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Objectives: Freezing of Gait (FOG) is one of the disabling symptoms in patients with Parkinson's Disease (PD). While it is difficult to early detect because of the sporadic occurrence of initial freezing events. Whether the characteristic of gait impairments in PD patients with FOG during the 'interictal' period is different from that in non-FOG patients is still unclear. Methods: The gait parameters were measured by wearable inertial sensors. Exploratory factor analysis was used to investigate the inherent structure of diverse univariate gait parameters, with the aim of identifying shared characteristics among the gait variables. Results: This cross-sectional study involved 68 controls and 245 PD patients (167 without FOG and 78 with FOG). The analysis yielded six distinct gait domains which were utilized to describe the impaired gait observed during the "interictal" period of FOG. Both PD-nFOG and PD-FOG groups exhibited significant impairments in the pace domain, kinematic domain, gait phase domain, and turning process domain compared to the healthy control. The gait phase domain was different in the PD-FOG group compared to the PD-nFOG group (p corrected = 0.004, Cohen's d = -0.46). And it was identified as independent risk factor for FOG (OR = 1.64, 95% CI = 1.05–2.55, p = 0.030), as well as other risk factors: gender (OR = 2.67, 95% CI = 1.19–5.99, p = 0.017), MDS-UPDRS IV score (OR = 1.23, 95% CI = 1.10–1.37, p < 0.001), and PIGD subscore (OR = 1.50, 95% CI = 1.30–1.73, p < 0.001). The model demonstrated a correct discrimination rate of 0.78 between PD-FOG and PD-nFOG, with an area under the receiver operating characteristic curve (AUC) of 0.87. Conclusions: FOG was found to be associated with abnormal alterations in the gait phase domain during the interictal period. Models constructed using gait phase domain, PIGD subscore, gender, and severity of motor complications can better differentiate freezers from no-freezers during 'interictal' period. [ABSTRACT FROM AUTHOR]

Leucine-rich repeat kinase 2 (LRRK2) is a ROCO family member which its mutation is closely related with Parkinson's disease, and LRRK2 is widely involved into the regulation of autophagy, vesicle transport and neuronal proliferation. However, the roles of LRRK2 during mammalian oocyte maturation are still largely unclear. In present study, we disturbed the activity of LRRK2 and showed its essential roles in porcine oocytes. We showed that LRRK2 stably expressed during oocyte maturation, and the loss of LRRK2 activity disturbed cumulus expansion and oocyte polar body extrusion, indicating its involvement into oocyte maturation. Further analysis indicated that LRRK2 was related with cytoskeleton dynamics since its inhibition caused spindle organization defect and chromosome misalignment, and both cytoplasmic and cortex actin decreased. Moreover, LRRK2 co-localized with mitochondria and its activity was essential for mitochondria distribution. Loss of LRRK2 activity altered the TMRE level, which ultimately induced ROS-related oxidative stress. Taken together, our data suggested the important roles of LRRK2 on mammalian oocyte maturation through its effects on cytoskeleton dynamics and mitochondria functions. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) exerts a considerable burden on the elderly. Studies on long-term costs for Parkinson's disease patients in Taiwan are not available. Objectives: This study aims to examine the medical resource utilization and medical costs including drug costs for PD patients in Taiwan over up to 15 years of follow-up. Methods: Incident PD patients and matched non-PD subjects were identified between 2003 and 2016 from the National Health Insurance (NHI) research database. Differences in annual healthcare utilization and costs between PD and non-PD subjects from 2003 to 2018 were predicted by generalized linear models. We performed analyses stratified by PD severity and also by age, gender, and duration of follow-up. Results: We identified 50,290 PD cases and 201,153 non-PD subjects. From the payer's perspective, the average total medical costs (drug costs) associated with PD and non-PD subjects were NT$631,080 (NT$222,810) and NT$480,880 (NT$140,120), respectively. Total medical and drug costs of PD after diagnosis remained high, from NT$138,487 per patient in the first year following diagnosis up to NT$154,676 per patient at year 15. The largest components of costs were for outpatient care (55% of total medical costs), and total drugs cost (35% of total medical costs). Patients with severe PD incurred higher total medical costs compared to those with moderate or mild PD, with outpatient and inpatient costs as well as drug costs rising with disease severity. Conclusions: This is the first study of its kind in Taiwan that comprehensively analyzes long-term healthcare utilization and costs among PD patients. PD imposes a significant economic burden in Taiwan, with medical (drug) costs being 1.31 (1.59) times that of non-PD individuals and costs increasing substantially with PD severity. Our findings can aid health policymakers in understanding the healthcare needs and medical costs of PD patients, supporting effective policy formulation. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disease affecting millions of people around the world. Conventional PD detection algorithms are generally based on first and second-generation artificial neural network (ANN) models which consume high energy and have complex architecture. Considering these limitations, a time-varying synaptic efficacy function based leaky-integrate and fire neuron model, called SEFRON is used for the detection of PD. SEFRON explores the advantages of Spiking Neural Network (SNN) which is suitable for neuromorphic devices. To evaluate the performance of SEFRON, 2 publicly available standard datasets, namely (1) UCI: Oxford Parkinson's Disease Detection Dataset and (2) UCI: Parkinson Dataset with replicated acoustic features are used. The performance is compared with other well-known neural network models: Multilayer Perceptron Neural Network (MLP-NN), Radial Basis Function Neural Network (RBF-NN), Recurrent Neural Network (RNN) and Long short-term memory (LSTM). The experimental results demonstrate that the SEFRON classifier achieves a maximum accuracy of 100% and an average accuracy of 99.49% on dataset 1. For dataset 2, it attains a peak accuracy of 94% and an average accuracy of 91.94%, outperforming the other classifiers in both cases. From the performance, it is proved that the presented model can help to develop a robust automated PD detection device that can assist the physicians to diagnose the disease at its early stage. [ABSTRACT FROM AUTHOR]

