Association between kidney function and Parkinson's disease risk: a prospective study from the UK Biobank.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative influenced by various clinical factors. The potential relationship between renal function and the risk of PD remains poorly understood. This study aims to explore the association between kidney function and the risk of developing PD. METHODS: A population-based cohort study was conducted using data from 400,571 UK Biobank participants. Renal function was assessed using the estimated glomerular filtration rate (eGFR), calculated from serum creatinine and cystatin C levels. The association between eGFR levels and PD risk was evaluated using univariate and multivariate Cox regression analyses, Restricted Cubic Spline (RCS) analysis, and Kaplan-Meier analysis. Additionally, a clinical prediction model was developed and its diagnostic accuracy was evaluated using ROC analysis. A heatmap was also constructed to examine the relationship between clinical factors and gray matter volume in various brain regions. RESULTS: Over a median observation period of 13.8 years, 2740 PD events were recorded. Cox regression and Kaplan-Meier analyses revealed a significant association between decreased eGFR and increased PD risk, particularly in participants with eGFR < 30 ml/min/1.73 m2. This association was confirmed across three adjusted models. RCS analysis demonstrated a nonlinear relationship between decreasing eGFR and increasing PD risk. Furthermore, changes in eGFR were correlated with alterations in subcortical gray matter volume in regions such as the frontal cortex, striatum, and cerebellum. The clinical prediction model showed high diagnostic accuracy with AUC values of 0.776, 0.780, and 0.824 for 4-, 8-, and 16-year predictions, respectively. CONCLUSION: Renal insufficiency is significantly associated with an increased risk of PD, highlighting the importance of maintaining good kidney function as a potential preventive measure against PD.

Pharmacological effects of Astragalus polysaccharides in treating neurodegenerative diseases.

Astragalus membranaceus widely used in traditional Chinese medicine, exhibits multiple pharmacological effects, including immune stimulation, antioxidation, hepatoprotection, diuresis, antidiabetes, anticancer, and expectorant properties. Its main bioactive compounds include flavonoids, triterpene saponins, and polysaccharides. Astragalus polysaccharides (APS), one of its primary bioactive components, have been shown to possess a variety of pharmacological activities, such as antioxidant, immunomodulatory, anti-inflammatory, antitumor, antidiabetic, antiviral, hepatoprotective, anti-atherosclerotic, hematopoietic, and neuroprotective effects. This review provides a comprehensive summary of the molecular mechanisms and therapeutic effects of APS in treating neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). It discusses how APS improve insulin resistance, reduce blood glucose levels, enhance cognitive function, and reduce Aß accumulation and neuronal apoptosis by modulating various pathways such as Nrf2, JAK/STAT, Toll, and IMD. For PD, APS protect neurons and stabilize mitochondrial function by inhibiting ROS production and promoting autophagy through the PI3K/AKT/mTOR pathway. APS also reduce oxidative stress and neurotoxicity induced by 6-hydroxydopamine, showcasing their neuroprotective effects. In MS, APS alleviate symptoms by suppressing T cell proliferation and reducing pro-inflammatory cytokine expression via the PD-1/PD-Ls pathway. APS promote myelin regeneration by activating the Sonic hedgehog signaling pathway and fostering the differentiation of neural stem cells into oligodendrocytes. This article emphasizes the significant antioxidant, anti-inflammatory, immunomodulatory, and neuroprotective pharmacological activities of APS, highlighting their potential as promising candidates for the treatment of neurodegenerative diseases.

The Evolving Use of Gold Nanoparticles as a Possible Reversal Agent for the Symptoms of Neurodegenerative Diseases: A Narrative Review.

