RESUMO
Skeletal muscle biopsy remains an important investigative tool in the diagnosis of a variety of muscle disorders. Traditionally, someone with a limb-girdle muscle weakness, myopathic changes on electrophysiology and raised serum creatine kinase (CK) would have a muscle biopsy. However, we are living through a genetics revolution, and so do all such patients still need a biopsy? When should we undertake a muscle biopsy in patients with a distal, scapuloperoneal or other patterns of muscle weakness? When should patients with myositis, rhabdomyolysis, myalgia, hyperCKaemia or a drug-related myopathy have a muscle biopsy? What does normal muscle histology look like and what changes occur in neurogenic and myopathic disorders? As with Kipling's six honest serving men, we hope that by addressing these issues we can all become more confident about when to request a muscle biopsy and develop clearer insights into muscle pathology.
Assuntos
Músculo Esquelético/patologia , Doenças Musculares/patologia , Miosite/patologia , Rabdomiólise/patologia , Adulto , Biópsia , Creatina Quinase/sangue , Feminino , Humanos , Masculino , Debilidade Muscular/diagnóstico , Debilidade Muscular/patologia , Doenças Musculares/diagnóstico , Miosite/diagnóstico , Rabdomiólise/diagnóstico , Adulto JovemRESUMO
Only a few cases of syndrome of inappropriate antidiuretic hormone secretion (SIADH) in the setting of amyotrophic lateral sclerosis (ALS) have been described in the literature. We present the case of an 81-year-old male who developed severe hyponatremia following elective total hip replacement. His past medical history included prostate cancer, which was under surveillance, and ischemic heart disease. He reported recent weight loss, worsening shortness of breath, and lethargy. SIADH was diagnosed on the basis of hyponatremia, elevated urinary sodium, and decreased serum osmolality, presumed secondary to surgery. Investigations revealed no occult malignancy and no other cause for hyponatremia. He was discharged when sodium levels had normalized, however, he then had several further admissions for hyponatremia, general fatigue, and breathlessness. His condition continued to decline, and he developed dysphagia, weakness, and tongue fasciculations. Neurological examination showed globally decreased power, increased tone, and fasciculations. MRI of the brain was normal. He did not respond to neostigmine treatment, and a presumed diagnosis of motor neuron disease was made. The patient passed away shortly after this, and a post-mortem confirmed the diagnosis of ALS. Drug, post-operative, and cancer-related causes were precluded by the timing of onset of hyponatremia. We present this case and an analysis of previously published cases alongside a discussion on the potential causative mechanisms.
Assuntos
Esclerose Lateral Amiotrófica/patologia , Secreções Corporais/metabolismo , Hiponatremia/patologia , Síndrome de Secreção Inadequada de HAD/patologia , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/diagnóstico , Encéfalo/patologia , Humanos , Hiponatremia/complicações , Hiponatremia/tratamento farmacológico , Síndrome de Secreção Inadequada de HAD/complicações , Síndrome de Secreção Inadequada de HAD/diagnóstico , Masculino , Vasopressinas/uso terapêuticoRESUMO
OBJECTIVE: Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events. DESIGN AND METHODS: Observational, inferential and experimental study, including: AIP mutation testing; reconstruction of 14 AIP-region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments. RESULTS: Nine European-origin, unrelated c.805_825dup-positive pedigrees (four familial, five sporadic from the UK, USA and France) included 16 affected (nine gigantism/four acromegaly/two non-functioning pituitary adenoma patients and one prospectively diagnosed acromegaly patient) and nine unaffected carriers. All pedigrees shared a 2.79 Mbp haploblock around AIP with additional haploblocks privately shared between subsets of the pedigrees, indicating the existence of an evolutionarily recent common ancestor, the 'English founder', with an estimated median tMRCA of 47 generations (corresponding to 1175 years) with a confidence interval (9-113 generations, equivalent to 225-2825 years). The mutation occurred in a small tandem repeat region predisposed to slipped strand mispairing. The resulting seven amino-acid duplication disrupts interaction with HSP90 and leads to a marked reduction in protein stability. CONCLUSIONS: The c.805_825dup allele, originating from a common ancestor, associates with a severe clinical phenotype and a high frequency of gigantism. The mutation is likely to be the result of slipped strand mispairing and affects protein-protein interactions and AIP protein stability.
