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1.
Med Sci (Paris) ; 40(6-7): 544-549, 2024.
Artigo em Francês | MEDLINE | ID: mdl-38986099

RESUMO

The enteric nervous system (ENS), often called the "second brain", plays a crucial role in regulating digestive functions. Dysfunctions of the ENS are associated with several diseases such as Parkinson's disease. Recent studies suggest that early digestive disorders, notably chronic constipation, may be early signs of this neurodegenerative disease. Three-dimensional imaging of the ENS offers new insights into early diagnosis, in particular through the analysis of intestinal biopsies. This new research axis raises questions about the intestinal cause of Parkinson's disease, and opens the door to a better understanding and earlier treatment of this disease.


Title: L'intestin, lanceur d'alerte, dans les prémices de la maladie de Parkinson. Abstract: Le système nerveux entérique (SNE), souvent qualifié de « deuxième cerveau ¼, joue un rôle crucial dans la régulation des fonctions digestives. Des dysfonctionnements du SNE sont associés à diverses maladies telles que la maladie de Parkinson. Des études récentes suggèrent que les troubles digestifs précoces, notamment la constipation chronique, pourraient être des signes avant-coureurs de cette maladie neurodégénérative. L'imagerie tridimensionnelle du SNE offre de nouvelles perspectives pour un diagnostic précoce via notamment l'analyse de biopsies intestinales. Ce nouvel axe de recherche soulève des questions sur l'origine intestinale de la maladie de Parkinson et ouvre la porte à une meilleure compréhension et une prise en charge anticipée de cette maladie.


Assuntos
Sistema Nervoso Entérico , Doença de Parkinson , Humanos , Doença de Parkinson/patologia , Doença de Parkinson/diagnóstico , Sistema Nervoso Entérico/patologia , Sistema Nervoso Entérico/fisiopatologia , Sistema Nervoso Entérico/fisiologia , Diagnóstico Precoce , Trato Gastrointestinal/patologia , Trato Gastrointestinal/fisiopatologia , Trato Gastrointestinal/fisiologia , Animais , Intestinos/patologia , Intestinos/fisiologia
3.
BMJ ; 386: e078341, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38986549

RESUMO

OBJECTIVES: To assess the clinical effectiveness of two speech and language therapy approaches versus no speech and language therapy for dysarthria in people with Parkinson's disease. DESIGN: Pragmatic, UK based, multicentre, three arm, parallel group, unblinded, randomised controlled trial. SETTING: The speech and language therapy interventions were delivered in outpatient or home settings between 26 September 2016 and 16 March 2020. PARTICIPANTS: 388 people with Parkinson's disease and dysarthria. INTERVENTIONS: Participants were randomly assigned to one of three groups (1:1:1): 130 to Lee Silverman voice treatment (LSVT LOUD), 129 to NHS speech and language therapy, and 129 to no speech and language therapy. LSVT LOUD consisted of four, face-to-face or remote, 50 min sessions each week delivered over four weeks. Home based practice activities were set for up to 5-10 mins daily on treatment days and 15 mins twice daily on non-treatment days. Dosage for the NHS speech and language therapy was determined by the local therapist in response to the participants' needs (estimated from prior research that NHS speech and language therapy participants would receive an average of one session per week over six to eight weeks). Local practices for NHS speech and language therapy were accepted, except for those within the LSVT LOUD protocol. Analyses were based on the intention to treat principle. MAIN OUTCOME MEASURES: The primary outcome was total score at three months of self-reported voice handicap index. RESULTS: People who received LSVT LOUD reported lower voice handicap index scores at three months after randomisation than those who did not receive speech and language therapy (-8.0 points (99% confidence interval -13.3 to -2.6); P<0.001). No evidence suggests a difference in voice handicap index scores between NHS speech and language therapy and no speech and language therapy (1.7 points (-3.8 to 7.1); P=0.43). Patients in the LSVT LOUD group also reported lower voice handicap index scores than did those randomised to NHS speech and language therapy (-9.6 points (-14.9 to -4.4); P<0.001). 93 adverse events (predominately vocal strain) were reported in the LSVT LOUD group, 46 in the NHS speech and language therapy group, and none in the no speech and language therapy group. No serious adverse events were recorded. CONCLUSIONS: LSVT LOUD was more effective at reducing the participant reported impact of voice problems than was no speech and language therapy and NHS speech and language therapy. NHS speech and language therapy showed no evidence of benefit compared with no speech and language therapy. TRIAL REGISTRATION: ISRCTN registry ISRCTN12421382.


