Serum Ceramides Research Articles

1579-P: Altered Serum Ceramides as Part of Dyslipidemia in Adolescents with Metabolic Dysfunction–Associated Steatotic Liver Disease

1579-P: Altered Serum Ceramides as Part of Dyslipidemia in Adolescents with Metabolic Dysfunction–Associated Steatotic Liver Disease

Precise Lipidomics Decipher Circulating Ceramide and Sphingomyelin Cycle Associated with the Progression of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a long-term autoimmune condition that causes joint and surrounding tissue inflammation. Lipid mediators are involved in inflammation and deterioration of the joints. Despite attempts to discover effective drug targets to intervene with lipid metabolism in the disease, progress has been limited. In this study, precise lipidomic technology was employed to quantify a broad range of serum ceramides and sphingomyelin (SM) in a large cohort, revealing an association between the accumulation of circulating ceramides and disturbed ceramide/SM cycles during the progression of RA. In our investigation, we discovered that eight ceramides exhibited a positive correlation with the activity of RA, thereby enhancing the accuracy of RA diagnosis, particularly in patients with serum antibody-negative RA. Furthermore, the enzyme SM phosphodiesterase 3 (SMPD3) was found to disrupt the circulating SM cycle and accelerate the progression of RA. The activity of SMPD3 can be inhibited by methotrexate, resulting in decreased metabolic conversion of SM to ceramide. These findings suggest that targeting the SM cycle may provide a new therapeutic option for RA.

Identification of diurnal rhythmic blood markers in bronchial asthma.

Asthma is a rhythmic inflammatory disease of the airway, regulated by the circadian clock. "Spill-over" of airway inflammation into the systemic circulation occurs in asthma and is reflected in circulating immune cell repertoire. The objective of the present study was to determine how asthma impacts peripheral blood diurnal rhythmicity. 10 healthy and 10 mild/moderate asthma participants were recruited to an overnight study. Blood was drawn every 6 h for 24 h. The molecular clock in blood cells in asthma is altered; PER3 is significantly more rhythmic in asthma compared to healthy controls. Blood immune cell numbers oscillate throughout the day, in health and asthma. Peripheral blood mononucleocytes from asthma patients show significantly enhanced responses to immune stimulation and steroid suppression at 16:00 h, compared to at 04:00 h. Serum ceramides show complex changes in asthma: some losing and others gaining rhythmicity. This is the first report showing that asthma is associated with a gain in peripheral blood molecular clock rhythmicity. Whether the blood clock is responding to rhythmic signals received from the lung or driving rhythmic pathology within the lung itself is not clear. Dynamic changes occur in serum ceramides in asthma, probably reflecting systemic inflammatory action. The enhanced responses of asthma blood immune cells to glucocorticoid at 16:00 h may explain why steroid administration is more effective at this time.

1359 Alterations in the levels and proportion of serum ceramides in children with atopic dermatitis

1359 Alterations in the levels and proportion of serum ceramides in children with atopic dermatitis

Fenretinide inhibits obesity and fatty liver disease but induces Smpd3 to increase serum ceramides and worsen atherosclerosis in LDLR−/− mice

Fenretinide is a synthetic retinoid that can prevent obesity and improve insulin sensitivity in mice by directly altering retinol/retinoic acid homeostasis and inhibiting excess ceramide biosynthesis. We determined the effects of Fenretinide on LDLR−/− mice fed high-fat/high-cholesterol diet ± Fenretinide, a model of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Fenretinide prevented obesity, improved insulin sensitivity and completely inhibited hepatic triglyceride accumulation, ballooning and steatosis. Moreover, Fenretinide decreased the expression of hepatic genes driving NAFLD, inflammation and fibrosis e.g. Hsd17b13, Cd68 and Col1a1. The mechanisms of Fenretinide’s beneficial effects in association with decreased adiposity were mediated by inhibition of ceramide synthesis, via hepatic DES1 protein, leading to increased dihydroceramide precursors. However, Fenretinide treatment in LDLR−/− mice enhanced circulating triglycerides and worsened aortic plaque formation. Interestingly, Fenretinide led to a fourfold increase in hepatic sphingomyelinase Smpd3 expression, via a retinoic acid-mediated mechanism and a further increase in circulating ceramide levels, linking induction of ceramide generation via sphingomyelin hydrolysis to a novel mechanism of increased atherosclerosis. Thus, despite beneficial metabolic effects, Fenretinide treatment may under certain circumstances enhance the development of atherosclerosis. However, targeting both DES1 and Smpd3 may be a novel, more potent therapeutic approach for the treatment of metabolic syndrome.

