RESUMO
Parkinson's disease is increasingly prevalent. It progresses from the pre-motor stage (characterised by non-motor symptoms like REM sleep behaviour disorder), to the disabling motor stage. We need objective biomarkers for early/pre-motor disease stages to be able to intervene and slow the underlying neurodegenerative process. Here, we validate a targeted multiplexed mass spectrometry assay for blood samples from recently diagnosed motor Parkinson's patients (n = 99), pre-motor individuals with isolated REM sleep behaviour disorder (two cohorts: n = 18 and n = 54 longitudinally), and healthy controls (n = 36). Our machine-learning model accurately identifies all Parkinson patients and classifies 79% of the pre-motor individuals up to 7 years before motor onset by analysing the expression of eight proteins-Granulin precursor, Mannan-binding-lectin-serine-peptidase-2, Endoplasmatic-reticulum-chaperone-BiP, Prostaglaindin-H2-D-isomaerase, Interceullular-adhesion-molecule-1, Complement C3, Dickkopf-WNT-signalling pathway-inhibitor-3, and Plasma-protease-C1-inhibitor. Many of these biomarkers correlate with symptom severity. This specific blood panel indicates molecular events in early stages and could help identify at-risk participants for clinical trials aimed at slowing/preventing motor Parkinson's disease.
Assuntos
Biomarcadores , Doença de Parkinson , Proteômica , Humanos , Doença de Parkinson/sangue , Doença de Parkinson/diagnóstico , Biomarcadores/sangue , Masculino , Proteômica/métodos , Feminino , Idoso , Pessoa de Meia-Idade , Aprendizado de Máquina , Transtorno do Comportamento do Sono REM/sangue , Transtorno do Comportamento do Sono REM/diagnóstico , Estudos de Casos e Controles , Espectrometria de MassasRESUMO
BACKGROUND: Sleep disorders are a prevalent non-motor symptom of Parkinson's disease (PD), although reliable biological markers are presently lacking. OBJECTIVES: To explore the associations between sleep disorders and serum neurofilament light chain (NfL) levels in individuals with prodromal and early PD. METHODS: The study contained 1113 participants, including 585 early PD individuals, 353 prodromal PD individuals, and 175 healthy controls (HCs). The correlations between sleep disorders (including rapid eye movement sleep behavior disorder (RBD) and excessive daytime sleepiness (EDS)) and serum NfL levels were researched using multiple linear regression models and linear mixed-effects models. We further investigated the correlations between the rates of changes in daytime sleepiness and serum NfL levels using multiple linear regression models. RESULTS: In baseline analysis, early and prodromal PD individuals who manifested specific behaviors of RBD showed significantly higher levels of serum NfL. Specifically, early PD individuals who experienced nocturnal dream behaviors (ß = 0.033; P = 0.042) and movements of arms or legs during sleep (ß = 0.027; P = 0.049) showed significantly higher serum NfL levels. For prodromal PD individuals, serum NfL levels were significantly higher in individuals suffering from disturbed sleep (ß = 0.038; P = 0.026). Our longitudinal findings support these baseline associations. Serum NfL levels showed an upward trend in early PD individuals who had a higher total RBDSQ score (ß = 0.002; P = 0.011) or who were considered as probable RBD (ß = 0.012; P = 0.009) or who exhibited behaviors on several sub-items of the RBDSQ. In addition, early PD individuals who had a high total ESS score (ß = 0.001; P = 0.012) or who were regarded to have EDS (ß = 0.013; P = 0.007) or who exhibited daytime sleepiness in several conditions had a trend toward higher serum NfL levels. CONCLUSION: Sleep disorders correlate with higher serum NfL, suggesting a link to PD neuronal damage. Early identification of sleep disorders and NfL monitoring are pivotal in detecting at-risk PD patients promptly, allowing for timely intervention. Regular monitoring of NfL levels holds promise for tracking both sleep disorders and disease progression, potentially emerging as a biomarker for evaluating treatment outcomes.
