Abstract

Astrocytes fulfill multiple homeostatic and regulatory functions in healthy CNS. In MS, reactive astrocytes can enhance the pathological process by impairing blood brain barrier function, recruiting and activating lymphocytes, decreasing homeostatic functions and by adopting a neurotoxic phenotype.

We have shown that a genetic risk variant for MS susceptibility dysregulates astrocyte functions, leading to increased astrocyte-mediated neurotoxicity and more lymphocyte infiltration in MS lesion tissue. This suggests that genetic risk for MS is mediated not only by peripheral immune cells but in part also by astrocytes.

In addition, we have shown that MS progression is associated with increased adenosine A_2A receptor expression in perilesional white matter, as measured by PET imaging. Moreover, we demonstrated that A_2AR is expressed by two astrocyte phenotypes in MS lesion, characterized by pan-activation and by high oxidative damage. Finally, in human astrocyte cultures, A_2AR signaling enhances oxidative damage in reactive human astrocytes. These findings indicate that A_2AR signaling in specific astrocyte populations may drive oxidative damage which contributes to MS progression.

In addition to genetic risk variants, astrocyte function has been shown to be modified by environmental toxins and gut bacterial metabolites. Astrocyte-intrinsic pathways that are affected by modifiers may provide targets for treatment of relapsing-remitting and progressive MS.

Abstract

Astrocytes fulfill multiple homeostatic and regulatory functions in healthy CNS. In MS, reactive astrocytes can enhance the pathological process by impairing blood brain barrier function, recruiting and activating lymphocytes, decreasing homeostatic functions and by adopting a neurotoxic phenotype.

We have shown that a genetic risk variant for MS susceptibility dysregulates astrocyte functions, leading to increased astrocyte-mediated neurotoxicity and more lymphocyte infiltration in MS lesion tissue. This suggests that genetic risk for MS is mediated not only by peripheral immune cells but in part also by astrocytes.

In addition, we have shown that MS progression is associated with increased adenosine A_2A receptor expression in perilesional white matter, as measured by PET imaging. Moreover, we demonstrated that A_2AR is expressed by two astrocyte phenotypes in MS lesion, characterized by pan-activation and by high oxidative damage. Finally, in human astrocyte cultures, A_2AR signaling enhances oxidative damage in reactive human astrocytes. These findings indicate that A_2AR signaling in specific astrocyte populations may drive oxidative damage which contributes to MS progression.

In addition to genetic risk variants, astrocyte function has been shown to be modified by environmental toxins and gut bacterial metabolites. Astrocyte-intrinsic pathways that are affected by modifiers may provide targets for treatment of relapsing-remitting and progressive MS.

Abstract

Astrocytes fulfill multiple homeostatic and regulatory functions in healthy CNS. In MS, reactive astrocytes can enhance the pathological process by impairing blood brain barrier function, recruiting and activating lymphocytes, decreasing homeostatic functions and by adopting a neurotoxic phenotype.

We have shown that a genetic risk variant for MS susceptibility dysregulates astrocyte functions, leading to increased astrocyte-mediated neurotoxicity and more lymphocyte infiltration in MS lesion tissue. This suggests that genetic risk for MS is mediated not only by peripheral immune cells but in part also by astrocytes.

In addition, we have shown that MS progression is associated with increased adenosine A_2A receptor expression in perilesional white matter, as measured by PET imaging. Moreover, we demonstrated that A_2AR is expressed by two astrocyte phenotypes in MS lesion, characterized by pan-activation and by high oxidative damage. Finally, in human astrocyte cultures, A_2AR signaling enhances oxidative damage in reactive human astrocytes. These findings indicate that A_2AR signaling in specific astrocyte populations may drive oxidative damage which contributes to MS progression.

In addition to genetic risk variants, astrocyte function has been shown to be modified by environmental toxins and gut bacterial metabolites. Astrocyte-intrinsic pathways that are affected by modifiers may provide targets for treatment of relapsing-remitting and progressive MS.

Background

Chronic active multiple sclerosis (MS) lesions, characterized by a hyperintense rim (rim+) on quantitative susceptibility mapping (QSM), have been shown to contain iron-enriched, activated microglia and macrophages. QSM is a potential biomarker to monitor treatments directed toward the CNS inflammation. Studies have suggested that dimethyl fumarate (DMF) may reduce the pro-inflammatory innate immune response in the CNS. A comparison to other disease modifying therapies (DMTs) is warranted to evaluate this potential benefit.

Objectives

To determine if dimethyl fumarate (DMF) reduces the iron load, as measured on QSM, in chronic active MS lesions at a greater rate than glatiramer acetate (GA) treatment.

Methods

Sixty-one patients (41 female, 20 male, mean age: 42.1 years +/- 10.9 and EDSS 0.82 +/- 1.2), were considered for this analysis. Fifty-six patients had relapsing-remitting MS and 5 had clinically-isolated syndrome; 37 patients were treated with DMF and 24 with GA. The two treatment groups had similar baseline clinical characteristics; however, DMF patients had less time on treatment as compared to GA (3.86 +/- 1.75 years vs 5.99 +/- 2.67 years, p<0.001). Patients had a QSM scan prior to treatment and a minimum of two on-treatment QSM MRIs. Lesions were classified as rim+ or rim- negative based upon a review of two independent reviewers. To compare longitudinal QSM change in the rim+ lesions among treatment groups, a linear mixed effects model was utilized.

Results

At baseline, patients treated with GA had more QSM rim+ lesions (9.4%) as compared to those starting DMF (4.5%), p=0.0004, however the number of patients having at least one rim+ lesion was similar (16 vs 18 patients) among the treatment groups. DMF patients with rim+ lesions had a longer disease duration as compared to rim+ GA patients (8.15 +/- 6.82 vs 3.55 +/- 4.85 years, p= 0.032). In the subset of patients with QSM rim+ lesions, there was a significantly larger decrease in susceptibility in rim+ lesions with DMF treatment as compared to GA, p< 0.0009. There was minimal reduction of susceptibility in rim- lesions, which was similar among treatment groups; all patients (p=0.92) and QSM rim+ only patients (p=0.11).

Conclusions

This study suggests that DMF reduces the iron load in rim+ MS lesions at a greater rate than GA. These results support QSM to evaluate the effectiveness of various DMTs on the CNS innate immune response in chronic active MS lesions.