Assuntos
Disartria , Terapia da Linguagem , Doença de Parkinson , Fonoterapia , Humanos , Doença de Parkinson/complicações , Disartria/etiologia , Disartria/terapia , Disartria/reabilitação , Masculino , Feminino , Fonoterapia/métodos , Idoso , Terapia da Linguagem/métodos , Reino Unido , Pessoa de Meia-Idade , Resultado do Tratamento , Treinamento da Voz , Medicina Estatal
4.
Chem Res Toxicol ; 37(7): 1071-1085, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38958636

RESUMO

Parkinson's disease (PD) affects more people worldwide than just aging alone can explain. This is likely due to environmental influences, genetic makeup, and changes in daily habits. The disease develops in a complex way, with movement problems caused by Lewy bodies and the loss of dopamine-producing neurons. Some research suggests Lewy bodies might start in the gut, hinting at a connection between these structures and gut health in PD patients. These patients often have different gut bacteria and metabolites. Pesticides are known to increase the risk of PD, with evidence showing they harm more than just dopamine neurons. Long-term exposure to pesticides in food might affect the gut barrier, gut bacteria, and the blood-brain barrier, but the exact link is still unknown. This review looks at how pesticides and gut bacteria separately influence PD development and progression, highlighting the harmful effects of pesticides and changes in gut bacteria. We have examined the interaction between pesticides and gut bacteria in PD patients, summarizing how pesticides cause imbalances in gut bacteria, the resulting changes, and their overall effects on the PD prognosis.


Assuntos
Microbioma Gastrointestinal , Doença de Parkinson , Praguicidas , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Praguicidas/metabolismo , Doença de Parkinson/microbiologia , Doença de Parkinson/metabolismo , Animais
5.
Int J Mol Sci ; 25(13)2024 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-38999992

RESUMO

Clinical differentiation of progressive supranuclear palsy (PSP) from Parkinson's disease (PD) is challenging due to overlapping phenotypes and the late onset of specific atypical signs. Therefore, easily assessable diagnostic biomarkers are highly needed. Since PD is a synucleopathy while PSP is a tauopathy, here, we investigated the clinical usefulness of serum oligomeric-α-synuclein (o-α-synuclein) and 181Thr-phosphorylated tau (p-tau181), which are considered as the most important pathological protein forms in distinguishing between these two parkinsonisms. We assessed serum o-α-synuclein and p-tau181 by ELISA and SIMOA, respectively, in 27 PSP patients, 43 PD patients, and 39 healthy controls (HC). Moreover, we evaluated the correlation between serum biomarkers and biological and clinical features of these subjects. We did not find any difference in serum concentrations of p-tau181 and o-α-synuclein nor in the o-α-synuclein/p-tau181 ratio between groups. However, we observed that serum p-tau181 positively correlated with age in HC and PD, while serum o-α-synuclein correlated positively with disease severity in PD and negatively with age in PSP. Finally, the o-α-synuclein/p-tau181 ratio showed a negative correlation with age in PD.


Assuntos
Biomarcadores , Doença de Parkinson , Paralisia Supranuclear Progressiva , alfa-Sinucleína , Proteínas tau , Humanos , Paralisia Supranuclear Progressiva/sangue , Paralisia Supranuclear Progressiva/diagnóstico , alfa-Sinucleína/sangue , Doença de Parkinson/sangue , Proteínas tau/sangue , Feminino , Masculino , Idoso , Biomarcadores/sangue , Pessoa de Meia-Idade , Fosforilação , Estudos de Casos e Controles , Diagnóstico Diferencial
6.
Int J Mol Sci ; 25(13)2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-39000225

RESUMO

GBA1-associated Parkinson's disease (GBA1-PD) is increasingly recognized as a distinct entity within the spectrum of parkinsonian disorders. This review explores the unique pathophysiological features, clinical progression, and genetic underpinnings that differentiate GBA1-PD from idiopathic Parkinson's disease (iPD). GBA1-PD typically presents with earlier onset and more rapid progression, with a poor response to standard PD medications. It is marked by pronounced cognitive impairment and a higher burden of non-motor symptoms compared to iPD. Additionally, patients with GBA1-PD often exhibit a broader distribution of Lewy bodies within the brain, accentuating neurodegenerative processes. The pathogenesis of GBA1-PD is closely associated with mutations in the GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase). In this review, we discuss two mechanisms by which GBA1 mutations contribute to disease development: 'haploinsufficiency,' where a single functional gene copy fails to produce a sufficient amount of GCase, and 'gain of function,' where the mutated GCase acquires harmful properties that directly impact cellular mechanisms for alpha-synuclein degradation, leading to alpha-synuclein aggregation and neuronal cell damage. Continued research is advancing our understanding of how these mechanisms contribute to the development and progression of GBA1-PD, with the 'gain of function' mechanism appearing to be the most plausible. This review also explores the implications of GBA1 mutations for therapeutic strategies, highlighting the need for early diagnosis and targeted interventions. Currently, small molecular chaperones have shown the most promising clinical results compared to other agents. This synthesis of clinical, pathological, and molecular aspects underscores the assertion that GBA1-PD is a distinct clinical and pathobiological PD phenotype, necessitating specific management and research approaches to better understand and treat this debilitating condition.


