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BACKGROUND AND OBJECTIVE: Parkinson's disease (PD) is the one of the most common neurodegenerative diseases. Many investigators have confirmed the possibility of using circulating miRNAs to diagnose PD. However, the results were inconsistent. Therefore, the aim of this meta-analysis was to systematically evaluate the diagnostic accuracy of circulating miRNAs in the diagnosis of PD. METHODS: We carefully searched PubMed, Embase, Web of Science, Cochrane Library, Wanfang database and China National Knowledge Infrastructure for relevant studies (up to January 1, 2022) based on PRISMA statement. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), the diagnostic odds ratio (DOR), and area under the curve (AUC) were calculated to test the diagnostic accuracy. Furthermore, subgroup analyses were performed to identify the potential sources of heterogeneity, and the Deeks' funnel plot asymmetry test was used to evaluate the potential publication bias. RESULTS: Forty-four eligible studies from 16 articles (3298 PD patients and 2529 healthy controls) were included in the current meta-analysis. The pooled sensitivity was 0.79 (95% CI: 0.76-0.81), specificity was 0.82 (95% CI: 0.78-0.84), PLR was 4.3 (95% CI: 3.6-5.0), NLR was 0.26 (95% CI: 0.23-0.30), DOR was 16 (95% CI: 13-21), and AUC was 0.87 (95% CI: 0.84-0.90). Subgroup analysis suggested that miRNA cluster showed a better diagnostic accuracy than miRNA simple. Moreover, there was no significant publication bias. CONCLUSIONS: Circulating miRNAs have great potential as novel non-invasive biomarkers for PD diagnosis.
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Biomarcadores , MicroARN Circulante , Enfermedad de Parkinson , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/diagnóstico , Humanos , Biomarcadores/sangre , MicroARN Circulante/sangre , Sensibilidad y Especificidad , MicroARNs/sangreRESUMEN
INTRODUCTION: Parkinson's disease represents a burdensome condition with complex manifestations. A licensed, standardized paper-based questionnaire is completed by both patients and physicians to monitor the progression and state of the disease. However, integrating the obtained scores into digital systems still poses a challenge. METHODS: Paper-based handwriting is intuitive and an efficient mode of human-computer interaction. Accordingly, we transformed a consumer-grade tablet into a device where an exact digital copy of the disease-specific questionnaire can be filled with the supplied pen. Utilizing a small convolutional neural network directly on the device and trained on MNIST data, we translated the handwritten digits to appropriate LOINC codes and made them accessible through a FHIR-compatible HTTP interface. RESULTS: When evaluating the usability from a patient-centric point of view, the System Usability Score revealed an excellent rating (SUS = 83.01) from the participants. However, we identified some challenges associated with the magnetic pen and the flat design of the device. CONCLUSION: In setups where certified medical devices are not required, consumer hardware can be used to map handwritten digits of patients to appropriate medical standards without manual intervention through healthcare professionals.
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Escritura Manual , Enfermedad de Parkinson , Enfermedad de Parkinson/complicaciones , Humanos , Programas Informáticos , Interfaz Usuario-Computador , Encuestas y Cuestionarios , Computadoras de Mano , Redes Neurales de la ComputaciónRESUMEN
Rationale: Ferroptosis-driven loss of dopaminergic neurons plays a pivotal role in the pathogenesis of Parkinson's disease (PD). In PD patients, Hspb1 is commonly observed at abnormally high levels in the substantia nigra. The precise consequences of Hspb1 overexpression in PD, however, have yet to be fully elucidated. Methods: We used human iPSC-derived dopaminergic neurons and Coniferaldehyde (CFA)-an Nrf2 agonist known for its ability to cross the blood-brain barrier-to investigate the role of Hspb1 in PD. We examined the correlation between Hspb1 overexpression and Nrf2 activation and explored the transcriptional regulation of Hspb1 by Nrf2. Gene deletion techniques were employed to determine the necessity of Nrf2 and Hspb1 for CFA's neuroprotective effects. Results: Our research demonstrated that Nrf2 can upregulate the transcription of Hspb1 by directly binding to its promoter. Deletion of either Nrf2 or Hspb1 gene abolished the neuroprotective effects of CFA. The Nrf2-Hspb1 pathway, newly identified as a defense mechanism against ferroptosis, was shown to be essential for preventing neurodegeneration progression. Additionally, we discovered that prolonged overexpression of Hspb1 leads to neuronal death and that Hspb1 released from ruptured cells can trigger secondary cell death in neighboring cells, exacerbating neuroinflammatory responses. Conclusions: These findings highlight a biphasic role of Hspb1 in PD, where it initially provides neuroprotection through the Nrf2-Hspb1 pathway but ultimately contributes to neurodegeneration and inflammation when overexpressed. Understanding this dual role is crucial for developing therapeutic strategies targeting Hspb1 and Nrf2 in PD.
