RESUMEN
BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) has been linked to an increased risk of early-onset Parkinson's disease. However, the pathophysiological mechanisms underlying parkinsonism remain poorly understood. OBJECTIVE: The objective is to investigate salivary total α-synuclein levels in 22q11.2DS patients with and without parkinsonian motor signs. METHODS: This cross-sectional study included 10 patients with 22q11.2DS with parkinsonism (Park+), ten 22q11.2DS patients without parkinsonism (Park-), and 10 age and sex-comparable healthy subjects (HS). Salivary and serum α-synuclein levels were measured using enzyme-linked immunosorbent assay. RESULTS: Salivary total α-synuclein concentration was significantly lower in Park (+) patients than in Park (-) patients and HS (P = 0.007). In addition, salivary α-synuclein showed good accuracy in discriminating Park (+) from Park (-) patients (area under the curve = 0.86) and correlated with motor severity and cognitive impairment. CONCLUSION: This exploratory study suggests that the parkinsonian phenotype of 22q11.2DS is associated with a reduced concentration of monomeric α-synuclein in biological fluids.
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Biomarcadores , Síndrome de DiGeorge , Trastornos Parkinsonianos , Saliva , alfa-Sinucleína , Humanos , Masculino , Femenino , Estudios Transversales , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Saliva/química , Saliva/metabolismo , Biomarcadores/sangre , Biomarcadores/metabolismo , Biomarcadores/análisis , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/sangre , Adulto , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/metabolismo , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/sangre , Adulto Joven , Persona de Mediana Edad , AdolescenteRESUMEN
There is increasing evidence for a role of inflammation in Parkinson's disease. Recent research in murine models suggests that parkin and PINK1 deficiency leads to impaired mitophagy, which causes the release of mitochondrial DNA (mtDNA), thereby triggering inflammation. Specifically, the CGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway mitigates activation of the innate immune system, quantifiable as increased interleukin-6 (IL6) levels. However, the role of IL6 and circulating cell-free mtDNA in unaffected and affected individuals harbouring mutations in PRKN/PINK1 and idiopathic Parkinson's disease patients remain elusive. We investigated IL6, C-reactive protein, and circulating cell-free mtDNA in serum of 245 participants in two cohorts from tertiary movement disorder centres. We performed a hypothesis-driven rank-based statistical approach adjusting for multiple testing. We detected (i) elevated IL6 levels in patients with biallelic PRKN/PINK1 mutations compared to healthy control subjects in a German cohort, supporting the concept of a role for inflammation in PRKN/PINK1-linked Parkinson's disease. In addition, the comparison of patients with biallelic and heterozygous mutations in PRKN/PINK1 suggests a gene dosage effect. The differences in IL6 levels were validated in a second independent Italian cohort; (ii) a correlation between IL6 levels and disease duration in carriers of PRKN/PINK1 mutations, while no such association was observed for idiopathic Parkinson's disease patients. These results highlight the potential of IL6 as progression marker in Parkinson's disease due to PRKN/PINK1 mutations; (iii) increased circulating cell-free mtDNA serum levels in both patients with biallelic or with heterozygous PRKN/PINK1 mutations compared to idiopathic Parkinson's disease, which is in line with previous findings in murine models. By contrast, circulating cell-free mtDNA concentrations in unaffected heterozygous carriers of PRKN/PINK1 mutations were comparable to control levels; and (iv) that circulating cell-free mtDNA levels have good predictive potential to discriminate between idiopathic Parkinson's disease and Parkinson's disease linked to heterozygous PRKN/PINK1 mutations, providing functional evidence for a role of heterozygous mutations in PRKN or PINK1 as Parkinson's disease risk factor. Taken together, our study further implicates inflammation due to impaired mitophagy and subsequent mtDNA release in the pathogenesis of PRKN/PINK1-linked Parkinson's disease. In individuals carrying mutations in PRKN/PINK1, IL6 and circulating cell-free mtDNA levels may serve as markers of Parkinson's disease state and progression, respectively. Finally, our study suggests that targeting the immune system with anti-inflammatory medication holds the potential to influence the disease course of Parkinson's disease, at least in this subset of patients.
