Article

Unbiased Tensor-Based Morphometry: Improved Robustness and Sample Size Estimates for Alzheimer's Disease Clinical Trials.

Imaging Genetics Center, Laboratory of Neuro Imaging, Dept. of Neurology, UCLA School of Medicine, Los Angeles, CA.
NeuroImage (Impact Factor: 6.36). 11/2012; 66. DOI: 10.1016/j.neuroimage.2012.10.086
Source: PubMed

ABSTRACT Various neuroimaging measures are being evaluated for tracking Alzheimer's disease progression in therapeutic trials, including measures of structural brain change based on repeated scanning of patients with magnetic resonance imaging (MRI). Methods to compute brain change must be robust to scan quality. Biases may arise if any scans are thrown out, as this can lead to the true changes being overestimated or underestimated. Here we analyzed the full ADNI-1 MRI dataset and assessed several sources of bias that can arise when tracking brain changes with structural brain imaging methods, as part of a pipeline for tensor-based morphometry (TBM). In all healthy subjects who completed MRI scanning at screening, 6, 12, and 24months, brain atrophy was essentially linear with no detectable bias in longitudinal measures. In power analyses for clinical trials based on these change measures, only 39AD and 95 MCI subjects were needed for a 24-month trial to detect a 25% reduction in the average rate of change using a two-sided test (α=0.05, power=80%). Further sample size reductions were achieved by stratifying the data into Apolipoprotein E (ApoE) ε4 carriers vs. non-carriers. We show how selective data exclusion affects sample size estimates, motivating an objective comparison of different analysis techniques based on statistical power and robustness. TBM is an unbiased, robust, high-throughput imaging surrogate marker for large, multi-site neuroimaging studies and clinical trials of AD and MCI.

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Available from: Clifford R Jack, Jun 16, 2014
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    • "In particular, local differences in brain tissue volume are evaluated by computing highdimensional nonlinear deformations to adjust the anatomy of each individual to match a custom-built group-average template and successively comparing maps of the Jacobian determinant (|J|) of the deformation fields in order to estimate the degree of tissue contraction/expansion at each location/ voxel (Ashburner and Friston, 2003; Chung et al., 2001; Fox et al., 2001; Freeborough and Fox, 1998; Hua et al., 2009, 2011, 2013; Riddle et al., 2004; Studholme et al., 2001; Thompson et al., 2000). TBM has been proven to be an unbiased, robust, high-throughput imaging marker in Alzheimer's disease (AD) and MCI and is particularly suited for longitudinal studies (Hua et al., 2013). "
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