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Brain atrophy in multiple sclerosis: How deep must we go?

Brain atrophy is a prominent feature of multiple sclerosis (MS). It is often seen at disease presentation, and current data suggest that it proceeds inexorably—even in progressive disease when new inflammatory lesions are rare. On a population level, there is evidence that more severe atrophy is associated with accelerated disability accumulation. Chronic inflammation and demyelination in MS can cause axonal destruction and neuronal death, which clearly can result in brain atrophy. Current approved treatments for MS, which reduce new inflammatory lesion formation, may delay but do not always prevent progressive disease, nor do they fully arrest brain atrophy. Thus, there is a need for new neuroprotective therapies, and atrophy is one attractive outcome measure for trials of these therapies. To date, whole-brain volume has been most commonly been used as a surrogate marker of atrophy in MS due to relative ease of measurement; however, there is growing evidence that gray matter volume loss is more pronounced than that of white matter and may have a stronger association with disability. The thalamus may be particularly susceptible to neurodegeneration due to the effects of demyelinating lesions within the thalamus as well as changes in thalamic input and outflow tracts resulting from cortical and white matter demyelination. Recently, improvements in image-processing methodologies that allow for improved automatic segmentation of different brain regions have made measurement of atrophy in specific brain regions more feasible on a large scale. In this issue, Eshaghi et al and Azevedo et al measure volume loss in specific gray matter regions longitudinally in people with MS with the aim of further characterizing gray matter atrophy and establishing it as a feasible outcome measure for future studies. Eshaghi et al’s large, multicenter, longitudinal study used a registration-based method to measure the volume of different brain regions and found that the rate of volume decline is fastest in the deep gray matter. They found no association between gray matter volume and T2/fluid-attenuated inversion recovery lesion load, suggesting 2 at least partially independent pathophysiologies—although certainly the relationship between lesion load and volume loss need not, in principle, be linear or even monotonic. Interestingly, rates of volume decline were similar between individuals with clinically relapsing and progressive disease, and all clinical phenotypes showed similar spatial patterns of gray matter loss. The authors also found that lower baseline gray matter volume was associated with higher disability and that the rate of deep gray matter atrophy, but not that of other regions, was associated with a small but significant worsening of disability. There was no difference in the rate of atrophy in untreated individuals versus those taking diseasemodifying therapies (predominantly first-line injectable therapies). Finally, they found that deep gray matter volume did not have prognostic value at the individual level. Azevedo et al looked more specifically at thalamic atrophy in a single-center study of relapse-onset MS cases. They found that the average rate of thalamic atrophy was higher in MS than in healthy controls, and that rates of atrophy determined by two different image-processing methods—one registration-based and one cross-sectional—were very similar. Similar to Eshaghi et al, they found a small but significant association between volume loss and worsening disability, and that disease-modifying therapy exposure did not impact thalamic volume. They also found that the rate of atrophy was constant over disease epochs and clinical phenotypes, suggesting—consistent with the vast preponderance of credible data—that relapsing–remitting, primary progressive, and secondary progressive MS are part of a pathophysiologic continuum rather than separate entities, and providing further rationale for targeting neurodegeneration early on in disease. Lastly, the authors used simulations to estimate sample size for future studies using thalamic atrophy as an outcome measure and estimated that approximately 100 subjects per arm, an achievable number for phase 2 trials, would be sufficient to show a clinically reasonable therapeutic effect. Together, these studies provide strong evidence that thalamic volume, and deep gray matter volume more broadly, are dramatically affected in MS. The thalamus appears particularly susceptible to atrophy even in healthy subjects, the reasons for which are not entirely clear but may be related to its position as a hub that can be affected by damage to many different parts of the brain. Further investigation into the rate and role of atrophy of other deep gray matter nuclei, in particular the caudate nucleus, is also warranted given Eshaghi et al’s results. Reassuringly, Eshaghi et al also demonstrate that thalamic volume can be measured reliably using available semiautomated techniques in multicenter studies with variable imaging protocols, consistent with other recent results. Although it is reasonable to hypothesize that stopping thalamic or even whole-brain atrophy would prevent accumulation of disability in MS, this has certainly not been proven. Whereas lower thalamic volume and higher rates of atrophy