11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment

Abstract

To date, most diagnostic imaging comparisons between amyloid labelling ligands and other imaging modalities have been between the use of amyloid labelling ligand (11)C Pittsburgh Compound B (PiB) and FDG-PET. Our objectives were to compare cognitive performance and diagnostic group-wise discrimination between cognitively normal, amnestic mild cognitive impairment (MCI) and Alzheimer's disease subjects with MRI-based measures of hippocampal volume and PiB retention, and secondly to evaluate the topographic distribution of PiB retention and grey matter loss using 3D voxel-wise methods. Twenty cognitively normal, 17 amnestic MCI and 8 probable Alzheimer's disease subjects were imaged with both MRI and PiB. PiB retention was quantified as the ratio of uptake in cortical to cerebellar regions of interest (ROIs) 40-60 min post-injection. A global cortical PiB retention summary measure was derived from six cortical ROIs. Statistical parametric mapping (SPM) and voxel-based morphometry (VBM) were used to evaluate PiB retention and grey matter loss on a 3D voxel-wise basis. Alzheimer's disease subjects had high global cortical PiB retention and low hippocampal volume; most cognitively normal subjects had low PiB retention and high hippocampal volume; and on average amnestic MCI subjects were intermediate on both PiB and hippocampal volume. A target-to-cerebellar ratio of 1.5 was used to designate subjects with high or low PiB cortical retention. All Alzheimer's disease subjects fell above this ratio, as did 6 out of 20 cognitively normal subjects and 9 out of 17 MCI subjects, indicating bi-modal PiB retention in the latter two groups. Interestingly, we found no consistent differences in learning and memory performance between high versus low PiB cognitively normal or amnestic MCI subjects. The SPM/VBM voxel-wise comparisons of Alzheimer's disease versus cognitively normal subjects provided complementary information in that clear and meaningful similarities and differences in topographical distribution of amyloid deposition and grey matter loss were shown. The frontal lobes had high PiB retention with little grey matter loss, anteromedial temporal areas had low PiB retention with significant grey matter loss, whereas lateral temporoparietal association cortex displayed both significant PiB retention and grey matter loss. A voxel-wise SPM conjunction analysis revealed that subjects with high PiB retention shared a common PiB retention topographical pattern regardless of clinical category, and this matched that of amyloid plaque distribution from autopsy studies of Alzheimer's disease. Both global cortical PiB retention and hippocampal volumes demonstrated significant correlation in the expected direction with cognitive testing performance; however, correlations were stronger with MRI than PiB. Pair-wise inter-group diagnostic separation was significant for all group-wise pairs for both PiB and hippocampal volume with the exception of the comparison of cognitively normal versus amnestic MCI, which was not significant for PiB. PiB and MRI provided complementary information such that clinical diagnostic classification using both methods was superior to using either in isolation.

Figures

Figure 1. Regions of interest that constitute the global cortical PiB retention value

Box plots with individual data points superimposed. The horizontal lines in the box plots represent the 25th, 50th, and 75th percentiles. The vertical line extending from the box reaches the most extreme data point within 1.5 inter-quartile ranges. Individual data points represent the subject's median target-to-cerebellar ratio over all voxels in the region of interest. The p-value shown is based on the three-sample Kruskal-Wallis test.

Figure 2. Regions of interest not part of the global cortical PiB retention value

Box plots with individual data points superimposed. The horizontal lines in the box plots represent the 25th, 50th, and 75th percentiles. The vertical line extending from the box reaches the most extreme data point within 1.5 inter-quartile ranges. Individual data points represent the subject's median target-to-cerebellar ratio over all voxels in the region of interest. The p-value shown is based on the three-sample Kruskal-Wallis test.

Figure 3. Group-wise separation for global cortical PiB and hippocampal W score

Box plots with individual data points superimposed. The horizontal lines in the box plots represent the 25th, 50th, and 75th percentiles. The vertical line extending from the box reaches the most extreme data point within 1.5 inter-quartile ranges. The p-value shown is based on the three-sample Kruskal-Wallis test. The CN subject with the largest PiB value is identified by the letter “A” and the CN subject with the smallest hippocampal W score is identified by the letter “B”. These two subjects are described in detail in the text.

Figure 4. Typical PiB subjects

The color scale bar represents cortical voxel-to-cerebellar retention ratio.

Figure 5. Atypical findings in CN subjects

Subject A has the highest global PiB cortical retention ratio in the study but an above average hippocampal W score and normal cognitive function. Subject B has a low hippocampal W score but low PiB retention and normal cognitive function. The color scale bar represents cortical voxel-to-cerebellar retention ratio.

Figure 6. Scatter plot showing relationship between global cortical PiB retention and hippocampal W score

Spearman rank correlation (p-value) indicated in the top left. Reference lines at a W score of zero and a global cortical PiB of 1.5 have been added to the plot to segregate the data into quadrants. The CN subject with the largest PiB value is identified by the letter “A” and the CN subject with the smallest hippocampal W score is identified by the letter “B”.

Figure 7. AD vs. CN Voxel Mapping. PiB (left)

SPM of PiB retention ratio. Corrected for multiple comparisons (FDR) and thresholded at p MRI (right): VBM of MRI grey matter density. Uncorrected for multiple comparisons and thresholded at p < 0.01. The color bar values indicate the value of the T statistic in each display.

Figure 8. PiB Conjunction analysis

The figure illustrates all voxels where PiB retention in AD > low PiB CN, and high PiB aMCI > low PiB CN, and high PiB CN > low PiB CN. Corrected for multiple comparisons (FDR) and thresholded at p < 0.01.