Genetic causal relationship between immune diseases and migraine: a Mendelian randomization study.

Background: Migraine has an increased prevalence in several immune disorders, but genetic cause-effect relationships remain unclear. Mendelian randomization (MR) was used in this study to explore whether immune diseases are causally associated with migraine and its subtypes. Methods: We conducted a two-sample bidirectional multivariate Mendelian randomization study. Single-nucleotide polymorphisms (SNP) for six immune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), allergic rhinitis (AR), asthma and psoriasis, were used as genetic instrumental variables. Summary statistics for migraine were obtained from 3 databases: the International Headache Genetics Consortium (IHGC), UK Biobank, and FinnGen study. MR analyses were performed per outcome database for each exposure and subsequently meta-analyzed. Reverse MR analysis was performed to determine whether migraine were risk factors for immune diseases. In addition, we conducted a genetic correlation to identify shared genetic variants for these two associations. Results: No significant causal relationship was found between immune diseases and migraine and its subtypes. These results were robust with a series of sensitivity analyses. Using the linkage disequilibrium score regression method (LDSC), we detected no genetic correlation between migraine and immune diseases. Conclusion: The evidence from our study does not support a causal relationship between immune diseases and migraine. The mechanisms underlying the frequent comorbidity of migraine and several immune diseases need to be further elucidated.

Development and validation of non-invasive prediction models for migraine in Chinese adults.

BACKGROUND: Migraine is a common disabling neurological disorder with severe physical and psychological damage, but there is a lack of convenient and effective non-invasive early prediction methods. This study aimed to develop a new series of non-invasive prediction models for migraine with external validation. METHODS: A total of 188 and 94 subjects were included in the training and validation sets, respectively. A standardized professional questionnaire was used to collect the subjects' 9-item traditional Chinese medicine constitution (TCMC) scores, Pittsburgh Sleep Quality Index (PSQI) score, Zung's Self-rating Anxiety Scale and Self-rating Depression Scale scores. Logistic regression was used to analyze the risk predictors of migraine, and a series of prediction models for migraine were developed. Receiver operating characteristic (ROC) curve and calibration curve were used to assess the discrimination and calibration of the models. The predictive performance of the models were further validated using external datasets and subgroup analyses were conducted. RESULTS: PSQI score and Qi-depression score were significantly and positively associated with the risk of migraine, with the area of the ROC curves (AUCs) predicting migraine of 0.83 (95% CI:0.77-0.89) and 0.76 (95% CI:0.68-0.84), respectively. Eight non-invasive predictive models for migraine containing one to eight variables were developed using logistic regression, with AUCs ranging from 0.83 (95% CI: 0.77-0.89) to 0.92 (95% CI: 0.89-0.96) for the training set and from 0.76 (95% CI: 0.66-0.85) to 0.83 (95% CI: 0.75-0.91) for the validation set. Subgroup analyses showed that the AUCs of the eight prediction models for predicting migraine in the training and validation sets of different gender and age subgroups ranged from 0.80 (95% CI: 0.63-0.97) to 0.95 (95% CI: 0.91-1.00) and 0.73 (95% CI: 0.64-0.84) to 0.93 (95% CI: 0.82-1.00), respectively. CONCLUSIONS: This study developed and validated a series of convenient and novel non-invasive prediction models for migraine, which have good predictive ability for migraine in Chinese adults of different genders and ages. It is of great significance for the early prevention, screening, and diagnosis of migraine.

Efficacy and safety of intranasal agents for the acute treatment of migraine: a systematic review and network meta-analysis.

