Predictors of the Rapid Progression in Prodromal Parkinson's Disease: A Longitudinal Follow-Up Study.

INTRODUCTION: Parkinson's disease (PD) is characterized by a prodromal phase preceding the onset of classic motor symptoms. The duration and clinical manifestations of prodromal PD vary widely, indicating underlying heterogeneity within this stage. This discrepancy prompts the question of whether specific factors contribute to the divergent rates of progression in prodromal PD. METHODS: This study included prodromal PD patients from the Parkinson's progression marker initiative. They were followed up to assess the disease progression. The data collected during the follow-up period were analyzed to identify potential predictors of rapid disease progression in prodromal PD. RESULTS: In this study, 61 individuals with prodromal PD were enrolled. Among them, 43 patients presented with both RBD and hyposmia, 17 had hyposmia alone, and 1 had RBD alone at baseline. 13 (21.3%) prodromal PD participants exhibited rapid disease progression, with two of these cases advancing to non-neurological diseases. Significant differences were observed between the rapid progression group and no rapid progression group in terms of MDS-UPDRS II score and UPSIT score. Longitudinal analysis showed a significant increase in the MDS-UPDRS III score and MDS-UPDRS total score in the rapid progression group. Regression analyses identified the MDS-UPDRS II score and UPSIT score as predictors of rapid disease progression in prodromal PD. CONCLUSION: Our study findings suggest that the MDS-UPDRS II score and UPSIT score may serve as clinical markers associated with rapid disease progression. Further research and development of precise biomarkers and advanced assessment methods are needed to enhance our understanding of prodromal PD and its progression patterns.

Association between vertebrobasilar artery geometry and vertebrobasilar stenosis, recurrence, and death in posterior circulation stroke and transient ischemic attack.

BACKGROUND: Intracranial atherosclerosis is one of the primary causes of posterior circulation stroke and transient ischemic attack (TIA), particularly in people of South and East Asian heritage. Focal vessel geometry may play a role in atherosclerosis progression. Thus, we investigated the relevance of vertebrobasilar artery (VBA) geometry and vertebrobasilar atherosclerotic stenosis, recurrence, and death in posterior circulation stroke and TIA. METHODS: Four hundred and twenty patients with posterior circulation ischemic stroke or TIA were included. The VBA geometric features, comprising the geometric configurations (Tuning fork, Walking, Lambda, and No confluence), vascular bends (multi-bending and oligo-bending), and VBA stenosis degrees, were defined based on computed tomography angiography (CTA) images. Recurrence of stroke or TIA and death were assessed through a 1-year follow-up. Additionally, the relationship between VBA geometric features, VBA stenosis, and prognosis were analyzed. RESULTS: Walking type and vascular multi-bending showed significant associations with more severe VBA stenosis and distribution, and these were also more frequently observed in patients with large-artery atherosclerosis (LAA) stroke (all P < 0.05). Sixty-four patients exhibited recurrent stroke or TIA, and 31 died during the 1-year follow-up. In the binary logistic regression analysis, Walking type (P = 0.018), Lambda type (P = 0.021), and multi-bending type (P = 0.004) were found to be independently associated with stroke recurrence, while No confluence type was independently associated with death (P = 0.010). CONCLUSIONS: The geometric characteristics of the VBA are associated with vertebrobasilar stenosis, LAA stroke, 1-year recurrence, and death in posterior circulation stroke and TIA. VBA geometry may be used to stratify the risk of stroke and TIA in the posterior circulation.

Pericarotid Adipose Tissue is Associated with Circulatory Markers of Inflammation and Carotid Atherosclerosis.

