Cognitive dysfunction involves 40-65% of multiple sclerosis patients and can have a great functional impact. It can be detected in all the disease phenotypes since the early stages of the disease, and tends to progress over time. Memory, complex attention, information-processing speed and executive functions are most commonly involved. The relationship between cognitive changes and magnetic resonance imaging (MRI) findings may involve changes in different areas, including white matter lesions, cortical and deep grey matter and normal appearing brain tissue on conventional MRI. The search for effective therapeutic strategies is a major undertaking, involving the use of both pharmacologic and rehabilitative approaches. Early treatment with disease-modifying drugs that can contain the disease burden in the brain seems to be highly advisable in order to prevent or delay the development of cognitive impairment.

Amyotrophic lateral sclerosis (ALS) is a progressive adult-onset neurodegenerative disease, that affects cortical, bulbar and spinal motor neurons, and it is considered a proteinopathy, in which pathological proteins (SOD1, TDP-43, and FUS) may accumulate and interfere with neuronal functions eventually leading to cell death. These proteins can be released from cells and transported in the body fluids by extracellular vesicles (EVs). EVs are spherical vesicles, which are classified mainly in microvesicles (MVs) and exosomes (EXOs) based on their biogenesis, size and surface markers. In this study we characterized MVs and EXOs isolated from plasma of sporadic ALS patients and healthy controls and determined their number, size and SOD1, TDP-43, and FUS protein composition. No variation was found in the number of EVs between ALS patients and controls. However, the mean size both for MVs and for EXOs resulted increased in ALS patients compared to controls. MVs derived from ALS patients were enriched in SOD1, TDP-43, phospho-TDP-43, and FUS proteins compared to CTRLs. SOD1 was generally more concentrated in EXOs than in MVs, while TDP-43 and FUS protein levels were slightly higher in MVs than in EXOs. We demonstrated that MVs and EXOs size were increased in ALS patients compared to controls and that MVs of ALS patients were enriched with toxic proteins compared to CTRLs. EXOs did not show any protein changes. These data may suggest that MVs can transport toxic proteins and might play a role in prion-like propagation of ALS disease.

This study provides Class IV evidence that in women with MS, the risk of relapses during pregnancy is higher in those who had been using natalizumab as compared to those who had been using interferon-β or no treatment.