6 APP| Published By AEIRC| https://doi.org/10.29052/2412-3188.v8.i1.2020.6-14 Ann. psychophysiol. ISSN 2412-3188 (Online) | 2410-1354 (Print) Original Article Assessment of Cortisol, Brain-Derived Neurotropic factor, C - reactive protein, Interleukin-6 levels and cognitive decline after trauma exposure Shamoon Noushad1,2 , Ujala Sajid3, Sadaf Ahmed2,3 & Basit Ansari1 1Department of Health & Physical Education, University of Karachi, Karachi-Pakistan. 2Psychophysiology Research Lab, MAHQ Biological Research Centre, University of Karachi, Karachi-Pakistan. 3Department of Physiology, University of Karachi, Karachi-Pakistan. Abstract Background: Studies have found that multiple neurobiological mechanisms are underlying the cause of Posttraumatic stress that influence the nervous and immune system leading to neurodegenerative and psychiatric comorbidities. The present study aims to assess and evaluate the serum Cortisol, C - reactive protein (CRP), Interleukin-6 (IL-6), Brain-Derived Neurotropic Factor (BDNF) levels and cognitive decline among subjects with trauma exposure and to determine the relationship between the above-specified stress biomarkers. Methodology: Two groups with trauma exposure (including natural disaster, any accident, physical and/or verbal violence, or any stressful condition) in the last twelve months were recruited. Groups were majorly divided based on TSC-40 (Trauma Symptom Checklist - 40) scores. Subjects with a TSC score > 40 were kept in the traumatized group, while those with TSC score < 40 were included in the control group. A total of 188 subjects above the age of 18 were recruited following inclusion criteria, cognition was measured using the Six-Item Cognitive Impairment Test (6-CIT), and serum samples were obtained for cortisol, CRP, BDNF, and IL-6 levels. Results: There was a significant difference in the serum BDNF (p<0.001) level among the traumatized subjects, i.e. 15.68 ± 3.55 ng/dl as compared to controls 26.65 ± 2.47 ng/dl; no significant difference was found in CRP levels (ns) in both groups with a slight increase among the traumatized subjects as compared to the controls, i.e. 4.29 ± 1.50 mg/dl vs. 3.42 ± 1.11 mg/dl. As indicated by the 6-CIT score, the cognitive decline was more pronounced among the traumatized subjects, i.e. 8.54 ± 2.13 compared to the control group 5.0 ± 1.81, with a significant positive difference (p<0.001). Conclusion: The finding suggests that traumatic stress is associated with Cognitive decline, BDNF and cortisol, whereas a non-significant association was found with IL-6 and CRP levels. Keywords Traumatic Stress, Cognitive Decline, Brain-Derived Neurotrophic Factor, C - reactive protein, Interleukin-6, Cortisol. Citation: Noushad S, Sajid U, Ahmed S. & Ansari B. Assessment of Cortisol, Brain-Derived Neurotropic factor, C - reactive protein and Interleukin-6 levels as well as cognitive decline after trauma exposure. APP.2021; 8(1):6-14 Corresponding Author Email: ujalasajid97@gmail.com DOI: 10.29052/2412-3188.v8.i1.2021.6-14 Received 01/01/2021 Accepted 07/04/2021 Published 01/06/2021 Copyright © The Author(s). 2021 This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The author(s) received no specific funding for this work. Conflicts of Interests: The authors have declared that no competing interests exist. https://doi.org/10.29052/2412-3188.v8.i1.2020. https://orcid.org/0000-0002-8078-4524 https://orcid.org/0000-0002-9635-0202 https://orcid.org/0000-0003-3919-2516 http://creativecommons.org/licenses/by/4.0/) http://creativecommons.org/licenses/by/4.0/) http://creativecommons.org/licenses/by/4.0/) 7 ISSN 2412-3188 (Online) | 2410-1354 (Print) APP| Published By AEIRC| Volume 8 Issue 1 Introduction Traumatic events and associated stress have been known to trigger several physical or mental health disabilities, including fatigue, sleep disturbances, anxiety disorder, depression etc. A debate has continued for decades until several studies have proposed a significant link between traumatic stress and its psychological impact on individuals' health and well-being1, 2. The drastic or life- threatening events, including accidents, natural disasters, physical and/or verbal violence, or any other stressful condition that is a source of trauma and alters the body's homeostasis, leads