Limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC) are characterized by phosphorylated TDP-43 aggregates in limbic regions, often co-occurring with Alzheimer's disease (AD) pathology, amplifying clinical and neuroimaging alterations. In vivo biomarkers for LATE-NC are lacking, but changes in CSF TDP-43 levels may reflect LATE-NC in AD patients. This study explored the correlation between CSF TDP-43 and [18F]FDG PET metrics in prodromal AD, providing insights into the impact of LATE-NC on AD brain metabolism.

We measured CSF TDP-43 levels using an ultrasensitive immunoassay in 27 MCI-AD patients. To analyze brain metabolism, we employed both a volume of interest (VOI)-based approach and a voxel-based analysis (VBA) of [18F]FDG PET scans. The VOI-based approach focused on metabolic values from regions associated with LATE-NC, such as the inferior (IT) and medial temporal (MT) regions, in previous studies. Through VBA, we explored the CSF TDP-43-related brain regions and their spatial association with relative hypometabolism compared with 40 healthy controls (HC), adjusting for relevant covariates.

CSF TDP-43 levels directly correlated with metabolism in the temporo-parietal cortex, particularly the bilateral precuneus, and showed spatial independence from relative hypometabolic areas. The VOI analysis revealed no significant correlations between TDP-43 and the MT-VOI, IT-VOI, or their ratio.

TDP-43 pathology in prodromal AD, as indicated by elevated CSF TDP-43 levels, contributes to metabolic disruptions in posterior parietal regions, particularly the precuneus. These changes diverge from typical amyloid- and tau-related alterations, offering indirect in vivo insights into TDP-43 co-pathology in prodromal AD.