Idiopathic Rapid Eye Movement Sleep Behavior Disorder (iRBD) Shares Similar Fecal Short-Chain Fatty Acid Alterations with Multiple System Atrophy (MSA) and Parkinson's Disease (PD).

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is considered as a prodromal stage of synucleinopathies. Fecal short-chain fatty acid (SCFA) changes in iRBD and the relationships with synucleinopathies have never been investigated. OBJECTIVES: To investigate fecal SCFA changes among iRBD, multiple system atrophy (MSA), and Parkinson's disease (PD), and evaluate their relationships. METHODS: Fecal SCFAs and gut microbiota were measured in 29 iRBD, 42 MSA, 40 PD, and 35 normal controls (NC) using gas chromatography-mass spectrometry and 16S rRNA gene sequencing. RESULTS: Compared with NC, fecal SCFA levels (propionic, acetic, and butyric acid) were lower in iRBD, MSA, and PD. Combinations of these SCFAs could differentiate NC from iRBD (AUC 0.809), MSA (AUC 0.794), and PD (AUC 0.701). Decreased fecal SCFAs were associated with the common reducing SCFA-producing gut microbiota in iRBD, MSA, and PD. CONCLUSIONS: iRBD shares similar fecal SCFA alterations with MSA and PD, and the combination of these SCFAs might be a potential synucleinopathies-related biomarker. © 2024 International Parkinson and Movement Disorder Society.

Identified S100A9 as a target for diagnosis and treatment of ulcerative colitis by bioinformatics analysis.

Ulcerative colitis (UC) is a chronic, recurrent inflammatory bowel disease. UC confronts with severe challenges including the unclear pathogenesis and lack of specific diagnostic markers, demanding for identifying predictive biomarkers for UC diagnosis and treatment. We perform immune infiltration and weighted gene co-expression network analysis on gene expression profiles of active UC, inactive UC, and normal controls to identify UC related immune cell and hub genes. Neutrophils, M1 macrophages, activated dendritic cells, and activated mast cells are significantly enriched in active UC. MMP-9, CHI3L1, CXCL9, CXCL10, CXCR2 and S100A9 are identified as hub genes in active UC. Specifically, S100A9 is significantly overexpressed in mice with colitis. The receiver operating characteristic curve demonstrates the excellent performance of S100A9 expression in diagnosing active UC. Inhibition of S100A9 expression reduces DSS-induced colonic inflammation. These identified biomarkers associated with activity in UC patients enlighten the new insights of UC diagnosis and treatment.

Salicylaldehyde-Cobalt(II)-Catalyzed C-H Alkoxylation of Indoles with Secondary Alcohols.

A straight and efficient protocol for the synthesis of hindered indole-ethers via C-H alkoxylation of indoles was developed by a cobalt-catalyzed cross-dehydrogenative coupling reaction with secondary alcohols. The selection of the salicylaldehyde-Co(II) catalyst enables the reaction to proceed under conditions without acid or base addition in the presence of limited alcohols. The protocol has broad substrate scope for both indole and secondary alcohols and exhibits good functional tolerance. The synthetic applications are proven by gram-scale reaction and further diversification of the product. Preliminary mechanistic investigations indicate that the activation of C-H bonds is not the rate-determining step of the reaction.

Life and disease status of patients with Parkinson's disease during and after zero-COVID in China: an online survey.