Background: Elevated concentrations of low-density lipoprotein cholesterol (LDL-C) are linked to dementia risk, and conversely, increased plasma concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein-A1 (Apo-A1) associate with decreased dementia risk. Inhibition of cholesteryl ester transfer protein (CETP) meaningfully affects the concentrations of these blood lipids and may therefore provide an opportunity to treat dementia. Methods: Drug target Mendelian randomization (MR) was employed to anticipate the on-target effects of lower CETP concentration (μg/mL) on plasma lipids, cardiovascular disease outcomes, autopsy confirmed Lewy body dementia (LBD), as well as Parkinson's dementia. Results: MR analysis of lower CETP concentration recapitulated the blood lipid effects observed in clinical trials of CETP-inhibitors, as well as protective effects on coronary heart disease (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.89; 0.96), heart failure, abdominal aortic aneurysm, any stroke, ischemic stroke, and small vessel stroke (0.90, 95%CI 0.85; 0.96). Consideration of dementia related traits indicated that lower CETP concentrations were associated higher total brain volume (0.04 per standard deviation, 95%CI 0.02; 0.06), lower risk of LBD (OR 0.81, 95%CI 0.74; 0.89) and Parkinson's dementia risk (OR 0.26, 95%CI 0.14; 0.48). APOE4 stratified analyses suggested the LBD effect was most pronounced in APOE-ε4 + participants (OR 0.61 95%CI 0.51; 0.73), compared to APOE-ε4- (OR 0.89 95%CI 0.79; 1.01); interaction p-value 5.81 × 10− 4. Conclusions: These results suggest that inhibition of CETP may be a viable strategy to treat dementia, with a more pronounced effect expected in APOE-ε4 carriers. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a neurodegenerative disorder that affects millions of people worldwide. Mobile technologies enable Parkinson's patients to improve their quality of life, manage symptoms, and enhance overall well-being through various applications (apps). There is no integrated list of specific capabilities available to cater to the unique needs of Parkinson's patient-focused mobile apps. Objective: This study aimed to identify the key features and capabilities prioritized in developing mobile apps for patients with Parkinson's disease (PWP) and rank the related apps in this field. Methods: We searched iTunes and Google Play for PWP apps with "Parkinson" or "Parkinson's" in their title or description. We evaluated existing mobile apps through a four-step process: identification, screening, eligibility, and feature analysis. We installed apps on Android and iOS devices, categorized their features/capabilities by the "use case model" and other additional identified features. We scored them using a tool called FARM (Feature-based Application Rating Method) and ranked PWP-related apps. Results: Thirty-three apps related to the PWP were included and evaluated. Almost half of the apps were available on both the Android and iOS platforms. Seventy-five percent of the genres were associated with health and fitness. Although the included apps utilized certain features, none of the capabilities were used simultaneously. According to the experts' opinions, 'large font' was the most important feature and was utilized in 70% of the mobile applications. Additionally, the average score for all Parkinson's disease-related applications was 17.71 (SD = 7.92). The app titled 'Swiss Parkinson' had the highest score. Conclusions: Integrating a relevant list of features used for Parkinson's patients' applications yielded valuable insights for the design of mobile applications tailored to patients' needs. These features are highly efficient in dealing with the specific obstacles related to this disease. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) and multiple system atrophy (MSA) are classified as α-synucleinopathies and are primarily differentiated by their clinical phenotypes. Delineating these diseases based on their specific α-synuclein (α-Syn) proteoform pathologies is crucial for accurate antemortem biomarker diagnosis. Newly identified α-Syn pathologies in PD raise questions about whether MSA exhibits a similar diversity. This prompted the need for a comparative study focusing on α-Syn epitope-specific immunoreactivities in both diseases, which could clarify the extent of pathological overlap and diversity, and guide more accurate biomarker development. Methods: We utilised a multiplex immunohistochemical approach to detect multiple structural domains of α-Syn proteoforms across multiple regions prone to pathological accumulation in MSA (n = 10) and PD (n = 10). Comparison of epitope-specific α-Syn proteoforms was performed in the MSA medulla, inferior olivary nucleus, substantia nigra, hippocampus, and cerebellum, and in the PD olfactory bulb, medulla, substantia nigra, hippocampus, and entorhinal cortex. Results: N-terminus and C-terminus antibodies detected significantly more α-Syn pathology in MSA than antibodies for phosphorylated (pS129) α-Syn, which are classically used to detect α-Syn. Importantly, C-terminus immunolabelling is more pronounced in MSA compared to PD. Meanwhile, N-terminus immunolabelling consistently detected the highest percentage of α-Syn across pathologically burdened regions of both diseases, which could be of biological significance. As expected, oligodendroglial involvement distinguished MSA from PD, but in contrast to PD, no substantial astrocytic or microglial α-Syn accumulation in MSA occurred. These data confirm glial-specific changes between these diseases when immunolabelling the N-terminus epitope. In comparison, N-terminus neuronal α-Syn was present in PD and MSA, with most MSA neurons lacking pS129 α-Syn proteoforms. This explains why characterisation of neuronal MSA pathologies is lacking and challenges the reliance on pS129 antibodies for the accurate quantification of α-Syn pathological load across α-synucleinopathies. Conclusions: These findings underscore the necessity of utilising a multiplex approach to detect α-Syn, most importantly including the N-terminus, to capture the entire spectrum of α-Syn proteoforms in α-synucleinopathies. The data provide novel insights toward the biological differentiation of these α-synucleinopathies and pave the way for more refined antemortem diagnostic methods to facilitate early identification and intervention of these neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a progressive neurodegenerative disease associated with functional and structural alterations beyond the nigrostriatal dopamine projection. However, the structural-functional (SC-FC) coupling changes in combination with subcortical regions at the network level are rarely investigated in PD. Methods: SC-FC coupling networks were systematically constructed using the structural connectivity obtained by diffusion tensor imaging and the functional connectivity obtained by resting-state functional magnetic resonance imaging in 53 PD and 72 age- and sex-matched healthy controls (HCs). Then, we explored how SC-FC coupling varied within and between several well-defined functional domains. Results: Results showed that the SC-FC coupling in patients with PD was globally reduced in comparison with HCs. Specifically, regional SC-FC decoupled in the inferior parietal lobule, occipitotemporal cortex, motor cortex, and higher-order association cortex in patients with PD. Moreover, PD showed intranetwork SC-FC decoupling in the visual network (VIS), limbic and higher-order association networks. Furthermore, internetwork decoupling mainly linked to the VIS, the somatomotor network (SOM), the dorsal attention network, and the default mode network, was observed, increased internetwork coupling was found between the subcortical network and the SOM in PD (all p < 0.05, FDR corrected). Conclusions: These findings suggest that PD is characterized by SC-FC decoupling in topological organization of multiscale brain networks, providing insights into the brain network mechanisms in PD. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) on cognitive function, depression, and walking ability in patients with Parkinson's disease. Methods: A comprehensive search was conducted in PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), VIP Database, and Wanfang Database. Randomized controlled trials (RCTs) on rTMS treatment in Parkinson's disease patients were retrieved, covering the period from the inception of each database to July 2024. The quality of the included studies was assessed using the Cochrane risk of bias tool. Two researchers independently screened the literature, extracted data, and assessed the risk of bias in the studies. Data synthesis and analysis were performed using RevMan 5.4 and Stata 17.0 software. Results: A total of 15 studies were included. The meta-analysis revealed that rTMS significantly improved the MOCA score (MD = 2.98, 95% CI 2.08, 3.88, P = 0.000), TUGT score (SMD=-0.72, 95% CI -1.43, 0.00, P = 0.048), FOG-Q score (SMD=-0.54, 95% CI -0.97, -0.11, P = 0.01), and UPDRS-III score (SMD=-0.66, 95% CI -0.84, -0.47, P = 0.000) in Parkinson's disease patients, and also alleviated depressive symptoms as measured by the HAMD (SMD=-0.43, 95% CI -0.72, -0.13, P = 0.004). Conclusions: rTMS can improve cognitive function, depressive symptoms, and walking ability in patients with Parkinson's disease. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction and α-synuclein (αSyn) aggregation are key contributors to Parkinson's Disease (PD). While genetic and environmental risk factors, including mutations in mitochondrial-associated genes, are implicated in PD, the precise mechanisms linking mitochondrial defects to αSyn pathology remain incompletely understood, hindering the development of effective therapeutic interventions. Here, we identify the loss of branched chain ketoacid dehydrogenase kinase (BCKDK) as a mitochondrial risk factor that exacerbates αSyn pathology by disrupting Complex I function. Our findings reveal a consistent downregulation of BCKDK in dopaminergic (DA) neurons from A53T-αSyn mouse models, PD patient-derived induced pluripotent stem (iPS) cells, and postmortem brain tissues. BCKDK deficiency leads to mitochondrial dysfunction, including reduced membrane potential and increased reactive oxygen species (ROS) production upon administration of a stressor, which in turn promotes αSyn oligomerization. Mechanistically, BCKDK interacts with the NDUFS1 subunit of Complex I to stabilize its function. Loss of BCKDK disrupts this interaction, leading to Complex I destabilization and enhanced αSyn aggregation. Notably, restoring BCKDK expression in neuron-like cells rescues mitochondrial integrity and restores Complex I activity. Similarly, in patient-derived iPS cells differentiated to form dopaminergic neurons, NDUFS1 and phosphorylated aSyn levels are partially restored upon BCKDK expression. These findings establish a mechanistic link between BCKDK deficiency, mitochondrial dysfunction, and αSyn pathology in PD, positioning BCKDK as a potential therapeutic target to mitigate mitochondrial impairment and neurodegeneration in PD. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a degenerative neurological disease that worsens over time. Ferroptosis has been proven to contribute to PD pathogenesis. CDG exhibits neuroprotective effects. However, CDG's potential mechanism in PD therapy remains uncertain. Purpose: The purpose of this investigation is to ascertain the specific molecular mechanisms of CDG against neuronal ferroptosis and present an alternative option for PD management. Methods: Network pharmacology along with LC–MS were used to identify possible targets and candidate pathways. Then RNA-sequencing combined in the in vitro and in vivo experiments were utilized to validate these findings. Results: According to network pharmacology prediction, NFE2L2, HMOX1 and PTGS2 may be the key genes for ferroptosis in PD. In the in vivo experiments, CDG ultimately improved the neurobehavior of PD rats by alleviating the damage of dopamine neurons, decreasing the levels of MDA, ROS and Fe2+, increasing the GSH level, inhibiting ferroptosis by decreasing ACSL4, TF, and PTGS2 expression levels, and increasing the GPX4, FTH, Nrf2, and HMOX1 levels. RNA-seq analysis showed the differential genes in Model and CDG group were all enriched in Nrf2 and HMOX1, and the enrichment analysis of these differential genes showed they were closely related to the ferroptosis. Subsequently, in vitro experiments, the CDG, OE-Nrf2 and OE-HMOX1 group showed more active cell vitality, with decreasing levels of MDA, ROS, Fe2+, ACSL4, TF and PTGS2, and increasing level GSH, GPX4, FTH, Nrf2 and HMOX1. Conclusion: CDG has a neuroprotective involvement in alleviating ferroptosis by regulating the Nrf2/HMOX1 pathway. Moreover, this research offers pharmacological evidence supporting the applications of CDG for treating PD. [ABSTRACT FROM AUTHOR]

Neuronal oscillations refer to rhythmic and periodic fluctuations of electrical activity in the central nervous system that arise from the cellular properties of diverse neuronal populations and their interactions. Specifically, gamma oscillations play a crucial role in governing the connectivity between distinct brain regions, which are essential in perception, motor control, memory, and emotions. In this context, we recapitulate various current stimulation methods to induce gamma entrainment. These methods include sensory stimulation, optogenetic modulation, photobiomodulation, and transcranial electrical or magnetic stimulation. Simultaneously, we explore the association between abnormal gamma oscillations and central nervous system disorders such as Alzheimer's disease, Parkinson's disease, stroke, schizophrenia, and autism spectrum disorders. Evidence suggests that gamma entrainment-inducing stimulation methods offer notable neuroprotection, although somewhat controversial. This review comprehensively discusses the functional role of gamma oscillations in higher-order brain activities from both physiological and pathological perspectives, emphasizing gamma entrainment as a potential therapeutic approach for neuropsychiatric disorders. Additionally, we discuss future opportunities and challenges in implementing such strategies. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is characterised by degeneration of ventral midbrain dopaminergic (DA) neurons and abnormal deposition of α-synuclein (α-syn) in neurons. Activation of the innate immune pathogen recognition receptor toll-like receptor 2 (TLR2) is associated with exacerbation of α-syn pathology. TLR2 is increased on neurons in the PD brain, and its activation results in the accumulation and propagation of α-syn through autophagy inhibition in neurons. In addition to the aggregation and propagation of pathological α-syn, dysfunction of astrocytes may contribute to DA neuronal death and subsequent clinical progression of PD. However, the role of astrocytes in TLR2-mediated PD pathology is less explored but important to address, given that TLR2 is a potential therapeutic target for PD. Methods: Induced pluripotent stem cells from three controls and three PD patients were differentiated into a midbrain model comprised of neurons (including DA neurons) and astrocytes. Cells were treated with or without the TLR2 agonist Pam3CSK4, and α-syn pathology was seeded using pre-formed fibrils. Confocal imaging was used to assess lysosomal function and α-syn pathology in the different cell types, as well as DA neuron health and astrocyte activation. Results: TLR2 activation acutely impaired the autophagy lysosomal pathway, and potentiated α-syn pathology seeded by pre-formed fibrils in PD neurons and astrocytes, leading to degeneration and loss of DA neurons. The astrocytes displayed impaired chaperone-mediated autophagy reducing their ability to clear accumulated α-syn, and increases of A1 neurotoxic phenotypic proteins SerpinG1, complement C3, PSMB8 and GBP2. Moreover, the phenotypic changes in astrocytes correlated with a specific loss of DA neurons. Conclusions: Taken together, these results support a role for astrocyte dysfunction in α-syn accumulation and DA neuronal loss following TLR2 activation in PD. [ABSTRACT FROM AUTHOR]

Background: Less dopaminergic neurons in people with Parkinson's disease result in a reliance on a slow and energy-intensive control, restricting their ability to complete routine everyday activities. Self-regulation takes an active learning approach to rehabilitation by enhancing the person's self-awareness and encourages self-reflection to overcome problems. Mental imagery assists the person to focus attention on the requirements for the task, making it a goal-directed action and allowing for faster movements. There is a growing body of evidence to support the use of self-regulation and mental imagery in rehabilitation to maintain or improve the performance of everyday activities for people with a neurological condition. Methods: A prospective pilot study using a single-group, pre-test and posttest design will test the feasibility and acceptability of a self-regulation and mental imagery programme to enhance performance of everyday activities and motor and cognitive function in people with Parkinson's disease. People who have a diagnosis of Parkinson's disease with mild-to-moderate severity and intact attention, comprehension and short-term memory will be recruited. The participants will receive a 6-week programme with one therapist-led session, a home programme and a telephone call each week. The programme uses self-regulation through a step-based problem-solving process and mental imagery to assist in movement planning. Appropriate rehabilitation strategies are used as solutions to tackle problems experienced, impacting performance in everyday activities. The attendance rate will be recorded to indicate the feasibility. A questionnaire will be administered post-intervention to collect feedback on programme acceptability. Patient outcomes will include Barthel index, Lawton Instrumental Activities of Daily Living Scale, Canadian Occupational Performance Measure and Timed Up and Go test. Trail Making Test and Montreal Cognitive Assessment will be collected pre- and post-intervention. Discussion: The programme aims to combine the metacognitive strategies of self-regulation and mental imagery to enable individuals with Parkinson's disease to improve the performance of everyday activities. If feasible, the programme has the potential to be further tested in a randomised controlled trial and benefit people with Parkinson's disease by enhancing their performance required in independent community living. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12621000903886, Registered on 12 July 2021 — retrospectively registered. [ABSTRACT FROM AUTHOR]

