Association of elevated cerebrospinal fluid levels of the longevity protein α-Klotho with a delayed onset of cognitive impairment in Parkinson's disease patients.

BACKGROUND AND PURPOSE: Parkinson's disease (PD) is an age-related condition characterized by substantial phenotypic variability. Consequently, pathways and proteins involved in biological aging, such as the central aging pathway comprising insulin-like growth factor 1-α-Klotho-sirtuin 1-forkhead box O3-peroxisome proliferator-activated receptor γ, may potentially influence disease progression. METHODS: Cerebrospinal fluid (CSF) levels of α-Klotho in 471 PD patients were examined. Of the 471 patients, 96 carried a GBA1 variant (PD GBA1), whilst the 375 non-carriers were classified as PD wild-type (PD WT). Each patient was stratified into a CSF α-Klotho tertile group based on the individual level. Kaplan-Meier survival curves and Cox regression analysis stratified by tertile groups were conducted. These longitudinal data were available for 255 patients. Follow-up times reached from 8.4 to 12.4 years. The stratification into PD WT and PD GBA1 was undertaken to evaluate potential continuum patterns, particularly in relation to CSF levels. RESULTS: Higher CSF levels of α-Klotho were associated with a significant later onset of cognitive impairment. Elevated levels of α-Klotho in CSF were linked to higher Montreal Cognitive Assessment scores in male PD patients with GBA1 mutations. CONCLUSIONS: Our results indicate that higher CSF levels of α-Klotho are associated with a delayed cognitive decline in PD. Notably, this correlation is more prominently observed in PD patients with GBA1 mutations, potentially reflecting the accelerated biological aging profile characteristic of individuals harboring GBA1 variants.

Transdermal delivery of resveratrol loaded solid lipid nanoparticle as a microneedle patch: a novel approach for the treatment of Parkinson's disease.

Parkinson's disease (PD), affecting millions of people worldwide and expected to impact 10 million by 2030, manifests a spectrum of motor and non-motor symptoms linked to the decline of dopaminergic neurons. Current therapies manage PD symptoms but lack efficacy in slowing disease progression, emphasizing the urgency for more effective treatments. Resveratrol (RSV), recognized for its neuroprotective and antioxidative properties, encounters challenges in clinical use for PD due to limited bioavailability. Researchers have investigated lipid-based nanoformulations, specifically solid lipid nanoparticles (SLNs), to enhance RSV stability. Oral drug delivery via SLNs faces obstacles, prompting exploration into transdermal delivery using SLNs integrated with microneedles (MNs) for improved patient compliance. In this study, an RSV-loaded SLNs (RSV -SLNs) incorporated into the MN patch was developed for transdermal RSV delivery to improve its stability and patient compliance. Characterization studies demonstrated favorable physical properties of SLNs with a sustained drug release profile of 78.36 ± 0.74%. The developed MNs exhibited mechanical robustness and skin penetration capabilities. Ex vivo permeation studies displayed substantial drug permeation of 68.39 ± 1.4% through the skin. In an in vivo pharmacokinetic study, the RSV-SLNs delivered through MNs exhibited a significant increase in Cmax, Tmax, and AUC0 - t values, alongside a reduced elimination rate in blood plasma in contrast to the administration of pure RSV via MNs. Moreover, an in vivo study showcased enhanced behavioral functioning and increased brain antioxidant levels in the treated animals. In-vivo skin irritation study revealed no signs of irritation till 24 h which permits long-term MNs application. Histopathological analysis showed notable changes in the brain regions of the rat, specifically the striatum and substantia nigra, after the completion of the treatment. Based on these findings, the development of an RSV-SLN loaded MNs (RSVSNLMP) patch presents a novel approach, with the potential to enhance the drug's efficiency, patient compliance, and therapeutic outcomes for PD, offering a promising avenue for advanced PD therapy.

The value of consciousness coaching in Parkinson's disease: Experiences and possible impact of holistic coaching.

