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The Journal of Pharmacology and... Jun 2024Through its pathological and genetic association to Parkinson's Disease (PD), α-synuclein (α-syn) remains a favorable therapeutic target that is being investigated...
Through its pathological and genetic association to Parkinson's Disease (PD), α-synuclein (α-syn) remains a favorable therapeutic target that is being investigated using various modalities, including many passive immunotherapy approaches clinically targeting different forms of α-syn and epitopes. Whereas published studies from some immunotherapy trials have demonstrated engagement in plasma, none have shown direct drug-antigen interactions in the disease-relevant compartment, the central nervous system (CNS). Cinpanemab (BIIB054) selectively targets pathological aggregated α-syn with low affinity binding to monomeric forms. The avidity-driven binding, low drug concentration, and the very low α-syn levels plus its heterogeneous nature in cerebrospinal fluid (CSF) made it not possible to measure drug-target interactions by conventional assays. Here we overcame these challenges by using zero-length crosslinking to stabilize the BIIB054-α-syn complexes and then quantified the crosslinked complexes using a Meso Scale Discovery (MSD) electrochemiluminescence assay. CSF samples from healthy volunteers (HV, n=46) and individuals with PD (PD, n=18) from study 228HV101 (Phase I clinical trial of BIIB054), demonstrated dose- and time- dependent binding of cinpanemab to α-syn with measurable complexes detected at doses {greater than or equal to}15 mg/kg. Complex formation displayed a direct positive correlation to drug concentration (Spearman rank correlation = 0.8295 (HV), 0.8032 (PD) p < 0.0001 (HV, PD)). The observed binding of cinpanemab to α-syn in CSF is consistent with its low intrinsic affinity for α-syn monomer and provides evidence that the drug is behaving with expected binding dynamics in the central nervous system compartment. A zero-length cross-linking method with MSD detection was developed to enable quantification of cinpanemab-α-syn complexes in Phase 1 clinical CSF samples by preventing signal loss caused by their rapid dissociation. Observed dose- and time-dependent binding were consistent with cinpanemab's affinity for α-syn and provided confidence that the drug had engaged its target at the desired site of action. This is the first demonstration of α-syn binding by an antibody in clinical samples from the CNS.
PubMed: 38936981
DOI: 10.1124/jpet.124.002199 -
JMIR Bioinformatics and Biotechnology Aug 2023Genetic testing is essential to identify research participants for clinical trials enrolling people with Parkinson disease (PD) carrying a variant in the...
BACKGROUND
Genetic testing is essential to identify research participants for clinical trials enrolling people with Parkinson disease (PD) carrying a variant in the glucocerebrosidase (GBA) or leucine-rich repeat kinase 2 (LRRK2) genes. The limited availability of professionals trained in neurogenetics or genetic counseling is a major barrier to increased testing. Telehealth solutions to increase access to genetics education can help address issues around counselor availability and offer options to patients and family members.
OBJECTIVE
As an alternative to pretest genetic counseling, we developed a web-based genetics education tool focused on GBA and LRRK2 testing for PD called the Interactive Multimedia Approach to Genetic Counseling to Inform and Educate in Parkinson's Disease (IMAGINE-PD) and conducted user testing and usability testing. The objective was to conduct user and usability testing to obtain stakeholder feedback to improve IMAGINE-PD.
METHODS
Genetic counselors and PD and neurogenetics subject matter experts developed content for IMAGINE-PD specifically focused on GBA and LRRK2 genetic testing. Structured interviews were conducted with 11 movement disorder specialists and 13 patients with PD to evaluate the content of IMAGINE-PD in user testing and with 12 patients with PD to evaluate the usability of a high-fidelity prototype according to the US Department of Health and Human Services Research-Based Web Design & Usability Guidelines. Qualitative data analysis informed changes to create a final version of IMAGINE-PD.
