RESUMEN
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
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: There is still a lack of knowledge about the relationship between metabolic syndrome (MetS) and Parkinson's disease (PD). This study aimed to determine whether MetS increases PD risk. METHODS: To identify relevant clinical studies, databases such as PubMed, Embase, and the Cochrane Library were searched in depth from the inception of databases until March 31, 2024. The study evaluated the correlation between MetS and the likelihood of developing PD through the computation of aggregated relative risks (RR) and their respective 95% confidence intervals (CIs) utilizing selnRR and lnRR. RESULTS: Seven studies were included in our systematic review. The meta-analysis revealed that patients with MetS have a 0.3-fold increased risk of developing PD (p = 0.001). Furthermore, the analysis revealed a positive correlation between central obesity and the incidence of PD, with an RR of 1.19 (95% CI, 1.16-1.22; p = 0.001), as well as a greater risk of PD in patients with elevated blood pressure, with an RR of 1.13 (95% CI, 1.07-1.19; p = 0.001); elevated serum triglyceride levels, with an RR of 1.09 (95% CI, 1.02-1.15; p = 0.001); lower serum HDL cholesterol levels, with an RR of 1.21 (95% CI, 1.15-1.28; p = 0.001); and elevated plasma fasting glucose levels, with an RR of 1.18 (95% CI, 1.11-1.26; p = 0.001). CONCLUSION: MetS can contribute to the incidence of Parkinson's disease, with individual components of MetS demonstrating comparable effects.
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Síndrome Metabólico , Enfermedad de Parkinson , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/sangre , Humanos , Síndrome Metabólico/epidemiología , Factores de RiesgoRESUMEN
BACKGROUND: Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by dopaminergic neuron degeneration and diverse motor and nonmotor symptoms. Early diagnosis and intervention are crucial but challenging due to reliance on clinical presentation. Recent research suggests potential biomarkers for early detection, including plasma netrin-1 (NTN-1), a protein implicated in neuronal survival. METHODS: This cross-sectional study recruited 105 PD patients and 65 healthy controls, assessing plasma NTN-1 levels and correlating them with clinical characteristics. Statistical analyses explored associations between NTN-1 levels and PD symptoms, considering demographic factors. RESULTS: PD patients exhibited significantly lower plasma NTN-1 levels compared to controls. NTN-1 demonstrated moderate potential as a PD biomarker. Positive correlations were found between NTN-1 levels and motor, depression, and cognitive symptoms. Multiple regression analysis revealed disease duration and NTN-1 levels as key factors influencing symptom severity. Gender also impacted symptom scores. CONCLUSION: Reduced plasma NTN-1 levels correlate with PD severity, suggesting its potential as a biomarker. However, further research is needed to elucidate the roles of NTN-1 in PD pathophysiology and validate its diagnostic and therapeutic implications. Understanding the involvement of NTN-1 may lead to personalized management strategies for PD.
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Biomarcadores , Netrina-1 , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/complicaciones , Masculino , Femenino , Netrina-1/sangre , Anciano , Estudios Transversales , Persona de Mediana Edad , Biomarcadores/sangre , Depresión/sangre , Depresión/etiología , Depresión/diagnósticoRESUMEN
The identification of mechanisms associated with Parkinson disease (PD) development in cognitive functioning would be of great usefulness to clarify PD pathogenesis and to develop preventive and therapeutic strategies. In this study, blood serum extracellular vesicle (EV) levels of the candidate microRNAs (small noncoding RNAs that play a role in gene expression regulation):,miR-7, miR-21, miR-153, miR-155, miR-200a and miR-214, have been investigated for association with PD in a group of 93 patients with cognitive parameters, PD symptoms, affected quality of life and some clinical characteristics. MiRNA was extracted from patients' blood serum EVs, transcribed into cDNA and their expression was evaluated using RT-PCR. The miR-153 and miR-200a showed the most plausible correlations with cognitive functioning parameters such as general intellectual functioning, psychomotor speed, mental flexibility, and nonverbal executive functions. Moreover, lower levels of miR-153 were associated with attention span, working memory and psychomotor speed with learning. Increased levels of miR-200a, miR-7, miR-214, and miR-155 were also linked with neurological functioning, such as bradykinesia, tremor, balance and others. Despite the fact that due to small sample size, our results should be considered as preliminary, our study suggests that miRNA expression in EVs could be associated with symptom severity, cognitive impairment and quality of life in PD.