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ADN Mitocondrial/sangre , Interleucina-6/sangre , Trastornos Parkinsonianos/sangre , Trastornos Parkinsonianos/genética , Proteínas Quinasas/genética , Ubiquitina-Proteína Ligasas/genética , Adulto , Anciano , Biomarcadores/sangre , Estudios Transversales , Femenino , Humanos , Inflamación/sangre , Inflamación/genética , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
OBJECTIVE: To develop a diagnostic model based on plasma-derived extracellular vesicle (EV) subpopulations in Parkinson disease (PD) and atypical parkinsonism (AP), we applied an innovative flow cytometric multiplex bead-based platform. METHODS: Plasma-derived EVs were isolated from PD, matched healthy controls, multiple system atrophy (MSA), and AP with tauopathies (AP-Tau). The expression levels of 37 EV surface markers were measured by flow cytometry and correlated with clinical scales. A diagnostic model based on EV surface markers expression was built via supervised machine learning algorithms and validated in an external cohort. RESULTS: Distinctive pools of EV surface markers related to inflammatory and immune cells stratified patients according to the clinical diagnosis. PD and MSA displayed a greater pool of overexpressed immune markers, suggesting a different immune dysregulation in PD and MSA vs AP-Tau. The receiver operating characteristic curve analysis of a compound EV marker showed optimal diagnostic performance for PD (area under the curve [AUC] 0.908; sensitivity 96.3%, specificity 78.9%) and MSA (AUC 0.974; sensitivity 100%, specificity 94.7%) and good accuracy for AP-Tau (AUC 0.718; sensitivity 77.8%, specificity 89.5%). A diagnostic model based on EV marker expression correctly classified 88.9% of patients with reliable diagnostic performance after internal and external validations. CONCLUSIONS: Immune profiling of plasmatic EVs represents a crucial step toward the identification of biomarkers of disease for PD and AP.
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Vesículas Extracelulares/inmunología , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/inmunología , Tauopatías/diagnóstico , Tauopatías/inmunología , Anciano , Anciano de 80 o más Años , Antígenos de Superficie , Biomarcadores/sangre , Estudios de Casos y Controles , Estudios Transversales , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/sangre , Atrofia de Múltiples Sistemas/clasificación , Atrofia de Múltiples Sistemas/diagnóstico , Atrofia de Múltiples Sistemas/inmunología , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/clasificación , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/inmunología , Trastornos Parkinsonianos/sangre , Trastornos Parkinsonianos/clasificación , Mapas de Interacción de Proteínas , Sensibilidad y Especificidad , Aprendizaje Automático Supervisado , Tauopatías/sangre , Tauopatías/clasificaciónRESUMEN
INTRODUCTION: To determine an exploratory multimodal approach including serum NFL and MR planimetric measures to discriminate Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). METHODS: MR planimetric measurements and NFL serum levels, with a mean time interval of 60 months relative to symptom onset, were assessed in a retrospective cohort of 11 progressive supranuclear palsy (PSP), 22 Parkinson's disease (PD), 16 multiple system atrophy (MSA) patients and 42 healthy controls (HC). A decision tree model to discriminate PD, PSP, and MSA was constructed using receiver operating characteristic curve analysis and Classification and Regression Trees algorithm. RESULTS: Our multimodal decision tree provided accurate differentiation of PD versus MSA and PSP patients using a serum NFL cut-off of 14.66 ng/L. The pontine-to-midbrain-diameter-ratio (Pd/Md) discriminated MSA from PSP at a cut-off value of 2.06. The combined overall diagnostic yield was an accuracy of 83.7% (95% CI 69.8-90.8%). CONCLUSION: We provide a clinically feasible decision algorithm which combines serum NFL levels and a planimetric MRI marker to differentiate PD, MSA and PSP with high diagnostic accuracy. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that the combination of serum NFL levels und MR planimetric measurements discriminates between PD, PSP and MSA.
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Algoritmos , Biomarcadores/análisis , Atrofia de Múltiples Sistemas/diagnóstico , Trastornos Parkinsonianos/diagnóstico , Anciano , Biomarcadores/sangre , Diagnóstico Diferencial , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/sangre , Trastornos Parkinsonianos/sangre , Curva ROCRESUMEN
OBJECTIVE: Parkinson's disease is characterised neuropathologically by α-synuclein aggregation. Currently, there is no blood test to predict the underlying pathology or distinguish Parkinson's from atypical parkinsonian syndromes. We assessed the clinical utility of serum neuronal exosomes as biomarkers across the spectrum of Parkinson's disease, multiple system atrophy and other proteinopathies. METHODS: We performed a cross-sectional study of 664 serum samples from the Oxford, Kiel and Brescia cohorts consisting of individuals with rapid eye movement sleep behavioural disorder, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome and controls. Longitudinal samples were analysed from Parkinson's and control individuals. We developed poly(carboxybetaine-methacrylate) coated beads to isolate L1 cell adhesion molecule (L1CAM)-positive extracellular vesicles with characteristics of exosomes and used mass spectrometry or multiplexed electrochemiluminescence to measure exosomal proteins. RESULTS: Mean neuron-derived exosomal α-synuclein was increased by twofold in prodromal and clinical Parkinson's disease when compared with multiple system atrophy, controls or other neurodegenerative diseases. With 314 subjects in the training group and 105 in the validation group, exosomal α-synuclein exhibited a consistent performance (AUC=0.86) in separating clinical Parkinson's disease from controls across populations. Exosomal clusterin was elevated in subjects with non-α-synuclein proteinopathies. Combined neuron-derived exosomal α-synuclein and clusterin measurement predicted Parkinson's disease from other proteinopathies with AUC=0.98 and from multiple system atrophy with AUC=0.94. Longitudinal sample analysis showed that exosomal α-synuclein remains stably elevated with Parkinson's disease progression. CONCLUSIONS: Increased α-synuclein egress in serum neuronal exosomes precedes the diagnosis of Parkinson's disease, persists with disease progression and in combination with clusterin predicts and differentiates Parkinson's disease from atypical parkinsonism.