Neurodegenerative diseases are broadly hallmarked by impaired energy metabolism and toxic intracellular accumulations such as damaged organelles or reactive oxygen species (ROS). Gold nanoparticles readily cross the blood-brain barrier and increase nicotinamide adenine dinucleotide + hydrogen (NADH) oxidation to nicotinamide adenine dinucleotide (NAD+), which is vital for intracellular energy generation, cellular repair, and protection from ROS. Thus, the use of gold nanoparticles to treat and potentially reverse cellular injury seen in neurodegenerative disease has been an area of ongoing research. This systematic review explores current literature regarding the use of gold nanoparticle therapy in the treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). In vitro studies of CNM-Au8 (Clene Nanomedicine, Salt Lake City, UT) have been shown to reduce TDP-43 aggregates associated with ALS. These studies also exhibited the neuroprotective effects of CNM-Au8 in rat primary neurons exposed to amyloid-beta peptides, which are associated with Alzheimer's disease. In animal models of MS, oral delivery of CNM-Au8 was demonstrated to produce robust and significant remyelination activity, oligodendrocyte maturation, and expression of myelin markers. In these same MS animal models, CNM-Au8 improved the motor function of cuprizone-treated mice in both open-field and kinematic gait studies. Recent phase II trials of CNM-Au8 in 13 patients with Parkinson's disease and 11 patients with stable relapsing MS demonstrated a statistically significant increase in the NAD+/NADH ratio across two cohorts. As the current data repeatedly suggest, these gold nanoparticles are efficacious for the treatment and reversal of symptoms across these varying neurodegenerative pathologies. Further opportunities exist for increasing human trials and eventually incorporating this new technology into existing treatment regimens.

The association between cytomegalovirus infection and neurodegenerative diseases: a prospective cohort using UK Biobank data.

Background: Certain viral infections have been linked to the development of neurodegenerative diseases. This study aimed to investigate the association between cytomegalovirus (CMV) infection and five neurodegenerative diseases, spinal muscular atrophy (SMA) and related syndromes, Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and disorders of the autonomic nervous system (DANS). Methods: This prospective cohort included white British individuals who underwent CMV testing in the UK Biobank from January 1, 2006 to December 31, 2021. A Cox proportional hazard model was utilized to estimate the future risk of developing five neurodegenerative diseases in individuals with or without CMV infection, adjusted for batch effect, age, sex, and Townsend deprivation index in Model 1, and additionally for type 2 diabetes, cancer, osteoporosis, vitamin D, monocyte count and leukocyte count in Model 2. Bidirectional Mendelian randomization was employed to validate the potential causal relationship between CMV infection and PD. Findings: A total of 8346 individuals, consisting of 4620 females (55.4%) and 3726 males (44.6%) who were white British at an average age of 56.74 (8.11), were included in this study. The results showed that CMV infection did not affect the risk of developing AD (model 1: HR [95% CI] = 1.01 [0.57, 1.81], P = 0.965; model 2: HR = 1.00 [0.56, 1.79], P = 0.999), SMA and related syndromes (model 1: HR = 3.57 [0.64, 19.80], P = 0.146; model 2: HR = 3.52 [0.63, 19.61], P = 0.152), MS (model 1: HR = 1.16 [0.45, 2.97], P = 0.756; model 2: HR = 1.16 [0.45, 2.97], P = 0.761) and DANS (model 1: HR = 0.65 [0.16, 2.66], P = 0.552; model 2: HR = 0.65 [0.16, 2.64], P = 0.543). Interestingly, it was found that participants who were CMV seronegative had a higher risk of developing PD compared to those who were seropositive (model 1: HR = 2.37 [1.25, 4.51], P = 0.009; model 2: HR = 2.39 [1.25, 4.54], P = 0.008) after excluding deceased individuals. This association was notably stronger in males (model 1: HR = 3.16 [1.42, 7.07], P = 0.005; model 2: HR = 3.41 [1.50, 7.71], P = 0.003), but no significant difference was observed in the female subgroup (model 1: HR = 1.28 [0.40, 4.07], P = 0.679; model 2: HR = 1.27 [0.40, 4.06], P = 0.684). However, a bidirectional Mendelian randomization analysis did not find a genetic association between CMV infection and PD. Interpretation: The study found that males who did not have a CMV infection were at a higher risk of developing PD. The findings provided a new viewpoint on the risk factors for PD and may potentially influence public health approaches for the disease. Funding: National Natural Science Foundation of China (81873776), Natural Science Foundation of Guangdong Province, China (2021A1515011681, 2023A1515010495).

Gene network analysis combined with preclinical studies to identify and elucidate the mechanism of action of novel irreversible Keap1 inhibitor for Parkinson's disease.

