Of the neurological patients recruited from the Hungarian population in the city of Szeged, 77 proved eligible to participate in an exploratory retrospective CSF analysis. Table 1 provides a summary of demographic data and clinical parameters. Nineteen patients with GBS represented demyelination affecting the PNS, and 34 patients with non-demyelinating disorders were considered as controls.
The IgG index exceeded the normal limit of 0. To identify lipid biomarker signatures of demyelination, we applied high sensitivity, high resolution shotgun mass spectrometry-based lipidomic method Supplementary Fig. Survey acquisitions were performed at high mass resolution. Lipid species were identified by LipidXplorer software Relative quantification was made by comparing the integrated signal intensities of identified peaks with those of the corresponding internal standards, whereas absolute quantification was made based on the amount of the extraction standard.
To resolve fatty acyl composition in glycerophospholipids, tandem MS2 or MS3 fragmentation experiments were performed. Our lipidomic platform allowed the broad-range coverage of the CSF lipidome within minutes; we identified and quantified lipid molecular species in 19 lipid classes including glycero- and glycerophospholipids, sphingolipids and cholesteryl ester for basic lipid structures and an illustration of CSF lipid class composition see Supplementary Fig.
Combining our data with the major characteristics of the plasma and brain lipidomes, in Fig. The abundance of the storage lipids cholesteryl ester and triglyceride in the CSF reflects plasma-specific features, whereas the sizeable amounts of sulfatides and cerebrosides reflect brain-specific components Supplementary Table S1 and Supplementary Fig. PC and SM are also major lipid classes in both plasma and brain, nevertheless, their species compositions are characteristically different. Metabolism and the origin of CSF lipids.
For lipid classes, colouring illustrates but does not quantify the origin contribution. Solid arrows display anabolic steps, whereas dashed arrows indicate those catabolic steps that are discussed in the present study. Next, we performed multivariate statistical analysis on our lipidomic data. The well distinguishable clusters indicated that characteristic changes occurred both in the lipid content Fig. Venn diagrams shown in Fig.
In order to identify relevant alterations, we grouped the changes according to lipid classes, lipid metabolic pathways, and brain- or plasma-specific features. We calculated the nonparametric effect size A and illustrated selected results on forest plots Fig. Forest plots were created by R 3. Sphingolipid metabolism is known to have a characteristic role in the CNS Because myelin is rich in sphingolipids, especially cerebrosides, sphingolipids may play a marker role in demyelination.
Although the total lipid content did not change, our lipidomic data revealed an elevation in almost all cerebroside and in several ceramide Cer species in the MS group compared with the controls Fig. The glycerolipid metabolism showed alterations too; levels of phosphatidic acid, diglyceride, lysolipid and low molecular weight triglyceride species were increased Fig. The total lipid content of CSF from patients with GBS showed a statistically significant fourfold increase compared to the controls from The elevation included practically all measured lipid classes Fig.
Cholesteryl ester, PC and SM displayed the largest differences, and the mostly elevated species were dominantly plasma-derived lipid components Supplementary Table S4. The increase in lipid content, expressed as fold change ratio of GBS to control , also revealed large variation between lipid classes from 1. The highest fold increases were detected for lysophosphatidylethanolamine In addition, well distinguishable changes occurred in the composition of CSF in the GBS group compared with the controls.
These changes were characterized by the elevation in the relative levels of several plasma-derived components accompanied by the reductions in brain-derived species Fig. In the absence of age-matched controls, we calculated partial correlation coefficients to control for the effect of age. Nevertheless, we note that age has negligible effect on lipid metabolite levels see e.
The number of cases with strong correlation was 50 and in the MS and GBS group, respectively, whereas in the control group it never exceeded the correlation value of 0. Lipid concentration strongly correlated with albumin index as well but there was no association with IgG index.
Correlation between CSF total protein and total lipid contents. Solid lines represent linear regression. We also assessed whether lipid levels were associated with disease-specific disability scores. However, we note that the EDSS value of 8. Noteworthy, correlations were positive for plasma-derived phosphatidylethanolamine, lysolipid, diglyceride and triglyceride components, whereas negative correlation was found for brain-specific sulfatide and GM3 ganglioside species Supplementary Table S7.
Finally, we calculated the differences between HFGS determined at nadir and discharge for each patient.
We detected no statistically significant differences between these categories with respect to the clinically diagnostic biomarker parameters protein content, albumin index, IgG index.
Interestingly, brain-derived sulfatide and PC species showed higher relative levels, whereas plasma-derived lysolipid, diglyceride and triglyceride species displayed lower values in patients in the clinically improving group Fig.
It suggests that the lower the relative accumulation of plasma-derived lipids in the CSF of a patient with GBS, the better the chance of clinical recovery. Association of relative lipid levels with HFGS improvement. P values were determined by Van der Waerden test. In the present study we report about a rapid and comprehensive lipid species analysis of the CSF lipidome, an insofar understudied area in CSF biomarker discovery. We presented the applicability of our method in this exploratory study that was aimed to better understand the role of lipidomic biomarkers in the pathology of demyelination in the CNS and PNS.
