Tuesday, 17 February 2015

Brain volume loss correlates with disability

Radue EW, Barkhof F, Kappos L, Sprenger T, Häring DA, de Vera A, von Rosenstiel P, Bright JR, Francis G, Cohen JA. Correlation between brain volume loss and clinical and MRI outcomes in multiple sclerosis. Neurology. 2015 Jan . pii: 10.1212/WNL.0000000000001281. [Epub ahead of print]

OBJECTIVE: We investigated the determinants and clinical correlations of MRI-detected brain volume loss (BVL) among patients with relapsing-remitting multiple sclerosis from the phase 3 trials of fingolimod: FREEDOMS, FREEDOMS II, and TRANSFORMS.
METHODS: Post hoc analyses were conducted in the intent-to-treat populations from each trial and in a combined dataset of 3,635 patients from the trials and their extensions. The relationship between brain volume changes and demographic, clinical, and MRI parameters was studied in pairwise correlations (Pearson) and in multiple regression models. The relative frequency of confirmed disability progression was evaluated in the combined dataset by strata of concurrent BVL at up to 4 years.
RESULTS:Increasing age, disease duration, T2 lesion volume, T1-hypointense lesion volume, and disability were associated with reduced brain volume (p < 0.001, all). The strongest individual baseline predictors of on-study BVL were T2 lesion volume, gadolinium-enhancing lesion count, and T1-hypointense lesion volume (p < 0.01, all). During each study, BVL correlated most strongly with cumulative gadolinium-enhancing lesion count, new/enlarged T2 lesion count (p < 0.001, both), and number of confirmed on-study relapses (p < 0.01). Over 4 years in the combined dataset (mean exposure to study drug, 2.4 years), confirmed disability progression was most frequent in patients with greatest BVL.
CONCLUSIONS:Rate of BVL in patients during the fingolimod trials correlated with disease severity at baseline and new disease 

activity on study, and was associated with worsening disability
A commenter recently asked about why brain volume loss was not used as an outcome measure, it is and I said that I think it may have problems but then you get the imagers saying hey it is fantastic and it correlates with disability, such as in this study.
One problem of brain volume  as it can shrink when anti-inflammation occurs, so ProfG argues that there needs to be a re-baseline a year after the potent DMT to allow this to happen and then you can see if nerve loss is occuring 

Should I eat cake...well happy to we all like a bit of cake....but I believe this could be a real problem because they are associating brain shrinkage with nerve loss. Yes, this is the case but brain atrophy is probably missing loads of brain loss because astrocytes and other cells are filling the space created by the nerve loss. In the spinal cord it is very clear this is happening.
In the mice the spinal cord volume drops by less than about 5% (Based on histology where water has been removed from the system) during EAE, but there may be 40-60% nerve loss. This is surely going to occur in MS too. In the case above the cords shrink by over 10% in progressive MS in RRMS about 5% what is the actual new loss are we missing stuff.

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