Multimodal brain network analysis enables a comprehensive understanding of neurological disorders by integrating information from multiple neuroimaging modalities. However, existing methods often struggle to effectively model the complex structures of multimodal brain networks. In this paper, we propose a novel tensor-based graph convolutional network (TGNet) framework that combines tensor decomposition with multi-layer GCNs to capture both the homogeneity and intricate graph structures of multimodal brain networks. We evaluate TGNet on four datasets—HIV, Bipolar Disorder (BP), and Parkinson's Disease (PPMI), Alzheimer's Disease (ADNI)—demonstrating that it significantly outperforms existing methods for disease classification tasks, particularly in scenarios with limited sample sizes. The robustness and effectiveness of TGNet highlight its potential for advancing multimodal brain network analysis. The code is available at https://github.com/rongzhou7/TGNet. [ABSTRACT FROM AUTHOR]

Background: A sustainable pandemic preparedness strategy is essential to ensure equitable access to healthcare for individuals with neurodegenerative diseases. Moreover, it is vital to provide clinicians and researchers in the neurodegenerative disease fields with resources and infrastructure to ensure continuity of their work during a (health) crisis. Methods: We established an international collaboration between researchers, clinicians, and patient representatives from the Netherlands, Poland, and the United Kingdom. We co-created a pandemic preparedness plan primarily informed by examples from those affected by or working in the field of Parkinson's disease, with potential application to other neurodegenerative diseases or the general population. This plan builds upon insights and experiences from four population-based studies during the COVID-19 pandemic. Between March and November 2023, we organised two hybrid meetings in Bristol (United Kingdom) and Rotterdam (the Netherlands), and two online meetings. Results: Research recommendations included three core factors in questionnaire design during health crises: 1) using existing, validated questions, 2) questionnaire adaptability and flexibility, and 3) testing within and outside the research group. Additionally, we addressed burden of participation, and we advocated for robust data sharing practices, underlining the importance of regulatory measures extending beyond the COVID-19 pandemic. We also shared clinical perspectives, including strategies to mitigate social isolation; challenges in virtual versus in-person consultations; and systemic changes to recognise and prevent moral injury in healthcare professionals. Conclusion: In this pandemic preparedness plan, we provide research and clinical recommendations tailored to the field of Parkinson's disease, with broader relevance to other neurodegenerative diseases and the general population. This establishes an essential framework for setting up new studies and safeguarding research and clinical practices when a new pandemic or other (health) crisis emerges. Keypoints: • A sustainable pandemic preparedness strategy is essential for equitable healthcare access and continuity of research and clinical practice in the neurodegenerative disease fields. • We established an international collaboration involving researchers, clinicians, and patient representatives from the Netherlands, Poland, and the UK, to co-create a pandemic preparedness plan, drawing upon their experiences in four population-based studies during the COVID-19 pandemic. • Research recommendations included key factors in remote data collection, strategies to reduce the burden of participation, and considerations in terms of data sharing and confidentiality. • Clinical strategies highlighted mitigating social isolation, challenges in virtual consultations, and preventing moral injury in healthcare professionals. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) and Parkinson's disease (PD) are leading neurodegenerative disorders marked by protein aggregation, with AD featuring amyloid-beta (Aβ) and tau proteins, and PD alpha-synuclein (αSyn). Dementia with Lewy bodies (DLB) often presents with a mix of these pathologies. This study explores naturally occurring autoantibodies (nAbs), including Immunoglobulin (Ig)G, IgM, and IgA, which target αSyn, Aβ and tau to maintain homeostasis and were previously found altered in AD and PD patients, among others. Main text: We extended this investigation across AD, PD and DLB patients investigating both the affinities of IgGs and levels of IgGs, IgMs and IgAs towards αSyn, Aβ and tau utilizing chemiluminescence assays. We confirmed that AD and PD patients exhibited lower levels of high-affinity anti-Aβ and anti-αSyn IgGs, respectively, than healthy controls. AD patients also showed diminished levels of high-affinity anti-αSyn IgGs, while anti-tau IgG affinities did not differ significantly across groups. However, DLB patients exhibited increased anti-αSyn IgG but decreased anti-αSyn IgM levels compared to controls and PD patients, with AD patients showing a similar pattern. Interestingly, AD patients had higher anti-Aβ IgG but lower anti-Aβ IgA levels than DLB patients. DLB patients had reduced anti-Aβ IgM levels compared to controls, and anti-tau IgG levels were lower in AD than PD patients, who had reduced anti-tau IgM levels compared to controls. AD patients uniquely showed higher anti-tau IgA levels. Significant correlations were observed between clinical measures and nAbs, with negative correlations between anti-αSyn IgG affinity and levels in DLB patients and a positive correlation with anti-αSyn IgA levels in PD patients. Disease-specific changes in nAb levels and affinity correlations were identified, highlighting altered immune responses. Conclusion: This study reveals distinctive nAb profiles in AD, DLB, and PD, pinpointing specific immune deficiencies against pathological proteins. These insights into the autoreactive immune system's role in neurodegeneration suggest nAbs as potential markers for vulnerability to protein aggregation, offering new avenues for understanding and possibly diagnosing these conditions. [ABSTRACT FROM AUTHOR]

Background: L-DOPA has been considered the first-line therapy for treating Parkinson's disease (PD) via restoring striatal dopamine (DA) to normalize the activity of local spiny projection neurons (SPNs) in the direct (dSPNs) pathway and the indirect (iSPNs) pathway. While the changes in striatal acetylcholine (ACh) induced by increasing DA have been extensively discussed, their validity remains controversial. Inhibition of striatal cholinergic signaling attenuates PD motor deficits. Interestingly, enhancing striatal ACh triggers local DA release, suggesting the pro-kinetic effects of ACh in movement control. Here, we investigated the in-vivo dynamics of ACh in the dorsolateral striatum (DLS) of the 6-OHDA-lesioned mouse model after L-DOPA administration, as well as its underlying mechanism, and to explore its modulatory role and mechanism in parkinsonian symptoms. Results: Using in vivo fiber photometry recordings with genetically encoded fluorescent DA or ACh indicator, we found L-DOPA selectively decreased DLS ACh levels in parkinsonian conditions. DA inhibited ACh release via dopamine D2 receptors and dSPNs-mediated activation of type-A γ-aminobutyric acid receptors on cholinergic interneurons. Restoring DLS ACh levels during L-DOPA treatment induced additional DA release by activating nicotinic acetylcholine receptors, thereby promoting the activity of dSPNs and iSPNs. Enhancing DLS ACh facilitated L-DOPA-induced turning behavior but not dyskinesia in parkinsonian mice. Conclusions: Our results demonstrated that enhancing striatal ACh facilitated the effect of L-DOPA by modulating DA tone. It may challenge the classical hypothesis of a purely competitive interaction between dopaminergic and cholinergic neuromodulation in improving PD motor deficits. Modulating ACh levels within the dopaminergic system may improve striatal DA availability in PD patients. [ABSTRACT FROM AUTHOR]

Background: The expansion of GGC repeats (typically exceeding 60 repeats) in the 5' untranslated region (UTR) of the NOTCH2NLC gene (N2C) is linked to N2C-related repeat expansion disorders (NREDs), such as neuronal intranuclear inclusion disease (NIID), frontotemporal dementia (FTD), essential tremor (ET), and Parkinson's disease (PD). These disorders share common clinical manifestations, including parkinsonism, dementia, seizures, and muscle weakness. Intermediate repeat sizes ranging from 40 to 60 GGC repeats, particularly those with AGC-encoded serine insertions, have been reported to be associated with PD; however, the functional implications of these intermediate repeats with serine insertion remain unexplored. Methods: Here, we utilized cellular models harbouring different sizes of N2C variant 2 (N2C2) GGC repeat expansion and CRISPR-Cas9 engineered transgenic mouse models carrying N2C2 GGC intermediate repeats with and without serine insertion to elucidate the underlying pathophysiology associated with N2C intermediate repeat with serine insertion in NREDs. Results: Our findings revealed that the N2C2 GGC intermediate repeat with serine insertion (32G13S) led to mitochondrial dysfunction and cell death in vitro. The neurotoxicity was influenced by the length of the repeat and was exacerbated by the presence of the serine insertion. In 12-month-old transgenic mice, 32G13S intensified intranuclear aggregation and exhibited early PD-like characteristics, including the formation of α-synuclein fibers in the midbrain and the loss of tyrosine hydroxylase (TH)-positive neurons in both the cortex and striatum. Additionally, 32G13S induced neuronal hyperexcitability and caused locomotor behavioural impairments. Transcriptomic analysis of the mouse cortex indicated dysregulation in calcium signaling and MAPK signaling pathways, both of which are critical for mitochondrial function. Notably, genes associated with myelin sheath components, including MBP and MOG, were dysregulated in the 32G13S mouse. Further investigations using immunostaining and transmission electron microscopy revealed that the N2C intermediate repeat with serine induced mitochondrial dysfunction-related hypermyelination in the cortex. Conclusions: Our in vitro and in vivo investigations provide the first evidence that the N2C-GGC intermediate repeat with serine promotes intranuclear aggregation of N2C, leading to mitochondrial dysfunction-associated hypermyelination and neuronal hyperexcitability. These changes contribute to motor deficits in early PD-like neurodegeneration in NREDs. [ABSTRACT FROM AUTHOR]

Background: Variants in the CTSB gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson's disease (PD). However, neither the specific CTSB variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis. Previous in vitro studies have found that catB can cleave monomeric and fibrillar alpha-synuclein, a key protein involved in the pathogenesis of PD that accumulates in the brains of PD patients. However, truncated synuclein isoforms generated by catB cleavage have an increased propensity to aggregate. Thus, catB activity could potentially contribute to lysosomal degradation and clearance of pathogenic alpha synuclein from the cell, but also has the potential of enhancing synuclein pathology by generating aggregation-prone truncations. Therefore, the mechanisms linking catB to PD pathophysiology remain to be clarified. Methods: Here, we conducted genetic analyses of the association between common and rare CTSB variants and risk of PD. We then used genetic and pharmacological approaches to manipulate catB expression and function in cell lines, induced pluripotent stem cell-derived dopaminergic neurons and midbrain organoids and assessed lysosomal activity and the handling of aggregated synuclein fibrils. Results: We find that catB inhibition impairs autophagy, reduces glucocerebrosidase (encoded by GBA1) activity, and leads to an accumulation of lysosomal content. In cell lines, reduction of CTSB gene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereas CTSB gene activation enhances fibril clearance. In midbrain organoids and dopaminergic neurons treated with alpha-synuclein fibrils, catB inhibition potentiates the formation of inclusions which stain positively for phosphorylated alpha-synuclein. Conclusions: These results indicate that the reduction of catB function negatively impacts lysosomal pathways associated with PD pathogenesis, while conversely catB activation could promote the clearance of pathogenic alpha-synuclein. [ABSTRACT FROM AUTHOR]