BACKGROUND: Intranasal agents may be ideal for the treatment of migraine patients. Many new acute intranasal-specific therapies have been developed, but few of them have been directly compared. The aim of this network meta-analysis (NMA) was to compare the efficacy and safety of various intranasal agents for the treatment of acute migraine in adult patients. METHODS: The Cochrane Register of Controlled Trials, Embase, and PubMed were searched from inception to 15 August 2023. Randomized controlled trials (RCTs) using intranasal agents (no restrictions on dose, formulation, dosing regimen or timing of the first dose) to treat adult patients with acute migraine were included. The primary efficacy endpoint was pain freedom at 2 h, and the primary safety endpoint was adverse events (AEs). The analysis process followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Nineteen studies (21 RCTs, 9738 participants) were included. Compared to the placebo, 5 mg of zolmitriptan using a conventional liquid nasal spray device was the most effective for pain freedom at 2 h [odds ratio (OR): 4.67, 95% confidence interval (CI): 3.43 to 6.43] and 24 h (OR: 5.49, 95% CI: 3.58 to 8.42) among all the interventions. Butorphanol nasal spray 1 mg was the most effective (OR: 8.62, 95% CI: 1.11 to 66.92) for pain freedom at 1 h, but with low-quality evidence. DFN-02 presented the highest freedom from nausea (OR: 4.95, 95% CI: 1.29 to 19.01) and phonophobia (OR: 5.36, 95% CI: 1.67 to 17.22) at 2 h, albeit with lower odds of achieving complete pain freedom. ROX-828 showed the highest improvement in freedom from photophobia at 2 h (OR: 4.03, 95% CI: 1.66 to 9.81). Dihydroergotamine nasal spray was significantly associated with the highest risk of AEs (OR: 9.65, 95% CI: 4.39 to 21.22) and was not recommended for routine use. Zavegepant nasal spray demonstrated the lowest risk of AEs (OR: 2.04, 95% CI: 1.37 to 3.03). The results of sensitivity analyses for the primary endpoints (pain freedom at 2 h and AEs) were generally consistent with those of the base case model. CONCLUSIONS: Compared with other new intranasal-specific therapies in treating migraine attacks, zolmitriptan nasal spray 5 mg was the most effective agent for pain freedom at 2 h. Zavegepant nasal spray 10 mg had the fewest adverse side effects.

Nucleus basalis of Meynert predicts cognitive changes in isolated REM sleep behavior disorder.

BACKGROUND: Degeneration of the nucleus basalis of Meynert (NBM) has been implicated in cognitive impairments in Parkinson's disease. The role of the NBM volumes in the cognitive function in isolated rapid eye movement (REM) sleep behavior disorder (iRBD) has not been explored. METHOD: We investigated changes in NBM volumes and their associations with cognitive deficits in iRBD. Baseline NBM volumes were compared between 29 iRBD patients and 29 healthy controls by using structural MRI data from the Parkinson Progression Marker Initiative database. Partial correlation analyses were used to evaluate cross-sectional relationships between baseline NBM volumes and cognitive performance in iRBD. Linear mixed models were applied to assess between-group differences in longitudinal cognitive changes, and whether baseline NBM volumes could predict longitudinal changes of cognition in iRBD. RESULTS: Compared with controls, NBM volumes were significantly reduced in iRBD patients. In patients with iRBD, higher NBM volumes were significantly associated with greater performance in global cognition function. In the longitudinal analyses, iRBD patients showed more severe and rapid decline on tests of global cognition compared to healthy controls. Furthermore, greater baseline NBM volumes were significantly associated with greater follow-up Montreal Cognitive Assessment (MoCA) scores, thus predicting less longitudinal cognitive changes in iRBD. CONCLUSION: This study provides important in vivo evidence for an association between the NBM degeneration and cognitive impairments in iRBD.

MAPT rs17649553 T allele is associated with better verbal memory and higher small-world properties in Parkinson's disease.

Currently, over 90 genetic loci have been found to be associated with Parkinson's disease (PD) in genome-wide association studies, nevertheless, the effects of these genetic variants on the clinical features and brain structure of PD patients are largely unknown. This study investigated the effects of microtubule-associated protein tau (MAPT) rs17649553 (C>T), a genetic variant associated with reduced PD risk, on the clinical manifestations and brain networks of PD patients. We found MAPT rs17649553 T allele was associated with better verbal memory in PD patients. In addition, MAPT rs17649553 significantly shaped the topology of gray matter covariance network and white matter network. Both the network metrics in gray matter covariance network and white matter network were correlated with verbal memory, however, the mediation analysis showed that it was the small-world properties in white matter network that mediated the effects of MAPT rs17649553 on verbal memory. These results suggest that MAPT rs17649553 T allele is associated with higher small-world properties in structural network and better verbal memory in PD.

An exploration on retro-construction of plasma drug concentration-time curves from corresponding urine excretion data and single-point plasma concentrations using a simplified and idealized method.