Assuntos
Biomarcadores , Proteínas de Neurofilamentos , Doença de Parkinson , Transtornos do Sono-Vigília , Humanos , Doença de Parkinson/sangue , Doença de Parkinson/diagnóstico , Doença de Parkinson/complicações , Masculino , Feminino , Proteínas de Neurofilamentos/sangue , Pessoa de Meia-Idade , Idoso , Transtornos do Sono-Vigília/sangue , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/epidemiologia , Biomarcadores/sangue , Transtorno do Comportamento do Sono REM/sangue , Transtorno do Comportamento do Sono REM/diagnóstico , Sintomas ProdrômicosRESUMO
BACKGROUND: Identifying individuals with Parkinson's disease (PD) already in the prodromal phase of the disease has become a priority objective for opening a window for early disease-modifying therapies. OBJECTIVE: The aim was to evaluate a blood-based α-synuclein seed amplification assay (α-syn SAA) as a novel biomarker for diagnosing PD in the prodromal phase. METHODS: In the TREND study (University of Tuebingen) biennial blood samples of n = 1201 individuals with/without increased risk for PD were taken prospectively over 4 to 10 years. We retrospectively analyzed blood samples of 12 participants later diagnosed with PD during the study to detect and amplify pathological α-syn conformers derived from neuronal extracellular vesicles using (1) immunoblot analyses with an antibody against these conformers and (2) an α-syn-SAA. Additionally, blood samples of n = 13 healthy individuals from the TREND cohort and n = 20 individuals with isolated rapid eye movement sleep behavior disorder (iRBD) from the University Hospital Cologne were analyzed. RESULTS: All individuals with PD showed positive immunoblots and a positive α-syn SAA at the time of diagnosis. Moreover, all PD patients showed a positive α-syn SAA 1 to 10 years before clinical diagnosis. In the iRBD cohort, 30% showed a positive α-syn SAA. All healthy controls had a negative SAA. CONCLUSIONS: We here demonstrate the possibility to detect and amplify pathological α-syn conformers in peripheral blood up to 10 years before the clinical diagnosis of PD in individuals with and without iRBD. The findings of this study indicate that this blood-based α-syn SAA assay has the potential to serve as a diagnostic biomarker for prodromal PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Biomarcadores , Doença de Parkinson , Sintomas Prodrômicos , alfa-Sinucleína , Humanos , Doença de Parkinson/sangue , Doença de Parkinson/diagnóstico , alfa-Sinucleína/sangue , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Biomarcadores/sangue , Transtorno do Comportamento do Sono REM/sangue , Transtorno do Comportamento do Sono REM/diagnóstico , Estudos RetrospectivosRESUMO
INTRODUCTION: Rapid eye movement (REM) sleep behavior disorder (RBD) is associated with an increased risk of developing Parkinson's disease (PD). Low uric acid (UA) levels are associated with the risk of development and progression of PD. Allantoin is the major oxidation product of UA and is considered as a biomarker of oxidative stress. We aimed to compare serum levels of UA, allantoin, and allantoin/UA ratio in RBD patients with those in healthy controls, and to examine their associations with clinical severity. METHODS: We evaluated serum levels of UA, allantoin, and allantoin/UA ratio in 38 RBD patients (one female, mean age 66.8 (SD 6.3) years) and in 47 controls (four females, 66.8 (7.6) years). All RBD patients were assessed according to an examination protocol, which included structured interview, Montreal Cognitive Assessment (MoCA), Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and dopamine transporter single-photon emission computed tomography (DAT-SPECT). The lower putaminal binding ratio from both hemispheres was used for analysis. RESULTS: Mean serum allantoin concentration and allantoin/UA ratio were significantly increased in the RBD group compared to controls (2.6 (1.8) vs. 1.4 (0.7) µmol/l, p = 0.0004, and 0.008 (0.004) vs. 0.004 (0.002), p < 0.0001, respectively). There were no significant differences in UA levels between the two groups. No significant associations between any biochemical parameter and RBD duration, putaminal binding ratio on DAT-SPECT, MDS-UPDRS, or MoCA score were found. CONCLUSION: Serum allantoin and allantoin/UA ratio are increased in RBD patients in comparison to controls, which may reflect increased systemic oxidative stress in prodromal synucleinopathy.
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Alantoína/sangue , Transtorno do Comportamento do Sono REM/sangue , Ácido Úrico/sangue , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Estresse Oxidativo , Sinucleinopatias/sangue , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
Synucleinopathies are neurodegenerative diseases with both central and peripheral immune responses. However, whether the peripheral immune changes occur early in disease and their relation to brain events is yet unclear. Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) can precede synucleinopathy-related parkinsonism and provides a prodromal phenotype to study early Parkinson's disease events. In this prospective case-control study, we describe monocytic markers in a cohort of iRBD patients that were associated with the brain-imaging markers of inflammation and neuronal dysfunction. Using 11C-PK11195 positron emission tomography (PET), we previously showed increased immune activation in the substantia nigra of iRBD patients, while 18F-DOPA PET detected reduced putaminal dopaminergic function. Here we describe that patients' blood monocytic cells showed increased expression of CD11b, while HLA-DR expression was decreased compared to healthy controls. The iRBD patients had increased classical monocytes and mature natural killer cells. Remarkably, the levels of expression of Toll-like receptor 4 (TLR4) on blood monocytes in iRBD patients were positively correlated with nigral immune activation measured by 11C-PK11195 PET and negatively correlated with putaminal 18F-DOPA uptake; the opposite was seen for the percentage of CD163+ myeloid cells. This suggesting a deleterious role for TLR4 and, conversely, a protective one for the CD163 expression. We show an association between peripheral blood monocytes and brain immune and dopaminergic changes in a synucleinopathy-related disorder, thus suggesting a cross-talk among periphery and brain during the disease.
