RESUMEN
The pilocarpine-induced (PILO) model has helped elucidate the electrophysiological and molecular aspects related to mesial temporal lobe epilepsy. It has been suggested that the extensive cell death and edema observed in the brains of these animals could be induced by increased inflammatory responses, such as the rapid release of the inflammatory cytokine interleukin 1 beta (Il1b). In this study, we investigate the role of endogenous Il1b in the acute phase of the PILO model. Our aim is twofold. First, we want to determine whether it is feasible to silence Il1b in the central nervous system using a non-invasive procedure. Second, we aim to investigate the effect of silencing endogenous Il1b and its antagonist, Il1rn.We used RNA interference applied non-invasively to knockdown Il1b and its endogenous antagonist Il1rn. We found that knocking down Il1b prior to pilocarpine injection increased the mortality rate of treated animals. Furthermore, we observed that, when exposing the animals to more Il1b by silencing its endogenous antagonist Il1rn, there was a better response to status epilepticus with decreased animal mortality in the acute phase of the PILO model. Thus, we show the feasibility of using a novel, less invasive approach to study genes involved in the inflammatory response in the central nervous system. Furthermore, our results provide suggestive evidence that modulating endogenous Il1b improves animal survival in the acute phase of the PILO model and may have effects that extend into the chronic phase.
Asunto(s)
Epilepsia del Lóbulo Temporal , Epilepsia , Estado Epiléptico , Animales , Pilocarpina/efectos adversos , Pilocarpina/metabolismo , Interleucina-1beta/metabolismo , Epilepsia/inducido químicamente , Epilepsia/genética , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/genética , Epilepsia del Lóbulo Temporal/metabolismo , Estado Epiléptico/inducido químicamente , Estado Epiléptico/genética , Estado Epiléptico/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismoRESUMEN
Neurological diseases are responsible for approximately 6.8 million deaths every year. They affect up to 1 billion people worldwide and cause significant disability and reduced quality of life. In most neurological disorders, the diagnosis can be challenging; it frequently requires long-term investigation. Thus, the discovery of better diagnostic methods to help in the accurate and fast diagnosis of neurological disorders is crucial. Circulating nucleic acids (CNAs) are defined as any type of DNA or RNA that is present in body biofluids. They can be found within extracellular vesicles or as cell-free DNA and RNA. Currently, CNAs are being explored as potential biomarkers for diseases because they can be obtained using non-invasive methods and may reflect unique characteristics of the biological processes involved in several diseases. CNAs can be especially useful as biomarkers for conditions that involve organs or structures that are difficult to assess, such as the central nervous system. This review presents a critical assessment of the most current literature about the use of plasma and serum CNAs as biomarkers for several aspects of neurological disorders: defining a diagnosis, establishing a prognosis, and monitoring the disease progression and response to therapy. We explored the biological origin, types, and general mechanisms involved in the generation of CNAs in physiological and pathological processes, with specific attention to neurological disorders. In addition, we present some of the future applications of CNAs as non-invasive biomarkers for these diseases.
Asunto(s)
Enfermedades del Sistema Nervioso , Biomarcadores , Ácidos Nucleicos Libres de Células , Humanos , Plasma , Calidad de VidaRESUMEN
Neurological diseases are responsible for approximately 6.8 million deaths every year. They affect up to 1 billion people worldwide and cause significant disability and reduced quality of life. In most neurological disorders, the diagnosis can be challenging; it frequently requires long-term investigation. Thus, the discovery of better diagnostic methods to help in the accurate and fast diagnosis of neurological disorders is crucial. Circulating nucleic acids (CNAs) are defined as any type of DNA or RNA that is present in body biofluids. They can be found within extracellular vesicles or as cell-free DNA and RNA. Currently, CNAs are being explored as potential biomarkers for diseases because they can be obtained using non-invasive methods and may reflect unique characteristics of the biological processes involved in several diseases. CNAs can be especially useful as biomarkers for conditions that involve organs or structures that are difficult to assess, such as the central nervous system. This review presents a critical assessment of the most current literature about the use of plasma and serum CNAs as biomarkers for several aspects of neurological disorders: defining a diagnosis, establishing a prognosis, and monitoring the disease progression and response to therapy. We explored the biological origin, types, and general mechanisms involved in the generation of CNAs in physiological and pathological processes, with specific attention to neurological disorders. In addition, we present some of the future applications of CNAs as non-invasive biomarkers for these diseases.
