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. 2020 Jul 30:12:238.
doi: 10.3389/fnagi.2020.00238. eCollection 2020.

Classification and Graphical Analysis of Alzheimer's Disease and Its Prodromal Stage Using Multimodal Features From Structural, Diffusion, and Functional Neuroimaging Data and the APOE Genotype

Affiliations

Classification and Graphical Analysis of Alzheimer's Disease and Its Prodromal Stage Using Multimodal Features From Structural, Diffusion, and Functional Neuroimaging Data and the APOE Genotype

Yubraj Gupta et al. Front Aging Neurosci. .

Abstract

Graphical, voxel, and region-based analysis has become a popular approach to studying neurodegenerative disorders such as Alzheimer's disease (AD) and its prodromal stage [mild cognitive impairment (MCI)]. These methods have been used previously for classification or discrimination of AD in subjects in a prodromal stage called stable MCI (MCIs), which does not convert to AD but remains stable over a period of time, and converting MCI (MCIc), which converts to AD, but the results reported across similar studies are often inconsistent. Furthermore, the classification accuracy for MCIs vs. MCIc is limited. In this study, we propose combining different neuroimaging modalities (sMRI, FDG-PET, AV45-PET, DTI, and rs-fMRI) with the apolipoprotein-E genotype to form a multimodal system for the discrimination of AD, and to increase the classification accuracy. Initially, we used two well-known analyses to extract features from each neuroimage for the discrimination of AD: whole-brain parcelation analysis (or region-based analysis), and voxel-wise analysis (or voxel-based morphometry). We also investigated graphical analysis (nodal and group) for all six binary classification groups (AD vs. HC, MCIs vs. MCIc, AD vs. MCIc, AD vs. MCIs, HC vs. MCIc, and HC vs. MCIs). Data for a total of 129 subjects (33 AD, 30 MCIs, 31 MCIc, and 35 HCs) for each imaging modality were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) homepage. These data also include two APOE genotype data points for the subjects. Moreover, we used the 2-mm AICHA atlas with the NiftyReg registration toolbox to extract 384 brain regions from each PET (FDG and AV45) and sMRI image. For the rs-fMRI images, we used the DPARSF toolbox in MATLAB for the automatic extraction of data and the results for REHO, ALFF, and fALFF. We also used the pyClusterROI script for the automatic parcelation of each rs-fMRI image into 200 brain regions. For the DTI images, we used the FSL (Version 6.0) toolbox for the extraction of fractional anisotropy (FA) images to calculate a tract-based spatial statistic. Moreover, we used the PANDA toolbox to obtain 50 white-matter-region-parcellated FA images on the basis of the 2-mm JHU-ICBM-labeled template atlas. To integrate the different modalities and different complementary information into one form, and to optimize the classifier, we used the multiple kernel learning (MKL) framework. The obtained results indicated that our multimodal approach yields a significant improvement in accuracy over any single modality alone. The areas under the curve obtained by the proposed method were 97.78, 96.94, 95.56, 96.25, 96.67, and 96.59% for AD vs. HC, MCIs vs. MCIc, AD vs. MCIc, AD vs. MCIs, HC vs. MCIc, and HC vs. MCIs binary classification, respectively. Our proposed multimodal method improved the classification result for MCIs vs. MCIc groups compared with the unimodal classification results. Our study found that the (left/right) precentral region was present in all six binary classification groups (this region can be considered the most significant region). Furthermore, using nodal network topology, we found that FDG, AV45-PET, and rs-fMRI were the most important neuroimages, and showed many affected regions relative to other modalities. We also compared our results with recently published results.

Keywords: APOE genotype; AV45-PET; Alzheimer’s disease; DTI; FDG-PET; multimodal fusion; rs-fMRI; sMRI.

