RESUMEN
Multiple sclerosis (MS) is an inflammatory autoimmune disorder of the central nervous system and the leading cause of progressive neurological disability in young adults. It decreases the patient's lifespan by about 10 years and affects women more than men. No medication entirely restricts or reverses neurological degradation. However, early diagnosis and treatment increase the possibility of a better outcome. To identify new MS biomarkers, we tested the expression of six potential markers (P2X4, P2X7, CXCR4, RGS1, RGS16 and VAV1) using qPCR in peripheral blood mononuclear cells (PBMC) of MS patients treated with interferon ß (IFNß), with glatiramer acetate (GA) or untreated. We showed that P2X7 and VAV1 are significantly induced in MS patients. In contrast, the expression of P2X4, CXCR4, RGS1 and RGS16 was not significantly modified by MS in PBMC. P2X7 and VAV1 are essentially induced in female patients, suggesting these markers are connected to sex-specific mechanisms. Strikingly, VAV1 expression is higher in healthy women than healthy men and IFNß treatment of MS reduced VAV1 expression in female MS patients while it up-regulated VAV1 in male MS patients. Our data point to the differential, sex-dependent value of MS markers and treatment effects. Although rgs16 expression in PBMC was not a valid MS marker in patients, the strong upregulation of P2X4 and P2X7 induced in the spinal cord of WT mice by EAE was abrogated in rgs16KO mice suggesting that rgs16 is required for P2X4 and P2X7 induction by neurological diseases.
Asunto(s)
Enfermedades Autoinmunes , Esclerosis Múltiple , Animales , Femenino , Humanos , Masculino , Ratones , Adulto Joven , Sistema Nervioso Central , Interferón beta/uso terapéutico , Leucocitos Mononucleares , Esclerosis Múltiple/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-vav/genéticaRESUMEN
An increasing amount of evidence is showing the therapeutic effects of rTMS on PD-related non-motor functions neuroanatomically linked to the DLPFC. This presents an ongoing need to apply an optimal combination of stimulation parameters to clinically heterogeneous patient populations, including those with neuropsychiatric problems and other comorbidities along with the neurodegenerative process. In this prospective pilot study, six patients with PD and treatment-resistant depression were thoroughly assessed and carefully monitored before, during, and after each stimulation procedure. The results can provide the basis for developing an extended rTMS protocol that is both effective and safe.
Asunto(s)
Trastorno Depresivo Resistente al Tratamiento/terapia , Enfermedad de Parkinson/terapia , Corteza Prefrontal/fisiopatología , Estimulación Magnética Transcraneal/métodos , Adulto , Anciano , Trastorno Depresivo Resistente al Tratamiento/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatología , Proyectos Piloto , Resultado del TratamientoRESUMEN
OBJECTIVES: Substantia nigra hyperechogenicity is a promising biomarker for Parkinson disease (PD). Substantia nigra hyperechogenicity has previously been established as a useful diagnostic criterion in several European and Asian patient cohorts. However, diagnostic cutoff values for substantia nigra hyperechogenicity remain unknown for most patient populations. This study validated the diagnostic accuracy of substantia nigra hyperechogenicity in a large cohort of patients with PD in Estonia. METHODS: The study included 300 patients with PD from Estonia, representing 10% of the national PD patient population, and 200 healthy control participants. To define the optimal cutoff value in the PD cohort, data from a single assessment versus repetitive assessments by transcranial sonography were compared. With the use of 3 repetitive assessments, the diagnostic accuracy of the data was measured. In addition, calculations for percentile values were used to define substantia nigra hyperechogenicity among controls. RESULTS: Our data showed that the multiassessment approach yielded higher diagnostic accuracy than a single assessment (P = .021). The highest diagnostic accuracy was achieved by using the measurement mean to define substantia nigra hyperechogenicity, which was 0.23 cm(2) (sensitivity, 88.7%; specificity, 92.2%), whereas single measurements detected PD with higher sensitivity (sensitivity, 93.2%; specificity, 85.1%). No significant difference was found between mean and median measurements (P= .18). CONCLUSIONS: This study indicates the diagnostic merit of transcranial sonography in PD diagnosis in an additional population and demonstrates that transcranial sonography of the substantia nigra is a relevant and useful diagnostic tool for patients with PD.
Asunto(s)
Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/epidemiología , Sustancia Negra/diagnóstico por imagen , Ultrasonografía Doppler Transcraneal/estadística & datos numéricos , Anciano , Estudios de Cohortes , Estonia/epidemiología , Humanos , Prevalencia , Reproducibilidad de los Resultados , Factores de Riesgo , Sensibilidad y EspecificidadRESUMEN
BACKGROUND AND OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CSs) and IV immunoglobulin (IVIG). This study was conducted to determine whether immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent patients with MG. METHODS: In this randomized double-blind placebo-controlled trial, CS-dependent patients with MG (Myasthenia Gravis Foundation of America Class II-Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/d) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every 3 weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (quantitative MG score ≥4 points from baseline). CS doses were increased (based on the current CS dose) in patients who worsened. Patients were withdrawn if worsening failed to improve within 6 weeks or if a second CS increase was required. The primary efficacy end point (at week 39) was a ≥50% reduction in CS dose. Secondary and safety end points were assessed throughout the study and follow-up (weeks 42 and 45). The study results and full protocol are available at clinicaltrials.gov/ct2/show/NCT02473965. RESULTS: The primary end point (≥50% reduction in CS dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary end points. Safety data indicated that IGIV-C was well tolerated. DISCUSSION: In this study, IGIV-C was not more effective than placebo in reducing daily CS dose. These results suggest that the effects of IGIV-C and CS are not synergistic and may be mechanistically different. TRIAL REGISTRATION INFORMATION: The trial was registered on clinicaltrialsregister.eu (EudraCT #: 2013-005099-17) and clinicaltrials.gov (identifier NCT02473965). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that IVIG infusions in adult patients with MG do not increase the percentage of patients achieving a ≥50% reduction in corticosteroid dose compared with placebo.
