A multimodal clinical diagnostic approach using MRI and ¹⁸F-FDG-PET for antemortem diagnosis of TDP-43 in cases with low–intermediate Alzheimer’s disease neuropathologic changes and primary age-related tauopathy

Objective: To evaluate the utility of clinical assessment scales for MRI and ¹⁸F-FDG-PET as potential in vivo predictive diagnostic tools for TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy in cases with low–intermediate Alzheimer's disease neuropathologic changes (ADNC) and primary age-related tauopathy (PART). Methods: We conducted a cross-sectional analysis on patients with antemortem MRI and ¹⁸F-FDG-PET scans and postmortem diagnosis of low–intermediate ADNC or PART (Braak stage ≤ III; Thal β-amyloid phase 0–5). We employed visual imaging scales to grade structural changes on MRI and metabolic changes on ¹⁸F-FDG-PET and statistically compared demographic and clinicopathological characteristics between TDP-43 positive and negative cases. Independent regression analyses were performed to assess further influences of pathological characteristics on imaging outcomes. Within-reader repeatability and inter-reader reliability were calculated (CI = 0.95). Additional quantitative region-of-interest analyses of MRI gray matter volumes and PET ligand uptake were performed. Results: Of the 64 cases in the study, 20 (31%) were TDP-43 (+), of which 12 (60%) were female. TDP-43 (+) cases were more likely to have hippocampal sclerosis (HS) (p = 0.014) and moderate–severe medial temporal lobe atrophy on MRI (p = 0.048). TDP-43(+) cases also showed a trend for less parietal atrophy on MRI (p = 0.086) and more medial temporal lobe hypometabolism on ¹⁸F-FDG-PET (p = 0.087) than TDP-43(–) cases. Regression analysis showed an association between medial temporal hypometabolism and HS (p = 0.0113). ICC values for MRI and PET within one reader were 0.75 and 0.91; across two readers were 0.79 and 0.82. The region-of-interest-based analysis confirmed a significant difference between TDP-43(+) and TDP-43(–) cases for medial temporal lobe gray matter volume on MRI (p = 0.014) and medial temporal metabolism on PET (p = 0.011). Conclusion: Visual inspection of the medial temporal lobe on MRI and FDG-PET may help to predict TDP-43 status in the context of low–intermediate ADNC and PART.