Thymic Alterations in GM2 Gangliosidoses Model Mice

BACKGROUND: Sandhoff disease is a lysosomal storage disorder characterized by the absence of β-hexosaminidase and storage of GM2 ganglioside and related glycolipids. We have previously found that the progressive neurologic disease induced in Hexb(-/-) mice, an animal model for Sandhoff disease, is associated with the production of pathogenic anti-glycolipid autoantibodies. METHODOLOGY/PRINCIPAL FINDINGS: In our current study, we report on the alterations in the thymus during the development of mild to severe progressive neurologic disease. The thymus from Hexb(-/-) mice of greater than 15 weeks of age showed a marked decrease in the percentage of immature CD4(+)/CD8(+) T cells and a significantly increased number of CD4(+)/CD8(-) T cells. During involution, the levels of both apoptotic thymic cells and IgG deposits to T cells were found to have increased, whilst swollen macrophages were prominently observed, particularly in the cortex. We employed cDNA microarray analysis to monitor gene expression during the involution process and found that genes associated with the immune responses were upregulated, particularly those expressed in macrophages. CXCL13 was one of these upregulated genes and is expressed specifically in the thymus. B1 cells were also found to have increased in the thy mus. It is significant that these alterations in the thymus were reduced in FcRγ additionally disrupted Hexb(-/-) mice. CONCLUSIONS/SIGNIFICANCE: These results suggest that the FcRγ chain may render the usually poorly immunogenic thymus into an organ prone to autoimmune responses, including the chemotaxis of B1 cells toward CXCL13

Alterations in striatal dopamine catabolism precede loss of substantia nigra neurons in a mouse model of juvenile neuronal ceroid lipofuscinosis

Batten disease, or juvenile neuronal ceroid lipofuscinosis UNCL), results from mutations in the CLN3 gene. This disorder presents clinically around the age of 5 years with visual deficits progressing to include seizures, cognitive impairment, motor deterioration, hallucinations, and premature death by the third to fourth decade of life. The motor deficits include coordination and gait abnormalities, myoclonic jerks, inability to initiate movements, and spasticity. Previous work from our laboratory has identified an early reduction in catechol-O-methyltransferase (COMT), an enzyme responsible for the efficient degradation of dopamine. Alterations in the kinetics of dopamine metabolism could cause the accumulation of undegraded or unsequestered dopamine leading to the formation of toxic dopamine intermediates. We report an imbalance in the catabolism of dopamine in 3 month Cln3(-/-) mice persisting through 9 months of age that may be causal to oxidative damage within the striatum at 9 months of age. Combined with the previously reported inflammatory changes and loss of post-synaptic D1 alpha receptors, this could facilitate cell loss in striatal projection regions and underlie a general locomotion deficit that becomes apparent at 12 months of age in Cln3(-/-) mice. This study provides evidence for early changes in the kinetics of COMT in the Cln3(-/-) mouse striatum, affecting the turnover of dopamine, likely leading to neuron loss and motor deficits. These data provide novel insights into the basis of motor deficits in JNCL and how alterations in dopamine catabolism may result in oxidative damage and localized neuronal loss in this disorder. (c) 2007 Elsevier B.V. All rights reserve

Immunosuppression alters disease severity in juvenile Batten disease mice

Autoantibodies to brain proteins are present in Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease) patients and in the Cln3(-/-) mouse model of this disease, suggesting an autoimmune component to pathogenesis. Using genetic or pharmaceutical approaches to attenuate this immune response in Cln3(-/-) mice, we demonstrate decreased neuroinflammation, decreased deposition of immunoglobulin G in the brain and protection of vulnerable neuron populations. Moreover, immune suppression results in a significant improvement in motor performance providing for the first plausible therapeutic approach for juvenile Batten disease. (C) 2010 Elsevier B.V. All rights reserved

Distinct patterns of serum immunoreactivity as evidence for multiple brain-directed autoantibodies in juvenile neuronal ceroid lipofuscinosis

