Biomarkers.

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 (T+, Braak stage ≥1) compared to tau negative subjects (T-). 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.