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Neuronas Dopaminérgicas , Ferroptosis , Chaperonas Moleculares , Factor 2 Relacionado con NF-E2 , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Chaperonas Moleculares/metabolismo , Chaperonas Moleculares/genética , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Ferroptosis/genética , Células Madre Pluripotentes Inducidas/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética , Animales , Ratones , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico HSP27/genética , Muerte CelularRESUMEN
Background: DATATOP was a study of early Parkinson's disease (PD) conducted in the 1980âs, before mandatory folic acid fortification in the United States. Our analysis of its baseline serum samples revealed a geometric mean vitamin B12 of 369âpg/mL and homocysteine (tHcy) of 9.5µmol/l. We also found that low B12 predicted greater worsening of ambulatory capacity (AC) and elevated tHcy (>15µmol/L) predicted greater declines in cognitive function. Objective: We sought to measure B12 and tHcy in contemporary trial participants with early PD who had not started dopaminergic treatment and to determine whether these analytes were associated with clinical progression. Methods: We measured B12 and tHcy from baseline and end-of-study blood samples from three recent clinical trials. Results: Baseline geometric mean B12 levels for these studies ranged from 484- 618âpg/ml and for tHcy ranged from 7.4- 10µmol/L. Use of B12-containing supplements ranged from 41- 61%, and those taking supplements had higher B12 and lower tHcy. Those who began levodopa, but were not taking B12-supplements, had greater end-of-study tHcy. There was no association of baseline tHcyâ>â15µmol/L with annualized change in Montreal Cognitive Assessment and no association of baseline B12 tertiles with change in AC. Conclusions: In these longitudinal trials, B12 levels were higher than for DATATOP, due in large part to increased B12-supplement intake, while tHcy levels were similar. Initiation of levodopa was associated with increases of tHcy in those not taking a B12-containing supplement. These smaller studies did not replicate prior findings of low B12 and elevated tHcy with features of progression, possibly due to higher baseline B12.
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Homocisteína , Enfermedad de Parkinson , Vitamina B 12 , Humanos , Vitamina B 12/sangre , Homocisteína/sangre , Masculino , Femenino , Anciano , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/tratamiento farmacológico , Persona de Mediana Edad , Progresión de la Enfermedad , Antiparkinsonianos/uso terapéutico , Levodopa/administración & dosificación , Levodopa/farmacología , Suplementos Dietéticos , Disfunción Cognitiva/sangre , Disfunción Cognitiva/etiología , Disfunción Cognitiva/tratamiento farmacológicoRESUMEN
BACKGROUND: Deprescribing of potentially inappropriate medications is recommended for older adults and may improve health outcomes and quality of life in persons living with Parkinson disease (PD). Patient attitudes, beliefs, and preferences play a crucial role in the success of deprescribing interventions. We aimed to examine the attitudes and beliefs about medication burden and deprescribing among persons living with PD. METHODS: We administered a survey to participants of Fox Insight, a prospective longitudinal study of persons living with PD. The survey included the revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire and additional questions about adverse drug effects. We used logistic regression models to explore potential predictors of treatment dissatisfaction and willingness to deprescribe. RESULTS: Of the 4945 rPATD respondents, 31.6% were dissatisfied with their current medications, and 87.1% would be willing to deprescribe medications. Male sex was associated with a greater willingness to deprescribe (adjusted odds ratio [aOR] 1.62, 95% confidence interval [CI] 1.37-1.93). A greater belief that the medication burden was high or that some medications were inappropriate was associated with treatment dissatisfaction (aORs 3.74, 95% CI 3.26-4.29 and 5.61, 95% CI 4.85-6.50), and more willingness to deprescribe (aORs 1.74, 95% CI 1.47-2.06 and 2.87, 95% CI 2.41-3.42). Cognitive impairment was the adverse drug effect participants were most concerned about when prescribed new medications to treat nonmotor symptoms. CONCLUSIONS: Persons with PD are often dissatisfied with their overall medication load and are open to deprescribing. Medications that are associated with cognitive impairment might be prioritized targets for deprescribing interventions in this population.
