|Authors: Sattler F, He J, Letendre S, Wilson C, Fitzsimmons C, Heaton R, Ellis R, Franklin D, Grant I, McCutchan A, for the CHARTER Group|
|Abstract:BACKGROUND: Waist circumference (WC) correlates with the severity of both HIV-associated neurocognitive disorder (HAND) and with neurocognitive impairment (NCI) in HIV-uninfected persons, but the mechanism of this relationship is unknown. We postulated that HIV+ patients with abdominal obesity have increased levels of systemic and CNS immuno-inflammatory mediators that damage the brain.
METHODOLOGY: To explore this hypothesis, we tested stored plasma and CSF from 152 participants from CHARTER study visits with: (a) WC measurements, (b) comprehensive neuromedical and neurocognitive assessment, c) no CNS confounding conditions (e.g. major trauma, stroke), and (d) plasma HIV RNA <1,000c/ml on cART. We performed assays of immuno-inflammatory biomarkers in plasma (IL-6, sCD163, and sCD14) and CSF (sCD40L, sTNFrII, MCP-1, sICAM, and MMP-9). NCI was assessed by a standardized battery of 7 test domains of cognition. The global deficit score (GDS) was calculated for each participant after adjustments for their age, race/ethnicity, and education and a value ≥0.5 defined NCI. Correlational and pathway analyses were performed to explore the relationships of WC as the primary predictor and the biomarkers as mediators in models of NCI.
RESULTS: Both higher WC and plasma levels of interleukin-6 (IL-6) correlated with worse GDS (WC: rho=0.21, p=0.009 and IL-6: rho=0.17, p=0.04). The correlation of WC with GDS was strongest in participants with the highest tertile of IL-6 levels (rho=0.39, p=0.005) compared to those with the lowest tertile (rho=-0.07, p=0.65). For patients with the highest tertile of CSF sCD40L, a marker of CNS macrophage and microglial activation, the correlation of IL-6 to GDS was stronger (rho=0.60, p<0.0001). In patients with GDS measures at ≥3 visits (6 month intervals) within ±1 year of the index visit, higher IL-6 levels predicted a positive (worsening) slope of GDS (rho=0.28, p=0.06), implying progressive NCI.
Pathway analysis produced a model that showed: (a) plasma IL-6 mediates the relationship of WC to GDS, (b) a second pathway from WC to GDS was not mediated by IL-6 and (c) participants in the highest tertile of CSF sCD40L levels exhibited the strongest relationship of both WC and IL-6 to GDS. Inclusion of sCD14 levels in the model strengthened the relationship of WC and IL-6 to GDS.
CONCLUSIONS: Abdominal obesity was related to cognitive impairment in patients with high levels of systemic inflammation (IL-6) and CNS immune activation (sCD40L). These data are consistent with our postulate that immuno-inflammatory mediators emanating from abdominal fat cause inflammation and immune activation that contribute to brain dysfunction, thereby, worsening NCI. These effects may be amplified by systemic immune activation due to intestinal translocation of bacterial products (increased sCD14).|