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Progression to Neuropsychological Impairment in Human Immunodeficiency Virus Infection Predicted by Elevated Cerebrospinal Fluid Levels of Human Immunodeficiency Virus RNA
Ronald J. Ellis, MD, PhD;
David J. Moore, BS;
Meredith E. Childers, MA;
Scott Letendre, MD;
J. Allen McCutchan, MD;
Tanya Wolfson, MA;
Stephen A. Spector, MD;
Karen Hsia, PhD;
Robert K. Heaton, PhD;
Igor Grant, MD;
for the HNRC Group
Arch Neurol. 2002;59:923-928.
ABSTRACT
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Background If cerebrospinal fluid (CSF) human immunodeficiency virus (HIV) RNA
levels are elevated before the development of neuropsychological (NP) impairment,
such an observation would support prospective monitoring of CSF HIV RNA levels
as well as therapeutic interventions designed to lower CSF HIV levels.
Objective To determine whether increased CSF HIV RNA levels at an earlier time
predict subsequent progression to NP impairment in HIV-infected subjects.
Methods We examined 139 subjects in a prospective cohort study. Comprehensive
NP, neuromedical, and laboratory evaluations were performed at initial and
follow-up visits at least 6 months apart. Human immunodeficiency virus RNA
levels in plasma and CSF were measured with a commercially available, polymerase
chain reaction–based assay. To assess the robustness of our findings,
we analyzed changes in NP performance over time in 2 ways. First, we used
masked clinical ratings of global NP performance to identify individuals who
were initially NP normal, and then determined, in a similarly blinded fashion,
which of these subjects subsequently became NP impaired. Second, in a separate
analysis, we assessed change in subjects' raw scores on each of a series of
NP test measures between baseline and follow-up.
Results Among subjects who were not impaired at the initial visit, higher levels
of HIV RNA in CSF significantly predicted progression to global NP impairment
at the follow-up evaluation. Cerebrospinal fluid HIV RNA levels outperformed
other clinical and laboratory measures in predicting progression to NP impairment.
Higher CSF HIV RNA levels were associated with worsening performance on tests
of attention, learning, and motor function.
Conclusion Because elevated CSF HIV RNA levels ( 200 copies/mL) predict subsequent
progression to NP impairment, monitoring of CSF viral load and therapy to
reduce CSF HIV RNA levels may be clinically warranted, even if impairment
is not identified at the time of lumbar puncture.
INTRODUCTION
THE EVENTS that lead to clinically evident neuropsychological (NP) impairment
in individuals with human immunodeficiency virus (HIV) infection are likely
to evolve over time, such that significant neuronal injury may cumulate over
periods ranging from months to years. Human immunodeficiency virus replication
itself may be an early "trigger," rather than a late proximate cause of neural
injury. In previous cross-sectional studies, levels of HIV RNA in cerebrospinal
fluid (CSF) were elevated in HIV-infected subjects with NP impairment at later
stages of disease.1-2 Such cross-sectional
studies do not adequately address the likely substantial delay between exposure
of central nervous system (CNS) tissues to replicating HIV and the subsequent
onset of NP impairment. In addition, if CSF HIV RNA levels were found to be
elevated before the development of NP impairment, a causal link between the
two would be supported.
If elevated CSF HIV RNA levels are important in the pathogenesis of
HIV-associated neurocognitive disorders, then they should predict deterioration
in the specific domains of NP ability known to be affected by HIV. Cognitive
abilities that are selectively vulnerable in HIV infection include attention
and working memory, learning, and motor skills.3
In the present study we evaluated 2 hypotheses: first, that individuals
with higher CSF HIV RNA levels are more likely to progress to NP impairment,
and second, that individuals with higher CSF HIV RNA levels will decline in
the skills most likely to be affected in HIV neurocognitive disorders (attention
and working memory, learning, and motor skills).
SUBJECTS AND METHODS
SUBJECTS
Participants were 133 men and 6 women with laboratory-confirmed HIV
infection prospectively enrolled in a longitudinal cohort study at the HIV
Neurobehavioral Research Center, San Diego, Calif. Subjects underwent comprehensive
NP and neuromedical evaluations, as well as lumbar punctures on 2 occasions
at least 6 months apart. Subjects with a history of major neurologic or psychiatric
disorders were excluded. Subjects were also excluded if neurologic signs,
CSF abnormalities, or magnetic resonance imaging studies were consistent with
brain opportunistic disease. Informed consent was obtained according to a
protocol approved by the institutional human subjects review panel.
