Patterns of Glucose Metabolism in [18F]FDG PET Indicate Regional Variability and Neurodegeneration in the Progression of Alzheimer's Dementia

Abstract

In disorders of cognitive impairment, such as Alzheimer's disease, neurodegeneration is the final common pathway of disease progression. Modulating, reversing, or preventing disease progression is a clinical imperative most likely to succeed following accurate and explanatory understanding of neurodegeneration, requiring enhanced consistency with quantitative measurements and expanded interpretability of complex data. The on-going study of neurodegeneration has robustly demonstrated the advantages of accumulating large amounts of clinical data that include neuroimaging, motiving multi-center studies such as the Alzheimer's Disease Neuroimaging Initiative (ADNI). Demonstrative advantages also arise from highly multivariate analysis methods, and this work reports advances provided by non-negative matrix factorization (NMF). NMF revealed patterns of covariance for glucose metabolism, estimated by positron emission tomography of [18F]fluorodeoxyglucose, in 243 healthy normal participants of ADNI. Patterns for glucose metabolism provided cross-sectional inferences for 860 total participants of ADNI with and without cerebral amyloidosis and clinical dementia ratings (CDR) ranging 0-3. Patterns for glucose metabolism were distinct in number and topography from patterns identified in previous studies of structural MRI. They were also distinct from well-establish topographies of resting-state neuronal networks mapped by functional magnetic resonance imaging. Patterns for glucose metabolism identified significant topographical landmarks relating age, sex, APOE e4 alleles, amyloidosis, CDR, and neurodegeneration. Patterns involving insular and orbitofrontal cortices, as well as midline regions of frontal and parietal lobes demonstrated the greatest neurodegeneration with progressive Alzheimer's dementia. A single pattern for the lateral parietal and posterior superior temporal cortices demonstrated preserved glucose metabolism for all diagnostic groups, including Alzheimer's dementia. Patterns correlated significantly with topical terms from the Neurosynth platform, thereby providing semantic representations for patterns such as attention, memory, language, fear/reward, movement and motor planning. In summary, NMF is a data-driven, principled, supervised statistical learning method that provides interpretable patterns of neurodegeneration. These patterns can help inform the understanding and treatment of Alzheimer's disease.