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Free Radical Biology & Medicine Jun 2024Disturbance in iron homeostasis has been described in Parkinson's disease (PD), in which iron regulatory protein 2 (IRP2) plays a crucial role. IRP2 deletion resulted in...
Disturbance in iron homeostasis has been described in Parkinson's disease (PD), in which iron regulatory protein 2 (IRP2) plays a crucial role. IRP2 deletion resulted in the misregulation of iron metabolism and subsequent neurodegeneration. However, growing evidence showed that the levels of IRP2 were increased in the substantial nigra (SN) in MPTP-induced PD mice. To further clarify the role of increased IRP2 in PD, we developed IRP2-overexpressed mice by microinjecting AAV-Ireb2 in the SN. These mice showed decreased motor ability, abnormal gait and anxiety. Iron deposits induced by increased TFR1 and dopaminergic neuronal loss were observed in the SN. When these mice were treated with MPTP, exacerbated dyskinesia and dopaminergic neuronal loss were observed. In addition, TP53 was post-transcriptionally upregulated by IRP2 binding to the iron regulated element (IRE) in its 3' untranslated region. This resulted in increased lipid peroxidation levels and induced ferroptosis through the SLC7A11-ALOX12 pathway, which was independent of GPX4. This study revealed that IRP2 homeostasis in the SN was critical for PD progression and clarified the molecular mechanism of ferroptosis caused by IRP2.
PubMed: 38936518
DOI: 10.1016/j.freeradbiomed.2024.06.020 -
Neuroscience Jun 2024The mammalian brain's complete dependence on oxygen for ATP production makes it highly susceptible to hypoxia, at high altitudes or in clinical scenarios including... (Review)
Review
The mammalian brain's complete dependence on oxygen for ATP production makes it highly susceptible to hypoxia, at high altitudes or in clinical scenarios including anemia or pulmonary disease. Hypoxia plays a crucial role in the development of various brain disorders, such as Alzheimer's, Parkinson's, and other age-related neurodegenerative diseases. On the other hand, a decrease in environmental oxygen levels, such as prolonged stays at high elevations, may have beneficial impacts on the process of ageing and the likelihood of death. Additionally, the utilization of controlled hypoxia exposure could potentially serve as a therapeutic approach for age-related brain diseases. Recent findings indicate that the involvement of HIF-1α and the NLRP3 inflammasome is of significant importance in the development of Alzheimer's disease. HIF-1α serves as a pivotal controller of various cellular reactions to oxygen deprivation, exerting influence on a multitude of physiological mechanisms such as energy metabolism and inflammatory responses. The NLRP3 plays a crucial role in the innate immune system by coordinating the initiation of inflammatory reactions through the assembly of the inflammasome complex. This review examines the information pertaining to the contrasting effects of hypoxia on the brain, highlighting both its positive and deleterious effects and molecular pathways that are involved in mediating these different effects. This study explores potential strategies for therapeutic intervention that focus on restoring cellular balance and reducing neuroinflammation, which are critical aspects in addressing this severe neurodegenerative condition and addresses crucial inquiries that warrant further future investigations.
PubMed: 38936458
DOI: 10.1016/j.neuroscience.2024.06.021 -
Ageing Research Reviews Jun 2024Parkinson's disease (PD) is estimated to impact up to 1% of the global population aged 60 years and older. Among the non-motor manifestations of idiopathic PD, radicular... (Review)
Review
Parkinson's disease (PD) is estimated to impact up to 1% of the global population aged 60 years and older. Among the non-motor manifestations of idiopathic PD, radicular neuropathic pain emerges as a noteworthy concern due to its potential for debility in affected individuals. In, this systematic review and meta-analysis we aimed to evaluate the prevalence of radicular neuropathic pain and thus provide evidence of how this painful symptom affects the lives of patients with idiopathic PD. We registered the research protocol for this study in PROSPERO (CRD42022327220). We searched the Embase, Scopus, and PubMed platforms for studies on PD and neuropathic pain until April 2023. The search yielded 36 articles considered to have a low risk of bias. The prevalence of radicular neuropathic pain in patients with PD was 12.7%, without a difference when we consider the duration of diagnosis (cut-off < 7 years) or levodopa dosage (cut-off <600mg/dL). Moreover, there was no variation in the prevalence of radicular neuropathic pain regarding a Hoehn and Yahr stage cut-off of <2.5 or >2.5. Of note, a limited number of patients received pain treatment (21.5%). We also found that the source of publication bias is the use of the Ford criteria (FC), suggesting that this type of diagnostic criteria may contribute to an underdiagnosis of radicular neuropathic pain in patients with PD. This study underlines the necessity for a more discerning and comprehensive approach to the diagnosis and management of radicular neuropathic pain in patients with idiopathic PD.
PubMed: 38936433
DOI: 10.1016/j.arr.2024.102374 -
Clinical Biomechanics (Bristol, Avon) Jun 2024Poor postural control has been reported in people with Parkinson's disease, which could be explained by the changes in muscular activation patterns related to...