BACKGROUND: Little is known about the impact of the COVID-19 pandemic on patients with Parkinson's disease (PD) at different stages of the pandemic. This study aims to assess the lives and disease status of PD patients during the zero-COVID policy period and after ending the zero-COVID policy. METHODS: This multicenter cross-sectional study included two online surveys among PD patients in China, from May 30 to June 30 in 2022 and from January 1 to February 28 in 2023, respectively. The survey questionnaires contained four sections: (1) status of COVID-19 infection; (2) impact on motor and non-motor symptoms; (3) impact on daily and social lives; and (4) impact on PD disease management. RESULTS: A total of 1764 PD patients participated in the first online survey, with 200 patients having lockdown experience and 3 being COVID-19-positive (0.17%). In addition, 537 patients participated in the second online survey, with 467 patients having COVID-19 infection (86.96%). (1) During zero-COVID, all of the COVID-19-positive patients had mild symptoms of COVID-19 and no death was reported. After zero-COVID, 83.51% of the COVID-19-positive patients had mild symptoms. The overall death rate and inpatient mortality rate of COVID-19-positive PD patients were 3.21% and 30.00%, respectively. (2) During zero-COVID, 49.43% of PD patients reported worsening of PD-related symptoms (lockdown vs. unlockdown, 60.50% vs. 48.02%, P = 0.0009). After zero-COVID, 54.93% of PD patients reported worsening of PD-related symptoms (COVID-19 positive vs. COVID-19 negative, 59.31% vs. 25.71%, P < 0.0001). (3) During zero-COVID, 62.36% of patients felt worried, and 'limited outdoor activities' (55.39%) was the top reason for mental health problems. After zero-COVID, 59.03% of patients felt worried, with 'poor health' (58.10%) being the top reason. The PD patients tended to change their daily activities from offline to online, and their economic and caregiver burdens increased both during and after zero-COVID. (4) Most PD patients would like to choose online rehabilitation during (69.56%) and after zero-COVID (69.27%). The demand for online medication purchasing also increased during (47.00%) and after zero-COVID (26.63%). CONCLUSIONS: The COVID-19 pandemic aggravated the motor and non-motor symptoms of PD patients either during or after the zero-COVID policy period. The PD patients also experienced prominent mental health problems, changes in daily activities, and increases in economic and caregiver burdens. The COVID-19 pandemic has changed ways of PD management with increasing demands for online medication purchasing and rehabilitation.

Tai Chi improves non-motor symptoms of Parkinson's disease: One-year randomized controlled study with the investigation of mechanisms.

BACKGROUND: Tai Chi was found to improve motor symptoms in Parkinson's disease (PD). Whether long-term Tai Chi training could improve non-motor symptoms (NMS) and the related mechanisms were unknown. OBJECTIVE: To investigate Tai Chi's impact on non-motor symptoms in PD and related mechanisms. METHODS: 95 early-stage PD patients were recruited and randomly divided into Tai Chi (N = 32), brisk walking (N = 31), and no-exercise groups (N = 32). All subjects were evaluated at baseline, 6 months, and 12 months within one-year intervention. Non-motor symptoms (including cognition, sleep, autonomic symptoms, anxiety/depression, and quality of life) were investigated by rating scales. fMRI, plasma cytokines and metabolomics, and blood Huntingtin interaction protein 2 (HIP2) mRNA levels were detected to observe changes in brain networks and plasma biomarkers. RESULTS: Sixty-six patients completed the study. Non-motor functions assessed by rating scales, e.g. PD cognitive rating scale (PDCRS) and Epworth Sleepiness scale (ESS), were significantly improved in the Tai Chi group than the control group. Besides, Tai Chi had advantages in improving NMS-Quest and ESS than brisk walking. Improved brain function was seen in the somatomotor network, correlating with improved PDCRS (p = 0.003, respectively). Downregulation of eotaxin and upregulation of BDNF demonstrated a positive correlation with improvement of PDCRS and PDCRS-frontal lobe scores (p ≤ 0.037). Improvement of energy and immune-related metabolomics (p ≤ 0.043), and elevation of HIP2 mRNA levels (p = 0.003) were also found associated with the improvement of PDCRS. CONCLUSIONS: Tai Chi improved non-motor symptoms in PD, especially in cognition and sleep. Enhanced brain network function, downregulation of inflammation, and enhanced energy metabolism were observed after Tai Chi training.

Effect of long-term Tai Chi training on Parkinson's disease: a 3.5-year follow-up cohort study.