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Cognición , Vesículas Extracelulares , MicroARNs , Enfermedad de Parkinson , Calidad de Vida , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/sangre , MicroARNs/genética , MicroARNs/sangre , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Masculino , Femenino , Anciano , Persona de Mediana EdadRESUMEN
Neurosteroids are pleiotropic molecules involved in various neurodegenerative diseases with neuroinflammation. We assessed neurosteroids' serum levels in a cohort of Parkinson's Disease (PD) patients with heterozygous glucocerebrosidase (GBA) mutations (GBA-PD) compared with matched cohorts of consecutive non-mutated PD (NM-PD) patients and healthy subjects with (GBA-HC) and without (NM-HC) GBA mutations. A consecutive cohort of GBA-PD was paired for age, sex, disease duration, Hoehn and Yahr stage, and comorbidities with a cohort of consecutive NM-PD. Two cohorts of GBA-HC and HC were also considered. Clinical assessment included the Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the Montreal Cognitive Assessment (MoCA). Serum samples were processed and analyzed by liquid chromatography coupled with the triple quadrupole mass spectrometry. Twenty-two GBA-PD (males: 11, age: 63.68), 22 NM-PD (males: 11, age: 63.05), 14 GBA-HC (males: 8; age: 49.36), and 15 HC (males: 4; age: 60.60) were studied. Compared to NM-PD, GBA-PD showed more hallucinations and psychosis (p < 0.05, Fisher's exact test) and higher MDS-UPDRS part-II (p < 0.05). Most of the serum neurosteroids were reduced in both GBA-PD and NM-PD compared to the respective control cohorts, except for 5α-dihydroprogesterone. Allopregnanolone was the only neurosteroid significantly lower (p < 0.01, Dunn's test) in NM-PD compared to GBA-PD patients. Only in GBA-PD, allopregnanolone, and pregnanolone levels correlated (Spearman) with a more severe MDS-UPDRS part-III. Allopregnanolone levels also negatively correlated with MoCA scores, and pregnanolone levels correlated with more pronounced bradykinesia. This pilot study provides the first observation of changes in neurosteroid peripheral levels in GBA-PD. The involvement of the observed changes in the development of neuropsychological and motor symptoms of GBA-PD deserves further attention.
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Glucosilceramidasa , Mutación , Neuroesteroides , Enfermedad de Parkinson , Fenotipo , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/sangre , Glucosilceramidasa/genética , Femenino , Masculino , Persona de Mediana Edad , Anciano , Neuroesteroides/sangreRESUMEN
The complexity and heterogeneity of PD necessitate advanced diagnostic and prognostic tools to elucidate its molecular mechanisms accurately. In this study, we addressed this challenge by conducting a pilot phospho-proteomic analysis of peripheral blood mononuclear cells (PBMCs) from idiopathic PD patients at varying disease stages to delineate the functional alterations occurring in these cells throughout the disease course and identify key molecules and pathways contributing to PD progression. By integrating clinical data with phospho-proteomic profiles across various PD stages, we identify potential stage-specific molecular signatures indicative of disease progression. This integrative approach allows for the discernment of distinct disease states and enhances our understanding of PD heterogeneity.