Sphingolipidomic profile and HDL subfractions in obese dyslipidemic type 2 diabetic patients

PurposeThe aim of the study was to investigate changes in serum sphingolipid levels and high density lipoprotein (HDL) subtypes with relation to low-density lipoprotein cholesterol (LDL-C), non-HDL-C and triglyceride (TG) levels in type 2 diabetes mellitus (T2DM) patients. MethodsBlood was obtained from 60 patients with T2DM. Levels of sphingosine-1-phosphate (S1P), C16-C24 sphingomyelins (SMs), C16-C24 ceramides (CERs), and C16 CER-1 P were determined by LC-MS/MS. Serum concentrations of cholesterol ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT) and apolipoprotein A-1 (apoA-I) were analyzed by enzyme-linked immunosorbent assay (ELISA). HDL subfraction analysis was performed by Disc polyacrylamide gel electrophoresis. ResultsC16 SM, C24 SM, C24-C16 CER and C16 CER-1 P levels were significantly increased in T2DM patients with LDL-C above 160 mg/dL, compared to those with LDL-C below 100 mg/dL. A significant correlation was observed between C24:C16 SM, C24:C16 CER ratios and LDL-C, non HDL-C levels. Higher serum levels of C24 SM, C24-C18 CER and C24:C16 SM ratio was seen in obese T2DM patients (BMI>30) compared to those with BMI 27–30. Patients with fasting TG levels below 150 mg/dL had significantly increased HDL-large and significantly decreased HDL-small fractions compared to those with fasting TG levels above 150 mg/dL. ConclusionObese dyslipidemic T2DM patients had increased levels of serum sphingomyelins, ceramides and HDL-small fractions. The ratio of serum C24:C16 SM, C24:C16 CER and long chain CER levels may be used as diagnostic and prognostic indicators of dyslipidemia in T2DM.

Serum Ceramide Species Are Associated with Liver Cirrhosis and Viral Genotype in Patients with Hepatitis C Infection.

Hepatitis C virus (HCV) infection affects ceramide metabolism, and, here, we have evaluated associations of eight serum ceramide species with viral load, viral genotype, and disease markers in 178 patients with chronic HCV. In this cohort, ceramide d18:1;O2/16:0 was higher in the serum of the 20 diabetic patients compared to the patients without this complication. Moreover, ceramide d18:1;O2/24:0 was negatively correlated with age. Of note, all but ceramide d18:1;O2/16:0 and 26:0 were diminished in the serum of patients with liver cirrhosis and, with the exception of ceramide d18:1;O2/16:0, were negatively correlated with the model for end-stage liver disease (MELD) score. Most of the serum ceramides are carried in low-density lipoprotein (LDL), which rises following effective direct-acting antiviral (DAA) therapy. Ceramide d18:1;O2/24:0 recovered in parallel with LDL, whereas ceramide d18:1;O2/18:0 declined. Genotype-3-infected patients had the lowest ceramide levels, which were comparable to other genotypes after DAA treatment. Notably, ceramide d18:1;O2/23:0 and 24:0 were negatively correlated with the MELD score in patients with liver cirrhosis at the end of DAA therapy. Long-chain (LC) ceramides show adverse effects, whereas very-long-chain (VL) species have protective functions in the liver. The ratio of VL/LC ceramides was higher in non-cirrhosis patients than cirrhosis patients and further increased at the end of therapy in this subgroup. In summary, our study shows that serum ceramide levels are related to liver cirrhosis and viral genotype. Whether the more favorable serum ceramide profile in non-cirrhosis patients, before and after DAA therapy, is of pathophysiological importance needs further investigation.