The cysteine residues of Keap1 such as C151, C273, and C288 are critical for its repressor activity on Nrf2. However, to date, no molecules have been identified to covalently modify all three cysteine residues for Nrf2 activation. Hence, in this study, our goal is to discover new Keap1 covalent inhibitors that can undergo a Michael addition with all three cysteine residues. The Keap1's intervening region was modeled using Modeller v10.4. Covalent docking and binding free energy were calculated using CovDock. Molecular dynamics (MD) was performed using Desmond. Various in-vitro assays were carried out to confirm the neuroprotective effects of the hit molecule in 6-OHDA-treated SH-SY5Y cells. Further, the best hit was evaluated in vivo for its ability to improve rotenone-induced postural instability and cognitive impairment in male rats. Finally, network pharmacology was used to summarize the complete molecular mechanism of the hit molecule. Chalcone and plumbagin were found to form the necessary covalent bonds with all three cysteine residues. However, MD analysis indicated that the binding of plumbagin is more stable than chalcone. Plumbagin displayed neuroprotective effects in 6-OHDA-treated SH-SY5Y cells at concentrations 0.01 and 0.1 µM. Plumbagin at 0.1 µM had positive effects on reactive oxygen species formation and glutathione levels. Plumbagin also improved postural instability and cognitive impairment in rotenone-treated male rats. Our network analysis indicated that plumbagin could also improve dopamine signaling. Additionally, plumbagin could exhibit anti-oxidant and anti-inflammatory activity through the activation of Nrf2. Cumulatively, our study suggests that plumbagin is a novel Keap1 covalent inhibitor for Nrf2-mediated neuroprotection in PD.

The akinetic crisis in Parkinson´s disease- the upper end of a spectrum of subacute akinetic states.

The akinetic crisis is defined as an acute, potentially life-threatening, levodopa-resistant, severe aggravation of rigidity, severe akinesia, associated with high fever, disturbance of consciousness, dysphagia and autonomic symptoms often due to disruption of dopaminergic medication or infections. The akinetic crisis is a relatively rare event, however subacute mild-moderate motor symptom deterioration in Parkinson´s disease (PD) patients is a frequent cause of hospitalization. In this review, we propose that the akinetic crisis is the upper end of a continuous spectrum of acute akinetic states depending on the degree of the progressive levodopa-resistance. Clinical symptomatology, risk factors, and instrumental diagnostics as the DAT-SPECT reflecting a biomarker of levodopa-resistance will be discussed to evaluate the spectrum of akinetic states. Pathophysiological considerations about the potential role of proinflammatory cytokines on the progressive levodopa-resistance will be discussed and therapeutical, consensus-based guidelines will be presented.

Microstructural alterations in white matter and related neurobiology based on the new clinical subtypes of Parkinson's disease.

Background and objectives: The advent of new clinical subtyping systems for Parkinson's disease (PD) has led to the classification of patients into distinct groups: mild motor predominant (PD-MMP), intermediate (PD-IM), and diffuse malignant (PD-DM). Our goal was to evaluate the efficacy of diffusion tensor imaging (DTI) in the early diagnosis, assessment of clinical progression, and prediction of prognosis of these PD subtypes. Additionally, we attempted to understand the pathological mechanisms behind white matter damage using single-photon emission computed tomography (SPECT) and cerebrospinal fluid (CSF) analyses. Methods: We classified 135 de novo PD patients based on new clinical criteria and followed them up after 1 year, along with 45 healthy controls (HCs). We utilized tract-based spatial statistics to assess the microstructural changes of white matter at baseline and employed multiple linear regression to examine the associations between DTI metrics and clinical data at baseline and after follow-up. Results: Compared to HCs, patients with the PD-DM subtype demonstrated reduced fractional anisotropy (FA), increased axial diffusivity (AD), and elevated radial diffusivity (RD) at baseline. The FA and RD values correlated with the severity of motor symptoms, with RD also linked to cognitive performance. Changes in FA over time were found to be in sync with changes in motor scores and global composite outcome measures. Furthermore, baseline AD values and their rate of change were related to alterations in semantic verbal fluency. We also discovered the relationship between FA values and the levels of α-synuclein and ß-amyloid. Reduced dopamine transporter uptake in the left putamen correlated with RD values in superficial white matter, motor symptoms, and autonomic dysfunction at baseline as well as cognitive impairments after 1 year. Conclusions: The PD-DM subtype is characterized by severe clinical symptoms and a faster progression when compared to the other subtypes. DTI, a well-established technique, facilitates the early identification of white matter damage, elucidates the pathophysiological mechanisms of disease progression, and predicts cognitively related outcomes. The results of SPECT and CSF analyses can be used to explain the specific pattern of white matter damage in patients with the PD-DM subtype.

Mechanism of Yishen Chuchan decoction intervention of Parkinson's disease based on network pharmacology and experimental verification.