Assuntos
Glucosilceramidase , Mutação , Doença de Parkinson , Humanos , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética
7.
Int J Mol Sci ; 25(13)2024 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-39000288

RESUMO

Parkinson's disease (PD) is a gradually worsening neurodegenerative disorder affecting the nervous system, marked by a slow progression and varied symptoms. It is the second most common neurodegenerative disease, affecting over six million people in the world. Its multifactorial etiology includes environmental, genomic, and epigenetic factors. Clinical symptoms consist of non-motor and motor symptoms, with motor symptoms being the classic presentation. Therapeutic approaches encompass pharmacological, non-pharmacological, and surgical interventions. Traditional pharmacological treatment consists of administering drugs (MAOIs, DA, and levodopa), while emerging evidence explores the potential of antidiabetic agents for neuroprotection and gene therapy for attenuating parkinsonian symptoms. Non-pharmacological treatments, such as exercise, a calcium-rich diet, and adequate vitamin D supplementation, aim to slow disease progression and prevent complications. For those patients who have medically induced side effects and/or refractory symptoms, surgery is a therapeutic option. Deep brain stimulation is the primary surgical option, associated with motor symptom improvement. Levodopa/carbidopa intestinal gel infusion through percutaneous endoscopic gastrojejunostomy and a portable infusion pump succeeded in reducing "off" time, where non-motor and motor symptoms occur, and increasing "on" time. This article aims to address the general aspects of PD and to provide a comparative comprehensive review of the conventional and the latest therapeutic advancements and emerging treatments for PD. Nevertheless, further studies are required to optimize treatment and provide suitable alternatives.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/terapia , Levodopa/uso terapêutico , Estimulação Encefálica Profunda/métodos , Antiparkinsonianos/uso terapêutico , Terapia Genética/métodos , Animais
8.
Int J Mol Sci ; 25(13)2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-39000460

RESUMO

Aberrant aggregation of misfolded alpha-synuclein (α-syn), a major pathological hallmark of related neurodegenerative diseases such as Parkinson's disease (PD), can translocate between cells. Ubiquitin-like 3 (UBL3) is a membrane-anchored ubiquitin-fold protein and post-translational modifier. UBL3 promotes protein sorting into small extracellular vesicles (sEVs) and thereby mediates intercellular communication. Our recent studies have shown that α-syn interacts with UBL3 and that this interaction is downregulated after silencing microsomal glutathione S-transferase 3 (MGST3). However, how MGST3 regulates the interaction of α-syn and UBL3 remains unclear. In the present study, we further explored this by overexpressing MGST3. In the split Gaussia luciferase complementation assay, we found that the interaction between α-syn and UBL3 was upregulated by MGST3. While Western blot and RT-qPCR analyses showed that silencing or overexpression of MGST3 did not significantly alter the expression of α-syn and UBL3, the immunocytochemical staining analysis indicated that MGST3 increased the co-localization of α-syn and UBL3. We suggested roles for the anti-oxidative stress function of MGST3 and found that the effect of MGST3 overexpression on the interaction between α-syn with UBL3 was significantly rescued under excess oxidative stress and promoted intracellular α-syn to extracellular transport. In conclusion, our results demonstrate that MGST3 upregulates the interaction between α-syn with UBL3 and promotes the interaction to translocate intracellular α-syn to the extracellular. Overall, our findings provide new insights and ideas for promoting the modulation of UBL3 as a therapeutic agent for the treatment of synucleinopathy-associated neurodegenerative diseases.