These studies were targeted either on SM analysis in demyelinating disorders of the PNS 26 , on the assessment of the sphingolipidome 27 or the global lipidome with a fatty acid-targeted approach 28 in patients with MS, or on the polar metabolome from patients with MS 29 and GBS The consequences, i.
In general, we detected a distinctive change in the absolute and relative lipid amounts in MS and GBS as compared to controls with non-demyelinating disorders. The strong association between the total protein content and lipid levels represents a new piece of information for both diseases.
For the GBS group, the massive elevation in lipid amounts was a distinctive and newly recognized feature of PNS demyelination. The elevation in SM agrees well with recently published results where targeted CSF lipid analysis revealed significantly higher SM content in patients with GBS compared to those with non-demyelinating disorders In the MS group, we could not observe increase in albumin index.
This could be in agreement with reports that propose albumin index may not be an accurate measure of blood—brain barrier dysfunction in MS Nevertheless, at the level of the lipidome, the enrichment of plasma-specific triglyceride species might be an indication of enhanced plasma leakage into the CSF of patients with MS.
On the other hand, the accumulation of sulfatides, ganglioside GM3 and cerebrosides in the GBS group, as well as the enrichment of cerebrosides in the MS group are indicative of demyelination. Considering the overall alterations in the CSF lipidomes, the selective accumulation of the myelin-specific cerebrosides seems to be a characteristic feature of CNS demyelination compared with that in the PNS.
An increase in the levels of cerebrosides in the CSF of patients with MS has already been reported In agreement with those findings, the palmitic acid-containing cerebroside species HexCer was one of the best predictive markers for MS as compared to controls in our study too.
As a common feature of demyelination, we detected upregulated levels of lipid metabolic intermediates in both disease groups. The distinctively high-fold increases of lysoPC, lysophosphatidylethanolamine and Cer in patients with GBS, as well as the increase of Cer, phosphatidic acid and diglyceride in patients with MS might point to a general activation of lipid degradation. The elevation of Cer species in the MS group agrees well with previous findings in the literature.
The Cer species were elevated in the CSF of patients with MS, and it was causatively linked to inducing neuronal mitochondrial dysfunction and axonal damage Other studies have demonstrated that Cer can be important mediator of oligodendrocyte death in the MS brain Furthermore, the activity of acid sphingomyelinase, which generates Cer from SM Fig.
It was also shown that acid sphingomyelinase plays a significant role in myelin repair and its inhibition promotes remyelination On the other hand, a novel observation was reported that the elevation of Cer and sphingosine occurred in the experimental model of MS via de novo Cer generation due to activation of serine palmitoyltransferase The increase in diglyceride in both MS and GBS can be the result of either phospholipase C activation, which removes the headgroup of glycerophospholipids, or lipoprotein lipase activation, which hydrolyses triglyceride Fig.
It was shown that the elevation and activity of lipoprotein lipase activity may be part of an acute response to scavenge and reutilize myelin-derived lipids in degenerating peripheral nerves 38 as well as by microglia 39 , Similarly, the elevation in phosphatidic acid might be due to phospholipase D induction, which cleaves the choline moiety from the headgroup of PC Fig.
PLD1 ablation markedly reduced symptomatology in experimental allergic encephalomyelitis raising the possibility that PLD1 inhibition may provide a useful approach in MS therapeutics In addition, phosphatidic acid-induced demyelination led to the development of pronounced peripheral neuropathy in a mouse model In line with these findings, we observed elevated levels of several lysolipid species in both GBS and MS compared to the controls.
This might be the result of phospholipase A 2 activation, which removes a fatty acyl tail from glycerophospholipids Fig. In addition, lysoPC is a known potent demyelinating agent either when injected into the spinal cord and other CNS regions or when applied to the PNS 43 , 44 , Since remyelination in the PNS is efficient and quick but limited by the presence of the demyelinating agent 46 , treatments to lower lysoPC might be considered in GBS therapeutics.
Altogether, several events that occur during and after demyelination might simultaneously contribute to the complex changes in the lipidomic profile in the CSF of patients with MS or GBS. These may include alterations in intrathecal lipid metabolism as it was demonstrated by the drastic change in the Cer species in patients with active MS lesions Concomitant changes in plasma and CSF lipid composition present an important subject for further investigation.
Indeed, the disturbance in the plasma lipidomic profile was observed in patients with GBS compared to healthy controls Moreover, the contribution of changes in the transport selectivity of lipids from plasma into the CSF or altered re-uptake selectivity of lipids from the CSF into blood should also be considered.
Although we could not show correlation between CSF lipid levels and EDSS in patients with MS in the present study, in a previous report, where follow-up data were available, the cerebroside species HexCer appeared to be a promising candidate biomarker of disease progression in MS In addition, the potential prognostic value of sulfatides or triglyceride can be valuable in a fast progressing disease.
Limitations of the present study include the relatively small size of the study population and that recruitment of patients was from a geographically restricted area of Europe. Nevertheless, the study groups represented well the neurological disorders in focus with regard to basic demographic and clinical parameters.
