Correlation analysis of peripheral platelet markers and disease phenotypes in Alzheimer's disease.

INTRODUCTION: Platelets serve as the primary peripheral reservoir of amyloid beta (Aß). However, there is limited research on platelet markers in routine blood examinations, particularly with regard to the large platelet ratio (P-LCR) in Alzheimer's disease (AD). METHODS: This study included 512 AD patients and 205 healthy controls (HCs). Platelet markers and apolipoprotein E (APOE) 4 status were assessed in all participants. RESULTS: The study revealed that P-LCR was significantly elevated in AD patients compared to HCs. In AD patients carrying APOE4, P-LCR significantly negatively correlated with Montreal Cognitive Assessment scores. There was an observed increasing trend in the rate of change in P-LCR with disease progression. Binary logistic regression analysis indicated that P-LCR may constitute a risk factor for AD, after adjusting for age, sex, APOE4, and body mass index. DISCUSSION: P-LCR is associated with disease severity in AD patients carrying APOE4. P-LCR may be a promising marker to reflect platelet activity in AD patients. HIGHLIGHTS: P-LCR significantly negatively correlated with MoCA scores in AD patients with APOE4. The rate of change in P-LCR showed an increasing trend with disease progression. P-LCR may be a risk factor for AD.

Cognitive impairment, neuroimaging abnormalities, and their correlations in myotonic dystrophy: a comprehensive review.

Myotonic dystrophy (DM) encompasses a spectrum of neuromuscular diseases characterized by myotonia, muscle weakness, and wasting. Recent research has led to the recognition of DM as a neurological disorder. Cognitive impairment is a central nervous system condition that has been observed in various forms of DM. Neuroimaging studies have increasingly linked DM to alterations in white matter (WM) integrity and highlighted the relationship between cognitive impairment and abnormalities in WM structure. This review aims to summarize investigations into cognitive impairment and brain abnormalities in individuals with DM and to elucidate the correlation between these factors and the potential underlying mechanisms contributing to these abnormalities.

Longitudinal evolution and plasma biomarkers for excessive daytime sleepiness in Parkinson's disease.

BACKGROUND: Excessive daytime sleepiness (EDS) is one of the most frequent non-motor symptoms in Parkinson's disease (PD); however, the pathogenesis of EDS is unclear, and there is a lack of information on plasma biomarkers for EDS in PD. We aimed to investigate the plasma biomarkers of EDS in a large PD cohort. METHODS: A total of 159 PD patients were included in the prospective cohort study and followed up annually for three years. Plasma biomarkers including glial fibrillary acidic protein, amyloid-beta, p-tau181, and neurofilament light chain (NfL), were measured using an ultrasensitive single-molecule array (SimoaTM) technology at each visit. EDS was evaluated using the Epworth Sleepiness Scale (ESS). RESULTS: The frequency of EDS in PD increased from 15.1% at baseline to 25.0% after three years. The mean ESS scores increased from 5.1 [Standard Deviation (SD): 4.8] at baseline to 6.1 [SD: 5.5] at the third year of follow-up. At baseline, compared with patients with PD without EDS, those with EDS were more likely to be male, had poorer cognitive performance, and more severe motor and non-motor symptoms. The adjusted generalized estimating equations models showed that higher plasma NfL levels (OR 1.047 [1.002-1.094], p = 0.042) were associated with EDS during follow-ups. The adjusted linear mixed-effects model showed that higher plasma NfL levels (ß 0.097 [0.012-0.183], p = 0.026) were associated with ESS scores during follow-ups. CONCLUSIONS: Higher plasma NfL levels were associated with EDS in PD, indicating an association between neuro-axonal degeneration and EDS in PD.

Plasma GFAP as a prognostic biomarker of motor subtype in early Parkinson's disease.

