Cortical hypometabolism reflects local atrophy and tau pathology in symptomatic Alzheimer’s disease
- 9 August 2021
- journal article
- research article
- Published by Oxford University Press (OUP) in Brain
- Vol. 145 (2), 713-728
- https://doi.org/10.1093/brain/awab294
Abstract
Posterior cortical hypometabolism measured with [18F]-Fluorodeoxyglucose (FDG)-PET is a well-known marker of Alzheimer’s disease-related neurodegeneration, but its associations with underlying neuropathological processes are unclear. We assessed cross-sectionally 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 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. Regression analyses were run within cohorts to identify variables associated with retrosplenial or inferior parietal FDG SUVR. On average, ADNI patients were older and were less impaired 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). Exploratory analyses across the cortex confirmed overall associations between hypometabolism and local tau pathology and thickness and revealed associations between medial temporal degeneration and hypometabolism in retrosplenial, orbitofrontal, and anterior cingulate cortices. Finally, our data did not support hypotheses of a detrimental effect of pathology in connected regions or of an effect of the APOE ε4 allele in impaired participants. Overall, in two independent groups of patients at symptomatic stages of Alzheimer’s disease, cortical hypometabolism mainly reflected structural neurodegeneration and tau, but not amyloid, pathology.Funding Information
- National Institutes of Health
- National Institute of Aging (NIH/NIA P50-AG23501, UCSF ADRC P50-AG023501, P30-AG062422, P01-AG019724, R01-AG045611, R01-AG034570, R01-AG032306, NIH/NINDS R01-NS050915, K99AG065501, K24-AG053435)
- Rainwater Charitable Foundation
- Alzheimer’s Association (AARF: 16–443577, AACSF: 19–617663)
- Alzheimer's Disease Neuroimaging Initiative
- National Institutes of Health (U01 AG024904)
- DOD ADNI (W81XWH-12–2-0012)
- National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering
- AbbVie, Alzheimer’s Association
- Alzheimer’s Drug Discovery Foundation
- Araclon Biotech
- BioClinica, Inc.
- Biogen
- Bristol-Myers Squibb Company
- CereSpir, Inc.
- Cogstate
- Eisai Inc.
- Elan Pharmaceuticals, Inc.
- Eli Lilly and Company
- EuroImmun
- F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.
- Fujirebio
- GE Healthcare
- IXICO Ltd
- Janssen Alzheimer Immunotherapy Research & Development, LLC.
- Johnson & Johnson Pharmaceutical Research & Development LLC.
- Lumosity
- Lundbeck
- Merck & Co., Inc.
- Meso Scale Diagnostics, LLC.
- NeuroRx Research; Neurotrack Technologies
- Novartis Pharmaceuticals Corporation
- Pfizer Inc.
- Piramal Imaging; Servier
- Takeda Pharmaceutical Company
- Transition Therapeutics
- ADNI clinical sites in Canada
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