The incidence of Parkinson's disease (PD) rises rapidly with the increase of age. With the advent of global aging, the number of patients with PD is rising along with the elderly population, especially in China. Previously, we found that Yishen chuchan decoction (YCD), prescribed based on clinical experience, has the potential of alleviating symptoms, delaying the progression, and controlling the development of PD. Nonetheless, the underlying mechanistic role is yet to be explored. Aim: This research examined the possible therapeutic effects of YCD in alleviating PD via a systematic approach with network pharmacology and experimental validation, aiming at providing a new understanding of traditional Chinese medicine management regarding PD. Methods: The chemical structure and properties of YCD were adopted from Traditional Chinese Medicine System Pharmacology Database (TCMSP), SwissADME, PubChem, and PubMed. The potential targets for YCD and PD were identified using Swiss Target Prediction, GeneCard, PubChem, and UniProt. The herbal-component-target network was created via the Cytoscape software. Moreover, by using the STRING database, the protein-protein interaction (PPI) network was screened. Gene function GO and KEGG pathway enrichment analyses were performed via the Metascape database. YCD-medicated Rat Serum from Sprague-Dawley (SD) Rats was prepared, and SH-SY5Y cells were preconditioned with rotenone to develop the PD model. To examine the impact of YCD on these cells and explore the mechanistic role of the p38 mitogen-activated protein kinase (MAPK) pathway, the cells were pretreated with either serum or a p38 MAPK pathway inhibitor. This study employed the Cell Counting Kit (CCK)-8 assay and Hoechst 33,342 staining to evaluate the viability and morphological changes induced by the YCD-medicated rat serum on rotenone-treated SH-SY5Y cells. Apoptosis was assessed by Flow cytometry. Immunofluorescence staining assessed the microtubule-associated protein 2 (MAP2) level. Enzyme-linked immunosorbent assay (ELISA) was employed to quantify the concentrations of inflammatory mediators interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Also, reactive oxygen species (ROS) and superoxide dismutase (SOD) levels were determined. Western Blotting measured the expression of total and phospho-p38 MAPK (p-p38). Results: This study identified 65 active components in YCD, which were found to target 801 specific genes. By screening, 63 potential core targets were identified from a pool of 172 overlapping targets between PD and YCD. These targets were examined by GO and KEGG analyses revealing their substantial correlation to MAPK, PI3K-Akt signaling pathways, positively controlling protein phosphorylation, and pathways of neurodegenerative diseases. SH-SY5Y cells were treated with 2 µM rotenone for 48 h, which reduced cell viability to 50 %, and reduced MAP2 expression, increased the rate of apoptosis, oxidative stress, inflammation, and p-p38 expressions. YCD-medicated rat serum significantly improved the viability, reduced the apoptosis rate, and increased the MAP2 expression. YCD-medicated serum increased SOD, reduced ROS and suppressed IL-6, IL-1ß and TNF-α levels, thus inhibiting oxidative stress and inflammation in rotenone-treated SH-SY5Y cells. Moreover, YCD-medicated serum substantially lowered the p-p38 expression induced by rotenone. SB203580, a specific inhibitor of p38 MAPK, could also inhibit the p-p38 expression, apoptosis, and restore morphological damage of cells, also improve inflammation and oxidative stress. Conclusion: YCD enhanced cell viability and reduced apoptosis rate, inflammation, and oxidative stress in vitro. These beneficial effects could potentially involve the suppression of p38 pathway and suppressed the phosphorylation of p38 MAPK.

Neurodegenerative diseases and catechins: (-)-epigallocatechin-3-gallate is a modulator of chronic neuroinflammation and oxidative stress.

Catechins, a class of phytochemicals found in various fruits and tea leaves, have garnered attention for their diverse health-promoting properties, including their potential in combating neurodegenerative diseases. Among these catechins, (-)-epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in green tea, has emerged as a promising therapeutic agent due to its potent antioxidant and anti-inflammatory effects. Chronic neuroinflammation and oxidative stress are key pathological mechanisms in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). EGCG has neuroprotective efficacy due to scavenging free radicals, reducing oxidative stress and attenuating neuroinflammatory processes. This review discusses the molecular mechanisms of EGCG's anti-oxidative stress and chronic neuroinflammation, emphasizing its effects on autoimmune responses, neuroimmune system interactions, and focusing on the related effects on AD and PD. By elucidating EGCG's mechanisms of action and its impact on neurodegenerative processes, this review underscores the potential of EGCG as a therapeutic intervention for AD, PD, and possibly other neurodegenerative diseases. Overall, EGCG emerges as a promising natural compound for combating chronic neuroinflammation and oxidative stress, offering novel avenues for neuroprotective strategies in the treatment of neurodegenerative disorders.