to traumatic stress3. Individuals with mental health problems such as Post-Traumatic Stress Disorder (PTSD) and major depressive disorder (MDD) or even psychiatric problems had mostly experienced certain traumatic incidences like early childhood trauma, sexual abuse, verbal abuse, and physical violation2,4-6. Moreover, the traumatic subjects tend to have a reduced ability to cope with fear and usually feel helpless most of the time7. This coping disability generally leads to PTSD that is considered a heterogeneous condition6 and characterized by successive traumatic reminders, avoidance of cue related to trauma, negative cognition, etc3, 8. In the current era, traumatic events are very common in one's life, leading to severe psychotic distress and neuronal impairment; it should be assisted by clinicians, psychologists or psychotherapists, either by interviewing the traumatized individual any formal psychometric testing or any assessment tool9. Early assessment and effective management has shown positive growth among the traumatized individuals depending upon the type and number of experiences of the traumatic event10. Normal brain development needs to be reviewed at different life stages to understand how traumatic stress initiates5. From childhood to later in life, the human brain undergoes several changes, be it structural or functional. It is essential to be well aware of the normal developmental changes to differentiate them based on the pathologies5. It is important to understand the changes in individual behaviour, both mentally and socially, caused by any stressful situation or trauma experiencing. Previous evidence from studies has associated childhood victimization or trauma, decades after exposure, with an elevation of inflammatory biomarkers measured8. Evidence suggests that the subjects who had suffered from childhood victimization or trauma have elevated levels of inflammatory biomarkers, including IL-6 and CRP, while relatively low levels of BDNF8,10. The involvement of neurobiological inflammatory markers in the pathogenesis of trauma is quite obvious. CRP is the most validated and widely studied biomarkers of the peripheral inflammation associated with trauma9, and elevated CRP levels indicate the increased risk of degenerative disorders11. Similarly, BDNF is one of the most extensively researched neurotrophic factors with the most established evidence of influencing synaptic plasticity and has a significant role in cellular proliferation and brain pathologies12,13. The down regulation of BDNF in association with traumatic history results in long-term changes in the neurobiology of the brain, suggesting BDNF as an essential biomarker of pathological conditions14. In the behavioural literature, both of the molecules that is IL-6 and CRP regarded as inflammatory biomarkers and used mostly in assessing the presence and severity of low-grade inflammation15-17. Chronic stress leads to various disease states through the activation of two major systems i.e. HPA – 8 ISSN 2412-3188 (Online) | 2410-1354 (Print) APP| Published By AEIRC| Volume 8 Issue 1 axis and the other is the sympathetic nervous system (SNS) axis, usually by the up- regulation of glucocorticoids (cortisol in humans) and catecholamines (epinephrine and norepinephrine)18. These two secreted molecules then perform their function by acting through their separate receptor mechanism on different cell types, including the immune cells and nerve cells18,16. Besides, it is suggested that chronic stress usually inhibits the secretion of proinflammatory cytokines that usually mediate cellular immunity. On the other hand, the stress can activate the anti-inflammatory cytokine that mediates humoral immunity. Based on this general hypothesis was led that chronic stress particularly leads towards the disease state through immunosuppression. However, there is still a gap in understanding the overall association of HPA axis activation that leads to alteration in the serum BDNF, IL-6, cortisol and CRP levels under pathological conditions. The present study aimed to assess and compare serum cortisol, CRP, IL-6, and BDNF levels among subjects with trauma exposure and to determine the relationship between the above-specified stress biomarkers. The outcome of this study suggests a