Parkinson's disease (PD) is a heterogeneous movement disorder with different motor subtypes including tremor dominant (TD), indeterminate and postural instability, and gait disturbance (PIGD) motor subtypes. Plasma glial fibrillary acidic protein (GFAP) was elevated in PD patients and may be regarded as a biomarker for motor and cognitive progression. Here we explore if there was an association between plasma GFAP and different motor subtypes and whether baseline plasma GFAP level can predict motor subtype conversion. Patients with PD classified as TD, PIGD or indeterminate subtypes underwent neurological evaluation at baseline and 2 years follow-up. Plasma GFAP in PD patients and controls were measured using an ultrasensitive single molecule array. The study enrolled 184 PD patients and 95 control subjects. Plasma GFAP levels were significantly higher in the PIGD group compared to the TD group at 2-year follow-up. Finally, 45% of TD patients at baseline had a subtype shift and 85% of PIGD patients at baseline remained as PIGD subtypes at 2 years follow-up. Baseline plasma GFAP levels were significantly higher in TD patients converted to PIGD than non-converters in the baseline TD group. Higher baseline plasma GFAP levels were significantly associated with the TD motor subtype conversion (OR = 1.283, P = 0.033) and lower baseline plasma GFAP levels in PIGD patients were likely to shift to TD and indeterminate subtype (OR = 0.551, P = 0.021) after adjusting for confounders. Plasma GFAP may serve as a clinical utility biomarker in differentiating motor subtypes and predicting baseline motor subtypes conversion in PD patients.

Ecosystem service valuation and multi-scenario simulation in the Ebinur Lake Basin using a coupled GMOP-PLUS model.

The Ebinur Lake Basin is an ecologically sensitive area in an arid region. Investigating its land use and land cover (LULC) change and assessing and predicting its ecosystem service value (ESV) are of great importance for the stability of the basin's socioeconomic development and sustainable development of its ecological environment. Based on LULC data from 1990, 2000, 2010, and 2020, we assessed the ESV of the Ebinur Lake Basin and coupled the grey multi-objective optimization model with the patch generation land use simulation model to predict ESV changes in 2035 under four scenarios: business-as-usual (BAU) development, rapid economic development (RED), ecological protection (ELP), and ecological-economic balance (EEB). The results show that from 1990 to 2020, the basin was dominated by grassland (51.23%) and unused land (27.6%), with a continuous decrease in unused land and an increase in cultivated land. In thirty years, the total ESV of the study area increased from 18.62 billion to 67.28 billion yuan, with regulation and support services being the dominant functions. By 2035, cultivated land increased while unused land decreased in all four scenarios compared with that in 2020. The total ESV in 2035 under the BAU, RED, ELP, and EEB scenarios was 68.83 billion, 64.47 billion, 67.99 billion, and 66.79 billion yuan, respectively. In the RED and EEB scenarios, ESV decreased by 2.81 billion and 0.49 billion yuan, respectively. In the BAU scenario, provisioning and regulation services increased by 6.05% and 2.93%, respectively. The ELP scenario, focusing on ecological and environmental protection, saw an increase in ESV for all services. This paper can assist policymakers in optimizing land use allocation and provide scientific support for the formulation of land use strategies and sustainable ecological and environmental development in the inland river basins of arid regions.

Recent Advances of Chitosan-Based Hydrogels for Skin-Wound Dressings.

The management of wound healing represents a significant clinical challenge due to the complicated processes involved. Chitosan has remarkable properties that effectively prevent certain microorganisms from entering the body and positively influence both red blood cell aggregation and platelet adhesion and aggregation in the bloodstream, resulting in a favorable hemostatic outcome. In recent years, chitosan-based hydrogels have been widely used as wound dressings due to their biodegradability, biocompatibility, safety, non-toxicity, bioadhesiveness, and soft texture resembling the extracellular matrix. This article first summarizes an overview of the main chemical modifications of chitosan for wound dressings and then reviews the desired properties of chitosan-based hydrogel dressings. The applications of chitosan-based hydrogels in wound healing, including burn wounds, surgical wounds, infected wounds, and diabetic wounds are then discussed. Finally, future prospects for chitosan-based hydrogels as wound dressings are discussed. It is anticipated that this review will form a basis for the development of a range of chitosan-based hydrogel dressings for clinical treatment.

Anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) via regulating the synaptic plasticity in hippocampus.