Serum dihydroceramides correlate with insulin sensitivity in humans and decrease insulin sensitivity in vitro

Serum ceramides, especially C16:0 and C18:0 species, are linked to CVD risk and insulin resistance, but details of this association are not well understood. We performed this study to quantify a broad range of serum sphingolipids in individuals spanning the physiologic range of insulin sensitivity and to determine if dihydroceramides cause insulin resistance in vitro. As expected, we found that serum triglycerides were significantly greater in individuals with obesity and T2D compared with athletes and lean individuals. Serum ceramides were not significantly different within groups but, using all ceramide data relative to insulin sensitivity as a continuous variable, we observed significant inverse relationships between C18:0, C20:0, and C22:0 species and insulin sensitivity. Interestingly, we found that total serum dihydroceramides and individual species were significantly greater in individuals with obesity and T2D compared with athletes and lean individuals, with C18:0 species showing the strongest inverse relationship to insulin sensitivity. Finally, we administered a physiological mix of dihydroceramides to primary myotubes and found decreased insulin sensitivity in vitro without changing the overall intracellular sphingolipid content, suggesting a direct effect on insulin resistance. These data extend what is known regarding serum sphingolipids and insulin resistance and show the importance of serum dihydroceramides to predict and promote insulin resistance in humans.

Duodenal-jejunal bypass reduces serum ceramides via inhibiting intestinal bile acid-farnesoid X receptor pathway.

BACKGROUNDBile acids play an important role in the amelioration of type 2 diabetes following duodenal-jejunal bypass (DJB). Serum bile acids are elevated postoperatively. However, the clinical relevance is not known. Bile acids in the peripheral circulation reflect the amount of bile acids in the gut. Therefore, a further investigation of luminal bile acids following DJB is of great significance.AIMTo investigate changes of luminal bile acids following DJB.METHODSSalicylhydroxamic acid (SHAM), DJB, and DJB with oral chenodeoxycholic acid (CDCA) supplementation were performed in a high-fat-diet/streptozotocin-induced diabetic rat model. Body weight, energy intake, oral glucose tolerance test, luminal bile acids, serum ceramides and intestinal ceramide synthesis were analyzed at week 12 postoperatively.RESULTSCompared to SHAM, DJB achieved rapid and durable improvement in glucose tolerance and led to increased total luminal bile acid concentrations with preferentially increased proportion of farnesoid X receptor (FXR) - inhibitory bile acids within the common limb. Intestinal ceramide synthesis was repressed with decreased serum ceramides, and this phenomenon could be partially antagonized by luminal supplementation of FXR activating bile acid CDCA.CONCLUSIONDJB significantly changes luminal bile acid composition with increased proportion FXR-inhibitory bile acids and reduces serum ceramide levels. There observations suggest a novel mechanism of bile acids in metabolic regulation after DJB.

Serum ceramides could predict durable diabetes remission following gastric bypass surgery

Morbid obesity is a major risk factor for the development of type 2 diabetes (T2D). One strategy to both lose weight and counteract T2D is bariatric surgery (RYGB). In a study published in this issue of Med, Poss etal. revealed that circulating ceramides could predict the durability of T2D remission independently of weight loss following RYGB.

Following Roux-en-Y gastric bypass surgery, serum ceramides demarcate patients that will fail to achieve normoglycemia and diabetes remission