Assuntos
Glutationa Transferase , Estresse Oxidativo , Ubiquitinas , alfa-Sinucleína , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Humanos , Glutationa Transferase/metabolismo , Glutationa Transferase/genética , Ubiquitinas/metabolismo , Ubiquitinas/genética , Regulação para Cima , Transporte Proteico , Doença de Parkinson/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/patologia , Ligação Proteica
9.
Rev Neurol ; 79(3): 71-76, 2024 Aug 01.
Artigo em Espanhol | MEDLINE | ID: mdl-39007858

RESUMO

INTRODUCTION: Parkinson's disease is characterised by the presence of motor symptoms including hypomimia, and by non-motor symptoms including alterations in facial recognition of basic emotions. Few studies have investigated this alteration and its relationship to the severity of hypomimia. OBJECTIVE: The objective is to study the relationship between hypomimia and the facial recognition of basic emotions in subjects with Parkinson's disease. SUBJECTS AND METHODS: Twenty-three patients and 29 controls were evaluated with the test battery for basic emotion facial recognition. The patients were divided into two subgroups according to the intensity of their hypomimia. RESULTS: The comparison in battery test performance between the minimal/mild hypomimia and moderate/severe hypomimia groups was statistically significant in favour of the former group. CONCLUSIONS: This finding shows a close relationship between expression and facial recognition of emotions, which could be explained through the mechanism of motor simulation.


TITLE: Relación entre la gravedad de la hipomimia y el reconocimiento de emociones básicas en la enfermedad de Parkinson.Introducción. La enfermedad de Parkinson se caracteriza por la presencia de síntomas motores, entre los que es significativa la presencia de hipomimia, y por síntomas no motores, en los que se destaca la alteración en el reconocimiento facial de emociones básicas. Son pocos los estudios que investiguen dicha alteración relacionada con la gravedad de la hipomimia. Objetivo. El objetivo es estudiar la relación entre la hipomimia y el reconocimiento facial de emociones básicas en sujetos con enfermedad de Parkinson. Sujetos y métodos. Se evaluó a 23 pacientes y 29 controles con la batería de reconocimiento facial de emociones básicas. El grupo de pacientes se dividió en dos subgrupos según la intensidad de la hipomimia. Resultados. La comparación en el rendimiento de las pruebas de la batería entre el grupo de hipomimia mínima/leve e hipomimia moderada/grave resultó estadísticamente significativa a favor del primer grupo. Conclusiones. Este hallazgo evidencia una estrecha relación entre la expresión y el reconocimiento facial de emociones, que podría explicarse a través del mecanismo de simulación motora.


Assuntos
Emoções , Reconhecimento Facial , Doença de Parkinson , Índice de Gravidade de Doença , Humanos , Doença de Parkinson/psicologia , Doença de Parkinson/complicações , Doença de Parkinson/fisiopatologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Reconhecimento Facial/fisiologia , Expressão Facial
10.
Sensors (Basel) ; 24(13)2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-39001075

RESUMO

INTRODUCTION: The current approach to assessing bradykinesia in Parkinson's Disease relies on the Unified Parkinson's Disease Rating Scale (UPDRS), which is a numeric scale. Inertial sensors offer the ability to probe subcomponents of bradykinesia: motor speed, amplitude, and rhythm. Thus, we sought to investigate the differential effects of high-frequency compared to low-frequency subthalamic nucleus (STN) deep brain stimulation (DBS) on these quantified facets of bradykinesia. METHODS: We recruited advanced Parkinson's Disease subjects with a chronic bilateral subthalamic nucleus (STN) DBS implantation to a single-blind stimulation trial where each combination of medication state (OFF/ON), electrode contacts, and stimulation frequency (60 Hz/180 Hz) was assessed. The Kinesia One sensor system was used to measure upper limb bradykinesia. For each stimulation trial, subjects performed extremity motor tasks. Sensor data were recorded continuously. We identified STN DBS parameters that were associated with improved upper extremity bradykinesia symptoms using a mixed linear regression model. RESULTS: We recruited 22 subjects (6 females) for this study. The 180 Hz STN DBS (compared to the 60 Hz STN DBS) and dopaminergic medications improved all subcomponents of upper extremity bradykinesia (motor speed, amplitude, and rhythm). For the motor rhythm subcomponent of bradykinesia, ventral contacts yielded improved symptom improvement compared to dorsal contacts. CONCLUSION: The differential impact of high- and low-frequency STN DBS on the symptoms of bradykinesia may advise programming for these patients but warrants further investigation. Wearable sensors represent a valuable addition to the armamentarium that furthers our ability to conduct objective, quantitative clinical assessments.