TSPO, translocator protein (18 kDa) ligands have demonstrated consistent antidepression and anxiolytic effects in several preclinical studies. This study aimed to examine whether YL-IPA08[N-ethyl-N-(2-pyridinylmethyl)-2-(3,4-ichlorophenyl) -7-methylimidazo [1,2-a] pyridine-3-acetamide hydrochloride], a potent and selective TSPO ligand synthesized by our institute, could alleviate anxiety-related behaviors induced by electric shock (ES) and investigate its underlying mechanism. As expected, we showed that chronic treatment with YL-IPA08 significantly reversed anxiety-related behaviors induced by electrical stimulation (0.5 mA, 12 times, duration 1s, interval 10s) exposure. Using the analysis of RNA-sequencing (RNA-seq) technology, it was found that the differential genes associated with the anxiolytic effect of YL-IPA08 were mainly related to synaptic plasticity. Furthermore, YL-IPA08 restored the decreased levels of brain-derived neurotrophic factor (BDNF), synapse-related protein (e.g. synapsin-1 and post-synaptic density95, PSD95), and the number of doublecortin (DCX) + neurons in the hippocampus of post-ES mice. In addition, YL-IPA08 also enhanced the dendritic complexity and dendritic spine density of hippocampal dentate gyrus (DG) granule neurons. Meanwhile, the induction of long-term potentiation (LTP) was significantly enhanced by YL-IPA08. In summary, the findings from the current study showed that YL-IPA08 exerted a clear anxiolytic effect, which might be partially mediated by promoting hippocampal neuroplasticity.

miR-548ag promotes DPP4 expression in hepatocytes through activation of TLR(7/8)/NF-κB pathway.

OBJECTIVE: In our previous study, we identified a notable increase in miR-548ag content after obesity, which contributes to the progression of Type 2 diabetes Mellitus(T2DM) through the up-regulation of Dipeptidyl Peptidase-4(DPP4) expression within the liver. However, the precise molecular mechanisms underlying the upregulation of DPP4 by miR-548ag remain elusive. Mature miRNAs rich in GU sequences can activate the TLR(7/8)/NF-κB signalling pathway, which transcriptionally activates DPP4 expression. Notably, the proportion of GU sequences in hsa-miR-548ag was found to be 47.6%. The study proposes a hypothesis suggesting that miR-548ag could potentially increase DPP4 expression in hepatocytes by activating the TLR(7/8)/NF-κB signalling pathway. METHODS: Male C57BL/6J mice were fed normal chow diet (NCD, n = 16) or high-fat diet (HFD, n = 16) for 12 weeks. For a duration of 6 weeks, NCD mice received intraperitoneal injections of a miR-548ag mimic, while HFD mice and db/db mice (n = 16) were administered intraperitoneal injections of a miR-548ag inhibitor. qRT-PCR and Western Blot were used to detect the expression level of miR-548ag, DPP4 and the activation of TLR(7/8)/NF-κB signalling pathway. HepG2 and L02 cells were transfected with miR-548ag mimic, miR-548ag inhibitor, TLR7/8 interfering fragment, and overexpression of miR-548ag while inhibiting TLR7/8, respectively. RESULTS: (1) We observed elevated levels of miR-548ag in the serum, adipose tissue, and liver of obese mice, accompanied by an upregulation of TLR7/8, pivotal protein in the NF-κB pathway, and DPP4 expression in the liver. (2) miR-548ag promotes DPP4 expression in hepatocytes via the TLR(7/8)/NF-κB signalling pathway, resulting in a reduction in the glucose consumption capacity of hepatocytes. (3) The administration of a miR-548ag inhibitor enhanced glucose tolerance and insulin sensitivity in db/db mice. CONCLUSIONS: MiR-548ag promotes the expression of DPP4 in hepatocytes by activating the TLR(7/8)/NF-κB signalling pathway. MiR-548ag may be a potential target for the treatment of T2DM.

Dynamic simulation of landscape ecological security and analysis of coupling coordination degree: A case study of Bole.

