Brain-predicted Age Difference Mediates the Association between Self-reported Pain and PROMIS Sleep Impairment in Persons with Knee Osteoarthritis.

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Knee osteoarthritis (KOA) is the most common cause of musculoskeletal pain (MSK), constituting a major public health burden. Sleep is among the multiple factors contributing to KOA-related pain, as sleep disturbance increases risk for worse pain-related outcomes in KOA. In addition, our lab found that brain cortical structure mediated the relationship between sleep qualities and pain severity in older adults with MSK. Further, using a machine-learning-based brain-aging biomarker (brain-PAD; brain-predicted age minus chronological age), we also found that individuals with high-impact KOA pain showed greater brain aging than their low-impact pain counterparts. Considering this, we examined whether brain-PAD mediated the relationship between KOA pain and sleep problems. KOA participants (mean age 57.9 years) were classified into low-impact (n=87), and high-impact (n=60) pain. Demographic, pain and sleep assessments were followed by a T1-weighted anatomical scan. Exploratory Spearman and Pearson partial correlations, controlling by age, sex and race, were used to determine associations of brain-PAD with clinical pain and sleep measures. We then tested if brain-PAD mediated the sleep-pain association using PROCESS 3.5 on SPSS 28. Brain-PAD correlated with the affective domain of the McGill Pain Questionnaire (MPQ) (r=0.215, p=0.010) and MPQ total score (r=0.181, p=0.033). Moreover, Brain-PAD significantly mediated (bootstrapped 95% CIs p<0.05) the effect of the short form PROMIS Sleep impairment total score on the MPQ affective, continuous and total score. Brain-PAD did not significantly mediate the sleep-pain effect. Our finding in this KOA sample extends our prior work demonstrating advanced brain aging among older individuals with chronic pain and more pain severity, implicating brain-PAD as a significant mediator of the sleep-KOA pain association. Future replication studies are needed, as well as studies to further understand if the brain can be a therapeutic target to reverse the possible effect of sleep problems on chronic pain. Funding from NIAR01AG067757.