Assuntos
Neurônios , Tomografia por Emissão de Pósitrons , Transtorno do Comportamento do Sono REM , Substância Negra , Idoso , Biomarcadores/sangue , Antígeno CD11b/sangue , Antígeno CD11b/imunologia , Feminino , Antígenos HLA-DR/sangue , Antígenos HLA-DR/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Neurônios/imunologia , Neurônios/metabolismo , Transtorno do Comportamento do Sono REM/sangue , Transtorno do Comportamento do Sono REM/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/imunologia , Substância Negra/diagnóstico por imagem , Substância Negra/imunologia , Substância Negra/metabolismo , Receptor 4 Toll-Like/sangue , Receptor 4 Toll-Like/imunologiaRESUMO
OBJECTIVE: To investigate serum inflammatory cytokine profiles in patients with isolated REM sleep behavior disorder (iRBD) and to explore whether these markers are associated with phenoconversion risk to α-synucleinopathies. METHODS: In this prospective cohort study, we analyzed serum samples from patients with polysomnography-confirmed iRBD (n = 30) and healthy controls (n = 12). We measured the following cytokines: interleukin (IL)-1ß, IL-2, IL-6, IL-10, and tumor necrosis factor-α (TNF-α). All patients underwent motor and non-motor evaluations and dopamine transporter imaging at baseline for predicting the phenoconversion risk. We followed the patients quarterly over up to 6 years to identify disease conversion. We also assessed longitudinal changes in cytokine levels from baseline at the 2- and 4-year follow-up visits. RESULTS: The baseline cytokine levels did not differ between the patients and controls. However, the TNF-α levels were significantly increased in a subgroup of the patients with multiple markers (≥3) for phenoconversion risk compared to those without (p = 0.008) and controls (p = 0.003). At longitudinal analyses, patients with TNF-α levels above the median showed a higher incidence of phenoconversion than those with lower TNF-α levels (47% vs. 7%; p = 0.008), and this significant association persisted after adjusting for covariates (p = 0.026). The cytokine levels over 4 years of follow-up period did not change significantly. CONCLUSIONS: Our data suggest a possible link between serum TNF-α and phenoconversion risk in iRBD. Further studies are warranted to confirm the role of peripheral TNF-α in the pathogenesis of neurodegeneration in this disorder.
Assuntos
Encéfalo/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/sangue , Sinucleinopatias/sangue , Fator de Necrose Tumoral alfa/sangue , Idoso , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Estudos de Coortes , Progressão da Doença , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Humanos , Interleucina-10/sangue , Interleucina-1beta/sangue , Interleucina-2/sangue , Interleucina-6/sangue , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Transtornos do Olfato/fisiopatologia , Polissonografia , Estudos Prospectivos , Transtorno do Comportamento do Sono REM/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/fisiopatologia , Fatores de Risco , Sinucleinopatias/diagnóstico por imagem , Sinucleinopatias/fisiopatologiaRESUMO
INTRODUCTION: Increasing evidence shows a strong association between idiopathic REM sleep behavior disorder (iRBD) and α-synucleinopathies. Recent studies have indicated an inflammatory mechanism in the pathogenesis of α-synucleinopathies. Whether peripheral inflammatory cytokines are altered in iRBD and can be biomarkers for predicting phenoconversion remains unclear. METHODS: We collected baseline plasma samples from 77 consecutive iRBD patients and 64 age- and sex-matched healthy controls. Ten cytokines were measured: Interferon (IFN)-γ, interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor (TNF)-α. All iRBD patients underwent clinical assessment tests at baseline, and 75 were prospectively followed and received assessments for parkinsonism or dementia. Cox regression analyses were used to evaluate the predictive value of plasma cytokines in a follow-up period of 6.0 years. RESULTS: TNF-α and IL-10 were significantly elevated in iRBD compared with controls (both p < 0.001). IL-6/IL-10 and IL-8/IL-10 were significantly reduced in iRBD than in controls (p = 0.001, p < 0.001, respectively). After a median follow-up of 3.7 years, 16 iRBD patients developed neurodegenerative synucleinopathies. iRBD patients with higher TNF-α/IL-10 levels were more likely to develop neurodegenerative diseases (adjusted HR 1.07, 95% CI 1.01-1.14). The coexistence of elevated TNF-α/IL-10 and possible mild cognitive impairment predicted an early conversion of iRBD to neurodegenerative synucleinopathies (adjusted HR 4.17, 95% CI 1.47-11.81). CONCLUSIONS: Our study supported the early involvement of peripheral inflammation in prodromal α-synucleinopathy. Plasma cytokines may be predictive of disease conversion in iRBD, while large-scale longitudinal studies are warranted to validate the assumption.
