Longitudinal MRI atrophy biomarkers: relationship to conversion in the ADNI cohort

Abstract

Atrophic changes in early Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI) have been proposed as biomarkers for detection and monitoring. We analyzed magnetic resonance imaging (MRI) atrophy rate from baseline to 1 year in 4 groups of participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI): AD (n = 152), converters from MCI to probable AD (MCI-C, n = 60), stable MCI (MCI-S, n = 261), and healthy controls (HC, n = 200). Scans were analyzed using multiple methods, including voxel-based morphometry (VBM), regions of interest (ROIs), and automated parcellation, permitting comparison of annual percent change (APC) in neurodegeneration markers. Effect sizes and the sample required to detect 25% reduction in atrophy rates were calculated. The influence of APOE genotype on APC was also evaluated. AD patients and converters from MCI to probable AD demonstrated high atrophy APCs across regions compared with minimal change in healthy controls. Stable MCI subjects showed intermediate atrophy rates. APOE genotype was associated with APC in key regions. In sum, APC rates are influenced by APOE genotype, imminent MCI to AD conversion, and AD-related neurodegeneration.

Figure 1. Group Differences in Pattern of Reduction in Grey Matter (GM) Density over 12 Months in the ADNI Cohort

Time x diagnosis group interactions demonstrate differences in atrophy progression reflected by reduction in GM density from baseline to 1-year in the ADNI cohort (n=643*; 143 AD, 57 MCI-C, 253 MCI-S, 190 HC). Interaction contrasts are displayed at a threshold of p<0.0001 (unc.) with a minimum cluster size (k) = 27 voxels. Cross-sections in (a–e) are (0, −9, 0, coronal) and (0, −23, −16, axial), left to right. Cross-section in (f) is (34, −29, 64, coronal). (*30 participants removed from comparisons due to failed image processing)

Figure 2. Annual Percent Change (APC) and Decline over 12 months of Selected MTL Imaging Biomarkers

Plots of the mean APC in (a, b) hippocampal GM density and (c, d) GM volume extracted using a hippocampal ROI extracted using a template derived on an independent sample of 40 healthy elderly controls (McHugh, et al., 2007, Saykin, et al., 2006, Shen, et al., 2010) and from MarsBaR, respectively (n=643*; 143 AD, 57 MCI-C, 253 MCI-S, 190 HC). AD and MCI-C participants show significantly greater APC in hippocampal GM density and hippocampal GM volume relative to MCI-S and HC. The APC in (e) hippocampal volume (n=673; 152 AD, 60 MCI-C, 261 MCI-S, 200 HC) extracted using Freesurfer showed a similar trend. (*30 participants removed from comparisons due to failed image processing)

Figure 3. Annual Percent Change (APC) of Entorhinal Cortex, Mean Frontal, Parietal, and Temporal Lobe Cortical Thickness Measures

APC in (a) entorhinal cortex thickness, and mean (b) frontal, (c) parietal, and (d) temporal lobar cortical thickness are significantly different across groups (n=673; 152 AD, 60 MCI-C, 261 MCI-S, 200 HC).

Figure 4. Annual Percent Change (APC) of Mean Frontal, Parietal, and Temporal Lobe GM Density and Volume Measures

The APC in mean frontal lobe (a) GM density and (b) GM volume, mean parietal lobe (c) GM density and (d) GM volume, and mean temporal lobe (e) GM density and (f) GM volume are significantly different across groups (n=643*; 143 AD, 57 MCI-C, 253 MCI-S, 190 HC; *30 participants removed due to failed image processing).

Figure 5. Effect Sizes of Comparisons between AD & HC and MCI-C & MCI-S for Selected Imaging Biomarkers

The effect sizes for selected baseline and APC values for the comparison of (a) AD and HC participants and (b) MCI-C and MCI-S participants are shown. Baseline MTL regions had the greatest effect sizes when comparing AD and HC, while APC in MTL regions demonstrated the greatest effect sizes in the MCI-C vs. MCI-S comparison. (n=643*; 143 AD, 57 MCI-C, 253 MCI-S, 190 HC; *30 participants removed due to failed image processing)

Figure 6. Impact of APOE ε4 Genotype on Annual Percent Change (APC) of Selected MTL Measures

The APC in bilateral mean hippocampal (a) GM density and (b) GM volume (n=643*; 143 AD, 57 MCI-C, 253 MCI-S, 190 HC), extracted using an independent sample of 40 healthy elderly controls (McHugh, et al., 2007, Saykin, et al., 2006, Shen, et al., 2010), as well as (c) hippocampal volume, and (d) EC thickness extracted using automated parcellation (n=673; 152 AD, 60 MCI-C, 261 MCI-S, 200 HC) show a significant effect of both diagnostic group and APOE ε4 genotype. (*30 participants removed due to failed image processing)