significant association between severity of trauma and decrease level of BDNF, along with slight elevation in the serum cortisol, CRP and IL- 6, highlighting the possible involvement of BDNF, CRP and IL-6 in the development of post-traumatic stress. Methodology This cross-sectional study was conducted from September to December 2019. Two groups with trauma exposure (including natural disaster, any accident, physical and/or verbal violence, or any stressful condition) in the last twelve months were recruited. Groups were majorly divided based on TSC-40 scores. Subjects with a TSC score > 40 were kept in a traumatized group, while those with < 40 scores were included in the control group. Subjects were recruited from the following three sites, i.e. University of Karachi, Markaz-e-Umeed and Kohi Goth Hospital. A total of 188 subjects above 18 years of age were recruited, with no evidence of any metastatic disease, were enrolled in the study. According to DSM-V, subjects having any codified psychiatric disorder, those on psychopharmacological treatment during the last three years and those who had gone through any structural, psychological intervention for at least six months during the last three years were kept under exclusion criteria. Pakistan medical association committee on ethics approved all recruitment and assessment procedures. All subjects included provided written informed consent after receiving a complete description of the study. For the investigation of traumatic symptoms, TSC-40 was used19. TSC-40 is a self-reported 40-item inquiry form based on a 4-point Likert scale. It evaluates symptomatology in adults associated with childhood or adult traumatic experiences and measures aspects of posttraumatic stress and other symptom clusters found in some traumatized individuals. TSC-40 consisting of six subscales: Anxiety, Depression, Dissociation, Sexual Abuse Trauma Index (SATI), Sexual problems and sleep disturbances; it requires approximately 10- 15 minutes to complete. Cognition was measured using the 6-CIT18. This short 2-3- minute test contains items on orientation, memory and concentration. Scoring ranges from 0-28, with higher scores indicating more cognitive impairment. Patients with a 6-CIT score of 10 points or lower were considered normal cognition; those with 6- CIT score ≥ 11 were categorized as cognitive 9 ISSN 2412-3188 (Online) | 2410-1354 (Print) APP| Published By AEIRC| Volume 8 Issue 1 impairment20. Venous blood was collected For estimation of CRP, Cortisol, IL-6 and BDNF into sampling tubes in the morning, the concentration of CRP (mg/dl), BDNF (ng/dl), Cortisol (mcg/dl), IL-6 (pg/ml) was measured using enzyme-linked immunosorbent assay. All the continuous variables like age, Cortisol, CRP, BDNF, and TSC-40 score were expressed as mean and standard deviation. In contrast, the categorical variables, including gender, ethnicity, occupation and religious preference, etc., were given frequency and percentages. Chi-square test and One-way Analysis of Variance (ANOVA) were used for comparison between the groups, and p<0.05 was considered statistically significant. Data were analyzed using SPSS Version 22.0. Results Out of 188 subjects, there were 88 traumatized and 100 controls. The majority were females, i.e. 75%, and only 25% were males, with a mean age of 29 ± 7.8 years. Most of the subjects belonged to different ethnicity, had different occupational statuses, religious preferences and political views, as shown in (Table 1). Table 1: Demographic characteristics of the subjects enrolled in the study. Baseline Characteristics n(%) Gender Male 47(25) Female 141(75) Ethnicity Sindhi 24(12.76) Balochi 23(12.23) Punjabi 18 (9.57) Pathan 21(11.17) Muhajir 80(42.55) Others 15(7.97) Prefer not to respond 7(3.19) Occupation Student (not working) 133(70.74) Student (part-time job/business) 13(6.91) Student (full-time job or business) 14(7.44) Business 11(5.85) Salaried Person 17(9.04) Religious preference Agnostic 2(1.06) Religious 165(87.76) Not religious but spiritual 14(7.44) Others 7(3.72) Political View Conservative 30(15.95) Moderate 118(62.76) Liberal 40(21.27) *Values are given as Mean ± SD or n(%) 10 ISSN 2412-3188 (Online) | 2410-1354 (Print) APP| Published By AEIRC| Volume 8 Issue 1 Individuals with trauma (TCS Score > 