The impact of smoking cessation on multiple sclerosis disease progression.

The negative impact of smoking in multiple sclerosis is well established; however, there is much less evidence as to whether smoking cessation is beneficial to progression in multiple sclerosis. Adults with multiple sclerosis registered on the United Kingdom Multiple Sclerosis Register (2011-20) formed this retrospective and prospective cohort study. Primary outcomes were changes in three patient-reported outcomes: normalized Multiple Sclerosis Physical Impact Scale (MSIS-29-Phys), normalized Multiple Sclerosis Walking Scale (MSWS-12) and the Hospital Anxiety and Depression Scale (HADS). Time to event outcomes were clinically significant increases in the patient-reported outcomes. The study included 7983 participants; 4130 (51.7%) of these had ever smoked, of whom 1315 (16.5%) were current smokers and 2815/4130 (68.2%) were former smokers. For all patient-reported outcomes, current smokers at the time of completing their first questionnaire had higher patient-reported outcomes scores indicating higher disability compared to those who had never smoked (∼10 points difference in MSIS-29-Phys and MSWS-12; 1.5-1.8 points for HADS-Anxiety and HADS-Depression). There was no improvement in patient-reported outcomes scores with increasing time since quitting in former smokers. Nine hundred and twenty-three participants formed the prospective parallel group, which demonstrated that MSIS-29-Phys [median (IQR) 5.03 (3.71, 6.34)], MSWS-12 [median (IQR) 5.28 (3.62, 6.94)] and HADS-Depression [median (IQR) 0.71 (0.47, 0.96)] scores worsened over a period of 4 years, whereas HADS-Anxiety remained stable. Smoking status was significant at Year 4; current smokers had higher MSIS-29-Phys and HADS-Anxiety scores [median (IQR) 3.05 (0.22, 5.88) and 1.14 (0.52, 1.76), respectively] while former smokers had a lower MSIS-29-Phys score of -2.91 (-5.03, -0.79). A total of 4642 participants comprised the time to event analysis. Still smoking was associated with a shorter time to worsening event in all patient-reported outcomes (MSIS-29-Phys: n = 4436, P = 0.0013; MSWS-12: n = 3902, P = 0.0061; HADS-Anxiety: n = 4511, P = 0.0017; HADS-Depression: n = 4511, P < 0.0001). Worsening in motor disability (MSIS-29-Phys and MSWS-12) was independent of baseline HADS-Anxiety and HADS-Depression scores. There was no statistically significant difference in the rate of worsening between never and former smokers. When smokers quit, there is a slowing in the rate of motor disability deterioration so that it matches the rate of motor decline in those who have never smoked. This suggests that smoking cessation is beneficial for people with multiple sclerosis.

Co-expression of PDGF alpha receptor and NG2 by oligodendrocyte precursors in human CNS and multiple sclerosis lesions.

Following inflammatory demyelination in multiple sclerosis (MS), partial remyelination occurs. Studies in rodents have indicated that oligodendrocyte precursor cells (OPCs) are responsible for this remyelination. Rodent OPCs are identified in situ with antibodies against platelet-derived growth factor alpha receptor (PDGFalphaR) and NG2 chondroitin sulfate proteoglycan. In human CNS tissue, studies of NG2 and PDGFalphaR expression are limited and controversy exists as to whether these molecules are specific OPC markers. This study has investigated whether PDGFalphaR and NG2 are co-expressed on OPCs in human CNS, and whether OPCs are associated with remyelination in MS. MS brain tissue was examined for PDGFalphaR and NG2 immunoreactivity and for expression of NG2 mRNA by in situ hybridisation. Putative OPCs, expressing both NG2 and PDGFalphaR, were present within normal-appearing white matter and within areas of active demyelination in MS, but not in chronic silent lesions. They were also seen in association with remyelination in MS tissue and with developmental myelination in human spinal cord. NG2+ cells that did not express PDGFalphaR were also detected. Given their lack of reactivity with microglial or astrocyte markers, these NG2+/PDGFalphaR- cells probably represented more mature OPCs that had lost PDGFalphaR expression. The distribution of OPCs observed in this study strongly suggests these cells are potential sources of remyelinating oligodendrocytes in active lesions in MS.

Glutamate uptake by oligodendrocytes: Implications for excitotoxicity in multiple sclerosis.

BACKGROUND: Excitotoxic damage is a common pathologic event in a number of neurologic diseases occurring after accumulation of excess extracellular glutamate in the CNS and subsequent overstimulation of glutamate receptors. In gray matter, astrocytes take up synaptically released glutamate and are thus key cells in maintaining glutamate homeostasis. In white matter, oligodendrocytes have been shown to express glutamate transporters, but their role in extracellular glutamate removal is unclear. OBJECTIVE: To investigate whether cultured human fetal oligodendrocytes functionally express the main glutamate transporters EAAT-1 and EAAT-2. METHODS: Cultures of fetal human oligodendrocytes were examined by immunocytochemistry and [3H]glutamate uptake, and the findings were correlated with glutamate transporter expression in normal and multiple sclerosis (MS) CNS tissue. RESULTS: Both EAAT-1 and EAAT-2 were expressed by human oligodendrocytes in vitro. Incubation of oligodendrocytes with the proinflammatory cytokine tumor necrosis factor-alpha (TNFalpha) reduced EAAT-1 expression and inhibited glutamate uptake by >75%. Furthermore, in normal human white matter, oligodendrocytes were found to be the predominant cells to express EAAT-1 and EAAT-2, both at the mRNA and at the protein level. A small number of astrocytes in white matter expressed these receptors, more so EAAT-1 than EAAT-2. In MS white matter, oligodendrocytes lost expression of EAAT-1 and EAAT-2 receptors in the lesion vicinity. CONCLUSIONS: Oligodendrocytes appear to be predominant cells for glutamate clearance in human white matter. Glutamate receptor expression and glutamate removal were defective in MS white matter, possibly mediated by TNFalpha, changes that might underlie high extracellular glutamate and an increased risk for glutamate excitotoxicity.

Human oligodendrocyte precursor cells in vitro: phenotypic analysis and differential response to growth factors.

Following experimental demyelination in rodents, oligodendrocyte precursor cells (OPCs) proliferate and differentiate into myelin-producing oligodendrocytes which effect robust remyelination. In contrast, remyelination in multiple sclerosis, the major human demyelinating disease, is generally limited and transient. Rodent OPCs have been well characterized in vitro and their response to growth factors documented. Since there appear to be appreciable species differences in OPC growth factor responsiveness, and since human precursors have proven difficult to culture, the present study has investigated mitogenic growth factors for cultured fetal human OPCs. Moreover, because markers for cultured human OPCs are not well established, we also examined which of the extensively used rodent OPC markers also label human precursors. Using a culture system modified for fetal human oligodendroglia, we have shown for the first time that the platelet-derived growth factor alpha receptor (PDGFalphaR) and A2B5 antigen are expressed together on human OPCs. Human precursors also expressed NG2 chondroitin sulfate proteoglycan, as did a proportion of O4+ preoligodendrocytes. Several growth factors known to affect rodent OPCs were tested and found to have similar effects on human cells. PDGF, neurotrophin 3 (NT3), and glial growth factor 2 (GGF2) promoted proliferation, while insulin-like growth factor-1 (IGF-1), exerted a maturational effect.