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Deprescripciones , Enfermedad de Parkinson , Humanos , Masculino , Femenino , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/psicología , Anciano , Persona de Mediana Edad , Estudios Longitudinales , Estudios Prospectivos , Antiparkinsonianos/uso terapéutico , Conocimientos, Actitudes y Práctica en Salud , Encuestas y Cuestionarios , Anciano de 80 o más AñosRESUMEN
Many neurodegenerative and psychiatric malignancies like Parkinson' disease (PD) originate from an imbalance of 17ß-Estradiol (E2) in the human brain. However, the peripheral side effects of the usage of E2 for PD therapy and less understanding of the molecular mechanism hinder establishing its neurotherapeutic potential. In the present work, systemic side effects were overcome by targeted delivery using Dopamine receptor D3 (DRD3) conjugated E2-loaded chitosan nanoparticles (Ab-ECSnps) that showed a promising delivery to the brain. E2 is a specific calpain inhibitor that fosters neurodegeneration by disrupting mitochondrial function, while B-cell-specific Moloney murine leukemia virus integration region 1 (BMI1), an epigenetic regulator, is crucial in preserving mitochondrial homeostasis. We showed the administration of Ab-ECSnps inhibits calpain's translocation into mitochondria while promoting the translocation of BMI1 to mitochondria, thereby conferring neurotherapeutic benefits by enhancing cell viability, increasing mitochondrial DNA copy number, and preserving mitochondrial membrane potential. Further, we showed a novel molecular mechanism of BMI1 regulation by calpain that might contribute to maintaining mitochondrial homeostasis for attenuating PD. Concomitantly, Ab-ECSnps showed neurotherapeutic potential in the in vivo PD model. We showed for the first time that our brain-specific targeted delivery might regulate calpain-mediated BMI1 expression, thereby preserving mitochondrial homeostasis to alleviate PD.
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Calpaína , Quitosano , Mitocondrias , Nanopartículas , Enfermedad de Parkinson , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Calpaína/metabolismo , Calpaína/genética , Animales , Enfermedad de Parkinson/tratamiento farmacológico , Nanopartículas/química , Quitosano/química , Humanos , Ratones , Epigénesis Genética/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Supervivencia Celular/efectos de los fármacos , Masculino , Ratones Endogámicos C57BLRESUMEN
Parkinson's disease (PD) is characterized by neuroinflammation, progressive loss of dopaminergic neurons, and accumulation of α-synuclein (α-Syn) into insoluble aggregates called Lewy pathology. The Line 61 α-Syn mouse is an established preclinical model of PD; Thy-1 is used to promote human α-Syn expression, and features of sporadic PD develop at 9-18 months of age. To accelerate the PD phenotypes, we injected sonicated human α-Syn preformed fibrils (PFFs) into the striatum, which produced phospho-Syn (p-α-Syn) inclusions in the substantia nigra pars compacta and significantly increased MHC Class II-positive immune cells. Additionally, there was enhanced infiltration and activation of innate and adaptive immune cells in the midbrain. We then used this new model, Line 61-PFF, to investigate the effect of inhibiting the JAK/STAT signaling pathway, which is critical for regulation of innate and adaptive immune responses. After administration of the JAK1/2 inhibitor AZD1480, immunofluorescence staining showed a significant decrease in p-α-Syn inclusions and MHC Class II expression. Flow cytometry showed reduced infiltration of CD4+ T-cells, CD8+ T-cells, CD19+ B-cells, dendritic cells, macrophages, and endogenous microglia into the midbrain. Importantly, single-cell RNA-Sequencing analysis of CD45+ cells from the midbrain identified 9 microglia clusters, 5 monocyte/macrophage (MM) clusters, and 5 T-cell (T) clusters, in which potentially pathogenic MM4 and T3 clusters were associated with neuroinflammatory responses in Line 61-PFF mice. AZD1480 treatment reduced cell numbers and cluster-specific expression of the antigen-presentation genes H2-Eb1, H2-Aa, H2-Ab1, and Cd74 in the MM4 cluster and proinflammatory genes such as Tnf, Il1b, C1qa, and C1qc in the T3 cluster. Together, these results indicate that inhibiting the JAK/STAT pathway suppresses the activation and infiltration of innate and adaptive cells, reducing neuroinflammation in the Line 61-PFF mouse model.
