Analysis of Mean Cortical Thickness
In Sample 1a, this analysis revealed an effect of AD, with the mild AD group showing 4.5% mean cortical thinning compared with OC (OC = 2.14 [SD = 0.08] mm, AD = 2.05 [0.11] mm; F(1) = 26.2, P < 0.001, Cohen's d = 1.02). Across the other 3 samples of participants, very similar effects were found. In Sample 2, mean cortical thickness of the AD group was 5.5% thinner than controls (OC = 2.03 [0.10] mm, AD = 1.92 [0.13] mm; F = 11.2, P < 0.002, Cohen's d = 1.0). In Sample 3, the AD group's mean cortical thickness was 6.5% thinner than controls (OC = 2.12 [0.09] mm, AD = 2.00 [0.11] mm; F = 19.5, P < 0.001, Cohen's d = 1.41). Finally, in Sample 4, scanned at 3.0 Tesla, mean cortical thickness of the AD group was 6.0% thinner than controls (OC = 2.16 [0.09] mm, AD = 2.03 [0.10] mm; F = 17.1, P < 0.001, Cohen's d = 1.34).
Similar analyses were also performed to investigate these measures in the 2 subject groups with milder levels of impairment (CDR = 0.5, Sample 1b). The group with very mild AD showed effects similar to, but of a lesser magnitude than, those of the mild AD group: 3.7% mean cortical thinning compared with controls (very mild AD = 2.06 [0.10] mm; F = 23.6, P < 0.001, Cohen's d = 0.87). The group with incipient AD showed no reduction in mean cortical thickness compared with controls (mean cortical thickness = 2.12 [0.11] mm; P = 0.32).
Regionally Specific Cortical Thinning in Mild AD: Exploratory Analysis across the Entire Cortical Mantle
In Sample 1a, the exploratory analysis of cortical thickness across the entire mantle revealed a set of specific regions that were thinner in AD than OC, as illustrated in . Regions of significant thinning were primarily located in limbic and heteromodal association areas, including rostral medial temporal, inferior temporal, temporal pole, precuneus, inferior parietal (supramarginal and angular gyri), superior parietal, inferior frontal, and superior frontal cortex. There were minor differences in the spatial location of regional thinning across hemispheres, but generally the regions were quite consistent bilaterally. Primary sensorimotor regions were largely spared.
Quantitative Analysis of Cortical Regions Vulnerable to AD
We next investigated the magnitude of AD-related thinning within each cortical region identified in the exploratory analysis. Cortical ROI label locations and group mean and standard error data are shown in . Data for Sample 1a is shown in the leftmost pair of bars in each graph in . Mean thickness, standard deviation, magnitude of group differences (in mm), percent thinning in AD compared with controls, and Cohen's d effect sizes are shown in .
Quantitative metrics of thinning by region within sample #1
Thinning due to AD was most prominent (in mm) in the rostral medial temporal cortex, with a mean magnitude of thinning of more than 0.4 mm (14% thinning in AD compared with OC). Other regions with more than 0.2 mm thinning included inferior temporal, temporal pole, inferior parietal (both angular and supramarginal gyri), and superior frontal regions, which ranged from 8.1% to 11.6% thinner in AD than OC. The regions with a relatively smaller magnitude of thinning (0.16–0.19 mm, or 7–8%) included precuneus, inferior frontal, and superior parietal regions. There was no significant thinning in the primary visual cortex (0.03 mm [2.2%], P = 0.19).
Consistency of Regional Cortical Thinning in Mild AD: Quantitative Analysis of Cortical Regions in 3 Separate Samples
The consistency of regionally specific cortical thinning was investigated in 3 additional samples of AD patients and OC individuals. This analysis was unbiased, as it employed cortical ROIs defined as above from Sample 1a and applied to separate samples of participants (by mapping each cortical ROI label from the average surface template to each individual via the spherical average surface, as described in Methods).
The magnitude of AD-related thinning within these cortical regions was remarkably consistent across the 3 additional samples. illustrates the mean thickness and standard error within regions across all 4 samples. provides details of measurements from Samples 2, 3, and 4, showing magnitude of group difference (AD vs. OC), percent thinning in AD, and effect sizes.
