Iron in CNS disease.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
B B Gelman
Publications and source records attributed to B B Gelman.
Diffuse microgliosis associated with cerebral atrophy in the acquired immunodeficiency syndrome.
The cause of cerebral atrophy in patients with acquired immunodeficiency syndrome (AIDS) is obscure because human immunodeficiency virus type 1 (HIV-1)-related histopathological changes hardly correlate with cerebral atrophy. In this study, brain ventricular expansion was compared to the frontal lobe density of mononuclear and astroglial cells at autopsy. Twenty-eight male patients with AIDS displaying varying degrees of atrophy were compared to 17 age-matched male control subjects without AIDS or atrophy. An index of ventricular expansion was measured in uniformly sliced, formalin-fixed brain specimens, and immunochemically marked cells in coronal sections of the left superior frontal gyrus (Brodmann area 8) were quantified by field counting and planimetry. In the cortex, diffuse ferritin-stained microglia and glial fibrillary acidic protein-positive astrocytes were about twice as numerous in the patients with AIDS. Sixty-five percent (18/28) of the patients with AIDS had a microglial cell density greater than 2 standard deviations above the control mean. Microglial cell density was correlated positively with the severity of ventricular expansion (r = 0.71, p < 0.0001), while hypertrophied astroglial cells were very weakly related. In white matter, Ham-56-positive macrophages and glial fibrillary acidic protein-positive astrocytes were not meaningfully correlated with the index of ventricular expansion. Brain ventricular expansion and diffuse cortical microgliosis are highly prevalent anomalies in patients with AIDS, and their interrelationship may be more important than previously recognized.
Acquired Immunodeficiency Syndrome↗
Morphometry, histopathology, and tomography of cerebral atrophy in the acquired immunodeficiency syndrome.
Patients with the acquired immunodeficiency syndrome (AIDS) commonly display evidence of gross cerebral atrophy, but its true incidence and pathophysiology in the general AIDS population are unknown. In this study, we measured cerebrospinal fluid (CSF) spaces in 64 consecutively autopsied patients with AIDS, compared them with age-matched non-AIDS subjects, and correlated them with the microscopic neuropathology at autopsy. Thirty-seven of the patients with AIDS (58%) had a CSF space index greater than two standard deviations above the mean of the age-matched control subjects. CSF spaces were expanded the most in frontal and temporal lobes; ventricular spaces were expanded more than sulcal spaces. Regression analysis between age and the measured CSF indexes showed that practically none of the deviation in patients with AIDS could be explained by age-related atrophy. Patients with atrophy were much more likely to have human immunodeficiency virus type 1-associated histopathological changes in their brains, but the relationships were too weak to establish the microscopic cause of the atrophy. Measurement of CSF spaces in antemortem computed tomographic (CT) scans from 47 of the patients with AIDS revealed the same regional pattern of brain wasting. CT diagnosis of cerebral atrophy was strongly concordant with the postmortem diagnosis, but its severity was diagnosed slightly more conservatively at autopsy. Thus, quantitative analysis of CSF spaces in a robust sampling of patients with AIDS confirms that cerebral atrophy is a sensitive, common, and frequently subtle indication of central nervous system human immunodeficiency virus type 1 infection that may occur independently from any single specific microscopic abnormality. Its presence, severity, and regional pattern are detected with reasonable consistency using CT scanning.
Acquired Immunodeficiency Syndrome↗
Schwann cell nerve growth factor receptor expression during initiation of remyelination.
