Monitoring the dynamics of axonal damage and brain atrophy in Multiple Sclerosis: how to measure the efficacy of remyelinating and neuroprotective drugs in humans
UCSF (USA) & IDIBAPS (Barcelona)
Although Multiple Sclerosis (MS) is described as a prototypic demyelinating disease, the basis of neurological disability is due primarily to axonal loss. However, both processes are strongly interlinked, being inflammatory damage the main responsible of both demyelination and axonal loss and being remyelination the most promising neuroprotective strategy. New imaging studies in patients with MS using brain magnetic resonance imaging (MRI) or retinal optic coherence tomography (OCT) has revealed that after acute inflammation (e.g. a relapse of optic neuritis), both axons and the soma of the projecting neurons are damaged in the first weeks and almost no further damage is observed after 3 months, defining after this time the severity of the resulting permanent disability. Considering that pathological studies has shown that most of the neuroaxonal damage is due to acute inflammation, imaging studies has shown that most of the neuroaxonal damage (retina or brain atrophy) is being produced in the first 5 years of the disease. Therefore, the disease activity (relapses) at the early stages of the disease defines the lesion burden of the CNS and the risk of suffering a more severe disease in the long term, with higher levels of disability. With aging and longer disease duration, although relapses decrease significantly, chronic compartmentalized inflammation inside the CNS seems to increase the neuroaxonal damage. Regarding the contribution of neurodegenerative processes to neuroaxonal damage, imaging studies has revealed that retrograde degeneration and transynaptic degeneration can operate over long periods after acute damage, although the extent of their contribution is limited compared with the damage of the CNS produced at earlier stages. Finally, in order to develop new remyelinating, neuroprotective or regenerative therapies for MS or other brain diseases, it will require new biomarkers to assess the efficacy of the drugs in clinical trials. Although we still lack validated biomarkers for such processes, imaging the CNS with MRI or OCT combined with electrophysiology (e.g. the latencies of the visual evoked potentials are very sensitive for the de/remyelination of the optic nerve) and even some molecular markers (e.g. neurofilaments), provides the opportunity of monitoring such biological processes and the efficacy of drugs aimed to restore the CNS damage.
This seminar is partially supported by the Campus of Biscay of the UPV/EHU.