Obesity is a prevalent health threat and risk factor for type 2 diabetes. In this study, we evaluate the relationship between ceramides, which inhibit insulin secretion and sensitivity, and markers of glucose homeostasis and diabetes remission or recursion in patients who have undergone a Roux-en-Y gastric bypass (RYGB). The Utah Obesity Study is a prospective cohort study, with targeted ceramide and dihydroceramide measurements performed on banked serum samples. The Utah Obesity Study consists of 1,156 participants in three groups: a RYGB surgery group, a non-surgery group denied insurance coverage, and severely obese population controls. Clinical examinations and ceramide assessments were performed at baseline and 2 and 12 years after RYGB surgery. Surgery patients (84% female, 42.2 ± 10.6 years of age at baseline) displayed lower levels of several serum dihydroceramides and ceramides at 2 and 12 years after RYGB. By contrast, neither the control group (77% female, 48.7± 6.4 years of age at baseline) nor the non-surgery group (95% female, 43.0± 11.4 years of age at baseline) experienced significant decreases in any species. Using a linear mixed effect model, we found that multiple dihydroceramides and ceramides positively associated with the glycemic control measures HOMA-IR and HbA1c. In surgery group participants with prevalent diabetes, ceramides inversely predict diabetes remission, independent of changes in weight. Ceramide decreases may explain the insulin sensitization and diabetes resolution observed in most RYGB surgery patients. Funded by the National Institutes of health (NIH), The Juvenile Diabetes Research Foundation, and the American Heart Association.

Effect of Korean Red Ginseng on Plasma Ceramide Levels in Postmenopausal Women with Hypercholesterolemia: A Pilot Randomized Controlled Trial.

Cardiovascular disease (CVD) is a crucial cause of death in postmenopausal women. Plasma ceramide concentrations are correlated with the development of atherosclerosis and are significant predictors of CVD. Here, we conducted a 4-week, double-blinded, placebo-controlled clinical pilot study to investigate the effect of Korean red ginseng (KRG) on serum ceramide concentrations in 68 postmenopausal women with hypercholesterolemia. Patients were randomly assigned to two groups: the experimental group (n = 36) received KRG and the control (n = 32) group received placebo, 2 g each, once daily. Serum ceramides were measured using liquid chromatography–tandem mass spectrometry at baseline and study completion, with changes in serum ceramide levels as the primary end point. We detected significantly greater mean changes in C16 ceramide levels (d18:1/16:0: −6.4 ± 6.3 pmol/mL vs. 14.6 ± 6.8 pmol/mL, respectively, p = 0.040; d18:1/22:0: −20.8 ± 24.4 pmol/mL vs. 71.1 ± 26.2 pmol/mL, respectively, p = 0.020). Additionally, changes in the median C16 (d18:1/16:0) and C22 (d18:1/22:0) ceramide levels were significantly greater in KRG-group subjects with metabolic syndrome than those without. Therefore, we found that KRG decreases the serum levels of several ceramides in postmenopausal women with hypercholesterolemia, suggesting it may be beneficial for preventing CVD in these individuals.

Development and validation of a RPLC-MS/MS method for the quantification of ceramides in human serum

Ceramides are key-role lipids involved in numerous central cellular processes. A plethora of studies have demonstrated that the levels of ceramides in blood circulation are related to different disease states, such as type 2 diabetes, cardiovascular diseases, ovarian cancer, multiple sclerosis and others. Herein, a RPLC-MS/MS method for the rapid quantification of ceramides Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1) in human blood serum was developed and validated. Different sample preparation strategies including SLE, LLE and QuECheRS were tested with the aim to attain effective, accurate and reproducible determination of ceramides in serum samples. Intra and inter-day accuracy were found to be between 80.0–111% and 87.8–106%, respectively, for all ceramides, while intra and inter-day precision were found to vary from 0.05% to 10.2% %RSD and 2.2% to 14.0% %RSD, respectively. The lower limits of quantification were 2.3 ng/mL for Cer(d18:1/16:0) and Cer(d18:1/18:0) and 1.4 ng/mL for Cer(d18:1/24:0) and Cer(d18:1/24:1). The method was evaluated in accordance to bioanalytical method guidelines and was used for the determination of serum ceramides of patients with coronary artery disease to evaluate its utility in clinical analyses.