Asunto(s)
Humanos , Enfermedades del Sistema Nervioso , Plasma , Calidad de Vida , Biomarcadores , Ácidos Nucleicos Libres de CélulasRESUMEN
BACKGROUND AND PURPOSE: Friedreich's ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide. It is characterized by early onset, sensory abnormalities and slowly progressive ataxia. All magnetic resonance imaging (MRI)-based studies have focused on the evaluation of adult patients. Therefore, we designed a cross-sectional multimodal MRI-based study to investigate the anatomical substrates involved in the early stages of FRDA. METHODS: We enrolled 37 patients (12 children) and 38 controls. All subjects underwent MRI in a 3T device to assess gray and white matter. We used measures from FreeSurfer and CERES to evaluate the cerebral and cerebellar cortices. The T1 multiatlas assessed deep gray matter. The diffusion tensor imaging multiatlas was used to investigate microstructural abnormalities in brain white matter and SpineSeg was used to assess the cervical spinal cord. All analyses were corrected for multiple comparisons. RESULTS: Comparison with age-matched controls showed that pediatric patients have spinal cord, inferior cerebellar peduncle and red nucleus damage. In contrast, adult patients showed more widespread white matter damage than pediatric patients. With regard to gray matter, we found cortical thinning at the left central sulcus and volumetric reduction in the thalami and hippocampi only in adult patients. Finally, values of fractional anisotropy in adult patients and radial diffusivity in pediatric patients from the inferior cerebellar peduncle correlated with disease duration and ataxia severity, respectively. CONCLUSIONS: Structural damage in FRDA begins in the spinal cord and inferior cerebellar peduncle as well as the red nucleus, and progresses to cerebral areas in adulthood. These results shed some light on the early stages of FRDA and highlight potential neuroimaging markers for therapeutic trials.
Asunto(s)
Ataxia de Friedreich , Sustancia Gris , Sustancia Blanca , Adolescente , Adulto , Anciano , Niño , Estudios Transversales , Femenino , Ataxia de Friedreich/diagnóstico por imagen , Ataxia de Friedreich/patología , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adulto JovenRESUMEN
Protein coding sequences represent only 2% of the human genome. Recent advances have demonstrated that a significant portion of the genome is actively transcribed as non-coding RNA molecules. These non-coding RNAs are emerging as key players in the regulation of biological processes, and act as "fine-tuners" of gene expression. Neurological disorders are caused by a wide range of genetic mutations, epigenetic and environmental factors, and the exact pathophysiology of many of these conditions is still unknown. It is currently recognized that dysregulations in the expression of non-coding RNAs are present in many neurological disorders and may be relevant in the mechanisms leading to disease. In addition, circulating non-coding RNAs are emerging as potential biomarkers with great potential impact in clinical practice. In this review, we discuss mainly the role of microRNAs and long non-coding RNAs in several neurological disorders, such as epilepsy, Huntington disease, fragile X-associated ataxia, spinocerebellar ataxias, amyotrophic lateral sclerosis (ALS), and pain. In addition, we give information about the conditions where microRNAs have demonstrated to be potential biomarkers such as in epilepsy, pain, and ALS.
