Persistent pain is associated with lower locus coeruleus integrity in older adults

Abstract

AbstractBackgroundPersistent pain has been recently linked to increased Alzheimer’s disease (AD) risk, calling for the identification of related AD biomarkers. One biomarker of interest is integrity of the locus coeruleus (LC), a brainstem region that is thought to be the earliest site of tau deposition in the brain. The LC is also the main projection site for norepinephrine (NE), a major neurotransmitter inhibiting pain via rostral and caudal LC projections. A recently proposed mechanism suggests that persistent pain alters LC‐NE function and advances AD pathology in this region, explaining increased AD risk. Here we examined the association between persistent pain and LC integrity in older adults.MethodData were derived from the Vietnam Era Twin Study of Aging (VETSA) in which community‐dwelling men were assessed across up to 12 years in 3 waves. At the third wave, 426 community‐dwelling men (mean age = 67.55) underwent MRI‐assessment sensitive to neuromelanin, a byproduct of LC NE production. Using neuromelanin signal intensities, we calculated contrast‐to‐noise ratios between LC regions (i.e., rostral and caudal) and a pontine tegmentum reference region. Higher contrast‐to‐noise ratios indicate better LC integrity. Persistent pain was defined as reporting 2 or more waves of moderate‐to‐severe pain on the SF‐36 Bodily Pain Scale (n = 80, 16.5%). Generalized linear models examined associations between persistent pain and LC integrity after weighting for survival effects and adjusting for demographic (i.e., age, race, young adult general cognitive ability, income) and health confounders (i.e., comorbidities, depressive symptoms, opioid use), and nested twin observations.ResultPersistent pain was associated with .21 standard deviation lower rostral LC integrity (95% CI: ‐.40 to ‐.03) and .23 standard deviation lower caudal LC integrity at the third wave (95% CI: ‐.44 to ‐.04).ConclusionPersistent pain was associated with worse LC integrity in older adults. Persistent pain related to worse integrity in both the rostral and caudal LC regions. These associations are consistent with the recent proposed mechanism emphasizing the role of pain on LC‐NE dysfunction, but this relationship may also be bidirectional. Longitudinal designs would be informative, as would studies looking at later dementia trajectories.