Assuntos
Citocinas/sangue , Transtorno do Comportamento do Sono REM/sangue , Transtorno do Comportamento do Sono REM/imunologia , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Inflamação/sangue , Inflamação/imunologia , Interleucina-10/sangue , Masculino , Pessoa de Meia-Idade , Sintomas Prodrômicos , Sinucleinopatias/sangue , Sinucleinopatias/imunologia , Fator de Necrose Tumoral alfa/sangueRESUMO
OBJECTIVE: To examine how urate concentrations are related to the risk of having possible REM sleep behavior disorder (pRBD) in a community-based cohort. METHODS: The study included 12,923 Chinese adults of the Kailuan Study, free of Parkinson disease (PD) and dementia. Plasma urate concentrations were measured in 2006, 2008, and 2010. Cumulative average urate concentration was used as primary exposure. In 2012, we determined pRBD status using a validated RBD questionnaire-Hong Kong (RBDQ-HK). Logistic regression analysis was performed to estimate the association between urate concentrations during 2006-2010 and odds of having pRBD in 2012 or pRBD case with symptom onset within 1 year. RESULTS: Higher average urate concentrations were associated with a lower odds of pRBD (P-trend <0.001). The adjusted odds ratio (OR), for the highest versus lowest urate quintiles, was 0.43 (95% confidence intervals (CIs) 0.32-0.57). Significant association was consistently observed when we examined the association of a single urate assessment (2006 or 2010) or the rate of change in urate concentrations during 2006-2010 with pRBD (P-trend <0.001 for all). However, restricting to pRBD onset during 2011-2012, we observed a nonsignificant trend between high urate concentration and high odds of pRBD (P-trend = 0.09). INTERPRETATION: Higher average urate concentrations were associated with a lower likelihood of having pRBD, but not new-onset pRBD. Because of its observational study design, the result should be interpreted with caution due to the possibility of residual confounding.
Assuntos
Transtorno do Comportamento do Sono REM/sangue , Transtorno do Comportamento do Sono REM/epidemiologia , Ácido Úrico/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Although primarily a neurodegenerative process, there is increasing awareness of peripheral disease mechanisms in Parkinson's disease. To investigate disease processes in accessible patient cells, we studied peripheral blood mononuclear cells in recently diagnosed PD patients and rapid eye movement-sleep behavior disorder patients who have a greatly increased risk of developing PD. We hypothesized that peripheral blood mononuclear cells may recapitulate cellular pathology found in the PD brain and investigated these cells for mitochondrial dysfunction and oxidative stress. METHODS: Peripheral blood mononuclear cells were isolated and studied from PD patients, rapid eye movement-sleep behavior disorder patients and age- and sex-matched control individuals from the well-characterized Oxford Discovery cohort. All participants underwent thorough clinical assessment. RESULTS: Initial characterization showed that PD patients had elevated levels of CD14 + monocytes and monocytes expressing C-C motif chemokine receptor 2. Mitochondrial dysfunction and oxidative stress were increased in PD patient peripheral blood mononuclear cells, with elevated levels of mitochondrial reactive oxygen species specifically in patient monocytes. This was combined with reduced levels of the antioxidant superoxide dismutase in blood cells from PD patients and, importantly, also in rapid eye movement-sleep behavior disorder patients. This mitochondrial dysfunction was associated with a concomitant increase in glycolysis in both PD and rapid eye movement-sleep behavior disorder patient blood cells independent of glucose uptake or monocyte activation. CONCLUSIONS: This work demonstrates functional bioenergetic deficits in PD and rapid eye movement-sleep behavior disorder patient blood cells during the early stages of human disease. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Glicólise/fisiologia , Leucócitos Mononucleares/ultraestrutura , Doenças Mitocondriais/etiologia , Doença de Parkinson/sangue , Doença de Parkinson/complicações , Estudos de Casos e Controles , Citocinas/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Citometria de Fluxo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Humanos , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Consumo de Oxigênio/fisiologia , Doença de Parkinson/patologia , Sintomas Prodrômicos , Transtorno do Comportamento do Sono REM/sangue , Transtorno do Comportamento do Sono REM/complicações , Transtorno do Comportamento do Sono REM/patologia , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores CCR2/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismoRESUMO
Idiopathic rapid eye movement sleep behavior disorder (iRBD) likely represents the prodromal stage of synucleinopathy. The present study investigated how levels of serum uric acid (UA) affect cognition and motor function in patients with iRBD. A total of 42 patients with iRBD and 45 healthy controls were included. All participants were given cognitive tests and motor assessments. Serum UA concentrations were measured. The patients were further divided into two groups (high or low UA) according to serum UA level. The level of serum UA was similar between the patients with iRBD and the healthy controls, whereas the patients showed impaired executive, memory, and visuospatial functions. The patients with low UA levels had longer durations of RBD. Lower scores involving attention, executive function, and language domain were also found in the patients with low UA, whereas the scores of the patients with high UA were similar to those of the healthy controls. Regarding memory domain, the low UA group had worse scores than the healthy controls, whereas the scores of high UA group fell between those of the low UA group and the healthy controls. Motor function was not affected in any of the groups. UA affects cognitive function but not motor function in patients with iRBD, which could contribute to its antioxidant and neuroprotective roles.