Asunto(s)
MicroARNs/fisiología , Enfermedades del Sistema Nervioso/genética , ARN Largo no Codificante/fisiología , MicroARN Circulante , Regulación de la Expresión Génica , Marcadores Genéticos/fisiología , Humanos , Enfermedades Neurodegenerativas/genética , Enfermedades Neuromusculares/genéticaRESUMEN
Protein coding sequences represent only 2% of the human genome. Recent advances have demonstrated that a significant portion of the genome is actively transcribed as non-coding RNA molecules. These non-coding RNAs are emerging as key players in the regulation of biological processes, and act as "fine-tuners" of gene expression. Neurological disorders are caused by a wide range of genetic mutations, epigenetic and environmental factors, and the exact pathophysiology of many of these conditions is still unknown. It is currently recognized that dysregulations in the expression of non-coding RNAs are present in many neurological disorders and may be relevant in the mechanisms leading to disease. In addition, circulating non-coding RNAs are emerging as potential biomarkers with great potential impact in clinical practice. In this review, we discuss mainly the role of microRNAs and long non-coding RNAs in several neurological disorders, such as epilepsy, Huntington disease, fragile X-associated ataxia, spinocerebellar ataxias, amyotrophic lateral sclerosis (ALS), and pain. In addition, we give information about the conditions where microRNAs have demonstrated to be potential biomarkers such as in epilepsy, pain, and ALS.
Asunto(s)
Humanos , MicroARNs/fisiología , ARN Largo no Codificante/fisiología , Enfermedades del Sistema Nervioso/genética , Marcadores Genéticos/fisiología , Regulación de la Expresión Génica , Enfermedades Neurodegenerativas/genética , MicroARN Circulante , Enfermedades Neuromusculares/genéticaRESUMEN
OBJECTIVE: To investigate whether the Cdc2-like kinase 2 (CLK2) is expressed in hypothalamic neurons and if it is, whether the hypothalamic CLK2 has a role in the regulation of energy balance. SUBJECTS: Swiss mice on chow or high-fat diet (HFD) and db/db mice on chow diet were used to address the role of CLK2 in the hypothalamus. RESULTS: Hypothalamic CLK2Thr343 phosphorylation, which induces CLK2 activity, is regulated in vivo by refeeding, insulin and leptin, in a PI3K (phosphoinositide 3-kinase)-dependent manner. The reduction of CLK2 expression in the hypothalamus, by chronic pharmacological inhibition with TG003 or by chronic knockdown with small interfering RNA was sufficient to abolish the anorexigenic effect of insulin and leptin, to increase body weight, fat mass, food intake and to decrease energy expenditure in mice on chow. In contrast, CLK2Thr343 phosphorylation in the hypothalamus in response to insulin, leptin or refeeding was impaired in mice on HFD or in db/db mice. Chronic CLK2 inhibition in the hypothalamus was associated with a slight increase in the fasting blood glucose levels, reduction in PEPCK (phosphoenolpyruvate carboxykinase) expression in the liver and enhanced glucose production from pyruvate, suggesting a regulation of hepatic glucose production. Further, overexpressing CLK2 in the mediobasal hypothalami of mice on HFD or in db/db mice by adenovirus partially reversed the obese phenotype. CONCLUSIONS: Thus, our results suggest that protein CLK2 integrates some important hypothalamic pathways, and may be a promising molecule for new therapeutic approaches for obesity and diabetes.
