Showing papers by "Herbert Budka published in 2004"

Predictors of survival in sporadic Creutzfeldt–Jakob disease and other human transmissible spongiform encephalopathies

Abstract: A collaborative study of human transmissible spongiform encephalopathies has been carried out from 1993 to 2000 and includes data from 10 national registries, the majority in Western Europe. In this study, we present analyses of predictors of survival in sporadic (n = 2304), iatrogenic (n = 106) and variant Creutzfeldt-Jakob disease (n = 86) and in cases associated with mutations of the prion protein gene (n = 278), including Gerstmann-Straussler-Scheinker syndrome (n = 24) and fatal familial insomnia (n = 41). Overall survival for each disease type was assessed by the Kaplan-Meier method and the multivariate analyses by the Cox proportional hazards model. In sporadic disease, longer survival was correlated with younger age at onset of illness, female gender, codon 129 heterozygosity, presence of CSF 14-3-3 protein and type 2a prion protein type. The ability to predict survival based on patient covariates is important for diagnosis and counselling, and the characterization of the survival distributions, in the absence of therapy, will be an important starting point for the assessment of potential therapeutic agents in the future.

Advances in broad bandwidth light sources for ultrahigh resolution optical coherence tomography.

Abstract: Novel ultra-broad bandwidth light sources enabling unprecedented sub-2 microm axial resolution over the 400 nm-1700 nm wavelength range have been developed and evaluated with respect to their feasibility for clinical ultrahigh resolution optical coherence tomography (UHR OCT) applications. The state-of-the-art light sources described here include a compact Kerr lens mode locked Ti:sapphire laser (lambdaC = 785 nm, delta lambda = 260 nm, P(out) = 50 mW) and different nonlinear fibre-based light sources with spectral bandwidths (at full width at half maximum) up to 350 nm at lambdaC = 1130 nm and 470 nm at lambdaC = 1375 nm. In vitro UHR OCT imaging is demonstrated at multiple wavelengths in human cancer cells, animal ganglion cells as well as in neuropathologic and ophthalmic biopsies in order to compare and optimize UHR OCT image contrast, resolution and penetration depth.

Neuropathology of white matter disease in Leber's hereditary optic neuropathy

Abstract: Leber's hereditary optic neuropathy (LHON) is associated with point mutations in the mitochondrial DNA (mtDNA), coding for a mitochondrial respiratory chain complex I subunit. It is characterized by bilateral, usually sequential, optic neuropathy and may co-occur with multiple sclerosis-like white matter lesions. Despite repeated clinical reports including MRI and histopathological examination of the visual system, neuropathological descriptions of LHON associated with multiple sclerosis-like syndrome are lacking. We present here the case of a female patient with a point mutation at nucleotide position T14484C, who suffered from relapsing episodes of visual loss of both eyes and consecutively developed Hashimoto thyroiditis as well as widespread demyelinating CNS lesions outside the visual system. She died of bronchopneumonia at the age of 44 years, after a disease duration of 19 years, with progressive deterioration, epileptic seizures and immobility. Immunohistochemical analysis on formalin-fixed and paraffin-embedded tissue reveals a spectrum of neuropathological changes, including actively and inactively demyelinating plaques in the white matter and optic nerve, vacuolation and cystic necrosis with CD8-positive T cells in the frontal lobe, axonal damage, and vacuolation of white matter. Tissue destruction is associated with upregulation of mitochondrial manganese superoxide dismutase within the lesions and an increase in the expression of inducible nitric oxide synthase within macrophages and microglia. This variable phenotype of extraoptic LHON disease suggests that mtDNA mutations may affect the nervous system on a common metabolic basis and occasionally may aggravate or initiate autoimmune pathology.

Ki-67 immunolabeling index is an accurate predictor of outcome in patients with intracranial ependymoma.