Assuntos
Alelos , Gigantismo/diagnóstico , Gigantismo/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Feminino , França , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Masculino , Linhagem , Mapeamento de Interação de Proteínas/métodos , Estabilidade Proteica , Estrutura Secundária de Proteína , Reino Unido , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: Increasingly, biomarkers have been identified that correlate with improved overall and progression-free survival (OS and PFS) in glioblastoma, including MGMT methylation status and mutations in the IDH1 gene. In this study, we investigated the clinical and biological factors associated with long-term survival in glioblastoma patients treated with chemoradiotherapy. METHOD: Demographic and clinical data were collected for all patients with glioblastoma diagnosed between May 2004 and September 2007, treated with chemoradiotherapy and with associated tissue samples available for biomarker analysis. MGMT methylation was determined by pyrosequencing. IDH1 mutation was identified by R132H immunohistochemistry. Univariate Cox regression analysis of factors associated with survival and Kaplan-Meier survival analysis was performed using the SPSS statistics package. RESULTS: One hundred patients were included in the study. Median follow-up was 12.2 months (range 1.6-102.4). Median OS was 12.1 months (95 % CI: 10.8-13.3) and median PFS was 8.2 months (95 % CI: 6.8-9.5). The 2-, 3- and 5-year survival was 18, 9 and 6 % respectively. Three patients are still alive at 7.4, 8.3 and 8.5 years after diagnosis. Cox proportional-hazards regression identified independent prognostic factors for OS, female (p = 0.019), MGMT methylation (p < 0.0001) and IDH1 mutation (p = 0.023), and for PFS, MGMT methylation (p = 0.001) and IDH1 mutation (p = 0.018). Kaplan-Meier survival analysis showed that MGMT(methylated)/IDH1(+ve) was associated with a significantly longer OS 66.8 months (95 % CI: 0.0-167.8) and PFS 16.9 months (95 % CI: 11.1-22.7) when compared with MGMT(methylated)/IDH1(-ve) OS 15.5 months (95 % CI: 11.6-19.4) and PFS 9.4 months (95 % CI: 8-10.8) (log-rank, P = 0.000) and MGMT(unmethylated)/IDH1(-ve) OS 11.1 months (95 % CI: 8.5-13.7) and PFS 6.3 months (95 % CI: 4.4-8.3) (log-rank, p = 0.000). CONCLUSIONS: While the importance of MGMT methylation is well established, we demonstrate that the combination of MGMT(methylated)/IDH1(+ve) is associated with considerably longer OS and PFS in this series of chemoradiotherapy-treated glioblastoma tumours. The long-term cognitive function and quality of life in these long-term survivors warrant investigation.
Assuntos
Neoplasias Encefálicas/genética , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/genética , Isocitrato Desidrogenase/genética , Mutação , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Intervalo Livre de Doença , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras GenéticasRESUMO
We report a 3-year-old boy with anti-N-methyl-D-aspartate receptor encephalitis with a typical syndrome of movement disorder and encephalopathy and evidence of herpes simplex virus (HSV) type 1 infection on brain biopsy. HSV type 1 infection and anti-N-methyl-D-aspartate receptor encephalitis are temporally linked in some cases: this case suggests that prodromal HSV type-1 infection may be clinically subtle and easily missed.
Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/complicações , Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico , Encéfalo/patologia , Encefalite por Herpes Simples/complicações , Encefalite por Herpes Simples/diagnóstico , Encefalite Antirreceptor de N-Metil-D-Aspartato/tratamento farmacológico , Antivirais/uso terapêutico , Autoanticorpos , Biópsia , Encéfalo/metabolismo , Encéfalo/virologia , Pré-Escolar , Encefalite por Herpes Simples/tratamento farmacológico , Encefalite por Herpes Simples/virologia , Herpesvirus Humano 1/classificação , Herpesvirus Humano 1/genética , Humanos , Imunossupressores/uso terapêutico , Imageamento por Ressonância Magnética , Masculino , Reação em Cadeia da Polimerase , Resultado do TratamentoRESUMO
Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.
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Envelhecimento , Astrócitos/citologia , Encéfalo/patologia , Tauopatias/patologia , Proteínas tau/metabolismo , Animais , Encéfalo/metabolismo , Humanos , Neuroglia/patologia , Tauopatias/metabolismoRESUMO
Sotos syndrome is a rare overgrowth syndrome with an increased risk of tumorigenesis. To our knowledge we report the first case of astrocytoma in an adult patient with Sotos syndrome and describe the clinical course.
Assuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Glioma/patologia , Síndrome de Sotos/patologia , Doenças Talâmicas/patologia , Adulto , Astrocitoma/complicações , Neoplasias Encefálicas/complicações , Progressão da Doença , Glioma/complicações , Humanos , Imageamento por Ressonância Magnética , Masculino , Síndrome de Sotos/complicações , Doenças Talâmicas/complicações , Tomografia Computadorizada por Raios X , Conduta ExpectanteRESUMO
AIMS: Frontotemporal lobar degeneration (FTLD) and motor neurone disease are linked by the possession of a hexanucleotide repeat expansion in C9ORF72, and both show neuronal cytoplasmic inclusions within cerebellar and hippocampal neurones which are TDP-43 negative but immunoreactive for p62 and dipeptide repeat proteins (DPR), these being generated by a non-ATG RAN translation of the expanded region of the gene. METHODS: Twenty-two cases of FTLD from Newcastle were analysed for an expansion in C9ORF72 by repeat primed PCR and Southern blot. Detailed case note analysis was performed, and blinded retrospective clinical impressions were achieved by review of clinical histories. Sections from all major brain regions were immunostained for TDP-43, p62 and DPR. The extent of TDP-43 and DPR pathology in expansion bearers was compared with that in 13 other previously identified cases from the Manchester Brain Bank with established disease. RESULTS: Three Newcastle patients bearing an expansion in C9ORF72 were identified. These three patients died prematurely, two from bronchopneumonia within 10 months and 3 years of onset, and one from myocardial infarction 3 years after onset. In all three, DPR were plentiful throughout all cerebral cortical regions, hippocampus and cerebellum, but TDP-43 pathological changes were sparse. The severity of DPR pathological changes in these three patients was similar to that in the Manchester series, although the extent of TDP-43 pathology was significantly less. CONCLUSION: Widespread accumulation of DPR within nerve cells may occur much earlier than that of TDP-43 in patients with FTLD bearing expansion in C9ORF72.
Assuntos
Encéfalo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Dipeptídeos/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Proteínas/genética , Idoso , Encéfalo/patologia , Proteína C9orf72 , Expansão das Repetições de DNA , Feminino , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Humanos , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , Neurônios/patologiaRESUMO
BACKGROUND: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. METHODS: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5â×â10(-8)) single-nucleotide polymorphisms. FINDINGS: We identified novel associations exceeding the genome-wide significance threshold (p<5â×â10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05â×â10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51â×â10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57â×â10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44â×â10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. INTERPRETATION: Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. FUNDING: The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.
Assuntos
Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Demência Frontotemporal/classificação , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
We discuss the 8th known case of a patient who presented with an intradural intramedullary spinal melanocytic schwannoma. In this report we will discuss the hypothesis regarding the pathogenesis of the development of intradural schwannomas, the imaging modality of choice and treatment options.
Assuntos
Melanose/patologia , Melanose/cirurgia , Neurilemoma/patologia , Neurilemoma/cirurgia , Neoplasias da Medula Espinal/patologia , Neoplasias da Medula Espinal/cirurgia , Adulto , Humanos , Laminectomia , Masculino , Procedimentos Neurocirúrgicos , Complicações Pós-Operatórias/reabilitação , Incontinência Urinária/etiologia , Incontinência Urinária/reabilitaçãoRESUMO
Pathological diagnosis remains the gold standard for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD), but being able to differentiate between CJD and non-prion diseases clinically is important because many of the non-prion, rapidly progressive dementias are treatable. Diagnostic criteria need both high sensitivity and specificity while remaining applicable to clinical practice. Despite extensive updates to the clinical criteria for sCJD, there remains a heavy emphasis on neurological signs. We describe a psychiatric presentation of sCJD that did not fulfill the diagnostic criteria until very late in a prolonged disease course and required biopsy for diagnosis.
Assuntos
Sintomas Comportamentais/diagnóstico , Sintomas Comportamentais/psicologia , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/psicologia , Idoso , Sintomas Comportamentais/complicações , Sintomas Comportamentais/patologia , Encéfalo/patologia , Síndrome de Creutzfeldt-Jakob/complicações , Síndrome de Creutzfeldt-Jakob/patologia , Feminino , HumanosRESUMO
BACKGROUND: Intracranial granulomatous masses presenting as space occupying lesions, although rare, have been described in the literature. Causes include infections, systemic granulomatous disorders, and iatrogenic from previous surgery. We present a case demonstrating that spontaneous intracranial granuloma can exist, often mimicking a brain tumor. CASE DESCRIPTION: A 62-year-old female presented with a short history of left sided partial seizures and a left hemiparesis. Magnetic resonance imaging revealed a right sided parafalcine lesion. Histopathology demonstrated chronic inflammation of granulomatous type. She responded to steroid treatment. CONCLUSION: She responded to steroid treatment. Our case demonstrated that spontaneous intracranial granuloma exists. Although rare, it should be considered in patients presenting with space occupying lesions. They can successfully be managed with steroid treatment.