Serum ceramide concentrations are associated with depression in patients after ischemic stroke-A two-center case-controlled study

Background and aimsThe present study aims to correlate the severity of post-stroke depression (PSD) and serum ceramide concentration. Materials and methodsIn this two-center case-control study, we prospectively collected clinical and demographical information from age and gender-matched 51 PSD patients, 56 non-post-stroke depression (Non-PSD) patients, and 39 patients with major depression (MD) to perform the suitable biochemical analysis to bring a correlation in causing depression in patients soon after the stroke. The ROC curve method was used to evaluate ceramide’s diagnostic efficacy in all three groups of patients. A follow-up analysis was also conducted based on PSD severity to associate serum ceramide levels and neuropsychiatric symptoms. The severity of the patient's depressive symptoms was assessed by using the self-rating depression scale (SDS). ResultsIn comparison between PSD and MD patients, three serum ceramide species were found to be significantly different. Compared with Non-PSD patients, PSD patients had significantly higher levels of all the four serum ceramides, and increasing levels ofC16:0, C18:0(VS MD) and C16: 0(VS Non-PSD) serve as a diagnostic tool and an independent risk factor in all three categories of patients. Moreover, the follow-up analysis results showed that, as the treatment progressed, the differences in the 3 serum ceramide species were statistically significant. ConclusionThere was a stage-specific association between serum ceramides and PSD, and the potential pathophysiological mechanism has to be investigated in future research.

88116 Effect of conjugated estrogens and bazedoxifene on glucose, energy and lipid metabolism in obese postmenopausal women

ABSTRACT IMPACT: A short treatment of 8 obese postmenopausal women with conjugated estrogens and bazedoxifene does not alter insulin sensitivity or ectopic fat but increases serum markers of hepatic de novo lipogenesis and production of triacylglycerides. OBJECTIVES/GOALS: Combining conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is a novel, orally-administered menopausal therapy. We investigated the effect of CE/BZA on insulin sensitivity, energy metabolism, and serum metabolome in postmenopausal women with obesity. METHODS/STUDY POPULATION: We conducted a randomized, double-blind, crossover pilot trial, testing the effect of CE/BZA on cardiometabolic health in postmenopausal women. Eight postmenopausal women (age 50-60 y, BMI 30-40 kg/m2) were randomization to an 8-week CE/BZA or placebo treatment separated by an 8-week washout period [NCT02274571]. The primary outcome was insulin sensitivity (hyperinsulinemic-euglycemic clamp), while secondary outcomes included body composition (DXA); resting metabolic rate (RMR); substrate oxidation (indirect calorimetry); ectopic lipids (1H-MRS); fat cell size, adipose and skeletal muscle gene expression (biopsies); inflammatory markers; and serum metabolome (LC/MS). RESULTS/ANTICIPATED RESULTS: CE/BZA had no effect on insulin sensitivity, body composition, ectopic fat, or substrate oxidation, but resulted in a non-significant increase in RMR (basal: p=0.06; high-dose clamp: p=0.08) compared to placebo. CE/BZA increased serum high-density lipoprotein cholesterol. CE/BZA also increased serum diacylglycerol (DAG) and triacylglycerol (TAG) species containing long-chain saturated, mono- and polyunsaturated fatty acids (FAs), and decreased long-chain acylcarnitines. These findings possibly reflect increased hepatic de novo FA synthesis and esterification into TAGs, and decreased FA oxidation, respectively (p<0.05). CE/BZA increased serum phosphatidylcholines, phosphatidylethanolamines, ceramides, and sphingomyelins, possibly reflecting the increase in lipoproteins (p<0.05). DISCUSSION/SIGNIFICANCE OF FINDINGS: A short treatment of postmenopausal women with CE/BZA did not alter insulin action or ectopic fat, but increased markers of hepatic de novo lipogenesis and TAG production. Study limitations include a small sample size and short treatment period. A larger, fully powered study is needed to validate the potential metabolic benefit of combining CE with BZA.

Beneficial Metabolic Effects of TREM2 in Obesity Are Uncoupled From Its Expression on Macrophages.