The ecological security of oasis cities in arid and semi-arid regions is highly susceptible to changes in regional landscape patterns and the degree of coordination between human activities and the environment. At the same time, the ecological security of urban landscapes also profoundly affects the success of regional economic and environmental coordination and development. This study is based on land use data from 1990, 2000, 2010, and 2020, as well as land use data from the natural development scenario (NLD), economic development scenario (ECD), ecological development scenario (ELD) and ecological-economic development scenario (EED) simulated by the patch-generating land use simulation (PLUS) model in 2030. From the perspective of production-living-ecological land (PLEL), it analyzes the changes in the past and future landscape ecological security and coupling coordination characteristics of Bole. The results show that from 1990 to 2020, Bole was mainly dominated by grassland ecological land (GEL) and other ecological land (OEL), accounting for a total proportion of 69.51%, with a large increase in production and living land area; the average value of landscape ecological risk is decreasing, and the landscape ecological security of Bole is developing towards benignity; the area of highly coupled coordination zone is decreasing continuously, while that of basic coordination zone and moderate coordination zone is increasing continuously. Under the 2030 EED scenario, the overall changes in various types of land use are not significant, and the average value of landscape ecological risk is the smallest, but it is higher than that in 2020 as a whole; under EED scenario, the area of highly coordinated zone and moderate coordinated zone is the largest among four scenarios, and the best coupling coordination level among the four scenarios. Landscape ecological security and its coupling coordination will be affected by land use patterns. Optimizing regional land use patterns is of great significance for improving urban landscape ecological security and sustainable high-quality development.

Genome-wide DNA methylation analysis related to ALS patient progression and survival.

BACKGROUND: Epigenetics contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS). We aimed to characterize the DNA methylation profiles associated with clinical heterogeneity in disease progression and survival among patients. METHODS: We included a cohort of 41 patients with sporadic ALS, with a median follow-up of 86.9 months, and 27 rigorously matched healthy controls. Blood-based genome-wide DNA methylation analysis was conducted. RESULTS: A total of 948 progression rate-associated differentially methylated positions, 298 progression rate-associated differentially methylated regions (R-DMRs), 590 survival time-associated DMPs, and 197 survival time-associated DMRs (S-DMRs) were identified, using complementary grouping strategies. Enrichment analysis of differentially methylated genes highlighted the involvement of synapses and axons in ALS progression and survival. Clinical analysis revealed a positive correlation between the average methylation levels of the R-DMR in PRDM8 and disease progression rate (r = 0.479, p = 0.002). Conversely, there was an inverse correlation between the average methylation levels of the R-DMR in ANKRD33 and disease progression rate (r = - 0.476, p = 0.002). In addition, patients with higher methylation levels within the S-DMR of ZNF696 experienced longer survival (p = 0.016), while those with elevated methylation levels in the S-DMR of RAI1 had shorter survival (p = 0.006). CONCLUSION: DNA methylation holds promise as a potential biomarker for tracking disease progression and predicting survival outcome and also offers targets for precision medicine.

Peripheral immunity relate to disease progression and prognosis in amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Abnormalities in the peripheral immune system in ALS have been paid attention; however, the results of changes in peripheral immune parameters were inconsistent. Methods: A total of 1109 ALS patients were enrolled in the study. All patients received clinical evaluation and peripheral immune parameters measurement. The outcomes were analyzed by correlation analysis, multiple linear regression and cox survival analysis. Results: We found that ALS patients had significantly higher percentage of CD4+ T cells (39.3 vs. 37.1%, p < 0.001) and CD4+/CD8+ ratio (1.88 vs. 1.72, p = 0.011), significantly lower IgG (11.73 vs.12.82, p < 0.001) and IgA (2130.70 vs. 2284.8, p = 0.013) compared with the health controls. In the multivariate linear model, we found that each increase of 1.262, 0.278, and 4.44E-4 in ALSFRS-R scores were significantly associated with each increment of lymphocyte count, IgG, and IgA, respectively. However, each decrease of 0.341, 0.068, and 0.682 in ALSFRS-R score was associated with each increment in neutrophils, CD4+ T cells, and CD4+/CD8+ ratio, respectively. Cox survival regression analysis showed that the death risk of ALS patients was related to the levels of C3 (HR 0.592, 95% CI 0.361-0.973). Conclusion: We found that there were differences in peripheral immune parameters of ALS patients with the severity of the disease, especially neutrophil, lymphocyte, CD4+ T, and IgG; C3 is an independent predictor of survival in ALS patients. More studies are needed to elucidate the mechanisms associated with altered immune parameters in ALS.

