The pyroptosis mediated biomarker pattern: an emerging diagnostic approach for Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) affects 1% of people over 60, and long-term levodopa treatment can cause side effects. Early diagnosis is of great significance in slowing down the pathological process of PD. Multiple pieces of evidence showed that non-coding RNAs (ncRNAs) could participate in the progression of PD pathology. Pyroptosis is known to be regulated by ncRNAs as a key pathological feature of PD. Therefore, evaluating ncRNAs and pyroptosis-related proteins in serum could be worthy biomarkers for early diagnosis of PD. METHODS: NcRNAs and pyroptosis/inflammation mRNA levels were measured with reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Luciferase assays were performed to confirm GSDME as a target of miR-675-5p and HMGB1 as a target of miR-1247-5p. In the serum of healthy controls (n = 106) and PD patients (n = 104), RT-qPCR was utilized to assess miR-675-5p, miR-1247-5p, and two related ncRNAs (circSLC8A1and lncH19) levels. The enzyme-linked immunosorbent assay measured serum levels of pyroptosis-related proteins in controls (n = 54) and PD patients (n = 70). RESULTS: Our data demonstrated that miR-675-5p and miR-1247-5p significantly changed in PD neuron and animal models. Overexpressed miR-675-5p or downregulated miR-1247-5p could regulate pyroptosis and inflammation in PD neuron models. Using the random forest algorithm, we constructed a classifier based on PD neuron-pyroptosis pathology (four ncRNAs and six proteins) having better predictive power than single biomarkers (AUC = 92%). Additionally, we verified the performance of the classifier in early-stage PD patients (AUC ≥ 88%). CONCLUSION: Serum pyroptosis-related ncRNAs and proteins could serve as reliable, inexpensive, and non-invasive diagnostic biomarkers for PD. LIMITATIONS: All participants were from the same region. Additionally, longitudinal studies in the aged population are required to explore the practical application value of the classifier.

Risk factors for motor complications in female patients with Parkinson's disease.

OBJECTIVE: To investigate the risk factors of motor complications in female patients with Parkinson's disease (PD) and the correlation between the occurrence of motor complications and sex hormone levels. METHODS: According to the occurrence and types of motor complications, 103 female PD patients were divided into two groups: patients with or without the wearing-off phenomenon, patients with or without dyskinesia. Binary logistic regression analysis was performed respectively to screen for the risk factors of the wearing-off phenomenon and dyskinesia in female PD patients. RESULTS: Among 103 female PD patients, 44 (42.72%) had motor complications. Patients with the wearing-off phenomenon and patients with dyskinesia had higher prolactin levels than patients without the wearing-off phenomenon and patients without dyskinesia, respectively. However, the difference was no longer significant when the two groups were corrected for multiple comparisons (P < 0.0028). Multivariate analysis found that younger age at onset and higher Hoehn-Yahr (H&Y) stage were identified as independent risk factors for the wearing-off phenomenon and younger age of onset was an independent risk factor for dyskinesia in female PD patients (P < 0.05). CONCLUSION: Female PD patients have a higher incidence of motor complications. Younger age of onset and higher H&Y stage were the risk factors of the wearing-off phenomenon, and younger onset age was the risk factor of dyskinesia in female PD patients. There may be a certain correlation between the occurrence of motor complications and sex hormone levels in female PD patients, which requires further verification.

Molecular beacon-based detection of circulating microRNA-containing extracellular vesicle as an α-synucleinopathy biomarker.

