The cortical signature of Alzheimer's disease: regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloid-positive individuals

Abstract

Alzheimer's disease (AD) is associated with neurodegeneration in vulnerable limbic and heteromodal regions of the cerebral cortex, detectable in vivo using magnetic resonance imaging. It is not clear whether abnormalities of cortical anatomy in AD can be reliably measured across different subject samples, how closely they track symptoms, and whether they are detectable prior to symptoms. An exploratory map of cortical thinning in mild AD was used to define regions of interest that were applied in a hypothesis-driven fashion to other subject samples. Results demonstrate a reliably quantifiable in vivo signature of abnormal cortical anatomy in AD, which parallels known regional vulnerability to AD neuropathology. Thinning in vulnerable cortical regions relates to symptom severity even in the earliest stages of clinical symptoms. Furthermore, subtle thinning is present in asymptomatic older controls with brain amyloid binding as detected with amyloid imaging. The reliability and clinical validity of AD-related cortical thinning suggests potential utility as an imaging biomarker. This "disease signature" approach to cortical morphometry, in which disease effects are mapped across the cortical mantle and then used to define ROIs for hypothesis-driven analyses, may provide a powerful methodological framework for studies of neuropsychiatric diseases.

Figure 1.

Flowchart of methodologic procedures employed in this study and specific analyses used to generate figures (Fig) and tables (Tbl). Shaded rows at bottom show the specific subject samples (S) that were used to generate each table and figure. For example, Samples 1a and 1b were used to generate Figure 4 and Table 4 (second shaded row). See Table 1 for details of diagnostic groups and demographic and clinical characteristics of each sample.

Figure 2.

The cortical signature of AD: map of cortical thinning across the hemispheres in AD. An exploratory analysis was conducted across the entire cortical surface to identify regional thinning in AD in Sample 1a. Surface maps of cortical thinning were generated by assessing the influence of AD on thickness (using the general linear model) at each vertex across the entire cortical mantle. 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. The color scale at the bottom represents the significance of the thickness difference with yellow indicating regions of most significant thinning in AD compared with OC. See Table 2 for quantitative metrics of the amount of thinning in each region.

Figure 3.

Consistency of regional thinning in AD. ROIs (top) were generated from exploratory analysis in subject Sample 1a (see Fig. 2) and applied to 3 new samples of OC and AD patients (Samples 2, 3, and 4) to test the hypothesis that these regions are thinner in AD than controls. Graphs show mean cortical thickness within each ROI across the 4 samples, illustrating the consistency of thinning despite the differences between the samples and MRI data acquisition (note that Sample 4 was scanned on 3.0T scanner). A primary visual cortex region was also used to illustrate minimal effects on this region (lower right). Error bars indicate 1 standard error of the mean. See Tables 2 and 3 for statistics. (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) Precunes, (I) Inferior frontal sulcus, (J) Primary visual cortex.

Figure 4.

Thinning in cortical ROIs in incipient and very mild AD participants. ROIs were generated from exploratory analysis in subject Sample 1a (see Fig. 2, same ROIs as used in Fig. 3) and applied to a new sample of Incipient and very mild AD patients (CDR = 0.5, Sample 1b) to test the hypothesis that these regions are thinner in the mildest clinical stages of AD than controls. Graphs show mean cortical thickness within each ROI across the 2 mildly impaired samples, in comparison to controls and mildly impaired (CDR = 1) AD patients (Sample 1a). A primary visual cortex region was also used to illustrate minimal effects on this region (lower right). Error bars indicate 1 standard error of the mean. See Table 3 for statistics. (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) Precunes, (I) Inferior frontal sulcus, (J) Primary visual cortex.

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 participants, showing areas where cortex is at least 0.15 mm thinner in AD group than OC group. Color scale shows magnitude of thinning from 0.15 mm (red) through 0.2 mm (yellow) in AD compared with OC.

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, and mild AD dementia. Bars represent mean thickness of the 9 cortical regions shown in Figure 2, normalized for age and standardized to Z scores (y axis). Error bars indicate 1 standard error of the mean. The leftmost 3 groups are all OC (CDR = 0, MMSE 25–30), ordered by PIB status unknown (unk) (N = 115), PIB negative (N = 35), and PIB positive (N = 9). The rightmost 3 groups are all PIB status unknown, but are progressively more impaired with clinical symptoms ranging from incipient AD (CDR = 0.5/CDR-SB = 1.2, N = 29), very mild AD (CDR = 0.5/CDR-SB = 3.5, N = 40), and mild AD (CDR = 1/CDR-SB = 5.5, N = 29). Figure includes data 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 Fig. 2, same ROIs as used in Fig. 3) and applied to a new sample of PIB+ and PIB- controls (CDR = 0, Sample 1c) to test the hypothesis that these regions undergo subtle thinning in asymptomatic AD. Bars represent mean thickness of each region shown in Figure 2, normalized for age and standardized to Z scores. Error bars indicate 1 standard error of the mean. (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) Precunes, (I) Inferior frontal sulcus.