Assuntos
Cognição/fisiologia , Memória/fisiologia , Transtorno do Comportamento do Sono REM/sangue , Ácido Úrico/sangue , Idoso , Idoso de 80 Anos ou mais , Atenção/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Transtorno do Comportamento do Sono REM/psicologiaRESUMO
OBJECTIVE: To perform a rigorous in-depth proteomics analysis to identify circulating biomarker signatures for idiopathic REM sleep behavior disorder (RBD), capable of providing new insights into the underlying pathogenic mechanisms and putative α-synuclein-related neurodegenerative processes. METHODS: Serum samples from patients with idiopathic RBD (n = 9) and healthy controls (n = 10) were subjected to a thorough liquid chromatography-mass spectrometry (MS)/MS proteomics analysis using ultimate 3,000 nanoLC interfaced to an ESI-orbitrap velos. Data were analyzed with a systems biology approach to identify altered pathways in RBD. RESULTS: We identified 259 proteins, 11 of which displayed significantly altered expression level in patients with RBD as compared to controls. Significant reduction in serum levels of dopamine ß-hydroxylase (DBH) and vitamin D binding protein (GC) were consistent with alterations in the norepinephrinergic (NErgic) and dopaminergic systems, respectively. Additional altered protein profiles indicated that immunity, inflammation, complement, and coagulation also play a role in RBD pathophysiology. CONCLUSIONS: Our results shed light on the protein signature profile, molecular pathways, and mechanisms involved in the pathogenesis of RBD and its clinical manifestation. This knowledge opens a new avenue towards more accurate and timely diagnosis and characterization of RBD, which might ultimately translate into new therapeutic strategies with disease-modifying effects. Further evaluation of the identified markers is required to confirm their diagnostic value and potential to guide clinical decision-making.
Assuntos
Biomarcadores/sangue , Transtorno do Comportamento do Sono REM/sangue , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteômica/métodosRESUMO
Idiopathic REM sleep behavior disorder (iRBD) is now considered a prodromal stage of an α-synucleinopathy-related to neurodegenerative disease such as Parkinson's diseases. Emerging evidence has shown that post-translational modification or glycosylation are implicated in dynamic disease mechanisms and the onset of many pathological conditions. We hypothesized that the characterization of the glycosylation pattern of patients with RBD would be of great value to understand the pathophysiology and underlying mechanisms and represent potentially useful biomarkers for disease-associated molecular changes. To test this hypothesis, we assessed the serum glycome of patients with RBD and compared to that of healthy controls. NanoRPLC-MS was used to generate quantitative N-glycan profiles while high-temperature PGC-LC-MS platform was employed to generate quantitative isomeric N-glycan profiles. By analyzing permethylated glycans derived from human blood sera on C18-LC-MS/MS, we identified 59 N-glycan structures in healthy (control) cohort, 56 N-glycans in RBD cohort. Sixteen N-glycans structures were found to be significantly altered in the RBD cohort (p < 0.05). N-glycans with the composition of HexNAc4 Hex5 Fuc1 , HexNAc5 Hex5 , and HexNAc4 Hex5 Fuc1 NeuAc1 presented the most substantial difference between controls and RBD patients (p < 0.01). HexNAc4 Hex5 Fuc1 NeuAc1 showed a relatively high abundance (3.1 ± 0.7% in the control cohort versus 4 ± 3% in the idiopathic RBD cohort). These N-glycans can be potential diagnostic biomarker candidates and provide a window into underlying neurodegenerative processes in patients with idiopathic RBD. In addition, 7 N-glycan isomers were significantly different between controls and RBD patients (p < 0.05). HexNAc4 Hex5 Fuc1 NeuAc1 (4511-2) and HexNAc4 Hex5 Fuc1 NeuAc2 (4512-2) showed the most substantial difference between the control and idiopathic RBD cohorts (p < 0.001). Levels of both these two isomeric structures were higher in the idiopathic RBD cohort. Further larger studies are required to assess the reproducibility of these findings and to elucidate the role played by the changes in glycan structures in the pathogenetic mechanisms of RBD. This information will be instrumental in developing molecular therapeutic targets to promote neuroprotection and prevention of neurodegeneration.