Assuntos
Estimulação Encefálica Profunda , Hipocinesia , Doença de Parkinson , Núcleo Subtalâmico , Humanos , Doença de Parkinson/terapia , Doença de Parkinson/fisiopatologia , Estimulação Encefálica Profunda/métodos , Estimulação Encefálica Profunda/instrumentação , Hipocinesia/terapia , Hipocinesia/fisiopatologia , Núcleo Subtalâmico/fisiopatologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso
11.
Exp Dermatol ; 33(7): e15125, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38946225

RESUMO

The 16th non-collagenous domain (NC16A) of BP180 is the main antigenic target of autoantibodies in bullous pemphigoid (BP) and mucous membrane pemphigoid (MMP). Commercially available assays detect serum autoantibodies against NC16A in the majority of BP (80%-90%) and in approximately 50% of MMP patients. However, a standardized test system for detecting antibodies against other regions of BP180 is still lacking. Moreover, anti-BP180 autoantibodies have been found in neurological conditions such as multiple sclerosis and Parkinson disease. This study aimed at identifying primary epitopes recognized by BP autoantibodies on the BP180 ectodomain. Serum samples of 51 BP and 30 MMP patients both without anti-NC16A reactivity were included along with 44 multiple sclerosis and 75 Parkinson disease sera. Four overlapping His-tagged proteins covering the entire BP180 ectodomain (BP180(ec)1-4) were cloned, expressed, purified and tested for reactivity by immunoblot. IgG antibodies to BP180(ec)3 were detected in 98% of BP, 77% of MMP and 2% of normal human sera. Only weak reactivity was detected for neurological diseases against BP180(ec)1, BP180(ec)2 and BP180(ec)4, in 3%, 11% and 7% of tested multiple sclerosis sera, respectively. 8% of Parkinson disease sera reacted with BP180(ec)2 and 9% with BP180(ec)4. In conclusion, this study successfully identified epitopes recognized by BP autoantibodies outside the NC16A domain in pemphigoid diseases. These findings contribute to a better understanding of the immune response in BP and MMP with potential implications for a future diagnostic assay for NC16A-negative pemphigoid patients.


Assuntos
Autoanticorpos , Autoantígenos , Colágeno Tipo XVII , Esclerose Múltipla , Colágenos não Fibrilares , Doença de Parkinson , Penfigoide Mucomembranoso Benigno , Penfigoide Bolhoso , Humanos , Doença de Parkinson/imunologia , Doença de Parkinson/sangue , Colágenos não Fibrilares/imunologia , Penfigoide Bolhoso/imunologia , Penfigoide Bolhoso/sangue , Autoantígenos/imunologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/sangue , Autoanticorpos/sangue , Autoanticorpos/imunologia , Penfigoide Mucomembranoso Benigno/imunologia , Penfigoide Mucomembranoso Benigno/sangue , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Epitopos/imunologia , Domínios Proteicos , Feminino , Masculino , Idoso
12.
Front Public Health ; 12: 1393535, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38947343

RESUMO

Background: There is a paucity of studies that compare older adults' attitudes toward Euthanasia in two different terminal illnesses. Moreover, these studies did not relate to potentially influencing psycho-social factors. The current study aimed to examine the impact of a diverse range of variables on attitudes among older adults toward Euthanasia in two medical conditions: cancer and Parkinson's disease. Methods: A total of 501 individuals aged 75 and above participated in the study. Attitudes toward Euthanasia were measured using vignettes which described two conditions: an 80-year-old man with metastatic cancer and another man in an advanced stage of Parkinson's disease. The questionnaire included measures of relevant experience (with a close family member or a friend dying from a terminal illness), self-efficacy, will to live, satisfaction with life, will to prolong life, fear of death and dying, social support, and psycho-social characteristics. The data were analyzed using hierarchical linear regression models. Results: A more positive attitude toward Euthanasia was found in the case of cancer compared to Parkinson's disease. Being a woman, having more years of education, lower level of religiosity, greater fear of death and dying and higher self-efficacy contributes to more favorable attitudes toward Euthanasia in both end-of life conditions. Conclusions: The finding that attitudes toward Euthanasia are statistically significantly more positive in the case of cancer compared to Parkinson's disease can be attributed to the greater prevalence of cancer in the population, and to the public's awareness of the suffering associated with each of these medical conditions. Beyond the important role of the socio-demographic characteristics of gender, education, and religiosity, it appears that fear of death and dying and self-efficacy are important psychological factors in explaining attitudes toward Euthanasia in both illnesses among older people. These findings shed light on older adults' attitudes toward Euthanasia in debilitating illnesses.