Obesity-induced white adipose tissue (WAT) hypertrophy is associated with elevated adipose tissue macrophage (ATM) content. Overexpression of the triggering receptor expressed on myeloid cells 2 (TREM2) reportedly increases adiposity, worsening health. Paradoxically, using insulin resistance, elevated fat mass, and hypercholesterolemia as hallmarks of unhealthy obesity, a recent report demonstrated that ATM-expressed TREM2 promoted health. Here, we identified that in mice, TREM2 deficiency aggravated diet-induced insulin resistance and hepatic steatosis independently of fat and cholesterol levels. Metabolomics linked TREM2 deficiency with elevated obesity-instigated serum ceramides that correlated with impaired insulin sensitivity. Remarkably, while inhibiting ceramide synthesis exerted no influences on TREM2-dependent ATM remodeling, inflammation, or lipid load, it restored insulin tolerance, reversing adipose hypertrophy and secondary hepatic steatosis of TREM2-deficient animals. Bone marrow transplantation experiments revealed unremarkable influences of immune cell–expressed TREM2 on health, instead demonstrating that WAT-intrinsic mechanisms impinging on sphingolipid metabolism dominate in the systemic protective effects of TREM2 on metabolic health.

Serum Ceramides as Prognostic Biomarkers of Large Thrombus Burden in Patients with STEMI: A Micro-Computed Tomography Study.

ST-elevation myocardial infarction (STEMI) remains one of the leading causes of mortality worldwide. The identification of novel metabolic and imaging biomarkers could unveil key pathophysiological mechanisms at the molecular level and promote personalized care in patients with acute coronary syndromes. We studied 38 patients with STEMI who underwent primary percutaneous coronary intervention and thrombus aspiration. We sought to correlate serum ceramide levels with micro-CT quantified aspirated thrombus volume and relevant angiographic outcomes, including modified TIMI thrombus grade and pre- or post-procedural TIMI flow. Higher ceramide C16:0 levels were significantly but weakly correlated with larger aspirated thrombus volume (Spearman r = 0.326, p = 0.046), larger intracoronary thrombus burden (TB; p = 0.030) and worse pre- and post-procedural TIMI flow (p = 0.049 and p = 0.039, respectively). Ceramides C24:0 and C24:1 were also significantly associated with larger intracoronary TB (p = 0.008 and p = 0.001, respectively). Receiver operating characteristic analysis demonstrated that ceramides C24:0 and C24:1 could significantly predict higher intracoronary TB (area under the curve: 0.788, 95% CI: 0.629–0.946 and 0.846, 95% CI: 0.706–0.985, respectively). In conclusion, serum ceramide levels were higher among patients with larger intracoronary and aspirated TB. This suggests that quantification of serum ceramides might improve risk-stratification of patients with STEMI and facilitate an individualized approach in clinical practice.

Lipid profile disturbances may predispose psoriatic patients to liver dysfunction.

IntroductionPsoriasis is a chronic inflammatory disease associated with metabolic disturbances and liver dysfunction. Both serum fatty acids (FA) and ceramides (Cer) have structural functions but also are signal molecules that could be involved in the pathogenesis of liver dysfunction.AimTo assess the concentration of the circulating FA and Cer in correlation with the alanine aminotransferase (ALT) blood level in psoriatic patients. In addition, we have examined the relationship between ALT concentration and severity of the disease and inflammation markers.Material and methodsEighty-five patients with psoriasis and 32 healthy controls were enrolled in the study. Patients were divided into 2 groups according to ALT blood levels. Serum concentration of 14 FA and 14 Cer were measured by gas-liquid chromatography. The results were correlated with the Psoriasis Area and Severity Index (PASI), serum lipid profile, and inflammatory markers.ResultsWe observed higher PASI score (p = 0.01) and higher C-reactive protein (p = 0.02) concentration in the group of psoriatic patients with high ALT. Serum ALT positively correlated with saturated fatty acids (SFA) (p = 0.01, r = 0.27) and SFA/unsaturated fatty acids (UFA) ratio (p = 0.01, r = 0.26). ALT negatively correlated with UFA level (p = 0.008, r = –0.28). Lignoceric ceramide positively correlated with ALT level (r = 0.22; p = 0.045) in psoriatic patients.ConclusionsPatients with severe psoriasis are predisposed to the development of liver dysfunction. We have demonstrated disturbances of serum fatty acid and sphingolipid profile in psoriatic patients, which may trigger liver disease.

