Manifestations Of Parkinson's Disease Research Articles

Alpha-synuclein Fibrils Inhibit Activation of the BDNF/ERK Signaling Loop in the mPFC to Induce Parkinson's Disease-like Alterations with Depression.

Depression (Dep) is one of the most common concomitant symptoms of Parkinson's disease (PD), but there is a lack of detailed pathologic evidence for the occurrence of PD-Dep. Currently, the management of symptoms from both conditions using conventional pharmacological interventions remains a formidable task. In this study, we found impaired activation of extracellular signal-related kinase (ERK), reduced levels of transcription and translation, and decreased expression of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC) of PD-Dep rats. We demonstrated that the abnormal phosphorylation of α-synuclein (pS129) induced tropomyosin-related kinase receptor type B (TrkB) retention at the neuronal cell membrane, leading to BDNF/TrkB signaling dysfunction. We chose SEW2871 as an ameliorator to upregulate ERK phosphorylation. The results showed that PD-Dep rats exhibited improvement in behavioral manifestations of PD and depression. In addition, a reduction in pS129 was accompanied by a restoration of the function of the BDNF/ERK signaling loop in the mPFC of PD-Dep rats.

Serum neurotransmitter analysis of motor and non-motor symptoms in Parkinson’s patients

Clinical symptoms of Parkinson’s disease (PD) are classified into motor and non-motor symptoms. Mental disorders, especially depression, are one of the major non-motor manifestations of PD. However, the underlying mechanisms remain poorly understood. In the present study, 21 neurotransmitters associated with mental disorders were measured in serum samples from patients and controls using the ultra-high performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) assay. Additionally, five clinical scales—the MDS Unified Parkinson’s Disease Rating Scale (UPDRS), the Non-Motor Symptoms Scale (NMSS), the Mini-Mental State Examination (MMSE), the Hamilton Anxiety Scale (HAMA), and the Hamilton Depression Scale (HAMD)—were used to evaluate the severity of both motor and non-motor symptoms in PD patients. Analysis of neurotransmitter metabolism revealed significant changes in the tryptophan (Trp) metabolic pathway in PD patients. Specifically, levels of Trp, kynurenine (KYN), kynurenic acid (KA), nicotinamide (NAM), and 5-methoxyltryptamine (MeOTA) were substantially decreased. Additionally, three other excitation/inhibiting amino acids—glutamic acid (Glu), 4-aminobutyric acid (GABA), and aspartic acid (Asp)—also declined. Moreover, neurotransmitter conversion ratios, such as KA/KYN, nicotinamide/niacin (NAM/NA), 5-hydroxytryptophan/tryptophan (5-HTP/Trp), and quinolinic acid/kynurenic acid (QA/KA), provided more dynamic insights into disrupted neurotransmitter metabolism. Correlation analyses between scale scores and neurotransmitter levels showed that concentrations of xanthurenic acid (XA) and the turnover rate of 3-hydroxykynurenine (3-HK) were negatively correlated with UPDRS scores, while 5-hydroxytryptamine (5-HT) and GABA levels were negatively correlated with non-motor symptoms in PD patients. In summary, this study elucidates, for the first time, the potential association and dynamics between altered neurotransmitter metabolism and the etiology of PD in terms of motor and non-motor functions. These findings offer novel biomarkers and therapeutic targets for the treatment of PD.

Weak association between total alpha‐synuclein reflex tear levels and non‐motor symptoms burden in Parkinson's disease