Asunto(s)
Inmunoglobulinas Intravenosas , Miastenia Gravis , Adulto , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Miastenia Gravis/tratamiento farmacológico , Método Doble Ciego , Corticoesteroides/uso terapéutico , Resultado del TratamientoRESUMEN
Substantia nigra (SN) hyper-echogenicity (SN+) describes an enlargement (>90th percentile) of the area of echogenicity at the anatomic site of the SN in the midbrain detected by transcranial sonography. This ultrasound sign has proven to be a valuable marker supporting the clinical diagnosis of Parkinson's disease (PD). Although there is considerable variation in the extent of echogenic signals at the anatomic site of the SN among PD patients, previous work suggests that SN+ is a stable marker throughout the course of the disease. The present study focused on two aspects: (i) determining whether SN+ values differ between the sides, mirroring the asymmetric character of the disease; and (ii) determining whether age has an influence on SN echogenicity. This cross-sectional study included 300 PD patients and 200 healthy controls. SN+ was measured planimetrically by transcranial sonography. Echogenicity was analyzed separately for onset and non-onset sides, with onset side defined as the SN contralateral to the side of the body that first manifested PD-related motor impairment. Age of the patients and healthy controls at study time was used for correlation. We found that the onset SN+ contralateral to the side of initial motor symptoms was on average 17.6% larger than its counterpart. However, we also found that contrary to the control group, where an increase in age was associated with an increase in size of SN+, age of PD patients was associated with a decline in size of the onset SN+. Furthermore, SN measured at the onset side of PD patients correlated significantly with patient age and Hoehn and Yahr stage, a scale that grades PD severity, although this was not the case for the non-onset side. The present study indicates that changes in SN echogenicity have a different dynamic depending on the onset side of the disease. The age at study time had a significantly negative effect on the size of onset SN+, the effect on the non-onset side was non-significant. We conclude that for appropriate PD analysis, onset SN+ is a more important marker than the average of both sides of SN. Furthermore, we found that among healthy controls, the size of SN+ increases with age.
Asunto(s)
Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/patología , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/patología , Ultrasonografía Doppler Transcraneal/métodos , Factores de Edad , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Despite advances in diagnostics and clinical recognition, depressive symptoms in Parkinson's disease (PD) exceeding normal limits remain effectively untreated. In this study, we report on the prevalence and severity of depressive symptoms as well as their association with brainstem raphe echogenicity in patients with PD and non-PD controls. The study included 266 Estonian PD patients and 168 age- and education-matched controls. Demographic and clinical data was documented. Brainstem raphe (BR) was visualized by transcranial sonography (TCS). The prevalence of depressive symptoms in the patient sample was found to be significantly higher than in controls. BR echogenicity in both patients and controls was directly related to their total BDI score, although we found a significantly greater reduction of BR echogenicity in patients with PD and depressive symptoms compared to depressed non-PD controls. The present results corroborate the hypothesis that morphological alteration of the BR is involved in the pathogenesis of depressive disorders. TCS of BR could be used as a non-invasive biomarker to improve detection of depressive symptoms in early PD stages where clinicians may not recognize affective disturbances in the context of PD phenomena.
Asunto(s)
Depresión/diagnóstico por imagen , Depresión/epidemiología , Enfermedad de Parkinson/diagnóstico por imagen , Núcleos del Rafe/diagnóstico por imagen , Ultrasonografía Doppler Transcraneal/métodos , Anciano , Estudios de Casos y Controles , Depresión/etiología , Estonia/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/psicología , Prevalencia , Núcleos del Rafe/patologíaRESUMEN
UNLABELLED: The aim of the study was to develop a culturally adapted translation of the 12-item smell identification test from Sniffin' Sticks (SS-12) for the Estonian population in order to help diagnose Parkinson's disease (PD). METHODS: A standard translation of the SS-12 was created and 150 healthy Estonians were questioned about the smells used as response options in the test. Unfamiliar smells were replaced by culturally familiar options. The adapted SS-12 was applied to 70 controls in all age groups, and thereafter to 50 PD patients and 50 age- and sex-matched controls. RESULTS: 14 response options from 48 used in the SS-12 were replaced with familiar smells in an adapted version, in which the mean rate of correct response was 87% (range 73-99) compared to 83% with the literal translation (range 50-98). In PD patients, the average adapted SS-12 score (5.4/12) was significantly lower than in controls (average score 8.9/12), p < 0.0001. A multiple linear regression using the score in the SS-12 as the outcome measure showed that diagnosis and age independently influenced the result of the SS-12. A logistic regression using the SS-12 and age as covariates showed that the SS-12 (but not age) correctly classified 79.0% of subjects into the PD and control category, using a cut-off of <7 gave a sensitivity of 76% and specificity of 86% for the diagnosis of PD. CONCLUSIONS: The developed SS-12 cultural adaption is appropriate for testing olfaction in Estonia for the purpose of PD diagnosis.