Cerebrospinal Fluid C18 Ceramide Associates with Markers of Alzheimer’s Disease and Inflammation at the Pre- and Early Stages of Dementia

Abstract

Background: Understanding how dysregulation in lipid metabolism relates to the severity of Alzheimer‘s disease (AD) pathology might be critical in developing effective treatments. Objective: To identify lipid species in cerebrospinal fluid (CSF) associated with signature AD pathology and to explore their relationships with measures reflecting AD-related processes (neurodegeneration, inflammation, deficits in verbal episodic memory) among subjects at the pre- and early symptomatic stages of dementia. Methods: A total of 60 subjects that had been referred to an Icelandic memory clinic cohort were classified as having CSF AD (n = 34) or non-AD (n = 26) pathology profiles. Untargeted CSF lipidomic analysis was performed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) for the detection of mass-to-charge ratio (m/z) features. CSF proteins reflecting neurodegeneration (neurofilament light [NFL]) and inflammation (chitinase-3-like protein 1 [YKL-40], S100 calcium-binding protein B [S100B], glial fibrillary acidic protein [GFAP]) were also measured. Rey Auditory Verbal Learning (RAVLT) and Story tests were used for the assessment of verbal episodic memory. Results: Eight out of 1008 features were identified as best distinguishing between the CSF profile groups. Of those, only the annotation of the m/z feature assigned to lipid species C18 ceramide was confirmed with a high confidence. Multiple regression analyses, adjusted for age, gender, and education, demonstrated significant associations of CSF core AD markers (Aβ 42: st.β= –0.36, p = 0.007; T-tau: st.β= 0.41, p = 0.005) and inflammatory marker S100B (st.β= 0.51, p = 0.001) with C18 ceramide levels. Conclusion: Higher levels of C18 ceramide associated with increased AD pathology and inflammation, suggesting its potential value as a therapeutic target.

Advances in Proteomic and Metabolomic Profiling of Neurodegenerative Diseases

“…Among the screened metabolites, glucosylceramides, lysophosphatidylcholines, and triacylglycerides were shown to be associated with CSF Aβ, while sphingomyelins and ceramides were found to be associated with CSF total tau and brain atrophy. Similarly, Teitsdottir et al (26) examined 60 individuals from an Icelandic memory clinic and reported that ceramide C18 was a distinguishing factor between AD patients and controls, a finding previously described elsewhere. Ceramides are second messengers that are created via sphingomyelin breakdown or synthesis from serine and palmitate.…”

Novel Insight in Idiopathic Normal Pressure Hydrocephalus (iNPH) Biomarker Discovery in CSF

“…While the relationship between sphingolipid dysregulation was established in AD, there is still uncertainty regarding the exact lipid species that are directly involved in neurodegeneration. It was collectively established that accumulation of Cer C16, C18 and C20 is a trait of AD patients [28][29][30][31]; however, the presence of very long chains Cers (C22 and C24) was observed for the first time in iNPH only and appeared to characterize this disorder. It is tempting to associate this feature to a protective role of these species toward APP and BACE1, inflammation, ER stress and ROS generation supported by proteomic data and from the literature.…”

Phenotypic Displays of Cholinergic Enzymes Associate With Markers of Inflammation, Neurofibrillary Tangles, and Neurodegeneration in Pre- and Early Symptomatic Dementia Subjects

“…The current study cohort and the selection criteria have been described earlier (Teitsdottir et al, 2020 , 2021 ). Subjects were recruited from the Icelandic MCI study cohort ( n = 165).…”

“…The collection of CSF and the measurements of protein concentrations have previously been described (Teitsdottir et al, 2020 , 2021 ). Collection of CSF was done via lumbar puncture with a 22-gauge spinal needle at the L3/4 or L4/5 interspace.…”