Abstract: Histopathologic grading of ependymomas is considered unreliable in terms of outcome prediction. Quantification of tumor cell proliferation may be useful for outcome prediction. We analyzed prognostic and predictive values of tumor cell proliferation rates using anti-Ki-67 antigen (MIB-1 antibody) and anti-topoisomerase-IIalpha (Topo-IIalpha) immunolabeling on tumor samples of 103 consecutive ependymoma patients 0.1 to 74.4 years of age. In this patient cohort, the following clinical and histopathologic parameters showed significant correlation with overall survival on univariate analysis: extent of resection, use of an operating microscope, radiologic imaging with computed tomography and/or magnetic resonance imaging, radiotherapy, tumor size (cutoff 3 cm), WHO grade, presence of tumor necrosis, increased cellularity, microvascular proliferation, and low/high Ki-67 and Topo-IIalpha indices (cutoff 20.5% and 9.4%, respectively). On multivariate analysis, incomplete resection and high Ki-67 index remained independent factors of adverse patient outcome. In Kaplan-Meier survival analysis, low ( or = 20.5%) Ki-67 indices predicted favorable (> or = 5 years) or unfavorable (<5 years) patient outcome at 79% and 70%, respectively. We conclude that Ki-67 immunolabeling index is an independent prognostic factor and accurate predictor of outcome in patients with intracranial ependymoma. Thus, assessment of Ki-67 index in intracranial ependymoma is useful for outcome prediction in the routine diagnostic setting.

Creutzfeldt-Jakob disease and inclusion body myositis: abundant disease-associated prion protein in muscle.

Abstract: Pathologicalprion protein (PrP(Sc)) is the hallmark of prion diseases affecting primarily the central nervous system. Using immunohistochemistry, paraffin-embedded tissue blot, and Western blot, we demonstrated abundant PrP(Sc) in the muscle of a patient with sporadic Creutzfeldt-Jakob disease and inclusion body myositis. Extraneural PrP(C)-PrP(Sc) conversion in Creutzfeldt-Jakob disease appears to become prominent when PrP(C) is abundantly available as substrate, as in inclusion body myositis muscle.

Value and limits of immunohistochemistry in differential diagnosis of clear cell primary brain tumors

Abstract: Clear cell histology is the hallmark of oligodendroglioma (OG) but also characterizes clear cell ependymoma (CCE) and central neurocytoma (CN). Immunohistochemistry for glial and neuronal proteins may support differential diagnosis. We investigated systematically diagnostic value and limits of immunohistochemistry using representative tumor specimens (>1 cm in diameter) of well-defined OGs, CCEs, and CNs (n=10, respectively). Antibodies comprised anti-neuron specific nuclear protein (NEUN), anti-synaptophysin, anti-neuron-specific enolase, anti-microtubule-associated protein 2, anti-phosphorylated neurofilament protein, anti-non-phosphorylated neurofilament protein, anti-glial fibrillary acidic protein (GFAP), anti-S100 protein, anti-vimentin (VIM), and anti-epithelial membrane antigen (EMA). Among the panel of antibodies anti-NEUN, anti-VIM and anti-EMA proved most useful for differential diagnosis. Prominent (>90%) anti-NEUN immunolabeling of tumor cells clearly distinguished CNs from OGs and CCEs. Anti-VIM immunolabeling and a characteristic cytoplasmic dot-like anti-EMA immunoreactivity pattern of tumor cells were detectable only in OGs and CCEs. Furthermore, prominent anti-VIM immunoreactivity and anti-EMA cell membrane staining including ring-like staining pattern is characteristic for CCEs. Additionally, a widespread gliofibrillary and minigemistocytic cytoplasmic anti-GFAP immunostaining pattern is restricted to some OGs. Our data indicate that immunohistochemistry using anti-NEUN, anti-VIM, and anti-EMA on representative tumor specimens allows clear-cut distinction of CNs vs OGs and CCEs. Anti-VIM, anti-EMA, and anti-GFAP support differential diagnosis of OGs vs CCEs. Nevertheless, it is noted that due to focal expression of glial proteins in CNs and, conversely, of neuronal proteins in OGs and CCEs, immunohistochemistry is of limited value on small tumor specimens.

Gerstmann-Sträussler-Scheinker disease. I. Human diseases.

