The Associations of Circulating Sphingolipid Levels with Future Loss of Vibration and Light Pressure Sensation in the Lower Limb

Background: Circulating sphingolipids have been implicated in central nervous system degenerative disorders, but their relationship with peripheral neuropathy remains unclear. Objectives: To evaluate associations between plasma sphingolipid levels and subsequent loss of vibration and light pressure sensation in the lower limbs of older adults. Methods: Plasma concentrations of 11 ceramide (Cer) and sphingomyelin (SM) species were measured in stored samples from 4612 participants in the Cardiovascular Health Study. Vibration sensation was assessed 4–6 years later in 2208 individuals using tuning fork testing, and light pressure sensation was evaluated 11–13 years later in 815 participants using monofilament testing. Sensory impairment was graded on a 3-point scale, with higher scores indicating greater loss. Ordinal logistic regression models examined associations between a doubling of sphingolipid levels and sensory decline, with stratification by diabetes status. Results: In primary models, no sphingolipid species showed significant associations with sensory outcomes. However, after adjusting for inflammatory markers, higher SM-16 levels were linked to increased odds of vibration sensation loss (OR 2.08; 95% CI: 1.11–3.90), while higher SM-24 levels were associated with reduced odds (OR 0.68; 95% CI: 0.46–0.998). Significant interactions with diabetes status were observed for light pressure sensation: SM-14 was associated with increased odds of sensory loss in participants with incident diabetes (OR 5.22; 95% CI: 1.58–17.29), and Cer-18 was associated with increased odds in those with prevalent diabetes (OR 2.38; 95% CI: 1.18–4.78). Conclusions: Elevated levels of specific ceramide and sphingomyelin species may be predictive of future peripheral sensory loss in older adults, with diabetes status influencing these associations.