HIV dementia. Incidence and risk factors.
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AIDS Dementia Complex↗
Biomedical subjects
J D Glass
Publications and source records attributed to J D Glass.
Serotonin modulates photic responses in the hamster suprachiasmatic nuclei.
The aim of the present study was to examine the effects of serotonin agonists on three elements of the photic response in the hamster suprachiasmatic nuclei (SCN). Both serotonin and the selective 5-HT1A agonist 8-OH-DPAT inhibited field potentials recorded in the SCN in response to optic nerve stimulation in the hypothalamic slice preparation. The effects of both drugs were dose related over a concentration range of 1-50 microM, and, in both cases, a maximal inhibition of approximately 60% was achieved at a concentration of 25-50 microM. Systemic administration of 8-OH-DPAT inhibited light-stimulated Fos expression in the SCN. A regionally selective pattern of inhibition was observed, with decreases restricted predominately to the ventral and dorsal borders of the SCN. Finally, systemic administration of 8-OH-DPAT was found to dose-dependently attenuate light-induced phase shifts of the free-running activity rhythm. The effects of 8-OH-DPAT on light-induced phase advances were dose dependent. Injection of 8-OH-DPAT at a dose of 0.5 mg/kg caused 57% inhibition of light-induced phase advances, while a dose of 5 mg/kg inhibited the phase advance by 82%. Injection of 0.05 mg/kg 8-OH-DPAT did not significantly inhibit light-induced phase advances. Injection of 5 mg/kg 8-OH-DPAT alone did not significantly alter the phase of the activity rhythm. Similarly, injection of 5 mg/kg 8-OH-DPAT 30 min prior to light stimulation at CT14 completely inhibited light-induced phase delays, while this dose of the drug did not alter the phase of the activity rhythm when administered alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Action Potentials↗
Retrograde transport of radiolabeled cytoskeletal proteins in transected nerves.
Slow axonal transport is the mechanism by which cytoskeletal proteins are distributed within the axon. This function has traditionally been considered an exclusively unidirectional, anterograde process. Previous observations of cytoskeletal redistribution in surviving, transected axons of the C57BL/Ola mouse led us to hypothesize a retrograde component of cytoskeletal transport. To test this hypothesis against previous methods of measuring slow transport of cytoskeleton, we radioactively pulse-labeled proteins in sensory neurons of C57BL/Ola mice and followed their redistribution by gel fluorography in ligated and unligated sciatic nerves. Slow axonal transport of cytoskeletal proteins proceeded with the same characteristics in C57BL/Ola as in standard C57BL/6 mice. In comparison to the transport profiles from unligated control nerves, in ligated nerves there was redistribution of radiolabeled neurofilament and tubulin proteins back toward the cell body during the 14 d experimental period. These observations demonstrate that pulse-labeled cytoskeletal proteins move bidirectionally in this experimental system, and may provide insight into the normal mechanisms of cytoskeletal maintenance.
Animals↗
Control of astrocytosis by interleukin-1 and transforming growth factor-beta 1 in human brain.
Astrocytosis is a common neurocellular manifestation of brain pathology in individuals with a variety of diseases. It is comprised of astrocytic hyperplasia (an increase in number of astrocytes) and astrocytic hypertrophy (an increase in size of astrocytes). The precise cause(s) of astrocytosis remains unknown. We morphometrically measured the relative extent of astrocytosis in brains of 22 individuals who died with seven different diseases. The relative amounts of interleukin-1 (IL-1) and transforming growth factor-beta 1 (TGF-beta 1) immunoreactive products (IRPs) were next assessed in sections serial to those in which astrocytosis was measured because these cytokines were shown in animal and in vitro experiments to be associated with astrocytosis. The data demonstrate that astrocytosis and these cytokines were co-localized in all examined human tissues. Relative increase in density of astrocytes was correlated with the increase in total IL-1 but not TGF-beta 1. In contrast, the increase in size of astrocytes was correlated with TGF-beta 1 associated only with astrocytes but not with total IL-1. Both IL-1 and TGF-beta 1 IRPs were present in GFAP IRP-containing and other cells, as assessed by double label immunocytochemistry. These observations suggest that IL-1 acts on astrocytes by both, paracrine and autocrine mechanisms whereas, TGF-beta 1 only acts by an autocrine mechanism. Because these correlations were statistically significant and also because a change in number and size of astrocytes constitutes the most frequent response of astrocytes to several diseases or injury, we conclude that these cytokines may mediate the most common pathological change in human brain.
