Spatial Dissociation of Atrophy and Hypophysiology in Alzheimer's Disease: Implications for Biomarkers

The Amyloid/Tau/Neurodegeneration (A/T/N) biomarker framework is used for in vivo pathological profiling of Alzheimer's disease. A binary (+/-) label is assigned for each pathology (A, T, N) based on its presence or absence as determined by imaging or fluid biomarkers. Using imaging, neurodegeneration is confirmed by either structural MRI (indicating atrophy) or 18F-FDG PET (indicating hypometabolism), implicitly assuming that both modalities identify equivalent pathology. Preliminary evidence suggests that atrophy and hypometabolism do not spatially co-localize and are likely caused by distinct underlying pathologies. Further, while MRI is widely available, many sites lack access to PET. Recent evidence indicates that hemodynamic indices, identified via functional MRI or SPECT, may be spatially concordant with hypometabolism identified by 18F-FDG-PET and able to serve as reliable proxies. Coordinate-based meta-analyses of voxel-based morphometry and voxel-based physiology reports in Alzheimer's disease, collectively analyzing 139 articles (4218 individuals) were performed to test the following hypotheses: (1) that atrophy and hypometabolism in AD are spatially dissociated; (2) that hemodynamic indices exhibit the same spatial distributions as hypometabolism identified by PET; (3) that regions of atrophy and hypometabolism involve different functional systems and cognitive operations. Results confirmed all three hypotheses. Separation of atrophy and hypometabolism into two distinct subcategories of neurodegeneration as well as the development of regionally specific biomarkers for each are in order.