Background: Recent years, exosomes have been increasing used to treat diseases, but there is little research on how exosomes affect the metabolism of the body after entering. Therefore, in this study, we discussed the changes of metabolic spectrum and determined the differentially expressed metabolites in the serum of cynomolgus monkeys after injecting exosomes. Six cynomolgus monkeys were divided into control group and exosomes group. After intravenous injection of exosomes, the peripheral blood serum of cynomolgus monkeys was collected at baseline, day 1, day 7 and day 14 respectively. An ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry-based non-targeted metabolomics platform was used to detect the metabolites. The metabolic spectra of two groups of cynomolgus monkeys were identified and compared, and the time series changes of metabolites in exosomes were described. Results: The results showed that there was significant difference in metabolic spectrum between the two groups. 45, 114, 49, 39 differentially expressed metabolites were identified in baseline, day 1, day 7, and day 14, respectively. 6-hydroxydopamine, a metabolite related to the regulation of nerve function, was also found. Tryptophan metabolism, choline metabolism in cancer, porphyrin and chlorophyll metabolism were involved in day 1. Sphingolipid metabolism and histidine metabolism were involved in day 7. Three pathways, including choline metabolism, sphingolipid metabolism and biotin metabolism in cancer were involved in day 14. Through time series analysis, it was found that the level of propionylcarnitine and biliverdin increased on day 1 after inoculation with exosomes, while the level of hippuric acid decreased. These changes of immune-related metabolites suggested that exosomes might participate in the immunoregulation reaction after entering the body of cynomolgus monkeys. Conclusions: In our current study, we found that exosomes injected intravenously affect the changes of metabolites and metabolic pathways in cynomolgus monkeys. Intravenous injection of exosomes may affect the metabolite 6-hydroxydopamine, sphingolipid metabolic pathway, and choline metabolic in cancer pathway, which is of some significance for the treatment of Parkinson's disease. In addition, exosomes may also affect the immune-related metabolites in vivo, such as propionylcarnitine, biliverdin, hippuric acid metabolites, as well as tryptophan metabolism pathway, sphingolipid metabolism pathway involved in immune regulation, which is of great significance for the future study of immune-regulatory mechanisms of exosomes. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) induces progressive deficits in motor and cognitive functions as well as impaired dual-task performance requiring both motor and cognitive functions. This systematic review and meta-analysis evaluated the effects of non-invasive brain stimulation (NIBS) on dual-task performance in patients with PD. Methods: 11 studies met the following inclusion criteria: (a) patients with PD, (b) NIBS intervention, (c) comparison with the sham stimulation group, (d) motor and cognitive performance outcomes during dual tasks, and (e) randomized controlled trials with parallel or crossover designs. Individual effect size (i.e., comparison) was quantified by comparing motor and cognitive performances changes during dual tasks between active NIBS and sham stimulation conditions. Thus, higher values of the overall effect size indicate more improvements in either motor or cognitive performances after NIBS. Moreover, moderator variable analyses determined whether NIBS effects on dual-task performances differed depending on targeted brain regions. Finally, meta-regression analyses determined whether NIBS effects on dual-task performances were associated with demographic characteristics. Results: The random-effects model meta-analysis revealed that NIBS significantly improved motor (73 comparisons from 11 studies) and cognitive (12 comparisons from four studies) performances during dual tasks in patients with PD. Specifically, anodal transcranial direct current stimulation protocols on the dorsolateral prefrontal cortex were effective. Moreover, greater improvements in motor performance during dual tasks significantly correlated with decreased age and increased proportion of females, respectively. Conclusion: This meta-analysis suggests that excitatory stimulation on the dorsolateral prefrontal cortex may be effective for improving dual-task performance in patients with PD. [ABSTRACT FROM AUTHOR]

Background: Added sugars intake is common among individuals with Parkinson's disease (PD), yet the link between added sugars intake and PD is not well understood. Our study aims to investigate the association between added sugars intake and PD. Methods: This study utilized data from the National Health and Nutrition Examination Survey (NHANES) from1990 to 2020. Added sugars intake was estimated based on a 24-hour dietary recall from participants. Multivariable logistic regression analysis was employed to explore the relationship between added sugars intake and the prevalence of PD. Restricted cubic spline (RCS) was used to explore the nonlinear association between added sugars intake and PD. To further observe whether the conclusions were consistent across different subgroups, we conducted subgroup analyses to investigate the association of added sugars intake with PD in different populations. Results: The study included 12,489 participants, of which 100 had PD. When weighted, the data represented 136,959,144 participants. The study revealed a positive association between added sugars intake and the prevalence of PD. In multivariable regression models adjusted for all confounding factors, compared with the lowest quartile of added sugars intake, the third quartile (OR = 2.99; 95% CI: 1.43–6.26) and those consuming more than 25% of their calories from added sugars (OR = 3.34; 95% CI: 1.03–10.86) had the highest risk of PD. The RCS curve showed an L-shaped nonlinear association between added sugars intake and PD. Two-segment linear regression by sex revealed that PD prevalence in women was linearly related to sugar intake (nonlinear P = 0.465), while men exhibited an L-shaped nonlinear relationship (nonlinear P = 0.03). Additionally, subgroup analysis showed that alcohol consumption and diabetes significantly influenced the association between added sugars intake and the prevalence of PD. Conclusion: These results highlight a positive association between added sugars intake and the prevalence of PD, particularly among women, heavy drinkers, and individuals with diabetes. [ABSTRACT FROM AUTHOR]

Nuclear pore complexes (NPCs) are embedded in the nuclear envelope and facilitate the exchange of macromolecules between the nucleus and cytoplasm in eukaryotic cells. The dysfunction of the NPC and nuclear transport plays a significant role in aging and the pathogenesis of various neurodegenerative diseases. Common features among these neurodegenerative diseases, including Parkinson's disease (PD), encompass mitochondrial dysfunction, oxidative stress and the accumulation of insoluble protein aggregates in specific brain regions. The susceptibility of dopaminergic neurons to mitochondrial stress underscores the pivotal role of mitochondria in PD progression. Disruptions in mitochondrial-nuclear communication are exacerbated by aging and α-synuclein-induced oxidative stress in PD. The precise mechanisms underlying mitochondrial impairment-induced neurodegeneration in PD are still unclear. Evidence suggests that perturbations in dopaminergic neuronal nuclei are linked to PD-related neurodegeneration. These perturbations involve structural damage to the nuclear envelope and mislocalization of pivotal transcription factors, potentially driven by oxidative stress or α-synuclein pathology. The presence of protein aggregates, pathogenic mutations, and ongoing oxidative stress can exacerbate the dysfunction of NPCs, yet this mechanism remains understudied in the context of oxidative stress-induced PD. This review summarizes the link between mitochondrial dysfunction and dopaminergic neurodegeneration and outlines the current evidence for nuclear envelope and nuclear transport abnormalities in PD, particularly in oxidative stress. We highlight the potential role of nuclear pore and nucleocytoplasmic transport dysfunction in PD and stress the importance of systematically investigating NPC components in PD. [ABSTRACT FROM AUTHOR]

The inflammatory processes that drive pathologies of the central nervous system (CNS) are complex and involve significant contributions from the immune system, particularly myeloid cells. Understanding the shared and distinct pathways of myeloid cell regulation in different CNS diseases may offer critical insights into therapeutic development. This review aims to elucidate the mechanisms underlying myeloid cell dysfunction and neuroinflammation in two groups of neurological pathologies with significant social impact and a limited efficacy of their treatments: the most common primary brain tumors –gliomas-, and the most prevalent neurodegenerative disorders -Alzheimer's and Parkinson's disease. Despite their distinct clinical manifestations, these diseases share key pathological features, including chronic inflammation and immune dysregulation. The role of myeloid cells in neuroinflammation has garnered special interest in recent years in both groups, as evidenced by the growing focus on therapeutic research centred on myeloid cells. By examining the cellular and molecular dynamics that govern these conditions, we hope to identify common and unique therapeutic targets that can inform the development of more effective treatments. Recent advances in single-cell technologies have revolutionized our understanding of myeloid cell heterogeneity, revealing diverse phenotypes and molecular profiles across different disease stages and microenvironments. Here, we present a comprehensive analysis of myeloid cell involvement in gliomas, Alzheimer's and Parkinson's disease, with a focus on phenotypic acquisition, molecular alterations, and therapeutic strategies targeting myeloid cells. This integrated approach not only addresses the limitations of current treatments but also suggests new avenues for therapeutic intervention, aimed at modulating the immune landscape to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background: The nigrostriatal dopamine (DA) system plays a critical role in regulating the sleep–wake state. The relationship between baseline striatal DA transporter (DAT) specific binding ratios (SBR) and rapid eye movement sleep behavior disorder (RBD) has been established. This study aimed to investigate the association between the progression of striatal DA dysfunction and sleep disturbances, including excessive daytime sleepiness (EDS) and probable RBD (pRBD), in patients with Parkinson's disease (PD). Methods: Data were obtained from the Parkinson's Progression Markers Initiative (PPMI). Six hundred twenty-one newly diagnosed PD patients and followed up for 4 years were included in this longitudinal study. EDS and pRBD were defined using the Epworth Sleepiness Scale (ESS) and RBD Screening Questionnaire (RBDSQ). Striatal DAT SBR was evaluated by [123I] FP-CIT SPECT. Results: Using a linear mixed-effects model across all contemporaneous data points, we found a negative correlation between striatal DAT SBR and sleep disturbances (EDS/pRBD). The interaction between striatal DAT SBR and year was specific to RBDSQ score (β = − 0.102, 95% CI: − 0.187 to − 0.017, p = 0.019), with no evidence of a similar interaction for ESS score. Additionally, the association between the alpha-synuclein gene (SNCA) and sleep disturbances was mediated by the SBR (ESS score: total effect = − 2.717, p = 0.022; direct effect = − 3.222, p = 0.007; indirect effect = 0.505, p < 0.05; RBDSQ score: total effect = 1.402, p = 0.026; direct effect = 1.209, p = 0.057; indirect effect = 0.193, p < 0.05). Conclusions: Our findings support the role of striatal DA dysfunction in sleep disturbances in early PD patients. Furthermore, we demonstrated that genetic variations in causative genes of PD contribute to the development of sleep disturbances. Striatal DAT imaging may be a useful risk indicator for sleep disturbances, providing early intervention strategies. [ABSTRACT FROM AUTHOR]