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Modelos Animales de Enfermedad , Enfermedades Neuroinflamatorias , Enfermedad de Parkinson , Factores de Transcripción STAT , Transducción de Señal , alfa-Sinucleína , Animales , Ratones , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/inmunología , Humanos , Ratones Transgénicos , Ratones Endogámicos C57BL , Quinasas Janus/metabolismo , Quinasas Janus/antagonistas & inhibidores , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/inmunología , Pirimidinas/farmacologíaRESUMEN
Importance: The gut-first hypothesis of Parkinson disease (PD) has gained traction, yet potential inciting events triggering Parkinson pathology from gut-related factors remain unclear. While Helicobacter pylori infection is linked to mucosal damage (MD) and PD, it is unknown how upper gastrointestinal MD from any source increases PD risk. Objective: To evaluate any association between upper endoscopy findings of MD and subsequent clinical PD diagnosis. Design, Setting, and Participants: This was a retrospective cohort study of patients with no PD history undergoing upper endoscopy with biopsy between January 2000 and December 2005, with final follow-up assessments completed July 31, 2023. The study was conducted within the Mass General Brigham system, a multicenter network in the greater Boston, Massachusetts, area. Patients with MD were matched 1:3 to patients without MD based on age, sex, and date of initial endoscopy. Exposure: MD, defined as erosions, esophagitis, ulcers, or peptic injury, observed on upper endoscopy or pathology reports. Main Outcomes and Measures: The relative risk of PD given a history of MD, estimated using incident rate ratio (IRR) and multivariate Cox proportional hazard ratios (HRs). Results: Of 9350 patients, participants had a mean (SD) age of 52.3 (20.3) years; 5177 (55.4%) were male; and 269 (2.9%) were Asian, 737 (7.9%) Black, and 6888 (73.7%) White. Most participants underwent endoscopy between the ages of 50 and 64 years (2842 [30.4%]). At baseline, patients with MD were more likely to have a history of H pylori infection, proton-pump inhibitor use, chronic nonsteroidal anti-inflammatory drug use, gastroesophageal reflux disease, smoking, constipation, and dysphagia. The mean (SD) follow-up time was 14.9 (6.9) years for the whole cohort, during which patients with MD were more likely to develop PD (IRR, 4.15; 95% CI, 2.89-5.97; P < .001) than those without MD, even after covariate adjustment (HR, 1.76; 95% CI 1.11-2.51; P = .01). Constipation, dysphagia, older age, and higher Charlson-Deyo Comorbidity Index were also associated with higher PD risk. Conclusions and Relevance: In this cohort study, a history of upper gastrointestinal MD was associated with elevated risk of developing a clinical PD diagnosis. Increased vigilance among patients with MD for future PD risk may be warranted.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Adulto , Factores de Riesgo , Endoscopía Gastrointestinal , Boston/epidemiologíaRESUMEN
This study aimed to develop and validate a multi-modality radiomics approach using T1-weighted and diffusion tensor imaging (DTI) to differentiate Parkinson's disease (PD) motor subtypes, specifically tremor-dominant (TD) and postural instability gait difficulty (PIGD), in early disease stages. We analyzed T1-weighted and DTI scans from 140 early-stage PD patients (70 TD, 70 PIGD) and 70 healthy controls from the Parkinson's Progression Markers Initiative database. Radiomics features were extracted from 16 brain regions of interest. After harmonization and feature selection, four machine learning classifiers were trained and evaluated for both three-class (HC vs TD vs PIGD) and binary (TD vs PIGD) classification tasks. The light gradient boosting machine (LGBM) classifier demonstrated the best overall performance. For the three-class classification, LGBM achieved an accuracy of 85% and an area under the receiver operating characteristic curve (AUC) of 0.94 using combined T1 and DTI features. In the binary classification task, LGBM reached an accuracy of 95% and AUC of 0.95. Key discriminative features were identified in the Thalamus, Amygdala, Hippocampus, and Substantia Nigra for the three-group classification, and in the Pallidum, Amygdala, Hippocampus, and Accumbens for binary classification. The combined T1 + DTI approach consistently outperformed single-modality classifications, with DTI alone showing particularly low performance (AUC 0.55-0.62) in binary classification. The high accuracy and AUC values suggest that this approach could significantly improve early diagnosis and subtyping of PD. These findings have important implications for clinical management, potentially enabling more personalized treatment strategies based on early, accurate subtype identification.