RESULTS
Qualitative data were reviewed by 3 evaluators. Themes were identified from feedback data of movement disorder specialists and patients with PD in user testing in 3 areas: content such as the topics covered, function such as website navigation, and appearance such as pictures and colors. Similarly, qualitative analysis of usability testing feedback identified additional themes in these 3 areas. Key points of feedback were determined by consensus among reviewers considering the importance of the comment and the frequency of similar comments. Refinements were made to IMAGINE-PD based on consensus recommendations by evaluators within each theme at both user testing and usability testing phases to create a final version of IMAGINE-PD.
CONCLUSIONS
User testing for content review and usability testing have informed refinements to IMAGINE-PD to develop this focused, genetics education tool for GBA and LRRK2 testing. Comparison of this stakeholder-informed intervention to standard telegenetic counseling approaches is ongoing.
PubMed: 38935961
DOI: 10.2196/45370 -
JMIR Formative Research Jun 2024The management of neurodegenerative diseases (NDDs) in older populations is usually demanding and involves care provision by various health care services, resulting in a...
Improving the Acceptability and Implementation of Information and Communication Technology-Based Health Care Platforms for Older People With Dementia or Parkinson Disease: Qualitative Study Results of Key Stakeholders.
BACKGROUND
The management of neurodegenerative diseases (NDDs) in older populations is usually demanding and involves care provision by various health care services, resulting in a greater burden on health care systems in terms of costs and resources. The convergence of various health services within integrated health care models, which are enabled and adopted jointly with information and communication technologies (ICTs), has been identified as an effective alternative health care solution. However, its widespread implementation faces formidable challenges. Both the development and implementation of integrated ICTs are linked to the collaboration and acceptance of different groups of stakeholders beyond patients and health care professionals, with reported discrepancies in the needs and preferences among these groups.
OBJECTIVE
Complementing a previous publication, which reported on the needs and requirements of end users in the development of the European Union-funded project PROCare4Life (Personalized Integrated Care Promoting Quality of Life for Older People), this paper aimed to report on the opinions of other key stakeholders from various fields, including academia, media, market, and decision making, for improving the acceptability and implementation of an integrated ICT-based health care platform supporting the management of NDDs.
METHODS
The study included 30 individual semistructured interviews that took place between June and August 2020 in 5 European countries (Germany, Italy, Portugal, Romania, and Spain). Interviews were mostly conducted online, except in cases where participants requested to be interviewed in person. In these cases, COVID-19 PROCare4Life safety procedures were applied.
RESULTS
This study identified 2 themes and 5 subthemes. User engagement, providing training and education, and the role played by the media were identified as strategic measures to ensure the acceptability of ICT-based health care platforms. Sustainable funding and cooperation with authorities were foreseen as additional points to be considered in the implementation process.
CONCLUSIONS
The importance of the user-centered design approach in ensuring the involvement of users in the development of ICT-based platforms has been highlighted. The most common challenges that hinder the acceptability and implementation of ICT-based health care platforms can be addressed by creating synergies among the efforts of users, academic stakeholders, developers, policy makers, and decision makers. To support future projects in developing ICT-based health care platforms, this study outlined the following recommendations that can be integrated when conducting research on users' needs: (1) properly identify the particular challenges faced by future user groups without neglecting their social and clinical contexts; (2) iteratively assess the digital skills of future users and their acceptance of the proposed platform; (3) align the functionalities of the ICT platform with the real needs of future users; and (4) involve key stakeholders to guide the reflection on how to implement the platform in the future.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)
RR2-10.2196/22463.
PubMed: 38935424
DOI: 10.2196/58501 -
Neural Regeneration Research Jun 2024Studies have shown that chitosan protects against neurodegenerative diseases. However, the precise mechanism remains poorly understood. In this study, we administered...
Chitosan alleviates symptoms of Parkinson's disease by reducing acetate levels, which decreases inflammation and promotes repair of the intestinal barrier and blood-brain barrier.