BACKGROUND: Tai Chi has shown beneficial effects on the motor and non-motor symptoms of Parkinson's disease (PD), but no study has reported the effect of long-term Tai Chi training. OBJECTIVE: To examine whether long-term Tai Chi training can maintain improvement in patients with PD. METHODS: Cohorts of patients with PD with Tai Chi training (n=143) and patients with PD without exercise as a control group (n=187) were built from January 2016. All subjects were assessed at baseline and in November 2019, October 2020 and June 2021. A logarithmic linear model was used to analyse rating scales for motor and non-motor symptoms. The need to increase antiparkinsonian therapies was presented as a Kaplan-Meier plot and as a box plot. The bootstrap method was used to resample for statistical estimation. RESULTS: Tai Chi training reduced the annual changes in the deterioration of the Unified Parkinson's Disease Rating Scale and delayed the need for increasing antiparkinsonian therapies. The annual increase in the levodopa equivalent daily dosage was significantly lower in the Tai Chi group. Moreover, patients benefited from Tai Chi training in motor symptoms, non-motor symptoms and complications. CONCLUSION: Tai Chi training has a long-term beneficial effect on PD, with an improvement in motor and non-motor symptoms and reduced complications. TRIAL REGISTRATION NUMBER: NCT05447975.

The causality between gut microbiome and liver cirrhosis: a bi-directional two-sample Mendelian randomization analysis.

Background and aim: Previous studies have reported an association between gut microbiota and cirrhosis. However, the causality between intestinal flora and liver cirrhosis still remains unclear. In this study, bi-directional Mendelian randomization (MR) analysis was used to ascertain the potential causal effect between gut microbes and cirrhosis. Methods: Large-scale Genome Wide Association Study (GWAS) data of cirrhosis and gut microbes were obtained from FinnGen, Mibiogen consortium, and a GWAS meta-analysis of Alcoholic cirrhosis (ALC). Two-sample MR was performed to determine the causal relationship between gut microbiota and cirrhosis. Furthermore, a bi-directional MR analysis was employed to examine the direction of the causal relations. Result: In MR analysis, we found that 21 gut microbiotas were potentially associated with cirrhosis. In reverse MR analysis, 11 gut microbiotas displayed potentially associations between genetic liability in the gut microbiome and cirrhosis. We found that the family Lachnospiraceae (OR: 1.59, 95% CI:1.10-2.29) might be harmful in cirrhotic conditions (ICD-10: K74). Furthermore, the genus Erysipelatoclostridium might be a protective factor for cirrhosis (OR:0.55, 95% CI:0.34-0.88) and PBC (OR:0.68, 95% CI:0.52-0.89). Combining the results from the MR analysis and reverse MR analysis, we firstly identified the Genus Butyricicoccus had a bi-directional causal effect on PBC (Forward: OR: 0.37, 95% CI:0.15-0.93; Reverse: OR: 1.03, 95% CI:1.00-1.05). Conclusion: We found a new potential causal effect between cirrhosis and intestinal flora and provided new insights into the role of gut microbiota in the pathological progression of liver cirrhosis.

Correlation of balance posturographic parameters during quiet standing with the berg balance scale in patients with parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is often clinically associated with posture instability and more easily falling. The Berg balance scale is a clinical indicator commonly used to subjectively evaluate a patient's balance ability. Meanwhile, computerized force platforms have been used in research on postural control. The various parameters obtained from posturography are interpreted to assess balance ability. The present study aims to explore the correlations between posturographic variables and the BBS, and furthermore to efficiently evaluate postural instability and fall risk of early and moderate PD patients. METHODS: A total of 46 PD patients were involved in the experiment. Patients were asked to perform BBS tests and force platform tests under eye open (EO) and eye closed (EC) conditions. The recorded COP signal was analyzed with the time domain statistical method, the frequency domain method of Power Spectral Density (PSD), and structural methods of Stabilogram Diffusion Analysis (SDA), Sway Density Plot (SDP) to retrieve different posturographic variables. The correlation between posturographic variables under EO and EC conditions with BBS was compared statistically. The significantly correlated posturographic parameters were then applied to analyze posturographic differences between different groups: faller vs. non-faller (patients with/without a history of falls in the past 12 months). RESULTS: Among the different posturographic parameters, the prediction ellipse area, the slope of the regression line at a high-frequency band of PSD in the medial-lateral (ML) direction, the crossover point of the regression lines of SDA in the anterior-posterior (AP) direction, and the distance between successive peaks of SDP had significant correlations with BBS. These selected BBS-related parameters also showed significant differences between faller and non-faller. The selected posturographic parameters can be used as effective indicators to evaluate the balance ability of Parkinson's disease patients.

Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets.

Microglia activation is observed in various neurodegenerative diseases. Recent advances in single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified microglia in specific states correlate with pathological hallmarks and are associated with specific functions. Microglia both exert protective function by phagocytosing and clearing pathological protein aggregates and play detrimental roles due to excessive uptake of protein aggregates, which would lead to microglial phagocytic ability impairment, neuroinflammation, and eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes microglia into a pro-inflammatory phenotype and accelerates disease progression. Microglia also act as a mobile vehicle to propagate protein aggregates. Extracellular vesicles released from microglia and autophagy impairment in microglia all contribute to pathological progression and neurodegeneration. Thus, enhancing microglial phagocytosis, reducing microglial-mediated neuroinflammation, inhibiting microglial exosome synthesis and secretion, and promoting microglial conversion into a protective phenotype are considered to be promising strategies for the therapy of neurodegenerative diseases. Here we comprehensively review the biology of microglia and the roles of microglia in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies and Huntington's disease. We also summarize the possible microglia-targeted interventions and treatments against neurodegenerative diseases with preclinical and clinical evidence in cell experiments, animal studies, and clinical trials.

Ketogenic diet alleviates cognitive dysfunction and neuroinflammation in APP/PS1 mice via the Nrf2/HO-1 and NF-κB signaling pathways.

Alzheimer's disease is a progressive neurological disorder characterized by cognitive decline and chronic inflammation within the brain. The ketogenic diet, a widely recognized therapeutic intervention for refractory epilepsy, has recently been proposed as a potential treatment for a variety of neurological diseases, including Alzheimer's disease. However, the efficacy of ketogenic diet in treating Alzheimer's disease and the underlying mechanism remains unclear. The current investigation aimed to explore the effect of ketogenic diet on cognitive function and the underlying biological mechanisms in a mouse model of Alzheimer's disease. Male amyloid precursor protein/presenilin 1 (APP/PS1) mice were randomly assigned to either a ketogenic diet or control diet group, and received their respective diets for a duration of 3 months. The findings show that ketogenic diet administration enhanced cognitive function, attenuated amyloid plaque formation and proinflammatory cytokine levels in APP/PS1 mice, and augmented the nuclear factor-erythroid 2-p45 derived factor 2/heme oxygenase-1 signaling pathway while suppressing the nuclear factor-kappa B pathway. Collectively, these data suggest that ketogenic diet may have a therapeutic potential in treating Alzheimer's disease by ameliorating the neurotoxicity associated with Aß-induced inflammation. This study highlights the urgent need for further research into the use of ketogenic diet as a potential therapy for Alzheimer's disease.

Association of fecal short-chain fatty acids with clinical severity and gut microbiota in essential tremor and its difference from Parkinson's disease.