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Imagen de Difusión Tensora , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/diagnóstico por imagen , Imagen de Difusión Tensora/métodos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Aprendizaje Automático , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Curva ROC , Temblor/diagnóstico por imagen , RadiómicaRESUMEN
BACKGROUND: Depression is widely recognized as a common non-motor symptom of Parkinson's disease (PD). Across different studies, the reported prevalence of depression in PD varies widely, ranging from 2.7% to 90%, but it is unclear whether this association is due to genetic or acquired factors. Whether there is a causal relationship remains unknown. The aim of this study was to use a two-sample Mendelian randomization (MR) approach to investigate the causal effect of PD on depression. METHODS: Analyses were conducted separately for individuals of European and East Asian ancestry using publicly available summary data from genome-wide association studies. Depression was divided into two categories: ever depressed for a whole week and major depressive disorder (MDD). PD data were used as the exposure and were obtained from the International Parkinson's Disease Genomics Consortium and the BioBank Japan PheWeb, while depression data were used as the outcome and were obtained from the ntegrative Epidemiology Unit (IEU) Open GWAS Project(A public GWAS databaseï¼ and the Psychiatric Genomics Consortium. The influence of PD on depression was assessed using inverse variance weighted (IVW), weighted median, MR-Egger, and weighted mode methods. Heterogeneity and pleiotropy were tested, and the results were validated using FinnGen GWAS data from version R9. RESULTS: In individuals of European ancestry, there was a causal relationship between PD and ever depressed for a whole week (IVW method, odds ratio [OR] = 0.990; 95% CI, 0.984-0.996; p = .002), but no causal relationship was observed between PD and MDD (IVW method, OR = 0.974; 95% CI, 0.942-1.009; p = .141). In individuals of East Asian ancestry, no causal relationship was observed between PD and ever depressed for a whole week (IVW method, OR = 1.001; 95% CI, 0.829-1.209; p = .990) and between PD and MDD (IVW method, OR = 1.017; 95% CI, 0.982-1.052; p = .342). The results of the three additional analysis methods were similar to those of the IVW method, and there was no heterogeneity according to Cochran's Q-test. There was no evidence of pleiotropy based on MR-Egger intercept test and MR-PRESSO. The FinnGen validation dataset supported these findings. The results are stable and reliable. CONCLUSION: The observed increase in depression among PD patients could potentially be attributed to modifiable acquired factors. Consequently, there is an urgent need to strengthen the management of PD patients in order to prevent the development of depression in the future.
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Pueblo Asiatico , Trastorno Depresivo Mayor , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/epidemiología , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/epidemiología , Pueblo Asiatico/genética , Población Blanca/genética , Depresión/genética , Depresión/epidemiología , Predisposición Genética a la EnfermedadRESUMEN
Introduction: Despite the effectiveness of exercise-based interventions on symptom management and disease progression, many people with Parkinson's Disease (PwPD) do not exercise regularly. In line with the ubiquitous use of digital health technology, the MoveONParkinson digital solution was developed, comprising a Web Platform and a Mobile App with a Conversational Agent (CA). The interface features were designed based on the principles of Social Cognitive Theory with the goal of fostering behavior change in PwPD for sustained exercise participation and improved disease management. Methods: Using a mixed methods approach, this study aimed to collect feedback, assess the acceptability of the Mobile App and the Web Platform, and evaluate the usability of the latter. Quantitative data, which included questionnaire responses and the System Usability Scale (SUS) scores, were analyzed using descriptive statistics, heatmaps, and correlation matrices. Qualitative data, comprising semi-structured and thinking-aloud interview transcripts, were subjected to an inductive thematic analysis. A total of 28 participants were involved in the study, comprising 20 physiotherapists (average age: 34.50 ± 10.4), and eight PwPD (average age: 65.75 ± 8.63; mean Hoehn & Yahr: 2.0 (± 0.76)). Results: Three main themes emerged from the thematic analysis of the interviews, namely: Self-management (Theme 1), User Engagement (Theme 2), and Recommendations (Theme 3). The assessment of the Mobile App and the CA (mean score: 4.42/5.0 ± 0.79) suggests that PwPD were able to navigate this interface without notable difficulties. The mean SUS score of 79.50 (± 12.40%) with a 95% confidence interval ranging from 73.70 to 85.30, reveal good usability. Discussion: These findings indicate a high level of acceptability of the MoveONParkinson digital solution, serving as a foundation for assessing its impact on exercise engagement and, subsequently, its influence on symptom management and quality of life of PwPD.