Assuntos
Cromatografia Líquida/métodos , Glicômica/métodos , Polissacarídeos/sangue , Transtorno do Comportamento do Sono REM/sangue , Espectrometria de Massas em Tandem/métodos , Adulto , Biomarcadores/sangue , Biomarcadores/química , Estudos de Casos e Controles , Humanos , Polissacarídeos/química , Análise de Componente Principal , Transtorno do Comportamento do Sono REM/diagnósticoRESUMO
OBJECTIVE: Rapid eye movement sleep behavior disorder (RBD) is characterized by dream enactment and loss of muscle atonia during rapid eye movement sleep. RBD is closely related to α-synucleinopathies including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Many studies have investigated the markers of imaging and neurophysiological, genetic, cognitive, autonomic function of RBD and their predictive value for neurodegenerative diseases. This report reviewed the progress of these studies and discussed their limitations and future research directions. DATA SOURCES: Using the combined keywords: "RBD", "neurodegenerative disease", "Parkinson disease", and "magnetic resonance imaging", the PubMed/MEDLINE literature search was conducted up to January 1, 2018. STUDY SELECTION: A total of 150 published articles were initially identified citations. Of the 150 articles, 92 articles were selected after further detailed review. This study referred to all the important English literature in full. RESULTS: Single-nucleotide polymorphisms in SCARB2 (rs6812193) and MAPT (rs12185268) were significantly associated with RBD. The olfactory loss, autonomic dysfunction, marked electroencephalogram slowing during both wakefulness and rapid eye movement sleep, and cognitive impairments were potential predictive markers for RBD conversion to neurodegenerative diseases. Traditional structural imaging studies reported relatively inconsistent results, whereas reduced functional connectivity between the left putamen and substantia nigra and dopamine transporter uptake demonstrated by functional imaging techniques were relatively consistent findings. CONCLUSIONS: More longitudinal studies should be conducted to evaluate the predictive value of biomarkers of RBD. Moreover, because the glucose and dopamine metabolisms are not specific for assessing cognitive cognition, the molecular metabolism directly related to cognition should be investigated. There is a need for more treatment trials to determine the effectiveness of interventions of RBD on preventing the conversion to neurodegenerative diseases.
Assuntos
Doenças Neurodegenerativas/fisiopatologia , Doença de Parkinson/fisiopatologia , Transtorno do Comportamento do Sono REM/fisiopatologia , Biomarcadores/sangue , Humanos , Proteínas de Membrana Lisossomal/genética , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/genética , Doença de Parkinson/sangue , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único/genética , Transtorno do Comportamento do Sono REM/sangue , Transtorno do Comportamento do Sono REM/genética , Receptores Depuradores/genética , Proteínas tau/genéticaRESUMO
Parkinson's disease (PD) is a frequent neurodegenerative process in old age. Accumulation and aggregation of the lipid-binding SNARE complex component α-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity have been intensely investigated. In view of the physiological roles of SNCA in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation) to identify effects of SNCA gain of function as potential disease biomarkers. Downregulation of complexin 1 (CPLX1) mRNA was correlated with genotype, but the expression of other Parkinson's disease genes was not. In global RNA-seq profiling of blood from presymptomatic PARK4 indviduals, bioinformatics detected significant upregulations for platelet activation, hemostasis, lipoproteins, endocytosis, lysosome, cytokine, Toll-like receptor signaling and extracellular pathways. In PARK4 platelets, stimulus-triggered degranulation was impaired. Strong SPP1, GZMH and PLTP mRNA upregulations were validated in PARK4. When analysing individuals with rapid eye movement sleep behavior disorder, the most specific known prodromal stage of general PD, only blood CPLX1 levels were altered. Validation experiments confirmed an inverse mutual regulation of SNCA and CPLX1 mRNA levels. In the 3'-UTR of the CPLX1 gene we identified a single nucleotide polymorphism that is significantly associated with PD risk. In summary, our data define CPLX1 as a PD risk factor and provide functional insights into the role and regulation of blood SNCA levels. The new blood biomarkers of PARK4 in this Turkish family might become useful for PD prediction.
