Plasma sCD14 is a biomarker associated with impaired neurocognitive test performance in attention and learning domains in HIV infection

Abstract

Objective: Mild forms of HIV-associated neurocognitive disorders (HAND) remain prevalent in the era of combination antiretroviral therapy (cART). Although elevated lipopolysaccharide (LPS) and immune activation are implicated in HAND pathogenesis, relationships of LPS and inflammatory markers to mild forms of HAND or impairment in specific cognitive domains are unknown. To examine these relationships, we compared plasma soluble CD14 (sCD14), CCL2, and LPS levels with neurocognitive test scores in a cART era cohort.

Methods: We analyzed plasma from HIV+ subjects (n = 97) with nadir CD4 counts <300 and high frequency of hepatitis C virus coinfection and illicit drug use for relationships between sCD14, CCL2, and LPS levels and neurocognitive test scores.

Results: Plasma sCD14 levels were higher in subjects with test scores indicating global impairment (P = 0.007), particularly in attention and learning domains (P = 0.015 and P = 0.03, respectively), regardless of HAND diagnosis. Plasma sCD14 levels correlated inversely with global, attention, and learning T scores (P = 0.036, 0.047, and 0.007, respectively) and yielded higher area under receiver operating characteristic values for predicting impaired scores than single-marker models based on plasma or cerebrospinal fluid viral load or CD4 count (area under receiver operating characteristic values = 0.71, 0.81, and 0.71, respectively) and in 4-marker models based on plasma sCD14 and 3 conventional markers compared with the 3-marker models.

Conclusions: Plasma sCD14 is a biomarker associated with impaired neurocognitive testing in attention and learning domains in HIV-infected individuals with advanced disease, suggesting involvement of cortical and limbic pathways by inflammatory processes in the cART era. Plasma sCD14 is a potential biomarker to monitor HAND progression and therapeutic responses.

Figure 1. Subjects with more severe HAND diagnoses have lower global T scores

Neurocognitive test scores were compared to each HAND diagnosis in HIV+ subjects. No NCI is followed in severity by ANI, in which subjects demonstrate neurocognitive impairment but have no daily functioning deficits, which in turn is followed in severity by MCMD, where mild neurocognitive impairment is combined with daily functioning deficits, and then HAD, in which patients evidence moderate to severe neurocognitive impairment and daily functioning impairments. Global T scores were lower with diagnoses of increased severity of neurocognitive impairment as compared to no NCI (top left panel). Domain T scores for attention, learning, and memory were significantly lower for all diagnoses of impairment, whereas T scores for fluency, SIP, executive function, and motor were generally associated only with more severe forms of neurocognitive impairment (i.e., HAD and MCMD) and NPI-O. (SIP, speed of information processing; NCI, neurocognitive impairment; ANI, asymptomatic neurocognitive impairment; MCMD, minor cognitive-motor disorder; HAD, HIV-associated dementia; NPI-O, other neuropsychiatric impairment). Median values are indicated as horizontal lines. Statistical significance between groups was calculated using the two-tailed Mann-Whitney test; significant differences (p<0.05) are indicated.

Figure 2. Higher plasma sCD14 levels are associated with global T scores indicating neurocognitive impairment

Subjects were grouped by global T <40 or ≥40 to compare biomarker levels. Only plasma sCD14 levels were significantly different between subjects with versus without impaired global T scores (second row, first panel), and correlated negatively with global T scores (second row, last panel). (VL, viral load). Median values are indicated as horizontal lines. Statistical significance between groups was calculated using the two-tailed Mann-Whitney test, and significance among continuous variables was calculated using Spearman rho correlation; significant differences (p<0.05) are indicated.

Figure 3. Higher plasma sCD14 levels are associated with impaired test performance in attention and learning domains

Plasma levels of sCD14, CD4 count, and plasma VL were compared to domain T scores in subjects grouped by T scores <40 or ≥40. A. Plasma sCD14 levels were elevated in subjects with attention and learning T scores <40, B. Lower CD4 counts in subjects with fluency and motor T scores <40. C. Higher plasma VL in subjects with motor T scores <40. D. Plasma sCD14 correlated negatively with attention and learning T scores, and plasma VL correlated negatively with motor T scores. (VL, viral load). Median values are indicated as horizontal lines. Statistical significance between groups was calculated using the two-tailed Mann-Whitney test, and correlations between continuous variables were analyzed using Spearman rho correlation; significant differences (p<0.05) are indicated.

Figure 4. HIV+ opiate users demonstrate impairment in global T scores and learning, memory, motor, and SIP domain T scores but no difference in plasma sCD14 levels compared to non-users

Global and domain T scores, as well as plasma biomarker levels and HIV disease markers, were compared between subjects with no current drug use, current opiate use (including 18 subjects using both opiates and cocaine), and current cocaine use. Subjects were categorized as opiate or cocaine users if they endorsed syndromic abuse and/or urine toxicology was positive for opiates (including methadone) or cocaine (n=35 and 22, respectively). Subjects with negative toxicology screening for opiates or cocaine and without PRISM or CIDI diagnosis of substance abuse were categorized as non-users (“None”, n=38). A. Opiate users had lower global T scores than cocaine users or non-users, and lower learning, memory, motor and SIP T scores than non-users. B. Current and nadir CD4 count, plasma VL, CSF VL, and plasma sCD14, CCL2, and LPS levels did not differ between groups. (SIP, speed of information processing; VL, viral load). Median values are indicated as horizontal lines. Statistical significance between groups was calculated using the two-tailed Mann-Whitney test; significant differences (p<0.05) are indicated.