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Aplicaciones Móviles , Motivación , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/terapia , Masculino , Femenino , Anciano , Persona de Mediana Edad , Adulto , Encuestas y Cuestionarios , Terapia por Ejercicio/métodos , Investigación Cualitativa , Manejo de la Enfermedad , InternetAsunto(s)
Enfermedad de Parkinson , Escalas de Valoración Psiquiátrica , Humanos , Enfermedad de Parkinson/psicología , Anciano , Masculino , Femenino , Escalas de Valoración Psiquiátrica/normas , Trastornos de Ansiedad/diagnóstico , Persona de Mediana Edad , Ansiedad/psicología , Ansiedad/diagnóstico , Anciano de 80 o más AñosRESUMEN
Patients with advanced Parkinson's disease often suffer from severe gait and balance problems, impacting quality of live and persisting despite optimization of standard therapies. The aim of this review was to systematically review the efficacy of STN-DBS programming techniques in alleviating gait disturbances in patients with advanced PD. Searches were conducted in PubMed, Embase, and Lilacs databases, covering studies published until May 2024. The review identified 36 articles that explored five distinct STN-DBS techniques aimed at addressing gait and postural instability in Parkinson's patients: low-frequency stimulation, ventral STN stimulation for simultaneous substantia nigra activation, interleaving, asymmetric stimulation and a short pulse width study. Among these, 21 articles were included in the meta-analysis, which revealed significant heterogeneity among studies. Notably, low-frequency STN-DBS demonstrated positive outcomes in total UPDRS-III score and FOG-Q, especially when combined with dopaminergic therapy. The most favorable results were found for low-frequency STN stimulation. The descriptive analysis suggests that unconventional stimulation approaches may be viable for gait problems in patients who do not respond to standard therapies.
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Estimulación Encefálica Profunda , Trastornos Neurológicos de la Marcha , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Estimulación Encefálica Profunda/métodos , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/complicaciones , Trastornos Neurológicos de la Marcha/terapia , Trastornos Neurológicos de la Marcha/etiología , Resultado del TratamientoRESUMEN
Using delay differential equations to study mathematical models of Parkinson's disease and Huntington's disease is important to show how important it is for synchronization between basal ganglia loops to work together. We used the delay circuit RLC (resistor, inductor, capacitor) model to show how the direct pathway and the indirect pathway in the basal ganglia excite and inhibit the motor cortex, respectively. A term has been added to the mathematical model without time delay in the case of the hyperdirect pathway. It is proposed to add a non-linear term to adjust the synchronization. We studied Hopf bifurcation conditions for the proposed models. The desynchronization of response times between the direct pathway and the indirect pathway leads to different symptoms of Parkinson's disease. Tremor appears when the response time in the indirect pathway increases at rest. The simulation confirmed that tremor occurs and the motor cortex is in an inhibited state. The direct pathway can increase the time delay in the dopaminergic pathway, which significantly increases the activity of the motor cortex. The hyperdirect pathway regulates the activity of the motor cortex. The simulation showed bradykinesia occurs when we switch from one movement to another that is less exciting for the motor cortex. A decrease of GABA in the striatum or delayed excitation of the substantia nigra from the subthalamus may be a major cause of Parkinson's disease. An increase in the response time delay in one of the pathways results in the chaotic movement characteristic of Huntington's disease.