Perivascular adipose tissue plays roles in vascular inflammation and atherosclerosis. The present study aimed to evaluate the association between pericarotid fat density (PFD) and circulatory inflammatory indicators, internal carotid artery (ICA) stenosis, and vulnerable carotid plaques. We retrospectively screened 498 consecutive patients who underwent both computed tomography angiography of the neck between January 2017 and December 2020. The PFD, ICA stenosis, and vulnerable carotid plaques were analyzed using established approaches. Laboratory data including C-reactive protein (CRP) levels, lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII) were recorded. PFD was positively correlated with CRP, NLR, PLR, and SII, and negatively correlated with LMR. A higher PFD was independently associated with extracranial ICA stenosis (1.179 [1.003-1.387], P = .040) and vulnerable carotid plaques (1.046 [1.021-1.072], P = .001) after adjusting for systemic inflammatory indicators. These findings suggested higher PFD is independently associated with circulating inflammatory indicators, extracranial ICA stenosis, and vulnerable carotid plaque.

LncRNA MEG8 ameliorates Parkinson's disease neuro-inflammation through miR-485-3p/FBXO45 axis.

OBJECTIVE: Studies suggest that LncRNA maternally expressed 8, small nucleolar RNA host gene (MEG8) contributes to inflammatory regulation, while the function and potential mechanisms of MEG8 in Parkinson's disease (PD) are unknown. This study aimed to assess the clinical value and biological function of MEG8 in PD. METHODS: One hundred and two PD patients, eighty-six AD patients, and eighty healthy controls were enrolled in this study. Lipopolysaccharide (LPS)-induced microglia BV2 constructs an in vitro cell model. RT-qPCR was conducted to quantify the levels of MEG8, miR-485-3p, and FBXO45 in serum and cells. ROC curve was employed to examine the diagnostic value of MEG8 in PD. Serum and cellular pro-inflammatory factor secretion were quantified by ELISA. Dual-luciferase reporter and RIP assay to validate the targeting relationship between miR-485-3p and FBXO45. RESULTS: MEG8 and FBXO45 were significantly decreased in the serum of PD patients and LPS-induced bv2, while miR-485-3p was increased (P < 0.05). ROC curve confirmed that serum MEG8 has high sensitivity and specificity to identify PD patients from healthy controls and AD patients, respectively. Elevated MEG8 alleviated LPS-induced inflammatory factor overproduction compared with LPS-induced BV2 (P < 0.05), but this alleviating effect was eliminated by miR-485-3p (P < 0.05). The LPS-induced inflammatory response was suppressed by the low expression of miR-485-3p but significantly reversed by silencing of FBXO45. MEG8 was a sponge for miR-485-3p and inhibited its levels and promoted FBXO45 expression (P < 0.05). CONCLUSION: Elevated MEG8 is a potential diagnostic biomarker for PD and may mitigate inflammatory damage in PD via the miR-485-3p/FBXO45 axis.

Deregulated miR-146a-3p alleviates disease progression in atherosclerosis through inactivating NF-κB: An experimental study.

BACKGROUND: Atherosclerosis (AS), as a complex chronic inflammatory disease, is 1 of the main causes of cardiovascular and cerebrovascular diseases. This study aimed to confirm the direct interaction between miR-146a-3p and NF-κB, and explore the role of miR-146a-3p/NF-κB in the regulation of inflammation in AS. METHODS: Bioinformatic prediction and dual-luciferase reporter assay were used to confirm the interaction between miR-146a-3p and NF-κB. Lipopolysaccharides stimulation was performed to establish AS inflammatory cell model, and the levels of pro-inflammatory cytokines were estimated using an enzyme-linked immunosorbent assay. miR-146a-3p and NF-κB expression were evaluated using reverse transcription quantitative PCR, and their clinical value was examined using a receiver operating characteristic curve. RESULTS: Inflammatory cell model showed increased IL-1ß, IL-6, and TNF-α. NF-κB was a target gene of miR-146a-3p, and mediated the inhibitory effects of miR-146a-3p on inflammatory responses in the cell model. In patients with AS, miR-146a-3p/NF-κB was associated with patients' clinical data and inflammatory cytokine levels, and aberrant miR-146a-3p and NF-κB showed diagnostic accuracy to distinguish AS patients from healthy populations. CONCLUSION: miR-146a-3p might inhibit inflammation by targeting NF-κB in AS progression, and miR-146a-3p/ NF-κB might provide novel biomarkers and therapeutic targets for the prevention of AS and related vascular events.