Asunto(s)
Quinasas CDC2-CDC28/metabolismo , Diabetes Mellitus Tipo 2/patología , Metabolismo Energético/fisiología , Hipotálamo/metabolismo , Resistencia a la Insulina/fisiología , Obesidad/patología , Fosforilación/fisiología , Animales , Quinasas CDC2-CDC28/farmacología , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Ingestión de Alimentos , Metabolismo Energético/efectos de los fármacos , Homeostasis/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Metabolismo de los Lípidos , Masculino , Ratones , Transducción de SeñalRESUMEN
OBJECTIVES: The prevalence of DYT1 (mutation in TOR1A) and DYT6 (mutation in THAP1) may vary in different populations, which can have important implications in clinical investigation. Our goal was to characterize patients with inherited and isolated dystonia and determine the frequency of mutations responsible for DYT1 and DYT6 in Brazilian patients. METHODS: Two movement disorder specialists examined 78 patients with idiopathic isolated dystonia using a standardized questionnaire, before sequencing TOR1A and THAP1 genes. RESULTS: Clinically, our cohort was similar to those described in the international literature. Molecular studies of 68 subjects revealed only one potentially deleterious variant in THAP1 (1/68 patients, 1.47%). This was a novel 10-bp deletion at the end of exon 1, g.5308_5317del (ng_011837.1), which is predicted to create an alternative splicing and the insertion of a premature stop codon. Although we did not observe any potentially deleterious mutations in TOR1A, we found the missense variant rs1801968 (TOR1A p.D216H), previously reported as either a modifier of dystonia phenotype or a predisposing factor for dystonia. However, we did not identify any phenotypic impact related to the missense variant rs1801968 (P = 0.3387). CONCLUSIONS: Although clinically similar to most cohorts with dystonia worldwide, the classical mutation (c.907_909delGAG) in TOR1A (causing DYT1) is absent in our patients. However, we found a potentially deleterious THAP1 mutation not previously reported. In addition, we found no association of rs1801968 with dystonia.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Proteínas de Unión al ADN/genética , Distonía/diagnóstico , Distonía/genética , Chaperonas Moleculares/genética , Mutación/genética , Proteínas Nucleares/genética , Adulto , Brasil/epidemiología , Estudios de Cohortes , Estudios Transversales , Distonía/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by expansion of the polyglutamine domain of the ataxin-3 (ATX3) protein. MJD/SCA3 is the most frequent autosomal dominant ataxia in many countries. The mechanism underlying MJD/SCA3 is thought to be mainly related to protein misfolding and aggregation leading to neuronal dysfunction followed by cell death. Currently, there are no effective treatments for patients with MJD/SCA3. Here, we report on the potential use of lithium carbonate and coenzyme Q10 to reduce cell death caused by the expanded ATX3 in cell culture. Cell viability and apoptosis were evaluated by MTT assay and by flow cytometry after staining with annexin V-FITC/propidium iodide. Treatment with lithium carbonate and coenzyme Q10 led to a significant increase in viability of cells expressing expanded ATX3 (Q84). In addition, we found that the increase in cell viability resulted from a significant reduction in the proportion of apoptotic cells. Furthermore, there was a significant change in the expanded ATX3 monomer/aggregate ratio after lithium carbonate and coenzyme Q10 treatment, with an increase in the monomer fraction and decrease in aggregates. The safety and tolerance of both drugs are well established; thus, our results indicate that lithium carbonate and coenzyme Q10 are good candidates for further in vivo therapeutic trials.
Asunto(s)
Ataxina-3/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Carbonato de Litio/farmacología , Enfermedad de Machado-Joseph , Proteínas Represoras/efectos de los fármacos , Ubiquinona/análogos & derivados , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Enfermedad de Machado-Joseph/tratamiento farmacológico , Ubiquinona/farmacologíaRESUMEN
We report here the first complete transcriptome analysis of the dorsal (dDG) and ventral dentate gyrus (vDG) of a rat epilepsy model presenting a hippocampal lesion with a strict resemblance to classical hippocampal sclerosis (HS). We collected the dDG and vDG by laser microdissection 15 days after electrical stimulation and performed high-throughput RNA-sequencing. There were many differentially regulated genes, some of which were specific to either of the two sub-regions in stimulated animals. Gene ontology analysis indicated an enrichment of inflammation-related processes in both sub-regions and of axonal guidance and calcium signaling processes exclusively in the vDG. There was also a differential regulation of genes encoding molecules involved in synaptic function, neural electrical activity and neuropeptides in stimulated rats. The data presented here suggests, in the time point analyzed, a remarkable interaction among several molecular components which takes place in the damaged hippocampi. Furthermore, even though similar mechanisms may function in different regions of the DG, the molecular components involved seem to be region specific.