NP TESTING, CLINICAL RATINGS, AND PROGRESSION TO NP IMPAIRMENT
Each participant completed a comprehensive NP test battery that assessed
8 major neurocognitive ability areas (Table
1). In accordance with the recommendations of the National Institute
of Mental Health Workshop on Neuropsychological Assessment Approaches in HIV
Infection,4 clinical ratings were based on
multiple NP tests within each ability area performed by a senior neuropsychologist
(R.K.H.). Briefly, clinical ratings were assigned by means of age-, education-,
sex-, and (when available) ethnicity-corrected T scores (all measures normalized
to a mean of 50 and an SD of 10). Performance on a specific test was considered
impaired when the T test score was more than 1 SD below the mean (T<40).
An "impaired" clinical rating for each ability area was assigned when a participant
performed below this cutoff point on 2 or more NP tests within an ability
area. A global rating of "impaired" was assigned to participants who were
rated as impaired in 2 or more separate ability areas. Thus, focal, isolated
deficits would not warrant a rating of global impairment. Previous work3, 5-6 has shown that these
clinical ratings are reliable and sensitive to brain dysfunction of diverse
causes.
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Table 1. Neuropsychological Tests Grouped by Domain*
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Participants were categorized into 4 groups according to their neurocognitive
performance at the 2 study visits. Subjects in the first group (NL-NL) were
rated as globally normal on NP tesing at both the initial and follow-up visits.
Those in the second group (IMP-IMP) were impaired at both visits. Subjects
in the third group (NL-IMP) were normal at the initial visit and worsened
to become NP impaired at the follow-up visit, while those in the fourth group
(IMP-NL) improved to become normal at the follow-up visit. Only subjects who
were NP normal at the initial visit were considered at risk to progress to
NP impairment at the second visit.
The individual tests of learning, attention and working memory, and
motor abilities used in this study are noted briefly by cognitive domain (Table 1). More detailed discussions of
these may be found elsewhere.7-10
ADDITIONAL CLINICAL EVALUATIONS
Each subject underwent a comprehensive neuromedical evaluation that
included medical and medication use history, neurologic and general physical
examinations, and laboratory studies including CD4 lymphocyte counts, routine
hematology and chemistry, and brain magnetic resonance imaging. Subjects were
classified by means of the Centers for Disease Control and Prevention HIV
Disease Classification.11 Participants were
also classified by antiretroviral (ARV) medication treatment status in 2 ways:
(1) taking ARVs or not taking ARVs at the initial visit and (2) new ARVs or
no new ARVs at the follow-up visit. Five to 15 mL of CSF was collected by
lumbar puncture, and samples were aliquoted and stored at -70°C
before measurement of HIV RNA.
LABORATORY MEASURES
We measured HIV RNA levels in plasma and CSF by reverse transcriptase
polymerase chain reaction (Amplicor HIV-1 Monitor Test; Roche Molecular Systems,
Inc, Pleasanton, Calif). For CSF, an ultrasensitive version of the assay with
a nominal detection limit of 50 copies/mL was used, while for plasma, the
standard assay (detection limit, 400 copies) was used. Values below the detection
limit were coded as 0. Blood CD4 lymphocyte counts were quantified by a fluorescence-activated
cell sorter. White and red blood cells in CSF were measured by manual microscopy.
STATISTICAL ANALYSES
To compare initial characteristics in the subject groups, analysis of
variance and the  2 test for proportions were used. To determine
the relative risk of global neurocognitive deterioration (change from global
rating of "normal" to global rating of "impaired") for different CSF HIV RNA
strata, we calculated odds ratios and confidence intervals. For this analysis,
a cutoff of greater than or equal to 200 copies/mL was chosen on the basis
of the utility of this cutoff in a previously published study.1
To evaluate predictors of declining performance on individual NP tests,
we performed regression analyses using data from all subjects in the study.