Abstract: Gerstmann-Straussler-Scheinker disease (GSS) is a slowly progressive hereditary autosomal dominant disease (OMIM: 137440) and the first human transmissible spongiform encephalopathy (TSE) in which a mutation in a gene encoding for prion protein (PrP) was discovered. Its true prevalence is difficult to estimate but figures within the range of 1-10/100,000,000 are quoted. GSS is defined as a neurodegenerative disease "in family with dominantly inherited progressive ataxia and/or dementia): encephalo(myelo)pathy with multi-centric PrP plaques". In this review, we summarise data on all the families with GSS. The hallmark of the GSS neuropathology is the multi-centric plaque but the pattern varies between families. In the second part of this review the experimental data using experimental models of GSS in transgenic mice are summarised as well as structural biology of mutated PrP in GSS.

Contribution of neuropathology to the understanding of human prion disease.

Abstract: Neuropathology is an important tool for definitive diagnosis of sporadic, genetic, and acquired prion disease. Classical neuropathological hallmark is the highly disease-specific spongiform change accompanied by neuronal loss, astro- and microgliosis. Spongiform change of the neuropil consists of either microcystic or confluent vacuoles and varies greatly within the same brain. In addition, the most important aspect of confirmatory diagnosis is the demonstration of disease-associated prion protein (PrPd) by immunohistochemistry or Western blotting. Different PrPd immunostaining patterns include patchy/perivacuolar surrounding spongiform change, diffuse/synaptic, perineuronal, or plaque type. The latter includes unicentric kurutype plaques or multicentric plaques as in the peculiar genetic prion disorder, Gerstmann-Straussler-Scheinker disease. PrPd immunostaining patterns correlate well with phenotypes defined by the polymorphic codon 129 and the type of protease resistant PrPd seen on Western blots. PrPd immunoreactivity in the cerebellum may be highly informative about disease subtypes. Although the central nervous system is the major site of PrPd accumulation, it may also be observed in peripheral nerves as adaxonal deposits; in skeletal muscle as granular immunoreactivity in particular in abundance in a unique instance of concomitant Creutzfeldt-Jakob disease and inclusion body myositis; as well as associated with dendritic cells and macrophages in vessel walls. A subset of inhibitory GABAergic neurons is selectively affected in experimental and human prion disease. The central pathogenetic cascade includes oxidative stress and apoptosis. Deposition of terminal complement components on neurons accompanies tissue damage.

The prion protein in human neuromuscular diseases

Abstract: The basis of human prion diseases affecting the nervous system is accumulation of a disease-associated conformer (PrPSc) of the normal cellular prion protein (PrPC). Earlier studies demonstrated increased expression of PrPC in inclusion body myositis (IBM), dermato-, and polymyositis, as well as neurogenic muscle atrophy. To define the spectrum and reliability of PrPC immunoreactivity, its expression was examined systematically in a series of pathologically characterized muscular disorders by means of immunohistochemistry, confocal laser microscopy, and immunogold electron microscopy. Anti-PrPC immunolabelling of rimmed vacuoles was observed in IBM, inclusions of myofibrillary myopathy, targets, regenerating, and atrophic fibres, mononuclear cells, in addition to ragged red fibres in mitochondrial myopathies, and focal sarcolemmal immunostaining in non-diseased controls. Quantitative analysis demonstrated that, in neurogenic muscle lesions, anti-PrPC staining detects a significantly broader spectrum of fibres than anti-vimentin or anti-NCAM. In dystrophic muscle, PrPC expression was mainly restricted to regenerating fibres. In IBM, PrPC expression was not confined to rimmed vacuoles or vacuolated fibres and only a small percentage (7.1%) of rimmed vacuoles were PrPC positive. Ultrastructurally, PrPC was observed in the cytoplasm of lymphocytes, in the myofibrillar network of targets, and in rimmed vacuoles. Knowledge of disease circumstances with altered expression of PrPC is important in the setting of a potentially increased chance for extraneural PrPC–PrPSc conversion. In addition, our observations suggest that PrPC may have a general stress–response effect in various neuromuscular disorders. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Rationale for diagnosing human prion disease

Abstract: Human prion diseases (PrD) like Creutzfeldt-Jakob disease (CJD) include sporadic, acquired and familial neurodegenerative disorders. The central events in the neuropathological process of PrDs are ...

