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

<b>Background:</b> Circulating sphingolipids have been implicated in central nervous system degenerative disorders, but their relationship with peripheral neuropathy remains unclear. <b>Objectives:</b> To evaluate associations between plasma sphingolipid levels and subsequent loss of vibration and light pressure sensation in the lower limbs of older adults. <b>Methods:</b> 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. <b>Results:</b> 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). <b>Conclusions:</b> 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.