RESUMEN
The molecular mechanisms by which the nuclear genome regulates the biosynthesis of mitochondrial DNA (mtDNA) are only beginning to be unravelled. A naturally occurring in vivo model for a defect in this cross-talk of two physically separate genomes is a human disease, an autosomal dominant progressive external ophthalmoplegia, in which multiple deletions of mtDNA accumulate in the patients' tissues. The assignment of this disease locus to 10q 23.3-24.3 is the first direct evidence for involvement of both nuclear and mitochondrial genomes in a single disorder.
Asunto(s)
Cromosomas Humanos Par 10 , ADN Mitocondrial/genética , Proteínas Mitocondriales , Proteínas Nucleares , Oftalmoplejía Externa Progresiva Crónica/genética , Secuencia de Bases , Causalidad , Aberraciones Cromosómicas/epidemiología , Aberraciones Cromosómicas/genética , Trastornos de los Cromosomas , Mapeo Cromosómico , Proteínas de Unión al ADN/genética , Femenino , Eliminación de Gen , Heterogeneidad Genética , Marcadores Genéticos , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Factores de Transcripción/genéticaRESUMEN
We describe a novel variant of Alzheimer's disease (AD) in a Finnish pedigree with 17 affected individuals of both sexes in three generations. The disease is characterized by progressive dementia which is, in most cases, preceded by spastic paraparesis. Neuropathological investigations revealed numerous, distinct, large, round and eosinophilic plaques as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton wool balls and were immunoreactive for Abeta but lacked a congophilic dense core or marked plaque-related neuritic pathology. Molecular genetic analysis revealed that the disease was caused by a deletion of exon 9 (delta9) of the presenilin 1 (PS1) gene from the mRNA: unlike previous examples of the delta9 variant, the deletion was not caused by a splice acceptor site mutation.
Asunto(s)
Enfermedad de Alzheimer/genética , Corteza Cerebral/patología , Variación Genética , Proteínas de la Membrana/genética , Placa Amiloide/genética , Eliminación de Secuencia , Paraplejía Espástica Hereditaria/genética , Edad de Inicio , Anciano , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/patología , Exones , Femenino , Finlandia , Humanos , Intrones , Masculino , Persona de Mediana Edad , Ovillos Neurofibrilares/patología , Linaje , Placa Amiloide/patología , Reacción en Cadena de la Polimerasa , Presenilina-1 , ARN Mensajero/biosíntesis , Paraplejía Espástica Hereditaria/complicaciones , Paraplejía Espástica Hereditaria/patologíaRESUMEN
Familial amyloidosis, Finnish type (FAF), is an autosomal dominant form of familial amyloid polyneuropathy. The novel amyloid fibril protein found in these patients is a degradation fragment of gelsolin, an actin-binding protein. We found a mutation (adenine for guanine) at nucleotide 654 of the gelsolin gene in genomic DNA isolated from five FAF patients. This site is polymorphic since the normal allele was also present in all the patients tested. This mutation was not found in two unaffected family members and 11 normal controls. The A for G transition causes an amino acid substitution (asparagine for aspartic acid) that was found at position 15 of the amyloid protein. The mutation and consequent amino acid substitution may lead to the development of FAF.
Asunto(s)
Amiloidosis/genética , Proteínas de Unión al Calcio/genética , Genes , Proteínas de Microfilamentos/genética , Mutación , Secuencia de Aminoácidos , Secuencia de Bases , ADN/genética , ADN/aislamiento & purificación , Finlandia , Gelsolina , Humanos , Linfocitos/metabolismo , Datos de Secuencia Molecular , Sondas de Oligonucleótidos , Reacción en Cadena de la PolimerasaRESUMEN
Multiple deletions of mitochondrial DNA (mtDNA) have recently been reported in familial progressive external ophthalmoplegia (PEO), in a case of progressive encephalomyopathy, and in inherited recurrent myoglobinuria. The inheritance of familial PEO has been autosomal dominant, which indicates that a mutation in an unknown nuclear gene results in several mtDNA deletions of different sizes in these patients. We report a patient with autosomal dominant PEO, whose major clinical symptom, however, was severe retarded depression. The morphological analyses of the tissue samples derived from autopsy showed various abnormalities in the mitochondria in all the tissues studied. The activities of the respiratory chain enzymes encoded by mtDNA were remarkably reduced in the skeletal muscle. The mtDNA analyses confirmed that besides myopathy, this patient had a multisystem disorder with widespread distribution of multiple deletions of mtDNA. The highest percentage of mutated mtDNA was found in the brain, skeletal muscle and the heart, the relative quantity of mutated mtDNA correlating to the severity of the clinical symptoms.