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Exosomas/metabolismo , Atrofia de Múltiples Sistemas/diagnóstico , Neuronas/metabolismo , Enfermedad de Parkinson/diagnóstico , Trastornos Parkinsonianos/diagnóstico , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios Transversales , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/sangre , Enfermedad de Parkinson/sangre , Trastornos Parkinsonianos/sangreRESUMEN
Objective: Parkin is the causative gene for autosomal recessive familial Parkinson's disease (PD), although it remains unclear how parkin dysfunction is involved with the general condition. Recently, serum and/or plasma metabolomics revealed alterations in metabolic pathways that might reflect pathomechanisms of idiopathic PD (iPD). Thus, we hypothesized that serum metabolomics of patients with homozygous or compound heterozygous parkin mutations (namely, PARK2) might reflect metabolic alterations due to parkin dysfunction. Methods: We enrolled 15 PARK2 patients (52 ± 17.6 years) confirmed with homozygous (seven cases) and compound heterozygous (eight cases) parkin mutations, along with 19 healthy age-matched controls (51 ± 11.5 years). We analyzed 830 metabolites from participants' serum using well-established metabolomics technologies, including ultra-high performance liquid chromatography/tandem mass spectroscopy. Results: Based on metabolic profiles, hierarchical matrix analysis can divide samples between control and PARK2 subjects. Profiles from PARK2 patients showed significantly higher levels of fatty acid (FA) metabolites and oxidized lipids, and significantly lower levels of antioxidant, caffeine, and benzoate-related metabolites. Interpretation: Metabolomics can identify specific metabolic alterations in PARK2 patients compared with controls. Alterations in FA metabolites suggest a relationship between parkin function and lipid metabolism. The elevation of oxidized lipids in combination with decreasing antioxidants may reflect general hyperoxidative stress. Decreasing benzoate-related metabolites might be due to the alteration in gut microbiota. Consequently, caffeine and its metabolites may be decreased due to malabsorption. These findings are similar to metabolic alterations in iPD. Thus, serum/plasma metabolomics may reflect the association between parkin dysfunction and parkinsonism.
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Biomarcadores/sangre , Metaboloma/genética , Trastornos Parkinsonianos/sangre , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/metabolismo , Adulto , Femenino , Voluntarios Sanos , Humanos , Metabolismo de los Lípidos , Masculino , Redes y Vías Metabólicas , Metabolómica , Persona de Mediana Edad , Suero , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
OBJECTIVE: To investigate the diagnostic value of serum neurofilament light chain (NFL) in patients with clear signs of parkinsonism but whose specific diagnosis was yet uncertain. METHODS: Serum samples were collected from patients with clear signs of parkinsonism but with uncertain diagnosis at the inclusion. Clinical diagnoses of Parkinson disease (PD) and atypical parkinsonism disorders (APDs) were established after 3 years of follow-up and updated again after a maximum of 12 years in case longer follow-up data were available. Serum NFL was quantified by single molecule array in patients with PD (n = 55) and APD (n = 29, multiple system atrophy = 22, progressive supranuclear palsy = 7) and 53 nonneurologic controls. RESULTS: Serum NFL levels were elevated and differentiated the APD group (mean 23.8 ± 10.3 ng/L) from PD (mean 10.4 ± 4.9 ng/L) and controls (mean 11.5 ± 6.5 ng/L, p < 0.0001) with accuracy levels up to 91% (sensitivity = 86% and specificity = 85%). Serum NFL strongly correlated with CSF NFL levels (r = 0.72, p < 0.0001) in all groups and with age in PD (r = 0.78, p < 0.0001) and controls (r = 0.66, p < 0.0001). In our cohort, the probability of having APD was 76% (positive predictive value) and of having PD 92% (negative predictive value). CONCLUSION: Serum NFL levels are markedly elevated in APD compared to PD and discriminate APDs from PD with high accuracy. Serum NFL may be a useful clinical biomarker to identify APD, even at stages when clinical symptoms are not yet conclusive. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that serum NFL levels accurately discriminate APDs from PD.