Initiation of remyelination is a promising therapeutic strategy to treat patients with demyelinating diseases, but specific factors that control remyelination are not clear. We first reported that expression of nerve growth factor receptor (NGFR) was increased during initiation of remyelination (Fan and Gelman, Journal of Neuropathology and Experimental Neurology 49: 312, 1990). In this study, we characterized the timing and cellular localization of NGFR expression in a model of segmental demyelination and remyelination using immunohistochemistry and monoclonal antibody 192-IgG, and compared it to an axonal neuropathy. At the onset of demyelination induced by tellurium (Te) poisoning, NGFR antigenicity was selectively expressed within and around demyelinating internodes in rat sciatic nerve. Dual fluorescence staining with myelin-specific antigen showed that NGFR colocalized with demyelinated internodal units with relative specificity; Schwann cell S-100 protein showed a concomitant down-regulation in injured internodes. Peak expression of NGFR occurred during the transition between demyelination and remyelination (day 8 of Te), then declined exponentially. NGFR expression was most prominent in the cytoplasm of daughter Schwann cells as they established contact with denuded axons, and was sharply repressed as compact myelin began to accumulate. Rare colocalization with neurofilament antigens revealed intraxonal deposits of NGFR in segmental demyelination. In the nerve crush model, Schwann cell NGFR expression was not segmentally distributed and was upregulated for a longer period of time. Our data establish that NGFR expression in the peripheral nervous system is not strictly linked to axon elongation, and that it probably functions during the initiation of myelination.
Animals↗
Siderotic cerebral macrophages in the acquired immunodeficiency syndrome.
Excessive hemosiderin-laden perivascular macrophages have been described in the brains of patients with the acquired immunodeficiency syndrome (AIDS) who underwent autopsy; its meaning remains unclear. In the brains of 53 patients with AIDS who consecutively underwent autopsy, we quantified the abnormality, elucidated its relationship to the pathologic features of AIDS, and asked if there was some relationship to endogenous iron storage and transport proteins in brain macrophages and microglia. The number of perivascular siderotic macrophages was significantly increased in patients with AIDS compared with age-matched control subjects. Macrophage siderosis was strongly correlated with the presence of disseminated mycobacterial infection and vacuolar myelopathy at autopsy; a generalized wasting (cachexia) also was related significantly. Many other pathologic abnormalities were not related, including putative human immunodeficiency virus-specific neuropathologic changes such as multinucleated cells and myelin pallor. Activated macrophages and microglial cells in the central nervous system had dense intracytoplasmic accumulation of ferritin (iron storage protein) in AIDS and non-AIDS patients. These results suggest that siderosis of cerebral macrophages is related to an ill-defined nonspecific systemic imbalance associated with the breakdown of abundant stores of endogenous intracellular ferritin. Understanding chronic "secondary" effects of human immunodeficiency virus type 1 infection will become increasingly important as improved survival in patients with AIDS is realized.
Acquired Immunodeficiency Syndrome↗
Macrophage apolipoprotein synthesis and endoneurial distribution as a response to segmental demyelination.
The synthesis and endoneurial distribution of apolipoproteins in response to myelin degradation was elucidated morphologically and biochemically in rodent models of segmental demyelination. At the onset of acute demyelination induced by tellurium (Te) poisoning, macrophages infiltrated the endoneurium and then began to express cytoplasmic immunoreactivity for apolipoprotein E (apo E). When demyelinating nerve slices were incubated with S35-methionine, radiolabeled apo E was released, showing that apo E was actively synthesized by the macrophages. Macrophages secreted apo E into the endoneurial spaces, leading to dense endoneurial accumulations. Other apolipoproteins (apo A1 and albumin) were not synthesized in the endoneurium, but they entered edematous nerves, presumably through an early breakdown in the blood-nerve barrier. During the phagocytosis of myelin, plasma-derived apolipoproteins accumulated within some of the macrophages. In chronic demyelination caused by lead poisoning, the cellular and extracellular distribution of apolipoproteins was similar to Te neuropathy; the amount of apo E accumulation and the macrophage density were proportional to the prevalence of active demyelination in teased fibers. Similar patterns of endoneurial apo E were present in an inherited form of demyelination in the twitcher mouse, after antibody-mediated demyelination, and in demyelination secondary to axonal degeneration. Human sural nerve biopsies had patterns of apolipoprotein E antigenicity that were comparable to the rodent models. We conclude that secretion of apo E by infiltrating macrophages is a generalized response to demyelination, and that endoneurial edema leads to the accumulation of certain plasma apolipoproteins within macrophages. These data suggest that endoneurial apolipoproteins and macrophages might mediate important functions in patients recovering from primary and secondary demyelination.
