Amyloid-associated alterations in metabolic connectivity patterns in ADNI participants

Abstract

While regional glucose hypometabolism is characteristic of Alzheimer's disease (AD), this feature has been shown to be primarily associated with the ApoE4 genotype, rather than fibrillar β-amyloid, during the pre-clinical/early stages of the disease process. However, derangements of metabolic connectivity are intimately related to β-amyloid plaque burden. In order to assess the specific alterations in metabolic connectivity in early disease, we have performed a quantitative analysis of correlation patterns derived from FDG positron emission tomography (PET) images from ADNI subjects with different levels of cortical β-amyloid. [18F]florbetapir PET, [18F]FDG PET, and 3D T1-weighted MR images were obtained from ADNI-GO/-2 study subjects classified as cognitively normal or mild cognitive impairment (MCI). PET volumes were registered to a customized MRI template in MNI stereotaxic space, and standardized uptake value ratio (SUVR) images were generated and projected onto each subject's cortical surface using Biospective's fully-automated PIANO TM image processing software. The amyloid burden for each subject was determined from a composite region-of-interest (ROI) on [18F]florbetapir images, and subjects were categorized into Amyloid-Low (Aβ L) and Amyloid-High (Aβ H) groups. We generated vertexwise correlation strength maps across the entire cerebral cortex, controlling for ApoE4 genotype, and assessed the relative alterations in short-/long-range and intra-/inter-hemispheric metabolic connections in each group. We observed statistically significant differences in short-/long-range and intra-/inter-hemispheric metabolic connections between the Aβ L and Aβ H groups in multiple cortical regions. For example, the entorhinal cortex showed greater reductions in inter- than intra-hemispheric correlations (especially with the contralateral medial temporal lobe, precuneus, and posterior lateral temporal-parietal cortex) in the Aβ H group. The angular gyrus demonstrated greater loss of long- than short-range metabolic correlations in the Aβ H group. We have employed metabolic connectivity analysis to examine disruptions of the cortical correlation architecture as a function of β-amyloid burden. The aberrant metabolic connections observed in the Aβ H group may be a consequence of variable spatio-temporal patterns of compensatory responses and/or cortical remodeling during the early stages of AD. The quantitative approach employed in this study may serve as a powerful, non-invasive imaging biomarker for early diagnosis/prognosis and objective evaluation of the efficacy of novel amyloid-lowering therapeutic agents.