Chronic musculoskeletal pain is a health burden that may accelerate the aging process.Accelerated brain aging and epigenetic aging have separately been observed in those with chronic pain. However, it is unknown whether these biological markers of aging are associated with each other in those with chronic pain. We aimed to explore the association of epigenetic aging and brain aging in middle-to-older age individuals with varying degrees of knee pain.Participants (57.91 ± 8.04 y) with low impact knee pain (n = 95), high impact knee pain (n = 53), and pain-free controls (n = 26) completed self-reported pain, a blood draw, and an MRI scan. We used an epigenetic clock previously associated with knee pain (DNAmGrimAge), the subsequent difference of predicted epigenetic and brain age from chronological age (DNAmGrimAge-Difference and Brain-PAD, respectively). There was a significant main effect for pain impact group (F (2,167) = 3.847, P = 0.023, rotational energy = 1/2Iω2= 0.038, ANCOVA) on Brain-PAD and DNAmGrimAge-difference (F (2,167) = 6.800, P = 0.001, I = mk2 = 0.075, ANCOVA) after controlling for covariates.DNAmGrimAge-Difference and Brain-PAD were modestly correlated (r =0.198; P =0.010).Exploratory analysis revealed that DNAmGrimAge-difference mediated GCPS pain impact, GCPS pain severity, and pain-related disability scores on Brain-PAD. Based upon the current study findings, we suggest that pain could be a driver for accelerated brain aging via epigenome interactions.

Purpose Knee OA-related pain varies in impact across individuals and may relate to central nervous system alterations like accelerated brain aging processes. We previously reported that older adults with chronic musculoskeletal pain had a significantly greater brain-predicted age, compared to pain-free controls, indicating an “older” appearing brain. Yet this association is not well understood. This cross-sectional study examines brain-predicted age differences associated with chronic knee osteoarthritis pain, in a larger, more demographically diverse sample with consideration for pain’s impact. Patients and Methods Participants (mean age = 57.8 ± 8.0 years) with/without knee OA-related pain were classified according to pain’s impact on daily function (ie, impact): low-impact (n=111), and high-impact (n=60) pain, and pain-free controls (n=31). Participants completed demographic, pain, and psychosocial assessments, and T1-weighted magnetic resonance imaging. Brain-predicted age difference (brain-PAD) was compared across groups using analysis of covariance. Partial correlations examined associations of brain-PAD with pain and psychosocial variables. Results Individuals with high-impact chronic knee pain had significantly “older” brains for their age compared to individuals with low-impact knee pain (p < 0.05). Brain-PAD was also significantly associated with clinical pain, negative affect, passive coping, and pain catastrophizing (p’s<0.05). Conclusion Our findings suggest that high impact chronic knee pain is associated with an older appearing brain on MRI. Future studies are needed to determine the impact of pain-related interference and pain management on somatosensory processing and brain aging biomarkers for high-risk populations and effective intervention strategies.

Background and Objectives Somatosensory function is critical for successful aging. Prior studies have shown declines in somatosensory function with age; however, this may be affected by testing site, modality, and biobehavioral factors. While somatosensory function declines are associated with peripheral nervous system degradation, little is known regarding correlates with the central nervous system and brain structure in particular. The objectives of this study were to examine age-related declines in somatosensory function using innocuous and noxious stimuli, across 2 anatomical testing sites, with considerations for affect and cognitive function, and associations between somatosensory function and brain structure in older adults. Research Design and Methods A cross-sectional analysis included 84 “younger” (n = 22, age range: 19–24 years) and “older” (n = 62, age range: 60–94 years) healthy adults who participated in the Neuromodulatory Examination of Pain and Mobility Across the Lifespan study. Participants were assessed on measures of somatosensory function (quantitative sensory testing), at 2 sites (metatarsal and thenar) using standardized procedures, and completed cognitive and psychological function measures and structural magnetic resonance imaging. Results Significant age × test site interaction effects were observed for warmth detection (p = .018, ηp2= 0.10) and heat pain thresholds (p = .014, ηp2= 0.12). Main age effects were observed for mechanical, vibratory, cold, and warmth detection thresholds (ps &lt; .05), with older adults displaying a loss of sensory function. Significant associations between somatosensory function and brain gray matter structure emerged in the right occipital region, the right temporal region, and the left pericallosum. Discussion and Implications Our findings indicate healthy older adults display alterations in sensory responses to innocuous and noxious stimuli compared to younger adults and, furthermore, these alterations are uniquely affected by anatomical site. These findings suggest a nonuniform decline in somatosensation in older adults, which may represent peripheral and central nervous system alterations part of aging processes.