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Progresión de la Enfermedad , Leucocitos Mononucleares , Enfermedad de Parkinson , Proteoma , Proteómica , Humanos , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/patología , Leucocitos Mononucleares/metabolismo , Proteoma/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Proteómica/métodos , Anciano , Fosfoproteínas/metabolismoRESUMEN
BACKGROUND AND OBJECTIVES: Parkinson disease (PD), which is a neurodegenerative disorder, includes several gastrointestinal symptoms that are similar to those of Celiac disease (CD). However, the presence of celiac antibodies in PD patients has not yet been studied. Our aim in this study is to compare anti-transglutaminase (ATA) and antigliadin antibodies (AGA) as well as gastrointestinal symptoms and nutrition habits between patients with Parkinson's disease (PD) and healthy controls. METHODS AND STUDY DESIGN: Serum AGA IgG and IgA and the ATA antibodies IgA and IgG were studied in 102 PD patients and 91 healthy controls. Gastrointestinal symptoms, specifically constipation, were investigated using the gastrointestinal system rating scale (GSRS) and the constipation rating scale (CRS). Dietary habits were also investigated and compared between the groups. RESULTS: No significant differences were found between the two groups in terms of celiac antibodies. As expected, the hypokinetic GSRS and CRS scores were significantly higher in the PD group (p<0.001). Dietary habits, especially carbohydrate-rich diets, had a negative impact on gastrointestinal symptoms in the PD patients. CONCLUSIONS: Studies have suggested a connection between PD and CD, which infers a probable non-celiac gluten intolerance and the need to offer PD patients an elimination diet. However, the results of our study did not support any link between celiac antibodies and PD. Notwithstanding, the negative impact of a carbohydrate-rich diet in PD patients still leaves a question regarding gluten sensitivity in these patients.
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Enfermedades Gastrointestinales , Gliadina , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/sangre , Masculino , Gliadina/inmunología , Femenino , Anciano , Persona de Mediana Edad , Enfermedades Gastrointestinales/inmunología , Enfermedades Gastrointestinales/etiología , Inmunoglobulina A/sangre , Enfermedad Celíaca/inmunología , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/sangre , Transglutaminasas/inmunología , Estreñimiento/inmunología , Estreñimiento/etiología , Inmunoglobulina G/sangre , Estudios de Casos y ControlesRESUMEN
BACKGROUND: Proton pump inhibitors (PPIs), which inhibit gastric acid secretion, are frequently prescribed to patients with Parkinson's disease (PD). Levodopa, the gold-standard treatment for PD, demonstrates enhanced solubility in acidic environments. Although PPIs increase gastric pH and may affect levodopa absorption, the effect of concomitant PPI use on levodopa pharmacokinetics in patients with PD remains unknown. This study aimed to investigate the effect of the concomitant use of esomeprazole, a PPI, on the pharmacokinetics of levodopa and carbidopa and clinical symptoms in patients with PD. METHODS: We prospectively enrolled 40 patients with PD and compared the pharmacokinetics of levodopa and carbidopa and clinical symptoms before and two weeks after the concomitant use of esomeprazole. RESULTS: The plasma concentrations of levodopa 30 min after concomitant oral administration of levodopa and esomeprazole were significantly lower (4.92 ± 4.10 µmol/L) than those without concomitant esomeprazole use (6.26 ± 3.75 µmol/L; p = 0.027). The plasma concentrations of carbidopa showed no significant differences with respect to concomitant esomeprazole use. Significant elevation was recorded in all subscores of the Movement Disorder Society-sponsored revision of the Unified Parkinson's disease Rating Scale scores after concomitant use of esomeprazole. No significant differences were observed between Helicobacter pylori-negative and Helicobacter pylori-positive patients. Non-elderly patients (age ≤ 70 years) tended to be more susceptible to the effect of esomeprazole on levodopa pharmacokinetics and clinical symptoms. CONCLUSIONS: The unnecessary use of PPIs should be avoided in patients with PD, especially in non-elderly patients, to improve absorption of levodopa.