Relationship between plasma NFL and disease progression in Parkinson's disease: a prospective cohort study.

OBJECTIVE: We aimed to examine the longitudinal change of plasma neurofilament light chain (NFL) level and explore its diagnostic and prognostic implications in Parkinson's disease (PD). METHODS: A total of 184 patients with early PD who completed 5-year annually repeated clinical assessments were included. Plasma NFL at baseline, 1 year, and 2 year were examined, which were quantified using the ultrasensitive Simoa technology. At baseline, blood from 86 sex- and age-matched healthy controls (HC) were obtained for comparison. RESULTS: Plasma NFL in PD patients at baseline was significantly higher than those in HC (P = 0.046), and significantly increased after 2 years (P = 0.046). Receiver operating characteristic curve indicated that a plasma NFL cut-off value of 10.79 pg/mL resulted in 39.7% sensitivity and 84.0% specificity, with an area under the curve of 0.635, to distinguish PD from HC (P < 0.001). Linear mixed-effect models indicated that baseline plasma NFL (> 9.24 pg/mL) correlated with a greater increase in the Unified Parkinson's Disease Rating Scale III (estimate = 0.651, P = 0.001) and Hoehn & Yahr stage (estimate = 0.072, P < 0.001), and also correlated with a greater decrease in the Montreal Cognitive Assessment (estimate = - 0.387, P < 0.001) during follow-up visits. CONCLUSIONS: Plasma NFL exhibits a tendency to increase with disease progression, and elevated baseline plasma NFL can serve as a predictor for accelerated motor deterioration and cognitive decline in PD. However, plasma NFL does not have high accuracy to distinguish individuals with early-stage PD from HC.

Gamma oscillations in the mPFC: A potential predictive biomarker of depression and antidepressant effects.

Gamma oscillations have attracted much attention in the field of mood disorders, but their role in depression remains poorly understood. This study aimed to investigate whether gamma oscillations in the medial prefrontal cortex (mPFC) could serve as a predictive biomarker of depression. Chronic restraint stress (CRS) or lipopolysaccharide (LPS) were used to induce depression-like behaviors in mice; local field potentials (LFPs) in the mPFC were recorded by electrophysiological techniques; We found that both CRS and LPS induced significant depression-like behaviors in mice, including increasing immobility durations in the forced swimming test (FST) and tail suspension test (TST) and increasing the latency to feed in the novelty-suppressed feeding test (NSFT). Electrophysiological results suggested that CRS and LPS significantly reduced low and high gamma oscillations in the mPFC. Furthermore, a single injection of ketamine or scopolamine for 24 h significantly increased gamma oscillations and elicited rapid-acting antidepressant-like effects. In addition, fluoxetine treatment for 21 days significantly increased gamma oscillations and elicited antidepressant-like effects. Taken together, our findings suggest that gamma oscillations are strongly associated with depression, yielding new insights into investigating the predictive biomarkers of depression and the time course of antidepressant effects.

Rare variant analysis of UQCRC1 in Chinese patients with early-onset Parkinson's disease.

Mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene has been identified as a causative gene for autosomal dominant Parkinson's disease (PD), with the p.Y314S variant potentially associated with polyneuropathy in PD patients. The objectives of our study were to screen for UQCRC1 variants in Chinese patients with early-onset PD (EOPD) and explore the role of UQCRC1 in EOPD. We investigated the rare variants in 913 EOPD patients in our cohort using whole-exome sequencing, assessing their link to PD at both allele and gene levels. A total of 7 rare variants (minor allele frequency < 0.1%) of UQCRC1 were identified. However, no excessive burden of rare UQCRC1 variants was suggested in the EOPD patients. Further analysis with larger sample size and diverse regions is needed to determine the role of UQCRC1 in PD.

Rare DNAJC7 Variants May Play a Minor Role in Chinese Patients with ALS.