Diagnosis of essential tremor (ET) at an early stage can be difficult, especially when distinguishing it from healthy controls (HCs) and Parkinson's disease (PD). Recently, stool sample analysis of gut microbiota and its metabolites provides new ways to detect novel biomarkers for neurodegenerative diseases. Short-chain fatty acids (SCFAs), as the main metabolites of gut microbiota, were reduced in the feces of PD. However, fecal SCFAs in ET have never been investigated. We aimed to investigate the fecal SCFA levels in ET, assess their relationships with clinical symptoms and gut microbiota, and identify their potential diagnostic abilities. Fecal SCFAs and gut microbiota in 37 ET, 37 de novo PD and 35 HC were measured. Constipation, autonomic dysfunction and tremor severity were evaluated by scales. ET had lower fecal propionic, butyric and isobutyric acid levels than HC. Combined propionic, butyric and isobutyric acid distinguished ET from HC with an AUC of 0.751 (95% CI: 0.634-0.867). ET had lower fecal isovaleric and isobutyric acid levels than PD. Isovaleric and isobutyric acid differentiated ET from PD with an AUC of 0.743 (95% CI: 0.629-0.857). Fecal propionic acid was negatively correlated with constipation and autonomic dysfunction. Isobutyric and isovaleric acid were negatively associated with tremor severity. Lowered fecal SCFAs were related to a decreased abundance of Faecalibacterium and Catenibacterium in ET. In conclusion, fecal SCFAs were decreased in ET and correlated with clinical severity and gut microbiota changes. Fecal propionic, butyric, isobutyric and isovaleric acid might be potential diagnostic and differential diagnostic biomarkers for ET.

Predicting the Prognosis of Multiple System Atrophy Using Cluster and Principal Component Analysis.

BACKGROUND: Multiple system atrophy (MSA) is an intractable neurodegenerative disorder with poorly understanding of prognostic factors. OBJECTIVE: The purpose of this retrospective longitudinal study was to explore the main predictors of survival of MSA patients with new clinical subtypes based on cluster analysis. METHODS: A total of 153 Chinese MSA patients were recruited in our study. The basic demographic data and motor and nonmotor symptoms were assessed. Cluster and principal component analysis (PCA) were used to eliminate collinearity and search for new clinical subtypes. The multivariable Cox regression was used to find factors associated with survival in MSA patients. RESULTS: The median survival time from symptom onset to death (estimated using data from all patients by Kaplan-Meier analysis) was 6.3 (95% CI = 6.1-6.7) years. The survival model showed that a shorter survival time was associated with motor principal component (PC)1 (HR = 1.71, 95% CI: 1.26-2.30, p < 0.001) and nonmotor PC3 (HR = 1.68, 95% CI: 1.31-2.10, p < 0.001) through PCA. Four clusters were identified: Cluster 1 (mild), Cluster 2 (mood disorder-dominant), Cluster 3 (axial symptoms and cognitive impairment-dominant), and Cluster 4 (autonomic failure-dominant). Multivariate Cox regression indicated that Cluster 3 (HR = 4.15, 95% CI: 1.73-9.90, p = 0.001) and Cluster 4 (HR = 4.18, 95% CI: 1.73-10.1, p = 0.002) were independently associated with shorter survival time. CONCLUSION: More serious motor symptoms, axial symptoms such as falls and dysphagia, orthostatic hypotension, and cognitive impairment were associated with poor survival in MSA via PCA and cluster analysis.

Smart G-quadruplex hydrogels: From preparations to comprehensive applications.

In recent years, the accelerated development of G-quadruplexes and hydrogels has driven the development of intelligent biomaterials. Based on the excellent biocompatibility and special biological functions of G-quadruplexes, and the hydrophilicity, high-water retention, high water content, flexibility and excellent biodegradability of hydrogels, G-quadruplex hydrogels are widely used in various fields by combining the dual advantages of G-quadruplexes and hydrogels. Here, we provide a systematic and comprehensive classification of G-quadruplex hydrogels in terms of preparation strategies and applications. This paper reveals how G-quadruplex hydrogels skillfully utilize the special biological functions of G-quadruplexes and the skeleton structure of hydrogels, and expounds its applications in the fields of biomedicine, biocatalysis, biosensing and biomaterials. In addition, we deeply analyze the challenges in preparation, applications, stability and safety of G-quadruplex hydrogels, as well as potential future development directions.

Links between COVID-19 and Parkinson's disease/Alzheimer's disease: reciprocal impacts, medical care strategies and underlying mechanisms.