Astrocytes↗
Serotonergic inhibition of light-induced fos protein expression and extracellular glutamate in the suprachiasmatic nuclei.
The present experiments were undertaken to explore a role for serotonin (5-HT) in modulating photic signal transduction and extracellular glutamate (Glu) concentration in the suprachiasmatic nuclei (SCN) of the Syrian hamster. Pretreatment with an i.p. injection of the serotonergic, quipazine, caused a marked decrease in the number of SCN cells expressing Fos protein-like immunoreactivity (Fos-LI) induced by a light pulse delivered during the latter part of the dark phase (7 h after lights-off; 55.6 +/- 7.5% of vehicle controls, P < 0.004). This effect of quipazine was dose-dependent and was limited principally to the ventrolateral region of the SCN. In a likewise manner, intra-SCN microinjection of quipazine inhibited light-induced Fos-LI in the ventrolateral SCN, indicating that the suppressive action of quipazine is centered in the SCN. In a separate experiment, localized perfusion of the SCN region with 5-HT using the microdialysis technique caused a significant reduction in the extracellular concentration of Glu. The effect was greater during the dark phase, compared to the light phase of the day-night cycle (60.7 +/- 6.8% vs. 39.3 +/- 6.8% maximal suppression, respectively; P < 0.05). Similar localized application of quipazine also decreased extracellular Glu (48.0 +/- 6.1% maximal suppression; P < 0.05). Collectively, these results are evidence for a serotonergic modulation of retinohypothalamic input in the SCN, which could involve a presynaptic inhibition of Glu release.
Animals↗
Gliosis in human brain: relationship to size but not other properties of astrocytes.
Gliosis is the most frequent and therefore important neurocellular reaction to brain insult occurring in diseases ranging from AIDS to infarction. Neuropathological diagnosis of gliosis is based on morphological changes of brain glial cells. Changes commonly agreed to reflect gliosis are qualitative increases in size, number and glial fibrillary acidic protein (GFAP) immunoreactivity of astrocytes. These parameters were morphometrically quantified in brain tissues of 22 individuals who died with 7 diseases and statistically compared to the extent of gliosis independently determined by 3 qualified observers. The data indicate that the extent of gliosis correlated with the increase in size of astrocytes in white matter (p = 0.67) and this relationship was statistically significant (P = 0.0006). In contrast, the extent of gliosis was not correlated with the density of astrocytes nor the intensity of GFAP staining.
Acquired Immunodeficiency Syndrome↗
Intracerebral cytokine messenger RNA expression in acquired immunodeficiency syndrome dementia.