Background: People with a chronic condition such as Parkinson's disease (PD) struggle with acceptance and finding meaning in life. Consciousness coaching could be a valuable addition in addressing these issues. Objective: We aim to evaluate the user experiences and potential effectiveness of consciousness coaching for people with PD (PwPD). Methods: We performed a pilot randomized controlled trial including PwPD in Hoehn & Yahr stage 1-3. People with cognitive impairments, severe psychiatric disorders, or those who did not have a clear issue to address with consciousness coaching, were excluded. PwPD were randomly allocated to either receiving 6 months of consciousness coaching in addition to usual care or to usual care alone. To explore experiences we performed semi-structured qualitative interviews with all PwPD in the intervention group. Potential effects were explored using questionnaires on quality of life, activities of daily life, self-management and non-motor symptoms at baseline and after 6 months. Results: We included 39 PwPD, 19 participants in the intervention group and 20 in the control group. Based on the interviews, we identified a number of themes and codes. In general PwPD experienced consciousness coaching as confronting but supportive in reaching their goals and in taking more responsibility for their lives. Quantitatively, we did not find a difference between groups for any of the outcomes. Conclusions: Consciousness coaching was considered valuable by most participants in this study and may be an interesting addition to PD treatment. We did not find any effects of the intervention on PD symptoms or quality of life.

Cognitive safety of focused ultrasound thalamotomy for tremor: 1-year follow-up results of the COGNIFUS part 2 study.

Introduction: In the COGNitive in Focused UltraSound (COGNIFUS) study, we examined the 6-month cognitive outcomes of patients undergoing MRgFUS thalamotomy. This study endorsed the safety profile of the procedure in terms of cognitive functions that cannot be evaluated in real-time during the procedure unlike other aspects. The aim of the COGNIFUS Part 2 study was to investigate the cognitive trajectory of MRgFUS patients over a 1-year period, in order to confirm long-term safety and satisfaction. Methods: We prospectively evaluated the cognitive and neurobehavioral profile of patients with essential tremor (ET) or Parkinson's Disease (PD) related tremor undergoing MRgFUS thalamotomy at 1 year-follow-up following the treatment. Results: The sample consists of 50 patients (male 76%; mean age ± SD 69.0 ± 8.56; mean disease duration ± SD 12.13 ± 12.59; ET 28, PD 22 patients). A significant improvement was detected at the 1 year-follow-up assessment in anxiety and mood feelings (Hamilton Anxiety rating scale 5.66 ± 5.02 vs. 2.69 ± 3.76, p ≤ <0.001; Beck depression Inventory II score 3.74 ± 3.80 vs. 1.80 ± 2.78, p = 0.001), memory domains (Rey Auditory Verbal Learning Test, immediate recall 31.76 ± 7.60 vs. 35.38 ± 7.72, p = 0.001 and delayed recall scores 5.57 ± 2 0.75 vs. 6.41 ± 2.48), frontal functions (Frontal Assessment Battery score 14.24 ± 3.04 vs. 15.16 ± 2.74) and in quality of life (Quality of life in Essential Tremor Questionnaire 35.00 ± 12.08 vs. 9.03 ± 10.64, p ≤ 0.001 and PD Questionnaire -8 7.86 ± 3.10 vs. 3.09 ± 2.29, p ≤ 0.001). Conclusion: Our study supports the long-term efficacy and cognitive safety of MRgFUS treatment for ET and PD.

Single-cell sequencing of the substantia nigra reveals microglial activation in a model of MPTP.

Background: N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin widely used to induce PD models, but the effect of MPTP on the cells and genes of PD has not been fully elucidated. Methods: Single-nucleus RNA sequencing was performed in the Substantia Nigra (SN) of MPTP mice. UMAP analysis was used for the dimensionality reduction visualization of the SN in the MPTP mice. Known marker genes highly expressed genes in each cluster were used to annotate most clusters. Specific Differentially Expressed Genes (DEGs) and PD risk genes analysis were used to find MPTP-associated cells. GO, KEGG, PPI network, GSEA and CellChat analysis were used to reveal cell type-specific functional alterations and disruption of cell-cell communication networks. Subset reconstruction and pseudotime analysis were used to reveal the activation status of the cells, and to find the transcription factors with trajectory characterized. Results: Initially, we observed specific DEGs and PD risk genes enrichment in microglia. Next, We obtained the functional phenotype changes in microglia and found that IGF, AGRN and PTN pathways were reduced in MPTP mice. Finally, we analyzed the activation state of microglia and revealed a pro-inflammatory trajectory characterized by transcription factors Nfe2l2 and Runx1. Conclusion: Our work revealed alterations in microglia function, signaling pathways and key genes in the SN of MPTP mice.

