Circulating sphingolipids and subclinical brain pathology: the cardiovascular health study.

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% APOE 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 [ß = 0.05, false-discovery rate corrected P (PFDR) = 0.004 and ß = 0.06, PFDR = < 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 (P 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), PFDR = 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.

Association of Tumor Necrosis Factor-α Inhibitors with Incident Dementia: Analysis Based on Population-Based Cohort Studies.

BACKGROUND AND OBJECTIVE: Preliminary evidence suggests a possible preventive effect of tumor necrosis factor-α inhibitors (TNFi) on incident dementia. The objective of the analysis was to investigate the association between TNFi and the risk of incident dementia in a population undergoing treatment for rheumatological disorders. METHODS: We followed patients aged ≥ 65 years with dementia and rheumatological conditions in two cohort studies, DANBIO (N = 21,538), a Danish clinical database, and AOK PLUS (N = 7112), a German health insurance database. We defined incident dementia using diagnostic codes and/or medication use and used Cox regression to compare the associations of TNFi with other rheumatological therapies on the risk of dementia. To ensure that the patients were receiving long-term medication, we included patients with rheumatic diseases and systemic therapies. RESULTS: We observed similar trends towards a lower risk of dementia associated with TNFi versus other anti-inflammatory agents in both cohorts (hazard ratios were 0.92 [95% confidence interval 0.76, 1.10] in DANBIO and 0.89 [95% confidence interval 0.63, 1.24] in AOK PLUS, respectively). CONCLUSIONS: Tumor necrosis factor-α inhibitors may decrease the risk of incident dementia although the association did not reach statistical significance in this analysis. Further research, ideally with randomization, is needed to gauge the potential of repurposing TNFi for dementia prevention and/or treatment.

Serum NfL and GFAP are associated with incident dementia and dementia mortality in older adults: The cardiovascular health study.

INTRODUCTION: Circulating neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have been independently associated with dementia risk. Their additive association, and their associations with dementia-specific mortality, have not been investigated. METHODS: We associated serum NfL, GFAP, total tau ,and ubiquitin carboxyl-terminal hydrolase-L1, measured in 1712 dementia-free adults, with 19-year incident dementia and dementia-specific mortality risk, and with 3-year cognitive decline. RESULTS: In adjusted models, being in the highest versus lowest tertile of NfL or GFAP associated with a hazard ratio (HR) of 1.49 (1.20-1.84) and 1.38 (1.15-1.66) for incident dementia, and 2.87 (1.79-4.61) and 2.76 (1.73-4.40) for dementia-specific mortality. Joint third versus first tertile exposure further increased risk; HR = 2.06 (1.60-2.67) and 9.22 (4.48-18.9). NfL was independently associated with accelerated cognitive decline. DISCUSSION: Circulating NfL and GFAP may, independently and jointly, provide useful clinical insight regarding dementia risk and prognosis.

The evolutionarily conserved miRNA-137 targets the neuropeptide hypocretin/orexin and modulates the wake to sleep ratio.

Hypocretin (Hcrt), also known as orexin, neuropeptide signaling stabilizes sleep and wakefulness in all vertebrates. A lack of Hcrt causes the sleep disorder narcolepsy, and increased Hcrt signaling has been speculated to cause insomnia, but while the signaling pathways of Hcrt are relatively well-described, the intracellular mechanisms that regulate its expression remain unclear. Here, we tested the role of microRNAs (miRNAs) in regulating Hcrt expression. We found that miR-137, miR-637, and miR-654-5p target the human HCRT gene. miR-137 is evolutionarily conserved and also targets mouse Hcrt as does miR-665. Inhibition of miR-137 specifically in Hcrt neurons resulted in Hcrt upregulation, longer episodes of wakefulness, and significantly longer wake bouts in the first 4 h of the active phase. IL-13 stimulation upregulated endogenous miR-137, while Hcrt mRNA decreased both in vitro and in vivo. Furthermore, knockdown of miR-137 in zebrafish substantially increased wakefulness. Finally, we show that in humans, the MIR137 locus is genetically associated with sleep duration. In conclusion, these results show that an evolutionarily conserved miR-137:Hcrt interaction is involved in sleep­wake regulation.

Sphingomyelins and ceramides: possible biomarkers for dementia?

PURPOSE OF REVIEW: Dementia is a public health challenge with no existing cure or early biomarkers. We review the evidence for blood-based measures of sphingomyelins and ceramides as potential novel biomarkers of dementia. RECENT FINDINGS: In recent years, lipids have been under investigation for their role in neurodegenerative diseases especially dementia and Alzheimer's disease. Increasing evidence from postmortem human brains suggests that alterations in the metabolism of sphingolipids could play a crucial part in dementia. Findings from epidemiological investigations of blood-based sphingomyelins and ceramides have been inconsistent. SUMMARY: This review focuses on blood-based measures of 10 specific ceramides and sphingomyelins (Cer C16:0, Cer C20:0, Cer C22:0, Cer C24:0, Cer C24:1 and SM C16:0, SM C20:0, SM C22:0, SM C24:0, SM C24:1) in relation to cognition and dementia. On the bais of 15 studies, there was no robust association between ceramide and sphingomyelin levels and prevalent or incident dementia. Cross-sectionally, Cer C16:0 and Cer C24:1 tends to be higher in dementia cases vs. controls.