The spectrum of synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), is characterized by α-synuclein (αSyn) pathology, which serves as the definitive diagnostic marker. However, current diagnostic methods primarily rely on motor symptoms that manifest years after the initial neuropathological changes, thereby delaying potential treatment. The symptomatic overlap between PD and MSA further complicates the diagnosis, highlighting the need for precise and differential diagnostic methods for these overlapping neurodegenerative diseases. αSyn misfolding and aggregation occur before clinical symptoms appear, suggesting that detection of pathological αSyn could enable early molecular diagnosis of synucleinopathies. Recent advances in seed amplification assay (SAA) offer a tool for detecting neurodegenerative diseases by identifying αSyn misfolding in fluid and tissue samples, even at preclinical stages. Extensive research has validated the effectiveness and reproducibility of SAAs for diagnosing synucleinopathies, with ongoing efforts focusing on optimizing conditions for detecting pathological αSyn in more accessible samples and identifying specific αSyn species to differentiate between various synucleinopathies. This review offers a thorough overview of SAA technology, exploring its applications for diagnosing synucleinopathies, addressing the current challenges, and outlining future directions for its clinical use. [ABSTRACT FROM AUTHOR]

Disturbances in the fatty acid lipidome are increasingly recognized as key drivers in the progression of various brain disorders. In this review article, we delve into the impact of Δ9 fatty acid desaturases, with a particular focus on stearoyl-CoA desaturase-1 (SCD1), within the setting of neuroinflammation, neurodegeneration, and brain repair. Over the past years, it was established that inhibition or deficiency of SCD1 not only suppresses neuroinflammation but also protects against neurodegeneration in conditions such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease. This protective effect is achieved through different mechanisms including enhanced remyelination, reversal of synaptic and cognitive impairments, and mitigation of α-synuclein toxicity. Intriguingly, metabolic rerouting of fatty acids via SCD1 improves the pathology associated with X-linked adrenoleukodystrophy, suggesting context-dependent benign and harmful effects of SCD1 inhibition in the brain. Here, we summarize and discuss the cellular and molecular mechanisms underlying both the beneficial and detrimental effects of SCD1 in these neurological disorders. We explore commonalities and distinctions, shedding light on potential therapeutic challenges. Additionally, we touch upon future research directions that promise to deepen our understanding of SCD1 biology in brain disorders and potentially enhance the clinical utility of SCD1 inhibitors. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a progressive degenerative neurological disorder that negatively affects the quality of life of affected individuals as well as their care givers. There is limited information in both epidemiological data and awareness level on PD in the Middle East. Considering the increasing prevalence of PD, the lack of awareness and negative attitudes toward PD pose a barrier in the provision of appropriate care for individuals with PD. Objective: This study aimed to validate scales to explore the knowledge and attitude towards PD among the general population in Lebanon and identify the associated factors related to the knowledge and attitude assessment. This study's results would guide awareness strategies in the country including public health strategies, campaigns and education sessions for the general population as well as targeted people. Methodology: An online cross-sectional study was conducted between July and September 2023 in Lebanon. Snowball sampling was used to recruit 400 Lebanese adults living in Lebanon. The validity and reliability of the knowledge and attitude scales were assessed, followed by a thorough statistical analysis to explore the factors associated with these scales. Results: The knowledge and attitude scales generated by this study were valid and reliable; Cronbach's alpha values for knowledge and attitude scales were 0.697 and 0.901, respectively. Using these scales, 91.8% demonstrated inappropriate knowledge and 93% showed positive attitude towards PD. Higher knowledge scores were significantly associated with female gender (Beta = 1.130), being a healthcare professional (Beta = 2.514), having heard about PD (Beta = 5.338), obtaining the source of information from electronic databases (Beta = 1.283), from pharmacist or physician (Beta = 1.212), from personal readings (Beta = 2.386), and having PD or knowing someone with PD; a friend or a family member (Beta = 1.179). However, being illiterate or having primary or secondary education (Beta = -0.874), having a higher household crowding index (Beta = -1.890), not knowing if contents from sources provide negative images about PD (Beta = − 1.908) and preferring not to say to which social class they belong (Beta = − 1.602) were significantly associated with lower knowledge scores. Believing that contents from sources provide negative images about PD (Beta = 8.246) was significantly associated with a higher attitude score, i.e., a more negative attitude towards PD. Conclusion: This study showed low levels of knowledge and an overall positive attitude towards PD in Lebanon. Factors associated with higher knowledge and attitude scores, including gender, education level, profession, knowing someone with the disease, household crowding index, social class, source of information and contents of such sources, reflect the need to consider those when implementing targeted corrective actions. Future studies can focus on educational campaigns to improve public awareness, reduce misconceptions and limit barriers to the early diagnosis and provision of optimal care to the affected patients. [ABSTRACT FROM AUTHOR]

Background: Over the past few years, the development of telerehabilitation has advanced rapidly. Patients with Parkinson's disease (PwPD) often have difficulty with mobility, making it challenging for them to perform centre-based exercise.This study aims to compare the effectiveness and adherence of home physical therapy (HPT) and telerehabilitation (TR) in mitigating motor symptoms and improving the quality of life in patients with mild to moderate Parkinson's disease. Methods: This randomized controlled trial included a total of 190 patients who underwent in-person eligibility assessment, with 100 allocated to the HPT group and 90 to the TR group. Both interventions consisted of home-based training sessions lasting 40–60 min and were conducted five times a week for 4 weeks. The primary outcome was the Unified Parkinson's Disease Rating Scale motor section (UPDRS3) score. Secondary outcomes included balance function, assessed using the Berg Balance Scale (BBS); risk of fall, evaluated through the Timed Up-and-Go test (TUG) and the Five Times Sit-to-Stand test (FTSST); gait, measured using the Freezing of Gait Questionnaire (FOGQ) and IDEEA activity monitor; muscle strength, evaluated using the isokinetic dynamometry; motor aspects of experiences of daily living (UPDRS2); and quality of life, assessed by Parkinson's Disease Questionnaire-39 (PDQ-39). Results: There was a significant difference in the UPDRS3, BBS, TUG, FTSST, FOGQ,step length, step velocity,preswing angle, UPDRS2 and PDQ-39 between baseline and 4 weeks in both groups. The decrease in the UPDRS3 score was significantly greater in the HPT group (-3.38 points) than in the RE group (-1.45 points) in the older age group (P = 0.021), but there was no significant between-group difference in the younger age group (P = 0.416). Similar changes favouring the HPT group were observed in the BBS, TUG, step velocity, and extension average torque. 7 (7%) patients in the HPT group and 12 (13%) patients in the TR group did not complete their daily exercise plan. Conclusions: Both HPT and TR have demonstrated effectiveness, safety, and feasibility in PwPD. However, the HPT program exhibited greater effectiveness among older patients and higher patient compliance compared to TR. Trial registration: Chictr.org.cn, ChiCTR2300071648. Registered on 22 May 2023—retrospectively registered, https://www.chictr.org.cn/showproj.html?proj=196313. [ABSTRACT FROM AUTHOR]

Background: Clinical practice suggests that older adults (i.e., ≥ 65 years of age) experience adverse drug reactions (ADRs) more often than younger patients (i.e., < 65 years of age). ADRs such as falls, extrapyramidal symptoms (EPS), metabolic disorders, sedation, and delirium are particularly worrisome and often associated with psychotropic drugs. Methods: This observational study investigated the risk for psychotropic drug-related ADRs in older (n = 99,099) and younger adults (n = 363,562) in psychiatric inpatients using data from the German pharmacovigilance program "Arzneimittelsicherheit in der Psychiatrie" (AMSP) from 1993–2016. The aim was to assess whether age influenced the risk of specific ADR types and if certain psychotropic drugs posed particular concerns. Results: The risk for ADRs did not differ between older and younger patients (relative risk 0.98, 95% confidence interval 0.92–1.05). However, older patients had a higher risk for delirium (2.35, 1.85–2.99), hyponatremia (3.74, 2.85–4.90), and orthostatic syncope (2.37, 1.72–3.26), as well as certain types of EPS, e.g., parkinsonism (1.89, 1.45–2.48) and Pisa-/metronome syndrome (3.61, 2.51–5.18). The risk for other ADRs, such as acute dystonia (0.20, 0.10–0.37), akathisia (0.47, 0.29–0.76), liver dysfunction (0.63, 0.48–0.82), weight gain (0.07, 0.04–0.14), sexual dysfunction (0.03, CI 0.00–0.25), and hyperprolactinemia/galactorrhea (0.05, 0.02–0.17) was significantly lower for older patients. Older patients treated with any type of antidepressant drug (1.33, 1.26–1.40)—especially selective serotonin reuptake inhibitors (1.57, 1.26–1.40) and selective serotonin-norepinephrine reuptake inhibitors (2.03, 1.80–2.29)—and lithium (1.74, 1.52–2.00) had a higher ADR risk than younger patients. Second-generation antipsychotic drugs had a lower (0.74, 0.71–0.77) and low-potency first-generation antipsychotic drugs a higher (1.19, 1.07–1.33) ADR risk in older patients. The risk for ADRs involving multiple drugs was higher in older patients (1.28, 1.22–1.34). ADRs in older patients were 6.4 times more likely to result in death. Conclusions: Clinicians and pharmacists should be aware of the types of ADRs and high-risk drugs across age groups and provide appropriate monitoring. Pharmacovigilance is crucial in psychiatric patients of all ages and should not be neglected, even for drugs generally considered "safe". [ABSTRACT FROM AUTHOR]

