Abstract
BackgroundMost patients with relapsing-remitting multiple sclerosis (RRMS) eventually enter a secondary progressive (SPMS) phase, characterized by increasing neurological disability. The mechanisms underlying transition to SPMS are unknown and effective treatments and biomarkers are lacking. Vascular endothelial growth factor-A (VEGF-A) is an angiogenic factor with neuroprotective effects that has been associated with neurodegenerative diseases. SPMS has a prominent neurodegenerative facet and we investigated a possible role for VEGF-A during transition from RRMS to SPMS.Methodology/Principal FindingsVEGF-A mRNA expression in peripheral blood mononuclear (PBMC) and cerebrospinal fluid (CSF) cells from RRMS (n = 128), SPMS (n = 55) and controls (n = 116) were analyzed using real time PCR. We demonstrate reduced expression of VEGF-A mRNA in MS CSF cells compared to controls (p<0.001) irrespective of disease course and expression levels are restored by natalizumab treatment(p<0.001). VEGF-A was primarily expressed in monocytes and our CSF findings in part may be explained by effects on relative monocyte proportions. However, VEGF-A mRNA expression was also down regulated in the peripheral compartment of SPMS (p<0.001), despite unchanged monocyte counts, demonstrating a particular phenotype differentiating SPMS from RRMS and controls. A possible association of allelic variability in the VEGF-A gene to risk of MS was also studied by genotyping for six single nucleotide polymorphisms (SNPs) in MS (n = 1114) and controls (n = 1234), which, however, did not demonstrate any significant association between VEGF-A alleles and risk of MS.Conclusions/SignificanceExpression of VEGF-A in CSF cells is reduced in MS patients compared to controls irrespective of disease course. In addition, SPMS patients display reduced VEGF-A mRNA expression in PBMC, which distinguish them from RRMS and controls. This indicates a possible role for VEGF-A in the mechanisms regulating transition to SPMS. Decreased levels of PBMC VEGF-A mRNA expression should be further evaluated as a biomarker for SPMS.
Highlights
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS)
No significant difference between relapsing-remitting multiple sclerosis (RRMS) in relapse and remission was found in cerebrospinal fluid (CSF) cells or peripheral blood mononuclear (PBMC)
There was a trend towards higher levels of Vascular endothelial growth factor-A (VEGF-A) expression in PBMC from RRMS sampled during a relapse as compared to patients in remission (Figure S1B)
Summary
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). A majority of patients initially display a relapsing-remitting disease course (RRMS), characterized by inflammatory demyelinating attacks, axonal injury and varying degree of repair [1]. Most RRMS patients with time enter a secondary progressive phase (SPMS), with failure of repair mechanisms leading to gradual neurodegeneration and a continuous accumulation of disability [1]. Studies on the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) have suggested a role for VEGF-A in the pathogenesis of these diseases and a genetic association between VEGF-A variants and these diseases has been demonstrated [12,13,14,15,16,17,18]. Most patients with relapsing-remitting multiple sclerosis (RRMS) eventually enter a secondary progressive (SPMS) phase, characterized by increasing neurological disability. Vascular endothelial growth factor-A (VEGF-A) is an angiogenic factor with neuroprotective effects that has been associated with neurodegenerative diseases.
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