DnaJ heat shock protein family member C7 gene (DNAJC7) has been identified as a genetic risk factor for amyotrophic lateral sclerosis (ALS). In our study, we aimed to screen for rare variants in DNAJC7 in a large cohort of Chinese ALS patients, and investigate the genotype-phenotype correlation of DNAJC7 in ALS. Four (0.19%) variants of DNAJC7 with minor allele frequency (MAF) < 0.1% among 2124 patients were identified, including 1 protein-truncating variant and 3 missense variants, all of which were predicted to be damaging. The patients carrying variants of DNAJC7 in our cohort tented to have a limb onset and a relatively slow disease progression. However, burden analysis did not show an enrichment of rare damaging variants in ALS patients compared to controls. Further analysis involving diverse regions and larger sample size is necessary to elucidate the role of DNAJC7 in the pathogenicity of ALS.

Endometrium procurement and transplantation restores fertility in rats.

RESEARCH QUESTION: Can rat endometrium be successfully procured and transplanted, and can a similar method be used to procure human endometrium? DESIGN: Rat endometrium was procured using an endometrium stripping method and transplanted into female Sprague-Dawley rats. Macroscopic and histological changes, endometrial receptivity-related protein concentrations and fertility were assessed. Additionally, a preliminary experiment was conducted to procure human endometrium using a similar method. RESULTS: Endometrium was successfully procured from both rats and humans, which contained intact endometrium and parts of the adjacent inner annulus myometrium. Endometrium auto-transplantation was conducted in rats and the procedure lasted a total of 41.3 ± 5.7 min with a mean blood loss of 0.09 ± 0.04 g. The transplanted endometrium survived well, but a fibrotic zone formed between the transplant and recipient tissue. Compared with sham rats, those with endometrium transplantation had similar endometrial thickness and endometrial gland numbers but reduced vascular density at 8 weeks after surgery. Endometrium transplantation also retained expression of the endometrial receptivity-related proteins leukaemia inhibitory factor and vascular endothelial growth factor. In contrast to non-pregnancy in the stripped horn, a mean of 5.0 ± 2.7 fetuses developed in the transplanted horn, and full-term live fetuses were conceived in the horns with transplanted endometrium. CONCLUSIONS: Endometrium procurement by stripping method can obtain an intact and functional endometrium, and endometrium transplantation can reconstruct the uterine cavity and restore fertility in rats.

Prevalence and prognostic significance of malnutrition in early-stage multiple system atrophy.

Background: Malnutrition is associated with poor survival in some diseases. However, the nutritional status in multiple system atrophy (MSA) is unknown, and the significance of malnutrition for the prediction of mortality in MSA has not been well established. Objective: We aimed to determine the prevalence of malnutrition and the prognostic value of malnutrition in patients with early-stage MSA. Methods: Patients diagnosed with early phase MSA (disease duration<3 years) were recruited, and they were followed every year until May 2023. The nutritional status of patients with MSA was assessed using the Controlling Nutritional Status (CONUT) score and Geriatric Nutritional Risk Index (GNRI). Kaplan-Meier survival analysis and Cox regression model were used to assess the prognostic value of malnutrition in MSA. Results: A total of 224 patients with probable MSA (106 MSA died and 118 were still alive) and 213 matched healthy controls (HCs) were enrolled. According to COUNT score and GNRI, patients with MSA had higher prevalence of malnutrition than HCs (44.6% vs. 14.1 and 17.9% vs. 0.9%, respectively). The median survival from symptom onset in patients with MSA in the malnutrition group was shorter than those in the normal-nutrition group (5.98 vs. 7.06 years, p = 0.012) by COUNT score. Additionally, malnutrition increased the risk of mortality in patients with MSA (HR = 1.556, p = 0.030) and MSA-P (HR = 1.973, p = 0.042) by COUNT score. Interpretation: Malnutrition was common in patients with early-stage MSA. Malnutrition increased the risk of mortality in patients with MSA, and early nutritional supplementation should be taken into consideration.

Freezing of gait in Parkinson's disease with glucocerebrosidase mutations: prevalence, clinical correlates and effect on quality of life.