CircHIVEP2 alleviates Parkinson's nerve damage and inflammatory response by targeting miR-485-3p.

OBJECTIVE: Dysregulation of covalently closed circular RNAs (circRNAs) has been associated with neurological disorders, the role of circHIVP2 in Parkinson's disease (PD) and its molecular mechanism is not well understood. METHODS: 127 patients with PD and 85 healthy people were enrolled. RT-qPCR was employed to examine the levels of circHIVEP2. ROC curve to explore the diagnostic. Mpp+ induced the SH-SY5Y to construct an in vitro PD cell model. Cell viability, apoptosis, and secretion levels of inflammatory factors were analyzed by CCK-8, flow cytometry, and ELISA assay. CircHIVEP2 targets miRNA predicted by bioinformatics database and validated by the dual luciferase reporter and RIP assays. RESULTS: CircHIVEP2 was typically lower in PD patients than in controls. CircHIVEP2 has certain specificity and sensitivity to recognize PD patients from healthy individuals. miR-485-3p, a target miRNA of circHIVEP2, was significantly elevated in PD patients. Additionally, MPP+ induction reduced cell viability and promoted apoptosis and inflammatory factor overproduction. However, overexpression of circHIVEP2 significantly inhibited the effects of MPP+, but this inhibition was significantly attenuated by elevated miR-485-3p. CONCLUSION: circHIVEP2 is a potential diagnostic biomarker for PD, and its upregulation mitigated MPP+-induced nerve damage and inflammation and this may be through targeted by the miR-485-3p.

[Mechanism of gypenoside XVII against cerebral ischemia/reperfusion injury based on nuclear factor erythroid 2-related factor 2/antioxidant responsive element signaling pathway].

OBJECTIVE: To explore the mechanism of gypenoside XVII against cerebral ischemia/reperfusion (I/R) through nuclear factor erythroid 2-related factor 2/antioxidant responsive element (Nrf2/ARE) signaling pathway. METHODS: Forty SPF Sprague Dawley (SD) rats were randomly divided into sham operated group, I/R model group, 25, 50 and 100 mg/kg gypenoside XVII groups (n = 8). Gypenoside XVII groups were administered 25, 50 or 100 mg/kg (0.01 mL/g) gypenoside XVII by intragastric administration for 14 days; the other two groups received the same dose of saline. Rat cerebral I/R model was established by modified line bolt method; rats in the sham operated group underwent the same procedure without producing substantial embolization. After 24 hours of reperfusion, the neurological deficit scores of the rats in each group were assessed. Rat abdominal aortic whole blood was collected and the serum reactive oxygen species (ROS), heme oxygenase-1 (HO-1), γ-glutamylcysteine synthase (γ-GCS), superoxide dismutase (SOD), quinone NADH oxidoreductase 1 (NQO1), and malondialdehyde (MDA) were detected. Then whole brain tissue was harvested and penumbra tissue was isolated from cerebral cortex, the general condition of rat brain tissue and the volume of cerebral infarction were evaluated, the histopathological changes in the brain were observed under light microscopy, the mRNA expressions of Nrf2 and Keap1 were measured by real-time fluorescent quantitative polymerase chain reaction (RT-qPCR), the protein expressions of Nrf2 and Keap1 were determined by Western blotting. RESULTS: After 24 hours of reperfusion, compared with the sham operated group, the score of neurological deficit and infarct volume were significantly increased, the NQO1, SOD and γ-GCS levels in serum were significantly decreased, MDA, HO-1 and ROS levels in serum were significantly increased, the Nrf2 and Keap1 mRNA and protein expressions in the ischemic penumbra were significantly increased in rats from I/R model group. Compared with the I/R model group, the neurological deficit scores (1.50±0.53, 1.37±0.52 vs. 2.75±0.46) and brain infarct volume [(19.8±5.1)%, (21.4±6.4)% vs. (42.3±5.8)%] were significantly reduced, serum NQO1, SOD, HO-1 and γ-GCS were significantly increased [NQO1 (ng/L): 186.05±10.38, 220.75±16.22 vs. 131.36±5.95, SOD (kU/L): 63.23±5.30, 72.70±8.62 vs. 36.75±6.55, HO-1 (ng/L): 60.57±7.93, 60.35±4.72 vs. 42.72±4.95, γ-GCS (kU/L): 8.81±0.53, 8.72±0.69 vs. 6.80±0.56], serum MDA and ROS levels were significantly reduced [MDA (µmol/L): 5.94±0.66, 5.61±0.53 vs. 10.88±1.34, ROS (kU/L): 69.11±4.23, 67.12±4.52 vs. 104.43±7.54], the mRNA and protein expressions of Nrf2 and Keap1 in the ischemic penumbra were significantly increased in rats from 50 mg/kg and 100 mg/kg gypenoside XVII groups [Nrf2 mRNA (2-ΔΔCt): 1.90±0.13, 2.13±0.18 vs. 1.48±0.11, Keap1 mRNA (2-ΔΔCt): 1.78±0.11, 1.85±0.10 vs. 1.43±0.10, Nrf2/ß-actin: 0.73±0.04, 0.79±0.03 vs. 0.60±0.03, Keap1/ß-actin: 0.71±0.01, 0.76±0.03 vs. 0.61±0.01], all the comparative differences were statistically significant (all P < 0.01); 25 mg/kg gypenoside XVII had no significant effect. CONCLUSIONS: Gypenoside XVII (50 mg/kg and 100 mg/kg) may play a role in anti-cerebral I/R injury by regulating NQO1, SOD, HO-1, γ-GCS, ROS and MDA through Nrf2/ARE signaling pathway.

