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1.
Mov Disord ; 38(11): 2103-2115, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37605305

RESUMEN

BACKGROUND: Mitochondrial membrane protein-associated neurodegeneration (MPAN) is caused by mutations in the C19orf12 gene. MPAN typically appears in the first two decades of life and presents with progressive dystonia-parkinsonism, lower motor neuron signs, optic atrophy, and abnormal iron deposits predominantly in the basal ganglia. MPAN, initially considered as a strictly autosomal recessive disease (AR), turned out to be also dominantly inherited (AD). OBJECTIVES: Our aim was to better characterize the clinical, molecular, and functional spectra associated with such dominant pathogenic heterozygous C19orf12 variants. METHODS: We collected clinical, imaging, and molecular information of eight individuals from four AD-MPAN families and obtained brain neuropathology results for one. Functional studies, focused on energy and iron metabolism, were conducted on fibroblasts from AD-MPAN patients, AR-MPAN patients, and controls. RESULTS: We identified four heterozygous C19orf12 variants in eight AD-MPAN patients. Two of them carrying the familial variant in mosaic displayed an atypical late-onset phenotype. Fibroblasts from AD-MPAN showed more severe alterations of iron storage metabolism and autophagy compared to AR-MPAN cells. CONCLUSION: Our data add strong evidence of the realness of AD-MPAN with identification of novel monoallelic C19orf12 variants, including at the mosaic state. This has implications in diagnosis procedures. We also expand the phenotypic spectrum of MPAN to late onset atypical presentations. Finally, we demonstrate for the first time more drastic abnormalities of iron metabolism and autophagy in AD-MPAN than in AR-MPAN. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Mosaicismo , Trastornos del Movimiento , Humanos , Proteínas Mitocondriales/genética , Hierro/metabolismo , Mutación/genética , Proteínas de la Membrana/genética , Fenotipo
2.
Neuropathol Appl Neurobiol ; 48(1): e12760, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34405431

RESUMEN

AIMS: Brain insulin resistance (i.e., decreased insulin/insulin-like growth factor-1 [IGF-1] signalling) may play a role in the pathophysiology of Parkinson's disease (PD), and several anti-diabetic drugs have entred clinical development to evaluate their potential disease-modifying properties in PD. A measure of insulin resistance is the amount of the downstream messenger insulin receptor substrate-1 that is phosphorylated at serine residues 312 (IRS-1pS312) or 616 (IRS-1pS616). We assessed IRS-1pS312 and IRS-1pS616 expression in post-mortem brain tissue of PD patients and a preclinical rat model based on viral-mediated expression of A53T mutated human α-synuclein (AAV2/9-h-α-synA53T). METHODS: IRS-1pS312 and IRS-1pS616 staining intensity were determined by immunofluorescence in both neurons and glial cells in the substantia nigra pars compacta (SNc) and putamen of PD patients and controls without known brain disease. We further explored a possible relation between α-synuclein aggregates and brain insulin resistance in PD patients. Both insulin resistance markers were also measured in the SNc and striatum of AAV2/9-h-α-synA53T rats. RESULTS: We found higher IRS-1pS312 staining intensity in nigral dopaminergic neurons and a trend for higher IRS-1pS312 staining intensity in putaminal neurons of PD patients. We observed no differences for IRS-1pS616 staining intensity in neurons or IRS-1pS312 staining intensity in glial cells. IRS-1pS312 showed high co-localisation within the core of nigral Lewy bodies. Like PD patients, AAV2/9-h-α-synA53T rats showed higher IRS-1pS312 staining intensity in the SNc and striatum than controls, whereas IRS-1pS616 was not different between groups. CONCLUSIONS: Our results provide evidence for brain insulin resistance in PD and support the rationale for repurposing anti-diabetic drugs for PD treatment.