Objectives: Mutations in glucocerebrosidase (GBA1) can change the clinical phenotype of Parkinson's disease (PD). This study aimed to explore the clinical characteristics of freezing of gait (FOG) in PD patients with GBA1 mutations. Methods: A whole-exome sequencing analysis was used to identify the GBA1 mutations (pathogenic or likely pathogenic) and exclude other PD-related gene mutations. A forward binary logistic regression model was conducted to identify the associated factors of FOG. The stepwise multiple linear regression analysis models were used to explore the effect of FOG on quality of life. Results: The prevalence of FOG in patients with GBA1 mutations (30/95, 31.6%) was significantly higher than those in patients without GBA1 mutations (152/760, 20%) (p = 0.009). A higher (i.e., worse) Unified PD Rating Scale part III score (OR = 1.126, 95%CI = 1.061-1.194, p < 0.001) and a lower (i.e., worse) Montreal Cognitive Assessment score (OR = 0.830, 95%CI = 0.713-0.967, p = 0.017) were significantly associated with FOG in PD patients with GBA1 mutations. The presence of FOG was significantly associated with the decreased (i.e., worse) score of PD Questionnaire 39 after adjustment for sex, age, disease duration, motor score, and non-motor score (B = 14.981, p = 0.001). Conclusion: FOG is a relatively common disabling symptom in PD patients with GBA1 mutations, which is affected by motor disability and cognitive decline. Quality of life is reduced in patients with FOG and GBA1 mutations.

Lnc-HIBADH-4 Regulates Autophagy-Lysosome Pathway in Amyotrophic Lateral Sclerosis by Targeting Cathepsin D.

Amyotrophic lateral sclerosis (ALS) is the most prevalent and lethal class of severe motor neuron diseases (MND) with no efficacious treatment. The pathogenic mechanisms underlying ALS remain unclear. Nearly 90% of patients exhibit sporadic onset (sALS). Therefore, elucidating the pathophysiology of ALS is imperative. Long non-coding RNA (lncRNA) is a large class of non-coding RNAs that regulate transcription, translation, and post-translational processes. LncRNAs contribute to the pathogenesis of diverse neurodegenerative disorders and hold promise as targets for interference in the realm of neurodegeneration. However, the mechanisms of which lncRNAs are involved in ALS have not been thoroughly investigated. We identified and validated a downregulated lncRNA, lnc-HIBADH-4, in ALS which correlated with disease severity and overall survival. Lnc-HIBADH-4 acted as a "molecular sponge" regulating lysosomal function through the lnc-HIBADH-4/miR-326/CTSD pathway, thereby impacting autophagy-lysosome dynamics and the levels of cell proliferation and apoptosis. Therefore, this study discovered and revealed the role of lnc-HIBADH-4 in the pathogenesis of ALS. With further research, lnc-HIBADH-4 is expected to provide a new biomarker in the diagnosis and treatment of ALS.

Orthostatic Hypotension in Multiple System Atrophy: Related Factors and Disease Prognosis.

BACKGROUND: Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by Parkinsonism, ataxia, and autonomic nervous failure. Orthostatic hypotension (OH) is the main feature of central vascular autonomic failure in MSA. OBJECTIVE: The study aimed elucidate the effects of OH on cognitive function, disease milestones, and survival. METHODS: A total of 444 patients with clinically established MSA were enrolled. Mild and severe OH were defined as a decrease in systolic blood pressure (SBP)/diastolic blood pressure (DBP) >20/10 mmHg and SBP/DBP ≥30/15 mmHg, respectively. RESULTS: In this study, 215 MSA patients presented without OH, 88 had mild OH, and 141 had severe OH. The proportion of MSA-C in the severe OH subgroup was significantly higher than that in the subgroup without OH (95/46 vs. 113/102, p = 0.021). The UMSARS I score and the frequency of supine hypertension (SH) in patients with OH were significantly higher than those in patients without OH (16.22 vs. 16.89 vs. 14.60, p < 0.001; 77/64 vs. 29/59 vs. 32/183, p < 0.001). Factors related to the severity of OH included sex (OR, 0.65; p = 0.031), onset age (OR, 0.98; p = 0.029), and SH (OR, 0.21; p < 0.001). The median survival time of patients with severe OH was significantly lower than that of patients without OH (6.79 vs. 8.13 years, p = 0.001). Consistently, Cox survival analysis found that compared with patients without OH, patients with severe OH had a significantly increased risk of death (OR, 2.22; p < 0.001). CONCLUSION: Our large cohort study of MSA provides additional evidence for the negative impact of severe OH on survival.