrials.gov, NCT0229391 5. Registered on November 19, 2014.

Fbxo7 and Pink1 play a reciprocal role in regulating their protein levels.

Pink1, Parkin and Fbxo7, three autosomal recessive familial genes of Parkinson's disease (PD), have been implicated in mitophagy pathways for quality control and clearance of damaged mitochondria, but the interplay of these three genes still remains unclear. Here we present that Fbxo7 and Pink1 play a reciprocal role in the regulation of their protein levels. Regardless of the genotypes of Fbxo7, the wild type and the PD familial mutants of Fbxo7 stabilize the processed form of Pink1, supporting the prior study that none of the PD familial mutations in Fbxo7 have an effect on the interaction with Pink1. On the other hand, the interaction of Fbxo7 with Bag2 further facilitates its capability to stabilize Pink1. Intriguingly, the stabilization of Fbxo7 by Pink1 is specifically observed in substantial nigra pars compacta but striatum and cerebral cortex. Taken together, our findings support the notion that Fbxo7 as a scaffold protein has a chaperon activity in the stabilization of proteins.

Development and application of a Chinese Version of the Language Screening Test (CLAST) in post-stroke patients.

Aphasia shows high incidence in stroke patients and seriously impairs language comprehension, verbal communication, and social activities. Therefore, screening aphasic patients during the acute phase of stroke is crucial for language recovery and rehabilitation. The present study developed a Chinese version of the Language Screening Test (CLAST) and validated it in post-stroke patients.The CLAST was adapted from the Language Screening Test developed by Constance et al to incorporate Chinese cultural and linguistic specificities, and administered to 207 acute stroke patients and 89 stabilized aphasic or non-aphasic patients. Based on the Western Aphasia Battery (WAB) test, its reliability and validity were assessed. A cut-off for the CLAST in Chinese patients was determined by ROC curve analysis.The CLAST comprised 5 subtests and 15 items, including 2 subscores, namely expression (8 points, assessing naming, repetition, and automatic speech) and receptive (7 points maximum, evaluating picture recognition, and verbal instructions) indexes. Analysis of the alternate-form reliability of the questionnaire showed a retest correlation coefficient of 0.945 (P < .001). Intraclass correlation coefficients of three rating teams were >0.98 (P < .001). Internal consistency analysis showed a Cronbach's alpha coefficient of 0.909 (P < .001). The non-aphasia group showed higher scores than the aphasia group (14.2 ±â€Š1.3 vs 10.6 ±â€Š3.8) (P < .01). The questionnaire showed good construct validity by factor analysis. ROC curve analysis showed high sensitivity and specificity for the CLAST, with a cut-off of 13.5.The CLAST is suitable for Chinese post-stroke patients during the acute phase, with high reliability, validity, sensitivity, and specificity.

Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis.

BACKGROUND: Genetic studies have shown that C9orf72, SOD1, TARDBP and FUS are the most common mutated genes in amyotrophic lateral sclerosis (ALS). Here, we performed a meta-analysis to determine the mutation frequencies of these major ALS-related genes in patients with ALS. METHODS: We performed an extensive literature research to identify all original articles reporting frequencies of C9orf72, SOD1, TARDBP and FUS mutations in ALS. The mutation frequency and effect size of each study were combined. Possible sources of heterogeneity across studies were determined by meta-regression, sensitivity analysis and subgroup analysis. RESULTS: 111 studies were included in the meta-analysis. The overall pooled mutation frequencies of these major ALS-related genes were 47.7% in familial amyotrophic lateral sclerosis (FALS) and 5.2% in sporadic ALS (SALS). A significant difference was identified regarding the frequencies of mutations in major ALS genes between European and Asian patients. In European populations, the most common mutations were the C9orf72 repeat expansions (FALS 33.7%, SALS 5.1%), followed by SOD1 (FALS 14.8%, SALS 1.2%), TARDBP (FALS 4.2%, SALS 0.8%) and FUS mutations (FALS 2.8%, SALS 0.3%), while in Asian populations the most common mutations were SOD1 mutations (FALS 30.0%, SALS 1.5%), followed by FUS (FALS 6.4%, SALS 0.9%), C9orf72 (FALS 2.3%, SALS 0.3%) and TARDBP (FALS 1.5%, SALS 0.2%) mutations. CONCLUSIONS: These findings demonstrated that the genetic architecture of ALS in Asian populations is distinct from that in European populations, which need to be given appropriate consideration when performing genetic testing of patients with ALS.

[Possible effect of N-Acetyl-L-cysteine on Aß(25-35)-induced tau hyperphosphorylation].

OBJECTIVE: To investigate the possible effect and mechanism of N-Acetyl-L-cysteine (NAC) on fibrillar Aß(25-35)-induced tau hyperphosphorylation. METHODS: The phosphorylation of tau was induced by Aß(25-35) in primary cortical neuron. Neurons were incubated in the absent or present Aß(25-35), or pre-incubated NAC then co-incubated in Aß. The measurement of ROS was performed on a microplate fluorometer. The proteins of p35/p25, cdk5, pT205 and pS404 were detected by Western blot. RESULTS: In Aß treated group, the ROS, pT205 and pS404 level were obviously higher than that in non-treated with Aß group for 12 h (t=-6.35, P<0.05; t=-5, P<0.05; t=-4.57, P<0.05). However, in neurons pre-incubated with (10 mmol/L) NAC and then co-incubated with 20 µmol/L Aß, the ROS, pT205 and pS404 level were significantly decreased compared with that of Aß group (t=3.47, P<0.05; t=3.88, P<0.05 and t=3.64, P<0.05); Upon Aß exposure for 12 h, cortical neurons showed a statistically significant increase in p25 when compared to the control group (t=-6.20, P<0.05). However, pre-treatment with NAC showed a decrease in p25 as compared to neurons treated with Aß alone for 12 h (t=4.72, P<0.05). CONCLUSION: NAC attenuated the Aß(25-35)-induced tau hyperphosphorylation through CDK5 pathway.