Prefrontal hypometabolism in AD is related to longitudinal amyloid accumulation in remote brain regions

In PET studies of patients with Alzheimer´s disease (AD) prominent hypometabolism can occur in brain-regions without major amyloid load. These “hypometabolism only” (HO)-areas may not be explained easily as consequence of local amyloid-toxicity. Aim of this longitudinal multimodal imaging study was the investigation of loco-regional and remote relationships between metabolism in HO-areas and longitudinal amyloid-increase in functionally connected brain-areas with particular focus on intrinsic functional connectivity as a relevant “linking” mechanism between pathology and dysfunction. Methods: 15 AD-patients underwent longitudinal examinations with 11 C-PIB- and 18 F-FDG-PET (mean FU-period 2years). The peak HO-region was identified by subtraction of equally thresholded statistical T-maps (hypometabolism minus amyloid-burden), resulting from voxel-based SPM group comparisons between the AD-patients and 15 healthy controls. Then functionally connected and non-connected brain-networks were identified by means of seed-based intrinsic functional connectivity analysis in resting state fMRI (rs-fMRI) data of healthy controls. Finally network-based, ROI-based and voxel-based correlations were calculated between longitudinal changes of normalized PiB-binding- and FDG-metabolism. Results: Positive voxel-based and ROI-based correlations were demonstrated between longitudinal PiB-increases in the HO-connected network, encompassing bilateral temporoparietal and frontal brain-regions, and metabolic changes in the peak HO-region as well as loco-regionally within several AD-typical brain-regions. Conclusions: Our results indicate that in AD amyloid-accumulation in remote but functionally connected brain-regions may significantly contribute to longitudinally evolving hypometabolism in brain-regions not strongly affected by local amyloid-pathology, supporting the amyloid- and network degeneration hypothesis.