Background: Despite the availability of various tools of modeling and simulation, clinical pediatric pharmacokinetic (PK) studies remain far less efficient than those on adults due to ethical constraints. One of the optimal solutions is to substitute urine to blood sampling based on explicit mathematic relationships between them. However, this idea is limited by three main knowledge gaps associated with urine data, i.e., complicated excretion equations with excessive parameters, insufficient frequency that is hard to fit, and the mere expression of amounts with no in vivo distribution volume information involved. Methods: To overcome these obstacles, we sacrificed the precision from mechanistic PK models with complex excretion equations to expediency of compartmental model in which a constant ke is used to cover all the internal parameters. And the total cumulative amounts of urinary drug excretion (Xu∞) were estimated and introduced to the excretion equation so that urine data were likely to be fitted using a semi-log-terminal linear regression method. In addition, urinary excretion clearance (CLr) could be calculated by single point plasma data to anchor the plasma concentration-time (C-t) curve based on the assumption that CLr was kept constant throughout the PK process. Results: After sensitivity analysis of two subjective judgements (the selection of the compartmental model and the selection of plasma time point to calculate CLr), the performance of the optimized models was assessed using desloratadine or busulfan as model drugs in a variety of PK scenarios, from i.v. bolus/infusion to p.o. administration, from a single dose to multiple doses, and from rats to children. The fitting plasma drug concentrations of the optimal model were close to the observed value. Meanwhile, the drawbacks inherent to the simplified and idealized modeling strategy were fully identified. Conclusions: The method proposed by this tentative proof-of-principle study was able to deliver acceptable plasma exposure curves and shed light on the future refinements.

Associations between anxiety, depression with migraine, and migraine-related burdens.

Background: Anxiety and depression are the most common psychiatric comorbidities in migraine, but their impact on the risk of developing migraine and their gender and age differences are unclear, and research on their associations with migraine-related burdens are limited. Objective: To systematically explore the association between anxiety and depression with migraine and migraine-related burdens, including the risk of developing migraine, as well as migraine frequency, severity, disability, headache impact, quality of life and sleep quality. Methods: A total of 170 migraineurs and 85 sex-and age-matched healthy control subjects were recruited consecutively for this study. Anxiety and depression were assessed using Zung's Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS), respectively. Logistic regression and linear regression analyses were used to explore the associations between anxiety and depression with migraine and its burdens. The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of SAS score and SDS score on migraine and its severe burdens. Results: After adjusting for confounders, anxiety and depression remained significantly associated with an increased risk of developing migraine, with odds ratios of 5.186 (95% CI:1.755-15.322) and 3.147 (95% CI:1.387-7.141), respectively. Meanwhile, there were significant additive interactions between the association of anxiety and depression with the risk of developing migraine in gender and age (P for interaction <0.05), and the stronger correlations were found in participants with an age ≤ 36 years old and females. In addition, anxiety and depression were significantly independently associated with the migraine frequency, severity, disability, headache impact, quality of life, and sleep quality in migraine patients (P trend <0.05). The area under the ROC curve (AUC) of SAS score in predicting developing migraine was significantly higher than that of SDS score [0.749 (95% CI: 0.691-0.801) vs. 0.633 (95% CI: 0.571-0.692), p < 0.0001]. Conclusion: Anxiety and depression were significantly independently associated with the increased risk of migraine and migraine-related burdens. Enhanced assessment of SAS score and SDS score is of great clinical value for the early prevention and treatment of migraine and its burdens.

Age and sex differentially shape brain networks in Parkinson's disease.

AIMS: Age and sex are important individual factors modifying the clinical symptoms of patients with Parkinson's disease (PD). Our goal is to evaluate the effects of age and sex on brain networks and clinical manifestations of PD patients. METHODS: Parkinson's disease participants (n = 198) receiving functional magnetic resonance imaging from Parkinson's Progression Markers Initiative database were investigated. Participants were classified into lower quartile group (age rank: 0%~25%), interquartile group (age rank: 26%~75%), and upper quartile group (age rank: 76%~100%) according to their age quartiles to examine how age shapes brain network topology. The differences of brain network topological properties between male and female participants were also investigated. RESULTS: Parkinson's disease patients in the upper quartile age group exhibited disrupted network topology of white matter networks and impaired integrity of white matter fibers compared to lower quartile age group. In contrast, sex preferentially shaped the small-world topology of gray matter covariance network. Differential network metrics mediated the effects of age and sex on cognitive function of PD patients. CONCLUSION: Age and sex have diverse effects on brain structural networks and cognitive function of PD patients, highlighting their roles in the clinical management of PD.