Baseline CSF HIV RNA levels and baseline NP performance were evaluated as
predictors of change in NP performance from baseline to follow-up. Because
we expected that the initial performance on a given NP test would be highly
predictive of change in per formance at follow-up, we included baseline NP
test performance in the model. This provided a means for controlling for individual
differences in cognitive ability. Then, we added to the model the principal
predictor of interest, CSF HIV RNA. In these models, the strength of the association
between CSF HIV RNA levels and change in NP test performance is reflected
in the partial ß coefficients and their corresponding F and P values. Readers interested in details of the statistical modeling
are referred to the next paragraph.
The models were constructed according to the following equation: NP
change = A + [B1 x (NP baseline)] + [B2 x (CSF HIV RNA)]. The
NP change is the difference between the initial visit and follow-up for each
of the NP tests being considered, NP baseline is the baseline score on the
NP test, and CSF HIV RNA is the viral load at baseline. A, B1, and B2 are
the coefficients estimated in the model. In addition to the goodness-of-fit
assessment of the regression model overall, partial t
tests (1-sided) are generally used to assess the significance of the coefficients
and are the target of interest. Of particular interest for us is B2, the coefficient
associated with the predictor CSF HIV RNA. Its significance indicates the
contribution of CSF HIV RNA to the model, after the effects of baseline NP
performance have been taken out. The  R2 value represents
the change in variance explained when moving from the model that predicts
subsequent NP performance from baseline performance and the model that includes
both baseline NP performance and CSF HIV RNA as predictors of future NP performance.
We selected a significance level of .01 for all statistical tests to
reduce the probability of type I error in multiple comparisons. Both CSF HIV
RNA and NP test scores were treated as continuous variables. The HIV-1 RNA
concentrations were log10-transformed before analysis. Analyses
were performed with JMP 3.112 and SPSS 6.1.13
RESULTS
DEMOGRAPHIC, CLINICAL, AND LABORATORY CHARACTERISTICS AND FOLLOW-UP
INTERVALS
Table 2 summarizes these
data. The 139 subjects included 133 men and 6 women, with an average age of
33.8 years (SD, 7.2), and an average education of 13.6 (1.8) years. Ninety-eight
(71%) were white, 20 (14%) were African American, 12 (9%) were Hispanic, 4
(3%) were of other ethnicities, and 5 (4%) did not report their racial background.
The median CD4 count at baseline was 378/µL (interquartile range [IQR],
238-523/µL); 34 subjects (24%) had CD4 lymphocyte counts less than 200/µL.
Eighty subjects (58%) were taking ARVs at the initial visit, and 52 (37%)
changed ARVs between the initial visit and follow-up. Initial study visits
occurred between February 1, 1990, and April 30, 1998. The median interval
between the initial study visit and the follow-up visit was 1.1 years (IQR,
1.0-1.8).
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Table 2. Demographic and Clinical Characteristics and Plasma and CSF
HIV RNA Levels of Subjects at the Initial Study Visit, According to Change
in Neurocognitive Performance*
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GLOBAL NP IMPAIRMENT RATINGS
At the initial visit, 94 subjects (68% of the total) were rated as globally
NP normal, and 45 (32%) were impaired. Of the 94 NP normal subjects, 18 (19%)
were impaired at the follow-up visit (the NL-IMP subgroup), and 76 (81%) remained
normal (the NL-NL subgroup). Of the 45 initially impaired subjects, 31 (69%)
remained impaired (IMP-IMP) and 14 (31%) improved to normal (IMP-NL). These
4 subgroups did not differ significantly with respect to age, education, or
medical characteristics (Table 2).
PREDICTING PROGRESSION TO GLOBAL NP IMPAIRMENT
We performed analyses to determine whether elevated CSF HIV RNA levels
at an earlier time were associated with a higher risk of progression to NP
impairment. For these analyses, only subjects rated NP normal at the initial
visit (n = 94) were considered to be at risk for progressing to NP impairment.
The follow-up interval for subjects who became impaired did not differ significantly
from that of subjects who remained normal (median [IQR]: NL-IMP, 1.2 [1.0-2.9];
NL-NL, 1.1 [0.98-1.7]; P = .10, Wilcoxon test). We
compared the predictive power of HIV RNA levels in CSF with those in plasma.
