Longitudinal brain metabolic changes from amnestic mild cognitive impairment to Alzheimer's disease

Abstract

A sensitive marker for monitoring progression of early Alzheimer's disease would help to develop and test new therapeutic strategies. The present study is aimed at investigating brain metabolism changes over time, as a potential monitoring marker, in patients with amnestic mild cognitive impairment, according to their clinical outcome (converters or non-converters), and in relation to their cognitive decline. Seventeen amnestic mild cognitive impairment patients underwent magnetic resonance imaging and 18FDG-positron emission tomography scans both at inclusion and 18 months later. Baseline and follow-up positron emission tomography data were corrected for partial volume effects and spatially normalized using magnetic resonance imaging data, scaled to the vermis and compared using SPM2. 'PET-PAC' maps reflecting metabolic per cent annual changes were created for correlation analyses with cognitive decline. In the whole sample, the greatest metabolic decrease concerned the posterior cingulate-precuneus area. Converters had significantly greater metabolic decrease than non-converters in two ventro-medial prefrontal areas, the subgenual (BA25) and anterior cingulate (BA24/32). PET-PAC in BA25 and BA24/32 combined allowed complete between-group discrimination. BA25 PET-PAC significantly correlated with both cognitive decline and PET-PAC in the hippocampal region and temporal pole, while BA24/32 PET-PAC correlated with posterior cingulate PET-PAC. Finally, the metabolic change in BA8/9/10 was inversely related to that in BA25 and showed relative increase with cognitive decline, suggesting that compensatory processes may occur in this dorso-medial prefrontal region. The observed ventro-medial prefrontal disruption is likely to reflect disconnection from the hippocampus, both indirectly through the cingulum bundle and posterior cingulate cortex for BA24/32, and directly through the uncinate fasciculus for BA25. Altogether, our findings emphasize the potential of 18FDG-positron emission tomography for monitoring early Alzheimer's disease progression.

Figure 1

Patterns of brain metabolic changes over 18 months in the whole aMCI sample (A), as well as in non-converters (B) and in converters (C) separately, as illustrated by projection of the SPM-T maps onto a 3D representation of the aMCI customized whole brain template.

Figure 2

Brain areas showing significantly greater metabolic decreases in converters compared to non-converters (A-left), used as VOIs represented onto 3D views of the aMCI whole brain template in further analyses (A-right), and significant positive correlation between metabolic decrease (PET-PAC maps) and global cognitive decline (Mattis-PAC – B) as illustrated by SPM-2 ‘Glass brain’ representation and projection of the SPM-T maps (thresholded at p<0.005; k>50 voxels) onto sagittal sections of the aMCI whole brain template. Peak MNI coordinates (xyz), size in voxels (k), and T and P values are indicated for each significant cluster, and correlation plot and R² values are also provided.

Figure 3

Brain areas showing significant negative correlation between PET-PAC maps and Mattis-PAC (A) or BA25 PET-PAC value (B) as illustrated by SPM-2 ‘Glass brain’ representations and projection of the SPM-T maps (thresholded at p<0.005; k>100 voxels) onto sagittal section of the aMCI whole brain template. Peak MNI coordinates (xyz), size in voxels (k), and T and P values are indicated for each significant cluster and the corresponding plots and R² values are also provided.

Figure 4

Illustration of the discriminant accuracy of the mean PET-PAC values in BA24/32 and BA25 separately, and of both values combined (2D representation) to separate converters from nonconverters.

Figure 5. VOI-based correlation analysis

Brain areas showing significant positive correlation between PET-PAC maps and PET-PAC values in BA25 (left), and BA24/32 (right), as illustrated in SPM-2 ‘Glass brain’ representations and projection of the SPM-T maps (thresholded at p<0.005; k>100 voxels) onto sagittal sections of the aMCI whole brain template. Peak and sub-peak MNI coordinates (xyz), size in voxels (k), and T and P values are indicated for each significant cluster and the corresponding plots and R² values are also provided. Hcp: hippocampus.