The rate of brain volume loss (BVL) from neurodegeneration and axonal loss is estimated to be two-fold higher in MS patients compared to age-matched healthy controls, and is an important determinant of cognitive dysfunction, according to the results of a new meta-analysis.

In a longitudinal analysis of MRIs over a mean 7.5 years of follow-up, the estimated percent brain volume change (PBVC) was -0.51%/year in MS patients compared to -0.27% for healthy controls (De Stefano et al. J Neurol Neurosurg Psychiatry 2016;87:93-99).

A systematic review has also analysed data from 18 studies of BVL and cognitive outcomes (Vollmer et al. Neurol Sci 2016;37:165-179). Overall, 6 of 6 studies reported a significant association between BVL and a decline in Symbol Digit Modalities Test (SDMT) scores, 12 of 14 studies found an association between BVL and Paced Auditory Serial Addition Test (PASAT) scores, and 6 of 7 studies found that BVL was associated with lower MS Functional Composite (MSFC) scores.

Of particular importance to cognition is grey-matter atrophy, notably of the thalamus and neocortex (Benedict et al. Mult Scler 2013;19:1478-1484. Calabrese et al. Arch Neurol 2009;66:1144-1150). Cortical volume has been reported to be the best predictor of cognitive efficiency, while thalamic volume is predictive of memory function (Pinter et al. Neuroimage Clin 2015;7:715-720).

Vollmer and colleagues concluded that BVL is a critical component of MS progression, and treatment decisions should be based on the need to minimize BVL and preserve cognitive functioning.

Comment
Dr. François Grand’Maison: The prevention of neurodegeneration as measured by BVL is increasingly an objective of treatment in early MS, hence NEDA-4 (absence of relapses, EDSS progression, MRI activity and atrophy). In the 1990s, the focus had been on preventing relapses and, in the 2000s, on preventing new T2 lesions.

Clearly, as championed by Vollmer and colleagues, brain reserve must be maintained in an attempt to preserve compensatory mechanisms and delay secondary progression. They recommend a combination of early effective DMTs, exercise and diet for all MS patients, including primary-progressive patients. They argue that PPMS and RRMS are the same disease genetically and pathologically. However, there is a window of opportunity to prevent progression with current therapies, as demonstrated by the alemtuzumab Cambridge cohort. In that study, most SPMS patients continued to progress in spite of treatment whereas most RRMS patients were stable or improved (Coles et al. J Neurol 2006;253:98-108). Unfortunately, there are no data on the effects of treatment of recently diagnosed PPMS.