Studies have shown that chitosan protects against neurodegenerative diseases. However, the precise mechanism remains poorly understood. In this study, we administered chitosan intragastrically to an MPTP-induced mouse model of Parkinson's disease and found that it effectively reduced dopamine neuron injury, neurotransmitter dopamine release, and motor symptoms. These neuroprotective effects of chitosan were related to bacterial metabolites, specifically short-chain fatty acids, and chitosan administration altered intestinal microbial diversity and decreased short-chain fatty acid production in the gut. Furthermore, chitosan effectively reduced damage to the intestinal barrier and the blood-brain barrier. Finally, we demonstrated that chitosan improved intestinal barrier function and alleviated inflammation in both the peripheral nervous system and the central nervous system by reducing acetate levels. Based on these findings, we suggest a molecular mechanism by which chitosan decreases inflammation through reducing acetate levels and repairing the intestinal and blood-brain barriers, thereby alleviating symptoms of Parkinson's disease.
PubMed: 38934394
DOI: 10.4103/NRR.NRR-D-23-01511 -
Frontiers in Neuroscience 2024Parkinson's disease (PD) is a common neurodegenerative disease with a rapid increase in incidence in recent years. Existing treatments cannot slow or stop the...
BACKGROUND
Parkinson's disease (PD) is a common neurodegenerative disease with a rapid increase in incidence in recent years. Existing treatments cannot slow or stop the progression of PD. It was proposed that neuroinflammation leads to neuronal death, making targeting neuroinflammation a promising therapeutic strategy. Our previous studies have demonstrated that rhein protects neurons by inhibiting neuroinflammation, and it has been found to exhibit neuroprotective effects in Alzheimer's disease and epilepsy, but its neuroprotective mechanisms and effects on PD are still unclear.
METHODS
PD animal model was induced by 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP). ELISA, RT-qPCR, western blot and Immunofluorescence were used to detect the levels of inflammatory cytokines and M1 polarization markers. The protein expression levels of signaling pathways were measured by western blot. Hematoxylin-eosin (HE) staining showed that rhein did not damage the liver and kidney. Two behavioral tests, pole test and rotarod test, were used to evaluate the improvement effect of rhein on movement disorders. The number of neurons in the substantia nigra was evaluated by Nissl staining. Immunohistochemistry and western blot were used to detect tyrosine hydroxylase (TH) and α-synuclein.
RESULTS
Rhein inhibited the activation of MAPK/IκB signaling pathway and reduced the levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and M1 polarization markers of microglia . In a mouse model of PD, rhein ameliorated movement disorders, reduced dopaminergic neuron damage and α-synuclein deposition.
CONCLUSION
Rhein inhibits neuroinflammation through MAPK/IκB signaling pathway, thereby reducing neurodegeneration, α-synuclein deposition, and improving movement disorders in Parkinson's disease.
PubMed: 38933815
DOI: 10.3389/fnins.2024.1396345 -
Frontiers in Pharmacology 2024Recent studies have demonstrated dysregulation of the autophagy pathway in patients with Parkinson's disease (PD) and in animal models of PD, highlighting its emerging... (Review)
Review
Recent studies have demonstrated dysregulation of the autophagy pathway in patients with Parkinson's disease (PD) and in animal models of PD, highlighting its emerging role in disease. In particular, several studies indicate that autophagy, which is an essential degradative process for the damaged protein homeostasis and the management of cell balance, can manifest significant variations according to gender. While some evidence suggests increased autophagic activation in men with PD, women may have distinct regulatory patterns. In this review, we examined the existing literature on gender differences in PD-associated autophagic processes, focusing on the autophagy related proteins (ATGs) and leucine rich repeat kinase 2 (LRRK2) genes. Also, this review would suggest that an in-depth understanding of these gender differences in autophagic processes could open new perspectives for personalized therapeutic strategies, promoting more effective and targeted management of PD.
PubMed: 38933683
DOI: 10.3389/fphar.2024.1408152 -
Frontiers in Computational Neuroscience 2024Parkinson's disease (PD) is a globally significant health challenge, necessitating accurate and timely diagnostic methods to facilitate effective treatment and...
