Elevated C-Reactive Protein in Older Men With Chronic Pain: Association With Plasma Amyloid Levels and Hippocampal Volume

Abstract

Background: Chronic pain leads to tau accumulation and hippocampal atrophy, which may be moderated through inflammation. In older men, we examined associations of chronic pain with Alzheimer's disease (AD)-related plasma biomarkers and hippocampal volume as moderated by systemic inflammation.

Methods: Participants were men without dementia. Chronic pain was defined as moderate-to-severe pain in 2+ study waves at average ages 56, 62, and 68. At age 68, we measured plasma amyloid-beta (Aβ42, n = 871), Aβ40 (n = 887), total tau (t-tau, n = 841), and neurofilament light chain (NfL, n = 915), and serum high-sensitivity C-reactive protein (hs-CRP, n = 968), a marker of systemic inflammation. A subgroup underwent structural MRI to measure hippocampal volume (n = 385). Analyses adjusted for medical morbidities, depressive symptoms, and opioid use.

Results: Chronic pain was related to higher Aβ40 (β = 0.25, p = .009), but hs-CRP was unrelated to AD-related biomarkers (ps > .05). There was a significant interaction such that older men with both chronic pain and higher levels of hs-CRP had higher levels of Aβ42 (β = 0.36, p = .001) and Aβ40 (β = 0.29, p = .003). Chronic pain and hs-CRP did not interact to predict levels of Aβ42/Aβ40, t-tau, or NfL. Furthermore, there were significant interactions such that Aβ42 and Aβ40 were associated with lower hippocampal volume, particularly when levels of hs-CRP were elevated (hs-CRP × Aβ42: β = -0.19, p = .002; hs-CRP × Aβ40: β = -0.21, p = .001), regardless of chronic pain status.

Conclusions: Chronic pain was associated with higher plasma Aβ, especially when hs-CRP was also elevated. Higher hs-CRP and Aβ levels were both related to smaller hippocampal volumes. Chronic pain, when accompanied by systemic inflammation, may elevate the risk of neurodegeneration in AD-vulnerable regions.

Keywords: Amyloid-beta; Chronic pain; Hippocampus; Inflammation; Plasma biomarkers.

Figure 1.

Association of hs-CRP with Aβ42 and with AB40 in men with chronic pain and without chronic pain (Aβ42 n = 871; Aβ40 n = 887). Aβ42 = amyloid-beta 42; Aβ40 = amyloid-beta 40; hs-CRP = high-sensitivity serum C-reactive protein. hs-CRP and Aβ42 and hippocampal volume values are z-scored for ease of interpretability.

Figure 2.

Differences in Aβ42 level and Aβ40 by severity of hs-CRP level in men with chronic pain and without chronic pain (CP+ versus CP−; Aβ42 n =871; Aβ40 n = 887). Aβ42 = amyloid-beta 42; Aβ40 = amyloid-beta 40; hs-CRP = high-sensitivity serum C-reactive protein. Aβ42 values were z-scored for ease of interpretability. hs-CRP levels represent tertiles of low (0 to 0.40 mg/dL), mild (0.40 to 2.60 mg/dL), moderate (2.61 to 4.70 mg/dL) and high values (4.71 to 19.00* mg/dL, *upper values winsorized at 3 SD or 19.00).

Figure 3.

The association of Aβ42 and hippocampal volume by hs-CRP level (n = 331). Aβ42 = amyloid-beta 42; Aβ40 = amyloid-beta 40; hs-CRP = high-sensitivity serum C-reactive protein. Aβ42 and hippocampal volume values were z-scored for ease of interpretability. hs-CRP levels represent tertiles of low (0 to 0.40 mg/dL), mild (0.40 to 2.60 mg/dL), moderate (2.61 to 4.70 mg/dL) and high values (4.71 to 19.00* mg/dL, *upper values winsorized at 3 SD or 19.00). The figure illustrates that the relationship of Aβ42 and hippocampal volume is steeper (ie, stronger) at higher levels of hs-CRP.