Early and precise diagnosis of α-synucleinopathies is challenging but critical. In this study, we developed a molecular beacon-based assay to evaluate microRNA-containing extracellular vesicles (EVs) in plasma. We recruited 1203 participants including healthy controls (HCs) and patients with isolated REM sleep behavior disorder (iRBD), α-synucleinopathies, or non-α-synucleinopathies from eight centers across China. Plasma miR-44438-containing EV levels were significantly increased in α-synucleinopathies, including those in the prodromal stage (e.g., iRBD), compared to both non-α-synucleinopathy patients and HCs. However, there are no significant differences between Parkinson's disease (PD) and multiple system atrophy. The miR-44438-containing EV levels negatively correlated with age and the Hoehn and Yahr stage of PD patients, suggesting a potential association with disease progression. Furthermore, a longitudinal analysis over 16.3 months demonstrated a significant decline in miR-44438-containing EV levels in patients with PD. These results highlight the potential of plasma miR-44438-containing EV as a biomarker for early detection and progress monitoring of α-synucleinopathies.

Cerebellar infarction caused by vertebral artery dissection: A case report.

RATIONALE: Vertebral artery dissection is an important cause of posterior circulation ischemic stroke in young and middle-aged people. We reported a young man with cerebellar infarction caused by dissection of the right vertebral artery. PATIENT CONCERNS: A 34-year-old man presented with intermittent dizziness, blurred vision, nausea, and transient tinnitus 10 days before admission. All these symptoms were gradually aggravated and followed by vomiting and unfavorable movement of the right limbs. All these symptoms gradually aggravated. DIAGNOSIS: Neurological examination on admission showed ataxia of the right limbs. Magnetic resonance imaging of the head revealed a right cerebellar infarction. High-resolution vessel wall magnetic resonance imaging showed dissection of the right vertebral artery. Whole-brain CT digital subtraction angiography revealed occlusion of the third segment (V3) of the right vertebral artery. This supports the diagnosis of vertebral artery dissection. INTERVENTIONS: The patient received anticoagulant treatment with warfarin. OUTCOMES: After 2 weeks of treatment, the patient showed remarkably alleviated dizziness and unfavorable movement of the right limbs. After 3 months of treatment, the modified Rankin Scale score was 0. MRI of the head revealed that the original right cerebellar focus was softened, and there were no newly formed infarct foci. LESSONS: When young and middle-aged patients without atherosclerotic risk factors encounter sudden dizziness, tinnitus, and unfavorable limb movement, vertebral artery dissection may be considered. Careful inquiry into the medical history may help make a final diagnosis. Further high-resolution vessel wall magnetic resonance imaging is an effective means to find arterial dissection. Early diagnosis and treatment for vertebral artery dissection has a favorable prognosis.

miR-218-5p and miR-320a-5p as Biomarkers for Brain Disorders: Focus on the Major Depressive Disorder and Parkinson's Disease.

Depression is one of the early and most persistent non-motor symptoms of Parkinson's disease (PD), which remains ignored, resulting in the underdiagnosis of PD. Unfortunately, scarce studies and the non-availability of diagnostic strategies cause countless complications, highlighting the need for appropriate diagnostic biomarkers. Recently, brain-enriched miRNAs regulating vital neurological functions have been proposed as potent biomarkers for therapeutic strategies. Therefore, the present study is aimed to identify the brain-enriched miR-218-5p and miR-320-5p in the serum of the Chinese depressed PD patients (n = 51) than healthy controls (n = 51) to identify their potency as biomarkers. For this purpose, depressive PD patients were recruited based on HAMA and HAMD scores and miR-218-5p and miR-320-5p and IL-6, and S100B levels were analyzed using real-time PCR (qRT-PCR) and ELISA assay, respectively. In silico analysis was performed to identify key biological pathways and hub genes involved in the psychopathology of depression in PD. Here, we found significantly downregulated miR-218-5p and miR-320-5p following higher levels of IL-6 and S100B in depressed PD patients than in control (p < 0.05). The correlation analysis revealed that both miRNAs were negatively correlated with HAMA and HAMD, and IL-6 scores, along with a positive correlation with PD duration and LEDD medication. ROC analysis showed AUC above 75% in both miRNAs in depressed PD patients, and in silico analysis revealed that both miRNA's targets regulate key neurological pathways such as axon guidance, dopaminergic synapse, and circadian rhythm. Additional analysis revealed PIK3R1, ATRX, BM1, PCDHA10, XRCC5, PPP1CB, MLLT3, CBL, PCDHA4, PLCG1, YWHAZ, CDH2, AGO3, PCDHA3, and PCDHA11 as hub-genes in PPI network. In summary, our findings show that miR-218-5p and miR-320-5p can be utilized as future biomarkers for depression in PD patients, which may aid in the early diagnosis and treatment of Parkinson's disease.