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OBJECTIVE: To determine whether cases of frontotemporal lobar degeneration (FTLD) do exist in elderly individuals and have clinical and neuropathological features distinct from those with presenile onset. DESIGN: Retrospective matched cohort study. SETTING: Regional Neuroscience Centre, North East England. PATIENTS: We compared clinicopathological features of 11 cases of FTLD in elderly individuals with 19 cases of presenile-onset FTLD. RESULTS: Retrospective case note analysis showed that most elderly patients with FTLD had behavioral features consistent with orbitofrontal and basofrontal involvement, similar to presenile-onset FTLD, though symptomatic memory loss was present in 91% (10 of 11) of elderly patients with FTLD compared with only 36% (7 of 19) of patients with presenile-onset FTLD. Neuropathologically, the group of elderly patients with FTLD comprised 7 with FTLDTDP-43, 1 with ubiquitin-positive FTLD, 2 with FTLD-tau/Pick disease, and 1 with FTLD-tau/neurofibrillary tanglepredominant dementia with TDP-43, a composition similar to presenile-onset FTLD. However, hippocampal sclerosis was more common in elderly patients with FTLD than patients with presenile-onset FTLD (82% vs 37%) and more severe in elderly patients with FTLD (P < .05). By contrast, severe atrophy of the frontal and temporal lobes was less common in elderly patients with FTLD (frontal: 45%; temporal: 27%) than patients with presenile-onset FTLD (frontal: 63%; temporal: 78%). Elderly patients with FTLD represented 3.2% of all elderly patients with dementia autopsied at Newcastle General Hospital. CONCLUSIONS: Frontotemporal lobar degeneration in elderly patients does exist as a separate entity from presenile-onset FTLD. Its main features include (1) clinically frequent memory loss and behavioral change predominating over language and semantic dysfunction and (2) neuropathologically prominent hippocampal sclerosis but less pronounced cortical lobar atrophy. Clinically, FTLD in elderly patients is underrecognized and should be considered in the elderly subjects presenting with an "atypical Alzheimer disease" phenotype.
Assuntos
Encéfalo/patologia , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
Frontotemporal lobar degeneration (FTLD) is an umbrella term for a heterogeneous group of young-onset dementias of uncertain prevalence and incidence worldwide. Atypical cases of FTLD with fused in sarcoma inclusions (aFTLD-U) have been described recently, but their molecular characterization is still due. Using shotgun mass spectrometry, we identified a total of 107 differentially expressed proteins in the prefrontal cortex, cerebellum and occipital lobe from aFTLD-U patients compared to controls. These proteins are involved in a range of biological pathways such as cellular transport in the prefrontal cortex, energy metabolism in the cerebellum, and protein metabolism in the occipital lobe. In addition, they were validated by selective reaction monitoring (SRM). Comparison of the aFTLD-U proteomic findings with similar studies of Alzheimer's disease and schizophrenia led to identification of proteins that may be related to dementias and psychoses, respectively. Further studies of aFTLD-U and other FTLD subtypes are warranted, although this will require intensive biobanking efforts.
