Shape abnormalities of subcortical and ventricular structures in mild cognitive impairment and Alzheimer's disease: detecting, quantifying, and predicting

Abstract

This article assesses the feasibility of using shape information to detect and quantify the subcortical and ventricular structural changes in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients. We first demonstrate structural shape abnormalities in MCI and AD as compared with healthy controls (HC). Exploring the development to AD, we then divide the MCI participants into two subgroups based on longitudinal clinical information: (1) MCI patients who remained stable; (2) MCI patients who converted to AD over time. We focus on seven structures (amygdala, hippocampus, thalamus, caudate, putamen, globus pallidus, and lateral ventricles) in 754 MR scans (210 HC, 369 MCI of which 151 converted to AD over time, and 175 AD). The hippocampus and amygdala were further subsegmented based on high field 0.8 mm isotropic 7.0T scans for finer exploration. For MCI and AD, prominent ventricular expansions were detected and we found that these patients had strongest hippocampal atrophy occurring at CA1 and strongest amygdala atrophy at the basolateral complex. Mild atrophy in basal ganglia structures was also detected in MCI and AD. Stronger atrophy in the amygdala and hippocampus, and greater expansion in ventricles was observed in MCI converters, relative to those MCI who remained stable. Furthermore, we performed principal component analysis on a linear shape space of each structure. A subsequent linear discriminant analysis on the principal component values of hippocampus, amygdala, and ventricle leads to correct classification of 88% HC subjects and 86% AD subjects.

Keywords: Alzheimer's disease; high field; large deformation diffeomorphic metric mapping; lateral ventricles; mild cognitive impairment; shape abnormality; subcortical structures; subsegmentations.

Figure 1

This figure shows the mean and the standard deviations of the Kappa Overlaps between the segmentations from the de‐noising pipeline and the original FreeSurfer segmented volumes. Black and white bars respectively denote left and right structures. Vent: lateral ventricles, thal: thalamus, caud: caudate, puta: putamen, pall: pallidum, hipp: hippocampus, amyg: amygdala.

Figure 2

This figure summarizes the procedure of selecting the optimal LDA classifier based on the PCs from all the fourteen structures, including three steps. Step 1 is to create all the combinations of PCs, resulting in a total of 127. Step 2 is to test the mean classification rate for each set of PCs, based on leave‐one‐out LDA. Step 3 is to select the LDA classifier with the highest mean correct classification rate in Step 2. Hi: hippocampus, am: amygdala, vl: lateral ventricle, th: thalamus, pu: putamen, pa: pallidum, ca: caudate.

Figure 3

This figure summarizes the leave‐one‐out cross‐validation procedure of testing the true classification rate that we would be able to yield using our procedure.

Figure 4

This figure illustrates the scheme of projecting the three subsegmentations of left hippocampus from a 7.0T high‐field MRI image to the template surface, including: manually segmenting the left hippocampus of the 7.0T MR scan into three regions—CA1, CA2+CA3+DG, and subiculum; generating the triangulated surface for the left hippocampus of the 7.0T data; projecting the three subregions of the volume onto the mother hippocampus surface; performing LDDMM‐surface mapping between the 7T hippocampus surface and our template surface; transferring the three subregions onto our template left hippocampus surface. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 5

This figure illustrates the subsegmentations of the left hippocampus (a), the right hippocampus (b), and the left amygdala (c) by projecting the boundaries onto the corresponding mother surface. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 6

a) and b) respectively show the group shape differences between HC and AD, HC and MCI, as well as MCI and AD measured in left and right amygdala. Both superior (left) and inferior (right) views are displayed for each group comparison. Negative color scale values indicate surface expansion in the latter group, and positive values indicate atrophy. The scale value quantifies the ratio of the local volume of the former group at a particular location to that of the latter group in logarithmic scale. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 7

a) and b) demonstrate the group shape differences between HC and AD, HC and MCI, MCI and AD of hippocampus in both hemispheres. Both superior (left) and inferior (right) views are displayed for each group comparison. Negative color scale values indicate surface expansion in the latter group, and positive values indicate atrophy. The scale value measures the ratio of the local volume of the former group to that of the latter group in logarithmic scale. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 8

Group shape differences detected in the lateral ventricles in both hemispheres. Colors corresponding to negative values indicate local expansion of surfaces in the latter group whereas positive values imply atrophy, compared with the former group. The more negative the value, the more prominent the expansion. The scale value measures the ratio of the local volume of the former group to that of the latter group in logarithmic scale. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 9

Surface deformation differences between HC and AD, HC and MCI, as well as MCI and AD in basal ganglia regions and the thalamus. Colors corresponding to negative values indicate local expansion of surfaces in the latter group, compared with the former group, whereas positive indicates atrophy in the latter group. The scale value quantifies the ratio of the local volume of the former group to that of the latter group in logarithmic scale. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 10

