Biomedical subjects
Publications and source records attributed to K Jellinger.
A paraganglioma of the orbit in a 21-year-old woman is presented, containing oculo-cutaneous melanin in many tumor cells, occasionally adjacent to neurosecretory granules, and in macrophages. This tumor expands the list of neuroectodermal tumors with potential melaninization.
Ultrastructural studies of 17 primary malignant CNS lymphomas revealed 6 tumors with abnormal intracytoplasmic and/or intranuclear membranous structures, most frequently associated with the endoplasmic reticulum or perinuclear envelope. In most cases, tubuloreticular inclusions and paired cisternae were present. Less frequent were accumulation of microtubules, concentric lamellar bodies, and rod-like or paracrystalline intranuclear inclusions. The specificity and significance of these membranous structures remain questionable because of their frequent occurrence in a variety of normal and pathological conditions. Some of these changes may be considered as cellular reactions to viral infections, others may indicate cellular activity or degeneration.
In post-mortem putamen samples from 27 schizophrenics and 27 controls D2 receptors were measured by Scatchard analysis using 3H-spiperone as a ligand. Maximum number of binding sites (Bmax) and apparent dissociation constant (KD) were significantly increased only in patients in whom neuroleptic medication had been given within a three-month period before death. When the neuroleptic medication had been withdrawn at least 3 month before death, there was a slight, but not significant, reduction in Bmax values and unchanged KD values. Withdrawal of neuroleptic drugs was followed by a normalization of the KD values within 2 weeks and a slower reduction of Bmax values. There were 6 schizophrenic patients with mainly positive schizophrenic symptoms and 17 patients with mainly negative symptoms; positive schizophrenic symptoms were not related to higher Bmax values. There was no difference in 3H-spiperone binding between patients with and without movement disorders (tardive dyskinesia or extrapyramidal symptoms).
Quinolinic acid (QA) content was measured in postmortem frontal and temporal cortex, putamen and cerebellum obtained from patients with senile dementia of Alzheimer type (SDAT), Huntington's disease (HD) and controls, using a gas chromatography/mass spectrometry method. There were no significant group differences in QA content of any of the regions examined. The data do not support the hypothesis that an accumulation of QA plays a role in neuronal degeneration occurring in the frontal and temporal cortex, putamen and cerebellum of patients with SDAT.
An antigenic profile of subcortical and cortical Lewy bodies was determined in the presence or absence of neurofibrillary tangles in the same brain using antisera and monoclonal antibodies to various cytoskeletal elements as well as to determinants not present in the normal cytoskeleton. The cores of many Lewy bodies were strongly reactive with a monoclonal antibody to paired helical filaments which has been shown to recognize ubiquitin. This antibody also stained Marinesco bodies in the same tissue sections. Two monoclonal antibodies to phosphorylated epitopes of neurofilament proteins (SM I 31, SM I 34) stained the peripheries of about 40% of all discernable Lewy bodies on untreated paraffin sections. Reactivity with a monoclonal antibody to neurofilaments (SM I 33) appeared only after pretreatment of the sections with phosphatase. Lewy bodies did not bind antibodies to tau protein. Our results show that, as previously shown for neurofibrillary tangles, Lewy bodies also contain ubiquitin. The uncovering of neurofilament epitopes by treatment with phosphatase indicates that abnormal phosphorylation of cytoskeletal elements may play a role in the pathogenesis of the Lewy body.
The regional distributions of iron, copper, zinc, magnesium, and calcium in parkinsonian brains were compared with those of matched controls. In mild Parkinson's disease (PD), there were no significant differences in the content of total iron between the two groups, whereas there was a significant increase in total iron and iron (III) in substantia nigra of severely affected patients. Although marked regional distributions of iron, magnesium, and calcium were present, there were no changes in magnesium, calcium, and copper in various brain areas of PD. The most notable finding was a shift in the iron (II)/iron (III) ratio in favor of iron (III) in substantia nigra and a significant increase in the iron (III)-binding, protein, ferritin. A significantly lower glutathione content was present in pooled samples of putamen, globus pallidus, substantia nigra, nucleus basalis of Meynert, amygdaloid nucleus, and frontal cortex of PD brains with severe damage to substantia nigra, whereas no significant changes were observed in clinicopathologically mild forms of PD. In all these regions, except the amygdaloid nucleus, ascorbic acid was not decreased. Reduced glutathione and the shift of the iron (II)/iron (III) ratio in favor of iron (III) suggest that these changes might contribute to pathophysiological processes underlying PD.