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Antiparkinsonianos , Carbidopa , Interacciones Farmacológicas , Esomeprazol , Levodopa , Enfermedad de Parkinson , Inhibidores de la Bomba de Protones , Humanos , Levodopa/farmacocinética , Levodopa/administración & dosificación , Levodopa/sangre , Esomeprazol/administración & dosificación , Esomeprazol/farmacocinética , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/sangre , Masculino , Femenino , Anciano , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/sangre , Persona de Mediana Edad , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/farmacocinética , Carbidopa/farmacocinética , Carbidopa/administración & dosificación , Estudios ProspectivosRESUMEN
Parkinson's disease (PD) is a neurodegenerative disorder characterized by diverse symptoms, where accurate diagnosis remains challenging. Traditional clinical observation methods often result in misdiagnosis, highlighting the need for biomarker-based diagnostic approaches. This study utilizes ultraperformance liquid chromatography coupled to an electrospray ionization source and quadrupole time-of-flight untargeted metabolomics combined with biochemometrics to identify novel serum biomarkers for PD. Analyzing a Brazilian cohort of serum samples from 39 PD patients and 15 healthy controls, we identified 15 metabolites significantly associated with PD, with 11 reported as potential biomarkers for the first time. Key disrupted metabolic pathways include caffeine metabolism, arachidonic acid metabolism, and primary bile acid biosynthesis. Our machine learning model demonstrated high accuracy, with the Rotation Forest boosting model achieving 94.1% accuracy in distinguishing PD patients from controls. It is based on three new PD biomarkers (downregulated: 1-lyso-2-arachidonoyl-phosphatidate and hypoxanthine and upregulated: ferulic acid) and surpasses the general 80% diagnostic accuracy obtained from initial clinical evaluations conducted by specialists. Besides, this machine learning model based on a decision tree allowed for visual and easy interpretability of affected metabolites in PD patients. These findings could improve the detection and monitoring of PD, paving the way for more precise diagnostics and therapeutic interventions. Our research emphasizes the critical role of metabolomics and machine learning in advancing our understanding of the chemical profile of neurodegenerative diseases.
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Biomarcadores , Aprendizaje Automático , Metabolómica , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/sangre , Biomarcadores/sangre , Metabolómica/métodos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Hipoxantina/metabolismo , Hipoxantina/sangre , Cafeína , Redes y Vías Metabólicas/fisiología , BrasilRESUMEN
Previous studies have shown that α-synuclein (α-Syn) aggregates derived from the brains of patients with Parkinson's disease (PD) and multiple system atrophy (MSA) exhibit different phosphorylation, cytotoxicity, and seeding activity. However, the mechanism underlying the differences remains poorly understood. Here, recombinant human α-Syn was incubated in the plasma of patients with PD and MSA, and the oligomers formed in the plasma (PD-O-α-Syn and MSA-O-α-Syn) were purified and analyzed for their phosphorylation, cytotoxicity and seeding activity. In vitro assays revealed that both PD-O-α-Syn and MSA-O-α-Syn were phosphorylated at serine 129. However, the phosphorylation degree of MSA-O-α-Syn was significantly higher than that of PD-O-α-Syn. In addition, MSA-O-α-Syn exhibited stronger cytotoxicity and seeding activity compared with PD-O-α-Syn. In vivo experiments showed that mice receiving intrastriatal inoculation of MSA-O-α-Syn developed more severe motor dysfunction and dopaminergic degeneration than mice receiving intrastriatal inoculation of PD-O-α-Syn. Compared with the mice inoculated with PD-O-α-Syn, the mice inoculated with MSA-O-α-Syn accumulated more phosphorylated and oligomerized α-Syn in the striatum and brain regions (substantia nigra, hippocampus and prefrontal cortex) away from the inoculated site. The results obtained suggest that α-Syn oligomers formed in PD and MSA plasma are different in phosphorylation, cytotoxicity, and seeding activity.
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Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , alfa-Sinucleína , alfa-Sinucleína/metabolismo , Atrofia de Múltiples Sistemas/patología , Atrofia de Múltiples Sistemas/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/sangre , Humanos , Animales , Fosforilación , Masculino , Ratones , Persona de Mediana Edad , Femenino , Anciano , Ratones Endogámicos C57BLRESUMEN
Melatonin (MTN) is a neuro-hormone released from the pineal gland. MTN secretion is regulated by different neuronal circuits, including the retinohypothalamic tract and suprachiasmatic nucleus (SCN), which are affected by light. MTN is neuroprotective in various neurodegenerative diseases, including Parkinson's disease (PD). MTN circulating level is highly blunted in PD. However, the underlying causes were not fully clarified. Thus, the present review aims to discuss the potential causes of blunted MTN levels in PD. Distortion of MTN circadian rhythmicity in PD patients causies extreme daytime sleepiness. The underlying mechanism for blunted MTN response may be due to reduction for light exposure, impairment of retinal light transmission, degeneration of circadian pacemaker and dysautonomia. In conclusion, degeneration of SCN and associated neurodegeneration together with neuroinflammation and activation of NF-κB and NLRP3 inflammasome, induce dysregulation of MTN secretion. Therefore, low serum MTN level reflects PD severity and could be potential biomarkers. Preclinical and clinical studies are suggested to clarify the underlying causes of low MTN in PD.