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Atrofia de Múltiples Sistemas/diagnóstico , Proteínas de Neurofilamentos/sangre , Enfermedad de Parkinson/diagnóstico , Parálisis Supranuclear Progresiva/diagnóstico , Anciano , Estudios de Casos y Controles , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/sangre , Enfermedad de Parkinson/sangre , Trastornos Parkinsonianos/sangre , Trastornos Parkinsonianos/diagnóstico , Sensibilidad y Especificidad , Parálisis Supranuclear Progresiva/sangreRESUMEN
PURPOSE: The natural clinical course of cerebral small vessel disease (CSVD) was not thoroughly described. The aim of this single center cohort study was to establish biochemical predictors of vascular events and death in CSVD patients during a 24-month follow-up. PATIENTS AND METHODS: A total of 130 functionally independent patients with marked MRI features of CSVD and recent lacunar stroke (n = 52,LS), vascular Parkinsonism (n = 28,VaP) or dementia (n = 50,VaD) were prospectively recruited. Serum markers of endothelial dysfunction, inflammation and hemostasis were determined at baseline. The primary outcome was defined as occurrence of death or any vascular events during the observation. RESULTS: The mean age was 72 ± 8.1 years, and 37.6% of the patients were women. The mean follow-up time was 22.3 ± 4.3 months, and 84.6% of patients had extensive white matter lesions on baseline MRI. The overall mortality rate was 6.9%, and vascular events or death occurred in 27% of the patients. Kaplan-Meier survival curves revealed no significant differences between CSVD groups (log rank p = 0.49). Cox regression analysis revealed that IL-1α (HR 1.4; 95%CI 1.09-1.8), IL-6 (1.4;1.1-2.2), hs-CRP (1.1;1.06-1.9), homocysteine (1.4;1.1-1.8), fibrinogen (1.4;1.05-2), and d-dimer (2.7;1.6-4.5) were significantly associated with the primary outcome. IL-1α (1.3;1.07-1.8), IL-6 (1.4;1.02-2.2), d-dimer (2.8;1.6-5) and homocysteine (1.4;1.1-1.8) remained significant after adjusting for age, sex and CSVD radiological markers. CONCLUSIONS: Our study demonstrated the important prognostic role of various circulation markers of inflammation in individuals with different clinical signs and radiological markers of CSVD. The strongest association occurred between IL-1α, IL-6 and recurrent stroke, other vascular events and death.
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Enfermedades de los Pequeños Vasos Cerebrales/sangre , Enfermedades de los Pequeños Vasos Cerebrales/patología , Interleucina-1alfa/sangre , Interleucina-6/sangre , Anciano , Anciano de 80 o más Años , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/mortalidad , Estudios de Cohortes , Demencia Vascular/sangre , Demencia Vascular/diagnóstico por imagen , Demencia Vascular/mortalidad , Demencia Vascular/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Trastornos Parkinsonianos/sangre , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/mortalidad , Trastornos Parkinsonianos/patología , Accidente Vascular Cerebral Lacunar/sangre , Accidente Vascular Cerebral Lacunar/diagnóstico por imagen , Accidente Vascular Cerebral Lacunar/mortalidad , Accidente Vascular Cerebral Lacunar/patologíaRESUMEN
INTRODUCTION: Recent studies have indicated that lysosomal dysfunction contributes to the development of idiopathic Parkinson's disease (PD). It is uncertain whether dysregulation of serum lysosomal acid hydrolase activity exists in sporadic PD patients compared with normal controls (NCs) and parkinsonian syndrome (PS) patients. METHODS: Sporadic PD patients without GBA1 mutations (nâ¯=â¯68) were matched with normal controls (nâ¯=â¯45), and parkinsonian syndrome patients (nâ¯=â¯32) in terms of family history, age, and sex. We measured the activities of lysosomal enzymes, α-galactosidase, ß-galactosidase, and ß-hexosaminidase and examined the possible correlations between lysosomal acid hydrolase activities with age in NCs, PD, and PS patients. RESULTS: ß-Galactosidase activity was significantly higher in the PD and PS than in the NC group (Pâ¯<â¯0.001). The ß-galactosidase to α-galactosidase and ß-hexosaminidase to ß-galactosidase activity ratios were more useful for distinguishing PD and PS patients from NCs (Pâ¯<â¯0.0001). Furthermore, α-galactosidase activity was significantly higher in PS patients than both PD and NC groups (pâ¯=â¯0.04). ß-Galactosidase and α-galactosidase activities exhibited a statistically significant negative correlation with age in NCs, and ß-hexosaminidase activity showed a positive correlation with age in PS. However, PD patients did not show any of these correlations. CONCLUSION: Our results suggest the presence of an unknown regulatory mechanism(s) of serum acid hydrolase activities with aging in the normal population and abnormalities in their regulation in PD and PS patients. However, the pattern of dysregulation in these two groups is different. Thus, serum lysosomal acid hydrolase activity can be used as a peripheral biomarker for PD.