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In his original 1911 publication Alois Alzheimer classified neurofibrillary tangles (ANT) into three morphologically defined subgroups according to their stage of maturation. The present study shows that changes in the morphological appearance of ANT during their maturation process are accompanied by changes in their antigenic profile. As shown by several immunocytochemical studies these abnormal phosphorylated microtubule-associated protein tau and of ubiquitin. In this study, immunoreactivity for the altered tau is not only seen in a subset of tangles but also in the cytoplasm of some nerve cells lacking ANT, which we believe to be at a stage of neuronal alteration preceding the formation of compact tangles (Stage 0 tangles). Similar numbers of Stage 0 tangles are present in the brains of age-matched non-demented individuals as in Alzheimer cases, but are absent in young controls lacking ANT. In extracellular "ghost tangles", the ultimate stage of neurofibrillary degeneration, immunoreactivity for tau is accessible to antibodies only when tissue sections are pretreated with formic acid to uncover the binding sites. In contrast to tau, presence/accessibility of an epitope residing on residues 50-65 of ubiquitin recognized by a monoclonal antibody raised to paired helical filaments (3-39) increases during the maturation of ANT and is most pronounced in "ghost tangles". Appearance/uncovering of the 3-39 epitope and masking of tau reactivity during tangle maturation may reflect degradation or conformational changes in the pathological filaments due to their aging and the final loss of their parent nerve cells.
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This paper reports the first Austrian case of infantile nemaline myopathy in a girl aged 19 years, presenting with congenital skeletal dysplasia, reduced body weight and slowly progressive limb girdle muscular atrophy, myopathic face and difficulty in swallowing. Electromyography revealed a combination of myopathic and neurogenic lesions, while electron microscopy of a muscle biopsy established the diagnosis. The patient's mother and two elder brothers showed no clinical features of the disease, but neurophysiological abnormalities were present, indicating an asymptomatic form of illness. The aetiology and pathogenesis of nemaline myopathy are unknown, but neurogenic factors cannot be excluded.
Rett syndrome is an increasingly recognized progressive disorder in females, commencing in infancy and characterized by autistic behavior, gait ataxia, stereotyped movements, seizures and generalized growth and mental retardation, possibly associated with disorders of central biogenic amine synthesis. The gene locus and pathogenesis of Rett syndrome are unknown. Autopsy studies in nine girls dying between 4 and 17 years, and sural nerve and muscle biopsies from two girls aged 3 and 17 years showed: (1) diffuse cortical atrophy/micrencephaly, with a decrease in brain weight by 12% to 34% of age-matched controls, apparently related to the duration of the disorder; (2) mild diffuse cortical atrophy with increased amounts of neuronal lipofuscin and occasional mild gliosis, but without signs of a storage disorder; (3) underpigmentation of the zona compacta nigrae, which showed fewer well-pigmented neurons for age and fewer melanin granules per neuron, while total numbers of nigral neurons and the substructure of neuromelanin were normal for age. No pathological changes were seen in other transmitter-specific brain stem nuclei; (4) immunoreactivity for tyrosine hydroxylase was slightly reduced in nigral and hypothalamic neurons, and the pituitary gland showed decreased immunoreaction for prolactin and growth hormone; (5) ultrastructurally, in frontal cortex and caudate nucleus, isolated abnormal neurites and reactive or degenerative axonal swellings were seen; the latter are possibly related to the nigral changes, suggesting some dysfunction of the dopaminergic nigrostriatal system, which is supported by neurochemical data; (6) preliminary biochemical studies revealed increased beta-endorphines in thalamus and cerebellum; (7) peripheral nerves demonstrated increase in small fibers without demyelination and increased numbers of neurofilaments in axons, suggesting distal axonopathy, while skeletal muscle showed alterations in the sarcoplasmic reticulum with circular profiles in the Z-filaments. These nonspecific changes may be interpreted as early signs of denervation. The variety of lesions in the central, neuroendocrine and peripheral neuromuscular systems in Rett syndrome are discussed with regard to their clinical and biochemical significance.
The appearance of circulating antineuronal antibodies (CANA) in patients with malignant tumors has been correlated with the occurrence of paraneoplastic neurological syndromes. However, the effect of CANA on the peripheral nervous system is poorly understood. The reactivity of sera from CANA-positive and -negative patients were investigated on cryostat sections of peripheral nerves and skeletal muscle, and on nerve tease-fiber preparations. Only CANA-positive sera showed staining of Schwann cell nuclei on cryostat sections, whereas nerve tease-fiber preparations and sections of skeletal muscle remained negative. Positive direct immunofluorescence of small cell lung cancer (SCLS) cells was confined to CANA-positive patients only. These findings suggest the existence of a common antigen between SCLC and Schwann cells.
Tyrosine hydroxylase (TH) contents in the caudate nucleus, putamen, and substantia nigra from control and parkinsonism brains were measured for the first time by a sandwich enzyme immunoassay. Both the TH protein content and TH activity (Vmax) were decreased in parallel in the parkinsonian brains as compared with those of the control brains. In contrast, TH "homospecific activity" (activity per enzyme protein) was significantly increased in the parkinsonian brains. The results indicate that the decrease of TH activity in parkinsonian brains is due to the decrease of TH protein content as a result of cell death. The increase in the "homospecific activity" of residual TH in parkinsonian brain suggests such molecular changes in TH molecules as result in a compensatory increase in TH activity.