Background: Pericytes play a crucial role in controlling inflammation and vascular functions in the central nervous system, which are disrupted in Parkinson's disease (PD). Still, there is a lack of studies on the impact of pericytes on neurodegenerative diseases, and their involvement in the pathology of PD is unclear. Our objective was to investigate the molecular and functional differences between healthy pericytes and pericytes with the LRRK2 G2019S mutation, which is one of the most common mutations associated with PD. Methods: Our study employed pericyte-like cells obtained from induced pluripotent stem cells produced from PD patients with the LRRK2 G2019S mutation as well as from healthy individuals. We examined the gene expression profiles of the cells and analyzed how the alterations reflect on their functionality. Results: We have shown differences in the expression of genes related to inflammation and angiogenesis. Furthermore, we observe modified migration speed in PD pericyte-like cells as well as enhanced secretion of inflammatory mediators, such as soluble VCAM-1 and MCP-1, in these pericyte-like cells following exposure to proinflammatory stimuli. Conclusions: In summary, our findings support the notion that pericytes play a role in the inflammatory and vascular changes observed in PD. Further investigation of pericytes could provide valuable insight into understanding the pathogenesis of PD. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether antiparkinsonism anticholinergics (AAs) increase hip fracture (HFx) risk in Parkinson's disease (PD) patients. This study examined associations between AAs, HFx and mortality in PD using Taiwan's National Health Insurance Database. Methods: Newly diagnosed PD patients ≥ 50yrs were categorized by AAs exposure: PD with AAs (≥ 90 days, n = 16,921), PD without AAs (never-exposed, n = 55,940), and demographically matched non-PD controls (n = 291,444). Competing risk of death was considered in Fine & Gray models analyzing HFx. Mortality was compared using Cox regression models. Results: Both PD groups were associated with higher HFx risk compared to non-PD controls (adjusted hazard ratio [HR] = 1.51 for PD with AAs; 1.53 without). No significant difference in HFx risk was observed between PD groups with and without AAs exposure. Both groups were associated with increased mortality compared to non-PD (adjusted HR = 2.24 with AAs; 2.44 without AAs). Among PD patients, those with AAs exposure were associated with lower mortality compared to those without AAs (adjusted HR = 0.93). Conclusions: PD was associated with increased HFx and mortality compared to non-PD, regardless of AAs exposure. AAs use was not associated with increased HFx risk and was associated with lower mortality. AAs use was not associated with increased fracture risk and was associated with lower mortality in PD, however further studies are needed to clarify these associations. [ABSTRACT FROM AUTHOR]

To investigate physiological function of α-synuclein is important for understanding its pathophysiological mechanism in synucleinopathies including Parkinson's disease. Employing knockout mice, we found that Snac/α-synuclein deletion induced aberrant projection of olfactory sensory neurons and hyposmia. We identified 9 axon guidance associated differentially expressed proteins using iTRAQ based Liquid Chromatograph Mass Spectrometer. NCK2 is most significantly down-regulated protein among them. We further found that either α-synuclein deletion or NCK2 deficiency induced Eph A4 inactivation. Re-expressing Snac/α-synuclein in its knockout neurons reversed the down-regulation of NCK2, as well as the inactivation of EphA4. Overexpression of Snac/α-synuclein in α-synuclein deleted mice reversed the down-regulation of NCK2 and pEphA4, and improved the olfactory impairment of mice. Correlation analysis showed that there is a significant correlation between the protein level of α-synuclein, NCK2, and pEphA4, respectively. Nonetheless, immunoprecipitation analysis showed that NCK2 was associated with both EphA4 and Rho A, suggesting that NCK2 as a scaffolding protein to modulate Eph A4/Rho A pathway. Moreover, Rho A activity was significantly lower in α-synuclein deficient mice. Thus, α-synuclein regulates olfactory neurons projection through NCK2 dependent EphA4/Rho A pathway. Malfunction of α-synuclein because of deletion may cause aberrant olfactory neurons projection. This extended our knowledge of α-synuclein functions, which may explain why olfaction is usually impaired in some synucleinopathies. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a chronic neurodegenerative disorder that currently has no curable strategies. More and more evidence suggests that endoplasmic reticulum (ER) stress plays an essential role in PD pathogenesis. Periplaneta americana L. (P. americana) is a traditional Chinese medicine with diverse therapeutic properties. This study aims to investigate the neuroprotective effect and underlying mechanism of P. americana in in vitro and in vivo PD models. Methods: The exposure of SH-SY5Y cells to 1-methyl-4-phenyl-pyridinium (MPP+) was used as the in vitro PD model. MTT assay, Hoechst staining, Calcein AM-PI staining and flow cytometry were performed to measure the cell viability and apoptosis. DCFH-DA and JC-1 assay were used to measure the intracellular ROS and mitochondrial membrane potential (Δψm), respectively. Western-blot and immunostaining were conducted to detect the expression of key molecules related with ER stress. For the in vivo PD model induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydro-pyridine (MPTP), the motor function of mice was assessed by behavioral tests, the level of TH was examined by western-blot and immunostaining, the expression of key molecules related with ER stress was measured by western-blot. Results: Periplaneta americana ethanol extract (PAE) concentration-dependently inhibited MPP+-induced cell loss and increased cell viability. PAE also remarkably attenuated ROS accumulation, the decline of Δψm as well as the excessive ER stress. The neuroprotective effects of PAE could be blocked by ROS inducer trimethylamine N-Oxide or ER stress activator tunicaymycin, while the antioxidant N-Acetyl-L-cysteine or ER stress inhibitor sodium 4-phenylbutyrate mimicked the effects of PAE. Furthermore, we found that PAE could activate AKT/GSK3β/β-catenin pathway. The effect of PAE on ROS production, Δψm and ER stress was blocked by AKT inhibitor MK-2206. In in vivo model, PAE significantly improved motor function, prevented dopaminergic neuronal loss and attenuated ER stress in substantia nigra and striatum of MPTP-treated mice. Similarly, the effects of PAE on MPTP-treated mice were also abolished by MK-2206. Conclusions: Our results suggest that P. americana exerts neuroprotective effects through inhibiting ER stress via AKT-dependent pathway. Periplaneta americana may represent a promising therapeutic agent for PD treatment and is worthy of further being exploited. [ABSTRACT FROM AUTHOR]

Background: Central Asia is known to face various ecological challenges that constitutes major risk factors for Parkinson's disease (PD). This study examines the burden of PD in Central Asia, a region where data on neurological disorders is notably sparse. Methods: Building on the latest Global Burden of Disease Study (GBD 2021), this study investigates the Years of Life Lost (YLLs), Years Lived with Disability (YLDs), and Disability-Adjusted Life Years (DALYs) associated with PD in Central Asia and its countries from 1990 to 2021. The authors calculated average annual percent change (AAPC) to analyze trends, and compared individual country estimates to global figures. Additionally, incorporating data from the World Bank, both Bayesian hierarchical and non-hierarchical frequentist regression models were employed to assess their impact on DALYs. Results: The DALYs varied across the study period, primarily driven by YLLs. While YLLs showed a uniform trend, YLDs were mostly incremental. Kazakhstan had the highest estimates across all metrics and was the only country aligned with global patterns. Age- and sex-specific estimates revealed substantial variations, with notably high figures found in male subjects from Tajikistan. The YLLs, YLDs, and DALYs for Kazakhstan, Uzbekistan, and Turkmenistan saw a significant increase in AAPCs. In contrast, Kyrgyzstan and Tajikistan saw declines, likely attributable to civic conflict and inter-country differences in population structure. Further comparison of DALY trends revealed significant deviations for all countries from the global pattern. Conclusion: This study showed an overall increase in PD burden from 1990 to 2021. These findings underscore the need for targeted strategies to reduce PD burden, with a particular focus on Kazakhstan. Integrating historical information is crucial for discussing the plausible mechanisms in studies sourced from the GBD. [ABSTRACT FROM AUTHOR]

Background: Mast cells (MCs) are tissue resident cells of the immune system, mainly known for their role in allergy. However, mounting evidence indicates their involvement in the pathology of age-related diseases, such as Alzheimer's disease, Parkinson's disease, and cancer. MC numbers increase in aged tissues, but how ageing affects MCs is poorly understood. Results: We show that MC ageing is associated with the increased expression of the cell cycle inhibitor p16 Ink4a, a marker and inducer of cellular senescence. Relying on this observation and the tight association of ageing with senescence, we developed a model of inducible senescence based on doxycycline-induced expression of p16Ink4a in cultured bone marrow derived MCs (BMMCs). Using this model, we show that senescent MCs upregulate IL-1β, TNF-α and VEGF-A. We also demonstrate that senescence causes marked morphological changes that impact MC function. Senescent MCs are larger, contain a larger number of secretory granules (SGs) and have less membrane protrusions. Particularly striking are the changes in their SGs, reflected in a significant reduction in the number of electron dense SGs with a concomitant increase in lucent SGs containing intraluminal vesicles. The changes in SG morphology are accompanied by changes in MC degranulation, including a significant increase in receptor-triggered release of CD63-positive extracellular vesicles (EVs) and the exteriorisation of proteoglycans, as opposed to a gradual inhibition of the release of β-hexosaminidase. Conclusions: The inducible expression of p16Ink4a imposes MC senescence, providing a model for tracking the autonomous changes that occur in MCs during ageing. These changes include both morphological and functional alterations. In particular, the increased release of small EVs by senescent MCs suggests an enhanced ability to modulate neighbouring cells. [ABSTRACT FROM AUTHOR]

Background: Microbial melanins possess a broad spectrum of biological activities. However, there is little understanding of their neuroprotective and neuronal cell differentiation properties. This study aimed to extract, purify, and modify melanins from two medicinal fungi (Daedaleopsis tricolor and Fomes fomentarius), and to evaluate their antioxidant activity, as well as their cell protective ability against neurotoxins. In addition, the study also investigated the feasibility of combining melanins or modified melanins with retinoic acid (RA) to induce neuronal differentiation. Methods: Melanin was extracted and purified using alkaline acid-based methods. Antioxidant activities and neuroprotective effects were evaluated using the DPPH (1,1-diphenyl-2-picrylhydrazyl) and MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assays, respectively. In addition, morphological changes of SH-SY5Y cells were recorded by using a Pannoramic MIDI scanner. Results: All melanins and arginine-modified melanins displayed mild DPPH scavenging activities, which were statistically lower than that of ascorbic acid (p < 0.05). In terms of neuroprotection, both melanins and arginine-modified melanins exhibited significant cell protection against H2O2 after 24 h exposure (p < 0.05). Notably, there is no significant difference between F. fomentarius melanin and its modified form as they both increased cell viability by about 20%. Contrarily, while D. tricolor melanin enhanced the cell viability with 16%, its modified form increased the cell viability with 21%. These activities, however, are significantly lower than the positive control (N-acetylcysteine, p < 0.05). Regarding MPTP, only the arginine-modified melanins of the two fungi significantly protected the cells after 24 h exposure to the toxin (p < 0.05). Specifically, F. fomentarius and D. tricolor modified melanins enhanced the cell viability with 10.2% and 11.1%, respectively, whereas that of the positive control was 13.2%. Interestingly, combining RA (10 µM) with 20 µg/mL of either F. fomentarius, or especially D. tricolor arginine-modified melanin, significantly promoted neuroblastoma cell differentiation into mature neuronal cells compared to using RA alone (p < 0.05). Conclusions: The arginine-modified melanins of D. tricolor and F. fomentarius have potential for neuroprotection against Parkinsonian neurotoxins. In addition, the arginine-modified melanin of D. tricolor may serve as an excellent material for research in neuroblastoma treatment. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD) are common complications of diabetes, arising from insulin resistance, inflammation, and other pathological processes in the central nervous system. The potential of numerous antidiabetic agents to modify neurodegenerative disease progression, both preclinically and clinically, has been assessed. These agents may provide additional therapeutic benefits beyond glycemic control. Introduced in the twenty-first century, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of antidiabetic drugs noted not only for their potent glucose-lowering effects but also for their cardiovascular and renal protective benefits. Various GLP-1RAs have been demonstrated to have significant benefits in in vitro and in vivo models of neurodegenerative diseases through modulating a variety of pathogenic mechanisms, including neuroinflammation, autophagy, mitochondrial dysfunction, and the abnormal phosphorylation of pathognomonic proteins. These agents also have substantial protective effects on cognitive and behavioral functions, such as motor function. However, clinical trials investigating GLP-1RAs in diseases such as AD, PD, mild cognitive impairment, psychiatric disorders, and diabetes have yielded mixed results for cognitive and motor function. This review examines the link between diabetes and neurodegenerative diseases, explores the effects of antidiabetic agents on neurodegeneration, provides a concise overview of the GLP-1 pathway, and discusses both preclinical and clinical trial outcomes of GLP-1RAs for neurodegenerative diseases, including their effects on cognition in AD and PD. This review also proposed new strategies for the design of future clinical trials on GLP-1 RAs for both AD and PD. [ABSTRACT FROM AUTHOR]