The pathogenesis of the dementia associated with human immunodeficiency virus (HIV) infection is unclear, but has been postulated to be due to indirect effects of HIV infection including the local production of cytokines. To determine which cytokines are produced in the nervous system and to identify any correlations with dementia, cytokine and HIV messenger RNA expression was analyzed by reverse transcriptase-polymerase chain reaction in the brains from 24 HIV-infected patients with and without dementia and 9 HIV-uninfected control subjects. Levels of tumor necrosis factor-alpha messenger RNA were significantly higher and levels of interleukin (IL)-4 messenger RNA were significantly lower in demented compared to nondemented HIV-infected patients. Demented patients also had lower IL-1 beta levels than did nondemented patients. No significant differences were detected in the amounts of leukemia inhibitory factor, IL-6, transforming growth factor-beta 1 and -beta 2, monokine induced by gamma interferon-2 (MIG-2), or interferon-gamma messenger RNAs. IL-10 and IL-2 messenger RNAs were undetectable in all brains examined. Cytokine messenger RNA levels in nondemented HIV-positive patients were similar to those in HIV-negative control subjects. HIV transcripts were more abundant in subcortical white matter than in the basal ganglia, cortex, or deep white matter. Our findings suggest a possible role for tumor necrosis factor-alpha in the development of neurological dysfunction. Increased levels of tumor necrosis factor-alpha messenger RNA were not associated with increased levels of IL-1 beta messenger RNA, suggesting differential regulation of these monokines in acquired immunodeficiency syndrome dementia.(ABSTRACT TRUNCATED AT 250 WORDS)
AIDS Dementia Complex↗
Rapid diagnosis of cytomegalovirus polyradiculitis in a patient with acquired immunodeficiency syndrome.
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AIDS-Related Opportunistic Infections↗
Cerebral white matter changes in acquired immunodeficiency syndrome dementia: alterations of the blood-brain barrier.
The cause of acquired immunodeficiency syndrome (AIDS) dementia, which is a frequent late manifestation of human immunodeficiency virus (HIV) infection, is unknown but radiological and pathological studies have implicated alterations in subcortical white matter. To investigate the pathological basis of these white matter abnormalities, we performed an immunocytochemical and histological analysis of subcortical white matter from AIDS patients with and without dementia, from pre-AIDS patients (asymptomatic HIV-seropositive patients), and from HIV-seronegative control subjects. Reduced intensity of Luxol fast blue staining, designated "diffuse myelin pallor," was detected in 8 of 15 AIDS dementia patients, 3 of 13 AIDS nondemented patients, and none of the pre-AIDS patients (n = 2) or control subjects (n = 9). In contrast to Luxol fast blue staining, sections stained immunocytochemically for myelin proteins did not show decreased staining intensities in regions of diffuse myelin pallor. In addition, neither demyelinated axons nor active demyelination were detected in light and electron micrographs of subcortical white matter from brains of patients with AIDS dementia. An increase in the number of perivascular macrophages and hypertrophy of astrocytes and microglia occurred in brain sections from HIV-infected patients. These changes were not specific to dementia or regions of diffuse myelin pallor and they occurred in both gray and white matter. In contrast to the lack of myelin pathology in AIDS dementia brains, significant accumulations of serum proteins in white matter glia were detected in the brains of 12 of 12 patients with AIDS dementia and 6 of 12 AIDS patients without dementia. Serum protein-immunopositive cortical neurons were detected in the frontal cortex of 11 of 12 patients with AIDS dementia and 3 of 12 nondemented AIDS patients. Seronegative control subjects showed minimal serum protein immunoreactivity in both cortex and white matter. We conclude therefore that alterations in the blood-brain barrier and not demyelination contribute to the development of AIDS dementia.
AIDS Dementia Complex↗
Prolonged survival of transected nerve fibres in C57BL/Ola mice is an intrinsic characteristic of the axon.
Transected axons in C57BL/Ola mice survive for extraordinary lengths of time as compared to those of normal rodents. The biological difference in the substrain that confers the phenotype of prolonged axonal survival is unknown. Previous studies suggest that 'defect' to be a property of the nervous system itself, rather than one of haematogenous cells. Neuronal or non-neuronal elements could be responsible for this phenotype. This study was undertaken to determine whether Schwann cells, the most numerous of the non-neuronal cells intrinsic to the peripheral nerve, are responsible for delayed degeneration of transected axons. We created sciatic nerve chimeras by transplanting nerve segments between standard C57BL/6 and C57BL/Ola mice, allowing regeneration of host axons through the grafts containing donor Schwann cells. These nerves were then transected and the time course of axonal degeneration was observed. The results show that fast or slow degeneration is a property conferred by the host, and therefore cannot be ascribed to the Schwann cells. Similarly, transected C57BL/Ola axons in explanted dorsal root ganglia cultures survived longer than transected axons from standard mice. Taken together these results indicate that the responsible abnormality is intrinsic to the C57BL/Ola axon.
