Philip Benjamin MBBS, Presenter: Nothing to Disclose

Andrew J. Lawrence, Abstract Co-Author: Nothing to Disclose

Andrew Mackinnon MD, MRCP, Abstract Co-Author: Nothing to Disclose

Eva Zeestraten, Abstract Co-Author: Nothing to Disclose

Brain volume and white matter lesions have been suggested as a surrogate marker of disease progression for use in clinical trials in cerebral small vessel disease (SVD). If these MRI findings are to be used as a reliable surrogate markers in clinical trials, power calculations are required not only to determine the sample sizes needed to show therapeutic efficacy, but also to help identify the most feasible outcome measures. We used serial brain magnetic resonance imaging (MRI) to prospectively evaluate the rate of brain atrophy and white matter hyperintensity (WMH) growth in SVD and investigated the sample sizes required to demonstrate a reduction in the rate of disease progression.

Data from the prospective SCANS study of patients with SVD was used for this analysis (n=121). SVD was defined as a clinical lacunar stroke with an anatomically corresponding MRI defined lacunar stroke as well as confluent leukoaraiosis. Multimodal MRI was performed yearly for a period of 3 years. Percentage whole brain volume change relative to baseline was measured directly using a registration based method (SIENA). WMHs were segmented and volumes were  calculated at each timepoint in individual subject space by summing binarised corrected segmentations.

For a 3 year trial duration the mean (SD) rate of whole brain atrophy was -1.985%(1.958). The mean (SD) percentage growth of WMH (WMHp) was 1.912% (1.168). Based on these figures, to detect a 25%, 20% and 15% treatment effect on brain atrophy at 80% power the minimum sample sizes required were 494 (247 in each arm), 766 (383 in each arm) and 1358 (679 in each arm) respectively. For WMH growth, the minimum sample size required to detect a 25%, 20% and 15% treatment effect at 80% power was 172 (86 in each arm), 270 (135 in each arm) and 476 (238 in each arm) respectively.

Whole brain volume change is measurable prospectively in SVD and is higher than the reported rate of atrophy in normal ageing. Whole brain volume change is therefore a feasible outcome measure for use in clinical trials in SVD although sample sizes are still moderate. Considerably smaller sample sizes are required if WMH volume is used as an outcome measure, however the impact of WMHs on cognitive impairment and disability in SVD remains uncertain.

Markers of disease progression in cerebral small vessel disease

Benjamin, P, Lawrence, A, Mackinnon, A, Zeestraten, E, Progression of Brain Atrophy and White Matter Hyperintensities in Cerebral Small Vessel Disease. Estimates of Sample Size to Detect Treatment Effects.  Radiological Society of North America 2014 Scientific Assembly and Annual Meeting, - ,Chicago IL. http://archive.rsna.org/2014/14019631.html