Asunto(s)
Deleción Cromosómica , ADN Mitocondrial/análisis , Trastorno Depresivo/genética , Discapacidad Intelectual/genética , Oftalmoplejía/genética , Humanos , Persona de Mediana Edad , Fosforilación Oxidativa , Reacción en Cadena de la PolimerasaRESUMEN
OBJECTIVE: To relate the expression of HIV regulatory proteins and HIV-specific mRNA in the brain cells of infected individuals with clinical neurological disease. DESIGN: Formalin-fixed postmortem brain tissue from 14 HIV-infected adult patients, with previous repeated neurological and neuroradiological examinations, was studied by immunohistochemical and molecular biological methods. Samples from non-infected brains served as controls. METHODS: Immunohistochemistry with monoclonal antibodies (MAb) was combined with in situ RNA hybridization. Target cells were identified with MAb to glial fibrillary acidic protein (GFAP; astrocytes), CD68 (activated macrophages) and Ricinus communis agglutinin (RCA-1; microglia, endothelial cells). For HIV, a panel of MAb against HIV Nef, Tat, Rev and Env proteins or probes specific for all classes of mRNA (nef), for singly or non-spliced mRNA (env) and for non-spliced mRNA (gag/pol) were used. RESULTS: Nef protein was detected in subcortical or subpial astrocytes in seven out of 14 samples, and in multinucleated giant cells in two cases. Gag/pol or env mRNA-expressing astrocytes were detected in four cases. In four out of five cases studied, HIV Rev, but not Tat, was also expressed in astrocytes. Six out of the seven patients with Nef-positive astrocytes had suffered from moderate to severe dementia. The patient with most rapidly progressing severe dementia showed extensive HIV mRNA expression together with Nef and Rev expression in astrocytes. CONCLUSION: In adult human brain, astrocytes are infected by HIV and preferentially express HIV Nef and Rev proteins but are also sometimes productively infected. Astrocyte infection is associated with moderate to severe dementia which agrees with recent knowledge on the housekeeping activities of astrocytes and their eventual role in learning and memory.
Asunto(s)
Complejo SIDA Demencia/virología , Astrocitos/virología , Encéfalo/virología , Productos del Gen nef/genética , Productos del Gen rev/genética , VIH/genética , Complejo SIDA Demencia/patología , Adulto , Astrocitos/patología , Encéfalo/patología , Femenino , Regulación Viral de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Masculino , ARN Mensajero/genética , Productos del Gen nef del Virus de la Inmunodeficiencia Humana , Productos del Gen rev del Virus de la Inmunodeficiencia HumanaRESUMEN
The neuronal ceroid-lipofuscinoses (NCL) are among the most common inherited neurodegenerative disorders of childhood. The genomic defect causing a variant late infantile neuronal ceroid-lipofuscinosis (vLINCL, also called CLN-5 or variant Jansky-Bielschowsky disease) has recently been localized to chromosome 13q22, thus delineating this disease as a separate entity. This particular form of NCL is clinically well defined, but lacks pathomorphological and biochemical description. The present analyses indicate that subunit c of the mitochondrial ATP synthase is the major protein in vLINCL brain storage cytosomes. These cytosomes also contain minor amounts of sphingolipid activator proteins (SAPs). The immunohistological distribution of subunit c and SAPs in the central nervous system (CNS) and visceral tissues closely resembles that of classical LINCL. Thus, despite clinical differences and the fact that various forms of NCL are caused by different genetic defects, variant and classical LINCL as well as juvenile NCL are all characterized by pronounced lysosomal accumulation of the same hydrophobic protein, subunit c of the mitochondrial ATP synthase.
