To determine whether cerebrospinal fluid (CSF) viral burden measurements can assist in the evaluation of human immunodeficiency virus (HIV)-associated neurocognitive disorders, we quantified HIV type 1 (HIV-1) RNA in CSF. Because previous findings suggested that disease stage, lymphocytic pleocytosis, and HIV-1 RNA levels in plasma may influence CSF viral burden, these variables were examined as potential modifying factors. HIV-1 RNA levels were quantified by using a reverse transcriptase-polymerase chain reaction assay. Performance on a comprehensive neuropsychological (NP) battery was noted in 97 prospectively enrolled, HIV-infected subjects. Among subjects with acquired immunodeficiency syndrome (AIDS) (<200 CD4+ lymphocytes), NP impairment was associated with significantly higher CSF RNA levels (3.1 vs 1.8 log10 copies/ml; p = 0.02); most impaired subjects met criteria for HIV-associated dementia or minor cognitive-motor disorder. In subjects without AIDS, CSF RNA and NP impairment were unrelated. Before AIDS, CSF RNA was strongly correlated to plasma RNA and to pleocytosis, but in AIDS, CSF and plasma RNA were independent. In conclusion, we found elevated CSF HIV-1 RNA levels in NP impaired subjects with AIDS. Before AIDS, systemic viral replication, possibly through CD4+ mononuclear cell trafficking, may govern virus levels in CSF, whereas in AIDS, CD4 cell depletion may unmask a correlation between increased productive central nervous system HIV infection and clinical neurocognitive disorders.
Dendritic and synaptic damage (without frank neuronal loss) may be seen in milder human immunodeficiency virus (HIV)‐related cognitive disorders. Synapse volume estimates, performed by stereological methods, could enhance the ability to detect subtle neuronal changes that may accompany cognitive impairment in HIV infection. For the present study, synaptic density and neuronal number were assessed by combined stereology/confocal microscopy and these measures were then correlated with ante‐mortem levels of cognitive performance in AIDS patients. Three‐dimensional stereological measures showed a significant correlation between reduced synaptic density and poor neuropsychological performance. To evaluate the specificity of any observed associations, additional variables including viral burden, astrogliosis and number of calbindin‐immunoreactive neurons were measured. Factor analysis of a set of neuropathological variables revealed two factors; one defined by synaptic density and volume fraction, calbindin pyramidal neuronal densities and viral burden; the second by astrocytosis and calbindin interneuron density. Only the first factor correlated significantly with neuropsychological functioning during life. It is concluded that a combination of factors including synaptic damage, specific neuronal loss and increasing viral load underlies HIV‐associated cognitive impairment. As synaptic damage is potentially reversible, early diagnosis and treatment of mild cogntive disorders may improve functioning and prevent the progression of brain disease.
The HIV-infected individuals with NP impairment had a higher risk of dying than those without impairment. This was particularly true for those meeting syndromic diagnostic criteria.
Patterns of memory performance were examined for 9 participants with HIV-associated dementia (HAD), 15 HIV-seropositive participants without dementia, and 15 HIV-seronegative controls. Episodic and semantic memory were assessed using the California Verbal Learning Test, the Boston Naming Test, and Verbal Fluency tests. The HAD group showed deficits in episodic memory, with relative sparing of semantic memory. In addition, results suggest a retrieval deficit in HAD rather than a deficit in retention of information. This pattern is consistent with the presence of a subcortical dementing process and supports findings from previous neuropathological, neuroimaging, and neuropsychological studies suggesting that subcortical brain dysfunction is frequently associated with HIV disease (e.g., Navia, Jordan, & Price, 1986).
Healthy Zambian adults (N = 324) were evaluated to determine to what degree a Western neuropsychological (NP) test battery, with African American norms adjusted for age, gender, and education could be used in healthy Zambians, including 157 (48.46%) men and 167 (51.54%) women with an average age of 38.48 (SD = 12.80) years and an average education level of 11.02 (SD = 2.58) years. The NP battery included tests of attention/working memory, executive function, verbal fluency, processing speed, verbal and visual episodic memory, and fine motor skills. The Zambian Achievement Test (ZAT) and the U.S. Wide Range Achievement Test-4 (WRAT-4) reading subtest also were administered to assess literacy and quality of education. Similar to findings in Western countries, the Zambian results show substantial age and education effects on most tests and smaller, less consistent effects of gender. Beyond the basic demographic effects, urban/rural background had small effects on some cognitive variables, and the ZAT (but not WRAT-4) reading level was a robust predictor of performance on many NP tests, even when other background characteristics were controlled. Women in the United States tend to outperform men on tests of processing speed and episodic memory, Zambian women showed modest but statistically significant disadvantages versus their male counterparts. The results show that tests developed in the United States may be used in Zambia, but development and use of local cultural norms remains very important and is a must. New demographically corrected norms were developed for the cohort that was examined.
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