In separate logistic regression analyses, higher CSF HIV RNA levels were significantly
associated with the later development of global NP impairment (2 = 6.0; P = .01). By comparison, higher plasma
HIV RNA levels showed a statistical trend toward significance (2 = 3.1; P = .08). When both plasma and CSF
levels were entered simultaneously into the logistic regression, the 2 (P values) for CSF and plasma were 3.4 (.06)
and 0.54 (.46), respectively, and the model 2 was 8.1 (P = .02). Because these comparisons of the predictive power
of HIV RNA levels were confounded by the different assay sensitivities (detection
limits) used for plasma and CSF, we repeated the analysis applying the less
sensitive (higher) cutoff (400 copies per milliliter) to both plasma and CSF
levels. In this analysis, higher CSF HIV RNA values at baseline were still
associated with subsequent neurocognitive impairment (2 =
3.8, P = .05).
To quantify the increase in risk associated with higher CSF HIV RNA
levels, we compared the rates at which NP impairment developed in the 61 subjects
(65%) with CSF HIV RNA levels of 200 copies or more per milliliter, with those
of the 33 subjects (35%) with CSF HIV RNA levels less than 200 copies per
milliliter. This cutoff (200 copies/mL) was chosen on the basis of data from
a previous study.1 Subjects with higher CSF
HIV RNA levels were significantly more likely to become impaired than those
with lower CSF HIV RNA levels (26% vs 6%; odds ratio, 5.5; 95% confidence
interval, 1.4-36; P = .03). We considered the possibility
that subjects with higher CSF HIV RNA levels were more likely to be classified
as having "borderline normal" NP functioning at the initial visit. This is
important because such subjects would be predicted to be more likely to cross
the threshold to become "mildly impaired" at a subsequent visit than subjects
who had normal (not borderline) NP performance at baseline. Indeed, we found
that progression to NP impairment was more common among subjects who were
borderline at baseline than among those who were normal, not borderline (12/42
vs 6/52; P = .06). Nevertheless, when both variables
were entered simultaneously into a logistic regression, CSF HIV RNA significantly
predicted progression to NP impairment (2 = 4.5; P = .03), while borderline NP status did not (2 = 2.1; P = .15).
To assess further the specificity of the association between CSF HIV
RNA levels and neurocognitive impairment, and to evaluate other potential
predictors of incident NP impairment, we performed similar logistic regression
analyses using other subject characteristics measured at the initial visit.
In contrast to CSF HIV RNA levels, future impairment was not predicted by
CD4 counts at the initial visit (2 = 1.79; P = .17), initial Centers for Disease Control and Prevention disease
stage classification (2 = 3.57; P
= .17), ARVs at the initial visit (2 = 0.39; P = .53), or changes in ARVs at follow-up (2 = 0.07; P = .79). In a stepwise logistic regression analysis adjusting
for baseline NP performance, future impairment was associated with higher
CSF HIV RNA levels, but no other markers significantly improved the model's
predictive ability (CD4 count, 2 = 1.42; P = .23; Centers for Disease Control and Prevention disease stage classification, 2 = 2.0; P = .37; age in years, 2 = 0.25; P = .62; education, 2
= 0.0; P = .99; initial ARV status, 2
= 0.49; P = .78).
Cerebrospinal fluid HIV RNA levels at the subjects' second visit were
significantly correlated with levels at the first visit (Spearman  =
0.48, P<.001). Among subjects who became NP impaired,
CSF HIV RNA levels were higher at the second visit (median [IQR], 3.3 [2.1-4.0]
vs 2.6 [1.7-3.4] log copies/mL), as well as at the first, implying that persistence
of increased CSF viral load impacted poorly on neurocognitive status.
RELATIONSHIPS BETWEEN CSF HIV RNA LEVELS AND PERFORMANCE ON SPECIFIC
NP TESTS
We hypothesized that elevated CSF HIV RNA levels would predict declines
in performance in the specific ability areas known to be selectively affected
in individuals with HIV neurocognitive disorders. These areas were attention
and working memory, learning, and motor skills. By contrast, we expected that
CSF HIV RNA levels would not predict changes in performance in other ability
areas. Since any decline from previous performance was of interest, we included
all subjects in this analysis, even those rated as globally NP impaired at
the initial visit. The outcome of interest was change in raw score from the
initial visit to follow-up on each NP test. In all cases, initial test performance
was a predictor of both subsequent test performance and change from initial
testing to follow-up. Therefore, we adjusted all regression models for baseline
performance. To account for the possibility that longer follow-up intervals
might be associated with greater declines in performance, we evaluated time
as an initial predictor in all of the regression models. Because none of the
models showed time to be a significant predictor, it was removed from the
models presented in Table 3.