Animals↗
Differential timing of amino acid and 5-HIAA rhythms in suprachiasmatic hypothalamus.
In vivo brain microdialysis was used to characterize the daily pattern of extracellular excitatory amino acids (EAA; glutamate and aspartate), glutamine and 5-hydroxyindoleacetic acid (5-HIAA) in the region of the suprachiasmatic nucleus (SCN) in freely behaving male Syrian hamsters. Diurnal variations in the extracellular concentrations of EAA and 5-HIAA observed under 14:10-h light-dark (LD) photoperiod were confirmed by cosinor analysis. Peak levels occurred during the night, with the mean acrophasis for 5-HI-AA concentration preceding that for EAA by 1-2 h. Release of EAA was stimulated by K(+)-induced depolarization in a Ca(2+)-dependent manner and was not affected by tetrodotoxin. In the absence of light cues (constant dim red light, < 0.4 lx; DD) there was a significant time-of-day effect in peak glutamate concentration (occurring during subjective night), but the rhythmic pattern of 5-HIAA output was lost. There was no apparent direct temporal linkage between peaks in extracellular EAA or 5-HIAA and bouts of wheel-running activity under LD or DD. These results are evidence that 1) the daily release pattern of extracellular glutamate, but not 5-HIAA, is circadian in nature; and 2) this rhythm in glutamate is not based on Na+ channel-dependent action potentials. Finally, a discordance in the timing of peak nocturnal extracellular 5-HIAA and EAA concentrations was evident, possibly reflecting an interplay between serotonergic and EAA pathways in the SCN.
Amino Acids↗
Clinical-neuropathologic correlation in HIV-associated dementia.
The structural abnormalities that correlate with the clinical manifestations of HIV-associated dementia (HIVD) are unclear. In a prospectively categorized group of patients with and without HIVD who were followed to autopsy, we correlated HIV-related neuropathologic changes with the presence and severity of HIVD. We also assessed the effect of antiretroviral therapy on the neuropathologic changes. Finally, using reverse transcriptase-polymerase chain reaction on homogenized brain tissue, we correlated the relative expression of mRNA for tumor necrosis factor-alpha (TNF-alpha) with cognitive impairment and with the patterns of neuropathologic changes. The presence of multinucleated giant cells and diffuse myelin pallor were specific for HIVD, but these pathologic changes occurred in only 50% of patients with dementia. Patients treated with antiretroviral agents for > 12 months were less likely to show multinucleated giant cells or diffuse myelin pallor. Levels of mRNA for TNF-alpha from frontal subcortical white matter were significantly greater in patients with HIVD than in AIDS patients without dementia or in seronegative controls. We conclude that routine histopathologic examination of the brain fails to detect multinucleated giant cells and diffuse myelin pallor in 50% of patients dying with HIVD. This suggests that more subtle neuropathologic correlates for the clinical manifestations of HIVD exist. Our observations of elevated levels of TNF-alpha mRNA in HIVD indicate that indirect mechanisms of brain dysfunction, such as abnormal cytokine expression, may contribute to the pathogenesis of HIVD.
AIDS Dementia Complex↗
Neurologic prognosis of cytomegalovirus polyradiculomyelopathy in AIDS.