Asunto(s)
Enfermedad de Parkinson , Animales , Encéfalo/metabolismo , Neuronas Dopaminérgicas/metabolismo , Humanos , Insulina/metabolismo , Enfermedad de Parkinson/metabolismo , Ratas , Sustancia Negra/metabolismo , alfa-Sinucleína/metabolismo
3.
Neurobiol Dis ; 118: 155-160, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30026036

RESUMEN

Slowly progressive, levodopa-responsive multiple system atrophy (MSA) may be misdiagnosed as Parkinson's disease (PD). Deep brain stimulation (DBS) is mostly ineffective in these patients and may even worsen the clinical course. Here we assessed whether neuropathological differences between patients with MSA who were treated with DBS of the subthalamic nucleus because of a misleading clinical presentation and typical disease cases may explain the more benign disease course of the former, and also the rapid clinical decline after surgery. The post-mortem assessment included the subthalamic nucleus, the globus pallidus, the thalamus and the putamen in five patients with MSA who received DBS and nine typical disease cases. There was no evidence for distinct neuroinflammatory profiles between both groups that could be related to the surgical procedure or that could explain the rapid clinical progression during DBS. Patients who received deep brain stimulation displayed a higher proportion of α-synuclein bearing neuronal cytoplasmic inclusions in the putamen compared with typical cases, while the number of surviving neurons was not different between groups. Our findings suggest that DBS does not induce neuroinflammatory changes in patients with MSA, at least several years after the surgery. We further hypothesize that the peculiar pattern of α-synuclein pathology may contribute to differences in the clinical phenotype, with a greater proportion of neuronal inclusions in the putamen being associated to a milder, "PD-like" phenotype with sustained levodopa response and slower disease progression.


Asunto(s)
Núcleo Caudado/patología , Estimulación Encefálica Profunda/tendencias , Atrofia de Múltiples Sistemas/patología , Atrofia de Múltiples Sistemas/terapia , Adulto , Anciano , Femenino , Humanos , Inflamación/patología , Inflamación/terapia , Masculino , Persona de Mediana Edad
4.
BMC Cancer ; 18(1): 653, 2018 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-29898691

RESUMEN

BACKGROUND: Although some countries have observed a stabilization in the incidence of CNS, an increasing incidence has been reported from multiple studies. Recent observations point out to the heterogeneity of incidence trends according to histological subtypes, gender and age-groups. Using a high-quality regional CNS tumor registry, this article describes the trends of CNS tumor incidence for main histological subtypes, including benign and malignant tumors, in the French department of Gironde from 2000 to 2012. METHODS: Crude and age-standardized incidence rates were calculated globally, by histological subtypes, malignant status, gender and age groups. For trends, annual percent changes (APC) were obtained from a piecewise log-linear model. RESULTS: A total of 3515 CNS tumors was registered during the period. The incidence of overall CNS tumors was 19/100000 person-years (8.3/100000 for neuroepithelial tumors and 7.3/100000 for meningeal tumors). An increased incidence of overall CNS tumors was observed from 2000 to 2012 (APC = + 2.7%; 95%-confidence interval (CI): 1.8-3.7). This trend was mainly explained by an increase in the incidence of meningiomas over the period (APC = + 5.4%, 95%-CI: 3.8-7.0). The increased incidence rate of CNS tumors was more pronounced in female and in older patients even though the incidence rate increased in all age groups. CONCLUSIONS: Part of the temporal variation may be attributed to improvement in registration, diagnosis and clinical practices but also to changes in potential risk factors. Thus, etiological studies on CNS tumors are needed to clarify this rising trend.