AbstractBackgroundAlpha‐synuclein (αSyn) is critical to the pathogenesis of Parkinson's disease (PD). Recognition of non‐motor symptoms as clinical manifestations of PD suggests aggregation of αSyn in extranigral areas.AimThis study aimed to evaluate the association between total αSyn levels in reflex tears with non‐motor symptoms.MethodsThis cross‐sectional study included 25 people living with PD (PwP) and 38 age‐matched healthy controls (HC). Total αSyn reflex tear levels were measured using an enzyme‐linked immunosorbent assay. PwP were evaluated using the Non‐Motor Symptoms Scale (NMSS), the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS), Hoehn and Yahr Stage (HY), and Montreal Cognitive Assessment (MoCA).ResultsTotal αSyn reflex tear levels were significantly higher in PwP when compared with HC (1.77 pg/mL [IQR 1.75–1.79] vs. 1.73 pg/mL [IQR 1.70–1.75], p < 0.001). The urinary domain was negatively correlated with total αSyn levels in tears (r = −0.416, p = 0.048). No correlation was observed between total αSyn levels in reflex tears with MDS‐UPDRS, HY, or MoCA.ConclusionsTotal αSyn levels in reflex tears can differentiate PD from HC. In addition, total αSyn reflex tear levels were associated with the urinary domain of NMSS but are not associated with motor and cognitive symptoms, nor HY. Therefore, our findings suggest that it does not reflect ongoing dopaminergic neurodegeneration.

Cholinergic Basal Forebrain Integrity and Cognition in Parkinson's Disease: A Reappraisal of Magnetic Resonance Imaging Evidence.

Cognitive impairment is a well-recognized and debilitating symptom of Parkinson's disease (PD). Degradation in the cortical cholinergic system is thought to be a key contributor. Both postmortem and in vivo cholinergic positron emission tomography (PET) studies have provided valuable evidence of cholinergic system changes in PD, which are pronounced in PD dementia (PDD). A growing body of literature has employed magnetic resonance imaging (MRI), a noninvasive, more cost-effective alternative to PET, to examine cholinergic system structural changes in PD. This review provides a comprehensive discussion of the methodologies and findings of studies that have focused on the relationship between cholinergic basal forebrain (cBF) integrity, based on T1- and diffusion-weighted MRI, and cognitive function in PD. Nucleus basalis of Meynert (Ch4) volume has been consistently reduced in cognitively impaired PD samples and has shown potential utility as a prognostic indicator for future cognitive decline. However, the extent of structural changes in Ch4, especially in early stages of cognitive decline in PD, remains unclear. In addition, evidence for structural change in anterior cBF regions in PD has not been well established. This review underscores the importance of continued cross-sectional and longitudinal research to elucidate the role of cholinergic dysfunction in the cognitive manifestations of PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Tree Shrew Model of Parkinson Disease: A Cost-Effective Alternative to Nonhuman Primate Models

The surge in demand for experimental monkeys has led to a rapid increase in their costs. Consequently, there is a growing need for a cost-effective model of Parkinson disease (PD) that exhibits all core clinical and pathologic phenotypes. Evolutionarily, tree shrews (Tupaia belangeri) are closer to primates in comparison with rodents and could be an ideal species for modeling PD. To develop a tree shrew PD model, we used the 1-methyl-4-phenylpyridinium (MPP+), a metabolite derived from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, to induce lesions in dopaminergic neurons of the unilateral substantia nigra. The induced tree shrew model consistently exhibited and maintained all classic clinical manifestations of PD for a 5-month period. The symptoms included bradykinesia, rest tremor, and postural instability, and ∼50% individuals showed apomorphine-induced rotations, a classic phenotype of unilateral PD models. All these are closely resembled the ones observed in PD monkeys. Meanwhile, this model was also sensitive to L-dopa treatment in a dose-dependent manner, which suggested that the motor deficits are dopamine dependent. Immunostaining showed a significant loss of dopaminergic neurons (∼95%) in the lesioned substantia nigra, which is a crucial PD pathological marker. Moreover, a control group of nigral saline injection did not show any motor deficits and pathological changes. Cytomorphologic analysis revealed that the size of nigral dopaminergic neurons in tree shrews is much bigger than that of rodents and is close to that of macaques. The morphologic similarity may be an important structural basis for the manifestation of the highly similar phenotypes between monkey and tree shrew PD models. Collectively, in this study, we have successfully developed a PD model in a small animal species that faithfully recapitulated the classic clinical symptoms and key pathological indicators of PD monkeys, providing a novel and low-cost avenue for evaluation of PD treatments and underlying mechanisms.