Exacerbation of delirium and epileptic seizures in an older man with idiopathic Parkinson's disease due to multiple prescriptions: a case report.

Introduction: Parkinson's disease (PD) is a disorder characterized by motor symptoms, such as rigidity, akinesia, and resting tremor, as well as non-motor symptoms, including psychiatric manifestations and autonomic failure. The prevalence of PD increases with age, and the condition is more common in men than in women. Conversely, polypharmacy has emerged as a paramount medical concern, especially among older patients, correlating with medicines' adverse effects, interactions between medicines, frequent admissions to the hospital, and a high risk of morbidity and mortality. Case description: We encountered an older male patient with idiopathic PD and mild renal dysfunction. Originally prescribed 14 types of medicines, including anti-PD drugs, the patient developed delirium and epileptic seizures during hospitalization. After reducing the number of medications, including amantadine, the symptoms significantly improved. This clinical course suggests that polypharmacy, in addition to PD itself, poses a significant risk of delirium and epileptic seizures, even in patients with mild renal dysfunction. Conclusion: This report is indicative of the risk of polypharmacy and highlights the importance of citing drug interactions for a correct diagnosis in patients presenting with complex symptoms.

Epigenetic associations of GPNMB rs199347 variant with alcohol consumption in Parkinson's disease.

Introduction: Alcohol consumption can induce a neuroinflammatory response and contribute to the progression of neurodegeneration. However, its association with Parkinson's disease (PD), the second most common neurodegenerative disorder, remains undetermined. Recent studies suggest that the glycoprotein non-metastatic melanoma protein B (GPNMB) is a potential biomarker for PD. We evaluated the association of rs199347, a variant of the GPNMB gene, with alcohol consumption and methylation upstream of GPNMB. Methods: We retrieved genetic and DNA methylation data obtained from participants enrolled in the Taiwan Biobank (TWB) between 2008 and 2016. After excluding individuals with incomplete or missing information about potential PD risk factors, we included 1,357 participants in our final analyses. We used multiple linear regression to assess the association of GPNMB rs199347 and chronic alcohol consumption (and other potential risk factors) with GPNMB cg17274742 methylation. Results: There was no difference between the distribution of GPNMB rs199347 genotypes between chronic alcohol consumers and the other study participants. A significant interaction was observed between the GPNMB rs199347 variant and alcohol consumption (p = 0.0102) concerning cg17274742 methylation. Compared to non-chronic alcohol consumers with the AA genotype, alcohol drinkers with the rs199347 GG genotype had significantly lower levels (hypomethylation) of cg17274742 (p = 0.0187). Conclusion: Alcohol consumption among individuals with the rs199347 GG genotype was associated with lower levels of cg17274742 methylation, which could increase expression of the GPNMB gene, an important neuroinflammatory-related risk gene for PD.

Association between dietary niacin intake and risk of Parkinson's disease in US adults: cross-sectional analysis of survey data from NHANES 2005-2018.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases and involves various pathogenic mechanisms, including oxidative stress and neuroinflammation. Niacin, an important cofactor in mitochondrial energy metabolism, may play a key role in the pathogenesis of PD. An in-depth exploration of the relationship between niacin and mitochondrial energy metabolism may provide new targets for the treatment of PD. The present study was designed to examine the association between dietary niacin intake and the risk of PD in US adults. Data from adults aged 40 years and older collected during cycles of the United States (US) National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018 were used. A multiple logistic regression model was used to analyze the relationship between dietary niacin intake and the risk of PD. Further linear tests using restricted cubic splines (RCS) were performed to explore the shape of the dose-response relationship. Subgroup stratification and interaction analyses were conducted according to years of education, marital status, smoking, and hypertension to evaluate the stability of the association between different subgroups. A total of 20,211 participants were included in this study, of which 192 were diagnosed with PD. In the fully adjusted multiple logistic regression model, dietary niacin intake was negatively associated with the risk of PD (OR: 0.77, 95%CI: 0.6-0.99; p = 0.042). In the RCS linear test, the occurrence of PD was negatively correlated with dietary niacin intake (nonlinearity: p = 0.232). In stratified analyses, dietary niacin intake was more strongly associated with PD and acted as an important protective factor in patients with fewer years of education (OR: 0.35, 95%CI: 0.13-0.93), married or cohabitating (OR: 0.71, 95%CI: 0.5-0.99), taking dietary supplements (OR: 0.6, 95%CI: 0.37 0.97), non-smokers (OR: 0.57, 95%CI: 0.39-0.85), those with hypertension (OR: 0.63, 95%CI: 0.63-0.95), coronary artery disease (OR: 0.77, 95%CI: 0.6-1), and stroke (OR: 0.75, 95%CI: 0.88-0.98), but the interaction was not statistically significant in all subgroups. Dietary niacin intake was inversely associated with PD risk in US adults, with a 23% reduction in risk for each 10 mg increase in niacin intake.