Asunto(s)
Variación Genética , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/metabolismo , Lipofuscinosis Ceroideas Neuronales/patología , Adulto , Anciano , Anciano de 80 o más Años , Western Blotting , Electroforesis en Gel de Poliacrilamida , Femenino , Humanos , Inmunoquímica , Masculino , Microscopía InmunoelectrónicaRESUMEN
Arteriovenous malformations (AVMs) are congenital lesions composed of abnormal vasculature, with no capillary component, and are clinically significant due to their tendency to spontaneously hemorrhage. The mechanisms regulating the genesis and progression of these lesions are unknown. In order to study the role of angiogenesis in AVMs, we have analyzed the expression of the endothelial cell mitogen vascular endothelial growth factor (VEGF) and a novel endothelial cell-specific receptor tyrosine kinase, Tie, by in situ hybridization and immunohistochemistry in these malformations and surrounding brain tissue. We have previously shown upregulation of Tie accompanying wound healing and tumor progression. In this study, we demonstrate significantly elevated levels of Tie mRNA and protein in AVM and surrounding brain vasculature. Upregulation of VEGF mRNA was observed in the cells of brain parenchyma adjacent to the AVM, and VEGF protein was detected in this tissue as well as in AVM endothelia. Normal brain, in comparison, expressed little or no Tie or VEGF. The significant upregulation of VEGF and Tie in AVMs may indicate some ongoing angiogenesis, possibly contributing to the slow growth and maintenance of the AVM, and could be of potential use in the therapeutic targeting of these lesions.
Asunto(s)
Vasos Sanguíneos/metabolismo , Endotelio Vascular/metabolismo , Malformaciones Arteriovenosas Intracraneales/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Regulación hacia Arriba , Adulto , Antígenos Nucleares , Biomarcadores , Vasos Sanguíneos/patología , División Celular , Niño , Factores de Crecimiento Endotelial/genética , Factores de Crecimiento Endotelial/metabolismo , Endotelio Vascular/patología , Femenino , Humanos , Malformaciones Arteriovenosas Intracraneales/patología , Linfocinas/genética , Linfocinas/metabolismo , Masculino , Persona de Mediana Edad , Proteínas Nucleares/metabolismo , ARN Mensajero/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Receptores TIE , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
Variant Alzheimer disease (varAD) is clinically characterized by the combination of presenile dementia with spastic paraparesis and is caused by certain mutations of the presenilin 1 (PS-1) gene. We now present the unusual neuropathological phenotype of varAD as seen in 5 affected members of the original Finnish family with a genomic deletion encompassing exon 9 of the PS-1 gene. Their primary and association cortices and hippocampus showed a profusion of eosinophilic, roundish structures with distinct borders termed "cotton wool" plaques (CWPs). The CWPs were immunoreactive for Abeta42/43 but weakly or not at all for Abeta40 isoforms of the amyloid beta peptide (Abeta). They were devoid of a congophilic core, and fibrillar amyloid could not be identified within them by electron microscopy. Confocal microscopy showed reduced density of axons within individual CWPs and only few CWP-related PHF-tau-positive dystrophic neurites. CWPs were particularly numerous in the medial motor cortex representing the lower extremities, and degeneration of the lateral corticospinal tracts was observed at the level of the medulla oblongata and the spinal cord. In addition to the predominant CWPs, variable numbers of diffuse and cored plaques were found in the cerebral cortex. Diffuse and non-neuritic cored amyloid plaques but no CWPs occurred in the cerebellum. In conclusion, varAD in this Finnish family is distinct from classic AD because of the degeneration of lateral corticospinal tracts, predominance of CWPs devoid of fibrillar amyloid cores in the cerebral cortex, and presence of non-neuritic amyloid plaques in the cerebellum.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Encéfalo/patología , Variación Genética , Paraparesia Espástica/complicaciones , Enfermedad de Alzheimer/patología , Exones/genética , Femenino , Eliminación de Gen , Humanos , Inmunohistoquímica , Masculino , Proteínas de la Membrana/genética , Microscopía Confocal , Microscopía Electrónica , Persona de Mediana Edad , Paraparesia Espástica/patología , Fenotipo , Presenilina-1 , Tractos Piramidales/patologíaRESUMEN