Frozen Shoulder and the Risk of Parkinson's Disease: A Danish Registry-Based Cohort Study.

Background: Frozen shoulder may be an early preclinical symptom of Parkinson's disease (PD). Objective: To examine PD risk after frozen shoulder diagnosis and to evaluate this disorder as a possible manifestation of parkinsonism preceding the clinical recognition of PD and possible target for screening. Methods: Danish population-based medical registries were used to identify patients aged ≥40 years with a first-time frozen shoulder diagnosis (1995-2016). A comparison cohort was randomly selected from the general population matched on age and sex. To address detection bias and the specificity of frozen shoulder diagnosis, we performed a sensitivity analysis, using similar matching criteria to select a cohort of patients with back pain diagnosis. The outcome was incident PD. Cumulative incidences and adjusted hazard ratios (HRs) were estimated with 95% confidence intervals (CIs). Results: We identified 37,041 individuals with frozen shoulder, 370,410 general population comparators, and 111,101 back pain comparators. The cumulative incidence of PD at 0-22 years follow-up was 1.51% in the frozen shoulder cohort, 1.03% in the general population cohort, and 1.32% in the back pain cohort. For frozen shoulder versus general population, adjusted HRs were 1.94 (CI: 1.20-3.13) at 0-1 years and 1.45 (CI: 1.24-1.70) at 0-22 years follow-up. For frozen shoulder versus back pain, adjusted HRs were 0.89 (CI: 0.54-1.46) and 1.01 (CI: 0.84-1.21), respectively. Conclusion: Patients with frozen shoulder had an increased PD risk compared with the general population, although the absolute risks were low. Frozen shoulder might sometimes represent early manifestations of PD. Detection bias probably cannot account for the increased PD risk during the long-term follow-up.

Measures of the coupling between fluctuating brain network organization and heartbeat dynamics.

In recent years, there has been an increasing interest in studying brain-heart interactions. Methodological advancements have been proposed to investigate how the brain and the heart communicate, leading to new insights into some neural functions. However, most frameworks look at the interaction of only one brain region with heartbeat dynamics, overlooking that the brain has functional networks that change dynamically in response to internal and external demands. We propose a new framework for assessing the functional interplay between cortical networks and cardiac dynamics from noninvasive electrophysiological recordings. We focused on fluctuating network metrics obtained from connectivity matrices of EEG data. Specifically, we quantified the coupling between cardiac sympathetic-vagal activity and brain network metrics of clustering, efficiency, assortativity, and modularity. We validate our proposal using open-source datasets: one that involves emotion elicitation in healthy individuals, and another with resting-state data from patients with Parkinson's disease. Our results suggest that the connection between cortical network segregation and cardiac dynamics may offer valuable insights into the affective state of healthy participants, and alterations in the network physiology of Parkinson's disease. By considering multiple network properties, this framework may offer a more comprehensive understanding of brain-heart interactions. Our findings hold promise in the development of biomarkers for diagnostic and cognitive/motor function evaluation.

Successful Management of Acute Subdural Hematoma in Deep Brain Stimulation Patient: A Case Report and Literature Review.

Deep brain stimulation (DBS) has emerged as an important therapeutic option for several movement disorders; however, the management of acute complications, such as acute subdural hematoma (ASDH), remains challenging. This is the case of a 71-year-old woman with Parkinson's disease who developed ASDH 12 years after bilateral DBS placement. On admission with altered consciousness, imaging revealed significant displacement of the DBS electrodes because of the hematoma. Emergent craniotomy with endoscopic evacuation was performed with preservation of the DBS system. Postoperatively, complete evacuation of the hematoma was confirmed, and the patient experienced significant clinical improvement. ASDH causes significant electrode displacement in patients undergoing DBS. After hematoma evacuation, the electrodes were observed to return to their proper position, and the patient exhibited a favorable clinical response to stimulation. To preserve the DBS electrodes, endoscopic hematoma evacuation via a small craniotomy may be useful.

Drug Evaluation of Parkinson's Disease Patient-Derived Midbrain Organoids Using Mesoporous Au Nanodot-Patterned 3D Concave Electrode.

