Changes in the locus coeruleus during the course of Alzheimer's disease and their relationship to cortical pathology.

Abstract

In Alzheimer's disease (AD), the locus coeruleus (LC) undergoes early and extensive neuronal loss, preceded by abnormal intracellular tau aggregation, decades before the onset of clinical disease. Neuromelanin-sensitive MRI has been proposed as a method to image these changes during life. Surprisingly, human post-mortem studies have not examined how changes in LC during the course of the disease relate to cerebral pathology following the loss of the LC projection to the cortex. Immunohistochemistry was used to examine markers for 4G8 (pan-Aβ) and AT8 (ptau), LC integrity (neuromelanin, dopamine β-hydroxylase [DβH], tyrosine hydroxylase [TH]) and microglia (Iba1, CD68, HLA-DR) in the LC and related temporal lobe pathology of 59 post-mortem brains grouped by disease severity determined by Braak stage (0-II, III-IV and V-VI). The inflammatory environment was assessed using multiplex assays. Changes in the LC with increasing Braak stage included increased neuronal loss (p< 0.001) and microglial Iba1 (p= 0.005) together with a reduction in neuromelanin (p< 0.001), DβH (p= 0.002) and TH (p= 0.041). Interestingly in LC, increased ptau and loss of neuromelanin were detected from Braak stage III-IV (p= 0.001). At Braak stage V/VI, the inflammatory environment was different in the LC vs TL, highlighting the anatomical heterogeneity of the inflammatory response. Here, we report the first quantification of neuromelanin during the course of AD and its relationship to AD pathology and neuroinflammation in the TL. Our findings of neuromelanin loss early in AD and before the neuroinflammatory reaction support the use of neuromelanin-MRI as a sensitive technique to identify early changes in AD.