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Table 3. Results of Regression Analyses Predicting Follow-up NP Test
Scores From Initial NP Test Scores and Baseline CSF HIV RNA Levels*
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The direction and strength of the association between CSF HIV RNA levels
and decline in NP test performance is reflected in the partial ß coefficients,
and associated F, R2, and P values for these models. Table 3 lists these values for each of the separate regressions
of CSF HIV RNA levels on NP test performance. Higher CSF HIV RNA levels at
baseline significantly (P<.01) predicted declines
in performance on the following tests: Story Learning (P<.001), Wechsler Adult Intelligence Scale–Revised Digit Span
(P = .003), and Grooved Pegboard, nondominant hand
(P = .007). In separate regressions examining whether
baseline CSF HIV RNA levels predicted declines in Finger Tapping, nondominant
hand (a measure of motor skills), and the Category Test (a measure of abstraction),
we found trends in the predicted direction that did not meet the prespecified
level of statistical significance. Although CSF HIV RNA levels were predictive
of decline in performance on some measures of learning, attention, and motor
skills, CSF HIV RNA levels were not related to declines in other NP domains
(Table 3). Specifically, CSF HIV
RNA levels were not significantly related to change in NP test performance
on any measures of verbal, complex perceptual motor, memory, abstraction and
executive functioning, or sensory abilities. This pattern of NP performance
suggests that elevated CSF HIV levels are related to changes in the specific
NP abilities typically associated with HIV and do not represent a more generalized
diffuse decline.
COMMENT
We found that, among subjects who were initially NP normal, elevated
CSF HIV RNA levels at an initial study visit significantly predicted progression
to NP impairment after a median follow-up of approximately 1 year. Elevated
plasma HIV RNA levels showed a weaker, nonsignificant relationship to incident
NP impairment. These findings are consistent with the hypothesis that increased
CSF viral burden in some patients may trigger a neurodegenerative process
that results in HIV-associated neurocognitive disorders.
A previous study14 contrasts with ours
in showing that elevated plasma HIV RNA levels were associated with incident
dementia. Differences in study methods, such as our study's examination of
CSF HIV RNA levels and the inclusion of baseline performance, and the specific
NP battery used may account for the different findings.
Our hypothesis that increased CSF viral burden may trigger subsequent
neurocognitive decline is supported by our observation that elevated CSF HIV
RNA levels predicted deterioration in the areas of learning, attention and
working memory, and motor function. Previous work has shown that these are
the abilities most likely to be impaired in subjects with HIV neurocognitive
disorders.3
Elevated CSF HIV RNA levels in this study were associated with worsening
performance on some, but not all, of the NP tests predicted to be sensitive
to neurocognitive changes in HIV. An example is the Figure Memory Test. Although
poor story learning performance was related to elevated CSF RNA levels at
the initial visit, figure learning performance did not show the same pattern.
Several factors may explain these findings. First, individual NP tests differ
substantially in their sensitivity to impairment. For example, "ceiling" and
"floor" effects may limit a test's ability to demonstrate change. The Figure
Memory Test has a more restricted range of scores than the Story Memory Test;
thus, measurement effects may have limited our ability to detect neurocognitive
changes with this measure. Second, individual NP tests do not represent pure
measures of specific NP abilities. For example, performance on the Figure
Memory Test depends heavily on visuoperceptual and visuoconstructional abilities
in addition to learning abilities. It is possible that changes in visuoperceptual
abilities depend on factors other than the status of HIV infection in the
CNS, such as current medication use or level of effort.
Not all subjects with initially elevated HIV RNA levels progressed to
NP impairment. Various factors may protect some individuals, or increase risk
in others, and virus-host interactions may be particularly important in this
regard. Thus, neurodegeneration may require not only the presence of HIV in
the CNS, but also the development of a specific host CNS immune response.
Alternatively, mechanisms such as increased secretion of fibroblast growth
factor may protect the host from the development of CNS disease.15
An important goal of future studies should be to determine combinations of
virus and host factors that predict the development of, or decreased susceptibility
to, HIV-induced CNS disease.