Asunto(s)
Neoplasias del Sistema Nervioso Central/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Francia/epidemiología , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Sistema de Registros , Distribución por Sexo , Adulto Joven
5.
Brain ; 140(5): 1420-1436, 2017 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-28334990

RESUMEN

See Stayte and Vissel (doi:10.1093/awx064) for a scientific commentary on this article. Multiple system atrophy is a fatal sporadic adult-onset neurodegenerative disorder with no symptomatic or disease-modifying treatment available. The cytopathological hallmark of multiple system atrophy is the accumulation of α-synuclein aggregates in oligodendrocytes, forming glial cytoplasmic inclusions. Impaired insulin/insulin-like growth factor-1 signalling (IGF-1) and insulin resistance (i.e. decreased insulin/IGF-1) have been reported in other neurodegenerative disorders such as Alzheimer's disease. Increasing evidence also suggests impaired insulin/IGF-1 signalling in multiple system atrophy, as corroborated by increased insulin and IGF-1 plasma concentrations in multiple system atrophy patients and reduced IGF-1 brain levels in a transgenic mouse model of multiple system atrophy. We here tested the hypothesis that multiple system atrophy is associated with brain insulin resistance and showed increased expression of the key downstream messenger insulin receptor substrate-1 phosphorylated at serine residue 312 in neurons and oligodendrocytes in the putamen of patients with multiple system atrophy. Furthermore, the expression of insulin receptor substrate 1 (IRS-1) phosphorylated at serine residue 312 was more apparent in inclusion bearing oligodendrocytes in the putamen. By contrast, it was not different between both groups in the temporal cortex, a less vulnerable structure compared to the putamen. These findings suggest that insulin resistance may occur in multiple system atrophy in regions where the neurodegenerative process is most severe and point to a possible relation between α-synuclein aggregates and insulin resistance. We also observed insulin resistance in the striatum of transgenic multiple system atrophy mice and further demonstrate that the glucagon-like peptide-1 analogue exendin-4, a well-tolerated and Federal Drug Agency-approved antidiabetic drug, has positive effects on insulin resistance and monomeric α-synuclein load in the striatum, as well as survival of nigral dopamine neurons. Additionally, plasma levels of exosomal neural-derived IRS-1 phosphorylated at serine residue 307 (corresponding to serine residue 312 in humans) negatively correlated with survival of nigral dopamine neurons in multiple system atrophy mice treated with exendin-4. This finding suggests the potential for developing this peripheral biomarker candidate as an objective outcome measure of target engagement for clinical trials with glucagon-like peptide-1 analogues in multiple system atrophy. In conclusion, our observation of brain insulin resistance in multiple system atrophy patients and transgenic mice together with the beneficial effects of the glucagon-like peptide-1 agonist exendin-4 in transgenic mice paves the way for translating this innovative treatment into a clinical trial.


Asunto(s)
Proteínas Sustrato del Receptor de Insulina/metabolismo , Resistencia a la Insulina , Atrofia de Múltiples Sistemas/metabolismo , Péptidos/farmacología , Ponzoñas/farmacología , Anciano , Anciano de 80 o más Años , Animales , Supervivencia Celular/efectos de los fármacos , Cuerpo Estriado/metabolismo , Neuronas Dopaminérgicas/fisiología , Exenatida , Femenino , Humanos , Proteínas Sustrato del Receptor de Insulina/biosíntesis , Proteínas Sustrato del Receptor de Insulina/sangre , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/sangre , Neuronas/metabolismo , Oligodendroglía/metabolismo , Fosforilación , Agregación Patológica de Proteínas/metabolismo , Putamen/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Lóbulo Temporal/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
6.
Clin Neuropathol ; 37(1): 6-15, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29154752

RESUMEN

A muscle biopsy is currently requested to assess the diagnosis of an idiopathic inflammatory myopathy overlapping with a systemic disease. During the past few years, the classification of inflammatory myopathy subtypes has been revisited progressively on the basis of correlations between clinical phenotypes, autoantibodies and histological data. Several syndromic entities are now more clearly defined, and the aim of the present review is to clarify the contribution of muscle biopsy in a setting of idiopathic inflammatory myopathies overlapping with systemic diseases.
.


