02485nas a2200253 4500008004100000022001400041245010100055210006900156260001600225300001400241490000700255520171100262100002201973700002001995700002502015700002202040700002402062700002402086700001902110700002002129700002202149700002402171856003602195 2021 eng d a1530-856100aCirculating Ceramides and Sphingomyelins and Risk of Mortality: The Cardiovascular Health Study.0 aCirculating Ceramides and Sphingomyelins and Risk of Mortality T c2021 Nov 26 a1650-16590 v673 a

BACKGROUND: Recent studies suggest that associations of ceramides (Cer) and sphingomyelins (SM) with health outcomes differ according to the fatty acid acylated to the sphingoid backbone. The purpose of this study was to assess associations of Cer and SM species with mortality.

METHODS: The study population included participants from the Cardiovascular Health Study (CHS), a community-based cohort of adults aged ≥65 years who were followed from 1992-2015 (n = 4612). Associations of plasma Cer and SM species carrying long-chain (i.e., 16:0) and very-long-chain (i.e., 20:0, 22:0, 24:0) saturated fatty acids with mortality were assessed using Cox proportional hazards models.

RESULTS: During a median follow-up of 10.2 years, 4099 deaths occurred. High concentrations of Cer and SM carrying fatty acid 16:0 were each associated with an increased risk of mortality. Conversely, high concentrations of several ceramide and sphingomyelin species carrying longer fatty acids were each associated with a decreased risk of mortality. The hazard ratios for total mortality per 2-fold difference in each Cer and SM species were: 1.89 (95% CI), 1.65-2.17 for Cer-16, 0.79 (95% CI, 0.70-0.88) for Cer-22, 0.74 (95% CI, 0.65-0.84) for Cer-24, 2.51 (95% CI, 2.01-3.14) for SM-16, 0.68 (95% CI, 0.58-0.79) for SM-20, 0.57 (95% CI, 0.49-0.67) for SM-22, and 0.66 (0.57-0.75) for SM-24. We found no association of Cer-20 with risk of death.

CONCLUSIONS: Associations of Cer and SM with the risk of death differ according to the length of their acylated saturated fatty acid. Future studies are needed to explore mechanisms underlying these relationships.

1 aFretts, Amanda, M1 aJensen, Paul, N1 aHoofnagle, Andrew, N1 aMcKnight, Barbara1 aSitlani, Colleen, M1 aSiscovick, David, S1 aKing, Irena, B1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/891003033nas a2200253 4500008004100000022001400041245009600055210006900151260000900220300001200229490000700241520227000248100002602518700001802544700002802562700001802590700002002608700002002628700002502648700002202673700002402695700002402719856003602743 2024 eng d a1664-229500aCirculating sphingolipids and subclinical brain pathology: the cardiovascular health study.0 aCirculating sphingolipids and subclinical brain pathology the ca c2024 a13856230 v153 a

BACKGROUND: Sphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults.

METHODS: Brain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40% male; and 25% ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP.

RESULTS: In the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [β = 0.05, false-discovery rate corrected () = 0.004 and β = 0.06,  = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex ( for interaction = <0.001), such that ceramide d18:1/20:0 associated with higher odds for infarcts in women [OR = 1.26 (95%CI: 1.07, 1.49),  = 0.03]. We did not observe any associations with GFAP blood levels, white matter grade, ventricular grade, mean bilateral hippocampal volume, or total brain volume.

CONCLUSION: Overall, our comprehensive investigation supports the evidence that ceramides and sphingomyelins are associated with increased aging brain pathology and that the direction of association depends on the fatty acid attached to the sphingosine backbone.

1 aMoseholm, Kristine, F1 aHorn, Jens, W1 aFitzpatrick, Annette, L1 aDjoussé, Luc1 aLongstreth, W T1 aLopez, Oscar, L1 aHoofnagle, Andrew, N1 aJensen, Majken, K1 aLemaitre, Rozenn, N1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/970402432nas a2200265 4500008004100000022001400041245011900055210006900174260001700243300001100260490000700271520159300278100002601871700002501897700001601922700002801938700002001966700002901986700002002015700002502035700002402060700002402084700002202108856003602130 2024 eng d a2352-872900aCirculating sphingolipids in relation to cognitive decline and incident dementia: The Cardiovascular Health Study.0 aCirculating sphingolipids in relation to cognitive decline and i c2024 Jul-Sep ae126230 v163 a

INTRODUCTION: Whether circulating levels of sphingolipids are prospectively associated with cognitive decline and dementia risk is uncertain.

METHODS: We measured 14 sphingolipid species in plasma samples from 4488 participants (mean age 76.2 years; 40% male; and 25% apolipoprotein E ( ε4 allele carriers). Cognitive decline was assessed annually across 6 years using modified Mini-Mental State Examination (3MSE) and Digital Symbol Substitution Test (DSST). Additionally, a subset of 3050 participants were followed for clinically adjudicated dementia.

RESULTS: Higher plasma levels of sphingomyelin-d18:1/16:0 (SM-16) were associated with a faster cognitive decline measured with 3MSE, in contrast, higher levels of sphingomyelin-d18:1/22:0 (SM-22) were associated with slower decline in cognition measured with DSST. In Cox regression, higher levels of SM-16 (hazard ration [HR] = 1.24 [95% confidence interval [CI]: 1.08-1.44]) and ceramide-d18:1/16:0 (Cer-16) (HR = 1.26 [95% CI: 1.10-1.45]) were associated with higher risk of incident dementia.

DISCUSSION: Several sphingolipid species appear to be involved in cognitive decline and dementia risk.

HIGHLIGHTS: Plasma levels of sphingolipids were associated with cognitive decline and dementia risk.Ceramides and sphingomyelins with palmitic acid were associated with faster annual cognitive decline and increased risk of dementia.The direction of association depended on the covalently bound saturated fatty acid chain length in analysis of cognitive decline.

1 aMoseholm, Kristine, F1 aCronjé, Héléne, T1 aKoch, Manja1 aFitzpatrick, Annette, L1 aLopez, Oscar, L1 aOtto, Marcia, C de Olive1 aLongstreth, W T1 aHoofnagle, Andrew, N1 aMukamal, Kenneth, J1 aLemaitre, Rozenn, N1 aJensen, Majken, K uhttps://chs-nhlbi.org/node/9743