Detecting ferroptosis and immune infiltration profiles in multiple system atrophy using postmortem brain tissue.

Background: The importance of ferroptosis and the immune system has been mentioned in the pathogenesis of α-synucleinopathy. The α-synuclein-immunoreactive inclusions that primarily affect oligodendrocytes are the hallmark of multiple system atrophy (MSA). Limited evidence implicates that iron and immune responses are involved in the pathogenesis of MSA, which is associated with neurodegeneration and α-synuclein aggregation. Methods: The RNA sequencing data were collected from the Gene Expression Omnibus database. MSA-C-related module genes were identified through weighted gene co-expression network analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to predict the potential molecular functions. The candidate ferroptosis-related genes associated with MSA-C were obtained using a machine-learning algorithm. CIBERSORT was used to estimate the compositional patterns of the 22 types of immune cells. Results: The tissues for sequencing were extracted from postmortem cerebellar white matter tissues of 11 MSA-C patients and 47 healthy controls. The diagnostic ability of the six MSA-C-related ferroptosis-related genes in discriminating MSA-C from the healthy controls demonstrated a favorable diagnostic value, with the AUC ranging from 0.662 to 0.791. The proportion of CD8+ T cells in MSA-C was significantly higher than in the controls (P = 0.02). The proportion of NK cells resting in MSA-C was significantly higher than in the controls (P = 0.011). Conclusion: Ferroptosis and T-cell infiltration may be important pathways of disease development in MSA-C, and targeting therapies for these pathways may be disease-modifying.

Synthetic role of miR-411-5p and CT perfusion information in predicting clinical outcomes after thrombolysis in acute cerebral infarction.