Asunto(s)
Autoanticuerpos/inmunología , Inflamación/patología , Músculos/patología , Miositis/patología , Animales , Biopsia/métodos , Humanos , Inflamación/diagnóstico , Fenotipo
7.
Clin Neuropathol ; 36 (2017)(1): 5-14, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-27966427

RESUMEN

The 2016 update of the WHO classification has introduced an integrated diagnostic approach that incorporates both tumor morphology and molecular information. This conceptual change has far-reaching implications, especially for neuropathologists who are in the forefront of translating molecular markers to routine diagnostic use. Adult diffuse glioma is a prototypic example for a group of tumors that underwent substantial regrouping, and it represents a major workload for surgical neuropathologists. Hence, we conducted a survey among members of the European Confederation of Neuropathological Societies (Euro-CNS) in order to assess 1) the extent to which molecular markers have already been incorporated in glioma diagnoses, 2) which molecular techniques are in daily use, and 3) to set a baseline for future surveys in this field. Based on 130 responses from participants across 40 nations neuropathologists uniformly rate molecular marker testing as highly relevant and already incorporate molecular information in their diagnostic assessments. At the same time however, the survey documents substantial differences in access to crucial biomarkers and molecular techniques across geographic regions and within individual countries. Concerns are raised concerning the validity of test assays with MGMT, 1p19q, and ATRX; being perceived as most problematic. Neuropathologists advocate the need for international harmonization of standards and consensus guidelines, and the majority is willing to actively engage in interlaboratory trials aiming at quality control (Figure 1).
.


Asunto(s)
Neoplasias Encefálicas/diagnóstico , Glioma/diagnóstico , Oncología Médica/normas , Neurología/normas , Patología Clínica/normas , Adulto , Biomarcadores de Tumor/normas , Humanos , Encuestas y Cuestionarios
8.
Clin Neuropathol ; 36(5): 222-226, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28332472

RESUMEN

Primary diffuse leptomeningeal gliomatosis (PDLG) is characterized by diffuse infiltration of the leptomeningeal space by neoplastic glial cells without evidence of intra-parenchymatous primary tumor. We report a case of PDLG in a 68-year-old man, who died 1 month after onset of symptoms. The diagnosis was made on autopsy data. We discuss the particularities of this entity, which is not registered in the WHO classification of tumors of the central nervous system (2016). In case of an unexplained inflammatory meningeal process and in the presence of atypical cells in the cerebrospinal fluid, PDLG needs to be considered. This diagnosis of PDLG has to be confirmed by meningeal imaging-guided biopsy, which must be repeated if necessary.
.


Asunto(s)
Glioma/diagnóstico , Carcinomatosis Meníngea/diagnóstico , Carcinomatosis Meníngea/patología , Anciano , Glioma/patología , Humanos , Masculino
9.
BMC Neurol ; 16: 122, 2016 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-27475058

RESUMEN

BACKGROUND: Few patients are reported with dementia with Lewy bodies before fifty years-old, which may partly reflect the difficulty of accurate diagnosis in young population. We report the case of a 44-year-old male with pathologically confirmed sporadic dementia with Lewy bodies, who did not fulfil the revised clinical criteria for this disease. CASE PRESENTATION: We document this atypical case with clinical and cognitive evaluation, imaging, biochemistry, genetics and pathology investigations. Creutzfeldt-Jakob disease was first suspected in this patient with no previous medical history, who developed acute and rapid cognitive impairment, L-dopa-non-responsive parkinsonism, and delusion. Positive 14-3-3 protein was initially detected in cerebrospinal fluid and until the late stages of the disease. Severe atrophy with no diffusion hypersignal was found on structural MRI as well as an extensive hypometabolism on (18)F-FDG-PET, in comparison to age-matched healthy volunteers. Genetic investigation found no alpha-synuclein gene mutation. The patient died within 5 years, and post-mortem examination found numerous Lewy bodies and Lewy neurites consistent with pure Lewy body disease. CONCLUSIONS: This comprehensively described case illustrates that dementia with Lewy bodies can occur in young patients with atypical clinical presentation. Biochemistry and neuroimaging investigations can sometimes be insufficient to allow accurate diagnostic. More specific markers to support such diagnosis are needed.


