Abstract
Age at onset is the main risk factor for disease progression in patients with relapsing-remitting multiple sclerosis (RR-MS). In this cross-sectional study, we explored whether older age is associated with specific disease features involved in the progression independent of relapse activity (PIRA). In 266 patients with RR-MS, the associations between age at onset, clinical characteristics, cerebrospinal fluid (CSF) levels of lactate, and that of several inflammatory molecules were analyzed. The long-term potentiation (LTP)-like plasticity was studied using transcranial magnetic stimulation (TMS). Older age was associated with a reduced prevalence of both clinical and radiological focal inflammatory disease activity. Older patients showed also increased CSF levels of lactate and that of the pro-inflammatory molecules monocyte chemoattractant protein 1 (MCP-1)/CCL2, macrophage inflammatory protein 1-alpha (MIP-1α)/CCL3, and interleukin (IL)-8. Finally, TMS evidenced a negative correlation between age and LTP-like plasticity. In newly diagnosed RR-MS, older age at onset is associated with reduced acute disease activity, increased oxidative stress, enhanced central inflammation, and altered synaptic plasticity. Independently of their age, patients with multiple sclerosis (MS) showing similar clinical, immunological, and neurophysiological characteristics may represent ideal candidates for early treatments effective against PIRA.
Highlights
Multiple sclerosis (MS) is an inflammatory immune-mediated disease of the central nervous system (CNS) with a highly variable disease course
No significant correlation was observed between age at onset and Expanded Disability Status Scale (EDSS) (p = 0.341), and no significant associations emerged between age at onset and sex (p = 0.915) or the presence of oligoclonal bands (OCB) (p = 0.125)
Linear regression showed that the age group was significantly associated with Bayesian risk estimate for MS at onset (BREMSO) after adjusting for all other clinical variables
Summary
Multiple sclerosis (MS) is an inflammatory immune-mediated disease of the central nervous system (CNS) with a highly variable disease course. While the relapsing-remitting (RR) course is better described in terms of episodical aggression of the brain by peripheral autoreactive T and B lymphocytes, factors involved in the progressive phenotypes [primary progressive (PP) and secondary progressive (SP)] are believed to take place in the CNS (Faissner et al, 2019). Oxidative stress, and exacerbated intrathecal inflammation may promote axonal damage and neurodegeneration, playing crucial roles in the progression independent of relapse activity (PIRA) (Faissner et al, 2019). Drugs approved as first-line agents in relapsing-remitting multiple sclerosis (RR-MS) significantly reduce relapse rate and disability worsening related to relapse activity, showing less or no effect in progressive MS phenotypes. The introduction of therapies effective in progressive MS, such as siponimod and ocrelizumab, stimulated the interest in understanding the determinants of progression
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