Cytomegalovirus (CMV) polyradiculomyelopathy is an uncommon but distinctive clinical syndrome in HIV-infected patients in which ascending motor weakness, areflexia, loss of sphincter control, paresthesias, and varying sensory impairment develop subacutely in association with a polymorphonuclear pleocytosis, increased protein, and hypoglycorrhachia in CSF. Responses to treatment with ganciclovir have varied in reported cases. We report three additional cases: two of these patients responded to treatment and the third was demonstrated to have CMV resistant to ganciclovir. We review other reported cases and identify factors predictive of ganciclovir resistance, which include persistent polymorphonuclear pleocytosis and hypoglycorrhachia on serial CSF studies, and positive CMV cultures from CSF or blood after induction therapy. We conclude that ganciclovir may be an effective therapy for CMV polyradiculomyelopathy, but the presence of these factors, or the development of the syndrome in a patient already being treated with ganciclovir, should prompt consideration of alternative antiviral therapy.
AIDS-Related Opportunistic Infections↗
Cytokine expression of macrophages in HIV-1-associated vacuolar myelopathy.
Macrophages are frequently present within the periaxonal and intramyelinic vacuoles that are located primarily in the posterior and lateral funiculi of the thoracic spinal cord in HIV-associated vacuolar myelopathy. But the role of these macrophages in the formation of the vacuoles is unclear. One hypothesis is that cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF)-alpha, are produced locally by macrophages and have toxic effects on myelin or oligodendrocytes. The resulting myelin damage eventually culminates in the removal of myelin by macrophages and vacuole formation. We studied thoracic spinal cord specimens taken at autopsy from HIV-positive (+) and HIV-negative individuals. The predominant mononuclear cells present in HIV+ spinal cords are macrophages. They are located primarily in the posterior and lateral funiculi regardless of the presence or absence of vacuolar myelopathy. Macrophages and microglia are more frequent in HIV+ than HIV-negative individuals and these cells frequently stain for class I and class II antigens, IL-1, and TNF-alpha. Activated macrophages positive for IL-1 and TNF-alpha are great increased in the posterior and lateral funiculi of HIV+ individuals with and without vacuolar myelopathy, suggesting they are present prior to the development of vacuoles. Cytokines, such as TNF-alpha, may be toxic for myelin or oligodendrocytes, leading to myelin damage and removal by macrophages and vacuole formation.
Acquired Immunodeficiency Syndrome↗
Daily profile of the extracellular concentration of glutamate in the suprachiasmatic region of the Siberian hamster.
Daily profiles of the extracellular concentrations of glutamate (GLU), aspartate, and glutamine in the region of the suprachiasmatic nuclei (SCN) of the Djungarian hamster were examined by in vivo microdialysis. Hamsters with a dialysis probe located in or near the SCN exhibited a diurnal variation in the extracellular concentration of GLU. Glutamate levels rose gradually during the latter half of the subjective day and through the night to reach peak levels near the time of lights-on. The extracellular concentration of GLU was significantly elevated (P < 0.05) during the latter half of the dark phase relative to the level at midday. The average peak in extracellular GLU was 217% of the midday value (P < 0.05; n = 5). Diurnal fluctuations were not consistently observed in the concentrations of aspartate in SCN dialysates. The nocturnal rise in extracellular GLU in the SCN was not attenuated by perfusion with 10 microM tetrodotoxin, although this concentration of tetrodotoxin completely blocked increases in extracellular GLU caused by simultaneous perfusion with 30 microM veratridine. Collectively, these results point to a diurnal rhythm in extracellular concentration of GLU in the SCN region which may not reflect diurnal variations in synaptic activity.
Animals↗
Suprachiasmatic nucleus neurochemistry in the conscious brain: correlation with circadian activity rhythms.
