Work

Lower LC activity during high arousal conditions is related to greater plasma P‐Tau217 concentration in older individuals

Year: 2023

Type: article

Abstract: Background The noradrenergic locus coeruleus (LC) nucleus is critical in regulating many brain functions and processes, including arousal and emotion. Autopsy studies suggested that the LC is one of the earliest regions harboring hyperphosphorylated tau. Previous imaging work demonstrated that lower novelty‐related LC activity correlates with tau deposition in the entorhinal cortex. Here, we investigated the variability in activity across the rostro‐caudal LC under different arousal levels and its relationship with plasma markers of phosphorylated tau, including p‐tau231, p‐tau217, and p‐tau181. Method 61 individuals (age range = [51,85], Male = 30) underwent a task‐based 7T BOLD‐fMRI scan and fasting blood draw. The task consisted of 100 high‐ or low‐arousing context images. The fMRI data were preprocessed using a brainstem‐specific denoising methodology to increase the LC signal‐to‐noise ratio. P‐tau181 and p‐tau231 were measured using in‐house Simoa methods, and p‐tau217 using MSD immunoassay. Voxel‐wise linear model analyses were performed to detect brainstem regions exhibiting significant high>low arousal (h>l) activation. Average h>l contrast values across activated voxels within an ex‐vivo validated LC region of interest (ROI) were extracted, and age‐ and sex‐adjusted associations between LC activity and p‐tau were evaluated using robust linear regression. Similar associations were also investigated for a control ROI defined ventral to the LC. Result We observed greater h>l activation of voxels in the bilateral LC (p<0.05 uncorrected–Fig.1A). We observed no regional differences in h>l activity along the LC rostral‐caudal axis (Fig.1B). Post‐hoc Mann‐Kendall trend analyses revealed a negative‐to‐positive trend in h>l LC activity across caudal‐to‐rostral LC. Lower h>l LC activity was associated with greater p‐tau217 (p = 0.042–Fig.2A). No significant associations were observed between h>l LC activity and either p‐tau231 or p‐tau181 (p>0.05–Fig.2B‐C), or between h>l activity in the control ROI and any plasma marker (p>0.05–Fig.2D‐F). Conclusion Our results show that lower h>l LC activation is associated with greater concentrations in p‐tau217. As p‐tau217 has been shown to correlate with LC neuronal loss, cortical tau‐ and amyloid‐β‐PET measures, our results suggest that LC dysfunction in higher states of arousal may signal LC degeneration. Future work includes investigating the mediating role of amyloid‐β on the observed relationship between h>l LC activation and p‐tau217.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz.079974