BACKGROUND: Our aim was to investigate the predictive value of microRNA (miR)-411-5p and computed tomography perfusion (CTP) parameters on the prognosis of acute cerebral infarction (ACI) patients receiving intravenous thrombolysis based on analyzing the expression changes of miR-411-5p before and after thrombolytic therapy. METHODS: Serum miR-411-5p expression in 96 patients with ACI was measured using quantitative real-time PCR. To evaluate prognosis, we measured National Institutes of Health Stroke Scale (NIHSS) scores before and 24 h after thrombolytic therapy in ACI patients and the modified Rankin scale (mRS) score at 3 months (90 days) after ACI onset. Influence factors analysis to predict the prognosis of patients who received thrombolytic therapy was performed by logistic regression analysis. Receiver operating characteristic analysis was used to evaluate the predictive accuracy and thresholds of factors associated with thrombolytic prognosis. RESULTS: Serum miR-411-5p at 24 h after thrombolysis and at 3 months after onset in ACI patients was upregulated. Additionally, the correlation of miR-411-5p with NIHSS score and CTP parameters were found. Moreover, miR-411-5p and two CTP parameters [cerebral blood flow (CBF) and cerebral blood volume (CBV)] were identified as independent predictors of short- and long-term prognosis following thrombolysis in ACI patients. Furthermore, miR-411-5p, CBF and CBV had high predictive accuracy for patient prognosis, and their combination had the best accuracy. CONCLUSION: miR-411-5p is increased by thrombolytic therapy in ACI patients, and miR-411-5p, CBF and CBV may serve as independent biomarkers for predicting short- and long-term prognosis following intravenous thrombolysis in ACI patients.

Association between metabolic syndrome components and impulse control disorders in Parkinson's disease.

Background: Current evidence on management of impulse control disorders (ICDs) in Parkinson's disease (PD) remains scarce, and exploring modifiable risk factors is crucial. Objective: We evaluated the profiles of ICDs in PD patients and aimed to determine the associations between ICDs, metabolic syndrome components and other clinical features. Methods: We enrolled patients diagnosed with PD in this study and conducted comprehensive clinical assessments. Results: We recruited 39 PD patients with ICDs and 66 PD patients without ICDs. Out of the 39 patients with ICDs, 19 (48.7%) had one impulse control disorder, while 20 (51.3%) had two or more. The most commonly reported symptom of ICDs was compulsive eating (48.7%). Significant differences were observed between the PD patients with and without ICDs in terms of their HbA1c levels, history of diabetes mellitus, dopamine agonist use, levodopa equivalent dose of dopamine agonists (LED DA), and Hamilton Depression Rating Scale (HAMD) scores. HbA1c levels were significantly higher in the PD patients with compulsive eating. Stepwise logistic regression analyses were performed with the dependent variables of ICDs (yes/no) and compulsive eating (yes/no). Among the 105 PD patients, those with ICDs exhibited higher levels of HbA1c, HAMD score and LED DA than those without ICDs (p < 0.01). Among 39 PD patients with ICDs, those with compulsive eating exhibited higher levels of HbA1c (OR = 2.148, 95% CI = 1.004-4.594, p < 0.05). Among 105 PD patients, those with compulsive eating exhibited higher levels of HbA1c, LED DA and HAMD score (p < 0.05). Conclusion: This study provides insights into the profiles of ICDs in PD patients and their associations with various clinical features. Compulsive eating was the most common ICDs symptom reported. Notably, HbA1c levels were found to be higher in patients with compulsive eating, indicating that poor blood glucose control may be a potential risk factor for ICDs in PD. However, it should be noted that the higher HbA1c levels could also be a consequence of compulsive eating rather than a causal factor for ICDs in PD. Further research is needed to confirm the modifiable risk factors for ICDs in PD.

Effects of resveratrol on learning and memory in rats with vascular dementia.

