Authors: Haughey N, Mielke M, Bandaru V, Sacktor N, Grant I,
Letendre S, Fox H, Chang L, Wozna V, Pardo C, McArthur J |
Abstract:Background: Approximately 50% of people infected with HIV will develop
neurocognitive impairment (NI). A biomarker that identifies those likely to decline or
improve in cognitive performance (DCP or ICP) would provide the opportunity for
intervention at the earliest stages of NI, and would be useful as a surrogate marker to
gage the effectiveness of neuroprotective therapeutics.
Methods: We used a lipidomic approach to analyze CSF from 348 subjects (291 HIV+;
57 HIV-) collected from multiple sites including: Johns Hopkins, CHARTER, University
of Hawaii and Puerto Rico. Baseline and follow-up CSF (within approximately 1 year)
were available for the majority (69.8%) of subjects, and most (85.3%) were taking an
ARV regimen at baseline. Initial screening studies lead us to focus on sphingomyelin
(SM), ceramide and sterol species as bioactive metabolites that are altered in the setting
of HIV-infection in accordance with NI. Multinomial logistic regressions were used to
examine the relationship between lipid levels, DCP and ICP.
Results: There were no cross sectional associations at baseline between any of the lipid
or sterol species measured and NI. Lower SM/ceramide ratios for C24:1 at baseline
predicted DCP (p=0.047). The predictive potential of this ratio appeared to be driven by
increases of ceramide. For sterols, we found that subjects with lower levels of multiple
cholesterol esters (CE) were more likely to exhibit DCP (p=0.046-0.007 depending on
the exact CE species). None of the SM or ceramide species predicted ICP. However,
subjects with higher baseline levels of two triglyceride species (POS, p = 0.005, and
POL, p=0.006) were more likely to exhibit ICP. We next determined if levels of these
metabolites changed over time, in association with DCP or ICP. In subjects with DCP,
there was evidence for progressive disruptions in multiple long-chain species of
ceramides. In those subjects who exhibited ICP, initially elevated triglyceride species
were lower at follow-up, suggesting a normalization of triglyceride metabolism.
Conclusions: These findings show that early changes in sphingolipid and sterol
metabolism predict changes in cognitive performance. These data identify pathways that
may be targets for neuroprotective therapy, and the metabolites of these pathways may
provide useful biomarkers to identify subjects at increased risk for NI. |