The cortical signature of prodromal AD: regional thinning predicts mild AD dementia

Abstract

Objective: We previously used exploratory analyses across the entire cortex to determine that mild Alzheimer disease (AD) is reliably associated with a cortical signature of thinning in specific limbic and association regions. Here we investigated whether the cortical signature of AD-related thinning is present in individuals with questionable AD dementia (QAD) and whether a greater degree of regional cortical thinning predicts mild AD dementia.

Methods: Participants included 49 older adults with mild impairment consistent with mild cognitive impairment (Clinical Dementia Rating [CDR] = 0.5) at the time of structural MRI scanning. Cortical thickness was measured in nine regions of interest (ROIs) identified previously from a comparison of patients with mild AD and controls.

Results: Longitudinal clinical follow-up revealed that 20 participants converted to mild AD dementia (progressors) while 29 remained stable (nonprogressors) approximately 2.5 years after scanning. At baseline, QAD participants showed a milder degree of cortical thinning than typically seen in mild AD, and CDR Sum-of-Boxes correlated with thickness in temporal and parietal ROIs. Compared to nonprogressors, progressors showed temporal and parietal thinning. Using receiver operating characteristic curves, the thickness of an aggregate measure of these regions predicted progression to mild AD with 83% sensitivity and 65% specificity.

Conclusions: Thinning in specific cortical areas known to be affected by Alzheimer disease (AD) is detectable in individuals with questionable AD dementia (QAD) and predicts conversion to mild AD dementia. This method could be useful for identifying individuals at relatively high risk for imminent progression from QAD to mild AD dementia, which may be of value in clinical trials.

Figure 2 Receiver operating characteristic curves of the performance by various morphometric measures for classifying questionable Alzheimer dementia (QAD) progressors vs QAD nonprogressors Optimal performance maximizing both sensitivity and specificity was determined by identifying the curve with the highest leftward point (white region of top graphs); bottom graphs show zoomed in views of areas in white from top graphs. (A) Comparing three standard volumetric variables, EV demonstrated highest sensitivity (72%) and specificity (65%). EV = entorhinal volume; HV = hippocampal volume; WBV = whole brain volume. (B) Comparing two global variables, mean cortical thickness demonstrated highest sensitivity (69%) and specificity (65%). MCT = mean cortical thickness. (C) Comparing two regional cortical thickness measures with EV, mean AD signature cortical thickness demonstrated highest sensitivity (83%) and specificity (65%). ADT = AD signature thickness; MTLT = medial temporal lobe thickness.

Figure 1 Regions of interest (ROIs) derived from previous exploratory analysis that identified foci of thinning in mild Alzheimer disease, and thinning in cortical ROIs in patients with questionable AD who later progressed to mild AD dementia (QAD-P) compared to QAD nonprogressors (QAD-NP) Top: ROIs derived from previous exploratory analysis that identified foci of thinning in mild AD. (A) Medial temporal cortex, (B) inferior temporal gyrus, (C) temporal pole, (D) angular gyrus, (E) superior frontal gyrus, (F) superior parietal lobule, (G) supramarginal gyrus, (H) precuneus, (I) inferior frontal sulcus. Bottom: Thinning in cortical ROIs in QAD-P compared to QAD-NP. Bar graphs show mean cortical thickness within each ROI in the two groups (middle two bars) and, for comparison purposes, in a sample of 115 older controls (OC, left bar) and 29 patients with mild AD (AD, right bar). Error bars indicate 1 SEM. *p < 0.05, **p < 0.005. See table 2 for additional detail.

Figure 3 Magnitude of cortical thinning in prodromal Alzheimer disease (AD) in millimeters, derived from sample of 29 questionable Alzheimer dementia (QAD) nonprogressor vs 20 progressor subjects Map shows parameter estimate of amount of thinning across cerebral cortex from general linear model analysis of 49 subjects, showing areas where cortex is at least 0.1 mm thinner in prodromal AD dementia group (progressors) than in nonprogressors. Maps are presented on the semi-inflated cortical surface of an average brain with dark gray regions representing sulci and light gray regions representing gyri. Non-neocortical regions and regions that are not part of the cortical mantle (such as the corpus callosum and thalamus) have been excluded from the analysis. Color scale shows magnitude of thinning from 0.1 mm (red) through 0.2 mm (yellow).