Abnormalities in lipid metabolism. Link to cholesterol??

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frodo
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Abnormalities in lipid metabolism. Link to cholesterol??

Post by frodo » Tue Jan 09, 2018 10:55 am

Could this be the reason why cholesterol lowering drugs work???

Lipid biochemical changes detected in NAWM of chronic MS by SCR imaging

http://pubs.rsc.org/en/content/articleh ... c7sc03992a

Abstract

Multiple sclerosis (MS) exhibits demyelination, inflammatory infiltration, axonal degeneration, and gliosis, affecting widespread regions of the central nervous system (CNS). While white matter MS lesions have been well characterized pathologically, evidence indicates that the MS brain may be globally altered, with subtle abnormalities found in grossly normal appearing white matter (NAWM).

These subtle changes are difficult to investigate by common methods such as histochemical stains and conventional magnetic resonance imaging. Thus, the prototypical inflammatory lesion likely represents the most obvious manifestation of a more widespread involvement of the CNS. We describe the application of spectral coherent anti-Stokes Raman Scattering (sCARS) microscopy to study such changes in chronic MS tissue particularly in NAWM. Subtle changes in myelin lipid biochemical signatures and intra-molecular disorder of fatty acid acyl chains of otherwise normal-appearing myelin were detected, supporting the notion that the biochemical involvement of the MS brain is far more extensive than conventional methods would suggest

Introduction

Multiple sclerosis (MS) is a leading cause of non-traumatic neurological disability in young adults with a global prevalence of ≈2.3 million. The underlying cause remains contentious despite decades of investigation. Patients diagnosed with the various clinical forms of MS (relapsing-remitting, primary progressive and secondary progressive) manifest with signs of neurological dysfunction leading to a decline in sensory, motor, cognitive, bowel/bladder and gait function. Traditionally, MS is considered to be a primary autoimmune inflammatory disease whereby a dysregulated peripheral immune system promotes an attack on the CNS, particularly against the insulating layer of myelin around axons. However, an alternative model proposes that MS may begin as a primary degenerative process, with the autoimmune and inflammatory reactions arising secondarily in response to the degenerating myelin. The most common phenotype of MS at presentation is relapsing-remitting (RR) disease, wherein patients largely recover during remission. However, approximately 25 years after disease onset the majority of patients will go on to develop a secondary progressive (SP) phase, with accumulation of irreversible disability. The gradual transition from RRMS to SPMS cannot be determined through any definitive clinical, imaging, immunologic, or pathologic criteria. A smaller but significant percentage present from the onset with primary progressive MS (PPMS), characterized by a gradual progressive clinical course with no relapses or remissions, and with inflammatory pathology that is less prominent. Longitudinal studies have also shown SPMS and PPMS patients to suffer a clinical decline at a similar rate. For the more common RRMS, the last two decades have seen a number of immuno-modulatory treatment options. However, the same cannot be said for the progressive MS phenotypes, with the aforementioned anti-inflammatory therapeutics generally shown to be ineffective at slowing accumulation of disability.

The MS lesion has been well studied since the report by Charcot in 1868.14 The characteristic pathology includes a combination of focal demyelination, inflammation, gliotic scar formation, and variable degrees of axonal destruction. While these lesions are the most obvious indication of CNS damage, the surrounding regions traditionally labeled as ‘normal-appearing’ white matter (NAWM) have been of particular interest. In the NAWM of MS brains, subtle abnormalities have been detected using advanced magnetic resonance imaging (MRI), including prolonged T1 and T2 relaxation times, reduced magnetization transfer ratios (MTR) and abnormalities on diffusion tensor imaging. MTR and immunohistochemistry correlated experiments show that these abnormalities appear to be dependent on proximity to focal white matter lesions with axonal swelling and increased numbers of microglia/macrophages detected distant from lesions. However, a decrease in MTR recordings have also been found preceding lesion formation. In patients with a relatively moderate lesion load, signs of progressive brain atrophy point towards more extensive abnormalities in the NAWM and new lesions have been found to form in the NAWM even before a breakdown of the blood–brain barrier. Taken together these observations suggest pathology that is more widespread than previously appreciated, extending far beyond the classic demyelinating plaque.

The myelin sheath, essential for action potential propagation, is a highly ordered structure composed of ≈70% lipid by dry weight, which exists in a tightly orchestrated balance with major myelin proteins to form the insulating layer around the axon. Historically, myelin lipids have been investigated less extensively than myelin proteins in situ because of their hydrophobicity and a complex variety of different lipid species. However, it has been shown that myelin lipid composition in MS patients differs from that of healthy individuals. More specifically, decreases in total lipid and phospholipid, especially ethanolamine plasmalogens, cerebrosides, sulfatides and sphingolipids have been reported.6,23–28 In contrast, cholesterol esters, the breakdown products of cholesterol, are increased in MS brain.27–30 Taken together, this suggests that lipid abnormalities might be critically important early events culminating in demyelination.

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