Assuntos
Atitude Frente a Morte , Eutanásia , Neoplasias , Doença de Parkinson , Humanos , Masculino , Feminino , Doença de Parkinson/psicologia , Idoso de 80 Anos ou mais , Idoso , Neoplasias/psicologia , Eutanásia/psicologia , Inquéritos e Questionários , Autoeficácia , Assistência Terminal/psicologia
13.
Neurology ; 103(3): e209620, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-38986057

RESUMO

BACKGROUND AND OBJECTIVES: The role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used 2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR. METHODS: We used summary statistics from a genome-wide association study (GWAS) to extract the association of 501 single-nucleotide polymorphisms (SNPs) with BMI and from the Courage-PD and international Parkinson Disease Genomics Consortium (iPDGC) to estimate their association with PD. Analyses are based on participants of European ancestry. We used the inverse-weighted method to compute odds ratios (ORIVW per 4.8 kg/m2 [95% CI]) of PD and additional pleiotropy robust methods. We performed analyses stratified by age, disease duration, and sex. For reverse MR, we used SNPs associated with PD from 2 iPDGC GWAS to assess the effect of genetic liability toward PD on BMI. RESULTS: Summary statistics for BMI are based on 806,834 participants (54% women). Summary statistics for PD are based on 8,919 (40% women) cases and 7,600 (55% women) controls from Courage-PD, and 19,438 (38% women) cases and 24,388 (51% women) controls from iPDGC. In Courage-PD, we found an inverse association between genetically predicted BMI and PD (ORIVW 0.82 [0.70-0.97], p = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (≤67 years, ORIVW 0.71 [0.55-0.92]) and cases with shorter disease duration (≤7 years, ORIVW 0.75 [0.62-0.91]). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (ORIVW 0.85 [0.74-0.99], p = 0.032) than men (ORIVW 0.92 [0.80-1.04], p = 0.18), but the interaction was not statistically significant (p-interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association. DISCUSSION: Using an independent data set (Courage-PD), we replicate an inverse association of genetically predicted BMI with PD, not explained by survival or incidence-prevalence biases. Moreover, reverse MR analyses support an inverse association between genetic liability toward PD and BMI, in favor of a bidirectional relation.


Assuntos
Índice de Massa Corporal , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Doença de Parkinson , Polimorfismo de Nucleotídeo Único , Humanos , Doença de Parkinson/genética , Doença de Parkinson/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Fatores de Risco
14.
Nat Commun ; 15(1): 5703, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38977662

RESUMO

Explaining predictions for drug repositioning with biological knowledge graphs is a challenging problem. Graph completion methods using symbolic reasoning predict drug treatments and associated rules to generate evidence representing the therapeutic basis of the drug. Yet the vast amounts of generated paths that are biologically irrelevant or not mechanistically meaningful within the context of disease biology can limit utility. We use a reinforcement learning based knowledge graph completion model combined with an automatic filtering approach that produces the most relevant rules and biological paths explaining the predicted drug's therapeutic connection to the disease. In this work we validate the approach against preclinical experimental data for Fragile X syndrome demonstrating strong correlation between automatically extracted paths and experimentally derived transcriptional changes of selected genes and pathways of drug predictions Sulindac and Ibudilast. Additionally, we show it reduces the number of generated paths in two case studies, 85% for Cystic fibrosis and 95% for Parkinson's disease.


Assuntos
Descoberta de Drogas , Reposicionamento de Medicamentos , Doença de Parkinson , Humanos , Descoberta de Drogas/métodos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Reposicionamento de Medicamentos/métodos , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Sulindaco/farmacologia , Sulindaco/uso terapêutico , Animais , Algoritmos
15.
BMC Neurosci ; 25(1): 33, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38977971

RESUMO

BACKGROUND: Parkinson's disease (PD), while often associated with its distinctive motor symptoms, can also exert a notable impact on the cardiovascular system due to the development of severe autonomic dysfunction. One of the initial indicators of PD is the appearance of cardiovascular dysautonomia. As such, it is vital to monitor and manage cardiovascular health of individuals with PD, as it may have clinical implications in the development of commonly recognized motor and non-motor aspects of the disease. To study the association of history of cardiovascular disease (CVD) with occurrence and severity of PD, here, we lend data on the association of CVD history with the frequency and the occurrence of idiopathic PD (iPD) using data from the Luxembourg Parkinson's study (iPD n = 676 patients and non-PD n = 874 controls). RESULTS: We report that patients with a history of CVD are at high risk of developing iPD (odds ratio; OR = 1.56, 95% confidence interval; CI 1.09-2.08). This risk is stronger in males and remains significant after adjustment with confounders (OR 1.55, 95% CI 1.05-2.30). This increased susceptibility to iPD is linked to the severity of iPD symptoms mainly the non-motor symptoms of daily living (MDS-UPDRS I) and motor complications (MDS-UPDRS IV) in the affected individuals. CONCLUSION: Individuals with history of CVD have a high risk of developing severe forms of iPD. This observation suggests that careful monitoring and management of patients with a history of cardiac problems may reduce the burden of iPD.