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Trastornos Parkinsonianos/sangre , alfa-Galactosidasa/sangre , beta-Galactosidasa/sangre , beta-N-Acetilhexosaminidasas/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/sangreRESUMEN
BACKGROUND: MicroRNAs are small noncoding RNAs involved in the post-transcriptional regulation of protein synthesis. Extracellular microRNAs are accessible in a stable form in biofluids. OBJECTIVES: The aim was to identify individual microRNAs and/or subsets of microRNAs in CSF with biomarker potential and thus identify specific putative pathophysiological pathways. METHODS: In a two-step exploratory study design of PD, MSA, PSP, and controls, we initially profiled CSF microRNAs in a pilot cohort (n = 40) by screening for 372 microRNAs. Subsequently, we attempted to validate findings in an independent study cohort in CSF (n = 118) and ethylenediaminetetraacetic acid plasma (n = 114). This study cohort encompassed 46 microRNAs, of which 26 were singled out from the pilot cohort, and an additional 20 microRNAs were added based on previous publications. The most accurate diagnostic microRNA classifiers were identified in a multivariable logistic regression model adjusted for age and sex. RESULTS: A set of three microRNAs in CSF discriminated PD and MSA from controls with good diagnostic accuracy by receiver operating characteristics curve evaluation. The microRNAs were for PD versus controls: miR-7-5p, miR-331-5p, and miR-145-5p (area under the curve = 0.88) and MSA versus controls: miR-7-5p, miR-34c-3p, and miR-let-7b-5p (area under the curve = 0.87). The classifier that best distinguished MSA and PD consisted of two microRNAs: miR-9-3p and miR-106b-5p (area under the curve = 0.73). A single microRNA, miR-106b-5p, provided the best discrimination between PD and PSP (area under the curve = 0.85) in the CSF. CONCLUSIONS: Levels of specific trios of CSF-microRNAs discriminate well between α-synucleinopathies (PD and MSA) and controls. The results need to be validated in larger, independent cohorts. © 2018 International Parkinson and Movement Disorder Society.
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MicroARN Circulante/líquido cefalorraquídeo , Enfermedad de Parkinson/líquido cefalorraquídeo , Enfermedad de Parkinson/genética , Trastornos Parkinsonianos/líquido cefalorraquídeo , Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Estudios de Cohortes , Femenino , Regulación de la Expresión Génica/genética , Humanos , Masculino , Trastornos Parkinsonianos/sangreRESUMEN
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, whose hallmark is the loss of dopamine terminals in the substantia nigra pars compacta (SNpc). PD is usually diagnosed after the appearance of motor symptoms, when about 70% of neurons in the SNpc have already been lost. Because of that, it is important to search for new methods that aid in the early diagnosis of PD. In recent years, microRNAs (miRs) have emerged as potential biomarkers for a variety of diseases and hold the potential to be used to aid in the diagnosis of PD. Therefore, the aim of this study was to characterize if specific miRs are differentially expressed in serum in a mouse model of PD. To induce PD-like damage, mice were subcutaneously injected with 25 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) by administering 10 doses over a period of 5 weeks, with 3.5 days between doses. Expression of 71 different microRNAs was quantified in serum separated from blood collected at day 35, using next-generation sequencing. Histological analysis and quantification of neurotransmitters were performed to confirm dopaminergic neurodegeneration. Chronic MPTP treatment induced loss of dopaminergic terminals in the SNpc and caudate putamen, confirmed by a decrease in the number of tyrosine hydroxylase and dopamine transporter positive cells. In addition, MPTP decreased the concentration of dopamine and its metabolites in the SNpc, simulating the damage observed in PD. From the 71 miRs analyzed, only 4 were differentially expressed after MPTP treatment. Serum levels of miR19b, miR124, miR126a and miR133b were significantly decreased in MPTP-treated mice compared to control. These data suggest that specific miRs are downregulated in a pre-clinical model of PD and hold the potential to be used as biomarkers to aid in the diagnosis of this disease. Further experiments need to be conducted to validate the use of these miRs as biomarkers of PD in additional pre-clinical models as well as in samples from patients diagnosed with PD.