Parkinson's disease (PD) is a globally significant health challenge, necessitating accurate and timely diagnostic methods to facilitate effective treatment and intervention. In recent years, self-supervised deep representation pattern learning (SS-DRPL) has emerged as a promising approach for extracting valuable representations from data, offering the potential to enhance the efficiency of voice-based PD detection. This research study focuses on investigating the utilization of SS-DRPL in conjunction with deep learning algorithms for voice-based PD classification. This study encompasses a comprehensive evaluation aimed at assessing the accuracy of various predictive models, particularly deep learning methods when combined with SS-DRPL. Two deep learning architectures, namely hybrid Long Short-Term Memory and Recurrent Neural Networks (LSTM-RNN) and Deep Neural Networks (DNN), are employed and compared in terms of their ability to detect voice-based PD cases accurately. Additionally, several traditional machine learning models are also included to establish a baseline for comparison. The findings of the study reveal that the incorporation of SS-DRPL leads to improved model performance across all experimental setups. Notably, the LSTM-RNN architecture augmented with SS-DRPL achieves the highest F1-score of 0.94, indicating its superior ability to detect PD cases using voice-based data effectively. This outcome underscores the efficacy of SS-DRPL in enabling deep learning models to learn intricate patterns and correlations within the data, thereby facilitating more accurate PD classification.
PubMed: 38933392
DOI: 10.3389/fncom.2024.1414462 -
Journal of Movement Disorders Jun 2024
PubMed: 38932634
DOI: 10.14802/jmd.23243 -
Neuroprotective Activity of a Non-Covalent Imatinib+TP10 Conjugate in HT-22 Neuronal Cells In Vitro.Pharmaceutics Jun 2024This study evaluated the probable relevance of a non-covalent conjugate of imatinib with TP10 in the context of a neuroprotective effect in Parkinson's disease. Through...
This study evaluated the probable relevance of a non-covalent conjugate of imatinib with TP10 in the context of a neuroprotective effect in Parkinson's disease. Through the inhibition of c-Abl, which is a non-receptor tyrosine kinase and an indicator of oxidative stress, imatinib has shown promise in preclinical animal models of this disease. The poor distribution of imatinib within the brain tissue triggered experiments in which a conjugate was obtained by mixing the drug with TP10, which is known for exhibiting high translocation activity across the cell membrane. The conjugate was tested on the HT-22 cell line with respect to its impact on MPP-induced oxidative stress, apoptosis, necrosis, cytotoxicity, and mortality. Additionally, it was checked whether the conjugate activated the ABCB1 protein. The experiments indicated that imatinib+PEG+TP10 reduced the post-MPP oxidative stress, apoptosis, and mortality, and these effects were more prominent than those obtained after the exposition of the HT-22 cells to imatinib alone. Its cytotoxicity was similar to that of imatinib itself. In contrast to imatinib, the conjugate did not activate the ABCB1 protein. These favorable qualities of imatinib+PEG+TP10 make it a potential candidate for further in vivo research, which would confirm its neuroprotective action in PD-affected brains.
PubMed: 38931899
DOI: 10.3390/pharmaceutics16060778 -
Pharmaceutics May 2024This review discusses the current progress in the clinical use of magnetic resonance-guided focused ultrasound (MRgFUS) and other ultrasound platforms to transiently... (Review)
Review
This review discusses the current progress in the clinical use of magnetic resonance-guided focused ultrasound (MRgFUS) and other ultrasound platforms to transiently permeabilize the blood-brain barrier (BBB) for drug delivery in neurological disorders and neuro-oncology. Safety trials in humans have followed on from extensive pre-clinical studies, demonstrating a reassuring safety profile and paving the way for numerous translational clinical trials in Alzheimer's disease, Parkinson's disease, and primary and metastatic brain tumors. Future directions include improving ultrasound delivery devices, exploring alternative delivery approaches such as nanodroplets, and expanding the application to other neurological conditions.
PubMed: 38931843
DOI: 10.3390/pharmaceutics16060719