Wavelet-based selection-and-recalibration network for Parkinson’s disease screening in OCT images

Background and Objective:Parkinson’s disease (PD) is one of the most prevalent neurodegenerative brain diseases worldwide. Therefore, accurate PD screening is crucial for early clinical intervention and treatment. Recent clinical research indicates that changes in pathology, such as the texture and thickness of the retinal layers, can serve as biomarkers for clinical PD diagnosis based on optical coherence tomography (OCT) images. However, the pathological manifestations of PD in the retinal layers are subtle compared to the more salient lesions associated with retinal diseases. Methods:Inspired by textural edge feature extraction in frequency domain learning, we aim to explore a potential approach to enhance the distinction between the feature distributions in retinal layers of PD cases and healthy controls. In this paper, we introduce a simple yet novel wavelet-based selection and recalibration module to effectively enhance the feature representations of the deep neural network by aggregating the unique clinical properties, such as the retinal layers in each frequency band. We combine this module with the residual block to form a deep network named Wavelet-based Selection and Recalibration Network (WaveSRNet) for automatic PD screening. Results:The extensive experiments on a clinical PD-OCT dataset and two publicly available datasets demonstrate that our approach outperforms state-of-the-art methods. Visualization analysis and ablation studies are conducted to enhance the explainability of WaveSRNet in the decision-making process. Conclusions:Our results suggest the potential role of the retina as an assessment tool for PD. Visual analysis shows that PD-related elements include not only certain retinal layers but also the location of the fovea in OCT images.

Sleep disorders and Parkinson's disease: is there a right direction?

In the last years, the hypothesis of a close relationship between sleep disorders (SDs) and Parkinson's disease (PD) has significantly strengthened. Whether this association is causal has been also highlighted by recent evidence demonstrating a neurobiological link between SDs and PD. Thus, the question is not whether these two chronic conditions are mutually connected, but rather how and when this relationship is expressed. Supporting this, not all SDs manifest with the same temporal sequence in PD patients. Indeed, SDs can precede or occur concomitantly with the onset of the clinical manifestation of PD. This review discusses the existing literature, putting under a magnifying glass the timing of occurrence of SDs in PD-neurodegeneration. Based on this, here, we propose two possible directions for studying the SDs-PD relationship: the first direction, from SDs to PD, considers SDs as potential biomarker/precursor of future PD-neurodegeneration; the second direction, from PD to SDs, considers SDs as concomitant symptoms in manifest PD, mainly related to primary PD-neuropathology and/or parkinsonian drugs. Furthermore, for each direction, we questioned SDs-PD relationship in terms of risk factors, neuronal circuits/mechanisms, and impact on the clinical phenotype and disease progression. Future research is needed to investigate whether targeting sleep may be the winning strategy to treat PD, in the context of a personalized precision medicine.

The Last Straw: How Stress Can Unmask Parkinson's Disease.

We discuss two people with Parkinson's disease (PD), in whom tremor manifested directly following a severely stressful event. Both were initially misdiagnosed with a functional neurological disorder. These stories highlight that stress can trigger the onset of clinical manifestations of PD, by unveiling an underlying disease that had been unfolding for many years. Thus, the sudden symptom onset after a stressful event is not unique to functional disorders, and may lead to avoidable feelings of guilt if people wrongly attribute PD to this event. It remains unclear what mechanism explains this phenomenon, and why symptoms persist after the stressful event has passed.

Analysis of the mechanism by which ketamine affects astrocytes in Parkinsonian rats through the PI3K/AKT axis.