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Encéfalo/metabolismo , MicroARNs/sangre , Trastornos Parkinsonianos/sangre , Animales , Biomarcadores/sangre , Encéfalo/patología , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/patologíaRESUMEN
L-DOPA-induced dyskinesia (LID) remains a significant problem in the management of Parkinson's disease (PD). In rodent and macaque models of PD, delta opioid receptor agonists have anti-parkinsonian actions while mu opioid antagonists can reduce the expression of LID. DPI-289 is a novel molecule with a unique combination of opioid receptor DAMA actions: delta agonist (Ki: 0.73 nM); mu antagonist (Ki: 12 nM). We demonstrated that DPI-289 has oral bioavailability and established its pharmacokinetic profile in both rat and primate. We hypothesised that these combined DAMA actions would provide an enhancement of L-DOPA effect without an associated increase in dyskinesia. In parkinsonian 6-OHDA lesioned rats and MPTP-lesioned macaques, DPI-289 provided anti-parkinsonian actions as monotherapy and an enhancement of L-DOPA benefit. Thus, acute administration of DPI-289 (3 mg/kg, p.o.) to 6-OHDA-lesioned rats produced a significant reduction in forelimb asymmetry (by 48%) that was maintained throughout the fifteen-day repeat-treatment period. Importantly, and in contrast to L-DOPA administration (6 mg/kg, i.p.), these benefits were not compromised by the development of abnormal involuntary movements. In the macaque, as monotherapy, DPI-289 (10 and 20 mg/kg) had significant, though incomplete, anti-parkinsonian actions lasting approximately 4 h. These benefits were not associated with dyskinesia. In fact, over the 6 h period of observation, DPI-289 (20 mg/kg) decreased parkinsonism by 19% and increased activity by 67% compared to vehicle treatment. By contrast, while high-dose L-DOPA (LDh) alone alleviated parkinsonism (for 3 h) this benefit was accompanied by significant dyskinesia that was disabling in nature. LDh provided a 50% reduction in parkinsonism over 6 h and 151% increase in activity. The combination of DPI-289 (20 mg/kg) and a low-dose of L-DOPA (LDl) provided anti-parkinsonian benefits greater than LDl alone without eliciting any significant dyskinesia. Treatment with LDl alone provided only transient statistically significant anti-parkinsonian benefit. However, the combination of LDl and DPI-289 reduced parkinsonism for 6 h (duration of monitoring), with parkinsonism being reduced by 35% and activity increased by 90% but with no increase in dyskinesia over that observed with LDl alone. Thus, DPI-289 has potential to improve the benefits of dopaminergic therapy in Parkinson's disease.
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Benzamidas/uso terapéutico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/efectos adversos , Antagonistas de Narcóticos/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Piperazinas/uso terapéutico , Receptores Opioides delta/agonistas , Receptores Opioides mu/antagonistas & inhibidores , Adrenérgicos/toxicidad , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/uso terapéutico , Animales , Benzamidas/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Discinesia Inducida por Medicamentos/etiología , Femenino , Cobayas , Macaca , Masculino , Ratones , Ratones Endogámicos C57BL , Movimiento/efectos de los fármacos , Antagonistas de Narcóticos/farmacocinética , Oxidopamina/toxicidad , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Trastornos Parkinsonianos/sangre , Trastornos Parkinsonianos/tratamiento farmacológico , Piperazinas/farmacología , Ratas Sprague-Dawley , Conducto Deferente/efectos de los fármacos , Conducto Deferente/metabolismoRESUMEN
Oxidative stress has been implicated in a range of neurodegenerative diseases, in particular, Parkinson's disease (PD). However, the pathogenic mechanism of its influence on PD progression remains unclear. In order to clarify this, PD models are generated by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intramuscular injection in eight rhesus monkeys. During the of progress PD pathogenesis, the activities of some major antioxidant enzymes, such as serum superoxide dismutase (SOD), glutathione peroxidase (GPX), and glutathione-s-transferase (GST), were measured, which show continuously decrease. While, the GSH and MDA content, as well as the expression of gamma-glutamylcysteine synthetase (GCS) and glutathione-s-transferase pi (GST-pi) exhibit robust increase. Taken together, this study shows the dynamic changes of antioxidant enzymes and lipid peroxidation in blood of PD monkeys during its progress, which will be important for the diagnosis and treatment of PD.