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Ritmo Circadiano , Melatonina , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/sangre , Melatonina/sangre , Melatonina/metabolismo , Ritmo Circadiano/fisiología , Animales , Núcleo Supraquiasmático/metabolismoRESUMEN
INTRODUCTION: A major component of Lewy bodies is phosphorylated α-synuclein. This post-translational modification of α-synuclein, phosphorylation, may consume a great amount of serum phosphorus. We aimed to investigate serum phosphorus levels and their associations with clinical phenotype and the degeneration of cardiac sympathetic and nigrostriatal dopaminergic neurons in patients with Parkinson's disease (PD). MATERIALS AND METHODS: We examined serum phosphorus levels in 127 participants (drug-naïve PD, 97; age- and sex-matched controls, 30). Associations of serum phosphorus levels with clinical features, heart-to-mediastinum (H/M) ratio on cardiac 123I-metaiodobenzylguanidine scintigraphy and striatal specific binding ratio of 123I-2-carbomethoxy-3-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) were examined. RESULTS: Serum phosphorus levels were 3.4 ± 0.5 mg/dL in patients with PD and were not different from those in controls after controlling for age and sex (p = 0.850). Serum phosphorus levels were significantly lower in patients with PD and decreased H/M ratio than in those with PD and normal H/M ratio (3.3 ± 0.4 mg/dL vs. 3.6 ± 0.5 mg/dL, p = 0.003). Lower serum phosphorus levels were significantly associated with more severe degeneration of nigrostriatal dopaminergic neurons in patients with PD and decreased H/M ratio. However, this association was not observed in patients with PD and normal H/M ratio. CONCLUSIONS: Serum phosphorus levels and their association with nigrostriatal dopaminergic degeneration are different between patients with decreased H/M ratio and those with normal H/M ratio. Serum phosphorus levels may reflect the degree of nigrostriatal dopaminergic degeneration in patients with decreased H/M ratio, namely, Body-First PD.
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Cuerpo Estriado , Enfermedad de Parkinson , Fósforo , Sustancia Negra , Humanos , Masculino , Femenino , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/diagnóstico por imagen , Fósforo/sangre , Anciano , Persona de Mediana Edad , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/metabolismo , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Tropanos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patologíaRESUMEN
Parkinson's disease displays clinical heterogeneity, presenting with motor and non-motor symptoms. Heterogeneous phenotypes, named brain-first and body-first, may reflect distinct α-synuclein pathology starting either in the central nervous system or in the periphery. The immune system plays a prominent role in the central and peripheral pathology, with misfolded α-synuclein being placed at the intersection between neurodegeneration and inflammation. Here, we characterized the inflammatory profile and immune-phenotype of peripheral blood mononuclear cells (PBMCs) from Parkinson's disease patients upon stimulation with α-synuclein monomer or oligomer, and investigated relationships of immune parameters with clinical scores of motor and non-motor symptoms. Freshly isolated PBMCs from 21 Parkinson's disease patients and 18 healthy subjects were exposed in vitro to α-synuclein species. Cytokine/chemokine release was measured in the culture supernatant by Multiplex Elisa. The immune-phenotype was studied by FACS-flow cytometry. Correlation analysis was computed between immune parameters and parkinsonian motor and non-motor scales. We found that Parkinson's disease patients exhibited a dysregulated PBMC-cytokine profile, which remained unaltered after exposure to α-synuclein species and correlated with both motor and non-motor severity, with a strong correlation observed with olfactory impairment. Exposure of PBMCs from healthy controls to α-synuclein monomer/oligomer increased the cytokine/chemokine release up to patient's values. Moreover, the PBMCs immune phenotype differed between patients and controls and revealed a prominent association of the Mos profile with olfactory impairment, and of NK profile with constipation. Results suggest that a deranged PBMC-immune profile may reflect distinct clinical subtypes and would fit with the recent classification of Parkinson's disease into peripheral-first versus brain-first phenotype.