Assuntos
Cerebelo/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Lobo Occipital/metabolismo , Córtex Pré-Frontal/metabolismo , Proteoma/metabolismo , Sequência de Aminoácidos , Transporte Biológico , Cerebelo/química , Metabolismo Energético , Humanos , Dados de Sequência Molecular , Lobo Occipital/química , Especificidade de Órgãos , Córtex Pré-Frontal/química , Mapas de Interação de Proteínas , Proteoma/análise , Proteômica , Reprodutibilidade dos Testes , Estatísticas não Paramétricas , Biologia de SistemasRESUMO
CONTEXT: Isolated involvement of the spinal cord is an uncommon presentation of neuro-Behçet's disease (NBD) and it is associated with a poor prognosis for functional recovery. METHOD: A case report of an 18-year-old Turkish man who presented with a progressive paraparesis and bladder dysfunction secondary to a longitudinally extensive transverse myelitis as the sole presentation of NBD. FINDINGS: Examination revealed a spastic paraparesis and a T7 sensory level. Magnetic resonance imaging revealed multiple enhancing lesions throughout the thoracic cord and cerebrospinal fluid showed intense neutrophilia. On further enquiry a family history of Behçet's disease was elicited. The patient subsequently reported a history of recurrent oral ulceration and intermittent occular inflammation. A diagnosis of NBD was made and intravenous high-dose steroids commenced with poor response. In view of the poor prognosis for functional recovery associated with spinal NBD the patient was treated with infliximab, an anti-tumour necrosis factor-alpha monoclonal antibody, leading to excellent recovery of function. CONCLUSION/CLINICAL RELEVANCE: Early treatment with infliximab may facilitate a favourable functional recovery and should be considered in cases of NBD with spinal cord involvement.
Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Síndrome de Behçet/tratamento farmacológico , Mielite Transversa/tratamento farmacológico , Adolescente , Síndrome de Behçet/complicações , Humanos , Infliximab , Imageamento por Ressonância Magnética , Masculino , Mielite Transversa/complicações , Vértebras Torácicas/patologiaRESUMO
We present the first characterization of the human occipital lobe (primary visual cortex) and cerebellum proteomes. Proteins were identified using a combination of gel electrophoresis and data-independent nanoflow liquid chromatography mass spectrometry (nLC-MS(E) ). The resulting data sets comprised 391 and 330 unique proteins in occipital lobe and cerebellum, respectively, present in at least 75% of the analyzed samples with 297 proteins found in common. These proteins have been associated previously with conditions, such as neurological disorder, progressive motor neuropathy, Parkinson's disease and schizophrenia. The unique proteins identified in the occipital lobe included the interesting finding of growth hormone and several members of the Ca²âº-dependent calmodulin kinase and serine/threonine protein phosphatase families. The complete mapping of these and other brain proteomes may help in the elucidation of neurological processes and identify potential targets for therapeutic strategies.
Assuntos
Cerebelo/química , Espectrometria de Massas/métodos , Proteínas do Tecido Nervoso/análise , Proteoma , Córtex Visual/química , Mapeamento Encefálico , Cromatografia Líquida/métodos , Eletroforese em Gel Bidimensional/métodos , Humanos , Proteoma/análiseRESUMO
Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Recent descriptions of a pathological sub-type that is ubiquitin positive, TDP-43 negative and immunostains positive for the Fused in Sarcoma protein (FUS) raises the question whether it is associated with a distinct clinical phenotype identifiable on clinical grounds, and whether mutations in the Fused in Sarcoma gene (FUS) might also be associated with FTLD. Examination of a pathological series of 118 cases of FTLD from two centres, showing tau-negative, ubiquitin-positive pathology, revealed FUS pathology in five patients, four classified as atypical FTLD with ubiquitin inclusions (aFTLD-U), and one as neuronal intermediate filament inclusion disease (NIFID). The aFTLD-U cases had youthful onset (22-46 years), an absence of strong family history, a behavioural syndrome consistent with frontotemporal dementia (FTD) and severe caudate atrophy. Their cognitive/behavioural profile was distinct, characterised by prominent obsessionality, repetitive behaviours and rituals, social withdrawal and lack of engagement, hyperorality with pica, and marked stimulus-bound behaviour including utilisation behaviour. They conformed to the rare behavioural sub-type of FTD identified previously by us as the "stereotypic" form, and linked to striatal pathology. Cognitive evaluation revealed executive deficits in keeping with subcortical-frontal dysfunction, but no cortical deficits in language, perceptuospatial skills or praxis. The patient with NIFID was older and exhibited aphasia and dyspraxia. No patient had clinical evidence of motor neurone disease during life, or a mutation in the FUS gene. In the complementary clinical study of 312 patients with clinical syndromes of FTLD, genetic analysis revealed a 6 bp deletion in FUS in 3 patients, of questionable significance. One presented a prototypical picture of FTD, another expressive language disorder, and the third semantic dementia. None showed the early onset age or distinctive 'stereotypic' picture of patients with aFTLD-U. We conclude that aFTLD-U is associated with a distinct clinical form of frontotemporal dementia, potentially allowing identification of such patients in life with a high degree of precision. Whether mutations in the FUS gene cause some cases of FTLD remains unresolved.