A primary localized, partly encapsulated melanotic tumour broadly attached to the occipital dura and tentorium was removed from a 27 year-old woman. It recurred almost four years later in the posterior fossa and was resected again. Although grossly resembling a meningioma, the tumour lacked the histological, immunocytochemical and ultrastructural features of meningiomas and was characterized by the presence of numerous melanosomes and premelanosomes in the cytoplasm of tumour cells and macrophages and was, therefore, classified as "meningeal melanocytoma". The clinical and pathological features of this and 15 other cases in the literature are reviewed. The neoplasm, mainly occurring in the posterior cranial fossa and spinal canal, may cause neurological deficits through expanding, but non-invasive growth. Its biological behaviour is variable, and recurrence may occur after incomplete resection, but transition into malignant melanoma has not been observed. Total resection of this rare pigmented tumour arising from the pial melanocytes is recommended.
Immunocytochemical demonstration of monoamine oxidase-A, monoamine oxidase-B and tyrosine hydroxylase was performed in the human brain stem using monoclonal antibodies to monoamine oxidase-A and monoamine oxidase-B and polyclonal antibodies to tyrosine hydroxylase. In most of the brain areas examined, except the serotonergic dorsal nucleus of raphe, the noradrenergic locus coeruleus and the dorsal efferent nucleus of vagus, tyrosine hydroxylase-positive neurons were in greater number than monoamine oxidase-A-stained or monoamine oxidase-B-stained neurons. The dorsal nucleus of raphe showed no tyrosine hydroxylase immunoreactivity, but reacted positively to serotonin- and monoamine oxidase-B antibodies, while monoamine oxidase-A staining was moderate. In none of the investigated brain areas did neurons exclusively react with monoamine oxidase-B antibodies without expressing monoamine oxidase-A in a few neurons, while in some areas neurons expressed both monoamine oxidase-A and tyrosine hydroxylase (locus coeruleus; dorsal efferent nucleus of vagus). The oculomotor nucleus stained only with monoamine oxidase-A antibodies, substantia nigra neurons reacted only with tyrosine hydroxylase antibodies. Glial staining in most of the brain areas examined seemed, with slight differences, to have the same intensity with monoamine oxidase-A and monoamine oxidase-B antibodies used. No glial staining was obtained with tyrosine hydroxylase antibodies.
Tyrosine hydroxylase (TH) activity of human postmortem brain tissues from controls and patients with Parkinson's disease (PD) was examined in the presence of Fe2+ and phosphorylation agents, such as cyclic AMP, exogenous protein kinase, calcium plus calmodulin (Ca2+-CaM), and ATP. TH activity from parkinsonian tissue was increased by 48% with statistical significance in the presence of exogenous protein kinase. Cyclic AMP alone had no effect, whereas Ca2+-CaM increased the activity by only 10%. The presence of acetylcholine resulted in a slight decrease in enzyme activity. Human TH was stimulated 13.17-fold in the presence of 1 mM Fe2+. For iron dependence, no significant differences could be shown for the Km values of TH in striata of PD, while the activity of TH was half of that of controls. Here stimulation with 1 mM Fe2+ raised the activity of TH 11-fold. Stimulation of rat, gerbil, pig, and human caudate nucleus TH with Fe2+ shows remarkable species differences. In particular, the sensitivity of human TH to stimulating processes is noteworthy. H2O2 decreases TH activity only at high concentrations. Species differences are noted for the combined incubation of Fe2+ and H2O2. In the gerbil caudate nucleus, H2O2 does not prevent the stimulating properties of Fe2+, while the pig shows a dose-dependent decline of TH activity. In conclusion, there are no significant changes in the stimulating properties of human caudate nucleus TH activity with Fe2+ in PD, while such differences are noted by using exogenous protein kinase. Furthermore, experimental evidence shows that TH activity declines at high concentrations of H2O2 only. Potentiation of this effect by Fe2+ seems to be species-dependent.
If the gamma-aminobutyric acid (GABA) inhibitory neurotransmitter system plays an important role in the mediation of hepatic encephalopathy (HE) in man, changes in the status of receptors for GABA in the brain may occur in patients with HE. To test this possibility, brains were obtained at autopsy from 11 patients who had died of causes unrelated to liver disease and from 11 patients who had died with chronic liver disease. Eight of the liver disease group had overt HE at the time of death. The specific binding of GABA to synaptic membranes isolated from frontal cortex was determined. Mean specific binding of GABA for patients with cirrhosis without overt HE was similar to that for control patients. In contrast, corresponding means for patients who had mild HE (stages I-III) and for patients who had severe HE (stage IV) were 45% higher (p less than 0.05) and 43% lower, respectively, than that for control patients. The mean specific binding of GABA was significantly greater for patients with mild HE than in patients with severe HE (p less than 0.025). Scatchard plots of the GABA binding data were curvilinear and consistent with a model of GABA receptors with two independent binding sites. Computer-assisted analysis of the binding data indicated that the altered GABA binding observed in patients with HE is attributable to changes in the affinity rather than the density of both GABA receptors (increased affinities in mild HE, and decreased affinities in hepatic coma). These findings are compatible with the hypothesis that alterations in GABAergic neurotransmission are associated with and contribute to the syndrome of HE in man.