Neuropathology of the Locus Coeruleus in Alzheimer's disease

Abstract

The LocusCoeruleus (LC) undergoes extensive neuronal loss in Alzheimer’s Disease (AD)early in the disease process. Depletion of cortical noradrenaline (NA)concentration as a result of LC degeneration, has proinflammatory effects onmicroglia and likely contributes to the neuroinflammation observed in AD.Furthermore, abnormal intracellular tau aggregation associated with AD is firstobserved within the LC, decades prior to disease onset and LC neuron loss. Thissuggests neuropathology in AD originates in the LC, however this has been underappreciated and under-investigated because of a lack of non-invasive, directmeasures of LC activity.
Using a high-resolution magnetic resonance imaging(MRI) technique, the LC can be visualised in vivo. This pilot study assessedthe feasibility of detecting signal intensity (SI) changes of the LC using adeveloped neuromelanin-sensitive imaging protocol in 24 participants with AD(12 mild AD, 12 moderate AD) and 24 age and gender matched cognitivelyunimpaired subjects. LC-SI was calculated by comparing maxima values in theanatomical location of the LC to a reference region in the adjacent pontinetegmentum to give a contrast ratio (LC-CR). LC-CR was lower in both the mildand moderate AD groups compared to controls (p<0.05), however there was nodifference in LC signal between mild and moderate AD groups. This suggests LCsignal decreases occur early in the disease and that NM-MRI of the LC could beused as a biomarker for AD diagnosis. LC-CR correlated with SMMSE score(p=0.032) but did not correlate with peripheral inflammatory blood markers orindirect measures of LC activity including pupil size and task-evoked bloodpressure changes.
Whilst LC cell loss and p-tau accumulation havebeen well studied in humans, surprisingly post-mortem studies have not examinedinflammatory changes occurring within the LC and how these relate to LC neuronloss, extracellular neuromelanin deposits and changes seen in LC projectionareas. Immunohistochemistry was used to examine markers for AD pathology, LCcell integrity, inflammation and neuromelanin in both the LC and temporalcortex of 60 post-mortem tissue samples grouped by disease severity determinedby Braak stage (0-II, III-IV and V-VI). In the LC, disease severity wasassociated with LC neuronal loss (p<0.001), Aβ (p<0.001) and p-tau(p<0.001) accumulation, increased extraneuronal neuromelanin deposits(p<0.001) and increased inflammation evidenced by increased motility of microglia(p<0.001). This correlated with p-tau (p<0.001) and Aβ pathology(p<0.001) but not inflammatory markers in the temporal cortex.
A better understanding of the role of the LC-NAsystem in AD may inform on whether the pharmacological elevation of NA would besuccessful in slowing disease progression and at which time-points it should beadministered. If NA manipulation was able to delay AD pathology, then earlydetection and monitoring of LC degeneration in vivo using NM-MRI as a biomarkerwould enable targeting of therapies

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