Wnt/ß-catenin pathway as a potential target for Parkinson's disease: a cohort study of romosozumab using routinely collected health data in Japan.

Introduction: Romosozumab is a monoclonal antibody approved for osteoporosis which targets sclerostin, an endogenous inhibitor of Wnt/ß-catenin pathway. Given the essential roles of the Wnt/ß-catenin pathway in various tissues, we hypothesized romosozumab treatment may influence other conditions. Methods: This cohort study included patients prescribed romosozumab or parathyroid receptor (PTHR) agonists after 1 January 2019, using a Japanese electronic medical record database. The outcomes of interest included autoimmune disease, interstitial pneumonia, cardiovascular outcome, Alzheimer's disease, Parkinson's disease (PD), serious infections, and malignancies. A stabilized inverse probability-weighted Cox proportional hazard model was used to estimate the hazard ratios. Age- and gender-based subgroup analyses were conducted. Exploratory outcomes based on three-digit International Classification of Diseases 10th Revision-based were also examined. Results: In total, 2,673 patients treated with romosozumab and 5,980 treated with PTHR agonists were identified, respectively. While most outcomes of interest showed no association with romosozumab, the risk of PD decreased with romosozumab (hazard ratio [95% confidence interval], 0.37 [0.14-0.94]) compared with PTHR agonist. Regarding the cardiovascular outcome, no notable association was identified overall; however, gender-based subgroup analysis suggested that male sex may be a potential risk factor with romosozumab treatment. Only 16 of 903 exploratory outcomes were potentially influenced by romosozumab. Conclusion: Romosozumab lowered the risk of PD development compared with PTHR agonist. The study also highlights the utility of routinely collected health data for drug repositioning. While further validation is warranted, the findings suggest that the Wnt-ß-catenin pathway holds promise as a therapeutic target for PD.

Recent Advances in the Synthesis of Antioxidant Derivatives: Pharmacological Insights for Neurological Disorders.

Neurological disorders, characterized by oxidative stress (OS) and inflammation, have become a major global health concern. Redox reactions play a vital role in regulating the balance of the neuronal microenvironment. Specifically, the imbalance leads to a significant weakening of the organism's natural defensive mechanisms. This, in turn, causes the development of harmful oxidative stress, which plays a crucial role in the onset and progression of neurodegenerative dis-eases. The quest for effective therapeutic agents has led to significant advancements in the syn-thesis of antioxidant derivatives. This review provides a comprehensive overview of the recent developments in the use of novel antioxidant compounds with potential pharmacological applica-tions in the management of neurological disorders. The discussed compounds encompass a di-verse range of chemical structures, including polyphenols, vitamins, flavonoids, and hybrid mole-cules, highlighting their varied mechanisms of action. This review also focuses on the mechanism of oxidative stress in developing neurodegenerative disease. The neuroprotective effects of these antioxidant derivatives are explored in the context of specific neurological disorders, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. The ultimate goal is to pro-vide effective treatments for these debilitating conditions and improve the quality of life for pa-tients.

Camptocormia in Parkinson's Disease: Systematic Review of Management Using Spine Surgery.