Brain organoids are being recognized as valuable tools for drug evaluation in neurodegenerative diseases due to their similarity to the human brain's structure and function. However, a critical challenge is the lack of selective and sensitive electrochemical sensing platforms to detect the response of brain organoids, particularly changes in the neurotransmitter concentration upon drug treatment. This study introduces a 3D concave electrode patterned with a mesoporous Au nanodot for the detection of electrochemical signals of dopamine in response to drugs in brain organoids for the first time. The mesoporous Au nanodot-patterned film was fabricated using laser interference lithography and electrochemical deposition. Then, the film was attached to a polymer-based 3D concave mold to obtain a 3D concave electrode. Midbrain organoids generated from Parkinson's disease (PD) patient-derived iPSCs with gene mutations (named as PD midbrain organoid) or normal midbrain organoids were positioned on the developed 3D concave electrode. The 3D concave electrode showed a 1.4 times higher electrochemical signal of dopamine compared to the bare gold electrode. And the dopamine secreted from normal midbrain organoids or PD midbrain organoids on the 3D concave electrode could be detected electrochemically. After the treatment of PD midbrain organoids with levodopa, the drug for PD, the increase in dopamine level was detected due to the activation of dopaminergic neurons by the drug. The results suggest the potential of the proposed 3D concave electrode combined with brain organoids as a useful tool for assessing drug efficacy. This sensing system can be applied to a variety of organoids for a comprehensive drug evaluation.

Motor cortex activation mediates associations between striatal dopamine depletion and manual dexterity in Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) presents with a progressive decline in manual dexterity, attributed to dysfunction in the basal ganglia-thalamus-cortex loop, influenced by dopaminergic deficits in the striatum. Recent research suggests that the motor cortex may play a pivotal role in mediating the relationship between striatal dopamine depletion and motor function in PD. Understanding this connection is crucial for comprehending the origins of manual dexterity impairments in PD. Therefore, our study aimed to explore how motor cortex activation mediates the association between striatal dopamine depletion and manual dexterity in PD. MATERIALS AND METHODS: We enrolled 26 mildly affected PD patients in their off-medication phase to undergo [18F]FDOPA PET/CT scans for evaluating striatal dopaminergic function. EEG recordings were conducted during bimanual anti-phase finger tapping tasks to evaluate motor cortex activity, specifically focusing on Event-Related Desynchronization in the beta band. Manual dexterity was assessed using the Purdue Pegboard Test. Regression-based mediation analysis was conducted to examine whether motor cortex activation mediates the association between striatal dopamine depletion and manual dexterity in PD. RESULTS: Mediation analysis revealed a significant direct effect of putamen dopamine depletion on manual dexterity for the affected hand and assembly tasks (performed with two hands), with motor cortex activity mediating this association. In contrast, while caudate nucleus dopamine depletion showed a significant direct effect on manual dexterity, motor cortex mediation on this association was not observed. CONCLUSION: Our study confirms the association between striatum dopamine depletion and impaired manual dexterity in PD, with motor cortex activity mediating this relationship.

Factors associated with a placebo effect in Parkinson's disease in clinical trials: a meta-analysis.

OBJECTIVES: Outcomes of clinical trials of treatment in patients with Parkinson's disease (PD) may be influenced by placebo effects. The aim of this study was to determine the factors associated with placebo effects in Parkinson's disease (PD) for guidance with design of future clinical trials. METHODS: Factors associated with placebo effects in PD were examined in a meta-analysis using a random effects model with pooling of placebo effects on the Unified Parkinson's Disease Rating Scale part III (UPDRS III) or Movement Disorder Society sponsored revision of UPDRS III (MDS-UPDRS III). The following prespecified variables were included in the analyses: with or without drug at baseline, with or without a placebo run-in phase, with or without motor fluctuation, published year, number of study sites, placebo administration period, age, sex, disease duration, and daily levodopa dose. Publication bias was assessed by visual inspection of funnel plots and adjusted using the trim-and-fill method. RESULTS: Thirty-eight articles with a total of 4828 subjects satisfied the inclusion criteria. There was a significant placebo effect using UPDRS III or MDS-UPDRS III (SMD = - 0.25; 95% CI - 0.35 to - 0.14; p < 0.001, I2 = 92%). Subgroup and/or multivariate meta-regression analyses revealed that placebo effects were associated with advanced PD (p = 0.04), drug exposure at baseline (p < 0.001), placebo administration period (p < 0.001), and disease duration (p < 0.01). CONCLUSIONS: The results of this study are important as guidance in design of future clinical trials in which the influence of placebo effects is minimized.