Parkinson's disease (PD) remains the most common neurodegenerative disease worldwide, seriously affecting the normal life of patients. Currently, there is no effective clinical cure for PD. In this study, the research team explored the effect of ketamine (KET) on PD, which can lay a reliable foundation for future KET treatment of PD. First, the research team established a PD rat model with 6-hydroxydopamine (6-OHDA). The detection showed that the maximum angle of the inclined plate stay, the number oftimes of grid crossings andstanding, and the ATPaseactivity in brain tissue were significantly lower in PD rats than in control rats, while the positive rate of α-synuclein in brain tissue was increased, showing typical pathological manifestations of PD. After using KET to intervene in PD rats, the behavioral and brain pathological changes were significantly alleviated, and the inflammation and oxidative stress damage of brain tissue were effectively reduced, suggesting the potential therapeutic effects of KET on PD. Furthermore, the use of KET inhibited the PI3K/AKT axis in the brain tissue of PD rats and promoted autophagy. Moreover, the significant suppression of the PI3K/AKT axis by KET was also demonstrated in the PD cell model established through lipopolysaccharide (LPS) inducement of astrocyte cell line HA1800. It is suggested that the mechanismof KET on PD is related to the inhibition of the PI3K/AKT axis.

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

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

Predictive Modelling for Parkinson's Disease Diagnosis using Biomedical Voice Measurements

INTRODUCTION: Parkinson's Disease (PD), a progressively debilitating neurological disorder impacting a substantial global population, stands as a significant challenge in modern healthcare. The gradual onset of motor and non-motor symptoms underscores the criticality of early detection for optimal treatment outcomes. In response to this urgency, novel avenues for early diagnosis are being explored, where the amalgamation of biomedical voice analysis and advanced machine learning techniques holds immense promise. Individuals afflicted by PD experience a nuanced deterioration of bodily functions, necessitating interventions that are most effective when initiated at an early stage. The potential of biomedical voice measurements to encode subtle health indicators presents an enticing opportunity. The human voice, an intricate interplay of frequencies and patterns, might offer insights into the underlying health condition.
 OBJECTIVES: This research embarks on a comprehensive journey to delve into the intricate connections between voice attributes and the presence of PD, with the aim of expediting its detection and treatment.
 METHODS: At the heart of this exploration is the Support Vector Machine (SVM) model, a versatile machine learning tool [1-2]. Functioning as a virtual detective, the SVM model learns from historical data to decipher the intricate patterns that differentiate healthy individuals from those with PD [3-4].
 RESULTS: Through the power of pattern recognition, the SVM becomes a predictive instrument, a potential catalyst in unravelling the latent manifestations of PD using the unique patterns harbored within the human voice. Embedded within this research are the practical demonstrations showcased through code snippets [5-7]. By synergizing the intricate voice measurements with the SVM model, we envision the emergence of a diagnostic paradigm where early PD detection becomes both accessible and efficient. This study not only epitomizes the synergy of voice and machine interactions but also attests to the transformative potential of technology within the domain of healthcare. .
 CONCLUSION: Ultimately, this research strives to harness the intricate layers of voice data, as exemplified through the provided model code [8-11], to contribute to the evolution of an advanced tool for PD prediction. By amalgamating the principles of machine learning and biomedical analysis, we aspire to expedite early PD diagnosis, thereby catalyzing more efficacious treatment strategies. In traversing this multidimensional exploration, we aspire to pave the path toward a future where technology plays an instrumental role in enhancing healthcare outcomes for individuals navigating the challenges of PD, ultimately advancing the pursuit of early diagnosis and intervention.

RAB3 phosphorylation by pathogenic LRRK2 impairs trafficking of synaptic vesicle precursors.