Animals↗
Intracerebral hemorrhage associated with cocaine abuse.
With the current epidemic of cocaine abuse, there have been many clinical reports of cocaine toxicity, including stroke. Autopsy findings were reported in only one case of intracerebral hemorrhage associated with cocaine abuse. We describe the autopsy toxicological findings in a case of sudden death in a young person due to intracerebral hemorrhage associated with cocaine abuse. In view of the present epidemic of cocaine abuse, cocaine toxicity should be considered in the differential diagnosis of intracerebral hemorrhage. We suggest that the pharmacodynamic effects of cocaine on the cerebral vasculature is the most likely cause.
Adult↗
Apolipoprotein E is released by rat sciatic nerve during segmental demyelination and remyelination.
Apolipoprotein E (apo E) is synthesized and released in greatly increased amounts by peripheral nerve following Wallerian degeneration; it has been suggested that this protein may function in the transport of degenerated myelin lipid. The purpose of this study was to determine if the amount of apo E released by rat peripheral nerve is increased following selective demyelination, in the absence of significant axonopathy. Using an immunoturbidimetric assay, release of apo E from excised sciatic nerve segments was measured during the phases of acute demyelination and remyelination caused by tellurium (Te) toxicity, during segmental demyelination in chronic lead (Pb) poisoning, and during Wallerian degeneration following nerve crush. Morphologic changes were examined in contralateral sciatic nerves by nerve-fiber teasing or by light and electron microscopy of transverse sections. As in previous studies, the amount of apo E released from the nerves was greatly increased following Wallerian degeneration due to nerve crush. In Te neuropathy, increased release of apo E was first detected on the fourth day of Te exposure, corresponding temporally to the acute onset of paralysis and segmental demyelination. Apolipoprotein E release rose steeply to a maximum of ten times the control values by day 9 and then gradually waned during the next five weeks, corresponding to a period of active remyelination and resolution of the neuropathy. In the demyelinating neuropathy of chronic lead poisoning, apo E release was increased four times over control animals after seven weeks of exposure, with less than 10% of teased fibers showing early paranodal demyelination and no evidence of remyelination.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Changes in cerebrospinal fluid IgG and apolipoprotein E indices in patients with multiple sclerosis during demyelination and remyelination.
Approximately 85% of patients with multiple sclerosis (MS) can be diagnosed by using magnetic resonance imaging and laboratory tests such as determination of the cerebrospinal fluid (CSF) IgG Index and electrophoresis to detect oligoclonal banding. However, these tests results are abnormal in MS patients whether they are in clinical remission or acute exacerbation. Because apolipoprotein E (apo E) is synthesized in the central and peripheral nervous system, particularly during remyelination, we propose that apo E might be a reliable marker of the remyelination that accompanies clinical remission in MS patients. We studied 33 patients with MS, 22 in remission and 11 in exacerbation, and 26 controls of comparable ages. The apo E Index, calculated from the concentrations of apo E and albumin in CSF and serum, allowed us to discriminate between MS patients in remission and MS patients in exacerbation (P less than 0.001); the IgG Index failed to show similar differences. However, combining the apo E and IgG indices gave maximum discrimination between controls, MS patients in remission, and those in exacerbation. This study suggests that apo E measurements should be included in the laboratory evaluation of MS patients.
Adult↗
Automated determination of apolipoprotein AI and apolipoprotein E in cerebrospinal fluid.
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Apolipoprotein A-I↗
Decreased structure-linked latency of lysosomal dipeptidyl aminopeptidase-I activity in Duchenne muscular dystrophy fibroblasts.