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Estrés Oxidativo , Trastornos Parkinsonianos/sangre , Trastornos Parkinsonianos/enzimología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/administración & dosificación , Animales , Glutatión Peroxidasa/sangre , Glutatión Transferasa/sangre , Inyecciones Intramusculares , Peroxidación de Lípido , Macaca mulatta , Actividad Motora/efectos de los fármacos , Trastornos Parkinsonianos/patología , Porción Compacta de la Sustancia Negra/efectos de los fármacos , Porción Compacta de la Sustancia Negra/patología , ARN Mensajero/sangre , Superóxido Dismutasa/sangreRESUMEN
We studied some structural and functional parameters of erythrocyte membranes in mice at the late presymptomatic and early symptomatic stages of experimental Parkinson's disease induced by administration of MPTP (hemolysis, microviscosity of different regions of the lipid bilayer, LPO intensity, activity of antioxidant enzymes, and kinetic properties of acetylcholinesterase). At the presymptomatic stage, significant deviations of the studied parameters from the normal were observed; they were similar in direction and magnitude to those in humans with Parkinson's disease. At the early symptomatic stage, most parameters tended to normal. Microviscosity of bulk lipids increased at the presymptomatic stage and decreased after appearance of clinical symptoms. This dynamics probably reflects activation of compensatory mechanisms aimed at inhibition of oxidative stress triggered by the development of the pathological process.
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Membrana Eritrocítica/metabolismo , Trastornos Parkinsonianos/sangre , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Acetilcolinesterasa/sangre , Animales , Membrana Eritrocítica/patología , Cinética , Peroxidación de Lípido , Masculino , Malondialdehído/sangre , Ratones Endogámicos C57BL , Estrés Oxidativo , Trastornos Parkinsonianos/inducido químicamente , Superóxido Dismutasa/sangreRESUMEN
There is emerging evidence that glial cells are involved in the neuropathological process in Parkinson's disease (PD) in addition to degeneration of neuronal structures. Recently, we confirmed the presence of an adaptive immune response against different glial-derived antigens in PD, with a possible role of anti-MAG, anti-MBP and anti-PLP antibodies in the disease progression. The aim of the present study was to assess humoral response against myelin-associated glycoprotein (MAG) in patients with parkinsonism (both idiopathic and atypical) to check whether these antibodies could serve as biomarkers of PD, its severity and progression. Anti-MAG autoantibodies were measured by an ELISA system in 99 PD patients, 33 atypical parkinsonism patients, and 36 control subjects. In PD patients, anti-MAG IgM autoantibodies were significantly higher in comparison to healthy control subjects (p = 0.038). IgM anti-MAG autoantibodies titers were also significantly higher in the whole group of patients with parkinsonism (either idiopathic or atypical) in comparison to healthy control subjects (1.88 ± 0.84 vs 1.70 ± 1.19, p = 0.017). This difference was mainly driven by the PD group, as the atypical parkinsonism group did not differ significantly from the control group in anti-MAG antibody levels (p = 0.51). A negative correlation between anti-MAG levels and disease duration was found in PD patients. Our study provides evidence for an increased production of autoantibodies against a protein of glial origin in PD. The negative correlation between anti-MAG antibodies and disease duration may suggest possible involvement of the immune system in disease progression. Increasing evidence that glia are involved in the neurodegenerative process to a greater extent than previously thought may turn out be useful in the search for biomarkers of the neurodegenerative process in PD.
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Autoanticuerpos/sangre , Glicoproteína Asociada a Mielina/inmunología , Trastornos Parkinsonianos/sangre , Trastornos Parkinsonianos/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Biomarcadores/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , Curva ROCAsunto(s)
Afasia Progresiva Primaria/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Mutación/genética , Trastornos Parkinsonianos/genética , Anciano , Afasia Progresiva Primaria/sangre , Afasia Progresiva Primaria/complicaciones , Afasia Progresiva Primaria/diagnóstico por imagen , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/sangre , Imagen por Resonancia Magnética , Trastornos Parkinsonianos/sangre , Trastornos Parkinsonianos/complicaciones , Trastornos Parkinsonianos/diagnóstico por imagen , ProgranulinasRESUMEN
Encephalopathy associated with autoantibodies to IgLON5 is a novel syndrome characterized by a distinct sleep disorder and brain-stem involvement. Since the initial description of this encephalopathy in 2014, only a few additional patients have been reported (Simabukuro et al., 2015). In this paper, we report a new case of anti-IgLON5 antibodies with major symptoms of chorea and parkinsonism, and responsive to immunotherapy.