Asunto(s)
Síndrome de Creutzfeldt-Jakob/diagnóstico , Enfermedad por Cuerpos de Lewy/diagnóstico , Proteínas 14-3-3/líquido cefalorraquídeo , Adulto , Encéfalo/patología , Trastornos del Conocimiento/diagnóstico , Síndrome de Creutzfeldt-Jakob/diagnóstico por imagen , Síndrome de Creutzfeldt-Jakob/patología , Deluciones/diagnóstico , Diagnóstico Diferencial , Resultado Fatal , Fluorodesoxiglucosa F18 , Estudios de Seguimiento , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico por imagen , Enfermedad por Cuerpos de Lewy/patología , Imagen por Resonancia Magnética/métodos , Masculino , Neuroimagen/métodos , Trastornos Parkinsonianos/diagnóstico , Tomografía de Emisión de Positrones/métodos
10.
Ann Pathol ; 36(3): 210-3, 2016 Jun.
Artículo en Francés | MEDLINE | ID: mdl-27210800

RESUMEN

Reticular (retiform) perineurioma is a rare variant of soft tissue perineurioma developed from the perineurium. This benign tumor is characterized by strands of spindle cells in a fibro-myxoid matrix surrounding pseudocystic mucoid spaces. We report a tibial nerve reticular perineurioma in a 35-year-old patient.


Asunto(s)
Neoplasias de la Vaina del Nervio/patología , Nervio Tibial/patología , Adulto , Humanos
11.
Mov Disord ; 30(13): 1802-12, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26260627

RESUMEN

BACKGROUND: MSA is a sporadic progressive neurodegenerative disorder characterized by a variable combination of parkinsonism, cerebellar ataxia, and autonomic dysfunction. The pathological hallmark of MSA is the accumulation of alpha-synuclein aggregates in the cytoplasm of oligodendrocytes along with neuronal loss and neuroinflammation, as well as blood-brain barrier dysfunction and myelin deterioration. Matrix metalloproteinases are zinc-dependent endopeptidases involved in the remodeling of the extracellular matrix, demyelination, and blood-brain barrier permeability. Several lines of evidence indicate a role for these enzymes in various pathological processes, including stroke, multiple sclerosis, Parkinson's, and Alzheimer's disease. METHODS: This study aimed to assess potential alterations of matrix metalloproteinase-1, -2, -3, and -9 expression or activity in MSA postmortem brain tissue. RESULTS: Gelatin zymography revealed increased matrix metalloproteinase-2 activity in the putamen, but not in the frontal cortex, of MSA patients relative to controls. Immunohistochemistry revealed increased number of glial cells positive for matrix metalloproteinase-1, -2, and -3 in the putamen and frontal cortex of MSA patients. Double immunofluorescence revealed that matrix metalloproteinase-2 and -3 were expressed in astrocytes and microglia. Only matrix metalloproteinase-2 colocalized with alpha-synuclein in oligodendroglial cytoplasmic inclusions. CONCLUSION: These results demonstrate widespread alterations of matrix metalloproteinase expression in MSA and a pattern of increased matrix metalloproteinase-2 expression and activity affecting preferentially a brain region severely affected (putamen) over a relatively spared region (frontal cortex). Elevated matrix metalloproteinase expression may thus contribute to the disease process in MSA by promoting blood-brain barrier dysfunction and/or myelin degradation.


Asunto(s)
Encéfalo/enzimología , Metaloproteinasas de la Matriz/metabolismo , Atrofia de Múltiples Sistemas/patología , Adulto , Anciano , Encéfalo/patología , Proteínas de Unión al Calcio , Proteínas de Unión al ADN/metabolismo , Densitometría , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Masculino , Proteínas de Microfilamentos , Persona de Mediana Edad , Neuroglía/metabolismo , Neuronas/metabolismo , Cambios Post Mortem , Adulto Joven , alfa-Sinucleína/metabolismo
12.
Transfusion ; 55(7): 1798-802, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25702952