Serum ceramide levels are altered in multiple sclerosis

Background: Sphingolipids are myelin components and inflammatory signaling intermediates. Sphingolipid metabolism may be altered in people with multiple sclerosis (PwMS), but existing studies are limited by small sample sizes. Objectives: To compare the levels of serum ceramides between PwMS and healthy controls (HCs) and to determine whether ceramide levels correlate with disability status, as well as optical coherence tomography (OCT)-derived rates of retinal layer atrophy. Methods: We performed targeted lipidomics analyses for 45 ceramides in PwMS (n = 251) and HCs (n = 68). For a subset of PwMS, baseline and 5-year Expanded Disability Status Scale (EDSS) assessments (n = 185), or baseline and serial spectral-domain OCT (n = 180) were assessed. Results: Several ceramides, including hexosylceramides, lactosylceramides, and dihydroceramides, were altered in PwMS compared with HCs. Higher levels of Cer16:0 were associated with higher odds of EDSS worsening at 5 years in univariable (odds ratio (OR) = 3.84, 95% confidence interval (CI) = 1.41–10.43) and multivariable analyses accounting for age, sex, and race (OR = 2.97, 95% CI = 1.03–8.59). Each 1 ng/mL higher concentration of Hex-Cer22:0 and DH-HexCer22:0 was associated with accelerated rates (μm/year) of ganglion cell + inner plexiform layer (–0.138 ± 0.053, p = 0.01; –0.158 ± 0.053, p = 0.003, respectively) and peripapillary retinal nerve fiber layer thinning (–0.305 ± 0.107, p = 0.004; –0.358 ± 0.106, p = 0.001, respectively). Conclusion: Ceramide levels are altered in PwMS and may be associated with retinal neurodegeneration and physical disability.

White Matter Injury Is Associated with Reduced Manual Dexterity and Elevated Serum Ceramides in Subjects with Cerebral Small Vessel Disease

Introduction: We have demonstrated that asymptomatic cerebral small vessel disease (cSVD) measured by white matter hyperintensity volume is associated with reduced manipulative manual dexterity on the Grooved Peg Board Test (GPBT) in middle-aged healthy individuals with a family history of early coronary artery disease. In this current study, we aim to identify the association of subcortical white matter microstructural impairment measured by diffusion tensor imaging, manual dexterity measured by GPBT and circulating serums ceramide, another marker for white matter injury. We hypothesize that lower regional fractional anisotropy (rFA) is associated with worse performance on GPBT and elevated serum ceramides in the same study population. Methods: rFA of 48 regions representing the subcortical white matters were analyzed in GeneSTAR participants in addition to serum ceramides and GPBT scores. Unadjusted univariable analyses with Bonferroni correction for multiple comparisons were completed using Spearman correlation for testing the associations between ceramides, rFA of subcortical white matter, and GPBT performance. Subsequently, sensitivity analyses were performed after excluding the participants that had any physical limitation that may influence their performance on GPBT. Finally, in the adjusted analysis using generalized estimating equation, linear regression models were performed for the areas that met significance threshold in the unadjusted analyses. Results: 112 subjects (age [49 ± 11], 51% female, 39.3% African American) were included. Adjusted analyses for the significant correlations that met the Bonferroni correction threshold in the unadjusted univariable analyses identified significant negative associations between rFA of the right fornix (RF) and log-GPBT score (β = −0.497, p = 0.037). In addition, rFA of RF negatively correlated with log serum ceramide levels (C18: β = −0.03, p = 0.003, C20: β = −0.0002, p = 0.004) and rFA of left genu of corpus callosum negatively correlated with log C18 level (β = −0.0103, p = 0.027). Conclusions: These results demonstrate that subcortical microstructural white matter disruption is associated with elevated serum ceramides and reduced manual dexterity in a population with cSVD. These findings suggest that injury to white matter tracts undermines neural networks, with functional consequences in a middle-aged population with cardiovascular risk factors.