To elucidate the mechanisms underlying the regulation of growth and differentiation of capillary hemangioblastoma we studied the expression of selected growth factors and growth factor receptors by immunocytochemistry. As stromal cells of capillary hemangioblastoma express high levels of vascular endothelial growth factor (VEGF) and placental growth factor (P1GF) mRNA, we studied the distribution of the corresponding VEGF and P1GF proteins. We also studied the expression of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptors (PDGFR) because their ligands have been reported to promote angiogenesis. The stromal cells expressed abundant EGFR and, in addition, some stromal cells expressed PDGFR-alpha but not PDGFR-beta. In contrast, the endothelial cells co-expressed PDGFR-alpha and PDGFR-beta. VEGF and P1GF were expressed by scattered stromal cells; however, more intense staining was observed in the endothelial cells of the intratumoral blood vessels, possibly indicating the secreted growth factors bound to their target receptors. We conclude that capillary hemangioblastomas express a variety of growth factor receptors and ligands, potentially involved in both autocrine and paracrine loops. The uniformly high EGFR expression is unique among brain tumors and may be associated with the typical morphology of capillary hemangioblastoma. The expression of highly angiogenic growth factors and their receptors may contribute to the rich vascularity of this enigmatic tumor.
Asunto(s)
Neoplasias del Sistema Nervioso Central/metabolismo , Sustancias de Crecimiento/biosíntesis , Hemangioblastoma/metabolismo , Proteínas de Neoplasias/biosíntesis , Receptores de Factores de Crecimiento/biosíntesis , Adulto , Anciano , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/metabolismo , Neoplasias Cerebelosas/patología , Receptores ErbB/biosíntesis , Receptores ErbB/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Sustancias de Crecimiento/genética , Hemangioblastoma/genética , Hemangioblastoma/patología , Humanos , Masculino , Bulbo Raquídeo , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Neovascularización Patológica/genética , Receptores de Factores de Crecimiento/genética , Neoplasias de la Médula Espinal/genética , Neoplasias de la Médula Espinal/metabolismo , Neoplasias de la Médula Espinal/patología , Enfermedad de von Hippel-Lindau/genética , Enfermedad de von Hippel-Lindau/metabolismo , Enfermedad de von Hippel-Lindau/patologíaRESUMEN
Proliferative activity and DNA index were analyzed and correlated with histology and survival in 30 primary central nervous system lymphomas (PCNSL) in immunocompetent patients. Proliferative activity was determined using mitotic activity index and volume-corrected mitotic index, percentage of Ki-67 (MIB-1) immunopositive nuclei and flow cytometric S-phase fraction. Twenty-nine PCNSL were of B-cell origin and one of T-cell; by Kiel classification there were 23% low grade and 77% high grade and by Working Formulation there were 7%, 73% and 20% low, intermediate and high grade tumors, respectively. Mean survival time for non-survivors (n = 26) was 11.5 months and median 6.5 months. When indicators of proliferative activity were evaluated against histological grading, correlation existed only between mitotic activity index and Kiel classification. None of the proliferation markers or DNA index correlated significantly with survival, but there was a trend for patients with higher volume-corrected mitotic index to have shorter survival. In conclusion, most PCNSL have poor prognosis irrespective of their histological grade and proliferative activity. Furthermore, because at present stereotactic biopsy is recommended for establishing the diagnosis, exact histological subtyping and determination of proliferation activity in such small samples appears to be of only marginal significance.
