AIDS-related Dementia Complex Research Articles

Memantine for dementia.

Memantine for dementia.

Kynurenine pathway metabolism and neuroinflammatory disease.

Immune-mediated activation of tryptophan (TRYP) catabolism via the kynurenine pathway (KP) is a consistent finding in all inflammatory disorders. Several studies by our group and others have examined the neurotoxic potential of neuroreactive TRYP metabolites, including quinolinic acid (QUIN) in neuroinflammatory neurological disorders, including Alzheimer's disease (AD), multiple sclerosis, amylotropic lateral sclerosis (ALS), and AIDS related dementia complex (ADC). Our current work aims to determine whether there is any benefit to the affected individuals in enhancing the catabolism of TRYP via the KP during an immune response. Under physiological conditions, QUIN is metabolized to the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+), which represents an important metabolic cofactor and electron transporter. NAD+ also serves as a substrate for the DNA ‘nick sensor’ and putative nuclear repair enzyme, poly(ADP-ribose) polymerase (PARP). Free radical initiated DNA damage, PARP activation and NAD+ depletion may contribute to brain dysfunction and cell death in neuroinflammatory disease.

Coincidental Observation of Global Hypometabolism in the Brain on PET/CT of an AIDS Patient With High-Grade Pulmonary Non-Hodgkin Lymphoma

AIDS-related dementia complex is the most severe form of cognitive dysfunction in a patient infected with human immunodeficiency virus. The use of FDG PET/CT to diagnose AIDS-related dementia complex has been studied previously and shows various specific metabolic patterns from striatal hypermetabolism in early asymptomatic stage to global hypometabolism in advanced stages. We present a case of a 49-year-old patient with long-standing human immunodeficiency virus infection, where global brain hypometabolism was noted coincidentally on FDG PET/CT done for initial staging of primary pulmonary non-Hodgkin lymphoma.

Positron emission tomography in patients suffering from HIV-1 infection

This paper reviews currently available PET studies performed either to improve our understanding of the pathogenesis of HIV-1 infection or to assess the value of PET imaging in the clinical decision making of patients infected with HIV-1 presenting with AIDS-related opportunistic infections and malignancies. FDG PET has shown that HIV-1 infection progresses by distinct anatomical steps, with involvement of the upper torso preceding involvement of the lower part of the torso, and that the degree of FDG uptake relates to viral load. The former finding suggests that lymphoid tissues are engaged in a predictable sequence and that diffusible mediators of activation might be important targets for vaccine or therapeutic intervention strategies. In lipodystrophic HIV-infected patients, limited available data support the hypothesis that stavudine-related lipodystrophy is associated with increased glucose uptake by adipose tissue as a result of the metabolic stress of adipose tissue in response to highly active antiretroviral treatment (HAART). Finally, in early AIDS-related dementia complex (ADC), striatal hypermetabolism is observed, whereas progressive ADC is characterized by a decrease in subcortical and cortical metabolism. In the clinical setting, PET has been shown to allow the differentiation of AIDS-related opportunistic infections and malignancies, and to allow monitoring of side effects of HAART. However, in patients suffering from HIV infection and presenting with extracerebral lymphoma or other human malignancies, knowledge of viraemia is essential when interpreting FDG PET imaging.

Trichosporon asahii infection in an advanced AIDS patient and literature review

Trichosporon asahii infection in an advanced AIDS patient and literature review

Toxoplasma gondii Prevents Neuron Degeneration by Interferon-γ-Activated Microglia in a Mechanism Involving Inhibition of Inducible Nitric Oxide Synthase and Transforming Growth Factor-β1 Production by Infected Microglia

Interferon (IFN)-gamma, the main cytokine responsible for immunological defense against Toxoplasma gondii, is essential in all infected tissues, including the central nervous system. However, IFN-gamma-activated microglia may cause tissue injury through production of toxic metabolites such as nitric oxide (NO), a potent inducer of central nervous system pathologies related to inflammatory neuronal disturbances. Despite potential NO toxicity, neurodegeneration is not commonly found during chronic T. gondii infection. In this study, we describe decreased NO production by IFN-gamma-activated microglial cells infected by T. gondii. This effect involved strong inhibition of iNOS expression in IFN-gamma-activated, infected microglia but not in uninfected neighboring cells. The inhibition of NO production and iNOS expression were parallel with recovery of neurite outgrowth when neurons were co-cultured with T. gondii-infected, IFN-gamma-activated microglia. In the presence of transforming growth factor (TGF)-beta1-neutralizing antibodies, the beneficial effect of the parasite on neurons was abrogated, and NO production reverted to levels similar to IFN-gamma-activated uninfected co-cultures. In addition, we observed Smad-2 nuclear translocation, a hallmark of TGF-beta1 downstream signaling, in infected microglial cultures, emphasizing an autocrine effect restricted to infected cells. Together, these data may explain a neuropreservation pattern observed during immunocompetent host infection that is dependent on T. gondii-triggered TGF-beta1 secretion by infected microglia.