Gain-of-function mutations in the LRRK2 gene cause Parkinson's disease (PD), characterized by debilitating motor and non-motor symptoms. Increased phosphorylation of a subset of RAB GTPases by LRRK2 is implicated in PD pathogenesis. We find that increased phosphorylation of RAB3A, a cardinal synaptic vesicle precursor (SVP) protein, disrupts anterograde axonal transport of SVPs in iPSC-derived human neurons (iNeurons) expressing hyperactive LRRK2-p.R1441H. Knockout of the opposing protein phosphatase 1H (PPM1H) in iNeurons phenocopies this effect. In these models, the compartmental distribution of synaptic proteins is altered; synaptophysin and synaptobrevin-2 become sequestered in the neuronal soma with decreased delivery to presynaptic sites along the axon. We find that RAB3A phosphorylation disrupts binding to the motor adaptor MADD, potentially preventing the formation of the RAB3A-MADD-KIF1A/1Bβ complex driving anterograde SVP transport. RAB3A hyperphosphorylation also disrupts interactions with RAB3GAP and RAB-GDI1. Our results reveal a mechanism by which pathogenic hyperactive LRRK2 may contribute to the altered synaptic homeostasis associated with characteristic non-motor and cognitive manifestations of PD.

Prevalence and Outcome of COVID-19 Among Parkinson’s Disease: A Report from Iran

Background: Parkinson's disease (PD) is a widely prevalent neurodegenerative disorder in the central nervous system, predominantly affecting older adults and frequently coexisting with other health conditions. The heightened vulnerability of individuals with chronic diseases and advanced age to adverse outcomes during the COVID-19 pandemic suggests an increased risk of COVID-19 infection in PD patients. Objectives: This cross-sectional study, conducted from July to September 2021, aimed to evaluate the impact of COVID-19 on PD patients by examining infection rates, associated complications, and outcomes. Methods: We utilized hospital records to reach out to 567 PD patients during the designated timeframe. If a patient had passed away, their families were contacted to ascertain whether COVID-19 was a contributing factor. Results: Among the 558 PD patients who participated, 25.4% were tested for COVID-19, with 42.2% of those tested returning positive results. Significantly, 34.4% of the positive cases required oxygen therapy, 32.8% were admitted to the hospital, and 9.8% needed intensive care unit (ICU) admission. The prevalence of COVID-19 among the families of the patients was 29.8%, with 13.7% requiring hospitalization and 4.2% resulting in death. Common complications included worsening of movement issues (21.3%), weight loss (19.7%), and urinary problems (14.8%). Early-onset Parkinson's was associated with a decreased risk of COVID-19 (OR: 0.976, 95% CI: 0.953 - 0.999, P = 0.037), whereas the use of Levodopa was linked to an increased risk of infection (OR: 3.672, 95% CI: 1.095 - 12.31, P = 0.037). Conclusions: This study underscores the changing clinical manifestations of PD during the COVID-19 pandemic. Further research is crucial to clarify the complex interaction between COVID-19 and Parkinson's disease.

Effect of Deep Brain Stimulation on Parkinson Disease Dementia: A Systematic Review and Meta-analysis.

Patients in the early stages of Parkinson disease (PD) may have subtle cognitive deficits, while overt cognitive deficits are usually manifestations of late-stage PD. There is still a debate on the outcome of deep brain stimulation (DBS) on the cognitive function of PD patients. This study aimed to investigate the effect of subthalamic nucleus (STN)-DBS on the dementia of PD patients after surgery compared to medical therapy and other procedures. We searched PubMed, Scopus, Cochrane Library, and Web of Science database on October 2020, with keywords: "Deep brain stimulation," "Parkinson disease," "dementia," and "memory." Reviews, abstracts, case presentations, and letters were excluded. In total, 491 studies were screened after removing the duplicates. The screening results yielded 81 articles to be screened for eligibility. Finally, 6 studies were included in this meta-analysis for synthesis. Overall, 800 patients were included in this meta-analysis, using the Mattis dementia rating scale (MDRS) and descriptive data from the articles extracted to assess global dementia. Our results suggest that the STN-DBS group showed a larger cognitive decline than the patients receiving the best medical treatment (BMT). However, comparing STN-DBS with globus pallidus interna stimulation and pallidotomy could not demonstrate a significant statistical effect on the global dementia of patients. More long-term studies with larger sample sizes are needed to validate current findings.