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Citocinas , Leucocitos Mononucleares , Enfermedad de Parkinson , alfa-Sinucleína , Humanos , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/sangre , alfa-Sinucleína/sangre , alfa-Sinucleína/inmunología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/inmunología , Masculino , Femenino , Anciano , Persona de Mediana Edad , Citocinas/sangre , Citocinas/metabolismo , Citocinas/inmunologíaRESUMEN
BACKGROUND: Sphingolipid dysregulation in Parkinson's disease (PD) may affect the release and uptake of striatal dopamine. However, the longitudinal relationship between sphingolipids, striatal dopaminergic degeneration, and clinical correlates in idiopathic PD (iPD) remain unclear. OBJECTIVE: To investigate the relationship between plasma sphingolipids, striatal dopamine transporter specific binding ratio (DAT-SBR) and clinical symptoms in iPD. METHODS: We included 283 iPD patients and 121 healthy controls (HC) from the Parkinson's Progression Markers Initiative (PPMI), utilizing available data on plasma sphingolipids (sphingomyelin [SM] and ceramide [CER]), striatal DAT-SBR and clinical assessments. Linear mixed models and mediation analyses were used to examine the relationship between sphingolipids, DAT-SBR, and clinical progression in iPD. RESULTS: Lower baseline SM levels were significantly associated with a faster decline in DAT-SBR in both the caudate (p = 0.015) and putamen (p = 0.002), with the putamen association remaining significant after Bonferroni correction (p = 0.015). No significant association was found for CER. Patients in the lowest quartile of baseline SM showed faster progression in MDS-UPDRS I (p = 0.013) and II (p = 0.011), while those in the lowest quartile of baseline CER showed faster progression in MDS-UPDRS II (p = 0.013) and III (p = 0.033). The progression rate of caudate DAT-SBR partially mediated the relationships between SM and progression in MDS-UPDRS I and II (p < 0.01). CONCLUSION: Sphingolipids are associated with worse dopaminergic degeneration and potentially linked to faster progression in iPD, holding the promise for identifying individuals with faster progression in iPD.
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Progresión de la Enfermedad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Enfermedad de Parkinson , Esfingolípidos , Humanos , Enfermedad de Parkinson/sangre , Masculino , Femenino , Anciano , Persona de Mediana Edad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Esfingolípidos/sangre , Esfingomielinas/sangre , Ceramidas/sangre , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Dopamina/sangre , Dopamina/metabolismoRESUMEN
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.
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Autoanticuerpos , Autoantígenos , Colágeno Tipo XVII , Esclerosis Múltiple , Colágenos no Fibrilares , Enfermedad de Parkinson , Penfigoide Benigno de la Membrana Mucosa , Penfigoide Ampolloso , Humanos , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/sangre , Colágenos no Fibrilares/inmunología , Penfigoide Ampolloso/inmunología , Penfigoide Ampolloso/sangre , Autoantígenos/inmunología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/sangre , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Penfigoide Benigno de la Membrana Mucosa/inmunología , Penfigoide Benigno de la Membrana Mucosa/sangre , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Epítopos/inmunología , Dominios Proteicos , Femenino , Masculino , AncianoRESUMEN
BACKGROUND AND OBJECTIVES: Identification of individuals at high risk of developing Parkinson disease (PD) several years before diagnosis is crucial for developing treatments to prevent or delay neurodegeneration. This study aimed to develop predictive models for PD risk that combine plasma proteins and easily accessible clinical-demographic variables. METHODS: Using data from the UK Biobank (UKB), which recruited participants across the United Kingdom, we conducted a longitudinal study to identify predictors for incident PD. Participants with baseline plasma proteins and no PD were included. Through machine learning, we narrowed down predictors from a pool of 1,463 plasma proteins and 93 clinical-demographic. These predictors were then externally validated using the Parkinson's Progression Marker Initiative (PPMI) cohort. To further investigate the temporal trends of predictors, a nested case-control study was conducted within the UKB. RESULTS: A total of 52,503 participants without PD (median age 58, 54% female) were included. Over a median follow-up duration of 14.0 years, 751 individuals were diagnosed with PD (median age 65, 37% female). Using a forward selection approach, we selected a panel of 22 plasma proteins for optimal prediction. Using an ensemble tree-based Light Gradient Boosting Machine (LightGBM) algorithm, the model achieved an area under the receiver operating characteristic curve (AUC) of 0.800 (95% CI 0.785-0.815). The LightGBM prediction model integrating both plasma proteins and clinical-demographic variables demonstrated enhanced predictive accuracy, with an AUC of 0.832 (95% CI 0.815-0.849). Key predictors identified included age, years of education, history of traumatic brain injury, and serum creatinine. The incorporation of 11 plasma proteins (neurofilament light, integrin subunit alpha V, hematopoietic PGD synthase, histamine N-methyltransferase, tubulin polymerization promoting protein family member 3, ectodysplasin A2 receptor, Latexin, interleukin-13 receptor subunit alpha-1, BAG family molecular chaperone regulator 3, tryptophanyl-TRNA synthetase, and secretogranin-2) augmented the model's predictive accuracy. External validation in the PPMI cohort confirmed the model's reliability, producing an AUC of 0.810 (95% CI 0.740-0.873). Notably, alterations in these predictors were detectable several years before the diagnosis of PD. DISCUSSION: Our findings support the potential utility of a machine learning-based model integrating clinical-demographic variables with plasma proteins to identify individuals at high risk for PD within the general population. Although these predictors have been validated by PPMI, additional validation in a more diverse population reflective of the general community is essential.
Asunto(s)
Biomarcadores , Proteínas Sanguíneas , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/epidemiología , Femenino , Masculino , Persona de Mediana Edad , Proteínas Sanguíneas/análisis , Anciano , Estudios Longitudinales , Estudios de Casos y Controles , Biomarcadores/sangre , Reino Unido/epidemiología , Aprendizaje Automático , Progresión de la Enfermedad , Valor Predictivo de las PruebasRESUMEN
Brain-derived neurotrophic factor (BDNF) and glycolipid metabolism have been implicated in cognitive impairments and depression among Parkinson's disease (PD). However, the role of sex differences in this relationship remains elusive. This study aimed to investigate the potential sex differences in the link between serum BDNF levels, glycolipid metabolism and cognitive performance among depressive PD patients. PD patients comprising 108 individuals with depression and 108 without depression were recruited for this study. Cognitive function was assessed using the Montreal Cognitive Assessment Beijing version (MOCA-BJ). The severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale (HAMD-17), while motor symptoms were evaluated using the Revised Hoehn and Yahr rating scale (H-Y) and the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III). Laboratory testing and enzyme-linked immunosorbent assay (ELISA) are used to measure serum levels of glycolipid metabolism and BDNF. Females showed superior performance in delayed recall (all p < 0.05), male PD patients exhibited higher scores in naming tasks compared to females in non-depression group. There was no sex differences in serum BDNF levels between depression and non-depression groups. Liner regression analysis indicated BDNF as an independent risk factor for language deficits in male PD patients with depression (p < 0.05), while cholesterol (CHOL) emerged as a cognitive influencing factor, particularly in delayed recall among male PD patients with depression (p < 0.05). Our study reveals extensive cognitive impairments in PD patients with depression. Moreover, BDNF and CHOL may contribute to the pathological mechanisms underlying cognitive deficits, particularly in male patients with depression.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Disfunción Cognitiva , Depresión , Glucolípidos , Enfermedad de Parkinson , Caracteres Sexuales , Humanos , Factor Neurotrófico Derivado del Encéfalo/sangre , Masculino , Femenino , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/complicaciones , Glucolípidos/sangre , Disfunción Cognitiva/sangre , Disfunción Cognitiva/etiología , Anciano , Persona de Mediana Edad , Depresión/sangre , Depresión/etiología , Escalas de Valoración Psiquiátrica , Pruebas NeuropsicológicasRESUMEN