Quantitative metrics of thinning by region within 3 additional samples of participants
Again, across all 3 additional samples, the medial temporal cortex showed the largest magnitude of thinning of all regions within each sample, ranging from 0.26 to 0.55 mm thinner in AD than OC. Temporal pole and inferior parietal regions showed consistently large effects, whereas inferior temporal, superior parietal, precuneus, and frontal regions were somewhat less consistent with respect to magnitude of thinning. Primary visual cortex again showed no effects in these 3 samples.
An additional analysis was performed to investigate thickness differences between the 4 samples. A main effect was found for Sample 2, with mean cortical thickness biased toward slightly thinner estimates without an interaction with diagnostic group.
Detection of Attenuated Regional Cortical Thinning in Individuals with Milder Symptoms of AD
We next investigated a sample (Sample 1b) of individuals with milder symptoms of AD to determine whether a lesser magnitude of cortical thinning would be detectable within regions known to be vulnerable to AD from the analyses above. All of these participants had an overall CDR rating of 0.5, but some were diagnosed with very mild AD (n = 40) and others were diagnosed with incipient AD (n = 29). See for demographic and clinical data on these participants. The AD-signature cortical ROI labels, as defined from Sample 1a, were again applied to this sample of individuals with very mild AD or incipient AD.
AD-related thinning was detected within these cortical regions in a remarkably consistent manner across the 2 milder groups. Most of the regions demonstrated a pattern suggestive of progressive thinning across the 4 groups, as illustrated in . The primary visual cortex showed no such effect. As depicted in , statistical analysis demonstrated that the all regions except the primary visual cortex were thinner in the very mild AD group than OC. Inspection of the percent thinning in very mild AD reveals a lesser degree of thinning in all regions than in the mild AD group. The magnitude of thinning in the incipient AD group is relatively small in all regions, with most differences in regional thickness compared with OC not reaching statistical significance (except angular and supramarginal gyri). The primary visual cortex ROI shows a remarkable degree of reliability with respect to absolute cortical thickness across the groups (lower right graph in ). illustrates the mean thickness and standard error within regions across the very mild AD and incipient AD groups, with the OC and mild AD groups shown for comparison. provides details of measurements from these 2 groups of participants.
Figure 4. Thinning in cortical ROIs in incipient and very mild AD participants. ROIs were generated from exploratory analysis in subject Sample 1a (see , same ROIs as used in ) and applied to a new sample of Incipient and very mild AD patients (CDR (more ...)
Quantitative metrics of thinning by region within incipient and very mild AD participants
Relationship of Regional Cortical Thinning to Severity of Clinical Impairment
We analyzed the relationship of the regional measures of cortical thickness to severity of symptoms of cognitive impairment within all the demented participants from Washington University (incipient AD, very mild AD, mild AD; N = 97). Correlational analyses were run with the CDR Sum-of-Boxes (CDR-SB) as the dependent measure. Although the overall CDR ratings (0.5 or 1) of these individuals indicated that they were very mildly or mildly demented, the CDR-SB provides a finer grading of impairment within this spectrum, ranging in this sample of 97 participants between 0.5 and 9.0. CDR-SB was inversely correlated with the thickness of a number of regions, including medial temporal, inferior temporal, temporal pole, angular gyrus, superior parietal, superior frontal, and inferior frontal cortex (Pearson R values ranging from −0.24 through −0.38, all P values < 0.02). These findings indicate that a greater level of clinical impairment is associated with a larger magnitude of thinning within these cortical regions. A stepwise multiple linear regression analysis was performed with each of these regions as independent variables and CDR-SB as the dependent variable. This model indicated that a linear combination of medial temporal, inferior temporal, and inferior frontal regions was the best predictor of CDR-SB (R = 0.51, F3,93 = 11.2, P < 0.001).
These correlative analyses with CDR-SB were also examined within the diagnostic groups. The mild AD group demonstrated trends for superior (R = −0.35, P = 0.06) and inferior frontal (R = −0.32, P = 0.08) regions, whereas the very mild AD group demonstrated an effect for the medial temporal cortex (R = −0.34, P = 0.03) and a trend for the angular gyrus (R = −0.28, P = 0.08). There were no effects in the incipient AD group.