Protection against gp120-induced neurotoxicity by an array of estrogenic steroids

gp120, the coat protein of HIV, can be neurotoxic and is thought to contribute to AIDS-related dementia complex. Such toxicity involves activation of glutamate receptors, mobilization of free cytosolic calcium, and generation of oxygen radicals. We have previously shown that the estrogen 17β-estradiol, in concentrations of 100 nM or higher, lessens the neurotoxicity of gp120 in hippocampal and cortical cultures, blunts gp120-induced calcium mobilization, and lessens the oxidative consequences. In this study, we examined the protective potential of other estrogens. We found gp120 neurotoxicity in hippocampal cultures to be significantly lessened by estrone, equilin and estriol, although with an order of magnitude less potent than 17β-estradiol. We also found all four estrogens to blunt gp120-induced calcium mobilization, with estriol being more efficacious than the other three estrogens. These findings give insight both into the mechanisms of estrogenic protection (e.g. receptor-dependent versus independent actions) as well as into the potential therapeutic use of estrogens against AIDS-related dementia complex.

Mechanisms of Estrogenic Protection against gp120-Induced Neurotoxicity

gp120, an HIV coat glycoprotein that may play a role in AIDS-related dementia complex (ADC), induces neuronal toxicity characterized by NMDA receptor activation, accumulation of intracellular calcium, and downstream degenerative events including generation of reactive oxygen species and lipid peroxidation. We have previously demonstrated estrogenic protection against gp120 neurotoxicity in primary hippocampal cultures. We here characterize the mechanism of protection by blocking the classical cytosolic estrogen receptors and by measuring oxidative end points including accumulation of extracellular superoxide and lipid peroxidation. Despite blocking ERα and ERβ with 1 μM tamoxifen, we do not see a decrease in the protection afforded by 100 nM 17 β-estradiol against 200 pM gp120. Additionally, 17α-estradiol, which does not activate estrogen receptors, protects to the same extent as 17β-estradiol. 17β-Estradiol does, however, decrease gp120-induced lipid peroxidation and accumulation of superoxide. Together the data suggest an antioxidant mechanism of estrogen protection that is independent of receptor binding.

The immune system and memory consolidation: a role for the cytokine IL-1β

Interleukin-1 beta (IL-1β), known to play a role in orchestrating the physiological and behavioral adjustments that occur during sickness, has also been shown to significantly influence memory consolidation. To support this assertion we present neurobiological evidence that the substrates for IL-1β to influence memory processing and neural plasticity exist. We then present behavioral evidence that central IL-1β administration and agents that induce central IL-1β activity impair the consolidation of memories that depend on the hippocampal formation but have no effect on the consolidation of hippocampal-independent memories. Further, we demonstrate that the impairments in hippocampal-dependent memory consolidation produced by agents that induce IL-1β activity are blocked by antagonizing the actions of IL-1β. Finally, we discuss these data in terms of their implications for a physiological role of IL-1β in memory consolidation processes and a potential role of IL-1β in producing memory impairments associated with stress, aging, Alzheimer's disease, and AIDS related dementia complex.

Involvement of inositol 1,4,5-trisphosphate-regulated stores of intracellular calcium in calcium dysregulation and neuron cell death caused by HIV-1 protein tat.