The association between restless leg syndrome and anxiety in Parkinson's disease: a case-control study.

OBJECTIVE: To shed light on the association between restless leg syndrome (RLS) and anxiety in Parkinson's disease (PD) population. METHODS: This was a case-control study including 129 PD participants with and without anxiety who presented to the Aerospace Center Hospital in Beijing, China. Anxiety was evaluated by using the Beck Anxiety Index score. RLS was assessed using the minimal diagnostic criteria of the International Restless Legs Study Group and RLS symptom frequency and treatment. We then examined the relationship between RLS and anxiety by logistic regression models and subgroup as well as interaction analyses. RESULTS: The proportion of RLS in PD with anxiety was significantly higher in the PD without anxiety (p < 0.001). The multivariate logistic regression models indicated that PD participants with RLS had a 5.98-fold higher risk of anxiety in PD than those without RLS (OR, 6.98; 95% CI, 2.77-17.59). Subgroup analyses indicated that PD with RLS tended to be associated with a greater risk of anxiety in all stratified subgroups (adjusted ORs >1). Furthermore, the interaction analyses revealed no interactive role in the association between RLS and anxiety. CONCLUSIONS: The present case-control study suggests that RLS is an independent risk factor for anxiety in PD patients. Early attention and targeted treatment for RLS may be necessary for mood management in PD. Larger prospective cohort studies are wanted to validate these findings.

Salsolinol Induces Parkinson's Disease Through Activating NLRP3-Dependent Pyroptosis and the Neuroprotective Effect of Acteoside.

Endogenous neurotoxin 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroiso-quinoline (Salsolinol, SAL) is a dopamine metabolite that is toxic to dopaminergic neurons in vitro and in vivo, and is involved in the pathogenesis of Parkinson's disease (PD). However, the molecular mechanism by which SAL induces neurotoxicity in PD remains challenging for future investigations. This study found that SAL induced neurotoxicity in SH-SY5Y cells and mice. RNA sequencing (RNAseq) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to detect differentially expressed genes in SAL-treated SH-SY5Y cells. We found that NLR family pyrin domain-containing 3 (NLRP3)-dependent pyroptosis was enriched by SAL, which was validated by in vitro and in vivo SAL models. Further, NLRP3 inflammasome-related genes (ASC, NLRP3, active caspase 1, IL-1ß, and IL-18) were increased at the mRNA and protein level. Acteoside mitigates SAL-induced neurotoxicity by inhibiting NLRP3 inflammasome-related pyroptosis in in vitro and in vivo PD models. In summary, the present study suggests for the first time that NLRP3-dependent pyroptosis plays a role in the pathogenesis of SAL-induced PD, and acteoside mitigates SAL-induced pyroptosis-dependent neurotoxicity in in vitro and in vivo PD models. The present results demonstrated a new mechanism whereby SAL mediates neurotoxicity by activating NLRP3-dependent pyroptosis, further highlighting SAL-induced pyroptosis-dependent neurotoxicity as a potential therapeutic target in PD.

Epigallocatechin-3-gallate: A phytochemical as a promising drug candidate for the treatment of Parkinson's disease.

Epigallocatechin 3-gallate (EGCG), an abundant polyphenolic component derived from green tea extract, possesses versatile bioactivities that can combat many diseases. During the last decade, EGCG was shown to be effective in experimental models of Parkinson's disease (PD). Several experimental studies have suggested that it has pleiotropic neuroprotective effects, which has enhanced the appeal of EGCG as a therapeutic strategy in PD. In this review, we compiled recent updates and knowledge of the molecular mechanisms underlying the neuroprotective effects of EGCG in PD. We focused on the effects of EGCG on apoptosis, oxidative stress, inflammation, ferroptosis, modulation of dopamine production, and the aggregation of α-synuclein. The review highlights the pharmacological features of EGCG and its therapeutic implications in PD. Taken together, the accumulated data indicate that EGCG is a promising neuroprotective compound for the treatment of PD.