Asunto(s)
Giro Dentado/metabolismo , Epilepsia/metabolismo , Regulación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Esclerosis Tuberosa/metabolismo , Animales , Giro Dentado/patología , Epilepsia/patología , Masculino , Ratas , Ratas Wistar , Esclerosis Tuberosa/patologíaRESUMEN
BACKGROUND AND PURPOSE: Non-motor manifestations are frequently overlooked in degenerative disorders and little is known about their frequency and clinical relevance in SPG4 hereditary spastic paraplegia (SPG4-HSP). METHODS: Thirty patients with SPG4-HSP and 30 healthy controls answered the Modified Fatigue Impact Scale, Epworth Sleepiness Scale, Brief Pain Inventory and Beck Depression Inventory. Student's t test was used to compare groups and linear regression was used to assess correlations. RESULTS: Patients had higher fatigue scores than controls (31.0 ± 16.5 vs. 14.5 ± 16.0, P = 0.002) as well as pain (3.4 ± 2.7 vs. 1.0 ± 1.6, P = 0.001) and depression (12.7 ± 8.9 vs. 4.4 ± 3.8, P < 0.001, respectively). Fatigue was associated with depression and possibly with disease severity (P = 0.008 and 0.07, respectively). CONCLUSIONS: Fatigue, pain and depression are frequent and often severe manifestations in patients with SPG4-HSP.
Asunto(s)
Depresión/fisiopatología , Fatiga/fisiopatología , Dolor/fisiopatología , Paraplejía Espástica Hereditaria/fisiopatología , Adenosina Trifosfatasas/genética , Adulto , Depresión/etiología , Fatiga/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Dolor/etiología , Paraplejía Espástica Hereditaria/complicaciones , EspastinaRESUMEN
INTRODUCTION: Thiazolidinediones (TZDs) enhanced body weight (BW) partially by increased adipogenesis and hyperphagia. Neuronal PPARγ knockout mice on high-fat diet (HFD) are leaner because of enhanced leptin response, although it could be secondary to their leanness. Thus, it still is an open question how TZDs may alter energy balance. Multiple factors regulate food intake (FI) and energy expenditure (EE), including anorexigenic hormones as insulin and leptin. Nonetheless, elevated hypothalamic AMPK activity increases FI and TZDs increase AMPK activity in muscle cells. Thus, the aim of the present study was to investigate whether Pioglitazone (PIO) treatment alters hypothalamic insulin and leptin action/signaling, AMPK phosphorylation, and whether these alterations may be implicated in the regulation of FI and EE. METHODS: Swiss mice on HFD (2 months) received PIO (25 mg kg(-1) per day-gavage) or vehicle for 14 days. AMPK and AdipoR1 were inhibited via Intracerebroventricular injections using Compound C (CompC) and small interference RNA (siRNA), respectively. Western blot, real-time PCR and CLAMS were done. RESULTS: PIO treatment increased BW, adiposity, FI, NPY mRNA and decreased POMC mRNA expression and EE in HFD mice. Despite higher adiposity, PIO treatment improved insulin sensitivity, glucose tolerance, decreased insulin and increased adiponectin serum levels. This result was associated with, improved insulin and leptin action/signaling, decreased α2AMPK(Ser491) phosphorylation and elevated Acetyl-CoA carboxylase and AMPK(Thr172) phosphorylation in hypothalamus. The inhibition of hypothalamic AMPK with CompC was associated with decreased adiposity, FI, NPY mRNA and EE in PIO-treated mice. The reduced expression of hypothalamic AdipoR1 with siRNA concomitantly with PIO treatment reverted PIO induced obesity development, suggesting that adiponectin may be involved in this effect. CONCLUSIONS: These results demonstrated that PIO, despite improving insulin/leptin action in hypothalamus, increases FI and decreases EE, partially, by activating hypothalamic adiponectin/AdipoR1/AMPK axis. Suggesting a novel mechanism in the hypothalamus by which TZDs increase BW.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Adiponectina/metabolismo , Hipoglucemiantes/farmacología , Hipotálamo/metabolismo , Tiazolidinedionas/farmacología , Animales , Dieta Alta en Grasa , Ingestión de Alimentos , Metabolismo Energético , Masculino , Ratones , Pioglitazona , ARN MensajeroRESUMEN
Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by expansion of the polyglutamine domain of the ataxin-3 (ATX3) protein. MJD/SCA3 is the most frequent autosomal dominant ataxia in many countries. The mechanism underlying MJD/SCA3 is thought to be mainly related to protein misfolding and aggregation leading to neuronal dysfunction followed by cell death. Currently, there are no effective treatments for patients with MJD/SCA3. Here, we report on the potential use of lithium carbonate and coenzyme Q10 to reduce cell death caused by the expanded ATX3 in cell culture. Cell viability and apoptosis were evaluated by MTT assay and by flow cytometry after staining with annexin V-FITC/propidium iodide. Treatment with lithium carbonate and coenzyme Q10 led to a significant increase in viability of cells expressing expanded ATX3 (Q84). In addition, we found that the increase in cell viability resulted from a significant reduction in the proportion of apoptotic cells. Furthermore, there was a significant change in the expanded ATX3 monomer/aggregate ratio after lithium carbonate and coenzyme Q10 treatment, with an increase in the monomer fraction and decrease in aggregates. The safety and tolerance of both drugs are well established; thus, our results indicate that lithium carbonate and coenzyme Q10 are good candidates for further in vivo therapeutic trials.
Asunto(s)
Humanos , Ataxina-3/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Carbonato de Litio/farmacología , Enfermedad de Machado-Joseph , Proteínas Represoras/efectos de los fármacos , Ubiquinona/análogos & derivados , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Enfermedad de Machado-Joseph/tratamiento farmacológico , Ubiquinona/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: Machado-Joseph disease (MJD/SCA3) is the most frequent spinocerebellar ataxia, characterized by brainstem, basal ganglia and cerebellar damage. Few magnetic resonance imaging based studies have investigated damage in the cerebral cortex. The objective was to determine whether patients with MJD/SCA3 have cerebral cortex atrophy, to identify regions more susceptible to damage and to look for the clinical and neuropsychological correlates of such lesions. METHODS: Forty-nine patients with MJD/SCA3 (mean age 47.7 ± 13.0 years, 27 men) and 49 matched healthy controls were enrolled. All subjects underwent magnetic resonance imaging scans in a 3 T device, and three-dimensional T1 images were used for volumetric analyses. Measurement of cortical thickness and volume was performed using the FreeSurfer software. Groups were compared using ancova with age, gender and estimated intracranial volume as covariates, and a general linear model was used to assess correlations between atrophy and clinical variables. RESULTS: Mean CAG expansion, Scale for Assessment and Rating of Ataxia (SARA) score and age at onset were 72.1 ± 4.2, 14.7 ± 7.3 and 37.5 ± 12.5 years, respectively. The main findings were (i) bilateral paracentral cortex atrophy, as well as the caudal middle frontal gyrus, superior and transverse temporal gyri, and lateral occipital cortex in the left hemisphere and supramarginal gyrus in the right hemisphere; (ii) volumetric reduction of basal ganglia and hippocampi; (iii) a significant correlation between SARA and brainstem and precentral gyrus atrophy. Furthermore, some of the affected cortical regions showed significant correlations with neuropsychological data. CONCLUSIONS: Patients with MJD/SCA3 have widespread cortical and subcortical atrophy. These structural findings correlate with clinical manifestations of the disease, which support the concept that cognitive/motor impairment and cerebral damage are related in disease.