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Figures

FIGURE 1
FIGURE 1
Overview of the multimodal framework. (A) Selection of five imaging modalities (sMRI, FDG-PET, AV45-PET, rs-fMRI, and DTI) and APOE genotype. (B) Extraction of regional features using NiftyReg, pyClusterROI, and PANDA toolboxes. (C) Extraction of voxel features using SPM12, DPARSF, and FSL toolboxes. (D) Leave-one-out cross-validation method. (E) Multiple kernel learning. (F) Diagnostic output.
FIGURE 2
FIGURE 2
Pipeline showing feature extraction process for rs-fMRI image.
FIGURE 3
FIGURE 3
MKL classification process.
FIGURE 4
FIGURE 4
ROC curve for (A) AD vs. HC, (B) MCIs vs. MCIc, (C) AD vs. MCIs, (D) AD vs. MCIc, (E) HC vs. MCIs, and (F) HC vs. MCIc using whole-brain parcelation analysis. The red solid line shows the result of a combined-ROI curve with single modality features.
FIGURE 5
FIGURE 5
Cohen’s kappa plot for AD vs. HC, MCIs vs. MCIc, AD vs. MCIs, AD vs. MCIc, HC vs. MCIs, and HC vs. MCIc are grouped using whole-brain parcellation analysis. The above graph clearly shows the benefit of the combined-ROI modality over any single modality.
FIGURE 6
FIGURE 6
Cohen’s kappa plot for AD vs. HC, MCIs vs. MCIc, AD vs. MCIs, AD vs. MCIc, HC vs. MCIs, and HC vs. MCIc are grouped using voxel-wise analysis. The above graph clearly shows the benefit of the combined-VOI modality over any single modality.
FIGURE 7
FIGURE 7
Affected region for (A) AD vs. HC, and (B) MCIs vs. MCIc is shown using AV45-PET image.
FIGURE 8
FIGURE 8
Selected WM voxels for the (A) AD vs. HC, and (B) MCIs vs. MCIc classification using DTI image.
FIGURE 9
FIGURE 9
ROC curves for (A) AD vs. HC, (B) MCIs vs. MCIc, (C) AD vs, MCIs, (D) AD vs, MCIc, (E) HC vs. MCIs, and (F) HC vs. MCIc using voxel-wise (VOI) analysis. The red solid line shows the result of the combined-VOI curve, including all single-modality features.
FIGURE 10
FIGURE 10
ROC curve for (A) AD vs. HC, (B) MCIs vs. MCIc, (C) AD vs, MCIs, (D) AD vs, MCIc, (E) HC vs. MCIs, and (F) HC vs. MCIc using combined-(VOI + ROI). The red solid line shows the result of the combined-(VOI + ROI) curve, with combined-ROI and combined-VOI features.
FIGURE 11
FIGURE 11
Weighted correlation matrices graph (of 384 regions) for AD, HC, MCIs, and MCIc for sMRI biomarkers.
FIGURE 12
FIGURE 12
Differences between the AD vs. HC group in global structural topology. The blue sphere represents characteristic path length, green sphere represents local efficiency, pink sphere represents modularity, purple sphere represents transitivity, and the dark red sphere represents 95% confidence intervals for these measures.
FIGURE 13
FIGURE 13
Differences between the MCIs vs. MCIc group and global structural topology. The blue sphere represents characteristic path length, green sphere represents local efficiency, pink sphere represents modularity, purple sphere represents transitivity, and the dark red sphere represents 95% confidence intervals for these measures.
FIGURE 14
FIGURE 14
Brain maps representing the most predictive regions for distinguishing between the AD vs. HC and MCIs vs. MCIs groups. Differences between groups in nodal measures. Nodes showing significant differences among groups in the nodal degree after FDR corrections. For both classification groups, AV45 and FDG show the most significantly affected regions. Dark blue shows the most significant region, whereas light red indicates the least significant region.
FIGURE 15
FIGURE 15
Comparison of EasyMKL classifier results with RBF-SVM classifier results based on obtained accuracy score. In the above figure, we can see that the combined-ROI, combined-VOI, and combined-(VOI + ROI) result obtained by EasyMKL classifier outperformed the results [combined-ROI, combined-VOI, and combined-(VOI + ROI)] obtained by the RBF-SVM classifier for all six classification groups.

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