Background:. The present study aimed at deriving regression-based reliable change indices (RCIs) for the Montreal Cognitive Assessment (MoCA) in an Italian cohort of non-demented Parkinson's disease (PD) patients. Methods: N = 33 consecutive, non-demented PD patients were followed-up at a 5-to-8-month interval (M = 6.6; SD = 0.6) with the MoCA. Practice effects and test-retest reliability were assessed via dependent-sample t-tests and intra-class correlation (ICC) coefficients, respectively. RCIs were derived separately for raw and demographically adjusted MoCA scores according to a standardized regression-based approach by accounting for both baseline confounders (i.e., demographics, disease duration and Unified Parkinson's Disease Rating Scale scores) and retest interval. Results: No practice effects were found (t(32) = 0.29; p =.778), with acceptable test-retest reliability being detected (ICC = 0.67). MoCA scores at T0 proved to be the only significant predictor of T1 MoCA performances within both the model addressing raw scores and that addressing adjusted scores (ps < 0.001). Conclusions: The present study provides Italian practitioners and researchers with regression-based RCIs for the MoCA in non-demented PD patients, which can be reliably adopted for retest interval ≥ 5 and ≤ 8 months without encountering any practice effect. [ABSTRACT FROM AUTHOR]

Background: The cannabigerol derivative VCE-003.2, which has activity at the peroxisome proliferator-activated receptor-γ has afforded neuroprotection in experimental models of Parkinson's disease (PD) based on mitochondrial dysfunction (6-hydroxydopamine-lesioned mice) and neuroinflammation (LPS-lesioned mice). Now, we aim to explore VCE-003.2 neuroprotective properties in a PD model that also involves protein dysregulation, other key event in PD pathogenesis. Methods: To this end, an adeno-associated viral vector serotype 9 coding for a mutated form of the α-synuclein gene (AAV9-SynA53T) was unilaterally delivered in the substantia nigra pars compacta (SNpc) of mice. This model leads to motor impairment and progressive loss of tyrosine hydroxylase-labelled neurons in the SNpc. Results: Oral administration of VCE-003.2 at 20 mg/kg for 14 days improved the performance of mice injected with AAV9-SynA53T in various motor tests, correlating with the preservation of tyrosine hydroxylase-labelled neurons in the SNpc. VCE-003.2 also reduced reactive microgliosis and astrogliosis in the SNpc. Furthermore, we conducted a transcriptomic analysis in the striatum of mice injected with AAV9-SynA53T and treated with either VCE-003.2 or vehicle, as well as control animals. This analysis aimed to identify gene families specifically altered by the pathology and/or VCE-003.2 treatment. Our data revealed pathology-induced changes in genes related to mitochondrial function, lysosomal cell pathways, immune responses, and lipid metabolism. In contrast, VCE-003.2 treatment predominantly affected the immune response through interferon signaling. Conclusion: Our study broadens the neuroprotective potential of VCE-003.2, previously described against mitochondrial dysfunction, oxidative stress, glial reactivity and neuroinflammation in PD. We now demonstrate its efficacy against another key pathogenic event in PD as α-synuclein dysregulation. Furthermore, our investigation sheds light on the molecular mechanisms underlying VCE-003.2 revealing its role in regulating interferon signaling. These findings, together with a favorable ADMET profile, enhance the preclinical interest of VCE-003.2 towards its future clinical development in PD. [ABSTRACT FROM AUTHOR]

Background: Knowledge of health care utilization at the end of life in Parkinson's disease (PD) is sparse. This study aims to investigate end of life health care utilization, characterized by emergency room (ER) visits, receipt of specialized palliative care (SPC), and acute hospital deaths in a Swedish population-based PD cohort. Methods: We conducted a retrospective cohort study on deceased patients (≥ 18 years) with a PD diagnosis during their last year of life (n = 922), based on health care-provider data from Region Stockholm´s data warehouse, for the study period 2015–2021. Univariable and multivariable logistic regression analyses tested associations and adjusted Odds ratios (aORs) were calculated. Results: During the last month of life, approx. half of the cohort had emergency room (ER) visits and risk of frailty (measured by Hospital Frailty Risk Score) significantly predicted these visits (aOR, 3.90 (2.75–5.55)). In total, 120 people (13%) received SPC during their last three months of life, which positively associated with risk for frailty, (aOR, 2.65 (1.43–4.94, p = 0.002). In total, 284 people (31%) died in acute hospital settings. Among community-dwellers, male gender and frailty were strongly associated with acute hospital deaths (aOR, 1.90 (1.15–3.13, p = 0.01) and 3.70 (1.96–6.98, p < 0.0001)). Conclusions: Rates of ER visits at end of life and hospital deaths were relatively high in this population-based cohort. Considering a high disease burden, referral to SPC at end of life was relatively low. Sex-specific disparities in health care utilization are apparent. Identifying people with high risk for frailty could assist the planning of optimal end-of-life care for people with PD. [ABSTRACT FROM AUTHOR]

Background: Where available, Parkinson's Nurse Specialists (PNS) provide a range of care, support, guidance, and advocacy for people with Parkinson's (PwP), and, where appropriate, their care partners (CP). Parkinson's is a complex and progressive condition. Consequently, evaluating health outcomes is not a reliable method to understand the value and impact of PNS. Previous research has identified PNS can improve the subjective well-being of PwP in the community, also that barriers to care include heavy caseloads and a lack of time. Yet little is known about the value of the role of the PNS, particularly about the impact of pharmacological management and review. This research aims to close this research gap by providing explanatory theories of the impact and value of PNS to PwP, their CP, and other professionals. Methods: A social constructivist grounded theory approach was used. Semi-structured interviews were conducted with three groups, PNS, PwP, and CP. Interviews were analysed using NVivo for coding and categorising and Word for memo-writing. Data was analysed inductively and iteratively to identify contexts, social processes, actions, and behaviours, before final emergent theories were identified. Results: 46 semi-structured interviews (PNS 18, PwP 19, CP 9) led to four data categories and 13 sub-categories that delineated PNS value. (1) Expert Counsel; provision of emotional support, education, and lifestyle guidance; CP inclusion; provision from diagnosis; and across all stages of Parkinson's. (2) Conduit of Care; signposting, referral, and connection to PwP, CP, others; PNS barriers and facilitators; (3) Team/Partnership; continuity and partnership, 'working together'; (4) Pharmacological Support, PNS prescribing; concordance; speed of treatment. Where PNS were accessible they could offer personalised support and partnership, so providing person-centred care that improves health and well-being. Conclusion: Where a PNS is accessible due to service availability and manageable caseloads, to provide person-centred care, they deliver several benefits to PwP and CP which improve health and perceived well-being. Where PNS are not available, PwP and CP often struggle to manage their Parkinson's with negative impacts on health and well-being. [ABSTRACT FROM AUTHOR]

Background: Inflammation significantly impacts Parkinson's disease (PD), yet the intricate relationship between inflammatory markers and PD remains elusive. Objective: To identify the peripheral biomarkers of PD and its correlation with the motor and non-motor symptoms of PD. Methods: 79 PD patients and 65 controls were included in this study. Clinical information and the serum levels of IL-8, IL-27, IL-33, β-NGF, AgRP, and TRAILR2 in the participants were collected. Appropriate scales were used to assess the symptoms of PD. For the factors with significant differences in the two groups, multivariable logistic regression was used to determine its relationship with PD. Moreover, spearman correlation was conducted to explore the correlation between the factors and PD related symptoms. The IL-27 level was compared between the cognitively healthy PD group and the mild cognitive impairment in PD (PD-MCI). The serum level of TRAILR2 was positively correlated with age and was not associated with other clinical characteristics related to PD. Results: Compared to controls, the serum levels of IL-27(P = 0.013) were increased whereas the levels of TRAILR2(P = 0.008) were decreased in PD patients. IL-8, IL-33, β-NGF, and AgRP showed no significant differences between the two groups. After controlling for the other variables, IL-27 was considered as an independent risk factor for PD in the multivariable logistic regression model. The receiver operating characteristic (ROC) curve for diagnosing PD with IL-27 yielded an area under the curve (AUC) of 0.621. Additionally, IL-27 level in PD patients was positively correlated with age, the disease duration, LEDD and negatively correlated with the MoCA scores. However, no significant difference was found in IL-27 levels between cognitively healthy PD and PD-MCI groups. Conclusion: Elevated serum IL-27 was a risk factor for PD and positively correlated with the cognitive decline in PD. [ABSTRACT FROM AUTHOR]

