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Francisco J. Quintana. Harvard Medical School and The Broad Institute of MIT and Harvard

Astrocytes play important roles in the central nervous system (CNS) during health and disease. In particular, it is now know that astrocytes play iimportant roles in CNS inflammation and neurodegeneration in MS and other neurologic diseases. Thus, the identification of factors that regulate astrocyte activity may shed light on CNS physiology and guide new therapies for human neurologic disorders. In this presentation we will discuss mechanisms used by astrocytes to control CNS pathology. In addition, we will discuss molecular pathways involved in the control of astrocyte function. For example, we recently found that microbial metabolites limit astrocyte pathogenic activities in the context of CNS inflammation, while environmental factors can boost these disease promoting activities. Finally, we will review ongoing efforts on the characterization of astrocyte heterogeneity in MS, and novel findings on how specific subsets and their interactions participate in MS pathology.

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The development of immunotherapies has led to major therapeutic progress in MS, with a robust impact on relapse rate. Concerning their influence on disability accrual, several long-term observational studies have suggested a reduced risk of decline in neurologic function in patients with relapsing-remitting MS. In the progressive forms of the disease, few trials with immunosuppressants have shown some relatively minor effect on progression of handicap. Irreversible neuronal/axonal damage and loss accounts for handicap progression, and takes place early in disease evolution, i.e. not only during the progressive phase, but also in the remitting phase. In this context, promoting remyelination, which results in prevention of neurodegeneration, represents a promising strategy to slow or suppress disability progression. Whether these remyelination strategies should be proposed to patients with progressive disease remains uncertain, with the risk of trial failure due to existing severe disability and neuronal damage. This is why most trials to date have included patients with RMS (MS with relapses, with either a relapsing-remitting or a progressive phenotype. To date, the few completed phase 2 trials have not demonstrated clinical impact, but some showed efficacy on imaging outcomes. Other trials included patients with optic neuritis, with some positive results on VEP latency. Even if a solid conclusion from these trials is premature, and with the lack of evidence that these stratégies can be extrapolated to progressive MS, these very recent results, suggesting that it might be possible through remyelination to prevent neurodegeneration, open exciting perspectives for prevention of disability progression in MS.

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Progressive multiple sclerosis (PMS) is characterized by increasing and irreversible accrual of neurological deficits independent from the inflammatory activity. Although disability progression occurs from disease onset in about 10-15% of patients (primary progressive multiple sclerosis, PPMS), in most cases, it arises after an initial relapsing-remitting phase (secondary progressive multiple sclerosis, SPMS). Given the recent development of treatments effective in PMS, there is growing interest to identify potential biomarkers and measures to identify, predict and monitor progression, as, at the state-of-the-art, it is a retrospective diagnosis.

Using magnetic resonance imaging (MRI), in addition to the assessment of white matter (WM) T2-hyperintense lesion volume and brain atrophy, several studies evaluated damage in critical CNS structures, such as the grey matter (GM) and the spinal cord. Compared to relapsing-remitting patients, the presence and the extent of cortical lesions and subpial demyelination are higher in PMS, who also experience a faster deep GM, cortical, and spinal cord atrophy.

Recently, WM lesions characterized by slow-rate progressive volume growth and peripheral iron rim were identified in MS patients. Several studies reported a higher proportion of these lesions in PMS, but this evidence remains controversial.

This lecture will discuss the state-of-the-art MRI measures and promising biomarkers that might explain, predict, and monitor progression in MS.