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

In disorders of cognitive impairment, such as Alzheimers 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 Alzheimers 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 {varepsilon}4 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 Alzheimers dementia. A single pattern for the lateral parietal and posterior superior temporal cortices demonstrated preserved glucose metabolism for all diagnostic groups, including Alzheimers 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 Alzheimers disease. Highlights{blacksquare} Data-driven non-negative matrix factorization (NMF) identified 24 canonical patterns of spatial covariance of cerebral glucose metabolism. The training data comprised healthy older participants (CDR = 0 without amyloidosis) cross-sectionally drawn from ADNI. {blacksquare}In healthy participants, mean SUVRs for specific patterns in precuneus, lateral parietal cortex, and subcortical areas including superficial white matter and striatum, demonstrated increasing glucose metabolism with advancing age. {blacksquare}In asymptomatic participants with amyloidosis, glucose metabolism increased compared to those who were asymptomatic without amyloid, particularly in medial prefrontal cortex, frontoparietal cortex, occipital white, and posterior cerebellar regions. {blacksquare}In symptomatic participants with amyloidosis, insular cortex, medial frontal cortex, and prefrontal cortex demonstrated the most severe losses of glucose metabolism with increasing CDR. Lateral parietal and posterior superior temporal cortices retained glucose metabolism even for CDR > 0.5. {blacksquare}NMF models of glucose metabolism are consistent with models arising from principal components, or eigenbrains, while adding additional regional interpretability. {blacksquare}NMF patterns correlated with regions catalogued in Neurosynth. Following corrections for spatial autocorrelations, NMF patterns revealed meta-analytic identifications of patterns with Neurosynth topics of fear/reward, attention, memory, language, and movement with motor planning. Patterns varied with degrees of cognitive impairment.