Peripheral Inflammatory Markers And Post Ischemic Stroke Depression:A Prospective Cohort Study

Objective: Inflammation may play an important role in the pathogenesis of post-stroke depression(PSD).However,current findings on association between inflammatory markers and PSD have been highly inconsistent,and the amount of evidence is much less than that of inflammatory markers with non-organic depression.The aim of this study was to explore the correlation of peripheral inflammatory markers with the risk of PSD,the mediating effects of inflammatory markers between acute ischemic stroke(AIS)and depressive symptomology,and the impact of inflammatory markers on the course of PSD.Methods: In this multicenter prospective cohort study,the primary or recurrent AIS patients from three tertiary hospitals in Central China between May 2018 and March 2020 were consecutively enrolled and followed up for 1 year.Part Ⅰ explored the linear and non-linear association between multiple peripheral inflammatory markers and the risk of PSD in acute,subacute and chronic phases after AIS.Part II examined the mediating effects of peripheral inflammatory markers in association between AIS severity and chronic phase post-stroke depressive symptomology,and further examined whether fibrinogen and other inflammatory markers play a chain mediating role between AIS severity and depressive symptomology based on current basic research results.Part III investigated the main trajectories of depressive symptomology after AIS,and further explored the impacts of inflammation and peripheral immunity on the trajectories of depressive symptomology based on repeated measurements.Results: Peripheral fibrinogen,white blood cell count(WBC),neutrophil count and monocyte count were associated with the risk of chronic phase PSD,with a non-linear association between monocyte count and the risk of chronic phase PSD.Meanwhile,fibrinogen,WBC and neutrophil count could partially mediate the association between AIS severity and depressive symptomology in chronic phase.Additionally,fibrinogen and neutrophil count might play a chain mediating role between AIS severity and depressive symptomology.The main trajectories of depressive symptomology after AIS included the mild-non depression group,early-onset remitting PSD,late-onset PSD,and persistent PSD.Elevated peripheral fibrinogen levels increased the risk of conversion from early PSD to persistent PSD.Chronic elevation of innate immune levels after AIS might not only increase the risk of conversion from early PSD to persistent PSD,but also increase the risk of lateonset PSD in patients without early PSD.In addition,elevated levels of peripheral adaptive immunity in convalescence of AIS might reduce the risk of conversion from early PSD to persistent PSD.Conclusions: Elevated peripheral fibrinogen,WBC,neutrophil count and monocyte count levels after AIS in non-infectious state increased the risk of chronic phase PSD.The depressogenic effects of AIS may be achieved to some extent by elevating the levels of peripheral inflammation.Fibrinogen might play an important role in the peripheral inflammation after AIS.The peripheral immune response after AIS might be related to the occurrence and development of PSD,and this relation had temporal heterogeneity.Part Ⅰ: Association between peripheral inflammatory markers and the risk of PSD at different phasesObjective: To explore the association of multiple inflammatory markers with the risk of PSD at different phases.Methods: This multicenter prospective cohort enrolled the primary or recurrent AIS patients from three tertiary hospitals in Central China between May 2018 and March 2020.Fasting blood samples were collected within 24 hours after admission for detection of inflammatory markers,and relevant baseline data was recorded.The depressive status was evaluated at acute phase(< 14 days),subacute phase(90 ± 7 days)and chronic phase(365 ± 14 days)after stroke.Binary logistic regression was performed to analyze the association of inflammatory markers with the risk of PSD at different phases.And restricted cubic spline(RCS)based on binary logistic regression model was used to further examine the non-linear association between each inflammatory marker and the risk of PSD at different phases on continuous scales.Results: A total of 467 eligible AIS patients finished the acute phase depression assessment,451 patients finished the subacute phase depression assessment,and 436 patients finished the chronic phase depression assessment.The results showed that fibrinogen,WBC,neutrophil count,and monocyte count were associated with the risk of chronic phase PSD.And there was an "inverted L-type" nonlinear association between monocyte count and risk of chronic phase PSD.When the monocyte count was less than 0.63 × 109/L,the risk of chronic phase PSD increased with the elevating levels of monocyte count,however,when the monocyte count exceeded this threshold,the risk was no longer increased.Conclusions: Peripheral fibrinogen,WBC,neutrophil count and monocyte count levels in non-infectious state were associated with the risk of chronic phase PSD.These findings could provide new evidence for the association between inflammatory markers and PSD.Part II: The chain mediating role of fibrinogen and neutrophil count in association between ischemic stroke severity and chronic phase depressive symptomologyObjective: Few studies have linked stroke severity,inflammatory markers and depression.This part aimed to investigate the mediating effects of peripheral inflammatory markers in association between AIS severity and chronic phase post-stroke depressive symptomology,and further examined whether fibrinogen and other inflammatory markers play a chain mediating role between AIS severity and chronic phase depressive symptomology based on current basic research results.Methods: A total of 436 AIS patients who had finished the chronic phase depression assessment were included for analysis.Four hypothetical mediation models were developed.The coefficients and 95% confidence intervals(CI)of each pathway were examined by multiple linear regression.The values of total,direct and indirect effects were calculated by maximum likelihood estimation(MLE),and 95%CI were calculated by bias-corrected percentile bootstrapping.Results: The results showed that fibrinogen,WBC and neutrophil count partially mediated the association between AIS severity and chronic phase depressive symptomology.The total indirect effect of inflammatory markers was 25.3% and there was a chain mediating effects of “AIS severity → fibrinogen → neutrophil count → chronic phase depressive symptomology”.Conclusions: The depressogenic effects of AIS may be achieved to some extent by elevating the levels of peripheral inflammation.In addition,fibrinogen and neutrophil count might play a chain mediating role between AIS severity and chronic phase depressive symptomology.These findings suggested that fibrinogen might play an important role in peripheral immune response after AIS,and the mechanisms were worthy to be further studied.Part III: Effects of peripheral inflammation and immune response on the trajectories of depressive symptomology after AISObjective: The course of depressive symptomology after AIS is fluctuating.This study aimed to further explore the effects of peripheral inflammation and immune response on the trajectories of depressive symptomology after AIS.Methods: This study enrolled a total of 427 AIS patients who had complete baseline data,at least two depression assessments within one year,and at least one repeated blood routine test in the non-infectious state in addition to admission.Latent class growth analysis(LCGA)was performed to delineate main trajectories of depressive symptoms after AIS.Multinomial logistic regression was applied to investigate the effects of peripheral inflammation and immunity on trajectories of depressive symptomology.Results: The main trajectories of depressive symptomology after AIS included mild-non depression(55.5%),early-onset remitting PSD(28.1%),late-onset PSD(10.3%)and persistent PSD(6.1%).The elevation of peripheral fibrinogen increased the risk of conversion from early PSD to persistent PSD.Additionally,chronic elevation of innate immune levels not only increased the risk of conversion from early PSD to persistent PSD,but also increased the risk of late-onset PSD in patients without early PSD.The elevation of adaptive immune levels in convalescence of AIS may contribute to the remission of early PSD.Conclusions: The peripheral immune response could influence the course of PSD,and this influence have temporal heterogeneity.These results might provide some vital clues for the inflammation hypothesis of PSD.