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Enfermedad de Huntington , Corteza Motora , Enfermedad de Parkinson , Enfermedad de Huntington/fisiopatología , Enfermedad de Huntington/metabolismo , Humanos , Enfermedad de Parkinson/fisiopatología , Corteza Motora/fisiopatología , Dinámicas no Lineales , Ganglios Basales/fisiopatología , Modelos Neurológicos , Modelos Teóricos , Simulación por Computador , Temblor/fisiopatologíaRESUMEN
Parkinson's disease (PD) stands as the second most common neurological disorder after Alzheimer's disease, primarily affecting the elderly population and significantly compromising their quality of life. The precise etiology of PD remains elusive, but recent research has shed light on potential factors, including the formation of α-synuclein aggregates, oxidative stress, neurotransmitter imbalances, and dopaminergic neurodegeneration in the substantia nigra pars compacta (SNpc) region of the brain, culminating in motor symptoms such as bradykinesia, akinesia, tremors, and rigidity. Monoamine oxidase (MAO) is an essential enzyme, comprising two isoforms, MAO-A and MAO-B, responsible for the oxidation of monoamines such as dopamine. Increased MAO-B activity is responsible for decreased dopamine levels in the SNpc region of mid brain which is remarkably associated with the pathogenesis of PD-like manifestations. Inhibitors of MAO-B enhance striatal neuronal responses to dopamine, making them valuable in treating PD, which involves dopamine deficiency. Clinically approved MAO-B inhibitors such as selegiline, L-deprenyl, pargyline, and rasagiline are employed in the management of neurodegenerative conditions associated with PD. Current therapeutic interventions including MAO-B inhibitors for PD predominantly aim to alleviate these motor symptoms but often come with a host of side effects that can be particularly challenging for the patients. While effective, they have limitations, prompting a search for alternative treatments, there is a growing interest in exploring natural products notably flavonoids as potential sources of novel MAO-B inhibitors. In line with that, the present review focuses on natural flavonoids of plant origin that hold promise as potential candidates for the development of novel MAO-B inhibitors. The discussion encompasses both in vitro and in vivo studies, shedding light on their potential therapeutic applications. Furthermore, this review underscores the significance of exploring natural products as valuable reservoirs of MAO-B inhibitors, offering new avenues for drug development and addressing the pressing need for improved treatments in PD-like pathological conditions. The authors of this review majorly explore the neuroprotective potential of natural flavonoids exhibiting notable MAO-B inhibitory activity and additionally multi-targeted approaches in the treatment of PD with clinical evidence and challenges faced in current therapeutic approaches.
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Flavonoides , Inhibidores de la Monoaminooxidasa , Monoaminooxidasa , Enfermedad de Parkinson , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Monoaminooxidasa/metabolismo , Humanos , Flavonoides/química , Flavonoides/farmacología , Flavonoides/uso terapéutico , Inhibidores de la Monoaminooxidasa/farmacología , Inhibidores de la Monoaminooxidasa/uso terapéutico , Inhibidores de la Monoaminooxidasa/química , Animales , Dopamina/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
Aging, a complex biological process, involves the progressive decline of physiological functions across various systems, leading to increased susceptibility to neurodegenerative diseases. In society, demographic aging imposes significant economic and social burdens due to these conditions. This review specifically examines the association of protein glycosylation with aging and neurodegenerative diseases. Glycosylation, a critical post-translational modification, influences numerous aspects of protein function that are pivotal in aging and the pathophysiology of diseases such as Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions. We highlight the alterations in glycosylation patterns observed during aging, their implications in the onset and progression of neurodegenerative diseases, and the potential of glycosylation profiles as biomarkers for early detection, prognosis, and monitoring of these age-associated conditions, and delve into the mechanisms of glycosylation. Furthermore, this review explores their role in regulating protein function and mediating critical biological interactions in these diseases. By examining the changes in glycosylation profiles associated with each part, this review underscores the potential of glycosylation research as a tool to enhance our understanding of aging and its related diseases.
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Envejecimiento , Enfermedades Neurodegenerativas , Procesamiento Proteico-Postraduccional , Humanos , Glicosilación , Envejecimiento/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Biomarcadores/metabolismo , Enfermedad de Parkinson/metabolismoRESUMEN
BACKGROUND: Deep Brain Stimulation (DBS) is FDA-approved for several movement disorders; such as Parkinson's disease, dystonia, and neuropsychiatric disorders. There are various reports of Body mass index (BMI) changes following different DBS targets in various disorders. AIM: A comprehensive systematic review and meta-analysis were conducted to investigate the impact of DBS on patients' Body Mass Index (BMI) and provide an in-depth overview of its underlying mechanisms. MATERIALS AND METHODS: We conducted research according to PRISMA guidelines. Our study assessed comprehensively electronic databases, including Pubmed, Scopus, Embase, web of science, and the Cochrane Library, up to May 2024. The random-effect model analysis was performed by the Comprehensive Meta-analysis software (CMA) version 3.0. As well, Cochran's Q test was used to determine the statistical heterogeneity of included studies. RESULT: This systematic review ultimately included 49 studies, 46 of which entered the meta-analysis. The total number of patients was 1478, consisting of Parkinson's disease (PD), dystonia, and the obsessive compulsive disorder (OCD) patients. The most common DBS target was subthalamic nucleus, followed by globus pallidus internus (GPi). Our meta-analysis depicted the BMI of participants significantly mount after DBS electrode implantation (SMD = -0.542, 95%CI: -0.678 to -0.406, and P-value < 0.001). However, moderate to high heterogeneity was detected among the studies (I2 = 67.566%). Additionally, the Daily energy intake (DEI) of patients significantly decreased after DBS (SMD: 0.457, 95%CI; 0.205 to 0.709, and P-value < 0.001). CONCLUSION: STN and GPi DBS can lead to weight gain through distinct central pathways in various movement and neuropsychiatric disorders, posing a potential risk for obesity, insulin resistance, and metabolic syndrome.
