Glucose metabolism reflects local atrophy and tau pathology in symptomatic Alzheimer’s disease

Abstract

AbstractPosterior cortical hypometabolism measured with [18F]-Fluorodeoxyglucose (FDG)-PET is a well-known marker of Alzheimer’s disease-associated neurodegeneration, but its associations with underlying neuropathological processes are unclear. We assessed the relative contributions of three potential mechanisms causing hypometabolism in the retrosplenial and inferior parietal cortices: local molecular (amyloid and tau) pathology and atrophy, distant factors including contributions from the degenerating medial temporal lobe or molecular pathology in functionally connected regions, and the presence of the apolipoprotein E (APOE) ε4 allele. Two hundred and thirty-two amyloid-positive cognitively impaired patients from two independent cohorts (University of California, San Francisco, UCSF, and Alzheimer’s Disease Neuroimaging Initiative, ADNI) underwent MRI and PET with FDG, amyloid-PET using [11C]-Pittsburgh Compound B, [18F]-Florbetapir, or [18F]-Florbetaben, and [18F]-Flortaucipir tau-PET within one year. Standard uptake value ratios (SUVR) were calculated using tracer-specific reference regions. Brain regions were defined in native space using FreeSurfer. Regression analyses were run within cohorts to identify variables associated with retrosplenial or inferior parietal FDG SUVR. On average, ADNI patients were older and had less severe cognitive impairment than UCSF patients. Regional patterns of hypometabolism were similar between cohorts, though there were cohort differences in regional gray matter atrophy. Local cortical thickness and tau-PET (but not amyloid-PET) were independently associated with both retrosplenial and inferior parietal FDG SUVR (ΔR2 = .09 to .21) across cohorts in models that also included age and disease severity (local model). Including medial temporal lobe volume improved the retrosplenial FDG model in ADNI (ΔR2 = .04, p = .008) but not UCSF (ΔR2 < .01, p = .52), and did not improve the inferior parietal models (ΔR2s < .01, ps > .37). Interaction analyses revealed that medial temporal volume was more strongly associated with retrosplenial FDG SUVR at earlier disease stages (p = .06 in UCSF, p = .046 in ADNI). Models including molecular pathology in functionally connected regions, defined based on task-free functional MRI data from the Neurosynth database, or APOE ε4 did not outperform local models. Overall, hypometabolism in cognitively impaired patients primarily reflected local atrophy and tau pathology, with an added contribution of medial temporal lobe degeneration at earlier disease stages. Our data did not support hypotheses of a detrimental effect of pathology in connected regions or the presence of the APOE ε4 allele in impaired participants. FDG-PET reflects structural neurodegeneration and tau, but not amyloid, pathology at symptomatic stages of Alzheimer’s disease.