HIV+ and HIV− participants were similar in mean age, years of education, educational quality as measured by the WRAT-R, race, and depressive symptoms (). Participants were 86% African American, 5% non-Hispanic white, 8% Hispanic, and 1% other. Groups differed significantly on self-reported recent drug use, 14% of HIV+ vs 42% of HIV− women, χ2 (1) = 4.91, p < 0.05, but not on previous drug use, current or past alcohol use, or current smoking. For HIV+ participants, the mean CD4 lymphocyte count at the time of testing was 443 (range, 0–1,345), and 22% had AIDS-defining (<200) CD4 counts.
Table 1 Participant characteristics as a function of serostatus
Sixty-nine percent were prescribed antiretroviral therapy at testing, including HAART (61%) and non-HAART therapy (8%).22
Current plasma viral load was undetectable for 47%, <10,000 for 25%, and >10,000 for 28% HIV+ participants. The hepatitis C antibody (HCV) test was positive for 33% of HIV− and 59% of HIV+ women, χ2
(1) = 2.54, NS.
Three sets of analyses were performed on neuropsychological outcomes (SPSS 15.0 for Windows, Chicago, IL). First, t tests were performed to examine group differences in unadjusted scores. Next, data were analyzed using a stepwise multivariate regression with HIV serostatus and recent drug use as predictor variables. As shown in , in both adjusted and unadjusted analyses, HIV+ women performed significantly worse than HIV− women on HVLT immediate and delayed recall, each Rey outcome, and Letter-Number Sequence subtest, p < 0.05. Finally, a stepwise multivariate regression with HIV+ women only was conducted using only demographic and clinical variables that correlated significantly with performance. Recent drug use predicted significantly lower scores on the Stroop Color trial. Analyses within HIV+ women showed no association between cognitive performance and HAART use. Higher viral load predicted lower scores on the Rey immediate recall, standardized β = −0.271, p < 0.05.
Table 2 Performance on behavioral measures of verbal memory and other cognitive abilities in HIV+ and HIV− women: Results from unadjusted and adjusted group comparisons
HIV+ and HIV− women with valid neuroimaging data did not differ significantly in mean age (41.1 vs 42.8 years), education (11.7 vs 12.3 years), WRAT-R scores (43.9 vs 42.0), mean percent correct on the fMRI verbal memory task (63% vs 62%), or frequency of positive HCV antibody results (57% vs 50%), depressive symptoms (58% vs 75%), or drug use (29% vs 50%), all p > 0.53. African Americans comprised 91% of this subsample. Three HIV+ women reported being on HAART. In this subsample, scores on the immediate HVLT trials were lower in HIV+ (mean = 21.85) vs HIV− women (29.00), t (9) = 2.42, p < 0.05. Scores on the HVLT delayed trial were also lower (7.28 vs 8.75), though this was not significant, p > 0.10. The average lag time between cognitive testing and MRI was 102 days, and women were scanned during the follicular phase. In HIV+ women, educational attainment (i.e., WRAT-R score) predicted all cognitive outcomes. Additionally, depressive symptoms predicted verbal learning, verbal delayed recall, and Rey Copy, and age predicted delayed recall. Recent illicit drug use predicted delayed recall (trend only) and letter-number sequencing. Disease characteristics predicted performance only on the inhibition trial of the Stroop (i.e., highest viral load, trend).
Table e-1 and show the results from the primary contrasts of interest in the hippocampus and parahippocampal gyrus. For the encoding contrast, there were no regions where HIV+ women showed greater activation compared to HIV− women. However, the HIV− group showed greater bilateral activation in the hippocampus and parahippocampal gyrus compared to HIV+ group. These differences were particularly pronounced in the left hemisphere (). This differential increase in activation by HIV− group reflects a combination of two influences: 1) greater activation in HIV− vs HIV+ women during the experimental encoding condition (i.e., encoding of unique words); and 2) greater activation in HIV+ vs HIV− group during the control encoding condition (i.e., repeated encoding of the same two words). In the recognition contrast, there were no regions where HIV− women showed greater activation compared to HIV+ women. However, the HIV+ group showed greater activation in the right hippocampus and bilateral parahippocampal gyrus (). This differential increase in activation by HIV+ vs HIV− group reflects 1) greater activation in the right parahippocampal gyrus and hippocampus in HIV+ vs HIV− women during the experimental recognition condition (i.e., recognition of unique words) and 2) greater activation in HIV− women in the left and right parahippocampal gyrus during the control recognition task (i.e., recognition of repeated words). In summary, compared to HIV− women, HIV+ women showed decreased hippocampal activation during encoding and increased hippocampal activation during recognition.
Figure 1 Greater activation in the hippocampus and parahippocampal gyrus in HIV− vs HIV+ women during encoding of novel words (experimental condition) minus repeated encoding of the same two words (control condition)
Figure 2 Greater activation in the hippocampus and parahippocampal gyrus in HIV+ vs HIV− women during recognition of unique words (experimental condition) minus repeated recognition of the same two words (control condition)
shows the correlations between the magnitude of signal intensity in the hippocampus and HVLT memory indices. Higher signal intensity in the left hippocampus during encoding was associated with better performance on the HVLT (see figure e-1). Thus, in a hippocampal region where HIV+ women showed less activation compared to HIV− women, less activation was associated with worse memory on standardized tests. Higher signal intensity in the right hippocampus during recognition was associated with worse performance on the HVLT (see figure e-1). Thus, in a hippocampal region where HIV+ women showed more activation compared to HIV− women, more activation was associated with worse memory. There were no correlations between hippocampal activation and performance on the scanner task (r range −0.38 to 0.15, all p > 0.24).
Table 3 Correlations between activation levels within significant clusters and scores on the Hopkins Verbal Learning Test
We also conducted a post hoc, exploratory whole-brain analysis, using a more conservative threshold of p < 0.01, a minimum cluster size of 30 voxels, and an uncorrected cluster threshold of p < 0.05 (see table e-2). For the encoding contrast, significantly greater activation was evident for HIV− vs HIV+ women in clusters including (A) right middle temporal cortex, parahippocampal gyrus, and hippocampus; (B) left parahippocampal gyrus, middle temporal cortex, and hippocampus; and (C) right superior frontal gyrus. For that same contrast, HIV+ vs HIV− women showed more activation in the right posterior cerebellum. For the recognition contrast, HIV− women vs HIV+ women showed greater activation in (A) right and left prefrontal cortex and (B) right precuneus, whereas HIV+ vs HIV− women showed greater activation in (A) left superior temporal gyrus and hippocampus and (B) right insular cortex. Thus, both the exploratory and ROI analyses indicate hippocampal dysfunction.