Integration and relative value of biomarkers for prediction of MCI to AD progression: spatial patterns of brain atrophy, cognitive scores, APOE genotype and CSF biomarkers

Abstract

This study evaluates the individual, as well as relative and joint value of indices obtained from magnetic resonance imaging (MRI) patterns of brain atrophy (quantified by the SPARE-AD index), cerebrospinal fluid (CSF) biomarkers, APOE genotype, and cognitive performance (ADAS-Cog) in progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) within a variable follow-up period up to 6 years, using data from the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1). SPARE-AD was first established as a highly sensitive and specific MRI-marker of AD vs. cognitively normal (CN) subjects (AUC = 0.98). Baseline predictive values of all aforementioned indices were then compared using survival analysis on 381 MCI subjects. SPARE-AD and ADAS-Cog were found to have similar predictive value, and their combination was significantly better than their individual performance. APOE genotype did not significantly improve prediction, although the combination of SPARE-AD, ADAS-Cog and APOE ε4 provided the highest hazard ratio estimates of 17.8 (last vs. first quartile). In a subset of 192 MCI patients who also had CSF biomarkers, the addition of Aβ1-42, t-tau, and p-tau181p to the previous model did not improve predictive value significantly over SPARE-AD and ADAS-Cog combined. Importantly, in amyloid-negative patients with MCI, SPARE-AD had high predictive power of clinical progression. Our findings suggest that SPARE-AD and ADAS-Cog in combination offer the highest predictive power of conversion from MCI to AD, which is improved, albeit not significantly, by APOE genotype. The finding that SPARE-AD in amyloid-negative MCI patients was predictive of clinical progression is not expected under the amyloid hypothesis and merits further investigation.

Keywords: Amyloid; Biomarkers of AD; Cerebrospinal fluid; Dementia; Early Alzheimer's disease; Magnetic resonance imaging; Mild cognitive impairment.

Fig. 1

(a) Visualization of the regions used to build the SPARE-AD index, when all 3 (GM, WM and brain CSF) RAVENS maps were used jointly. (Left) Temporal lobe and hippocampus of the left hemisphere; (right) temporal lobe and hippocampus of the right hemisphere. Images are in radiology convention. The color scale is graded (low to high) based on relevance of different brain regions for classification into AD/CN, herein measured by the frequency by which a region was selected by the 10 models produced by the 10-fold cross-validation. (b) ROC curve and performance graph of AD and CN classification results using GM, WM and brain CSF tissue density maps, obtained via fully cross-validated procedures. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Survival curves for (a) SPARE-AD index alone; (b) ADAS-Cog alone; (c) the combination of SPARE-AD and ADAS-Cog; (d) the combination of SPARE-AD and APOE ε4; (e) the combination of ADAS-Cog and APOE ε4, and (f) the combination of SPARE-AD, ADAS-Cog and APOE ε4.

Fig. 3

Violin plot depicting baseline SPARE-AD scores stratified by clinical diagnosis, MCI-SC (blue) and MCI-LS (red), and presence or absence of AD-like CSF Aβ_1–42 values. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

(a) Maps of the p value produced by optimally-discriminative voxel-based analysis (ODVBA) (Zhang and Davatzikos, 2011) showing differences between MCI-LS and MCI-SC based on the normal Aβ_1–42 subsample. Significantly more GM atrophy for hippocampus, prefrontal lobe and precuneus in MCI-SC relative to MCI-LS. The maps were thresholded at the p = 0.01 level. (b) 3D renderings of statistically significant differences between MCI-LS and MCI-SC. normal Aβ_1–42 subsample (right); pathological Aβ_1–42 subsample (left). The maps were thresholded at the p = 0.01 level.