Background: Autophagy dysfunction in glial cells is implicated in the pathogenesis of Parkinson's disease (PD). The previous study reported that α-synuclein (α-Syn) disrupted autophagy in cultured microglia. However, the mechanism of microglial autophagy dysregulation is poorly understood. Methods: Two α-Syn-based PD models were generated via AAV-mediated α-Syn delivery into the mouse substantia nigra and striatal α-Syn preformed fibril (PFF) injection. The levels of microglial UNC-51-like kinase 1 (Ulk1) and other autophagy-related genes in vitro and in PD mice, as well as in the peripheral blood mononuclear cells of PD patients and healthy controls, were determined via quantitative PCR, western blotting and immunostaining. The regulatory effect of signal transducer and activator of transcription 1 (STAT1) on Ulk1 transcription was determined via a luciferase reporter assay and other biochemical studies and was verified through Stat1 knockdown or overexpression. The effect of α-Syn on glial STAT1 activation was assessed by immunohistochemistry and western blotting. Changes in microglial status, proinflammatory molecule expression and dopaminergic neuron loss in the nigrostriatum of PD and control mice following microglial Stat1 conditional knockout (cKO) or treatment with the ULK1 activator BL-918 were evaluated by immunostaining and western blotting. Motor behaviors were determined via open field tests, rotarod tests and balance beam crossing. Results: The transcription of microglial ULK1, a kinase that controls autophagy initiation, decreased in both in vitro and in vivo PD mouse models. STAT1 plays a critical role in suppressing Ulk1 transcription. Specifically, Stat1 overexpression downregulated Ulk1 transcription, while Stat1 knockdown increased ULK1 expression, along with an increase in LC3II and a decrease in the SQSTM1/p62 protein. α-Syn PFF caused toll-like receptor 4-dependent activation of STAT1 in microglia. Ablation of Stat1 alleviated the decrease in microglial ULK1 expression and disruption of autophagy caused by α-Syn PFF. Importantly, the ULK1 activator BL-918 and microglial Stat1 cKO attenuated neuroinflammation, dopaminergic neuronal damage and motor defects in PD models. Conclusions: These findings reveal a novel mechanism by which α-Syn impairs microglial autophagy and indicate that targeting STAT1 or ULK1 may be a therapeutic strategy for PD. [ABSTRACT FROM AUTHOR]

Nanobodies (Nbs) are antibody fragments derived from heavy-chain-only IgG antibodies found in the Camelidae family as well as cartilaginous fish. Their unique structural and functional properties, such as their small size, the ability to be engineered for high antigen-binding affinity, stability under extreme conditions, and ease of production, have made them promising tools for diagnostics and therapeutics. This potential was realized in 2018 with the approval of caplacizumab, the world's first Nb-based drug. Currently, Nbs are being investigated in clinical trials for a broad range of treatments, including targeted therapies against PDL1 and Epidermal Growth Factor Receptor (EGFR), cardiovascular diseases, inflammatory conditions, and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. They are also being studied for their potential for detecting and imaging autoimmune conditions and infectious diseases such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A variety of methods are now available to generate target-specific Nbs quickly and efficiently at low costs, increasing their accessibility. This article examines these diverse applications of Nbs and their promising roles. Only the most recent articles published in the last five years have been used to summarize the most advanced developments in the field. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the nigrostriatal pathway, leading to dopamine deficiency and motor impairments. Current treatments, such as L-DOPA, provide symptomatic relief but result in off-target effects and diminished efficacy over time. This study explores an alternative approach by investigating the activation of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Specifically, we explore the effects of phosphodiesterase (PDE) inhibition and guanylate cyclase-C (GUCY2C) activation on tyrosine hydroxylase Ser40 phosphorylation and their impact on motor behavior in a 6-hydroxydopamine (6-OHDA) Parkinson's disease model. Results: Our findings demonstrate that increasing cyclic nucleotide levels through PDE inhibition and GUCY2C activation significantly enhances tyrosine hydroxylase Ser40 phosphorylation. In a Pitx3-deficient mouse model, which mimics the loss of dopaminergic neurons seen in Parkinson's disease, Ser40 phosphorylation remained manipulable despite reduced tyrosine hydroxylase protein levels. Moreover, we observed no evidence of tyrosine hydroxylase degradation due to Ser40 phosphorylation, challenging previous reports. Furthermore, both PDE inhibition and GUCY2C activation resulted in improved motor behavior in the 6-OHDA Parkinson's disease mouse model, highlighting the potential therapeutic benefits of these approaches. Conclusions: This study underscores the therapeutic potential of enhancing tyrosine hydroxylase Ser40 phosphorylation to improve motor function in Parkinson's disease. Both PDE inhibition and GUCY2C activation represent promising non-invasive strategies to modulate endogenous dopamine biosynthesis and address motor deficits. These findings suggest that targeting cyclic nucleotide pathways could lead to novel therapeutic approaches, either as standalone treatments or in combination with existing therapies like L-DOPA, aiming to provide more durable symptom relief and potentially mitigate neurodegeneration in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Background: Repetitive transcranial magnetic stimulation (rTMS) has been used to treat various neurological disorders. However, the molecular mechanism underlying the therapeutic effect of rTMS on Parkinson's disease (PD) has not been fully elucidated. Neuroinflammation like regulatory T-cells (Tregs) appears to be a key modulator of disease progression in PD. If rTMS affects the peripheral Tregs in PD remains unknown. Methods: Here, we conducted a prospective clinical study (Chinese ClinicalTrials. gov: ChiCTR 2100051140) involving 54 PD patients who received 10-day rTMS (10 Hz) stimulation on the primary motor cortex (M1) region or sham treatment. Clinical and function assessment as well as flow cytology study were undertaken in 54 PD patients who were consecutively recruited from the department of neurology at Zhujiang hospital between September 2021 and January 2022. Subsequently, we implemented flow cytometry analysis to examine the Tregs population in spleen of MPTP-induced PD mice that received rTMS or sham treatment, along with quantitative proteomic approach reveal novel molecular targets for Parkinson's disease, and finally, the RNA interference method verifies the role of these new molecular targets in the treatment of PD. Results: We demonstrated that a 10-day rTMS treatment on the M1 motor cortex significantly improved motor dysfunction in PD patients. The beneficial effects persisted for up to 40 days, and were associated with an increase in peripheral Tregs. There was a positive correlation between Tregs and motor improvements in PD cases. Similarly, a 10-day rTMS treatment on the brains of MPTP-induced PD mice significantly ameliorated motor symptoms. rTMS reversed the downregulation of circulating Tregs and tyrosine hydroxylase neurons in these mice. It also increased anti-inflammatory mediators, deactivated microglia, and decreased inflammatory cytokines. These effects were blocked by administration of a Treg inhibitor anti-CD25 antibody in MPTP-induced PD mice. Quantitative proteomic analysis identified TLR4, TH, Slc6a3 and especially Syt6 as the hub node proteins related to Tregs and rTMS therapy. Lastly, we validated the role of Treg and rTMS-related protein syt6 in MPTP mice using the virus interference method. Conclusions: Our clinical and experimental studies suggest that rTMS improves motor function by modulating the function of Tregs and suppressing toxic neuroinflammation. Hub node proteins (especially Syt6) may be potential therapeutic targets. Trial registration: Chinese ClinicalTrials, ChiCTR2100051140. Registered 15 December 2021, https://www.chictr.org.cn/bin/project/edit?pid=133691 rTMS is a safe and non-invasive method for Parkinson's disease. In this study, we showed the proportion of CD4+CD25+CD127- regulatory T-cells (Tregs) in the peripheral blood was significantly increased after rTMS treatment. Similar effects of rTMS treatment were verified in MPTP-induced PD mice. Proteomic analysis and RNA interference analyses identified TLR4, TH, Slc6a3 and especially Syt6 as hub node proteins that can be modulated by rTMS therapy in PD. [ABSTRACT FROM AUTHOR]

Background and aim: Depression in Parkinson's disease (DPD) has a high incidence rate among patients with Parkinson's disease (PD). It is a common nonmotor symptom of PD that seriously affects the quality of life of patients. Thus, improving DPD is important for improving the quality of life of patients. Psychotherapy for depression is limited for many reasons, and only a few patients are able to benefit from this therapy. Several studies have demonstrated that relaxation therapy, playing, and exercise therapy are effective treatments for depression. In recent years, virtual reality (VR) has rapidly developed as a form of rehabilitation due to its immersive characteristics and accessibility. It has also been applied in the psychological treatment of phobia and anxiety. However, no relevant research on the treatment of DPD has been conducted using VR. This study aims to assess the effects of immersive VR-assisted training on patients with DPD. Methods: This single-blind randomized controlled trial will recruit 74 patients with DPD. The patients will then be randomly allocated into two groups. The patients in the VR group (n = 37) will receive VR-assisted training (40 min) three times a week for 8 weeks. The patients in the non-VR training group (n = 37) will receive treatment as usual. The outcome measures will be assessed before intervention, and after 8 weeks, 3 months, and 6 months of the intervention. The primary outcomes will include the Hamilton Depression Scale-24. The secondary outcomes will include the 36-Item Short-Form Health Survey questionnaire, neuroinflammation factors (brain-derived neurotrophic factor, interleukin-6, and C-reactive protein), and functional magnetic resonance imaging. Discussion: The traditional treatment of depression has limited resources and requires a lot of time and energy. It is not suitable for patients with PD having mobility difficulties and residing in remote areas. VR can make up for limitations in traditional treatment methods. An advantage of VR is that it makes patients more invested in active participation. This study may provide an improved method for the clinical treatment of patients with DPD, which is suitable for clinical decision-making and future practice. Trial registration: The study has been registered in the Chinese Clinical Trial Registry ChiCTR2200065843, November 16, 2022. https://www.chictr.org.cn/showproj.html?proj=174551 {2a and 2b} [ABSTRACT FROM AUTHOR]

Background: In Parkinson's patients, intestinal dysbiosis can occur years before clinical diagnosis, implicating the gut and its microbiota in the disease. Recent evidence suggests the gut microbiota may trigger body-first Parkinson Disease (PD), yet the underlying mechanisms remain unclear. This study aims to elucidate how a dysbiotic microbiome through intestinal immune alterations triggers PD-related neurodegeneration. Methods: To determine the impact of gut dysbiosis on the development and progression of PD pathology, wild-type male C57BL/6 mice were transplanted with fecal material from PD patients and age-matched healthy donors to challenge the gut-immune-brain axis. Results: This study demonstrates that patient-derived intestinal microbiota caused midbrain tyrosine hydroxylase positive (TH +) cell loss and motor dysfunction. Ileum-associated microbiota remodeling correlates with a decrease in Th17 homeostatic cells. This event led to an increase in gut inflammation and intestinal barrier disruption. In this regard, we found a decrease in CD4 + cells and an increase in pro-inflammatory cytokines in the blood of PD transplanted mice that could contribute to an increase in the permeabilization of the blood–brain-barrier, observed by an increase in mesencephalic Ig-G-positive microvascular leaks and by an increase of mesencephalic IL-17 levels, compatible with systemic inflammation. Furthermore, alpha-synuclein aggregates can spread caudo-rostrally, causing fragmentation of neuronal mitochondria. This mitochondrial damage subsequently activates innate immune responses in neurons and triggers microglial activation. Conclusions: We propose that the dysbiotic gut microbiome (dysbiome) in PD can disrupt a healthy microbiome and Th17 homeostatic immunity in the ileum mucosa, leading to a cascade effect that propagates to the brain, ultimately contributing to PD pathophysiology. Our landmark study has successfully identified new peripheral biomarkers that could be used to develop highly effective strategies to prevent the progression of PD into the brain. [ABSTRACT FROM AUTHOR]