Group differences, between every two of the three groups, measured in the surfaces of all the seven structures in the left hemisphere. Warm color denotes regions where the corresponding structure has significant atrophy in the latter group when compared with the former group. Cool color suggests local expansion of the structure in the latter group when compared with the former group. Am: amygdala, hi: hippocampus, vent: lateral ventricle, thal: thalamus, puta: putamen, pal: globus pallidus, caud: caudate. The scale value measures the ratio of the local volume around a particular vertex of the former group to that of the latter group in logarithmic scale. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 11

Group shape variations of all the seven structure in the right hemisphere. Colors corresponding to positive values indicate regions on the structure where there is significant atrophy in the latter group when compared with the former group. Colors corresponding to the negative values suggest local expansion on the structure in the latter group, compared with the former one. Am: amygdala, hi: hippocampus, vent: lateral ventricle, thal: thalamus, puta: putamen, pal: globus pallidus, caud: caudate. The scale value measures the ratio of the local volume of the former group to that of the latter group in the logarithmic scale. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 12

a)–c) respectively show the shape differences between HC and AD, HC and MCI, as well as MCI and AD in the four subregions of left amygdala. Different color scale ranges have been adopted for different comparisons. Warm color indicates regions where atrophy was detected in the latter group as compared with the former group. Cool color indicates local expansion in the region in the latter group when compared with the former group. The scale value measures the ratio of the local volume around each vertex of the template surface measured in the former group to that measured in the latter group in logarithmic scale. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 13

Group shape differences detected in the three subregions of left hippocampus—CA1, subiculum, and CA2+CA3+DG. Colors corresponding to positive values indicate atrophying regions in the latter group while negative indicates expanding regions in the latter group as compared with the former group. The color scale value quantifies the ratio of the local volume of the former group to that of the latter group in the logarithmic scale. Different color scale ranges have been used for different comparisons. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 14

Group shape differences between HC and AD, HC and MCI, as well as MCI and AD, detected respectively in CA1, subiculum, and CA2+CA3+DG of the right hippocampus. Warm color suggests atrophy while cool color suggests expansion in the latter group when compared with the former group. The scale value measures the ratio of the local volume of the former group to that of the latter group in logarithmic scale. Different color scale ranges have been used for different comparisons. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 15

PCA of the initial momentum matrices of the left hippocampus and the left amygdala. Each subfigure shows the permutation test results for group comparison based on the first M PCs that account for 95% of the total variability. Shown are: (1) $\widehat{\mathit{F}}({\mathit{T}}^2)$ value (solid blue line) of each group comparison (total of three comparisons); (2) p = 0.0001 (red dot line), p = 0.001 (blue dot line), and p = 0.05 (black dot line) for reference; (3) p‐value derived from the 40,000 permutation tests (solid green line). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 16

a) and b) display group differences, detected in the left and right amygdala, between the two subtypes MCI‐stable and MCI‐AD. Positive values indicate atrophy in MCI‐AD while negative indicates expansion as compared with MCI‐stable. The scale value measures the ratio of the local volume around each vertex on the template surface of the MCI‐stable group to that of the MCI‐AD in logarithmic scale. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 17

Hippocampal shape differences between MCI‐stable and MCI‐AD. Warm color indicates regions on the hippocampus where significant atrophy has been detected in MCI‐AD when compared with MCI‐stable, whereas cool color indicates expansion. The scale value measures the ratio of the local volume of the hippocampus in MCI‐stable to that in MCI‐AD in the logarithmic scale. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 18

Shape differences between MCI‐stable and MCI‐AD detected on lateral ventricles in both hemispheres. The color corresponding to value 0 suggests no regional shape variation. Colors corresponding to negative values suggest expanding regions in MCI‐AD when compared with MCI‐stable, while those corresponding to positive values indicate atrophy in MCI‐AD. The scale value measures the ratio of the local volume of the lateral ventricle in MCI‐stable to that in MCI‐AD in logarithmic scale. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 19

Shape difference between MCI‐stable and MCI‐AD in terms of the four subregions of left amygdala – basolateral (panel (a)), basomedial (panel (b)), centromedial (panel (c)), and lateral nucleus (panel (d)). Warm color suggests atrophying regions in MCI‐AD while cool color suggests expanding regions when compared with MCI‐stable. The scale value measures the ratio of the local volume of each subregion in MCI‐stable to the local volume in MCI‐AD in logarithmic scale. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 20

Shape differences between MCI‐stable and MCI‐AD detected on the three subregions of the hippocampus. Positive values indicate atrophying regions in MCI‐AD while negative values indicate expanding regions as compared with MCI‐stable. The scale value measures the ratio of the local volume of the former group to that of the latter group in logarithmic scale. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 21

Automated volume segmentations of caudate from FreeSurfer for representative subjects. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]