Asunto(s)
Supervivencia Celular , Sistema Nervioso Central/patología , ADN/genética , Linfoma/genética , Linfoma/patología , Adulto , Anciano , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Índice Mitótico , Pronóstico , Factores de TiempoRESUMEN
Aspartylglucosaminuria (AGU) is a recessively inherited lysosomal storage disorder caused by the deficiency of the aspartylglucosaminidase (AGA) enzyme. The hallmark of AGU is slowly progressing mental retardation but the progression of brain pathology has remained uncharacterized in humans. Here we describe the long-term follow-up of mice carrying a targeted AGU-mutation in both alleles. Immunohistochemistry, histology, electron microscopy, quantitative magnetic resonance imaging (MRI) and behavioral studies were carried out to evaluate the CNS affection of the disease during development. The lysosomal storage vacuoles of the AGA -/- mice were most evident in central brain regions where MRI also revealed signs of brain atrophy similar to that seen in the older human patients. By immunohistochemistry and MRI examinations, a subtle delay of myelination was observed in AGA -/- mice. The life span of the AGA -/- mice was not shortened. Similar to the slow clinical course observed in human patients, the AGA -/- mice have behavioral symptoms that emerge at older age. Thus, the AGU knock-out mice represent an accurate model for AGU, both histopathologically and phenotypically.
Asunto(s)
Aspartilglucosaminuria , Sistema Nervioso Central/patología , Monitoreo Fisiológico/métodos , Animales , Aspartilglucosilaminasa/orina , Conducta Animal/fisiología , Humanos , Immunoblotting , Inmunohistoquímica , Discapacidad Intelectual/enzimología , Discapacidad Intelectual/patología , Imagen por Resonancia Magnética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Electrónica , Vaina de Mielina/fisiología , Proteínas del Tejido Nervioso/metabolismo , ARN Mensajero/análisisRESUMEN
Multiple deletions of mitochondrial DNA (mtDNA) have recently been described in a number of patients with neurological disorders. Most cases have been clinically characterized by autosomal dominant inheritance, adult onset, and a slowly progressive course with external ophthalmoplegia and muscle weakness. Some patients have had evidence of central or peripheral nervous system involvement or episodes of myoglobinuria. Muscle biopsy findings include ragged-red fibres (RRF), muscle fibres with absent COX-activity and abundant abnormal mitochondria with paracrystalline inclusions. Biochemically, a generalized reduction in the activities of mtDNA-encoded enzymes is observed in skeletal muscle. Southern blotting or PCR analysis reveal multiple populations of deleted mtDNA. The deletions occur at multiple sites between the replication initiation sites, involving a large portion of mtDNA, and most deletions seem to be flanked by direct sequence repeats, shown to be "hot spots" in the case of single large deletions. Apparently, a defect in a nuclear gene results in multiple deletions of mtDNA. Both clinical, genetic and molecular genetic observations indicate heterogeneity of this new disease category, apparently based on a disturbance in the "cross-talk" between the nuclear and the mitochondrial genomes.
Asunto(s)
ADN Mitocondrial/genética , Complejo IV de Transporte de Electrones/genética , Encefalomiopatías Mitocondriales/genética , Eliminación de Secuencia , Femenino , Humanos , Masculino , Mitocondrias Musculares/enzimología , Mitocondrias Musculares/patología , Mitocondrias Musculares/ultraestructura , Encefalomiopatías Mitocondriales/enzimología , Encefalomiopatías Mitocondriales/patología , Músculos/patología , Linaje , Reacción en Cadena de la Polimerasa , Sarcolema/patología , Sarcolema/ultraestructuraRESUMEN
Northern epilepsy is an autosomal recessive childhood onset epilepsy syndrome, clinically characterized by generalized tonic-clonic seizures with onset at 5 to 10 years of age and subsequent slowly progressive mental deterioration. The patients may reach 50 or 60 years of age. A mutation responsible for the disease has recently been identified in a novel gene on chromosome 8p23, encoding a putative membrane protein with an unknown function. The present study, based on three autopsied patients, is the first neuropathological analysis of the disease, and showed intraneuronal accumulation of cytoplasmic autofluorescent granules. The granules were strongly stained by the Luxol fast blue, periodic acid-Schiff, and Sudan black B methods in paraffin sections, and were immunoreactive for subunit c of the mitochondrial ATP synthase and sphingolipid activator proteins A and D. The intraneuronal storage was highly selective: the third layer of the isocortex and the hippocampal CA2, CA3, and CA4 sectors were severely affected, while other layers of the isocortex, the CA1 sector, and the cerebellar cortex were only minimally involved. The membrane-bound storage cytosomes showed a curvilinear ultrastructure with admixture of some granular components. Western blotting and N-terminal sequence analysis of purified storage material identified subunit c as the major component. These findings establish Northern epilepsy as a new form of neuronal ceroid-lipofuscinosis with an exceptionally protracted course.