Non-motor symptoms in multiple system atrophy: A comparative study with Parkinson's disease and progressive supranuclear palsy.

Background: Non-motor symptoms (NMS) are compulsory clinical features for the clinical diagnosis of multiple system atrophy (MSA), some of which precede motor symptoms onset. To date, few studies have systematically investigated NMS in MSA and the timing of presenting NMS as the disease progresses. Clinically, MSA is difficult to be differentiated from Parkinson's disease (PD) and progressive supranuclear palsy (PSP), and the differences in NMS between MSA and PD/PSP remain unclear. The aim of this study was to compare the burden of NMS between MSA and PD/PSP and to delineate the timing of NMS presentation relative to the onset of motor symptoms in MSA. Methods: A total of 61, 87, and 30 patients with MSA, PD, and PSP, respectively, were enrolled in this study. NMS was systematically assessed in all patients using the NMS scale (NMSS), and the onset of NMS relative to the onset of motor symptoms in MSA was investigated. Results: MSA group had higher total NMSS scores (82.15 ± 46.10) than the PD (36.14 ± 30.78) and PSP (50.30 ± 55.05) groups (p < 0.001 overall). The number distribution pattern of the NMS was significantly different among the three parkinsonian disorders (p < 0.001 overall). In total, 85.2% of patients with MSA had more than 10 NMS, which was significantly higher than PD (28.7%) and PSP (33.3%). The frequency and scores of many NMSS subdomains and symptoms were higher in MSA than in PD and PSP (all p < 0.05). Multivariate logistic regression analysis revealed that patients with fainting, lack of motivation, swallowing, and loss of sexual interest could be attributed to MSA rather than PD or PSP, while patients with loss of concentration and forgetfulness were characteristic features of PD or PSP rather than MSA. REM-sleep behavior disorder (RBD), constipation, problems having sex, and loss of sexual interest preceded the motor symptoms onset of MSA by 2.81 ± 4.51, 1.54 ± 6.32, 1.35 ± 4.70, and 0.45 ± 3.61 years, respectively. Conclusion: The NMS spectrum in MSA differs from that of PD and PSP. Patients with MSA have a higher NMS burden than patients with PD or PSP. RBD, constipation, problems having sex, and loss of sexual interest may become early diagnostic clinical markers of MSA.

Effects of Health Qigong Exercises on Physical Function on Patients with Parkinson's Disease.

PURPOSE: To measure motor function improvements in patients with Parkinson's disease (PD) using Health Qigong exercises. PATIENTS AND METHODS: Fifty-two PD patients (Hoehn and Yahr stages I to IV) were randomly divided into experimental and control groups. Twenty-six PD patients in the experimental group were intervened with routine medicine and fitness Qigong exercise. The other 26 PD patients as the control group were treated only with regular medication. Twelve-week intervention had been conducted for the study, and participants completed the scheduled exercises 4 times per week for 60 minutes each time. Data which included the one-legged blind balance, physical coordination, and gait was collected before, during, and after the intervention. Comparisons were made between the experimental and control groups through the repeated measures analysis of variance. RESULTS: A total of 40 participants (77% response rate) completed the study. There was no significant difference in baseline data. After 12 weeks of Health Qigong therapy, the length of time the one-legged blind balance test had increased (P < 0.01), and the time it took to TUG test was reduced (P < 0.01). Joint range of motion and gait significantly improved. The control group's there were no significant differences in the above variables, except for joint range of motion, which decreased. CONCLUSION: Health Qigong exercises can significantly improve physical functions in patients with PD, especially for the balance ability, gait, joint range of motion in patients with PD. It can reduce their activity risk factor and improve their quality of life.