Preventing brain atrophy should be the gold standard of effective therapy in multiple sclerosis (after the first year of treatment): Commentary

Abstract

MULTIPLE SCLEROSIS MSJ JOURNALCerebral atrophy has been used for centuries by pathologists as a marker of the loss of cerebral tissue due to injury or degeneration, and the tissue damage and loss associated with atrophy has been well documented. Thus, atrophy as a marker of neurodegeneration has incontrovertible face validity, at least over the long term. So, why is the use of whole brain atrophy as an outcome measure in multiple sclerosis (MS) the subject of debate?Magnetic resonance imaging (MRI)-based computational methods provide sensitive and reproducible measures of brain volumes that are capable of detecting changes on the order of 0.2%: changes that are much smaller than those described at the time of postmortem examination. The interpretation of such small changes, particularly over the short term, involves subtleties that are not relevant over the long term. For example, small physiological fluctuations, due to shifts in water, 1 can produce brain volume fluctuations of this order. Furthermore, the accelerated atrophy seen after initiation of some anti-inflammatory therapies, often referred to as pseudoatrophy, also complicates the interpretation of changes in brain volume. Although the pathophysiological mechanisms responsible for pseudoatrophy are still unclear, pseudoatrophy appears to be related to the nature of the anti-inflammatory therapy and the amount of inflammation present at the start of therapy.Despite these limitations, as argued by Rudick and Fisher, a substantial body of evidence supports the use of whole brain atrophy, at least after the first year following initiation of anti-inflammatory therapy, as a marker of the end-stage of tissue injury of whatever sort and, as such, as a candidate for the best MRI marker of effective therapy in MS.Filippi and Rocca also value atrophy as an outcome measure but, because it is an end-stage process, argue for outcome measures that provide a more pathologically specific indication of the processes that contribute to tissue loss, including gray matter (GM) atrophy, magnetization transfer imaging (MTI), diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (MRS). Each of these measures has advantages and disadvantages.Since GM is less inflamed than white matter (WM) in MS, it should be less susceptible to pseudoatrophy. However, the correct segmentation of GM on MRI is challenging 2 and less precise than the segmentation of whole brain. Changes in magnetization transfer have relative specificity for changes in myelin density, which is of particular interest in MS. However, the changes that occur in whole brain magnetization transfer are extremely small 3 and, as in the case of whole brain atrophy, the interpretation of such small changes may involve subtleties related not only to remyelination but also to other physiological changes that affect myelin density, such as changes in brain water or the relative partial volume of other cell types. DTI seems to be less pathologically specific for axons or myelin than one would like. MRS is patho...

The Effect of Disease-Modifying Drugs on Brain Atrophy in Relapsing-Remitting Multiple Sclerosis: A Meta-Analysis

“…Evaluating the prevention of brain atrophy as a reliable outcome measure of drug effectiveness is currently an active topic in MS research [ 6 , 23 , 7 ]. Previously, assessment of drug effectiveness mainly belongs to changes for T2 lesion load, gadolinium-enhancing lesions and T1 black hole lesions.…”

“…Although inflammation and focal demyelination are the pathological hallmarks of MS, the occurrence of brain atrophy is currently a classical characteristic of cross-sectional and longitudinal imaging studies beginning at the earliest stage of the disease and proceeding throughout the disease course [ 5 ]. Because brain atrophy represents the net effect of primary disease-related pathophysiological processes, including demyelination, axonal loss and neurodegeneration, quantifying brain volume changes may represent a promising MRI outcome measure to evaluate the expected or unexpected (neuroprotective) effects of DMDs [ 6 , 7 ].…”

The importance of studying sex differences in disease: The example of multiple sclerosis

“…Compared to the pretreatment phase, there was slowing in the rate of whole brain atrophy by 67% during testosterone treatment (Sicotte, Giesser et al 2007). Whole brain atrophy in MS is driven by gray matter atrophy, and gray matter atrophy has been used as a biomarker for permanent disability (Pirko, Lucchinetti et al 2007, Fisniku, Chard et al 2008, Rudick, Lee et al 2009, Arnold and De Stefano 2013, Hofstetter, Naegelin et al 2014, Lavorgna, Bonavita et al 2014, Sormani, Arnold et al 2014). Thus, further analysis of the same MRIs by other investigators focused on gray matter.…”

Correlation between brain volume change and T2 relaxation time induced by dehydration and rehydration: Implications for monitoring atrophy in clinical studies

“…While the effect of shifting hydration level is typically uncontrolled and somewhat random, thus adding noise, the pseudoatrophy effect adds bias because a particular group, e.g., treated vs. placebo, can be more affected. Overall, the pseudoatrophy effect complicates the interpretation of brain atrophy results as it counteracts or even overshadows the expected treatment effect in clinical trials and has led some to assess the treatment effect on atrophy only from the second year on ( Arnold and De Stefano, 2013 ; Miller et al, 2007 ; Rudick et al, 1999 ).…”