Asunto(s)
Epilepsia Tónico-Clónica/clasificación , Lipofuscinosis Ceroideas Neuronales/clasificación , Adulto , Electroforesis en Gel Bidimensional , Epilepsia Tónico-Clónica/genética , Epilepsia Tónico-Clónica/metabolismo , Epilepsia Tónico-Clónica/patología , Humanos , Inmunohistoquímica , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Lipofuscinosis Ceroideas Neuronales/metabolismo , Lipofuscinosis Ceroideas Neuronales/patología , LinajeRESUMEN
The tissues from three patients with late-infantile NCL originally described by Max Bielschowsky became available to apply modern techniques such as fluorescence microscopy, electron microscopy and immunohistochemistry. While regular tinctorial preparations of the tissues documented a neuronal storage disorder in all three patients' tissues, the accumulated material proved to be autofluorescent, showed the ultrastructure of curvilinear lipopigments, and reacted strongly with an antibody against the subunit-C of mitochondrial ATP synthase, a major component of lipopigments in NCL and also with an antibody against sphingolipid activator proteins. Thus, these modern morphological techniques demonstrated that the originally described three siblings with late-infantile "amaurotic familial idiocy" really had neuronal ceroid-lipofuscinosis of the late-infantile or Jansky-Bielschowsky type, according to current diagnostic criteria. This type of archival study may also contribute to the mosaic of medical history.
Asunto(s)
Lipofuscinosis Ceroideas Neuronales/historia , Lipofuscinosis Ceroideas Neuronales/patología , Patología/historia , Encéfalo/patología , Colorantes , Historia del Siglo XX , Humanos , Microscopía Electrónica , Microscopía Fluorescente , Lipofuscinosis Ceroideas Neuronales/enzimología , Neuronas/ultraestructura , Adhesión en ParafinaRESUMEN
Neuropathological diagnostic criteria for Creutzfeldt-Jakob disease (CJD) and other human transmissible spongiform encephalopathies (prion diseases) are proposed for the following disease entities: CJD--sporadic, iatrogenic (recognised risk) or familial (same disease in 1st degree relative): spongiform encephalopathy in cerebral and/or cerebellar cortex and/or subcortical grey matter; or encephalopathy with prion protein (PrP) immunoreactivity (plaque and/or diffuse synaptic and/or patchy/perivacuolar types). Gerstmann-Sträussler-Scheinker disease (GSS) (in family with dominantly inherited progressive ataxia and/or dementia): encephalo(myelo)pathy with multicentric PrP plaques. Familial fatal insomnia (FFI) (in member of a family with PRNP178 mutation): thalamic degeneration, variable spongiform change in cerebrum. Kuru (in the Fore population). Without PrP data, the crucial feature is the spongiform change accompanied by neuronal loss and gliosis. This spongiform change is characterised by diffuse or focally clustered small round or oval vacuoles in the neuropil of the deep cortical layers, cerebellar cortex or subcortical grey matter, which might become confluent. Spongiform change should not be confused with non-specific spongiosis. This includes status spongiosus ("spongiform state"), comprising irregular cavities in gliotic neuropil following extensive neuronal loss (including also lesions of "burnt-out" CJD), "spongy" changes in brain oedema and metabolic encephalopathies, and artefacts such as superficial cortical, perineuronal, or perivascular vacuolation; focal changes indistinguishable from spongiform change may occur in some cases of Alzheimer's and diffuse Lewy body diseases. Very rare cases might not be diagnosed by these criteria. Then confirmation must be sought by additional techniques such as PrP immunoblotting, preparations for electron microscopic examination of scrapie associated fibrils (SAF), molecular biologic studies, or experimental transmission.