Direct chemical induction of hepatocyte-like cells with capacity for liver repopulation.

BACKGROUND AND AIMS: Cell fate can be directly reprogrammed from accessible cell types (e.g., fibroblasts) into functional cell types by exposure to small molecule stimuli. However, no chemical reprogramming method has been reported to date that successfully generates functional hepatocyte-like cells that can repopulate liver tissue, casting doubt over the feasibility of chemical reprogramming approaches to obtain desirable cell types for therapeutic applications. APPROACH AND RESULTS: Here, through chemical induction of phenotypic plasticity, we provide a proof-of-concept demonstration of the direct chemical reprogramming of mouse fibroblasts into functional hepatocyte-like cells using exposure to small molecule cocktails in culture medium to successively stimulate endogenous expression of master transcription factors associated with hepatocyte development, such as hepatocyte nuclear factor 4a, nuclear receptor subfamily 1, group I, member 2, and nuclear receptor subfamily 1, group H, member 4. RNA sequencing analysis, metabolic assays, and in vivo physiological experiments show that chemically induced hepatocytes (CiHeps) exhibit comparable activity and function to primary hepatocytes, especially in liver repopulation to rescue liver failure in fumarylacetoacetate hydrolase -/- recombination activating gene 2 -/- interleukin 2 receptor, gamma chain -/- mice in vivo . Single-cell RNA-seq further revealed that gastrointestinal-like and keratinocyte-like cells were induced along with CiHeps, resembling the activation of an intestinal program within hepatic reprogramming as described in transgenic approaches. CONCLUSIONS: Our findings show that direct chemical reprogramming can generate hepatocyte-like cells with high-quality physiological properties, providing a paradigm for establishing hepatocyte identity in fibroblasts and demonstrating the potential for chemical reprogramming in organ/tissue repair and regeneration therapies.

Baseline free water within the visual processing system predicts future psychosis in Parkinson disease.

BACKGROUND AND PURPOSE: As psychosis is associated with decreased quality of life, increased institutionalization, and mortality in Parkinson disease (PD), it is essential to identify individuals at risk for future psychosis. This longitudinal study aimed to investigate whether diffusion tensor imaging (DTI) metrics of white matter hold independent utility for predicting future psychosis in PD, and whether they could be combined with clinical predictors to improve the prognostication of PD psychosis. METHODS: This study included 123 newly diagnosed PD patients collected in the Parkinson's Progression Markers Initiative. Tract-based spatial statistics were used to compare baseline DTI metrics between PD patients who developed psychosis and those who did not during follow-up. Binary logistic regression analyses were performed to identify the clinical and white matter markers predictive of psychosis. RESULTS: Among DTI measures, both higher baseline whole brain (odds ratio [OR] = 1.711, p = 0.016) free water (FW) and visual processing system (OR = 1.680, p < 0.001) FW were associated with an increased risk of future psychosis. Baseline FW remained a significant indicator of future psychosis in PD after controlling for clinical predictors. Moreover, the accuracy of prediction of psychosis using clinical predictors alone (area under the curve [AUC] = 0.742, 95% confidence interval [CI] = 0.655-0.816) was significantly improved by the addition of the visual processing system FW (AUC = 0.856, 95% CI = 0.781-0.912; Delong method, p = 0.022). CONCLUSIONS: Baseline FW of the visual processing system incurs an independent risk of future psychosis in PD, thus providing an opportunity for multiple-modality marker models to include a white matter marker.

Translational pharmacokinetics of a novel bispecific antibody against Ebola virus (MBS77E) from animal to human by PBPK modeling & simulation.