RESUMEN

BACKGROUND: In thrombotic thrombocytopenic purpura (TTP), platelet (PLT) transfusion is contraindicated unless a life-threatening hemorrhage occurs. However, when PLT count is low (<20 × 10(9) /L), their benefit-risk balance before central venous catheter (CVC) insertion for plasma exchange (PE) has not specifically been addressed in guidelines. CASE REPORTS: We report two cases in which PLTs were transfused before CVC insertion for PE, resulting in fatal myocardial infarction or neurologic complications. DISCUSSION: To date, there is a paucity of high-quality, evidence-based information on prophylactic PLT transfusion for CVC placement in TTP. Several monocenter series report that CVC could be inserted safely without PLT transfusion by experienced teams under ultrasound guidance. Uncertainty makes most physicians uncomfortable with this decision and this is a common reason why PLT transfusion remains a "precautionary" albeit misguided position. CONCLUSION: We propose a practical algorithm to avoid unnecessary PLT transfusion before CVC insertion for rapid PE in the initial management of TTP patients. We recommend no prophylactic PLT transfusion but CVC insertion in a compressible vein under ultrasound guidance by an experienced team or quick PE started on two peripheral veins if possible. PLTs should only be transfused in case of severe bleeding in association with plasma infusion and CVC insertion for immediate PE.


Asunto(s)
Cateterismo Venoso Central , Intercambio Plasmático , Transfusión de Plaquetas/métodos , Púrpura Trombocitopénica Trombótica/sangre , Púrpura Trombocitopénica Trombótica/terapia , Adulto , Anciano , Femenino , Humanos , Masculino , Recuento de Plaquetas , Púrpura Trombocitopénica Trombótica/patología
13.
Muscle Nerve ; 52(4): 673-80, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25809233

RESUMEN

INTRODUCTION: X-linked myopathy with excessive autophagy (XMEA) is an X-linked recessive myopathy due to recently reported mutations in the VMA21 gene. METHODS: Four men from 2 separate families were studied. The clinical presentation, genetic data, muscle biopsy, and muscle MRI were analyzed. RESULTS: A known VMA21 mutation, c.163+4A>G, and a new mutation, c.163+3A>G, respectively, were found in the 2 families. The clinical course was characterized by onset in childhood and progressive muscle weakness with a limb-girdle pattern. Muscle biopsy revealed a mild myopathy with an increased number of giant autophagic vacuoles. Whole-body muscle MRI showed that pelvic girdle and proximal thighs were the most and earliest affected territories, with sparing of rectus femoris muscles. Muscle changes essentially consisted of degenerative fatty replacement. CONCLUSIONS: This study highlights a distinctive MRI pattern of muscle involvement, which can be helpful for diagnosis of XMEA, even before muscle biopsy or genetic analysis.


Asunto(s)
Autofagia , Músculo Esquelético/patología , Miopatías Estructurales Congénitas/patología , Adolescente , Adulto , Biopsia , Humanos , Imagen por Resonancia Magnética , Masculino , Músculo Esquelético/ultraestructura , Mutación/genética , Miopatías Estructurales Congénitas/genética , ATPasas de Translocación de Protón Vacuolares/genética
14.
Clin Neuropathol ; 34(4): 193-8, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25828776

RESUMEN

A 59-year-old man, ex-professional boxer, met clinical criteria for probable Alzheimer's disease. The patient agreed to be included in a clinico-pathological study with donation to the brain bank, and he died at 71. The brain was grossly atrophic, with a prominent atrophy of the entorhinal cortex and hippocampus, and with pallor of the substantia nigra. Immunohistochemistry with anti-τ A4 revealed abundant and diffuse deposits in the neo-cortex, whereas amyloid angiopathy was absent. Coupled anti-τ AT8 immunohistochemistry and Congo red staining showed no neuritic plaques. τ-AT8-positive glial tangles and neurofibrillary tangles involved preferentially the superficial cortical layers, and were irregularly concentrated in the depth of cortical sulci and near vessels. Neurofibrillary degeneration was marked in amygdala, hippocampus, substantia nigra, and locus ceruleus. Enlarged and/or distorted axons were numerous in hippocampus and mid-brain. TDP 43-positive neuronal inclusions were numerous in amygdala and hippocampus. There was no synucleinopathy. These observations are in accordance with the previously reported data on chronic traumatic encephalopathy. The discussion is focused on professional boxing as it becomes evident that repetitive trauma on the brain provokes the deposition of abnormal proteins involved in neurodegeneration.