Asunto(s)
Ganglios Basales/patología , Tronco Encefálico/patología , Corteza Cerebral/patología , Enfermedad de Machado-Joseph/patología , Adulto , Atrofia/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND AND PURPOSE: In Friedreich's ataxia (FRDA), frataxin deficiency results in iron redistribution in the dentate nuclei (DNC). Clusters of iron cause inhomogeneities in a magnetic field and result in a reduction in T2 relaxation time (T2). METHODS: T2 was prospectively evaluated in DNC, putamen, substantia nigra (SN), cerebellar white matter (CWM) and caudate and the correlation with clinical parameters was investigated. Thirty-five patients (range 9-51 years) and 44 controls (12-49 years) underwent T2 multi-echo sequence in a 3T scanner. Twenty-three patients (12-50 years) and 19 controls (14-49 years) were reassessed after 1 year. T2 was evaluated using specialized software (Aftervoxel) and severity of disease was quantified with the Friedreich Ataxia Rating Scale (FARS). RESULTS: T2 of both DNC was significantly shorter in the FRDA group at baseline (right, 58.6 ± 8.3 ms vs. 63.7 ± 8.1 ms, P = 0.013; left, 56.7 ± 7.7 ms vs. 62.6 ± 6.8 ms, P = 0.001). No significant difference was found between groups regarding the SN, putamen, CWM and caudate T2. DNC T2 values correlated with age, FARS total score and FARS III subscore on both sides. Prospectively, there was a significant reduction of T2 in FRDA patients in right and left DNC (P = 0.001 and 0.009) but not in other structures. Amongst controls, none of the regions significantly changed after 1 year. DNC T2 change over time correlated with GAA expansions and clinical deterioration (expressed by a change in FARS scores). CONCLUSIONS: DNC T2 values are abnormal in FRDA, progress over time and correlate with ataxia severity. These results strongly suggest that DNC relaxometry can be a useful neuroimaging marker in FRDA.
Asunto(s)
Núcleos Cerebelosos , Progresión de la Enfermedad , Ataxia de Friedreich/diagnóstico , Imagen por Resonancia Magnética/métodos , Neuroimagen/métodos , Adolescente , Adulto , Biomarcadores , Niño , Estudios Transversales , Femenino , Estudios de Seguimiento , Ataxia de Friedreich/genética , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Huntington's disease (HD) is a neurologic disorder that is not completely understood; its fundamental physiological mechanisms and chemical effects remain somewhat unclear. Among these uncertainties, we can highlight information about the concentrations of brain metabolites, which have been widely discussed. Concentration differences in affected, compared to healthy, individuals could lead to the development of useful tools for evaluating the progression of disease, or to the advance of investigations of different/alternative treatments. The aim of this study was to compare the thalamic concentration of metabolites in HD patients and healthy individuals using magnetic resonance spectroscopy. We used a 2.0-Tesla magnetic field, repetition time of 1500 ms, and echo time of 135 ms. Spectra from 40 adult HD patients and 26 control subjects were compared. Quantitative analysis was performed using the LCModel method. There were statistically significant differences between HD patients and controls in the concentrations of N-acetylaspartate+N-acetylaspartylglutamate (NAA+NAAG; t-test, P<0.001), and glycerophosphocholine+phosphocholine (GPC+PCh; t-test, P=0.001) relative to creatine+phosphocreatine (Cr+PCr). The NAA+NAAG/Cr+PCr ratio was decreased by 9% and GPC+PCh/Cr+PCr increased by 17% in patients compared with controls. There were no correlations between the concentration ratios and clinical features. Although these results could be caused by T1 and T2 changes, rather than variations in metabolite concentrations given the short repetition time and long echo time values used, our findings point to thalamic dysfunction, corroborating prior evidence.
