Locus Coeruleus MRI Contrast is Associated with Complement Factor C3b in Cerebrospinal Fluid

Background Degeneration of the Locus coeruleus (LC) is associated with Alzheimer’s disease (AD) pathology and cognitive decline. Recent evidence from animal models indicates that this relationship may be mediated by neuroinflammation. Here we examined how LC MRI contrast is related to CSF biomarkers of neuroinflammation in humans. Method The LC as well as the Substantia nigra (SN) were visualized and segmented using neuromelanin‐sensitive T 1 ‐weighted FLASH‐MRI images acquired at 3T and MRI contrast values were calculated as previously described (Betts et al., 2019b). A cohort of 65 participants with MRI contrast and CSF data from the DZNE longitudinal cognitive impairment and dementia (DELCODE) study (20 HC, 22 SCD, 16 MCI, 7 AD dementia; 53.8% female) were included in the analyses. We performed correlational analyses to test for associations between LC and SN contrast with a panel of 4 Principal Components (PC) created from a Principial Component Analysis on 16 individual inflammation‐related CSF biomarkers (Fig. 1). Both bivariate and partial correlation analyses were performed between PCs and MRI contrast values using sex, age, site and CSF levels of AD pathology, namely Aß42/40‐ratio and phosphorylated tau, as covariates (see Fig. 2). Result We found a significant positive association between LC MRI contrast and the inflammatory component PC4 including the proinflammatory complement factors C3 and C3b across the entire sample (r = 0.365, p = 0.003). Additional post‐hoc correlational analyses showed this association with LC MRI contrast was mainly due to a correlation with C3b (r = 0.349, p = 0.004). A significant positive association was still observed (r = 0.347, p = 0.008) in a subgroup of individuals comprising healthy older adults and individuals with a risk of AD dementia (HC, SCD and MCI) as shown in Fig. 2. In contrast, no significant associations between SN MRI contrast and any neurodegenerative or inflammatory measure were observed indicating effects were specific to the LC. Conclusion The results demonstrate LC MRI contrast is associated with complement factors in CSF, in particular complement factor C3b in healthy older adults and individuals with a risk of AD dementia. Further analyses are required to determine if elevated complement factors may predict degeneration of the LC and subsequent cognitive decline.