HIV-1 infection commonly leads to neuronal cell death and a debilitating syndrome known as AIDS-related dementia complex. The HIV-1 protein Tat is neurotoxic, and because cell survival is affected by the intracellular calcium concentration ([Ca2+]i), we determined mechanisms by which Tat increased [Ca2+]i and the involvement of these mechanisms in Tat-induced neurotoxicity. Tat increased [Ca2+]i dose-dependently in cultured human fetal neurons and astrocytes. In neurons, but not astrocytes, we observed biphasic increases of [Ca2+]i. Initial transient increases were larger in astrocytes than in neurons and in both cell types were significantly attenuated by antagonists of inositol 1,4,5-trisphosphate (IP3)-mediated intracellular calcium release [8-(diethylamino)octyl-3,4,5-trimethoxybenzoate HCI (TMB-8) and xestospongin], an inhibitor of receptor-Gi protein coupling (pertussis toxin), and a phospholipase C inhibitor (neomycin). Tat significantly increased levels of IP3 threefold. Secondary increases of neuronal [Ca2+]i in neurons were delayed and progressive as a result of excessive calcium influx and were inhibited by the glutamate receptor antagonists ketamine, MK-801, (+/-)-2-amino-5-phosphonopentanoic acid, and 6,7-dinitroquinoxaline-2,3-dione. Secondary increases of [Ca2+]i did not occur when initial increases of [Ca2+]i were prevented with TMB-8, xestospongin, pertussis toxin, or neomycin, and these inhibitors as well as thapsigargin inhibited Tat-induced neurotoxicity. These results suggest that Tat, via pertussis toxin-sensitive phospholipase C activity, induces calcium release from IP3-sensitive intracellular stores, which leads to glutamate receptor-mediated calcium influx, dysregulation of [Ca2+]i, and Tat-induced neurotoxicity.

Mechanisms of transport of nucleosides and nucleoside analogues in choroid plexus

Nucleoside and nucleobase analogues are being used to treat a number of viral infections of the central nervous system (CNS) including herpes-simplex encephalitis, cytomegalovirus retinitis, and AIDS-related dementia complex. Delivery of nucleoside analogues to the CNS is considered a key challenge in the treatment of these diseases. In this review, we focus on the mechanisms of transport of nucleosides and nucleoside analogues in the choroid plexus. First, the structure and function of the choroid plexus are reviewed. Then, we focus on the mechanisms of nucleoside transport in mammalian cells. Specific emphasis is placed on the molecular and functional characteristics of various nucleoside transporters. A discussion is then devoted to the mechanisms of nucleoside transport in choroid plexus. Current knowledge of nucleoside transport systems in choroid plexus in several animal species is summarized followed by a short section on the mechanisms of transport of nucleobases in the choroid plexus. Finally, a brief section on future directions is included.

Glucocorticoid modulation of gp120-induced effects on calcium-dependent degenerative events in primary hippocampal and cortical cultures.

The HIV coat protein gp120 has been implicated in damaging the nervous system and may play a role in AIDS-related dementia complex. The glycoprotein triggers the release of a glutamatergic agent from infected microglia and macrophages, causing NMDA receptor- and calcium-dependent excitotoxic damage to neurons. We have previously shown that glucocorticoids, the adrenal steroids secreted during stress, worsen gp120 neurotoxicity and calcium mobilization in various brain regions. This study explores events down-stream of gp120-induced calcium mobilization, specifically, generation of reactive oxygen species (ROS) and subsequent lipid peroxidation, destruction of the cytoskeleton through spectrin proteolysis, and the glucocorticoid modulation of these events in primary hippocampal cultures. We observe that 200 pM gp120 causes a significant accumulation of ROS, including superoxide, and of lipid peroxidation. Counter to our predictions, pretreatment with the glucocorticoid corticosterone (CORT) did not worsen the effects of gp120 on ROS accumulation, but did increase lipid peroxidation. We also observed that neither gp120 alone nor gp120 plus CORT caused detectable proteolysis of the cytoskeletal protein spectrin, whose breakdown has been shown to be a damaging consequence of calcium excess in other models of necrotic neuronal injury.

Glucocorticoids interact with gp120 in causing neurotoxicity in striatal cultures

A significant subset of HIV-positive patients suffer from AIDS-Related Dementia Complex (ADC), an array of neurologic and neuropsychologic impairments. The HIV coat protein gp120 has been implicated in the deleterious neurologic consequences of HIV infection, damaging neurons through a glutamatergic and calcium-dependent pathway. We have previously reported that glucocorticoids, the adrenal steroids secreted during stress, can exacerbate the neurotoxic and calcium-mobilizing effects of gp120 in hippocampal and cortical cultures. Because both the symptomatology of ADC, as well as the neuropathologic profile of post-mortem HIV brains suggests an involvement of the striatum, we examined whether glucocorticoids could also augment the damaging effects of gp120 in primary striatal cultures. We observe that neither gp120 nor the glucocorticoid corticosterone, when administered alone, cause neurotoxicity or mobilization of free cytosolic calcium; however, a combination of the two caused significant toxicity and neuron death. This, along with our prior findings of gp120–glucocorticoid interactions, is striking, given the heavy clinical use of synthetic glucocorticoids for management of pulmonary complications of HIV infection.

Energy dependency of glucocorticoid exacerbation of gp120 neurotoxicity.