Our findings have implications for future research and clinical practice.
The observation that neurocognitive decline was associated with HIV RNA levels
in CSF, but not plasma, suggests that CSF viral load measurements may be important
in assessing the risk of future neurocognitive decline in HIV-infected individuals.
In at-risk subjects, interventions targeted at lowering both plasma and CSF
viral load may be clinically warranted. Our findings also support the inclusion
of NP tests that assess learning, attention and working memory, and motor
function in batteries used to evaluate neurocognitive function in HIV-infected
individuals.
AUTHOR INFORMATION
Accepted for publication November 2, 2001.
Author contributions: Study concept and design (Drs Ellis, Spector, and Grant); acquisition of data (Drs Ellis, Letendre, McCutchan, Spector, Hsia, and Heaton; Mr
Moore; and Ms Childers); analysis and interpretation of data (Drs Ellis, Letendre, McCutchan, Spector, and Heaton; Mr Moore;
and Mss Childers and Wolfson); drafting of the manuscript (Dr Ellis and Mr Moore); critical revision of the manuscript for important
intellectual content (Drs Ellis, Letendre, McCutchan, Spector,
Hsia, Heaton, and Grant; Mr Moore; and Mss Childers and Wolfson); statistical
expertise (Mr Moore and Ms Wolfson); obtained funding (Drs Ellis, Letendre, McCutchan, Spector, and Grant); administrative,
technical, or material support (Drs Ellis, Letendre, McCutchan,
Hsia, Heaton, and Grant and Ms Childers); study supervision (Dr Ellis).
The HIV Neurobehavioral Research Center is supported by center award
P30 MH62512-01 from the National Institute of Mental Health, Bethesda, Md.
Dr Ellis is supported by grant RO1 MH58076 from the National Institute of
Mental Health.
The views expressed in this article are those of the authors and do
not reflect the official policy or position of the Department of the Navy,
Department of Defense, or the US government.
Study Group
San Diego HIV Neurobehavioral Research Center Group
Director: Igor Grant, MD. Codirectors: J. Hampton Atkinson, MD; J. Allen McCutchan, MD. Center Manager: Thomas D. Marcotte, PhD. Naval Hospital, San Diego: Mark R. Wallace, MD (principal investigator). Neuromedical Component: J. Allen McCutchan, MD (principal
investigator); Ronald J. Ellis, MD, PhD; Scott Letendre, MD; Rachel Schrier,
PhD. Neurobehavioral Component: Robert K. Heaton,
PhD (principal investigator); Mariana Cherner, PhD; Julie Rippeth, PhD. Imaging Component: Terry Jernigan, PhD (principal investigator);
John Hesselink, MD. Neuropathology Component: Eliezer
Masliah, MD (principal investigator). Clinical Trials Component: J. Allen McCutchan, MD; Ronald J. Ellis, MD, PhD; Scott Letendre,
MD; J. Hampton Atkinson, MD. Data Management Unit:
Daniel R. Masys, MD (principal investigator); Michelle Frybarger, BA (data
systems manager). Statistics Unit: Ian Abramson,
PhD (principal investigator); Reena Deutsch, PhD; Tanya Wolfson, MA.
Corresponding author and reprints: Ronald J. Ellis, MD, PhD, HIV
Neurobehavioral Research Center, University of California, San Diego, 150
W Washington St, 2nd Floor, San Diego, CA 92103 (e-mail: roellis{at}ucsd.edu).
From the Department of Neurosciences (Dr Ellis and Ms Childers), HIV
Neurobehavioral Research Center (HNRC) (Drs Ellis, Letendre, McCutchan, Heaton,
and Grant, Mr Moore, and Mss Childers and Wolfson), and Departments of Psychiatry
(Mr Moore and Drs Heaton and Grant), Medicine (Drs Letendre and McCutchan),
and Pediatrics (Drs Spector and Hsia), University of California, San Diego
(UCSD); San Diego State University/UCSD Joint Doctoral Program in Clinical
Psychology (Mr Moore); and Veterans Affairs Healthcare System (Dr Grant),
San Diego. The San Diego HNRC Group is affiliated with the University of California,
San Diego, the Naval Hospital, San Diego, and the San Diego Veterans Affairs
Healthcare System.
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