BACKGROUND
Poor postural control has been reported in people with Parkinson's disease, which could be explained by the changes in muscular activation patterns related to antigravitational muscles. This study aims to measure the muscle activation of antigravitational muscles during balance tasks in individuals, with and without Parkinson's.
METHODS
Sixteen (16) participants (9 with Parkinson's), aged ≥65 yrs., performed 2 × 30-s trials of 4 balance tasks (bipodal and semi-tandem opened eyes and closed eyes) on a force platform (center of pressure measurement); while surface electromyography measurements were obtained bilaterally on the multifidus at L5, biceps femoris and medialis gastrocnemius. Electromyography amplitude analysis was processed by the Root Mean Square (250 ms window epochs) and normalized by the peak of activation during the balance task, to determine each muscle's activity level.
FINDINGS
The Parkinson's group reported lower muscle activation than control across tasks (in mean for multifidus = 8%, biceps femoris = 16%, gastrocnemius = 7%), although not statistically significant. Parkinson's reported significantly poorer postural control than control, mainly for the center of pressure sway ellipse area (p = 0.016) from challenge balance tasks such as semi-tandem.
INTERPRETATION
Poor postural control was confirmed in the Parkinson's group, but not significantly associated by the changes from muscle activation of trunk and lower limbs, during balance performance.
PubMed: 38936292
DOI: 10.1016/j.clinbiomech.2024.106298 -
Neuropeptides Jun 2024Central nervous system (CNS) disorders are one of the leading health problems today, accounting for a large proportion of global morbidity and mortality. Most these... (Review)
Review
Central nervous system (CNS) disorders are one of the leading health problems today, accounting for a large proportion of global morbidity and mortality. Most these disorders are characterized by high levels of oxidative stress and intense inflammatory responses in degenerated neuronal tissues. While extensive research has been conducted on CNS diseases, but few breakthroughs have been made in treatment methods. To date, there are no disease-modifying drugs available for CNS treatment, underscoring the urgent need for finding effective medications. Bee venom (BV), which is produced by honeybee workers' stingers, has been a subject of interest and study across various cultures. Over the past few decades, extensive research has focused on BV and its therapeutic potentials. BV consists a variety of substances, mainly proteins and peptides like melittin and phospholipase A2 (PLA2). Research has proven that BV is effective in various medical conditions, including pain, arthritis and inflammation and CNS disorders such as Multiple sclerosis, Alzheimer's disease and Parkinson's disease. This review provides a comprehensive overview of the existing knowledge concerning the therapeutic effects of BV and its primary compounds on various CNS diseases. Additionally, we aim to shed light on the potential cellular and molecular mechanisms underlying these effects.
PubMed: 38936137
DOI: 10.1016/j.npep.2024.102451 -
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 -
JAMA Network Open Jun 2024Varenicline is the most effective sole pharmacotherapy for smoking cessation. If used in combination with nicotine replacement therapy (NRT), cessation rates may be... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Varenicline is the most effective sole pharmacotherapy for smoking cessation. If used in combination with nicotine replacement therapy (NRT), cessation rates may be further improved, but the efficacy and safety of the combination need to be evaluated.
OBJECTIVE
To examine whether hospitalized smokers treated with varenicline and NRT lozenges achieve higher prolonged smoking abstinence rates compared with those treated with varenicline alone.
DESIGN, SETTING, AND PARTICIPANTS
A double-blind, placebo-controlled randomized clinical trial was conducted in adult medical or surgical inpatients of 5 Australian public hospitals with a history of smoking 10 cigarettes or more per day, interested in quitting, and available for 12-month follow-up between May 1, 2019, and May 1, 2021 (final 12-month data collection in May 2022). Data analysis was performed from June 1 to August 30, 2023.
INTERVENTIONS
A 12-week varenicline regimen was initiated during hospitalization at standard doses in all participants. Participants were randomized to additionally use NRT (2 mg) or placebo lozenges if there was an urge to smoke. Behavioral support (Quitline) was offered to all participants.
MAIN OUTCOMES AND MEASURES
The primary outcome was biochemically verified sustained abstinence at 6 months. Secondary outcomes included self-reported prolonged abstinence, 7-day point prevalence abstinence (3, 6, and 12 months), and medicine-related adverse events.
RESULTS
A total of 320 participants (mean [SD] age, 52.5 [12.1] years; 183 [57.2%] male) were randomized. The conduct of biochemical verification was affected by COVID-19 restrictions; consequently, the biochemically verified abstinence in the intervention vs control arms (18 [11.4%] vs 16 [10.1%]; odds ratio [OR], 1.14; 95% CI, 0.56-2.33) did not support the combination therapy. The secondary outcomes in the intervention vs control arms of 7-day point prevalence abstinence at 6 months (54 [34.2%] vs 37 [23.4%]; OR, 1.71; 95% CI, 1.04-2.80), prolonged abstinence at 12 months (47 [29.9%] vs 30 [19.1%]; OR, 1.77; 95% CI, 1.05-3.00), and 7-day point prevalence abstinence at 12-months (48 [30.6%] vs 31 [19.7%]; OR, 1.79; 95% CI, 1.07-2.99) significantly improved with the combination therapy. The self-reported 6-month prolonged abstinence (61 [38.6%] vs 47 [29.7%]; OR, 1.49; 95% CI, 0.93-2.39) favored the combination therapy but was not statistically significant. Medicine-related adverse events were similar in the 2 groups (102 [74.5%] in the intervention group vs 86 [68.3%] in the control group).