The goal of this study was to construct a PBPK model to accelerate the translation of MBS77E, a humanized bispecific antibody against the Ebola virus. In-depth nonclinical pharmacokinetic studies in rats, monkeys, wild-type mice and transgenic mice were conducted. The pH-dependent affinities (KD) of MBS77E to recombinant FcRn of different species were determined by surface plasmon resonance analysis. A mechanistic whole-body PBPK model of MBS77E was developed and validated in the assessment of PK profiles and tissue distributions in preclinical models. This PBPK model was finally used to predict human PK behaviors of MBS77E. Simulations from the PBPK model with measured and fitted parameters were able to yield good predictions of the serum and tissue pharmacokinetic parameters of MBS77E within 2-fold errors. The predicted serum concentration in humans was able to maintain a sufficiently high level for more than 14 days after 50 mg/kg i.v. administrating. This achievement unlocks that PBPK modeling is a powerful tool to gain insights into the properties of antibody drugs. It guided experimental efforts to obtain necessary information before entry into humans.

Blood cells and hematological parameters of the mountain dragon, Diploderma micangshanensis (Squamata: Lacertilia: Agamidae).

Hematological characteristics reflect the health status of animals and their physiological adaptation to the environment. However, few studies focused on the species of Diploderma. In this study, the blood cells and the hematological parameters of Diploderma micangshanensis, a species endemic to China, were examined based on 48 healthy adult (32 males and 16 females). The blood cells and hematological parameters of D. micangshanensis were similar to those of other lizard species. Although the values of erythrocyte morphometric characters and hematological parameters varied between males and females, the differences were only significant in the case of the hematocrit and erythrocyte size, which may allow for higher oxygen availability in males. Hemoglobin, mean corpuscular hemoglobin concentration, and mean corpuscle volume were strongly affected by the snout-vent length and/or body mass, which reflect the physiological adaptation to the oxygen requirement of different individuals. This is the first report of hematological data from a species of Diploderma, and the results will provide data for research on the adaptive evolution and health assessment in this species and other congeners.

Increased free water in the substantia nigra in idiopathic REM sleep behaviour disorder.

Imaging markers sensitive to neurodegeneration in the substantia nigra are critically needed for future disease-modifying trials. Previous studies have demonstrated the utility of posterior substantia nigra free water as a marker of progression in Parkinson's disease. In this study, we tested the hypothesis that free water is elevated in the posterior substantia nigra of idiopathic REM sleep behaviour disorder, which is considered a prodromal stage of synucleinopathy. We applied free-water imaging to 32 healthy control subjects, 34 patients with idiopathic REM sleep behaviour disorder and 38 patients with Parkinson's disease. Eighteen healthy control subjects and 22 patients with idiopathic REM sleep behaviour disorder were followed up and completed longitudinal free-water imaging. Free-water values in the substantia nigra were calculated for each individual and compared among groups. We tested the associations between posterior substantia nigra free water and uptake of striatal dopamine transporter in idiopathic REM sleep behaviour disorder. Free-water values in the posterior substantia nigra were significantly higher in the patients with idiopathic REM sleep behaviour disorder patients than in the healthy control subjects, but were significantly lower in patients with idiopathic REM sleep behaviour disorder than in patients with Parkinson's disease. In addition, we observed significantly negative associations between posterior substantia nigra free-water values and dopamine transporter striatal binding ratios in the idiopathic REM sleep behaviour disorder patients. Longitudinal free-water imaging analyses were conducted with a linear mixed-effects model, and showed a significant Group × Time interaction in posterior substantia nigra, identifying increased mean free-water values in posterior substantia nigra of idiopathic REM sleep behaviour disorder over time. These results demonstrate that free water in the posterior substantia nigra is a valid imaging marker of neurodegeneration in idiopathic REM sleep behaviour disorder, which has the potential to be used as an indicator in disease-modifying trials.

Altered structure and functional connectivity of the central autonomic network in idiopathic rapid eye movement sleep behaviour disorder.

Evidence suggests peripheral autonomic structures may contribute to autonomic dysfunction in idiopathic rapid eye movement sleep behaviour disorder (iRBD). However, whether the central autonomic network (CAN) is affected in iRBD remains unclear. Magnetic resonance imaging data were acquired from 65 participants (32 patients with iRBD and 33 matched healthy controls). We investigated the CAN in patients with iRBD using a combined voxel-based morphometry and resting-state functional connectivity analysis and characterised the relationships between alterations of the CAN and autonomic symptoms. Patients with iRBD had significantly reduced grey matter volume in the brainstem, anterior cingulate and insula compared with healthy controls. Functional connectivity analysis revealed reduced functional connectivity between the brainstem and the cerebellum posterior lobe, temporal lobe and anterior cingulate in patients with iRBD. In patients with iRBD, both reduced grey matter volume and decreased functional connectivity of the CAN were negatively correlated with the Scales for Outcomes in Parkinson's Disease-Autonomic scores. The present study demonstrated that both the structure and the functional connectivity of the CAN were abnormal in patients with iRBD. In addition, correlation analysis suggested that CAN abnormalities may also play a role in the development of autonomic symptoms in iRBD.