Asunto(s)
Enfermedad de Huntington/metabolismo , Espectroscopía de Resonancia Magnética , Enfermedades Talámicas/metabolismo , Tálamo/fisiopatología , Adolescente , Adulto , Anciano , Ácido Aspártico/análogos & derivados , Ácido Aspártico/análisis , Estudios de Casos y Controles , Creatina/análisis , Deuterio , Dipéptidos/análisis , Femenino , Glicerilfosforilcolina/análisis , Humanos , Masculino , Persona de Mediana Edad , Actividad Motora , Fosfocreatina/análisis , Fosforilcolina/análisis , Enfermedades Talámicas/diagnóstico , Repeticiones de Trinucleótidos , Adulto JovenRESUMEN
Huntington's disease (HD) is a neurologic disorder that is not completely understood; its fundamental physiological mechanisms and chemical effects remain somewhat unclear. Among these uncertainties, we can highlight information about the concentrations of brain metabolites, which have been widely discussed. Concentration differences in affected, compared to healthy, individuals could lead to the development of useful tools for evaluating the progression of disease, or to the advance of investigations of different/alternative treatments. The aim of this study was to compare the thalamic concentration of metabolites in HD patients and healthy individuals using magnetic resonance spectroscopy. We used a 2.0-Tesla magnetic field, repetition time of 1500 ms, and echo time of 135 ms. Spectra from 40 adult HD patients and 26 control subjects were compared. Quantitative analysis was performed using the LCModel method. There were statistically significant differences between HD patients and controls in the concentrations of N-acetylaspartate+N-acetylaspartylglutamate (NAA+NAAG; t-test, P<0.001), and glycerophosphocholine+phosphocholine (GPC+PCh; t-test, P=0.001) relative to creatine+phosphocreatine (Cr+PCr). The NAA+NAAG/Cr+PCr ratio was decreased by 9% and GPC+PCh/Cr+PCr increased by 17% in patients compared with controls. There were no correlations between the concentration ratios and clinical features. Although these results could be caused by T1 and T2 changes, rather than variations in metabolite concentrations given the short repetition time and long echo time values used, our findings point to thalamic dysfunction, corroborating prior evidence.
Asunto(s)
Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Enfermedad de Huntington/metabolismo , Espectroscopía de Resonancia Magnética , Enfermedades Talámicas/metabolismo , Tálamo/fisiopatología , Ácido Aspártico/análisis , Ácido Aspártico/análogos & derivados , Estudios de Casos y Controles , Creatina/análisis , Deuterio , Dipéptidos/análisis , Glicerilfosforilcolina/análisis , Actividad Motora , Fosfocreatina/análisis , Fosforilcolina/análisis , Repeticiones de Trinucleótidos , Enfermedades Talámicas/diagnósticoRESUMEN
UNLABELLED: Machado-Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3) may rarely presents a parkinsonian phenotype. Considering that mutations in the glucocerebrosidase (GBA) gene have been associated with Parkinson disease, we investigated whether these would be more prevalent in MJD/SCA3 patients with parkinsonian manifestations than in those without them. METHODS: MJD/SCA3 patients with parkinsonian features were identified and compared to relatives and to a MJD/SCA3 control group with no such features. The GBA gene was sequenced and, in a subset of patients and in normal volunteers, GBA enzyme activity was measured. RESULTS: We have identified nine index MJD/SCA3 patients with parkinsonian manifestations. Overall, GBA sequence variations were found in 3/9 MJD/SCA3 index cases with parkinsonian manifestations (33%) and in 0/40 MJD/SCA3 controls without parkinsonism (p=0.03, Fisher exact test). The GBA sequence variations found were p.K(-27)R, p.E326K, and p.T369M. The latter two sequence variations were also found in two symptomatic relatives with no parkinsonian manifestations. A MJD/SCA3 relative belonging to the first positive pedigree and carrier of the p.K(-27)R mutation also presented parkinsonian manifestations. GBA activity in MJD/SCA3 patients was similar to those found in the normal control group. CONCLUSION: Sequence variations at the GBA gene may play a role as a minor, modifying gene of MJD/SCA3 phenotype. This hypothetical role was not related to changes in GBA activity in peripheral leukocytes.