Background:  Leptin is a central nervous system (CNS) hormone produced by peripheral fat cells. CNS exposure to leptin is regulated via specific, active transport of leptin into the CSF from blood. Rat experiments demonstrate that leptin enhances hippocampal synaptic plasticity and NMDA receptor function. Leptin may also modify neurocognitive function in humans. We hypothesized that low CSF leptin (CSFL) levels and deficits in CNS uptake of leptin, operationalized as low CSF-to-serum leptin ratios (CSLR), are associated with cognitive deficits.

Methods:  Paired CSF and serum samples from HIV⁺ and HIV^­ persons who underwent formal neuropsychological (NP) testing were analyzed for leptin using commercially available assays. The NP test battery included learning, attention, memory, processing speed, abstraction, dexterity, and verbal fluency measures. Global and domain-specific impairments were determined using clinical ratings for derived deficit scores based on demographically corrected test scores. Between-group comparisons were performed according to cognitive deficit status. Log transformation of skewed variables was done prior to group analyses. Multiple linear regression analyses determined predictive factors of NP scores in both the entire cohort and the HIV⁺ only group.

Results:  Among 84 men (42 HIV⁺, 42 HIV^­), CSFL was lower in subjects with memory deficits (p = 0.05) and higher in those with verbal (p <0.01) and attention (p = 0.06) deficits, as compared with subjects with normal NP test scores in these domains. CSLR was markedly lower in those with memory (p <0.001) and learning (p <0.01) deficits, as compared to those performing within the normal range. In multivariate analyses controlling for age, HIV status, and body mass index, CSFL (β = ­1.2, p <0.01 for learning; β = ­0.9, p = 0.01 for memory) and CSLR (β = ­1, p <0.001 for learning; β = ­0.9, p <0.001 for memory) remained as significant predictors of memory and learning but not verbal or attention NP test scores. Among HIV⁺ subjects, both CSFL (β = ­0.6, p = 0.27 for learning; β = ­1.3, p <0.01 for memory) and CSLR (β = ­0.9, p = 0.02 for learning; β = ­1.1, p = 0.001 for memory) were inversely related to memory and learning domain test scores in analyses controlling for CD4 count, AIDS status, and CSF HIV viral load.

Conclusions:  Decreased CSFL and CSLR are associated with neurocognitive deficits, specifically in memory and learning. Leptin may be important for memory and learning in humans, and may be useful as a clinical biomarker for neurocognitive function.