Neuroprotective effects of flavonoids: endoplasmic reticulum as the target.

The incidence of neurological disorders, particularly age-related neurodegenerative pathologies, exhibits an alarming upward trend, while current pharmacological interventions seldom achieve curative outcomes. Despite their diverse clinical presentations, neurological diseases often share a common pathological thread: the aberrant accumulation of misfolded proteins within the endoplasmic reticulum (ER). This phenomenon, known as ER stress, arises when the cell's intrinsic quality control mechanisms fail to cope with the protein-folding burden. Consequently, misfolded proteins accumulate in the ER lumen, triggering a cascade of cellular stress responses. Recognizing this challenge, researchers have intensified their efforts over the past two decades to explore natural compounds that could potentially slow or even reverse these devastating pathologies. Flavonoids constitute a vast and heterogeneous class of plant polyphenols, with over 10,000 identified from diverse natural sources such as wines, vegetables, medicinal plants, and organic products. Flavonoids are generally divided into six different subclasses: anthocyanidins, flavanones, flavones, flavonols, isoflavones, and flavonols. The diverse family of flavonoids, featuring a common phenolic ring backbone adorned with varying hydroxyl groups and additional modifications, exerts its antioxidant activity by inhibiting the formation of ROS, as evidenced by research. Also, studies suggest that polyphenols such as flavonoids can regulate ER stress through apoptosis and autophagy. By understanding these mechanisms, we can unlock the potential of flavonoids as novel therapeutic agents for neurodegenerative disorders. Therefore, this review critically examines the literature exploring the modulatory effects of flavonoids on various steps of the ER stress in neurological disorders.

Mechanistic Insight into Intestinal α-Synuclein Aggregation in Parkinson's Disease Using a Laser-Printed Electrochemical Sensor.

Aggregated deposits of the protein α-synuclein and depleting levels of dopamine in the brain correlate with Parkinson's disease development. Treatments often focus on replenishing dopamine in the brain; however, the brain might not be the only site requiring attention. Aggregates of α-synuclein appear to accumulate in the gut years prior to the onset of any motor symptoms. Enteroendocrine cells (specialized gut epithelial cells) may be the source of intestinal α-synuclein, as they natively express this protein. Enteroendocrine cells are constantly exposed to gut bacteria and their metabolites because they border the gut lumen. These cells also express the dopamine metabolic pathway and form synapses with vagal neurons, which innervate the gut and brain. Through this connection, Parkinson's disease pathology may originate in the gut and spread to the brain over time. Effective therapeutics to prevent this disease progression are lacking due to a limited understanding of the mechanisms by which α-synuclein aggregation occurs in the gut. We previously proposed a gut bacterial metabolic pathway responsible for the initiation of α-synuclein aggregation that is dependent on the oxidation of dopamine. Here, we develop a new tool, a laser-induced graphene-based electrochemical sensor chip, to track α-synuclein aggregation and dopamine level over time. Using these sensor chips, we evaluated diet-derived catechols dihydrocaffeic acid and caffeic acid as potential inhibitors of α-synuclein aggregation. Our results suggest that these molecules inhibit dopamine oxidation. We also found that these dietary catechols inhibit α-synuclein aggregation in STC-1 enteroendocrine cells. These findings are critical next steps to reveal new avenues for targeted therapeutics to treat Parkinson's disease, specifically in the context of functional foods that may be used to reshape the gut environment.

Intranasal delivery of liposome encapsulated flavonoids ameliorates l-DOPA induced dyskinesia in hemiparkinsonian mice.

In the present study, we explored the development of a novel noninvasive liposomal drug delivery material for use in intranasal drug delivery applications in human diseases. We used drug entrapment into liposomal nanoparticle assembly to efficiently deliver the drugs to the nasal mucosa to be delivered to the brain. The naturally occurring flavonoid 7,8-dihydroxyflavone (7,8-DHF) has previously been shown to have beneficial effects in ameliorating Parkinson's disease (PD). We used both naturally occurring 7,8-DHF and the chemically modified form of DHF, the DHF-ME, to be used as a drug candidate for the treatment of PD and l-DOPA induced dyskinesia (LID), which is the debilitating side effect of l-DOPA therapy in PD. The ligand-protein interaction behavior for 7,8-DHF and 6,7-DHF-ME was found to be more effective with molecular docking and molecular stimulation studies of flavonoid compounds with TrkB receptor. Our study showed that 7,8-DHF delivered via intranasal route using a liposomal formulation ameliorated LID in hemiparkinsonian mice model when these mice were chronically administered with l-DOPA, which is the only current medication for relieving the clinical symptoms of PD. The present study also demonstrated that apart from reducing the LID, 7,8-DHF delivery directly to the brain via the intranasal route also corrected some long-term signaling adaptations involving ΔFosB and α Synuclein in the brain of dopamine (DA) depleted animals.