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Proteínas Adaptadoras de Transporte Vesicular/genética , Biomarcadores/sangue , Predisposição Genética para Doença , Doença por Corpos de Lewy/sangue , Proteínas do Tecido Nervoso/genética , Doença de Parkinson/genética , Transtorno do Comportamento do Sono REM/sangue , RNA/sangue , alfa-Sinucleína/deficiência , Feminino , Heterozigoto , Humanos , Doença por Corpos de Lewy/genética , Pessoa de Meia-Idade , Doença de Parkinson/sangue , Transtorno do Comportamento do Sono REM/fisiopatologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , alfa-Sinucleína/sangue , alfa-Sinucleína/genéticaRESUMO
Recently, we reported downregulated circulating levels of the microRNAs miR-19b, miR-29a, and miR-29c in Parkinson disease. Here we investigated the expression of these microRNAs in serum samples from 56 patients with idiopathic rapid eye movement sleep behavior disorder, before and after their conversion into a synucleinopathy. Compared to controls, we found that the expression level of miR-19b is downregulated in patients with idiopathic rapid eye movement sleep behavior disorder and antedates the diagnosis of Parkinson disease and dementia with Lewy bodies after 4.67 ± 2.61 years of follow-up. Our findings indicate that dysregulation of the microRNA miR-19b occurs in the prodromal stage of synucleinopathies.
Assuntos
Progressão da Doença , MicroRNAs/sangue , Transtorno do Comportamento do Sono REM/sangue , Transtorno do Comportamento do Sono REM/diagnóstico , Sinucleínas/sangue , Idoso , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: To investigate clinical features and potential mechanisms involving α-synuclein oligomer and inflammation in patients with Parkinson disease (PD) and probable REM sleep behavior disorder (PRBD). METHODS: We used the REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) to evaluate patients with PD and classified each as PRBD or not probable (NPRBD). Data collection included demographic information and evaluation of clinical symptoms using a series of rating scales. We tested for α-synuclein oligomer and inflammatory factors in CSF and serum. Data analyses included comparisons between PRBD and NPRBD groups and correlation analyses among RBDSQ score and levels of the above factors. RESULTS: The frequency of PRBD in patients with PD was 30.67%. The PRBD group had longer disease duration, more advanced disease stage, more severe motor symptoms, and other more severe nonmotor symptoms, including depression, anxiety, and fatigue. Levels of α-synuclein oligomer in CSF and serum in the PRBD group were elevated compared with NPRBD and control groups. RBDSQ score was increased with the elevated α-synuclein oligomer level in CSF, interleukin 1ß and nitric oxide levels in CSF, and prostaglandin E2 level in serum in the PD group. The level of α-synuclein oligomer in CSF was enhanced with the deterioration of motor symptoms, and the elevated levels of interleukin 1ß, nitric oxide, and tumor necrosis factor α in CSF in the PRBD group. CONCLUSIONS: PRBD is common in patients with PD, especially those with longer disease duration and more severe motor and nonmotor symptoms. Elevated α-synuclein levels in CSF and serum may be correlated with PRBD through inflammation in central and peripheral nervous systems.
Assuntos
Doença de Parkinson/sangue , Doença de Parkinson/líquido cefalorraquidiano , Transtorno do Comportamento do Sono REM/sangue , Transtorno do Comportamento do Sono REM/líquido cefalorraquidiano , alfa-Sinucleína/sangue , alfa-Sinucleína/líquido cefalorraquidiano , Idoso , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Inflamação/sangue , Inflamação/líquido cefalorraquidiano , Inflamação/diagnóstico , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Transtorno do Comportamento do Sono REM/diagnósticoRESUMO
BACKGROUND: Rapid eye movement (REM) sleep behavior disorder (RBD) is associated with a high risk of developing Parkinson's disease (PD). Higher urate levels are associated with a lower risk of PD. We conducted a study to evaluate plasma urate levels in patients with RBD and their role in the development of PD. METHODS: We evaluated plasma urate levels in a cohort of 24 patients with idiopathic RBD. Patients were divided into 2 groups according to the presence or absence of PD. Other known markers of the risk of developing PD, such as olfaction testing, and substantia nigra (SN) hyperechogenicity, were evaluated in the 2 groups. RESULTS: No differences were observed regarding age, years of evolution of the RBD, SN hyperechogenicity, or plasma urate levels between the 2 groups. In patients without PD, there was a positive correlation between years of evolution of RBD and the levels of uric acid (R(2) =0.88). Patients without PD and those who had more than 5 years of RBD exhibited higher levels of uric acid than patients with PD (P=0.02). CONCLUSIONS: Higher levels of plasma urate were associated with a longer duration of RBD without converting to PD. Future prospective studies would be needed to confirm this finding. Disorder Society
Assuntos
Transtorno do Comportamento do Sono REM/sangue , Ácido Úrico/sangue , Feminino , Humanos , Modelos Lineares , Masculino , Doença de Parkinson , Polissonografia , Transtorno do Comportamento do Sono REM/complicações , Estudos Retrospectivos , Estatísticas não ParamétricasRESUMO