Crude lysosomal pellets were prepared from skin fibroblasts grown from patients having Duchenne muscular dystrophy, and from normal controls. Disruption of the lysosomes by nonionic detergents resulted in the expression of latent activity of the enzyme dipeptidyl aminopeptidase-I(DAP-I). Duchenne lysosomes showed less structure-linked latency than those from normal controls, and sedimentation studies demonstrated that the difference was not caused by increased leakage of the enzyme from lysosomes. Permeability properties of the lysosomes for an artificial substrate revealed no difference of the apparent Km. However, in intact lysosomes the apparent K, for Cl- of this chloride-requiring enzyme was found to be lower in DMD lysosomes. The apparent increase in entry for Cl- was closely related with the decreased amount of the DAP-I latency. High concentrations of extra-lysosomal Cl- corrected the abnormality.
Cathepsins↗
Structural changes in lysosomes from cultured human fibroblasts in Duchenne's muscular dystrophy.
We have previously reported a decreased activity of the lysosomal enzyme dipeptidyl aminopeptidase-I (DAP-I) in cultured fibroblasts from patients with Duchenne's muscular dystrophy (DMD). Here we report that electron microscope examination of these cells reveals the presence of abundant lamellar bodies, a morphologic abnormalities commonly associated with impaired lysosomal function. Morphometric analysis of these cytoplasmic figures in dystrophic cells shows a sevenfold increase relative to normal controls (P less than 0.01). Analysis of lysosomal density profiles by density gradient centrifugation reveals similar patterns in normal and DMD cells. Treatment of lysosomes wit the nonionic detergent Triton X-100 causes an activation of DAP-I. This activation, attributable to structure-linked latency, is markedly diminished in DMD cells which show an optimal activation of only 180% compared to 255% for control fibroblasts (P less than 0.01). These data suggest an alteration in the properties of the lysosomal membrane in DMD fibroblasts. This suggestion is also supported by studies on the release of DAP-I from lysosomes by osmotic shock which show it to be a membrane-associated enzyme with membrane-binding characteristics intermediate between those of tightly bound beta-glucosidase and those of unbound N-acetylgalactosaminidase. The latency characteristics of these other lysosomal enzymes are not altered in the DMD cells, indicating that the effect is specific for DAP-I.
Cathepsins↗
Decreased lysosomal dipeptidyl aminopeptidase I activity in cultured human skin fibroblasts in Duchenne's muscular dystrophy.
Several lysosomal enzymes were assayed in cultured human skin fibroblasts from patients with Duchenne's muscular dystrophy (DMD) and age- and sex-matched control patients (N). The activity of four glycosidases, cathepsin B(1), and total autoproteolysis at pH 4.0 were unchanged between the groups, but dipeptidyl aminopeptidase I (DAP-I, or cathepsin C) in the DMD cells was found to be only 30% as active as in the control cells (P < 0.003). This difference is not the result of a redistribution or loss of enzyme during homogenization because the difference occurs in all homogenate fractions. DAP-I activity existing in N and DMD fibroblasts behaves identically with respect to activation by chloride ion, activation by the sulfhydryl reducing agent dithiothreitol, changes in hydrogen ion concentration (pH), changes in substrate concentration (i.e., apparent K(m) values), and changes in temperature (i.e., apparent activation energies). Mixtures of N and DMD cell sonicates display an additivity in DAP-I activity. These results support the conclusion that the catalytic function of the DAP-I molecule is equivalent between N and DMD fibroblasts, and that the decrease in tissue-specific DAP-I activity probably results from the fact that fewer enzyme molecules are present in the DMD cells. These results are also an indication that these nonmuscle cells are expressing some of the phenotypic aspects of the genetic defect in DMD. Cultured human skin fibroblasts may therefore be a useful cellular model in DMD research.
Cathepsins↗
Neonatal lead toxicity and in vitro lipid peroxidation of rat brain.