A method for the synchronization of inertial sensor signals and local field potentials from deep brain stimulation systems.

OBJECTIVE: Recent innovative neurostimulators allow recording local field potentials (LFPs) while performing motor tasks monitored by wearable sensors. Inertial sensors can provide quantitative measures of motor impairment in people with subthalamic nucleus deep brain stimulation. To the best of our knowledge, there is no validated method to synchronize inertial sensors and neurostimulators without an additional device. This study aims to define a new synchronization method to analyze disease-related brain activity patterns during specific motor tasks and evaluate how LFPs are affected by stimulation and medication. Approach: Twelve male subjects treated with subthalamic nucleus deep brain stimulation were recruited to perform motor tasks in four different medication and stimulation conditions. In each condition, a synchronization protocol was performed consisting of taps on the implanted device, which produces artifacts in the LFPs that an inertial sensor can simultaneously record. Main results: In 64% of the recruited subjects, induced artifacts were detected at least once. Among those subjects, 83% of the recordings could be correctly synchronized offline. The remaining recordings were synchronized by video analysis. Significance: The proposed synchronization method does not require an external system and can be easily integrated into clinical practice. The procedure is simple and can be carried out in a short time. A proper and simple synchronization will also be useful to analyze subthalamic neural activity in the presence of specific events (e.g., freezing of gait events) to identify predictive biomarkers. .

Mechanism and therapeutic targets of the involvement of a novel lysosomal proton channel TMEM175 in Parkinson's disease.

Parkinson's disease (PD), recognized as the second most prevalent neurodegenerative disease in the aging population, presents a significant challenge due to the current lack of effective treatment methods to mitigate its progression. Many pathogenesis of PD are related to lysosomal dysfunction. Moreover, extensive genetic studies have shown a significant correlation between the lysosomal membrane protein TMEM175 and the risk of developing PD. Building on this discovery, TMEM175 has been identified as a novel potassium ion channel. Intriguingly, further investigations have found that potassium ion channels gradually close and transform into hydrion "excretion" channels in the microenvironment of lysosomes. This finding was further substantiated by studies on TMEM175 knockout mice, which exhibited pronounced motor dysfunction in pole climbing and suspension tests, alongside a notable reduction in dopamine neurons within the substantia nigra compacta. Despite these advancements, the current research landscape is not without its controversies. In light of this, the present review endeavors to methodically examine and consolidate a vast array of recent literature on TMEM175. This comprehensive analysis spans from the foundational research on the structure and function of TMEM175 to expansive population genetics studies and mechanism research utilizing cellular and animal models.A thorough understanding of the structure and function of TMEM175, coupled with insights into the intricate mechanisms underpinning lysosomal dysfunction in PD dopaminergic neurons, is imperative. Such knowledge is crucial for pinpointing precise intervention targets, thereby paving the way for novel therapeutic strategies that could potentially alter the neurodegenerative trajectory of PD.