Pooled Multicenter Mapping Analysis of the Magnitude of Cortical Thinning in Mild AD
For this analysis, a general linear model was constructed that included all 4 mild AD and all 4 OC groups. Each participant contributed a cortical thickness estimate mapped to the group using spherical registration. The contrast of interest was AD versus OC, and was weighted according to the number of participants in each group. The parameter estimate of difference in cortical thickness between AD and OC was then used to generate a map of the magnitude of cortical thinning in AD. Note that this map is quantitative revealing the estimated size (in mm) of cortical thinning. Thus, this map reflects our best estimate of the topography and magnitude of cortical thinning in mild AD.
illustrates the results of the pooled analysis, which was undertaken to map the magnitude of thinning across the entire cerebral cortex in Samples 1a, 2, 3, and 4 comparing AD with OC (total N
= 267). Areas of the cortex in which the magnitude of AD-related thinning exceeds 0.15 mm are shown, using a color scale to indicate the magnitude of thinning. The spatial topography of regional thinning parallels that illustrated with the statistical map of Sample 1a alone (). The areas with the greatest magnitude of thinning across this large multicenter dataset, such as medial temporal cortex, are quite similar to those indicated by the ROI analyses of thinning within each sample above. The congruence of the effects detected with this pooled analysis and those detected above using hypothesis-driven replication samples supports the feasibility of pooled analyses of cortical thickness in multisite/multiscanner data using the high-throughput computational analysis system. A Supplementary Table
provides the estimates of the magnitude of thinning in AD for the entire pooled sample.
Figure 5. Magnitude of cortical thinning in AD in millimeters, derived from pooled analysis of 4 samples of participants (Samples 1a, 2, 3, and 4). Map shows parameter estimate of amount of thinning across cerebral cortex from general linear model analysis of 267 (more ...)
Detection of Regional Cortical Thinning in Amyloid-Positive Asymptomatic Older Individuals
We next investigated a sample (Sample 1c) of individuals evaluated in the same fashion as that described above for Sample 1a, and who were considered to be asymptomatic OC (CDR = 0). Based on PIB-PET scans, they were dichotomized into OC participants with (amyloid-positive, N = 9) or without (amyloid-negative, N = 35) PIB amyloid binding. We sought to determine whether subtle cortical thinning might be detectable within regions known to be vulnerable to AD from the analyses above. See for demographic and clinical data on these participants. The AD-signature cortical ROI labels, as defined from Sample 1a, were again applied to this sample of amyloid-positive or amyloid-negative OC individuals.
AD-related thinning was detected within the temporal pole (5.8% thinning, P = 0.04) and a trend was present in the superior frontal cortex (4.6% thinning, P = 0.06) in the amyloid-positive OC group compared with the amyloid-negative OC group. Most other regions demonstrated a pattern suggestive of subtle thinning (see ), but the small sample size lacked power for statistical demonstration of effects. Thus, the thickness measures from all 9 ROIs were averaged to create a single mean “AD cortical signature” thickness measure. A trend toward thinning in this mean AD cortical signature measure was present in the amyloid-positive OC group compared with the amyloid-negative OC group (P = 0.09). This finding was further supported by a post hoc comparison that demonstrated thinning in the mean AD cortical signature measure of the amyloid-positive OC group compared with the larger OC (amyloid status unknown, N = 115) group from Sample 1a (P < 0.05). Mean thickness of the entire cortex in the amyloid-positive group (2.17 ± 0.11 mm) did not differ from that of the amyloid-negative group (2.13 ± 0.7 mm) nor from that of the larger OC group from Sample 1a (all P values > 0.19). illustrates the AD cortical signature measure (mean and standard error of the mean) across the amyloid-positive OC, amyloid-negative OC, and other 4 groups from Samples 1a, 1b, and 1c.
Figure 7. Consistent subtle thinning appears to be present in many cortical ROIs in amyloid (PIB)-positive OC (CDR = 0) compared with amyloid (PIB)–negative controls. ROIs were generated from exploratory analysis in subject Sample 1a (see , same ROIs (more ...)
Figure 6. Mean thickness of AD cortical signature regions is decreased in amyloid (PIB)-positive OC (CDR = 0), and demonstrates progressive thinning as the symptoms of AD dementia become progressively more prominent across the spectrum of Incipient, very mild, (more ...)