Autoantibodies to glutamic acid decarboxylase (GAD65) have been reported in sera from the Cln3(-/-) mouse model of juvenile neuronal ceroid lipofuscinosis (JNCL), and in individuals with this fatal paediatric neurodegenerative disorder. To investigate the existence of other circulating autoreactive antibodies, we used sera from patients with JNCL and other forms of neuronal ceroid lipofuscinosis (NCL) as primary antisera to stain rat and human central nervous system sections. JNCL sera displayed characteristic patterns of IgG, but not IgA, IgE or IgM immunoreactivity that was distinct from the other forms of NCL. Immunoreactivity of JNCL sera was not confined to GAD65-positive (GABAergic) neurons, but also stained multiple other cell populations. Preadsorption of JNCL sera with recombinant GAD65 reduced the intensity of the immunoreactivity, but did not significantly change its staining pattern. Moreover, sera from Stiff Person Syndrome and Type I Diabetes, disorders in which GAD65 autoantibodies are present, stained with profiles that were markedly different from JNCL sera. Collectively, these studies provide evidence of the presence of autoreactive antibodies within multiple forms of NCL, and are not exclusively directed towards GAD6

Características tomográficas de los pacientes con diagnóstico de Accidente Cerebrovascular Atendidos en el servicio de urgencias en una clínica de alta complejidad de Neiva

Introduction: Cerebrovascular diseases represent one of the main causes of mortality and functional disability in developed countries. Objective: to identify the tomographic characteristics, its main causes and the compromised areas of the brain, of the patients with a diagnosis of cerebrovascular accident (CVA) who attended the emergency consultation in a highly complex clinic in the city of Neiva in the period covered between April 1 and June 30, 2018. Materials and Methods: Prospective observational descriptive study. The data were obtained between April 1 and June 30, 2018, through the clinical history of 47 patients with a diagnosis of CVA who attended the emergency consultation in a high complexity clinic in the city of Nevia and included in his study a simple skull tomography. Results: This pathology occurred more frequently in males of an age range between 61 to 78 years. Of the municipalities of the department of Huila, the city of Neiva, presented 32 cases, being the place with the highest number of cases, represented by 68%. Conclusions: According to the information obtained, ischemic lesions occur predominantly in the area of ​​the middle cerebral artery. It was detected that diabetes and excess consumption of calories are fundamental risk factors.Introducción: las enfermedades cerebrovasculares representan una de las principales causas de mortalidad e invalidez funcional en los países desarrollados. Objetivo: identificar las características tomográficas, sus principales causas y las áreas comprometidas del cerebro, de los pacientes con diagnóstico de Accidente Cerebrovascular (ACV) que asistieron a la consulta de urgencias en una clínica de alta complejidad de la ciudad de Neiva en el periodo comprendido entre 1 de abril y 30 de junio de 2018. Materiales y Método: estudio descriptivo observacional prospectivo. Los datos se obtuvieron entre el 1 de abril y 30 de junio de 2018, a través de la historia clínica de 47 pacientes  con diagnóstico de ACV que asistieron a la consulta de urgencias en una clínica de alta complejidad en la ciudad de Neiva y que incluyeron en su estudio una tomografía de cráneo simple. Resultados: esta patología se presentó con mayor frecuencia en personas de género masculino en un rango de edad entre los 61 a 78 años. De los municipios del departamento del Huila, la ciudad de Neiva, presentó 32 casos, siendo el lugar con mayor número de casos, representado en un 68%. Conclusiones: de acuerdo con la información obtenida, las lesiones isquémicas se presentan predominantemente en el área de la arteria cerebral media. Se detectó que la diabetes y el exceso de consumo de calorías son factores de riesgo fundamentales

Immunosuppression alters disease severity in juvenile Batten disease mice

Autoantibodies to brain proteins are present in Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease) patients and in the Cln3(-/-) mouse model of this disease, suggesting an autoimmune component to pathogenesis. Using genetic or pharmaceutical approaches to attenuate this immune response in Cln3(-/-) mice, we demonstrate decreased neuroinflammation, decreased deposition of immunoglobulin G in the brain and protection of vulnerable neuron populations. Moreover, immune suppression results in a significant improvement in motor performance providing for the first plausible therapeutic approach for juvenile Batten disease. (C) 2010 Elsevier B.V. All rights reserved