Lipid profile of cerebrospinal fluid

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frodo
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Lipid profile of cerebrospinal fluid

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Lipid profile of cerebrospinal fluid in multiple sclerosis patients: a potential tool for diagnosis

https://www.nature.com/articles/s41598-019-47906-x

Discussion

MS is a chronic disease which is present in young adults. Nowadays diagnosis is based on four principles: (i) pattern and epidemiologic context of symptoms, (ii) cerebral/spinal magnetic resonance imaging lesions suggestive from demyelination with time and space dissemination, (iii) presence of oligoclonal bands in CSF and not in serum and (iv) the exclusion of other diagnoses32. Early diagnosis leads to early treatment, the approach that has the best outcomes in terms of progression and disability. A test for the diagnosis of the disease is urgently needed in this setting. Lipidomics is a powerful tool for the study of multifactorial diseases such as MS, and can be used to determine changes in compartments and structures that are fundamentally involved in the disease, such as myelin25,26. In our study, we have used lipidomics to demonstrate that MS patients present a different lipid profile at the time of diagnosis compared with non-MS subjects, underlining the importance of these molecules in this disease and the value of lipid signature characterization as a diagnostic tool. In this line, the description of the CSF lipidomic profile in the time of diagnosis could help to better understand the physiopathology of MS in early stages, to define the role of lipid metabolism in disease progression and to propose new biomarkers for monitoring the disease. Further, this information could be useful for new drugs development.

Both CSF and plasma are excellent sources of biological information which are easy to access33. However, unlike blood, CSF provides information from the CNS due to its proximity and contact. Additionally, it is useful for determining the progression of the disease from onset and can even help to predict disease development. In our study, an initial non-targeted approach in the CSF revealed statistically significant differences in 155 lipid species, 47 of which were identified based on their exact mass, retention time, and isotopic distribution. These results suggest that lipids might be useful biomarkers at the time of diagnosis.

Further, multivariate statistics was applied in order to define a specific lipidomic signature. In this line, Although applying hierarchical clustering analyses and PCA method using all the lipid species we did not see a specific pattern for MS pathology when only those 25 the lipid species with de lowest p-value were used a much better clusterization was obtained. When supervised methods were applied, a perfect clusterization of patients was possible. Thus, 15 lipids were detected as the most relevant for distinguishing both groups, of which 8 were identified based on exact mass, retention time and isotopic distribution: four glycerolipids, one FA, two sterol lipids and one glycerophospholipid.

The identified lipids belong to five different families, including sphingolipids. It is noteworthy that fingolimod, an effective treatment for MS, is an antagonist of sphingosine-1-phosphate (sphingolipid). This highlights the importance of this lipid family, whose levels, according to our results, are altered in CSF following disease onset. Another lipid family that showed differences was glycerolipids. Specifically, an up-regulation of diglycerides and a down-regulation of triglycerides was determined. This finding would be compatible with a defect of the acyl-CoA:diacylglycerol acyltransferase enzyme, which is related to a worse insulin sensitivity, a recently reported observation in patients with MS. Hence, our results are in agreement with other studies that have found alterations in lipids, such as ceramides in CSF, brain phosphatidylcholines, and phospholipids and sphingolipids in white substance of the brain. Finally, mammalian cell membranes including myelin are composed mainly of phosphatidylcholines and phosphatidylethanolamines, levels of which also differed between MS patients and non-MS group in our study. Overall, differences in myelin sheath in CNS could mean more susceptibility to auto-antibody attack.

A specific analysis of the CSF FA composition revealed fewer differences than in the lipidome. Of the 26 different FAs analysed, differences were obtained in only two. C20:0 or arachidic acid is a saturated FA (SFA) that, in our analysis, was increased in MS patients. Importantly, SFAs are implicated in inflammation, a very relevant pathological process that occurs even before diagnosis of the disease. We also detected differences in alfa linolenic acid (C18:3n3). Although several FA deregulations have been found in neurological disorders such as Alzheimer’s disease, Parkinson’s disease and depression in brain tissue, to the best of our knowledge, the increase of alfa linolenic acid (C18:3n3) in CSF at the time of diagnosis in MS patients has not been previously described. Indeed, in our study, patients presented almost twice as much of this essential FA. It has been reported that alpha linolenic acid has neuroprotective properties in an animal model of Parkinson’s disease. Importantly, a prospective study has shown that alpha linolenic acid intake is inversely related to MS risk. Although data on alfa linolenic acid intake were not collected in this study, it is worth remarking that an up-regulation of this FA at the time of diagnosis was found only in MS patients.

The main limitation of this study could be the number of patients enrolled and that all of them are from a restricted geographic area of Spain and from the same hospital. As a retrospective study the data being used was not designed to be used in a study. The fact that the non-MS group was not composed of healthy controls may be considered a limitation of our study. However, we would like to stress the fact that, despite the heterogeneity of this group, important differences in terms of the lipidomic profile were determined. Indeed, our approach could distinguish MS patients from other neuro-inflammatory disease carriers at the time of diagnosis based on their lipidomic signature. Finally, it is important to stress that, due to ethical considerations, lumbar puncture in healthy subjects is not permitted, so the inclusion of patients with other diseases is necessary to perform studies of this nature. Apart from the population and clinical factors, a limitation of the present study is that we are far from understanding the biological significance of this compositional complexity.

In conclusion, MS causes changes in the lipidomic CSF profile that could be considered as a potential diagnostic tool. This tool would make therapeutic decisions easier improving patients’ quality of life. Moreover, this investigation opens new perspectives for the understanding of why lipids are altered at disease onset and which pathways could be deregulated in MS and in other neurodegenerative diseases.
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