Asunto(s)
Síndrome de Creutzfeldt-Jakob/patología , Enfermedades por Prión/patología , Enfermedad de Gerstmann-Straussler-Scheinker/patología , HumanosRESUMEN
Despite many sensational and intimidating reports in the mass media, transmissible spongiform encephalopathies (prion disease) are not contagious in the usual sense. Successful transmission requires both specific material (an affected individual's tissue, from or adjacent to CNS) and specific modes (mainly penetrating contact with the recipient). Nevertheless, specific safety precautions are mandatory to avoid accidental transmission and to decontaminate any infectivity. Autopsy is essential for definite diagnosis of these disorders. Recommendations are given here for performance of the autopsy, for neuropathology service and appropriate decontamination; they are based on the current literature and on precautions taken in most laboratories with experience in handling tissue from transmissible spongiform encephalopathies. In particular, special care must be taken to avoid penetrating wounds, possible contamination should be kept to a minimum, and potential infectious material must be adequately decontaminated by specific means.
Asunto(s)
Síndrome de Creutzfeldt-Jakob/transmisión , Enfermedades por Prión/transmisión , Seguridad , Manejo de Especímenes , Autopsia , Síndrome de Creutzfeldt-Jakob/patología , Descontaminación , Humanos , Enfermedades por Prión/patologíaRESUMEN
Familial amyloidosis, Finnish type (FAF), is an autosomal dominant form of amyloidosis which is related to a point mutation in the gelsolin gene localized on chromosome 9. The mutation corresponds to codon 187 of the secreted form of gelsolin, and is expressed in the amyloid fibril at residue 15. Our original FAF patient was demented, and neuropathological analysis showed Alzheimer type brain lesions associated with both classical and cortical Lewy bodies. Furthermore, antiserum against the gelsolin-derived FAF amyloid reacted strongly with both classical and cortical Lewy bodies of this FAF patient. In preliminary experiments similar results were obtained in cases of Parkinson's disease and diffuse Lewy body disease. These observations may indicate a role for gelsolin in the pathogenesis of Parkinson's disease and related conditions.
Asunto(s)
Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Proteínas de Unión al Calcio/metabolismo , Cuerpos de Lewy/metabolismo , Proteínas de Microfilamentos/metabolismo , Anciano , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/inmunología , Amiloidosis/patología , Encéfalo/patología , Gelsolina , Histocitoquímica , Humanos , Cuerpos de Lewy/inmunología , MasculinoRESUMEN
Apolipoprotein E genotyping was carried out in a stratified random sample of 52 patients with Alzheimer's disease, 48 patients with vascular or mixed dementia, and 49 nondemented controls in a population-based study of people aged 85 and older (the Vantaa 85+ Study). Our results indicate that the apolipoprotein E epsilon 4 allele is associated with approximately a twofold increase in clinically diagnosed Alzheimer's disease in this very old general population aged 85+. When combined with previous studies, our data also suggest that the association is decreasing with age. In contrast, there appears to be no relation between apolipoprotein E alleles and clinically diagnosed vascular dementia.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Apolipoproteínas E/metabolismo , Demencia Vascular/metabolismo , Anciano , Anciano de 80 o más Años , Alelos , Femenino , Genotipo , Humanos , MasculinoRESUMEN
We have isolated storage cytosomes from brain tissue of patients with infantile neuronal ceroid-lipofuscinosis. The purified storage bodies were subjected to compositional analysis which revealed a high content of proteins, accounting for 43% of dry weight. Saposins A and D, also known as sphingolipid activator proteins (SAPs), were shown to constitute a major portion of the accumulated protein using gel electrophoresis and sequence analysis. This is the first time that saposins have been found to be stored in any form of neuronal ceroid-lipofuscinosis.