α-synuclein is thought to play a key role in Parkinson's disease (PD) because it is the major protein in Lewy bodies, and because its gene mutations, duplication, and triplication are associated with early-onset PD. There are conflicting reports as to whether serum and plasma concentrations of α-synuclein and anti-α-synuclein antibodies differ between PD and control subjects. The objectives of this study were to compare the levels of α-synuclein and its antibodies between individuals with typical PD (n=14), atypical Parkinson syndromes (n=11), idiopathic rapid eye movement sleep behavior disorder (n=10), and healthy controls (n=9), to assess the strength of association between these serum proteins, and to determine group sizes needed for a high probability (80% power) of detecting statistical significance for 25% or 50% differences between typical PD and control subjects for these measurements. Analysis of log-transformed data found no statistically significant differences between groups for either α-synuclein or its antibodies. The concentrations of these proteins were weakly correlated (Spearman rho=0.16). In subjects with typical PD and atypical Parkinson syndromes, anti-α-synuclein antibody levels above 1.5 µg/ml were detected only in subjects with no more than four years of clinical disease. Power analysis indicated that 236 and 73 samples per group would be required for an 80% probability that 25% and 50% differences, respectively, in mean α-synuclein levels between typical PD and control subjects would be statistically significant; for anti-α-synuclein antibodies, 283 and 87 samples per group would be required. Our findings are consistent with those previous studies which suggested that serum concentrations of α-synuclein and its antibodies are not significantly altered in PD.
Assuntos
Anticorpos/sangue , Anticorpos/imunologia , Doença de Parkinson/sangue , Transtorno do Comportamento do Sono REM/sangue , alfa-Sinucleína/sangue , alfa-Sinucleína/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Ghrelin, an orexigenic peptide, has multiple functions, which include promoting gastrointestinal motility and influencing higher brain functions. Experimental data suggest that ghrelin has neuroprotective potential in the MPTP mouse model of Parkinson's disease (PD). PD patients show delayed gastric emptying and other symptoms that may relate to disturbed excretion of ghrelin. No data are available on postprandial ghrelin response in patients with PD and idiopathic REM sleep behaviour disorder (iRBD)--a condition considered a putative preclinical stage of PD. We measured fasting and postprandial ghrelin serum concentrations in 20 healthy controls, 39 (including 19 drug-naïve) PD patients and 11 iRBD patients using a commercial radioimmunoassay for total ghrelin. For statistical analysis we employed ANCOVA and post-hoc testing with Bonferroni's method. Controls showed a decrease of mean fasting ghrelin serum concentrations in the early postprandial phase, followed by a recuperation starting 60 min after the test meal and reaching a maximum at 300 min. This recuperation was less pronounced in PD and iRBD; the slope of relative postprandial ghrelin recovery was different between the investigated groups (p = 0.007). Post-hoc testing showed a difference between controls and PD patients (p = 0.002) and between controls and iRBD patients (p = 0.037). The dynamic regulation of ghrelin in response to food intake is partially impaired in subjects at putative preclinical (iRBD) and clinical stages of PD. Reduced ghrelin excretion might increase the vulnerability of nigrostriatal dopaminergic neurons as suggested by animal studies. The impaired ghrelin excretion might qualify as a peripheral biomarker and be of diagnostic or therapeutic value.
Assuntos
Grelina/sangue , Doença de Parkinson/sangue , Período Pós-Prandial/fisiologia , Transtorno do Comportamento do Sono REM/sangue , Idoso , Análise de Variância , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Área Sob a Curva , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Jejum , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , Período Pós-Prandial/efeitos dos fármacos , Índice de Gravidade de Doença , Fatores de TempoRESUMO
STUDY OBJECTIVES: More than 85% of the patients presenting to sleep centers with idiopathic REM sleep behavior disorder (RBD) are men. It has been hypothesized that sex hormone abnormalities may be related to this male predominance. The aim of our study was to determine the serum sex hormone levels in consecutive idiopathic RBD male patients who presented to our sleep center. SETTING: University hospital sleep disorders center. PARTICIPANTS: Fourteen male idiopathic RBD patients and 16 healthy matched controls. INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: Serum levels of total testosterone, calculated free testosterone, calculated bioavailable testosterone, luteinizing hormone, follicle stimulating hormone, estradiol-17 beta, sex-hormone binding globulin, and prolactin were not different between idiopathic RBD patients and controls. CONCLUSION: Serum sex hormone levels are normal in idiopathic RBD, indicating that androgenic abnormalities may not account for its male predominance and pathophysiology.