Assuntos
Doenças Cardiovasculares , Doença de Parkinson , Humanos , Doença de Parkinson/epidemiologia , Doença de Parkinson/complicações , Masculino , Feminino , Estudos Transversais , Idoso , Pessoa de Meia-Idade , Doenças Cardiovasculares/epidemiologia , Fatores de Risco , Luxemburgo/epidemiologia
16.
J Transl Med ; 22(1): 635, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38978048

RESUMO

BACKGROUND: Circadian rhythm (CR) disturbance is intricately associated with Parkinson's disease (PD). However, the involvement of CR-related mechanisms in the pathogenesis and progression of PD remains elusive. METHODS: A total of 141 PD patients and 113 healthy participants completed CR-related clinical examinations in this study. To further investigate the CR-related mechanisms in PD, we obtained datasets (GSE7621, GSE20141, GSE20292) from the Gene Expression Omnibus database to identify differentially expressed genes between PD patients and healthy controls and further selected CR-related genes (CRRGs). Subsequently, the least absolute shrinkage and selection operator (LASSO) followed by logistic algorithms were employed to identify the hub genes and construct a diagnostic model. The predictive performance was evaluated by area under the curve (AUC), calibration curve, and decision curve analyses in the training set and external validation sets. Finally, RT‒qPCR and Western blotting were conducted to verify the expression of these hub genes in blood samples. In addition, Pearson correlation analysis was utilized to validate the association between expression of hub genes and circadian rhythm function. RESULTS: Our clinical observational study revealed that even early-stage PD patients exhibited a higher likelihood of experiencing sleep disturbances, nocturnal hypertension, reverse-dipper blood pressure, and reduced heart rate variability compared to healthy controls. Furthermore, 4 CR-related hub genes (AGTR1, CALR, BRM14, and XPA) were identified and subsequently incorporated as candidate biomarkers to construct a diagnostic model. The model showed satisfactory diagnostic performance in the training set (AUC = 0.941), an external validation set GSE20295 (AUC = 0.842), and our clinical centre set (AUC = 0.805). Additionally, the up-regulation of CALR, BRM14 and the down-regulation of AGTR1, XPA were associated with circadian rhythm disruption. CONCLUSION: CR disturbance seems to occur in the early stage of PD. The diagnostic model based on CR-related genes demonstrated robust diagnostic efficacy, offering novel insights for future clinical diagnosis of PD and providing a foundation for further exploration into the role of CR-related mechanisms in the progression of PD.


Assuntos
Ritmo Circadiano , Doença de Parkinson , Humanos , Doença de Parkinson/genética , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , Ritmo Circadiano/genética , Masculino , Feminino , Pessoa de Meia-Idade , Estudos de Casos e Controles , Idoso , Curva ROC , Regulação da Expressão Gênica , Perfilação da Expressão Gênica , Modelos Biológicos , Bases de Dados Genéticas
17.
Genome Biol ; 25(1): 184, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38978133

RESUMO

BACKGROUND: Although disease-causal genetic variants have been found within silencer sequences, we still lack a comprehensive analysis of the association of silencers with diseases. Here, we profiled GWAS variants in 2.8 million candidate silencers across 97 human samples derived from a diverse panel of tissues and developmental time points, using deep learning models. RESULTS: We show that candidate silencers exhibit strong enrichment in disease-associated variants, and several diseases display a much stronger association with silencer variants than enhancer variants. Close to 52% of candidate silencers cluster, forming silencer-rich loci, and, in the loci of Parkinson's-disease-hallmark genes TRIM31 and MAL, the associated SNPs densely populate clustered candidate silencers rather than enhancers displaying an overall twofold enrichment in silencers versus enhancers. The disruption of apoptosis in neuronal cells is associated with both schizophrenia and bipolar disorder and can largely be attributed to variants within candidate silencers. Our model permits a mechanistic explanation of causative SNP effects by identifying altered binding of tissue-specific repressors and activators, validated with a 70% of directional concordance using SNP-SELEX. Narrowing the focus of the analysis to individual silencer variants, experimental data confirms the role of the rs62055708 SNP in Parkinson's disease, rs2535629 in schizophrenia, and rs6207121 in type 1 diabetes. CONCLUSIONS: In summary, our results indicate that advances in deep learning models for the discovery of disease-causal variants within candidate silencers effectively "double" the number of functionally characterized GWAS variants. This provides a basis for explaining mechanisms of action and designing novel diagnostics and therapeutics.