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial of the combination of varenicline and NRT lozenges in hospitalized adult daily smokers, the combination treatment improved self-reported abstinence compared with varenicline alone, without compromising safety, but it did not improve biochemically validated abstinence.
TRIAL REGISTRATION
anzctr.org.au Identifier: ACTRN12618001792213.
Topics: Humans; Varenicline; Male; Female; Smoking Cessation; Tobacco Use Cessation Devices; Middle Aged; Double-Blind Method; Adult; Smoking Cessation Agents; Australia; Hospitalization; Smokers; Aged; Treatment Outcome; Nicotine Replacement Therapy
PubMed: 38935378
DOI: 10.1001/jamanetworkopen.2024.18120 -
Neurotoxicity Research Jun 2024Endoplasmic reticulum (ER) stress and oxidative stress (OS) are often related states in pathological conditions including Parkinson's disease (PD). This study...
Endoplasmic reticulum (ER) stress and oxidative stress (OS) are often related states in pathological conditions including Parkinson's disease (PD). This study investigates the role of anti-oxidant protein paraoxonase 2 (PON2) in ER stress and OS in PD, along with its regulatory molecule. PD was induced in C57BL/6 mice using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treatment and in SH-SY5Y cells using 1-methyl-4-phenylpyridinium. PON2 was found to be poorly expressed in the substantia nigra pars compacta (SNc) of PD mice, and its overexpression improved motor coordination of mice. Through the evaluation of tyrosine hydroxylase, dopamine transporter, reactive oxygen species (ROS), and C/EBP homologous protein (CHOP) levels and neuronal loss in mice, as well as the examination of CHOP, glucose-regulated protein 94 (GRP94), GRP78, caspase-12, sarco/endoplasmic reticulum calcium ATPase 2, malondialdehyde, and superoxide dismutase levels in SH-SY5Y cells, we observed that PON2 overexpression mitigated ER stress, OS, and neuronal apoptosis both in vivo and in vitro. Forkhead box A1 (FOXA1) was identified as a transcription factor binding to the PON2 promoter to activate its transcription. Upregulation of FOXA1 similarly protected against neuronal loss by alleviating ER stress and OS, while the protective roles were abrogated by additional PON2 silencing. In conclusion, this study demonstrates that FOXA1-mediated transcription of PON2 alleviates ER stress and OS, ultimately reducing neuronal apoptosis in PD.
Topics: Animals; Endoplasmic Reticulum Stress; Oxidative Stress; Mice, Inbred C57BL; Endoplasmic Reticulum Chaperone BiP; Apoptosis; Aryldialkylphosphatase; Humans; Cell Line, Tumor; Male; Mice; Hepatocyte Nuclear Factor 3-alpha; Neurons
PubMed: 38935306
DOI: 10.1007/s12640-024-00709-z -
International Journal of Computer... Jun 2024Parkinson disease (PD) is a common progressive neurodegenerative disorder in our ageing society. Early-stage PD biomarkers are desired for timely clinical intervention...
PURPOSE
Parkinson disease (PD) is a common progressive neurodegenerative disorder in our ageing society. Early-stage PD biomarkers are desired for timely clinical intervention and understanding of pathophysiology. Since one of the characteristics of PD is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, we propose a feature extraction method for analysing the differences in the substantia nigra between PD and non-PD patients.
METHOD
We propose a feature-extraction method for volumetric images based on a rank-1 tensor decomposition. Furthermore, we apply a feature selection method that excludes common features between PD and non-PD. We collect neuromelanin images of 263 patients: 124 PD and 139 non-PD patients and divide them into training and testing datasets for experiments. We then experimentally evaluate the classification accuracy of the substantia nigra between PD and non-PD patients using the proposed feature extraction method and linear discriminant analysis.
RESULTS
The proposed method achieves a sensitivity of 0.72 and a specificity of 0.64 for our testing dataset of 66 non-PD and 42 PD patients. Furthermore, we visualise the important patterns in the substantia nigra by a linear combination of rank-1 tensors with selected features. The visualised patterns include the ventrolateral tier, where the severe loss of neurons can be observed in PD.
CONCLUSIONS
We develop a new feature-extraction method for the analysis of the substantia nigra towards PD diagnosis. In the experiments, even though the classification accuracy with the proposed feature extraction method and linear discriminant analysis is lower than that of expert physicians, the results suggest the potential of tensorial feature extraction.
PubMed: 38935246
DOI: 10.1007/s11548-024-03175-2