Microstructural assessment of the locus coeruleus‐entorhinal cortex pathway and association with ATN markers in patients with cognitive impairment

Abstract Background This study investigated microstructural features of the locus coeruleus to entorhinal cortex pathway (LC‐EC) in relation to amyloid (A), tau (T), neurodegeneration (N) markers and cognitive impairment in memory clinic patients. Method 124 participants were recruited from the Geneva Memory Clinic (n=30 cognitively unimpaired – CU; n=80 MCI and n=14 dementia ‐ CI) and underwent clinical assessment, 3T MRI scan including diffusion weighted imaging, amyloid PET, and tau PET. Diffusivity indices (fractional anisotropy ‐ FA, mean, axial and radial diffusivities ‐ MD, AxD, RD) were assessed in the LC‐EC pathway using a probabilistic atlas. A, T, N markers were assessed both as continuous and dichotomous measures. Differences in LC‐EC microstructure according to ATN markers and diagnosis were assessed with ANOVA models (FDR correction). Linear regression models were used to test whether LC‐EC pathway microstructure predicted cognitive impairment independently of ATN markers. Result Lower FA (p=0.020) and higher MD, RD and AxD (p<0.005) was observed in participants with tau positivity in the EC (TEC+, Braak stage >1) compared to tau negative subjects (TEC‐). Higher MD, RD and AxD was observed in neurodegeneration positive (N+, medial temporal atrophy) versus negative (N‐) participants (p<0.001), and CI versus CU (p<0.016). There was no difference in LC‐TE microstructure between amyloid positive (A+) and negative (A‐) subjects (p>0.05) nor between tau positive (T+; Braak stage >4) and negative (T‐) subjects (p>0.05). The regression model showed that RD of the LC‐EC tract was associated with clinical diagnosis and mini mental state examination score independently of ATN markers (p<0.05). Conclusion Our results indicate that LC‐EC microstructural measures, specifically RD, are sensitive in detecting CI and provide complementary information over ATN biomarkers. Associations with T suggest that LC‐TE microstructural alterations show regional specificity in the EC.