Distinct associations of corticolimbic hypometabolism and atrophy patterns correlate with postmortem neuropathologies in cognitively impaired individuals

Biological heterogeneity in cognitively impaired individuals has been described by distinct hypometabolic (FDG-PET) and atrophy (MRI) corticolimbic neurodegeneration patterns. However, the neuroimaging modalities can show different patterns at the individual-level. This study investigated whether postmortem neuropathologies may explain these differences. The study includes 245 individuals, 69 with cognitive impairment who underwent in vivo neuroimaging and neuropathological assessment and 176 cognitively unimpaired individuals as a reference group. Neurodegeneration patterns were identified in both in vivo FDG-PET and MRI, and their link to postmortem AD (amyloid-beta, tau) and non-AD (CAA, alpha-synuclein, TDP-43, and hippocampal sclerosis) pathologies was examined. In vivo individual-level differences of hypometabolic and atrophy neurodegeneration patterns could be associated to different AD and non-AD pathologies postmortem. The patterns significantly differed by neuropathology and neuronal loss at the regional-level but not global-level. Specifically, limbic predominant atrophy was related to distant (neocortical) amyloid, tau, and arteriolosclerosis while limbic predominant hypometabolism with local (mediotemporal) tau and arteriolosclerosis. Both limbic atrophy and hypometabolism reflected local (mediotemporal) TDP-43 and neuronal loss, with limbic hypometabolism additionally reflecting neocortical neuronal loss. Cortical predominant atrophy and hypometabolism were correlated with local (neocortical) alpha synuclein. Neurodegeneration patterns differentially reflect underlying pathologies. Specifically, limbic predominant patterns were more frequently associated with TDP-43 pathology and hippocampal sclerosis, whereas cortical predominant patterns more often reflected cerebrovascular disease and alpha-synuclein pathology. Differences between corticolimbic hypometabolic and atrophy patterns were observed only in cases with postmortem-confirmed AD pathology, suggesting that non-AD pathologies (TDP-43, hippocampal sclerosis, cerebrovascular disease, and alpha-synuclein) may differentially modify AD-related neurodegeneration.