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Autoanticuerpos/sangre , Moléculas de Adhesión Celular Neuronal/sangre , Corea/sangre , Inmunoglobulinas Intravenosas/administración & dosificación , Inmunoterapia/métodos , Trastornos Parkinsonianos/sangre , Corea/diagnóstico , Corea/tratamiento farmacológico , Femenino , Humanos , Persona de Mediana Edad , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/tratamiento farmacológicoRESUMEN
BACKGROUND: Mild parkinsonian signs (MPS) are common in older people and are associated with an increased risk of different neurodegenerative diseases. This study prospectively evaluates the longitudinal course of cognitive performance in older individuals with MPS. METHODS: From the TREND study, 480 individuals neurologically healthy at baseline, aged between 50 and 80 years, with complete follow-up data for three assessments within a mean of 43.8 months, were included in this analysis. Participants underwent a detailed cognitive test battery, evaluation of prodromal markers for neurodegenerative diseases and history of vascular diseases at each study visit. In addition, plasma levels of amyloid-beta (Aß)1-40 and Aß1-42 were evaluated longitudinally. RESULTS: In 52 (11 %) of the 480 participants, MPS could be detected at baseline. These individuals had cognitive deficits significantly more often compared with controls at each time point and their cognitive performance showed a steeper decline during follow-up. In addition, their levels of plasma Aß1-42 were significantly lower than those of controls, and declined more rapidly over time. CONCLUSIONS: This longitudinal study shows that MPS are associated with cognitive decline and decrease in plasma Aß1-42, possibly indicating an ongoing neurodegenerative process.
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Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/etiología , Trastornos Parkinsonianos/complicaciones , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/sangre , Apolipoproteínas E/genética , Grosor Intima-Media Carotídeo , Depresión/etiología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Examen Neurológico , Trastornos de la Motilidad Ocular/etiología , Trastornos del Olfato/diagnóstico , Trastornos del Olfato/etiología , Trastornos Parkinsonianos/sangre , Trastornos Parkinsonianos/genética , Sueño REM/fisiologíaRESUMEN
INTRODUCTION: Neurodegeneration is known basis of several different Parkinson syndromes. The most common Parkinson syndrome is the Parkinson's disease. Distinction between different Parkinson syndromes is based on pathology or genetic findings. Recent studies indicate that several major variants of PS have some characteristics of a prion disease and may therefore be transmissible. Married couples offer a unique opportunity to study person-to-person transmission and the role of shared environments as the cause of parkinsonism. METHODS: Autopsy is offered to patients seen at the Movement Disorders Clinic Saskatchewan at no cost. Five couples seen in our clinic, where each spouse had a clinical diagnosis of parkinsonism, came to autopsy. RESULTS: Median duration of marriage was 42 years before the Parkinson syndrome first manifested in a spouse. Three couples were pathologically or genetically discordant for Parkinson variant. Each spouse in the other two couples had Parkinson's disease. One couple had onset separated by 20 years and one partner had a strong family history of Parkinson's disease. CONCLUSION: Our data indicate that neither of the Parkinson's disease, Progressive Supranuclear Palsy and Multiple System Atrophy are transmitted by sexual or other intimate contact. The data also indicate against shared environments as the cause of these disorders.
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Matrimonio , Trastornos Parkinsonianos , Esposos/psicología , Anciano , Anciano de 80 o más Años , Autopsia , Ambiente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Parkinsonianos/sangre , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/patologíaRESUMEN
OBJECTIVES: Potassium channels participate in cellular and molecular signalling pathways regulating the life and death of neurons. In this study, effect of pretreatment with potassium channel blockers of 4-aminopyridine (4-AP) and tetraethylammonium (TEA) on the behavioural symptoms of 6-hydroxydopamine (6-OHDA)-induced Parkinsonism was evaluated. METHODS: 6-OHDA was injected into right striatum of adult male Wistar rats using stereotaxic surgery. Severity of 6-OHDA-induced Parkinsonism was assessed by conventional behavioural tests. 4-AP and TEA were injected twice per day intraperitoneally, before 6-OHDA injection to 15 days after that. Also, malondialdehyde (MDA) concentration as a marker of oxidative stress was measured in rat sera. RESULTS: Pretreatment with 4-AP (0.5 and 1 mg/kg) and TEA (2 and 5 mg/kg) attenuated significantly behavioural symptoms of 6-OHDA-induced Parkinsonism. Application of both 4-AP and TEA together was more effective than the effect of each one of these blockers alone. 6-OHDA increased MDA concentration but pretreatment with 4-AP prevented of 6-OHDA-induced increase in MDA. On the other hand, pretreatment with TEA and combination of TEA and 4-AP could not prevent of 6-OHDA-induced oxidative stress. DISCUSSION: Since severity of behavioural symptoms of 6-OHDA-induced Parkinsonism is correlated to the degree of nigral dopaminergic cell death, we suggest that antiparkinsonism effect of TEA and 4-AP was mediated by their neuroprotective effect. Because, both Parkinsonism in rat and PD in human, the main pathophysiological hallmark, is neurodegeneration of dopaminergic neurons in substantia nigra, we suggest doing clinical trials for evaluation of effectiveness of 4-AP and TEA in slowing down of PD progress.