Asunto(s)
Boxeo/lesiones , Lesiones Encefálicas/complicaciones , Lesiones Encefálicas/patología , Demencia/etiología , Demencia/patología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad
15.
Proc Natl Acad Sci U S A ; 109(24): 9611-6, 2012 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-22647602

RESUMEN

Parkinson disease (PD) is a progressive neurodegenerative disorder pathologically characterized by the loss of dopaminergic neurons from the substantia nigra pars compacta and the presence, in affected brain regions, of protein inclusions named Lewy bodies (LBs). The ATP13A2 gene (locus PARK9) encodes the protein ATP13A2, a lysosomal type 5 P-type ATPase that is linked to autosomal recessive familial parkinsonism. The physiological function of ATP13A2, and hence its role in PD, remains to be elucidated. Here, we show that PD-linked mutations in ATP13A2 lead to several lysosomal alterations in ATP13A2 PD patient-derived fibroblasts, including impaired lysosomal acidification, decreased proteolytic processing of lysosomal enzymes, reduced degradation of lysosomal substrates, and diminished lysosomal-mediated clearance of autophagosomes. Similar alterations are observed in stable ATP13A2-knockdown dopaminergic cell lines, which are associated with cell death. Restoration of ATP13A2 levels in ATP13A2-mutant/depleted cells restores lysosomal function and attenuates cell death. Relevant to PD, ATP13A2 levels are decreased in dopaminergic nigral neurons from patients with PD, in which ATP13A2 mostly accumulates within Lewy bodies. Our results unravel an instrumental role of ATP13A2 deficiency on lysosomal function and cell viability and demonstrate the feasibility and therapeutic potential of modulating ATP13A2 levels in the context of PD.


Asunto(s)
Adenosina Trifosfatasas/metabolismo , Lisosomas/metabolismo , Enfermedad de Parkinson/patología , Línea Celular , Técnicas de Silenciamiento del Gen , Humanos , Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/metabolismo
16.
Nat Genet ; 38(1): 24-6, 2006 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-16369530

RESUMEN

We report duplication of the APP locus on chromosome 21 in five families with autosomal dominant early-onset Alzheimer disease (ADEOAD) and cerebral amyloid angiopathy (CAA). Among these families, the duplicated segments had a minimal size ranging from 0.58 to 6.37 Mb. Brains from individuals with APP duplication showed abundant parenchymal and vascular deposits of amyloid-beta peptides. Duplication of the APP locus, resulting in accumulation of amyloid-beta peptides, causes ADEOAD with CAA.


Asunto(s)
Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/genética , Encéfalo/patología , Angiopatía Amiloide Cerebral/genética , Duplicación de Gen , Edad de Inicio , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/análisis , Estudios de Casos y Controles , Angiopatía Amiloide Cerebral/epidemiología , Angiopatía Amiloide Cerebral/patología , Femenino , Genes Dominantes , Humanos , Masculino , Repeticiones de Microsatélite , Reacción en Cadena de la Polimerasa/métodos
18.
J Peripher Nerv Syst ; 19(4): 333-42, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25582874