The HIV envelope glycoprotein, gp120, a well documented neurotoxin, may be involved in AIDS-related dementia complex. gp120 works through an NMDA receptor- and calcium-dependent mechanism to damage neurons. We have previously demonstrated that both natural and synthetic glucocorticoids (GCs) exacerbate gp120-induced neurotoxicity and calcium mobilization in hippocampal mixed cultures. GCs, steroid hormones secreted during stress, are now shown to work in conjunction with gp120 to decrease ATP levels and to work synergistically with gp120 to decrease the mitochondrial potential in hippocampal cultures. Furthermore, energy supplementation blocked the ability of GCs to worsen gp120's effects on neuronal survival and calcium mobilization. A GC-induced reduction in glucose transport in hippocampal neurons, as previously documented, may contribute to this energetic dependency. These results may have clinical significance, considering the common treatment of severe cases of Pneumocystis carinii pneumonia, typical of HIV infection, with large doses of synthetic GCs.

Endocrine modulation of the neurotoxicity of gp120: implications for AIDS-related dementia complex.

HIV infection often involves the development of AIDS-related dementia complex, a variety of neurologic, neuropsychologic, and neuropathologic impairments. A possible contributor to AIDS-related dementia complex is the HIV envelope glycoprotein gp120, which damages neurons via a complex glutamate receptor- and calcium-dependent cascade. We demonstrate an endocrine modulation of the deleterious effects of gp120 in primary hippocampal and cortical cultures. Specifically, we observe that gp120-induced calcium mobilization and neurotoxicity are exacerbated by glucocorticoids, the adrenal steroids secreted during stress. Importantly, this deleterious synergy can occur between gp120 and synthetic glucocorticoids (such as prednisone or dexamethasone) that are used clinically in high concentrations to treat severe cases of the Pneumocystis carinii pneumonia typical of HIV infection. Conversely, we also observe that estradiol protects neurons from the deleterious actions of gp120, reducing toxicity and calcium mobilization.

Slowed synthesis of DNA and methionine is a pathogenetic mechanism common to dementia in down's syndrome, AIDS and Alzheimer's disease?

This is a presentation of the hypothesis of a pathogenetic mechanism common to the dementia seen in Alzheimer's disease (AD) Down's Syndrome (DS) and the acquired immunodeficiency syndrome (AIDS). As there is experimental evidence of defective DNA repair capacity in AD and DS, unrepaired damage to DNA occurs in these diseases and may lead to complete breakdown of cellular function and ultimate cell death. Combalamin and folate are coordinated in a vulnerable key position in the synthesis of DNA and S-adenosylmethionine (SAM). Cobalamin folate deficiency, a significant feature in senile dementia of Alzheimer type and in AIDS-related dementia complex, will result in concomitant slowed synthesis of DNA and SAM. The enzyme cystathionine-beta-synthetase (CBS) has been localized to the chromosome band 21q22.3. Owing to gene dosage, CBS activity is increased in trisomy 21. As a consequence, cobalamin folate metabolism is inhibited, which leads to slowing of DNA and SAM synthesis in DS patients. Amyloidosis is a hallmark of AD and DS brain neuropathology and recent experimental findings support the view that amyloid or amyloid precursors stimulate DNA synthesis, which is in agreement with the hypothesis presented in this paper. In summary, demented patients with cobalamin folate deficiency, trisomy 21 and human immunodeficiency virus (HIV) infection display a simultaneous downregulation of DNA and SAM synthesis, which may indicate a pathway common to the dementia seen in AD, DS and AIDS.

Intrathecal production of HIV antibodies in suspected AIDS encephalopathy.

Thirty-one serum and CSF samples from 21 HIV-antibody-positive patients with neurological deficits were examined to prove or exclude intrathecal production of HIV antibodies. By dilution, sera were adjusted to the IgG concentration of the corresponding CSF samples. Both samples were then serially diluted in log2 steps down to the detection limit and were tested in an anti-HIV ELISA. From the dilution obtained at the cut-off level, a quotient QHIV was derived as an indicator of intrathecal production of HIV antibodies. Six of a total of eight samples with a QHIV value of greater than or equal to 2 were correlated which the clinical diagnosis of AIDS-related dementia complex (ARDC). However, a QHIV less than 1 did not exclude the development of ARDC, as was shown during follow-up in one case. Different methods are compared for the determination of intrathecal production of IgG and anti-HIV. A quotient QHIV greater than or equal to 2 is suggested to be highly indicative of intrathecal production of anti-HIV as well as of the development of ARDC.