BACKGROUND: Globally, Parkinson's disease (PD) is one of the common neurodegenerative diseases in the elderly with increasing morbidity and disability, and its clinical pathogenesis is not clear. OBJECTIVE: To compare the differences in disease severity and blood biomarkers levels and their correlation between patients with early-onset Parkinson's disease (EOPD) and late-onset Parkinson's disease (LOPD). METHODS: A total of 342 patients diagnosed with PD were retrospectively collected. PD patients were categorized into EOPD (24 patients) and LOPD (318 patients) according to the age of onset of the disease. The Hoehn-Yahr (HY) staging was used to assess the severity of the disease in PD patients. Subjective rating scales such as the Mini-mental State Examination (MMSE) were used to assess the motor and non-motor functions of the patients. The differences of objective blood biomarkers such as triglyceride (TG) between the two groups were investigated. The correlation between them and PD was explored by logistic analysis. RESULTS: Percentage of EOPD group with HY staged as intermediate to late and Scales for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT), Movement Disorder Society-Unified Parkinson's disease Rating Scale-III (MDS-UPDRS-III), Montreal Cognitive Assessment (MoCA) score and TG, non-high-density lipoprotein-cholesterol (N-HDL-C), homocysteine (HCY), apolipoprotein B (Apo-B), free triiodothyronine (FT3), free thyroxine (FT4), high-sensitivity C-reactive protein (hs-CRP) levels were lower than those in the LOPD group (P < 0.05); and the proportion of HY staged as early stage, Hamilton Anxiety Scale (HAMA) and Fatigue severity scale (FSS) scores and the levels of vitamin B12 were higher than those in the LOPD group (P < 0.05). The results of Multifactorial Logistic regression analysis showed that N-HDL-C [OR = 1.409, 95 % CI (1.063, 1.868)], Apo-B [OR = 0.797, 95 % CI (0.638, 0.997)], Vitamin B12 [OR = 0.992, 95 % CI (0.987, 0.998)] and hs-CRP [OR = 1.124, 95 % CI (1.070, 1.182)] were independent factors affecting the severity of PD, with significant differences between groups (P < 0.05). CONCLUSION: N-HDL-C, Apo-B, Vitamin B12, and hs-CRP levels play an important role in the progression of PD.
Asunto(s)
Biomarcadores , Enfermedad de Parkinson , Índice de Severidad de la Enfermedad , Humanos , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/psicología , Masculino , Estudios Retrospectivos , Femenino , Anciano , China/epidemiología , Persona de Mediana Edad , Biomarcadores/sangre , Edad de Inicio , Triglicéridos/sangre , Pruebas de Estado Mental y Demencia , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Uric acid, as an important antioxidant substance in human body, has attracted much attention in relation to the risk of Parkinson's disease (PD). However, the causal relationship between them is still controversial. We perform a meta-analysis to summarize the available evidence from cohort studies on the association between high uric acid and the risk of PD. METHODS: We searched the Cochrane Library, PubMed, Medline, and Embase to obtain the Odds Ratio (OR) of high uric acid and PD and pooled the data using RevMan software (v5.4; Cochrane library). RESULTS: A total of 18 studies involving more than 840,774 participants were included. Overall, we found a significant association (ORâ =â 0.84; 95% CI: 0.77-0.91) between high uric acid and PD. Subgroup analysis was stratified by gender, indicating more statistically significant protective effects of serum urate in men (ORâ =â 0.66; 95% CI: 0.54-0.81) than that of in women (ORâ =â 0.86; 95% CI: 0.76-0.98). People under the age of 60 (ORâ =â 0.53, 95% CI: 0.33-0.86) are more likely to benefit from high uric acid than people over age of 60 (ORâ =â 0.73, 95% CI: 0.63-0.86). The resistance of high uric acid to PD in LRRK2 mutation carriers (ORâ =â 0.22, 95% CI: 0.11-0.45) is stronger than that in non-manifesting LRRK2 mutation carriers (ORâ =â 0.37, 95% CI: 0.16-0.85). In addition, a dose-response trend of serum urate to reduce PD risk was also observed (ORâ =â 0.68; 95% CI: 0.48-0.93). CONCLUSION: Our study confirms a significant association between high uric acid and the risk of PD, especially in men under 60 years old, and a dose-response trend of uric acid to reduce PD risk was also observed. Furthermore, LRRK2 mutation carriers are more likely to benefit from high uric acid than non-manifesting LRRK2 mutation carriers.