RESUMEN

Peripheral neuropathy (PN) has been reported in idiopathic and hereditary forms of parkinsonism, but the pathogenic mechanisms are unclear and likely heterogeneous. Levodopa-induced vitamin B12 deficiency has been discussed as a causal factor of PN in idiopathic Parkinson's disease, but peripheral nervous system involvement might also be a consequence of the underlying neurodegenerative process. Occurrence of PN with parkinsonism has been associated with a panel of mitochondrial cytopathies, more frequently related to a nuclear gene defect and mainly polymerase gamma (POLG1) gene. Parkin (PARK2) gene mutations are responsible for juvenile parkinsonism, and possible peripheral nervous system involvement has been reported. Rarely, an association of parkinsonism with PN may be encountered in other neurodegenerative diseases such as fragile X-associated tremor and ataxia syndrome related to premutation CGG repeat expansion in the fragile X mental retardation (FMR1) gene, Machado-Joseph disease related to an abnormal CAG repeat expansion in ataxin-3 (ATXN3) gene, Kufor-Rakeb syndrome caused by mutations in ATP13A2 gene, or in hereditary systemic disorders such as Gaucher disease due to mutations in the ß-glucocerebrosidase (GBA) gene and Chediak-Higashi syndrome due to LYST gene mutations. This article reviews conditions in which PN may coexist with parkinsonism.


Asunto(s)
Enfermedad de Parkinson/complicaciones , Enfermedades del Sistema Nervioso Periférico/etiología , Humanos
19.
J Peripher Nerv Syst ; 19(1): 44-9, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24494664

RESUMEN

Intracellular protein aggregates are common pathological hallmarks of many neurodegenerative disorders, and a defect in axonal transport is also incriminated. Here, we studied intra-axonal abnormal protein aggregation and axonopathy by using immunohistochemistry and electron microscopy on peripheral nerve biopsies from 12 patients with chronic axonal peripheral neuropathy (PN) of unknown etiology. Among these patients, three had idiopathic Parkinson's disease (PD). Intra-axonal ubiquitin aggregates were more numerous in the patients with PD. Intra-axonal aggregates of tau AT8 were found in five patients without PD. Phosphorylated α-synuclein aggregation was absent in all cases, while intra-axonal colocalization of 14-3-3 ß and ubiquitin was observed in two PD cases. Electron microscopy revealed enlarged axons crowded with organelles in six cases, including the three patients with PD, thus attesting a slowing of the axoplasmic flux. The number of ubiquitin aggregates was correlated with features of reduced axonal flux, while no such correlation was found for tau and 14-3-3 ß. Age did not correlate with the number of tau, ubiquitin, and 14-3-3 aggregates. Thus, both ubiquitin and/or abnormal tau intra-axonal aggregates may be found in chronic axonal PN. Ubiquitin aggregates might reduce the axonal flux or result from a disease producing slowing of axonal transport.


Asunto(s)
Axones/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Nervios Periféricos/metabolismo , alfa-Sinucleína/metabolismo , Proteínas 14-3-3/metabolismo , Anciano , Anciano de 80 o más Años , Axones/patología , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/patología , Nervios Periféricos/patología , Enfermedades del Sistema Nervioso Periférico/patología
20.
Clin Neuropathol ; 33(3): 172-8, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24618073

RESUMEN

Simultaneous combined superficial peroneal nerve and peroneous brevis muscle biopsy, via the same cutaneous incision, allows examination of several tissue specimens and significantly improves the diagnosis of systemic diseases with peripheral nerve involvement. Vasculitides are certainly the most frequently diagnosed on neuro-muscular biopsies, but this procedure is also well advised to asses a diagnosis of sarcoidosis or amyloidosis. More occasionally, combined nerve and muscle biopsy may reveal an unpredicted diagnosis of cholesterol embolism, intra-vascular lymphoma, or enables complementary diagnosis investigations on mitochondrial cytopathy or storage disease.


Asunto(s)
Biopsia/métodos , Enfermedades Musculares/patología , Enfermedades Neuromusculares/patología , Enfermedades del Sistema Nervioso Periférico/patología , Guías de Práctica Clínica como Asunto , Diagnóstico Diferencial , Humanos , Músculo Esquelético/patología , Enfermedades Musculares/diagnóstico , Enfermedades Neuromusculares/diagnóstico , Nervios Periféricos/patología , Enfermedades del Sistema Nervioso Periférico/diagnóstico
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