Spectrum and frequency of non-motor disorders in Parkinson’s patients in the Kursk Region

Introduction. Parkinson's disease (PD) is characterized by a long period of latent neurodegenerative process. Some patients experience non-motor manifestations in the form of autonomic (constipation, dizziness, fainting, and sleep, smell, and urination disorders), mental (anxiety and depression), and cognitive disorders that occur several years before the onset of motor symptoms [1]. Purpose of the study: to determine the spectrum and frequency of non-motor disorders in patients with Parkinson’s disease in the Kursk Region, as well as to assess the degree of their severit y. Materials and method. We examined 32 patients (18 women and 14 men) with an established diagnosis of PD (mixed type), who were treated at the Kursk Regional Multidisciplinary Clinical Hospital. The age of the patients ranged from 59 to 76 years. The mean age was 69.03±5.71 years, and the duration of the disease was 6.93±8.08 years. Non-motor symptoms and their severity were assessed using the UPDRS (Part I) and the NMSS-PD. Sleep disturbances were assessed according to the Epworth Sleepiness Scale (ESS). The Hospital Anxiety and Depression Scale (HADS) was used to study the neuropsychological status of the patients. Cognitive status was assessed according to the MMSE, Frontal Assessment Battery, and the clock drawing test. Results. Non-motor symptoms occurred in 87.5 % of the patients in the study population and are an equally significant part of the PD clinical picture. These manifestations are most often represented by autonomic (87.5 %), mental (68.7 %), and cognitive (72 %) disorders, which have a different spectrum and frequency in this group of patients. Conclusion. Non-motor manifestations of PD require special attention from a neurologist. The clinical picture of such disorders is varied. Early detection and adequate correction of non-motor disorders contributes to the main goal of PD therapy — to improve the qualit y of life of patients.

Ultra-Widefield Imaging of the Retinal Macrovasculature in Parkinson Disease Versus Controls With Normal Cognition Using Alpha-Shapes Analysis.

To investigate retinal vascular characteristics using ultra-widefield (UWF) scanning laser ophthalmoscopy in Parkinson disease (PD). Individuals with an expert-confirmed clinical diagnosis of PD and controls with normal cognition without PD underwent Optos California UWF imaging. Patients with diabetes, uncontrolled hypertension, glaucoma, dementia, other movement disorders, or known retinal or optic nerve pathology were excluded. Images were analyzed using Vasculature Assessment and Measurement Platform for Images of the Retina (VAMPIRE-UWF) software, which describes retinal vessel width gradient and tortuosity, provides vascular network fractal dimensions, and conducts alpha-shape analysis to further characterize vascular morphology (complexity, Opαmin; spread, OpA). In the PD cohort, 53 eyes of 38 subjects were assessed; in the control cohort, 51 eyes of 33 subjects were assessed. Eyes with PD had more tortuous retinal arteries in the superotemporal quadrant (P = 0.043). In eyes with PD, alpha-shape analysis revealed decreased OpA, indicating less retinal vasculature spread compared to controls (P = 0.032). Opαmin was decreased in PD (P = 0.044), suggesting increased vascular network complexity. No differences were observed in fractal dimension in any region of interest. This pilot study suggests that retinal vasculature assessment on UWF images using alpha-shape analysis reveals differences in retinal vascular network spread and complexity in PD and may be a more sensitive metric compared to fractal dimension. Retinal vasculature assessment using these novel methods may be useful in understanding ocular manifestations of PD and the development of retinal biomarkers.

Hexaconazole exposure may lead to Parkinson via disrupting glucocerebrosidase and parkin: molecular interaction, dynamics, MMPBSA and DFT based in-silico predictive toxicology.