Introduction: Psychological factors have been associated with knee osteoarthritis pain severity and treatment outcomes, yet their combined contribution to phenotypic heterogeneity is poorly understood. In particular, empirically derived psychological profiles must be replicated before they can be targeted or considered for treatment studies. The objectives of this study were to (1) confirm previously identified psychological profiles using unsupervised clustering methods in persons with knee osteoarthritis pain, (2) determine the replicability of profiles using supervised machine learning in a different sample, and (3) examine associations with clinical pain, brain structure, and experimental pain. Methods: Participants included two cohorts of individuals with knee osteoarthritis pain recruited as part of the multisite UPLOAD1 ( n = 270, mean age = 56.8 ± 7.6, male = 37%) and UPLOAD2 ( n = 164, mean age = 57.73 ± 7.8, male = 36%) studies. Similar psychological constructs (e.g. optimism, coping, somatization, affect, depression, and anxiety), sociodemographic and clinical characteristics, and somatosensory function were assessed across samples. UPLOAD2 participants also completed brain magnetic resonance imaging. Unsupervised hierarchical clustering analysis was first conducted in UPLOAD1 data to derive clusters, followed by supervised linear discriminative analysis to predict group membership in UPLOAD2 data. Associations among cluster membership and clinical variables were assessed, controlling for age, sex, education, ethnicity/race, study site, and number of pain sites. Results: Four distinct profiles emerged in UPLOAD1 and were replicated in UPLOAD2. Identified psychological profiles were associated with psychological variables ( ps < 0.001), and clinical outcomes ( ps = 0.001–0.03), indicating good internal and external validation of the cluster solution. Significant associations between psychological profiles and somatosensory function and brain structure were also found. Conclusions: This study highlights the importance of considering the biopsychosocial model in knee osteoarthritis pain assessment and treatment.

ContextVitamin D is an essential, fat soluble micronutrient long-known for its effects on calcium homeostasis and bone health. With advances in technology, it is being discovered that Vitamin D exerts its effects beyond the musculoskeletal system. Vitamin D has since been noted in nervous system health and functioning, and is becoming a target of interest in brain health, aging, and chronic pain outcomes.ObjectivesWe and others have previously shown that deficient Vitamin D status is associated with greater pain severity across a variety of conditions, however the reason as to why this relationship exists is still being understood. Here, we sought to examine associations between Vitamin D status and brain structure in those with chronic knee pain.MethodsStructural MRI imaging techniques and whole brain analyses were employed and serum Vitamin D were collected on 140 participants with chronic pain. Covariates included age, sex, race and site, as these data were collected at two separate institutions. ANOVAs using the clinical cut points for Vitamin D status (deficient, insufficient, and optimal) as well as continuous regression-based Vitamin D effects were employed to observe differences in brain volume. P-value was set to 0.017 after correction for multiple comparisons.ResultsWe discovered that individuals in our sample (age = 50+; 63.6% female; 52.1% Non-Hispanic Black) who were either clinically deficient (&lt;20 ng/mL) or insufficient (20–30 ng/mL) in serum Vitamin D had significant differences in the gray matter of the left circular insular cortex, left inferior temporal gyrus, right middle temporal gyrus, as well as decreased white matter surface area in the right inferior temporal gyrus compared to those considered to have optimal levels (&gt;30 ng/mL) of serum Vitamin D.ConclusionEvidence from these data suggests that Vitamin D, or lack thereof, may be associated with pain outcomes by mediating changes in regions of the brain known to process and interpret pain. More research understanding this phenomenon as well as the effects of Vitamin D supplementation is warranted.

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