Neonatal rats were given aqueous lead acetate intragastrically from d 2--20 of life at doses of 0, 25, 75, and 225 mg Pb/kg.d. Blood Pb concentrations on d 21 were (mean +/- SE) 27 +/- 4 (control), 150 +/- 26, 263 +/- 63, and 518 +/- 97 microgram/100 ml, respectively. Growth was significantly depressed only in animals given the highest dose of Pb (225 mg/kg.d). Hematocrits were significantly decreased by d21 at all doses of Pb. Malondialdehyde (MDA) formation in 750 x g (10 min) brain supernatants induced spontaneously by aerobic incubation at 37 degrees C was not altered by Pb on d 7 and 14, but a slight decrease was observed on d 21. The extent of MDA formation induced by enzymatically generated superoxide anion was not altered by Pb toxicity during the first 21 d of life. Addition of Pb to 750 x g (10 min) brain supernatants in vitro significantly decreased MDA formation at Pb concentrations of 10(-5) M and higher. These results show that the central nervous system toxicity of Pb in neonatal rats is not associated with accelerated in vitro lipid peroxidation of brain tissue.
Animals↗
Brain lipofuscin concentration and oxidant defense enzymes in lead-poisoned neonatal rats.
Neonatal rats were given aqueous lead acetate intragastrically from d 2-20 of life at doses of 0, 10, 50, and 225 mg Pb/kg.d. Blood Pb concentrations on d 21 were (mean +/- SE) 23 +/- 3 (control), 63 +/- 19, 246 +/- 55, and 994 +/- 223 microgram/100 ml, and brain Pb concentrations were 14 +/- 2, 60 +/- 5, 114 +/- 15, and 275 +/- 26 microgram/100 g, respectively. Growth was significantly depressed only in rats given the highest dose of Pb (225 mg/kg.d). Solvent-extractable lipofuscin pigment concentration of brain tissue progressively decreased over the 21-d duration of the experiment but was not significantly altered at any dose of Pb. Brain glutathione peroxidase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase activities were stimulated on d 20 at the maximal dose of Pb, but the activities of brain superoxide dismutases and catalase were not altered by Pb exposure. Locomotor activity was significantly increased in the male animals on d 20, but only at the highest dose of Pb. These results indicate that Pb toxicity in neonatal rats is not associated with accelerated in vivo lipid peroxidation in the brain, but that certain oxidant defense mechanisms in the brain are stimulated by Pb.
Aging↗
The effect of lead on oxidative hemolysis and erythrocyte defense mechanisms in the rat.
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Anemia, Hemolytic↗
Cerebrospinal fluid and plasma apolipoproteins in patients with multiple sclerosis.
Apolipoprotein (apo) E is synthesized by cells of the central and peripheral nervous systems, and its synthesis and secretion in the peripheral nervous systems, and its synthesis and secretion in the peripheral nervous system of animals are greatly stimulated following Wallerian degeneration. It has been suggested that apo E functions in the metabolism of myelin lipids, but its physiologic role in nervous tissue has not been elucidated. To determine if apo E might play a role in demyelinating neuropathy, the concentrations were examined of apos E and A-1 in the cerebrospinal fluid (CSF) and plasma of patients with multiple sclerosis during clinical remission, and in patients with no neurologic disease. Serum and CSF albumin concentrations were measured to account for the possible influences of serum apo E concentration and/or altered blood-brain barrier permeability on the CSF apo E pool. A CSF index for apo E and apo A-1 was calculated in the same manner presently used for calculation of immunoglobulin G (IgG) production in the nervous system of patients with multiple sclerosis (MS). The results showed that the concentrations of apo E, apo Al, and albumin in the CSF of the MS patients were not significantly altered. The concentration of apo E in the serum, however, was significantly (p less than 0.001) decreased by 44 percent in the MS patients. The difference was relatively specific for serum apo E because the serum apo Al and albumin concentrations were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