OBJECTIVE: Postural abnormalities are a debilitating symptom of Parkinson's disease (PD) that may require spinal intervention. Camptocormia is a unique abnormality most seen in PD, defined by a severe forward-flexion of the trunk that completely resolves when supine. The condition presents a challenge due to an undefined pathophysiology and optimal therapeutic approach in a high-risk patient population. In this study, the authors systematically reviewed the literature regarding the use of spine surgery for the treatment of camptocormia in PD. METHODS: PubMed, Embase, Web of Science, and Cochrane Library were systematically queried for studies involving spine surgery as treatment of PD-associated camptocormia. Studies involving nonsurgical management, deep brain stimulation (DBS), non-camptocormic PD patients undergoing surgery, or were out of scope were excluded. RESULTS: The search resulted in 5 studies, with a total of 19 PD patients with camptocormia who underwent spine surgery (73.7% female). The mean age was 69.5 years (range, 59 - 83), and mean PD duration was 69.5 months (range, 36 - 84). Out of 19 patients, 11 required surgical revision (57.9%), with an average of 0.68 revisions per patient (range, 0-2). Radiographic and patient-reported outcomes were inconsistently reported yet showed improvement. Ultimately, 18 patients were reported to have positive outcomes. CONCLUSION: Despite an increased risk of complication and revision that is inherent to PD patients, spine surgery has been proven as a reasonable alternative that should be prospectively studied further, as 18/19 patients had favorable outcomes.

Targeting the RUNX3-miR-186-3p-DAT-IGF1R axis as a therapeutic strategy in a Parkinson's disease model.

With the increasing age of the population worldwide, the incidence rate of Parkinson's disease (PD) is increasing annually. Currently, the treatment strategy for PD only improves clinical symptoms. No effective treatment strategy can slow down the progression of the disease. In the present study, whole transcriptome sequencing was used to obtain the mRNA and miRNA expression profiles in a PD mouse model, which revealed the pathogenesis of PD. The transcription factor RUNX3 upregulated the miR-186-3p expression in the PD model. Furthermore, the high miR-186-3p expression in PD can be targeted to inhibit the DAT expression, resulting in a decrease in the dopamine content of dopaminergic neurons. Moreover, miR-186-3p can be targeted to inhibit the IGF1R expression and prevent the activation of the IGF1R-P-PI3K-P-AKT pathway, thus increasing the apoptosis of dopaminergic neurons by regulating the cytochrome c-Bax-cleaved caspase-3 pathway. Our research showed that the RUNX3-miR-186-3p-DAT-IGF1R axis plays a key role in the pathogenesis of PD, and miR-186-3p is a potential target for the treatment of PD.

Remote levodopa challenge test in Parkinson's disease: Feasibility, reliability, validity and economic value.

BACKGROUND AND PURPOSE: The aim was to demonstrate the feasibility, reliability and validity of an in-home remote levodopa challenge test (LCT), as delivered through an online platform, for patients with Parkinson's disease (PwPD). METHODS: Patients with Parkinson's disease eligible for deep brain stimulation surgery screening were enrolled. Participants sequentially received an in-home remote LCT and an in-hospital standard LCT (separated by 2.71 weeks). A modified Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III omitting rigidity and postural stability items was used in the remote LCT. The reliability of the remote LCT was evaluated using the intraclass correlation coefficient and the concurrent validity was evaluated using the Pearson's correlation coefficient r between the levodopa responsiveness of the remote and standard LCT. RESULTS: Out of 106 PwPD screened, 80 (75.5%) completed both the remote and standard LCT. There was a good reliability (intraclass correlation coefficient 0.81, 95% confidence interval 0.69-0.88) and a strong correlation (r = 0.84, 95% confidence interval 0.77-0.90) between the levodopa responsiveness of the remote and standard LCT. The mean cost for PwPD was estimated to be reduced by 91% by using the remote LCT. CONCLUSION: The remote LCT is feasible, reliable and valid and may reduce healthcare-related costs for PwPD and their caregivers.

LncRNA KCNQ1OT1 promotes NLRP3 inflammasome activation in Parkinson's disease by regulating pri-miR-186/mature miR-186/NLRP3 axis.

Increasing evidence indicated that neuroinflammation was involved in progression of Parkinson's disease (PD). Long noncoding RNAs (lncRNAs) played important roles in regulating inflammatory processes in multiple kinds of human diseases such as cancer diabetes, cardiomyopathy, and neurodegenerative disorders. The mechanisms by which lncRNAs regulated PD related inflammation and dopaminergic neuronal loss have not yet been fully elucidated. In current study, we intended to explore the function and potential mechanism of lncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) in regulating inflammasome activation in PD. Functional assays confirmed that knockdown of KCNQ1OT1 suppress microglial NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and attenuated dopaminergic neuronal loss in PD model mice. As KCNQ1OT1 located in both cytoplasm and nucleus of microglia, we demonstrated that KCNQ1OT1 promoted microglial NLRP3 inflammasome activation by competitive binding with miR-186 in cytoplasm and inhibited pri-miR-186 mediated NLRP3 silencing through recruitment of DiGeorge syndrome critical region gene 8 (DGCR8) in nucleus, respectively. Our study found a novel lncRNA-pri-miRNA/mature miRNA-mRNA regulatory network in microglia mediated NLRP3 inflammasome activation and dopaminergic neuronal loss, provided further insights for the treatment of Parkinson's disease.

