Detecting neurodegenerative pathology in multiple sclerosis before irreversible brain tissue loss sets in

Abstract

BackgroundMultiple sclerosis (MS) is a complex chronic inflammatory and degenerative disorder of the central nervous system. Accelerated brain volume loss, or also termed atrophy, is currently emerging as a popular imaging marker of neurodegeneration in affected patients, but, unfortunately, can only be reliably interpreted at the time when irreversible tissue damage likely has already occurred. Timing of treatment decisions based on brain atrophy may therefore be viewed as suboptimal.Main bodyThis Narrative Review focuses on alternative techniques with the potential of detecting neurodegenerative events in the brain of subjects with MS prior to the atrophic stage. First, metabolic and molecular imaging provide the opportunity to identify early subcellular changes associated with energy dysfunction, which is an assumed core mechanism of axonal degeneration in MS. Second, cerebral hypoperfusion has been observed throughout the entire clinical spectrum of the disorder but it remains an open question whether this serves as an alternative marker of reduced metabolic activity, or exists as an independent contributing process, mediated by endothelin-1 hyperexpression. Third, both metabolic and perfusion alterations may lead to repercussions at the level of network performance and structural connectivity, respectively assessable by functional and diffusion tensor imaging. Fourth and finally, elevated body fluid levels of neurofilaments are gaining interest as a biochemical mirror of axonal damage in a wide range of neurological conditions, with early rises in patients with MS appearing to be predictive of future brain atrophy.ConclusionsRecent findings from the fields of advanced neuroradiology and neurochemistry provide the promising prospect of demonstrating degenerative brain pathology in patients with MS before atrophy has installed. Although the overall level of evidence on the presented topic is still preliminary, this Review may pave the way for further longitudinal and multimodal studies exploring the relationships between the abovementioned measures, possibly leading to novel insights in early disease mechanisms and therapeutic intervention strategies.

Cognitive Decline in Multiple Sclerosis Is Related to the Progression of Retinal Atrophy and Presence of Oligoclonal Bands: A 5-Year Follow-Up Study

“…The course of the disease is usually relapsing-remitting from onset (1,3). Studies have also shown the involvement of both inflammatory and neurodegenerative processes from the early stages of the disease (2,4,5). However, it remains unknown whether early degeneration is an independent process in MS or whether it is secondary to inflammation (2,5).…”

Cognitive Impairment and Brain Reorganization in MS: Underlying Mechanisms and the Role of Neurorehabilitation

“…and altered network connectivity, could serve toward this goal. Therefore, there is an urgent need to identify this high-risk subpopulation of pwMS, and, since it is not possible to be achieved early in the disease course through clinical and conventional neuroimaging grounds only (88), we have to find biomarkers (molecular, metabolic, imaging, and clinical) to detect earlier CNS pathology "before structural tissue damage has become definite" (89). Impaired cognition is associated with early increases in FC, which then decreases due to the exhaustion of compensating mechanisms, forming the "inverted U" rs-FC curve (89).…”

“…Therefore, there is an urgent need to identify this high-risk subpopulation of pwMS, and, since it is not possible to be achieved early in the disease course through clinical and conventional neuroimaging grounds only (88), we have to find biomarkers (molecular, metabolic, imaging, and clinical) to detect earlier CNS pathology "before structural tissue damage has become definite" (89). Impaired cognition is associated with early increases in FC, which then decreases due to the exhaustion of compensating mechanisms, forming the "inverted U" rs-FC curve (89). Indeed, patients who converted to MS exhibited "significantly greater network connectivity at baseline than nonconverters" and a "subsequent connectivity loss over time, not observed in the non-converters' network" (30,90).…”

Approved and Emerging Disease Modifying Therapies on Neurodegeneration in Multiple Sclerosis

“…While in most cases increased BVL or a high rate of BVL can indicate a poor prognosis, it is difficult to generalize all such instances under the same trend [ 9 ]. Several studies have used other imaging biomarkers for axonal loss, such as thalamic volume, gray matter fraction, corpus callosum area, “black holes,” and spinal cord atrophy to predict the course of the disease as is seen using clinical measures [ 3 , 10 , 11 ]. However, BVL is the preferred biomarker to assess neurodegeneration and even though its use has not been implemented in common clinical practice, it is used mainly in the research setting.…”