Neuroprotective Efficacy of the Glucocorticoid Receptor Modulator PT150 in the Rotenone Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder worldwide. Current treatments for PD largely center around dopamine replacement therapies and fail to prevent the progression of pathology, underscoring the need for neuroprotective interventions. Approaches that target neuroinflammation, which occurs prior to dopaminergic neuron (DAn) loss in the substantia nigra (SN), represent a promising therapeutic strategy. The glucocorticoid receptor (GR) has been implicated in the neuropathology of PD and modulates numerous neuroinflammatory signaling pathways in the brain. Therefore, we investigated the neuroprotective effects of the novel GR modulator, PT150, in the rotenone mouse model of PD, postulating that inhibition of glial inflammation would protect DAn and reduce accumulation of neurotoxic misfolded ⍺-synuclein protein. C57Bl/6 mice were exposed to 2.5mg/kg/day rotenone by intraperitoneal injection for 14 days. Upon completion of rotenone dosing, mice were orally treated at day 15 with 30mg/kg/day or 100mg/kg/day PT150 in the 14-day post-lesioning incubation period, during which the majority of DAn loss and α-synuclein (α-syn) accumulation occurs. Our results indicate that treatment with PT150 reduced both loss of DAn and microgliosis in the nigrostriatal pathway. Although morphologic features of astrogliosis were not attenuated, PT150 treatment promoted potentially neuroprotective activity in these cells, including increased phagocytosis of hyperphosphorylated α-syn. Ultimately, PT150 treatment reduced the loss of DAn cell bodies in the SN, but not the striatum, and prohibited intra-neuronal accumulation of α-syn. Together, these data indicate that PT150 effectively reduced SN pathology in the rotenone mouse model of PD.

New opportunities for antioxidants in amelioration of neurodegenerative diseases.

This comprehensive review elucidates the critical role of antioxidants to mitigate oxidative stress, a common denominator in an array of neurodegenerative disorders. Oxidative stress-induced damage has been linked to the development of diseases such as Alzheimer's, Parkinson's, Huntington's disease and amyotrophic lateral sclerosis. This article examines a wide range of scientific literature and methodically delineates the several methods by which antioxidants exercise their neuroprotective benefits. It also explores into the complex relationship between oxidative stress and neuroinflammation, focusing on how antioxidants can alter signaling pathways and transcription factors to slow neurodegenerative processes. Key antioxidants, such as vitamins C and E, glutathione, and polyphenolic compounds, are tested for their ability to combat reactive oxygen and nitrogen species. The dual character of antioxidants, which operate as both direct free radical scavengers and regulators of cellular redox homeostasis, is investigated in terms of therapeutic potential. Furthermore, the study focuses on new antioxidant-based therapy techniques and their mechanisms including Nrf-2, PCG1α, Thioredoxin etc., which range from dietary interventions to targeted antioxidant molecules. Insights into ongoing clinical studies evaluating antioxidant therapies in neurodegenerative illnesses offer an insight into the translational potential of antioxidant research. Finally, this review summarizes our present understanding of antioxidant processes in neurodegenerative illnesses, providing important possibilities for future study and treatment development.

Noradrenergic cardiac denervation is associated with gait velocity in Parkinson disease: a dual ligand PET study.

PURPOSE: Preliminary data suggest that gait abnormalities in Parkinson disease (PD) may be associated with sympathetic cardiac denervation. No kinematic gait studies were performed to confirm this observation. We aimed to correlate spatiotemporal kinematic gait parameters with cardiac sympathetic denervation as determined by cardiac [11C]HED PET in PD. METHODS: Retrospective database analysis of 27 PD patients with cardiac sympathetic denervation. All patients underwent spatiotemporal kinematic gait assessment (medication 'off' state), cardiac [11C]HED and dopaminergic brain [11C]DTBZ PET scans. We employed a hierarchical regression approach to examine associations between the extent of cardiac denervation, dopaminergic nigrostriatal neurodegeneration, and three gait parameters - velocity, step length and cadence. RESULTS: More extensive cardiac denervation was associated with slower velocity (estimate: -1.034, 95% CI [-1.65, -0.42], p = 0.002), shorter step length (estimate: -0.818, 95% CI [-1.43, -0.21], p = 0.011) and lower cadence (estimate: -0.752, 95% CI [-1.28, -0.23], p = 0.007) explaining alone 30% (Adjusted-R²: 0.297), 20% (Adjusted-R²: 0.202) and 23% (Adjusted-R²: 0.227) of the variability, respecivetly. These associations remained independent of striatal dopaminergic impairment and confounding factors such as age, Hoehn and Yahr (HY) stages, peripheral neuropathy, cognition, and autonomic symptoms. In contrast, striatal dopaminergic denervation was significantly associated with step length (estimate: 0.883, 95% CI [0.29, 1.48], p = 0.005), explaining about 24% of the variability but was dependent of HY stage. CONCLUSIONS: More severe cardiac noradrenergic denervation was associated with lower gait velocity, independent of striatal dopaminergic denervation and HY stage, impacting both step length and cadence. These results suggest independent contributions of the peripheral autonomic system degeneration on gait dynsfunction in PD.