Assuntos
Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Humanos , Doença de Parkinson/genética , Predisposição Genética para Doença , Aprendizado Profundo , Esquizofrenia/genética , Elementos Silenciadores Transcricionais/genética
18.
Int J Mol Sci ; 25(13)2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-39000550

RESUMO

The effect of the modulators of the mitochondrial ATP-dependent potassium channel (mitoKATP) on the structural and biochemical alterations in the substantia nigra and brain tissues was studied in a rat model of Parkinson's disease induced by rotenone. It was found that, in experimental parkinsonism accompanied by characteristic motor deficits, both neurons and the myelin sheath of nerve fibers in the substantia nigra were affected. Changes in energy and ion exchange in brain mitochondria were also revealed. The nucleoside uridine, which is a source for the synthesis of the mitoKATP channel opener uridine diphosphate, was able to dose-dependently decrease behavioral disorders and prevent the death of animals, which occurred for about 50% of animals in the model. Uridine prevented disturbances in redox, energy, and ion exchanges in brain mitochondria, and eliminated alterations in their structure and the myelin sheath in the substantia nigra. Cytochemical examination showed that uridine restored the indicators of oxidative phosphorylation and glycolysis in peripheral blood lymphocytes. The specific blocker of the mitoKATP channel, 5-hydroxydecanoate, eliminated the positive effects of uridine, suggesting that this channel is involved in neuroprotection. Taken together, these findings indicate the promise of using the natural metabolite uridine as a new drug to prevent and, possibly, stop the progression of Parkinson's disease.


Assuntos
Mitocôndrias , Canais de Potássio , Rotenona , Uridina , Animais , Uridina/farmacologia , Uridina/metabolismo , Ratos , Canais de Potássio/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Masculino , Modelos Animais de Doenças , Doença de Parkinson/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , Substância Negra/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Fármacos Neuroprotetores/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Ratos Wistar , Ácidos Decanoicos/farmacologia , Hidroxiácidos/farmacologia
19.
Int J Biol Sci ; 20(9): 3302-3316, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38993558

RESUMO

Background: Parkinson's disease (PD) is marked by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor and cognitive dysfunctions. The molecular mechanisms underlying synaptic alterations in PD remain elusive, with a focus on the role of Itga5 in synaptic integrity and motor coordination and TAT-Itga5 was designed to suppress PTEN activity in this investigation. Methods: This study utilized MPTP-induced PD animal models to investigate the expression and role of Itga5 in the striatum. Techniques included quantitative PCR, Western blotting, immunostaining, CRISPR-CasRx-mediated knockdown, electrophysiological assays, behavioral tests, and mass spectrometry. Results: Itga5 expression was significantly reduced in MPTP-induced PD models. In these models, a marked decrease in dendritic spine density and a shift towards thinner spines in striatal GABA neurons were observed, suggesting impaired synaptic integration. Knockdown of Itga5 resulted in reduced dendritic branching, decreased mushroom spines, and increased thin spines, altering synaptic architecture. Electrophysiological analyses revealed changes in action potential and spontaneous excitatory postsynaptic currents, indicating altered synaptic transmission. Motor behavior assessments showed that Itga5 deficiency led to impairments in fine motor control and coordination. Furthermore, Itga5 was found to interact with PTEN, affecting AKT signaling crucial for synaptic development and motor coordination. Conclusion: The study demonstrates that Itga5 plays a critical role in maintaining synaptic integrity and motor coordination in PD. The Itga5-PTEN-AKT pathway represents a potential therapeutic target for addressing synaptic and motor dysfunctions in PD.


Assuntos
PTEN Fosfo-Hidrolase , Doença de Parkinson , Transdução de Sinais , Animais , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/genética , Masculino , Camundongos , Corpo Estriado/metabolismo , Camundongos Endogâmicos C57BL , Integrina alfa5/metabolismo , Integrina alfa5/genética , Sinapses/metabolismo , Modelos Animais de Doenças
20.
Artigo em Inglês | MEDLINE | ID: mdl-39005242

RESUMO

Background: Deep brain stimulation (DBS) can be an effective therapy to control motor signs in patients with Parkinson's disease (PD). However, subthalamic nucleus (STN) DBS can induce undesirable psychiatric adverse effects, including elevated mood. Case report: We reported a video case of a 73-year-old male implanted with bilateral STN DBS who experienced stimulation-induced elevated mood. A correlation between mood changes and enhanced activation of the ventromedial region in the left STN was observed. Discussion: This video case report illustrates STN DBS-induced elevated mood and enhances early symptom recognition for patients and diagnostic awareness for professionals.


Assuntos
Estimulação Encefálica Profunda , Doença de Parkinson , Núcleo Subtalâmico , Humanos , Estimulação Encefálica Profunda/efeitos adversos , Masculino , Núcleo Subtalâmico/fisiopatologia , Idoso , Doença de Parkinson/terapia , Doença de Parkinson/fisiopatologia , Gravação em Vídeo
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