Breast cancer survivorsCancer-related cognitive impairmentCognitive functionDepressionInflammation

Depression, Inflammation, and Intestinal Permeability: Associations with Subjective and Objective Cognitive Functioning throughout Breast Cancer Survivorship

  • 2023
  • Annelise A. Madison, Rebecca Andridge, Anthony H. Kantaras, et al.
Why this matters for your gut health

About one in three breast cancer survivors has lingering cognitive complaints and objective cognitive impairment. Depression, chronic inflammation and a “leaky gut” are all risk factors for cognitive decline, and they can reinforce one another. This large study suggests that depressed survivors who also have high inflammation or high intestinal permeability perceive their concentration and memory problems as worse. Subjective cognitive problems reduce quality of life, self-confidence and relationships, so they deserve clinical attention even when test scores look similar.

Summary

This is a secondary analysis of four breast cancer survivor studies (613 women, 1015 study visits, per the abstract). It tested whether clinically significant depressive symptoms (CES-D ≥ 16), combined with high inflammation (an index of CRP, IL-6 and TNF-α) or high intestinal permeability (measured by lipopolysaccharide-binding protein, LBP), predicted worse subjective or objective cognition. All models were adjusted for education, age, BMI, cancer treatment, time since treatment, study visit and fatigue. Depression combined with high inflammation or high LBP was linked to poorer self-reported focus and marginally poorer memory. On neuropsychological tests, depression alone predicted worse performance across several domains, regardless of inflammation or gut permeability. Inflammation alone did not reliably predict cognition, while higher LBP predicted slower response times on some tasks. The authors suggest that survivors with inflammation- or leaky-gut-associated depression may be more aware of their cognitive deficits.

Key findings

  • 26% of visits (n = 285) met the cutoff for clinically significant depressive symptoms. Elevated CRP (>3 mg/L) was more common at depressed visits (34.0%) than at non-depressed visits (25.8%).
  • Depression and inflammation interacted to predict Kohli focus problems (p = 0.010) and marginally memory problems (p = 0.091), but not BCPT scores. The effect was strongest in depressed women with high inflammation.
  • Depression and intestinal permeability (LBP) interacted to predict focus problems (p = 0.038) and marginally memory problems (p = 0.086), but not BCPT scores.
  • Depression alone predicted worse subjective cognition on all three measures: BCPT (p ≤ 0.001), Kohli focus (p < 0.001) and Kohli memory (p < 0.001).
  • Inflammation alone did not predict subjective cognitive function (all p > 0.79), and LBP alone did not either (all p > 0.12).
  • On objective tests, depressed survivors had more CPT commission errors (p = 0.009), poorer target detection (p = 0.0008), lower 2-back accuracy (p = 0.027), fewer words on the FAS verbal fluency test (p = 0.011), poorer HVLT recall (p = 0.003) and slower Trail B times (p = 0.004).
  • Depression combined with inflammation or LBP did not exacerbate most objective deficits. HVLT total recall went in the opposite direction: depressed women recalled fewer words only at low or average inflammation, not at high levels.
  • Higher LBP alone predicted slower 2-back response times (p = 0.016) and slower Trail A completion (p = 0.024), independent of fatigue. This may point to psychomotor slowing.
  • Substituting CRP alone for the inflammatory index gave weaker results.
  • Limitations: the analyses were cross-sectional, the CES-D cutoff is not a clinical diagnosis, and only Study 4 had the full neuropsychological battery (smaller sample, less power). The sample was mostly White, highly educated women.
  • The authors call for more support for survivors with depression and immune dysregulation. They speculate that anti-inflammatory approaches such as omega-3 supplementation might help, but this is untested here.

Read the full paper
VIEW PDF
Citation

Madison AA, Andridge R, Kantaras AH, Renna ME, Bennett JM, Alfano CM, Povoski SP, Agnese DM, Lustberg M, Wesolowski R, Carson WE III, Williams NO, Reinbolt RE, Sardesai SD, Noonan AM, Stover DG, Cherian MA, Malarkey WB, Kiecolt-Glaser JK. Depression, Inflammation, and Intestinal Permeability: Associations with Subjective and Objective Cognitive Functioning throughout Breast Cancer Survivorship. Cancers. 2023;15(17):4414. doi:10.3390/cancers15174414

Related Research Papers
n