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Índice de Masa Corporal , Estimulación Encefálica Profunda , Enfermedad de Parkinson , Estimulación Encefálica Profunda/métodos , Humanos , Enfermedad de Parkinson/terapia , Globo Pálido , Núcleo Subtalámico/cirugía , Distonía/terapia , Trastorno Obsesivo Compulsivo/terapiaRESUMEN
Coronavirus disease 2019 (COVID-19) has been associated with a variety of neurological manifestations (i.e., anosmia, ageusia, myalgia, headache) and neurological syndromes (i.e., encephalopathy, ischemic and hemorrhagic stroke, myelitis, encephalitis) underlying different pathogenetic mechanisms. COVID-19 has also been associated with various movement disorders including acute or subacute parkinsonism. However, to date, only few cases of parkinsonism linked to COVID-19 have been reported, nevertheless raising the possibility of a post-viral parkinsonian syndrome. Furthermore, various studies in vitro and in animal models have highlighted a close relationship between SARS-CoV-2 virus and α-synuclein, leading to the hypothesis that COVID-19 could represent a factor favoring the long-term development of α-synucleopathies. In this chapter, we will discuss the pathophysiological mechanisms related to movement disorders' manifestations of COVID-19 focusing on the possible overlap between pathogenetic mechanisms of Parkinson's Disease and COVID-19.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/complicaciones , COVID-19/fisiopatología , COVID-19/virología , SARS-CoV-2/patogenicidad , alfa-Sinucleína/metabolismo , Enfermedades de los Ganglios Basales/fisiopatología , Enfermedades de los Ganglios Basales/etiología , Enfermedades de los Ganglios Basales/virología , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/complicaciones , AnimalesRESUMEN
BACKGROUND: Speech changes significantly impact the quality of life for Parkinson's disease (PD) patients. Deep Brain Stimulation (DBS) of the Subthalamic Nucleus (STN) is a standard treatment for advanced PD, but its effects on speech remain unclear. This study aimed to investigate the relationship between STN-DBS and speech changes in PD patients using comprehensive clinical assessments and tractography. METHODS: Forty-seven PD patients underwent STN-DBS, with preoperative and 3-month postoperative assessments. Speech analyses included acoustic measurements, auditory-perceptual evaluations, and fluency-intelligibility tests. On the other hand, structures within the volume tissue activated (VTA) were identified using MRI and DTI. The clinical and demographic data and structures associated with VTA (Corticospinal tract, Internal capsule, Dentato-rubro-thalamic tract, Medial forebrain bundle, Medial lemniscus, Substantia nigra, Red nucleus) were compared with speech analyses. RESULTS: The majority of patients (36.2-55.4% good, 29.7-53.1% same) exhibited either improved or unchanged speech quality following STN-DBS. Only a small percentage (8.5-14.9%) experienced deterioration. Older patients and those with worsened motor symptoms postoperatively were more likely to experience negative speech changes (p < 0.05). Interestingly, stimulation of the right Substantia Nigra correlated with improved speech quality (p < 0.05). No significant relationship was found between other structures affected by VTA and speech changes. CONCLUSIONS: This study suggests that STN-DBS does not predominantly negatively impact speech in PD patients, with potential benefits observed, especially in younger patients. These findings underscore the importance of individualized treatment approaches and highlight the need for further long-term studies to optimize therapeutic outcomes and better understand the effects of STN-DBS on speech.