40) had significantly lower levels of BDNF, i.e. 15.68 ± 3.55 ng/dl, and slightly higher levels of CRP 4.29 ± 1.50 mg/dl as compared to controls (Table 2). Table 2: Comparative assessment of traumatic symptom and biomarkers among the traumatized and control subjects Variable Traumatized (Group) Controls (Group) p-value Mean ± SD TSC-40 Score 56.72±11.91 27.76±9.28 <0.001* 6-CIT Score 8.54±2.13 5.0±1.81 <0.001* CRP (mg/dl) 4.29±1.50 3.42±1.11 ns BDNF (ng/dl) 15.68±3.55 26.65±2.47 <0.001* Cortisol (mcg/dl) 26.17±3.65 20.37±3.71 <0.001* IL-6 (pg/ml) 2.90±0.63 2.44±2.08 ns *p-value < 0.05 is considered significant; ns: non-significant *TSC-40-Traumatic Symptom Checklist; 6-CIT-Six Item Cognitive Impairment Test; CRP-C-reactive protein; BDNF-Brain Derived Neurotropic Factor; IL-6-Interleukin 6 Figure 1: Comparison of subscales scores of TSC-40 among the control and traumatized groups of study Figure 1 shows the mean value of the subscales score of TSC-40 among the traumatized and control subjects. Depression was significantly very high in traumatized subjects (X̅=14.02) compared to the control subjects (X̅=7.25). In contrast, the anxiety level was significantly also very high in traumatized residents (X̅=13.85) as compared to the control subjects (X̅=6.35). Dissociation, SATI, and Sleep disturbance level were almost equal in traumatized subjects with a mean value of 11.11, 9.22 and 10.45. Among all the subscales scores, both traumatize subjects and control subjects scored the lowest in the Sexual problem subscale; traumatized subjects (X̅=3.76) and control subjects (X̅=1.02). 11.1 13.85 14.02 9.22 10.45 3.76 5.96 6.35 7.25 4.96 5.69 1.02 Dissociation Anxiety Depression Sati Sleep Disturbance Sexual Problem Traumatized Control 11 ISSN 2412-3188 (Online) | 2410-1354 (Print) APP| Published By AEIRC| Volume 8 Issue 1 Discussion The present study aimed to investigate the role of biomarkers in post-traumatic stress, focusing on the serum concentration of cortisol, BDNF, IL-6 and CRP among the traumatized and control subjects. The subjects who were deemed traumatized as per the findings from TSC-40, with comparatively high depression and anxiety index, were compared to those who scored less and considered as controls (Figure 1). The BDNF and CRP level was measured to find the association of inflammation with the underlying posttraumatic stress mechanism. Rosen et al., 2017 have suggested that systemic inflammation is associated with stress pathology with a positive CRP association with posttraumatic stress severity21. Moreover, a meta-analysis of random effects suggested that individuals who had experienced any type of childhood trauma (sexual, physical or emotional) had elevated baseline peripheral CRP levels17. A follow-up study by Laurin and his colleagues suggested that psychological distress is associated with increased CRP concentration and inflammatory mechanisms reflecting processes that further contribute to cognitive decline in later life22. Similarly, in our study, the mean CRP level was elevated among the traumatized subjects compared to the controls, i.e. 4.29 ± 1.50 mg/dl vs. 3.42 ± 1.11 mg/dl (Table 2). Although the association wasn't significant as per the evidence, there was a prominent variation in the mean CRP level among the two groups. We found significant down regulation in the serum BDNF concentration among the traumatic subjects 15.68 ± 3.55 ng/dl as compared to the controls 26.65 ± 2.47 ng/dl (p<0.05) (Table 2). A recent study confirmed that the serum BDNF level decline among individuals with a history of a traumatic event or those with mental health illnesses14; the study indicated a significant decline in the serum BDNF concentration among patients reporting childhood sexual abuse and depressive episodes21. Moreover, Angelucci et al., in their study, suggested the involvement of BDNF in the pathophysiology of PTSD23. The role of BDNF in enhancing learning and memory in the hippocampus is evident24, and the present study revealed a positive correlation in the down-regulation of BDNF (Table 2). Our results show the positive correlation of cortisol with the TSC-40 score. The positive correlation shows that if the TSC-40 score increases, then the cortisol level also increases and vice versa. The increased score of TSC-40 indicates