Evaluating Alzheimer's disease progression using rate of regional hippocampal atrophy

Abstract

Alzheimer's disease (AD) is characterized by neurofibrillary tangle and neuropil thread deposition, which ultimately results in neuronal loss. A large number of magnetic resonance imaging studies have reported a smaller hippocampus in AD patients as compared to healthy elderlies. Even though this difference is often interpreted as atrophy, it is only an indirect measurement. A more direct way of measuring the atrophy is to use repeated MRIs within the same individual. Even though several groups have used this appropriate approach, the pattern of hippocampal atrophy still remains unclear and difficult to relate to underlying pathophysiology. Here, in this longitudinal study, we aimed to map hippocampal atrophy rates in patients with AD, mild cognitive impairment (MCI) and elderly controls. Data consisted of two MRI scans for each subject. The symmetric deformation field between the first and the second MRI was computed and mapped onto the three-dimensional hippocampal surface. The pattern of atrophy rate was similar in all three groups, but the rate was significantly higher in patients with AD than in control subjects. We also found higher atrophy rates in progressive MCI patients as compared to stable MCI, particularly in the antero-lateral portion of the right hippocampus. Importantly, the regions showing the highest atrophy rate correspond to those that were described to have the highest burden of tau deposition. Our results show that local hippocampal atrophy rate is a reliable biomarker of disease stage and progression and could also be considered as a method to objectively evaluate treatment effects.

Figure 1. Illustration of the methods.

(A) On the left side of this panel, we illustrate the triangulated surface of the template hippocampus and the manually defined seven points (in red). On the right side, the seven points drawn on the subject’s hippocampus are shown in blue, and the ICP algorithm is illustrated which minimises the sum of distances (di) between the red and blue points. (B) Illustration of the deformation field mapping onto the triangulated hippocampal surface resulting in different colours for inward (blue) and outward (orange) deformation.

Figure 2. Mean atrophy rate.

Mean atrophy rate in mm/year for the left and right hippocampi in patients with AD (A), MCI (B) and controls (C). On the right hippocampus, projected borders of subfields CA1, CA2–3, dentate gyrus (DG) and subiculum (Sub) are indicated with grey outlines.

Figure 3. Significant atrophy rates.

Statistical maps showing the -log(p-values) for significant (p0.05 corr.) atrophy rates for the left and right hippocampi in patients with AD (A), MCI (B) and controls (C). Significance level (p0.05 corr.) is indicated in the colour bar.

Figure 4. Statistical maps of atrophy rate differences among groups.

Statistical maps showing significantly higher atrophy rate in AD versus control (A), MCI versus control (B), and AD versus MCI (C). Significance level (p0.05 corr.) is indicated in the colour bar.

Figure 5. ROI analysis of atrophy rates in progressive and stable MCI.

Bar plots of atrophy rates in the left and right hippocampal ROIs (shown in Figure 4) for pMCI (n = 39) and sMCI (n = 44). *: p0.05, **: p0.001 Bonferroni adjusted p-values.