Abnormal intrinsic brain activity of the putamen is correlated with dopamine deficiency in idiopathic rapid eye movement sleep behavior disorder.

OBJECTIVES: To investigate the changes in spontaneous neuronal activity of the striatum in idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) patients using regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) analysis. Furthermore, we tested the association between abnormal spontaneous brain activity and dopamine deficit in patients with iRBD. METHODS: Fifteen iRBD patients and 15 matched healthy controls received resting state magnetic resonance imaging (MRI) and neuropsychological assessments. ReHo and ALFF in subregions of the striatum were calculated and compared between groups in a voxel-by-voxel manner. In addition, 15 iRBD patients and seven healthy controls underwent dopamine transporter single photon computed emission tomography (DAT-SPECT) imaging. Correlation analysis was also performed to investigate whether the altered spontaneous brain activity could be correlated with dopamine deficiency in iRBD patients. RESULTS: We found that iRBD patients, compared with healthy controls, exhibited significantly reduced ReHo in the bilateral putamen. Patients also had significantly decreased tracer uptake in the bilateral putamen and left caudate. In addition, a significantly positive correlation was observed between the mean ReHo value and the tracer uptake ratio in the left putamen of iRBD patients. CONCLUSIONS: We detected abnormal spontaneous brain activity of the bilateral putamen in iRBD patients. These findings could be complementary to the Braak staging model and could help to clarify the pathophysiology of iRBD.

Dynamic functional connectivity impairments in idiopathic rapid eye movement sleep behavior disorder.

INTRODUCTION: Previous functional magnetic resonance imaging (fMRI) studies typically analyzed static functional connectivity (sFC) to reveal the pathophysiology of iRBD and overlooked the dynamic nature of brain activity. Thus, we aimed to explore whether iRBD showed abnormalities of brain network dynamics using the dynamic functional connectivity (dFC) approach. METHODS: Resting-state fMRI data from 33 iRBD patients and 38 matched healthy controls were analyzed using an independent component analysis, sliding window correlation and k-means clustering. Relationships between clinical symptoms and abnormal dFC were evaluated using Spearman's correlation analysis. RESULTS: Four distinct connectivity states were identified to characterize and compare dFC patterns. We demonstrated that iRBD had fewer occurrences and a shorter dwell time in the infrequent and strongly connected State 1, but with more occurrences and a longer dwell time in the frequent and sparsely connected State 2. In addition, iRBD patients showed significantly decreased FC in certain dFC states compared to healthy controls. More importantly, the impairments in the temporal properties of State 2 were found to be associated RBDSQ scores in the patient group. CONCLUSIONS: This study detected dFC impairments in iRBD patients and provided new insights into the pathophysiology of iRBD, which might contribute to the development of disease-modifying drugs in future clinical trials.

SNPs in SNCA, MCCC1, DLG2, GBF1 and MBNL2 are associated with Parkinson's disease in southern Chinese population.

Numerous single nucleotide polymorphisms (SNPs), which have been identified as susceptibility factors for Parkinson's disease (PD) as per genome-wide association studies, have not been fully characterized for PD patients in China. This study aimed to replicate the relationship between 12 novel SNPs of 12 genes and PD risk in southern Chinese population. Twelve SNPs of 12 genes were detected in 231 PD patients and 249 controls, using the SNaPshot technique. Meta-analysis was used to assess heterogeneity of effect sizes between this study and published data. The impact of SNPs on gene expression was investigated by analysing the SNP-gene association in the expression quantitative trait loci (eQTL) data sets. rs8180209 of SNCA (allele model: P = .047, OR = 0.77; additive model: P = .047, OR = 0.77), rs2270968 of MCCC1 (dominant model: P = .024, OR = 1.52), rs7479949 of DLG2 (recessive model; P = .019, OR = 1.52), rs10748818 of GBF1 (additive model: P < .001, OR = 0.37), and rs4771268 of MBNL2 (recessive model: P = .003, OR = 0.48) were replicated to be significantly associated with the increased risk of PD. Noteworthy, a meta-analysis of previous studies suggested rs8180209, rs2270968, rs7479949 and rs4771268 were in line with those of our cohort. Our study replicated five novel functional SNPs in SNCA, MCCC1, DLG2, GBF1 and MBNL2 could be associated with increased risk of PD in southern Chinese population.