The aim of the research reported here was to provide information on the neurochemical processes that underlie the generation and entrainment of mammalian circadian rhythms. The studies were centered principally around the in vivo brain microdialysis technique for assessing the daily pattern of neurotransmitter activity in the suprachiasmatic hypothalamus of freely behaving Syrian and Siberian hamsters. This approach yielded several findings related to the activities of serotonergic and excitatory amino acid systems in the region of the suprachiasmatic nuclei (SNC). Specifically, we found that (1) there were daily variations in the extracellular concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and glutamate (GLU) in the SCN region (highest levels of 5-HIAA occurred soon after lights-off, whereas GLU peaked later in the dark phase); (2) the daily rhythm of GLU, but not serotonin, in the SCN region appeared to be circadian in nature and was not driven by an external influence; (3) the rhythm in GLU measured in SCN microdialysate involved a tetrodotoxin-insensitive mechanism and did not appear to be directly linked to the expression of locomotor behavior; and (4) direct application of serotonin receptor agonists via the microdialysis probe suppressed the concentration of extracellular GLU in the SCN region, suggesting that serotonin may modulate GLU release in the SCN.
Animals↗
Redistribution of cytoskeletal proteins in mammalian axons disconnected from their cell bodies.
Mice of the strain C57/BL/Ola exhibit a delay of Wallerian degeneration, such that axons survive for several weeks after a nerve transection that separates the axons from the cell bodies. In this Ola strain we have examined the distribution of cytoskeletal proteins in a 5 mm segment of the sciatic nerve for as long as 2 weeks after proximal and distal transections that prevent entry or exit of proteins via axonal transport. By 7 d after transections, there was a marked accumulation of alpha- and beta-tubulin, actin, and nonphosphorylated neurofilament epitopes at the proximal and at the distal ends of the transected axons, and loss of these proteins from the center of the isolated nerve segment. Highly phosphorylated neurofilament epitopes did not redistribute along the nerve, but there was a gradual loss of phosphorylated neurofilament immunoreactivity. These observations indicate the potential for bidirectional transport of a substantial portion of certain cytoskeletal proteins within axons of the PNS.
Actins↗
Cytokine expression in the brain during the acquired immunodeficiency syndrome.
The pathogenesis of central nervous system (CNS) disease in acquired immunodeficiency syndrome (AIDS) is poorly understood but may be related to specific effects of the immune system. Cytokines such as tumor necrosis factor and interleukin-1 may have toxic effects on CNS cells and have been postulated to contribute to the pathogenesis of the neurological complications of human immunodeficiency virus (HIV) infection. To characterize viral and immunological activity in the CNS, frozen specimens taken at autopsy from the cerebral cortex and white matter of HIV-seropositive and -seronegative individuals were stained immunocytochemically for mononuclear cells, major histocompatibility complex (MHC) antigens, HIV, astrocytes, and the cytokines interleukin-1 and -6, tumor necrosis factor-alpha and -beta, and interferon gamma. Levels of soluble CD4, CD8, and interleukin-2 receptor, as well as interferon gamma, tumor necrosis factor-alpha, beta 2-microglobulin, neopterin, and interleukin-6 and -1 beta were assayed in the cerebrospinal fluid and plasma of many of these individuals during life. The HIV-seropositive group included individuals without neurological disease, those with CNS opportunistic infections, and those with HIV encephalopathy. Perivascular cells, consisting primarily of macrophages with some CD4+ and CD8+ T cells and rare B cells, were consistently MHC class II positive. MHC class II antigen was also present on microglial cells, which were frequently positive for tumor necrosis factor-alpha. HIV p24 antigen, when present, was found on macrophages and microglia. Endothelial cells were frequently positive for interleukin-1 and interferon gamma and less frequently for tumor necrosis factor and interleukin-6. There were gliosis and significant increases in MHC class II antigen, interleukin-1, and tumor necrosis factor-alpha in HIV-positive patients compared to HIV-negative brains. Cerebrospinal fluid from most of the patients tested had increased levels of tumor necrosis factor, beta 2-microglobulin, and neopterin. There was no correlation in HIV-positive individuals between levels of cytokines and the presence or absence of CNS disease. These data indicate that there is a relative state of "immune activation" in the brains of HIV-positive compared to HIV-negative individuals, and suggest a potential role for the immune system in the pathogenesis of HIV encephalopathy.
Acquired Immunodeficiency Syndrome↗