The impact of coronavirus disease 2019 (COVID-19) pandemic on patients with neurodegenerative diseases and the specific neurological manifestations of COVID-19 have aroused great interest. However, there are still many issues of concern to be clarified. Therefore, we review the current literature on the complex relationship between COVID-19 and neurodegenerative diseases with an emphasis on Parkinson's disease (PD) and Alzheimer's disease (AD). We summarize the impact of COVID-19 infection on symptom severity, disease progression, and mortality rate of PD and AD, and discuss whether COVID-19 infection could trigger PD and AD. In addition, the susceptibility to and the prognosis of COVID-19 in PD patients and AD patients are also included. In order to achieve better management of PD and AD patients, modifications of care strategies, specific drug therapies, and vaccines during the pandemic are also listed. At last, mechanisms underlying the link of COVID-19 with PD and AD are reviewed.

The XINDI Study: A Randomized Phase III Clinical Trial Evaluating the Efficacy and Safety of Safinamide as Add-On Therapy to Levodopa in Chinese Patients with Parkinson's Disease with Motor Fluctuations.

BACKGROUND: Levodopa remains the gold standard for the treatment of Parkinson's disease, but its long-term use is associated with motor complications whose management is still a significant challenge. Safinamide is a multimodal drug with proven efficacy as an adjunct to levodopa. OBJECTIVE: The objective of this study was to investigate the efficacy and safety of safinamide as an add-on to levodopa in Chinese patients with Parkinson's disease with motor fluctuations. METHODS: The XINDI study was a phase III, randomized, double-blind, placebo-controlled, multicenter study, with a 2-week screening period and a 16-week treatment period. The starting dose of safinamide (or placebo) was 50 mg once daily, increased to 100 mg once daily at day 15. Patients aged ≥  18 years, with idiopathic Parkinson's disease of >3 years duration, Hoehn and Yahr stage 1-4, and daily OFF time ≥  1.5 h, were eligible. Patients should follow a stable oral levodopa regimen and may receive concomitant treatment with stable doses of other anti-Parkinson drugs, except monoamine oxidase-B inhibitors. Patients with severe disabling peak-dose or biphasic dyskinesia, unpredictable or widely swinging fluctuations, other forms of parkinsonism, a history of dementia or severe cognitive dysfunction, major psychiatric illnesses, and/or clinically significant medical illnesses were excluded. The primary efficacy endpoint was the change from baseline to week 16 in the mean daily OFF time. Secondary efficacy endpoints included the Unified Parkinson's Disease Rating Scale, the Numerical Rating Scale, the Clinical Global Impression scale, and the 39-Item Parkinson's Disease Questionnaire scale. The statistical analysis of the efficacy parameters was conducted using an analysis of co-variance, except for the Clinical Global Impression scale scores that were assessed using the Wilcoxon-Mann-Whitney test. Safety was evaluated through the frequency of adverse events and serious adverse events, physical examination, vital signs, 12-lead electrocardiograms, and laboratory exams. All safety endpoints were summarized using descriptive statistics. RESULTS: The trial enrolled 307 patients. At week 16, the difference in the change of the mean total daily OFF time between safinamide and placebo groups was 1.10 h (p < 0.0001). This change was significantly greater in the safinamide group starting from week 2, suggesting a rapid onset of drug efficacy. ON time, Unified Parkinson's Disease Rating Scale, Clinical Global Impression scale, and the 39-Item Parkinson's Disease Questionnaire showed statistically significant improvements. There were no significant between-group differences for adverse events or serious adverse events. CONCLUSIONS: Safinamide, as add-on therapy to levodopa, significantly reduced motor fluctuations and improved motor symptoms and quality of life of Chinese patients with idiopathic Parkinson's disease. The improvements observed in the Unified Parkinson's Disease Rating Scale total and motor scores were also clinically significant. No safety concerns were identified, confirming the good tolerability profile of the drug. CLINICAL TRIAL REGISTRATION: NCT03881371, registered on 19 March, 2019, https://clinicaltrials.gov/NCT03881371 .