No abstract

Infection with human immunodeficiency virus type 1 (HIV-1) is frequently complicated in its late stages by the AIDS dementia complex, a neurological syndrome characterized by abnormalities in cognition, motor performance, and behavior. This dementia is due partially or wholly to a direct effect of the virus on the brain rather than to opportunistic infection, but its pathogenesis is not well understood. Productive HIV-1 brain infection is detected only in a subset of patients and is confined largely or exclusively to macrophages, microglia, and derivative multinucleated cells that are formed by virus-induced cell fusion. Absence of cytolytic infection of neurons, oligodentrocytes, and astrocytes has focused attention on the possible role of indirect mechanisms of brain dysfunction related to either virus or cell-coded toxins. Delayed development of the AIDS dementia complex, despite both early exposure of the nervous system to HIV-1 and chronic leptomeningeal infection, indicates that although this virus is "neurotropic," it is relatively nonpathogenic for the brain in the absence of immunosuppression. Within the context of the permissive effect of immunosuppression, genetic changes in HIV-1 may underlie the neuropathological heterogeneity of the AIDS dementia complex and its relatively independent course in relation to the systemic manifestations of AIDS noted in some patients.

There is good evidence that the kynurenine pathway (KP) and one of its products, quinolinic acid (QUIN), play a role in the pathogenesis of neurological diseases, in particular AIDS dementia complex. Although QUIN has been shown to be produced in neurotoxic concentrations by macrophages and microglia, the role of astrocytes in QUIN production is controversial. Using cytokine-stimulated cultures of human astrocytes, we assayed key enzymes and products of the KP. We found that human astrocytes lack kynurenine hydroxylase so that large amounts of kynurenine and the QUIN antagonist kynurenic acid were produced. However, the amounts of QUIN that were synthesized were subsequently completely degraded. We then showed that kynurenine in concentrations comparable with those produced by astrocytes led to signi®cant production of QUIN by macrophages. These results suggest that astrocytes alone are neuroprotective by minimizing QUIN production and maximizing synthesis of kynurenic acid. However, it is likely that, in the presence of macrophages and/or microglia, astrocytes become indirectly neurotoxic by the production of large concentrations of kynurenine that can be secondarily metabolized by neighbouring or in®ltrating monocytic cells to form the neurotoxin QUIN.

This study examined the validity of the four standard psychological paradigms that have been operationally defined within the CogState brief computerized cognitive assessment battery. Construct validity was determined in a large group of healthy adults. CogState measures of processing speed, attention, working memory, and learning showed strong correlations with conventional neuropsychological measures of these same constructs (r's = .49 to .83). Criterion validity was determined by examining patterns of performance on the CogState tasks in groups of individuals with mild head injury, schizophrenia, and AIDS dementia complex. Each of these groups was impaired on the CogState performance measures (Cohen's d's = -.60 to -1.80) and the magnitude and nature of this impairment was qualitatively and quantitatively similar in each group. Taken together, the results suggest that the cognitive paradigms operationally defined in the CogState brief battery have acceptable construct and criterion validity in a neuropsychological context.