Therefore, our sample was justifiably suitable to perform an exploratory lipidomic study. An additional limitation is the absence of age-matched controls; nevertheless, the correlation analysis showed that age-dependence of lipid metabolite levels was negligible in our cohort.
There is also a theory that the virus confuses the immune system, allowing the cell to attack the myelin. Many people with Guillain-Barre syndrome report that they contracted the disease after becoming ill with either a virus or a respiratory infection. This could suggest that their immune system did not respond properly to the previous virus. Below we look at possible triggers in multiple sclerosis vs. Guillain-Barre triggers mentioned above.
Recognizing MS triggers is important if people want to reduce flare-ups. Here are the common multiple sclerosis triggers. Keeping on top of signs and symptoms and trying to control triggers is key to avoiding unwanted complications. People who suffer from multiple sclerosis have an increased risk of urinary tract infections since their bladder nerves can be disrupted. Osteoporosis, pressure sores, aspiration, pneumonia, and depression are also complications associated with MS.
Some people with Guillain-Barre syndrome also experience complications. They could include, being unable to walk and thus requiring a wheelchair, problems with sense of touch, loss of coordination, and extreme muscle weakness.
There is a small chance — about one in 20 — of dying from Guillain-Barre syndrome. Normally, this happens as a result of complications during the first few weeks of the condition. Respiratory failure, serious infection, and heart rhythm disorders are usually the biggest factors.
Since there is no cure for multiple sclerosis, the approach is to manage the symptoms and try to prevent flare-ups. There are physical therapies, muscle relaxants, and other medications that can be administered to reduce fatigue, discomfort, depression, and other symptoms associated with MS. Again, there is no cure for Guillain-Barre syndrome, but there are treatments that can ease pain and lessen the duration of the illness. Multiple sclerosis in Isfahan, Iran: past, present and future.
Multiple sclerosis and amyotrophic lateral sclerosis: is there a link? Mult Scler. Assessment of current diagnostic criteria for Guillain-Barre syndrome. Annals of Neurology. Forrester C, Lascelles RG.
Association by polyneuritis and multiple sclerosis. Journal of Neurology Neurosurgery and Psychiatry. Inflammatory demyelinating polyradiculitis in a patient with multiple sclerosis. Archives of Neurology. Best PV. Acute polyradiculoneuritis associated with demyelinated plaques in the central nervous system: report of a case. Acta Neuropathologica. Journal of Neurology. Combined central and peripheral acute demyelination. The Italian Journal of Neurological Sciences. Guillain-Barre syndrome after thalamotomy for tremor in MS.
European Journal of Neurology. Peripheral neuropathy in multiple sclerosis. Peripheral nervous system pathology in relapsing experimental allergic encephalomyelitis. Journal of Neurocytology. Peripheral nerve abnormality in multiple sclerosis. A case of childhood multiple sclerosis with peripheral neuropathy. Multiple sclerosis associated with peripheral demyelinating neuropathy.
Clinical Neuropathology. Spreading of autoimmunity from central to peripheral myelin: two cases of clinical association between multiple sclerosis and chronic inflammatory demyelinating polyneuropathy. Neurological Sciences. Soluble complement receptor type 1 in serum and cerebrospinal fluid of patients with Guillain-Barre syndrome and multiple sclerosis.
Journal of Neuroimmunology. Soluble intercellular adhesion molecule-I sICAM-I in serum and cerebrospinal fluid of demyelinating diseases of the central and peripheral nervous system. Multiple Sclerosis. Chronic demyelinating peripheral neuropathy associated with multifocal central nervous system demyelination. Evidence for central nervous system demyelination in chronic inflammatory demyelinating polyradiculoneuropathy.
Central lesions in chronic inflammatory demyelinating polyneuropathy: an MRI study. Evoked potentials suggest cranial nerves and CNS involvement in chronic relapsing polyradiculoneuropathy. European Neurology. Central nervous system pathology in patients with the Guillain-Barre syndrome. Patterns and significance of concomitant central and peripheral inflammatory demyelination.
Neurological Research. Antibodies to P2 and P1 myelin antigens in experimental allergic neuritis and allergic encephalomyelitis. Minisci, D. Romito, I. Cancelli, and G. Vedeler, R. Matre, S. Sadallah, and J. Trojano, C. Avolio, M.
Ruggieri et al. Thomas, R. Walker, and P. View at: Google Scholar J. Mendell, S. Kolkin, J. Kissel, K. Weiss, D. Chakeres, and K. View at: Google Scholar T. Feasby, A. Hahn, W. Koopman, and D. Gigli, A. Carlesimo, M. Valente et al. Maier, M. Schmidbauer, B. Pfausler, E. Schmutzhard, and H. Rezania, B. Arnason, and B. Zweiman, A. Moskovitz, and A. View at: Google Scholar C. Vedeler, K. Myhr, and H. McCombe, P. Clark, and J. View at: Google Scholar W.
Eaton, N. Rose, A. Kalaydjian, M. Pedersen, and P. Nielsen, M. Frisch, K. Rostgaard et al. Langer-Gould, K. Albers, S. Van Den Eeden, and L. Tam, S. O'Brien, I. Petersen, A. Islam, A. Hayward, and L.
0コメント