SNCA Hypomethylation in Rapid Eye Movement Sleep Behavior Disorder Is a Potential Biomarker for Parkinson's Disease.

BACKGROUND: α-Synuclein has been related to the pathogenesis of Parkinson's disease (PD), but it has not thoroughly been investigated in idiopathic rapid eye movement sleep behavior disorder (iRBD). OBJECTIVE: We aimed to explore whether there were different distributions of α-synuclein at a genetic and/or protein level in patients with iRBD. METHODS: We included 30 patients with iRBD, 30 patients with PD, and 30 age- and sex-matched healthy controls (HCs) in this study. The SNCA methylation and mRNA levels were determined using bisulfite sequencing and quantitative reverse transcription polymerase chain reaction. The plasma levels of exosome α-synuclein were measured using Meso Scale Discovery. RESULTS: SNCA methylation showed different distribution among HC, iRBD and PD groups (HC vs RBD: p = 0.011; HC vs PD: p < 0.001; RBD vs PD: p = 0.027). However, plasma exosomal α-synuclein levels were only elevated in patients with PD compared to those in HCs (p = 0.027), and were associated with the SNCA methylation only in the PD group (p = 0.030, r = -0.397). CONCLUSION: SNCA hypomethylation in leukocytes existed both in patients with iRBD and those with PD, indicating that SNCA methylation could be a potential biomarker for early PD diagnosis.

Autonomic dysfunction in Parkinson's disease: Implications for pathophysiology, diagnosis, and treatment.

Parkinson's disease (PD) is a neurodegenerative disease with a 200 year-long research history. Our understanding about its clinical phenotype and pathogenesis remains limited, although dopaminergic replacement therapy has significantly improved patient outcomes. Autonomic dysfunction is an essential category of non-motor phenotypes that has recently become a cutting edge field that directs frontier research in PD. In this review, we initially describe the epidemiology of dysautonomic symptoms in PD. Then, we perform a meticulous analysis of the pathophysiology of autonomic dysfunction in PD and propose that the peripheral autonomic nervous system may be a key route for α-synuclein pathology propagation from the periphery to the central nervous system. In addition, we recommend that constipation, orthostatic hypotension, urinary dysfunction, erectile dysfunction, and pure autonomic failure should be viewed as prodromal dysautonomic markers in PD prediction and diagnosis. Finally, we summarize the strategies currently available for the treatment of autonomic dysfunction in PD and suggest that high-quality, better-designed, randomized clinical trials should be conducted in the future.

Reaction Mechanism of Etherification of Rice Straw with Epichlorohydrin in Alkaline Medium.

Wood plastic composites (WPCs) made from plant fibres and plastics have gained more and more attention. Studies have been focused on preparation and mechanical performance of WPCs. While mechanism of chemical modification of cereal straw has rarely been reported. In the present work, rice straw was etherified with epichlorohydrin (EPI) and the mechanism of etherification was investigated. Natural rice straw (NRS) was pretreated with NaOH to move most of hemicellulose and lignin. The alkali treated rice straw (ARS), whose dominant component being cellulose, was etherified with EPI at 120 °C for 1-8 h in toluene with NaOH as catalyst. NRS, ARS and etherified rice straw (ERS) were characterized and analyzed by FT-IR, solid CP/MAS 13C-NMR, elemental analysis and neutral sugar analysis. The etherification reaction was finished within 5 h, and C3H6O units were introduced into the structure of cellulose, leading to the increase of contents of C and H in ERS. The etherification process of ARS in alkaline medium was divided into three stages, during which two hydroxyl groups were replaced by two ether bonds successively, and a new hydroxyl group was formed in the last step. The number of hydroxyl groups in ERS was reduced, and reduction of hydrophilicity of ERS could be expected.