The purpose of the present study was to study the effects of resveratrol on cognitive function in rats with vascular dementia and to investigate the molecular mechanisms of its neuroprotective effects. Forty­five SD rats were randomly divided into 3 groups: The control group (Con group, n=15), the model group (VD group, n=15) and the resveratrol­treated VD group (Res group, n=15). The VD rats (the VD group and the Res group) were generated by bilateral common carotid artery occlusion. The rats in the Res group received daily resveratrol treatment intraperitoneally for 4 weeks. Cognitive function was tested using the Morris water maze test. The levels of SOD and MDA (oxidative stress indicators) were detected by ELISA kits. The protein expression of Bax, Bcl­2 and caspase­3 was detected by western blotting. Compared with the rats in the Con group, the rats in the VD group exhibited decreased cognitive function, significantly increased hippocampal content of MDA, Bax and caspase­3 (P<0.05), and significantly reduced hippocampal expression of SOD and Bcl­2 (P<0.05). Compared with the rats in the VD group, the rats in the Res group exhibited increased cognitive ability, reduced hippocampal content of MDA, Bax and caspase­3 (P<0.05), and increased hippocampal expression of SOD and Bcl­2 (P<0.05). Resveratrol treatment significantly improved the spatial learning and memory of the VD rats. The mechanism associated with the neuroprotective effects of resveratrol may be closely related to the inhibition of the apoptosis pathway and oxidative stress injury.

[The role of thromboxane A2 receptor gene promoter polymorphism in acute cerebral infarction].

OBJECTIVE: To investigate the association between thromboxane A2 receptor (TXA2R) gene promoter rs2271875, rs768963 polymorphism and acute cerebral infarction in Chinese Han population. METHODS: A prospective study was conducted. From October 2009 to May 2013, 223 patients with cerebral infarction (cerebral infarction group) and 142 cohorts with normal physical examination results (control group) from Taizhou City Central Hospital in Zhejiang Province were enrolled. Triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) were determined by enzymatic colorimetry, whereas blood glucose was determined with hexokinase. The genotypes of rs2271875 and rs768963 polymorphism in TXA2R gene were detected by the polymerase chain reaction-ligase detection reaction (PCR-LDR) technique. Differences in gender, age, serum TG, TC, HDL-C, LDL-C, concentration of blood glucose, and blood pressure (systolic pressure, diastolic pressure) between cerebral infarction group and control group were compared as well as TXA2R promoter rs2271875, rs768963 genotype and allele frequencies distribution. RESULTS: The significant differences in males (147 cases vs. 57 cases, χ(2)=23.385, P=0.000), serum TG (2.02±1.14 mmol/L vs. 1.56±0.79 mmol/L, t=4.663, P=0.000), blood glucose (6.40±2.50 mmol/L vs. 5.28±0.92 mmol/L, t=6.084, P=0.000), systolic pressure (146.64±21.34 mmHg vs. 135.73±18.09 mmHg, t=5.234, P=0.000), diastolic blood pressure (86.29±11.79 mmHg vs. 80.74±11.23 mmHg, t=4.468, P=0.000) between cerebral infarction patients and controls were found. The results from multi-logistic regression analysis suggested that male was an independent risk factor for cerebral infarction [odds ratio (OR) 3.300, 95% confidence interval (95%CI) 1.905-5.175, P=0.000]. There were statistically significant differences between infarction group and the control group both in aspects of genotype (TT: 0.112 vs. 0.183, TC: 0.498 vs. 0.535, CC: 0.390 vs. 0.282, χ(2)=6.298, P=0.043) and the allele frequency distribution (T: 0.361 vs. 0.451, C: 0.639 vs. 0.549, χ(2)=5.839, P=0.016) of TXA2R gene rs768963. No statistical significant difference was found in rs2271875 in respect of genotype (GG: 0.336 vs. 0.352, GA: 0.480 vs. 0.451, AA: 0.184 vs. 0.197, χ (2)=0.302, P=0.859) and the allele frequency distribution (G: 0.576 vs. 0.577, A: 0.424 vs. 0.423, χ(2)=0.001, P=0.974). Coefficient of both linkage disequilibrium (D') of rs2271875 and rs768963 was 0.684. When the pair was haplotype AT, the frequency in the infarction group was significantly lower than that in the control group (0.034 vs. 0.081, χ(2)=7.883, P=0.005). CONCLUSIONS: rs768963 gene mutation, but not that of the rs2271875, showed significant correlation with the occurrence of cerebral infarction. There was a loose linkage disequilibrium between rs2271875 and rs768963 of TXA2R. Haplotype AT reduces the risk of cerebral infarction.