Locus coeruleus tau validates and informs high-resolution MRI in aging and at earliest Alzheimer's pathology stages.

Abstract

The locus coeruleus (LC) has been identified as a site that develops phosphorylated tau pathology earlier than cerebral cortex. We present data using high-resolution postmortem MRI and validated tau histopathology in controls and the earliest Braak and Braak (BB) stages (BBI-BBII) in LC. The high-resolution ex vivo MRI provides a 3D volume (quantitative), while the histology reveals tau specificity and severity burden (semi-quantitative). We mapped our highly regionally specific LC data onto high-resolution 3D MRI reconstructions of the same samples used in histology (n = 11). We noted significant structural subatrophy between BB 0 and II (30.0% smaller volumes, p = 0.0381), a trend which primarily affected the rostral-most LC (49.2% smaller average volume, p = 0.0381). We show histopathology data on both the LC and neighboring dorsal raphe caudal (DRc), which were assessed at multiple rostrocaudal levels and mapped with highly sensitive tau severity spatial matrices. We observed significant LC tau accumulation between BB I and II (37.6% increase, p < 0.0001), which may reflect pathology change prior to presumptive cognitive impairment at BB III. Tau pathology was most severe in the middle portion of the LC (11.3% greater compared to rostral LC, p = 0.0289) when including BB III. We noted a significant rostrocaudal gradient of DRc tau severity (58.2% decrease between rostral and caudal DRc, p < 0.0001), suggesting selective regional vulnerabilities of both nuclei. Our study represents a rigorous approach to investigating LC and DRc pathology, having multiple histology sections per sublevel and high-resolution MRI to measure the whole LC, without missing slices in a histological only approach. Taken together, our findings provide novel validated data that demonstrate the tau pathology occurring in the LC and DRc during preclinical AD stages, and alongside spatial reconstructions that will serve as valuable references for in vivo LC imaging.