Hexaconazole is a known fungicide for agricultural purposes. It has bioaccumulation ability which makes it important for its toxicological characterization. There are various neurological impacts of pollutants on human health. Therefore, in this study, we have done predictive analyses of the interaction mechanism of hexaconazole by molecular interaction analysis, molecular dynamics simulation, and Poisson-Boltzmann surface area (MM-PBSA) to assess hexaconazole's potency to disrupt the homeostasis of glucocerebrosidase (-7.9kcal/mol) and parkin (-5.67kcal/mol) proteins which have significant roles in the manifestation of Parkinson disease. The findings reveal that hexaconazole has the potency to form stable interactions with glucocerebrosidase and parkin. This research provides a molecular and atomic-level understanding of how hexaconazole exposure may disrupt the homeostasis of glucocerebrosidase and parkin. The root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration, and hydrogen bonding exhibited the potent molecular interactions of hexaconazole, which may lead to neurological manifestations such as Parkinson disease.

Associations of serum neuromarkers with clinical features of Parkinson's disease

To evaluate the clinical and laboratory correlation of biomarkers with anti- and pro-apoptotic activity with the severity of motor and non-motor symptoms depending on the progression rate of Parkinson's disease (PD). A wide range of non-motor symptoms (emotional-affective, cognitive, psychotic and behavioral disorders, fatigue, sleep disorders and autonomic disorders) was evaluated using validated scales and a number of serum neuromarkers responsible for neuroplasticity and neuronal survival processes (BDNF, PDGF, cathepsin D) in 71 patients with PD (mean age 65 (55; 70) years, disease duration 7 (4; 9) years, age of onset 57 (49; 62) years). The concentration of biomarkers (BDNF, PDGF and cathepsin D) was the lowest in the group of patients with a rapid PD progression rate (p<0.001, p=0.001 and p=0.031, respectively), the severity of motor and most non-motor symptoms was higher (p=0.023 and p=0.001, respectively) compared to middle and slow progression rate. There were correlations between BDNF concentration and the severity of depression (r=-0.63, p<0.001), apathy (r=-0.48, p<0.001), impulsive behavioral disorders (r=0.500, p<0.001), level of cognitive functions (r=0.54, p<0.001), motor symptoms (r=-0.43, p<0.001); between PDGF level and the severity of motor manifestations of PD (r=-0.30, p=0.011), depression (r=-0.70, p<0.001), apathy (r=-0.460, p<0.001), the degree of severity of behavioral disorders (r=0.742, p<0.001). No significant correlations were observed between the level of cathepsin D and the severity of clinical manifestations of PD, which indicates the connection of cathepsin D with the general pathogenesis of PD. The possibility of using serum proteins of the neurotrophin subfamily and the protein associated with autophagy, cathepsin D, as biomarkers that determine the prognosis of PD, is considered.

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

Frozen shoulder may be an early preclinical symptom of Parkinson's disease (PD). 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. 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). 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. 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.

The role of sphingosine-1-phosphate in the development and progression of Parkinson's disease.

Parkinson's disease (PD) could be viewed as a proteinopathy caused by changes in lipids, whereby modifications in lipid metabolism may lead to protein alterations, such as the accumulation of alpha-synuclein (α-syn), ultimately resulting in neurodegeneration. Although the loss of dopaminergic neurons in the substantia nigra is the major clinical manifestation of PD, the etiology of it is largely unknown. Increasing evidence has highlighted the important role of lipids in the pathophysiology of PD. Sphingosine-1-phosphate (S1P), a signaling lipid, has been suggested to have a potential association with the advancement and worsening of PD. Therefore, better understanding the mechanisms and regulatory proteins is of high interest. Most interestingly, S1P appears to be an important target to offers a new strategy for the diagnosis and treatment of PD. In this review, we first introduce the basic situation of S1P structure, function and regulation, with a special focus on the several pathways. We then briefly describe the regulation of S1P signaling pathway on cells and make a special focused on the cell growth, proliferation and apoptosis, etc. Finally, we discuss the function of S1P as potential therapeutic target to improve the clinical symptoms of PD, and even prevent the progression of the PD. In the context of PD, the functions of S1P modulators have been extensively elucidated. In conclusion, S1P modulators represent a novel and promising therapeutic principle and therapeutic method for PD. However, more research is required before these drugs can be considered as a standard treatment option for PD.