Abstract TMP29: Plasma Proteomics Demonstrates Immune Dysregulation in Chronic Post-Stroke Fatigue

Abstract

Introduction: Post-stroke fatigue is a common and impactful complaint of stroke survivors. As with fatigue from other causes, our understanding of the biological underpinnings of post-stroke fatigue is poor. Here we used plasma proteomics to better understand post-stroke fatigue. Methods: We report here on 97 participants 5 months to 10 years after ischemic stroke. Functional Assessment of Chronic Illness-Fatigue (FACIT) scale was used to assess fatigue. Disability and self-reported mood was measured using the modified Rankin Scale (mRS) and the Stroke Impact Scale’s mood subset (SIS3), respectively. We dichotomized participants into non-fatigued (FACIT >41) and fatigued (FACIT ≤41) groups and employed a binary logistic regression to examine associations with clinical variables. Aptamer-based proteomics (Somalogic) was used to quantify 7288 plasma proteins, after which we performed pathway analyses. Results: Fatigue was present in 49.4% of our cohort. 39.2% was female and the mean age was 64.2±12.8. When adjusted for age and sex, a prior diagnosis of hypertension (OR=2.7, 95% CI 1.09-6.75, p=0.032) or any psychiatric disorder (OR=8.8, 95% CI 2.54-31, p<0.001) was associated with fatigue. Adjustment for time since stroke did not affect these associations. Higher mRS (rho=-0.49) and worse SIS3 (rho=0.59) were associated with more fatigue. 215 proteins had an absolute correlation coefficient greater than 0.3 and differed between fatigued and non-fatigued patients (p<0.001). Pathway analysis revealed dysregulation of both innate and adaptive immune responses and cytoskeletal regulation. The JAK/STAT pathway was highly dysregulated. In fatigued patients, plasma levels of several components were significantly elevated (log2Fc); CCL5 (0.81), JAK2 (0.73), and STAT3(0.53). The largest downregulation was in fetuin (AHSG, log2Fc -5.5), which contributes to the most down regulated pathway, regulation of ossification, and is an immunosuppressant. Conclusion: Immune dysregulation after stroke may be associated with fatigue, particularly upregulation of the JAK/STAT pathway and downregulation of fetuin. More studies are needed to replicate these findings and to probe mechanisms.