Morphometry of synaptophysin immunoreactive ganglion cells in Auerbach plexus in patients with colorectal cancer. Is this a new prognostic factor

Abstract: In this and a companion paper we present immunohistochemical and ultrastructural data on hamsters infected with the Echigo-1 strain of Creutzfeldt-Jakob disease. Ultrastructurally, two types of vacuoles were readily discriminated in the brain: the grey matter vacuoles of spongiform change and intramyelin vacuoles. The vacuoles were always membrane-bound; the membranes were single or double. The axons were entirely missing from the plane of the sections or, if visible, were shrunken and attached to the innermost layer of the myelin. It was noteworthy that some vacuoles indented cell bodies or processes and thus were reminiscent of the intraneuronal vacuoles typical for natural scrapie, BSE and CWD in ungulates and cervids but not of the vacuoles encountered in rodent models of scrapie and CJD. We also noticed vacuoles distending myelinated fibres in which the axons had become dystrophic. Some axons underwent Wallerian degeneration while others met the criteria for dystrophic neuritis. Both alterations existed in the same areas. Typical dystrophic neurites contained abnormal subcellular organelles, mainly electron-dense lysosomal inclusions. Other neurites contained numerous multi-vesicular bodies and autophagic vacuoles. Nuclear paracrystalline rod-like inclusions were occasionally visible in neurons while other inclusions comprised spiroplasma-like inclusions in synaptic boutons. The robust cellular reactions consisted of reactive astrocytes and macrophages filled with cellular debris. It is of note that complex autophagic vacuoles were observed in the cytoplasm of neurons.

Presence of D110 antigen expressing immunocompetent cells in glioblastoma associates with prolonged survival

Abstract: Monoclonal antibody D110 has recently been described as a novel marker of hypoxic tissue damage, reacting with a so far unknown antigen with preferential expression in the central nervous system. The aim of the study was to investigate D110 immunoreactivity in glioblastoma, its association with the expression of hypoxia-related proteins and its impact on patient outcome. A total of 114 consecutive adult patients who underwent first operation of primary glioblastoma were included in this study. We evaluated D110 immunoreactivity qualitatively and semi-quantitatively and correlated it with expression of hypoxia inducible factor 1 alpha (HIF-1alpha), expression of vascular endothelial growth factor (VEGF), and with patient survival using univariate and multivariate statistical analysis. We observed D110 immunolabelling in 85.1% of the cases. D110 immunoreactivity was detectable in infiltrating HLA-DR and CD68 expressing cells, most likely microglial cells or haematogenous cells of monocyte/macrophage lineage. In the peripheral lymphoreticular system, immunohistochemistry disclosed selective D110 labelling of Langerhans cells and of dendritic cells of the thymic medulla. Univariate statistical analysis revealed significantly longer survival of patients whose glioblastomas contained D110 immunoreactive infiltrating cells. There was no association between presence of D110 immunoreactive cells and expression of HIF-1alpha and VEGF. We conclude that D110 immunoreactivity in glioblastoma does not seem to be related to tissue hypoxia. D110 identifies immunocompetent cells, which positively influence survival of glioblastoma patients.

Echigo-1: a panencephalopathic strain of creutzfeldt-jakob disease. I. neuropathological and immunohistochemical studies.

Abstract: We demonstrate an unusually intensive accumulation of prion protein (PrP) on neuronal membranes in hamsters infected with the Echigo-1 panencephalopathic strain of Creutzfeldt-Jakob disease. This stands in strong contrast with the poor vacuolation in this model. Several distinct patterns of PrP(TSE) deposit were observed in the brain. The first type consisted of a fine granular "synaptic"/diffuse type of accumulation which, especially in the cerebral cortex, appeared laminar. Deposits frequently coalesced to form plaque-like structures. The second pattern consisted of perivascular plaque-like accumulations. When a vessel was cut longitudinally, these formed long linear arrays of plaques and smaller globules. The third, and most striking, consisted of perineuronal deposits. These formed small dots and coarser globules which were densely situated on the neuronal membrane on both cell bodies and their processes.

Feasibility of ultrahigh resolution optical coherence tomography for imaging brain tissue morphology and function

Abstract: The feasibility of ultrahigh resolution optical coherence tomography to image both healthy and pathological brain tissue morphology as well as the morphology and functional response of neuron cells is investigated.