that people whose scores were above 40 have a high level of cortisol and the people whose TSC-40 score was below 40 have a low level of cortisol25. As a biomarker of stress, the cortisol is linked to the TSC-40 score, which determines the level of cortisol and trauma of an individual26. Thus, our finding also indicates higher the TSC-40 score, the higher the level of cortisol and this increase in cortisol level, the person can be identified in a chronic traumatic stress27. TSC-40 scores below 40 showed a decrease in levels of the IL-6, while the TSC- 40 scores above 40 showed an increase in IL- 6 levels though it was insignificant, as shown in table1that may indicate the initiation of low-grade inflammation28. Cognitive impairment is one of the core features of degenerative disorders, and studies showed a significantly high association between traumatic events, degeneration of brain cells and cognitive dysfunction29. The cognitive impairment among the traumatized subjects was significantly high compared to the control group, with a decreased level of BDNF. Studies have suggested that BDNF plays a 12 ISSN 2412-3188 (Online) | 2410-1354 (Print) APP| Published By AEIRC| Volume 8 Issue 1 critical role in enhancing learning and memory in the hippocampus30. The results of 6-CIT of a traumatized group show a positive correlation between the decreased level of BDNF levels with cognitive impairment pathology. There was a slight elevation in CRP and IL6 concentration in traumatized subjects compared to the control group, suggesting that higher CRP levels may be a marker of memory and learning impairment in traumatic subjects. Noble, J. M. et al., 2010, in a cross-sectional analysis, suggested that increased CRP level can be a marker of memory and an increased risk of cognitive decline31. Since the results show a very slight elevation in CRP levels of traumatized individuals, hence basis on the results, we cannot suggest an association between cognitive impairment and an increase in IL6 and CRP. These overall results indicate that some other undefined factors may be modifying the observed associations of traumatic events with degeneration of brain cells, related immune influences, and susceptibility to cause psychiatric conditions later in life by way of inflammatory processes32. Still, it is possible that changes in BDNF and cortisol while non-significance of IL6 and CRP can be assumed to certain specific characteristic symptoms of traumatic stress32,33. However, further exploration of the role of environmental interactions and immune mechanisms is still a challenge34. The limitations of the current study that hinder further insight include its focus on a cross- sectional association based on one-time assessments of inflammatory markers, undervaluing the explicit inflammation markers' role in stress disorders and lack of longitudinal study design. The symptomatic expositions and potential confounders interfering with the immune system should be monitored in longitudinal and case- control settings to clarify these ambiguities. Conclusion The finding suggests that traumatic stress is associated with Cognitive decline, BDNF and cortisol, highlighting the possible involvement of these biomarkers in developing associated symptomatic neurobiological alterations. Whereas the changes in IL-6 and CRP were non- significant in the association with traumatic scores. However, there is a possible role of the explicit inflammation markers, and related mechanisms that are needed to be explored by further large-scale descriptive studies or randomized controlled trials are required to elucidate the mechanism. Acknowledgment The authors are thankful to the participating institutes for the support and collaboration, and we also like to acknowledge the study participants for their kind cooperation. References 1. Jeenger J, Singroha V, Sharma M, Mathur DM. C-reactive protein, brain-derived neurotrophic factor, interleukin-2, and stressful life events in drug-naive first- episode and recurrent depression: A cross- sectional study. Indian J psychiatry. 2018;60(3):334. 2. Giacobbo BL, Doorduin J, Klein HC, Dierckx RA, Bromberg E, de Vries EF. Brain-derived neurotrophic factor in brain disorders: focus on neuroinflammation. 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