Impact of Stimulation Frequency on Verbal Fluency Following Bilateral Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease.

OBJECTIVE: The effects of stimulation frequency on verbal fluency (VF) following subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) are not well understood. The present study examines the impact stimulation frequency has on VF following bilateral STN-DBS in PD. METHODS: Prospective study of 38 consecutive patients with PD with low frequency STN-DBS (LFS) (n = 10) and high frequency STN-DBS (HFS) (n = 14), and a non-operated PD control group consisting of patients with fluctuating response to dopaminergic medication (n = 14) homogeneous in age, education, disease duration, and global cognitive function. Patients were evaluated on VF tasks (letter, semantic, action verbs, alternating). A one-way analysis of variance (ANOVA) was conducted to assess distinctions between groups. Pre- and post-surgical comparisons of fluencies were performed for operated groups. A mixed ANOVA was applied to the data to evaluate the interaction between treatment (HFS vs. LFS) and time (pre- vs. post-surgery). Strategy use (clustering and switching) was evaluated. RESULTS: Semantic and letter fluency performance revealed significant differences between HFS and LFS groups. Pre- and post-surgical comparisons revealed HFS negatively affected letter, semantic, and action fluencies, but LFS had no effect on VF. No interaction effect or main effect of treatment was found. Main effect of time was significant for semantic and action fluencies indicating a decrease in postoperative fluency performance. Patients with LFS produced larger average cluster sizes than patients with HFS. CONCLUSION: LFS may be less detrimental to VF, but these findings suggest that VF decline following STN-DBS is not caused by stimulation frequency alone.

Safety and efficiency of deep brain stimulation in the elderly patients with Parkinson's disease.

AIMS: Deep brain stimulation (DBS) is not routinely performed in elderly patients (≥75 years old) to date because of concerns about complications and decreased benefit. This study aimed to evaluate the safety and efficacy of DBS in elderly patients with Parkinson's disease. METHODS: A retrospective analysis was performed using data from 40 elderly patients from four centers who were treated with neurosurgical robot-assisted DBS between September 2016 and December 2021. These patients were followed up for a minimum period of 2 years, with a subgroup of nine patients followed up for 5-7 years. Patient demographic characteristics, surgical information, pre- and postoperative motor scores, non-motor scores, activities of daily living, and complications were retrospectively analyzed. RESULTS: The mean surgical procedure duration was 1.65 ± 0.24 h, with a mean electrode implantation duration of 1.10 ± 0.23 h and a mean pulse generator implantation duration of 0.55 ± 0.07 h. The mean pneumocephalus volume, electrode fusion error, and Tao's DBS surgery scale were 16.23 ± 12.81 cm3, 0.81 ± 0.23 mm, and 77.63 ± 8.08, respectively. One patient developed a skin infection, and the device was removed. The Unified Parkinson's disease rating scale, Unified Parkinson's disease rating scale of Part III, tremor, rigidity, bradykinesia, axial, and Barthel index for activities of daily living (ADL-Barthel) scores significantly improved at the 2-year follow-up (p < 0.05). The levodopa equivalent daily dose (LEDD) was significantly reduced at the 2-year follow-up (p < 0.05). However, the Montreal cognitive assessment, Hamilton depression scale, and Hamilton anxiety scale scores did not significantly change during the 2-year follow-up (p > 0.05). Additionally, in the subgroup with a 5-year follow-up, the motor symptoms, ADL-Barthel score, and cognitive function worsened over time compared to baseline. However, there was still an improvement in motor symptoms and ADL with DBS on-stimulation compared with the off-stimulation state. The LEDD increased 5 years after surgery compared to that at baseline. Eleven patients had passed away during follow-up, the mean survival time was 38.3 ± 17.3 months after surgery, and the mean age at the time of death was 81.2 (range 75-87) years. CONCLUSION: Robot-assisted DBS surgery for the elderly patients with Parkinson's disease is accurate and safe. Motor symptoms and ADL significantly improve and patients can benefit from long-term neuromodulation, which may decrease the risk of death.