Abstract
Interleukin 7 (IL-7) is involved in B and T cell development and differentiation. Recent work suggests IL-7 may be altered in depression; however, we have previously shown that gender and blood fraction oftentimes impacts putative biomarker relationships among those with and without Alzheimer’s disease (AD). The current study examined the impact of blood fraction (serum versus plasma) and gender on the IL7 depression link in a sample of elders with and without AD. Non-fasting serum (150 AD cases 150 controls) and plasma (100 AD cases, 100 controls) IL-7 levels were assayed via electrochemiluminescence. The correlation between serum and plasma for IL-7 was 0.34. In the total sample, serum (r2 = 0.16, p = 0.006) and plasma (r2 = −0.20, p = 0.007) IL-7 levels were significantly, but inversely, correlated with GDS-30 scores. When split by gender, serum IL-7 levels were significantly positively associated with GDS scores among men (r2 = 0.34, p = 0.001) whereas plasma IL-7 levels (r2 = −0.23, p = 0.008) were significantly negatively associated with GDS scores among women. A logistic regression model predicting depression status (GDS30 > = 10) included age, gender, education, plasma, and serum IL-7 levels, found both significantly associated with depression status, but in opposite directions. Our findings support a significant link between IL-7 and depression; however, we further highlight the importance of blood fraction and gender when examining this relationship. Additionally, these findings further support the need for additional work that could lead to targeted therapeutic interventions utilizing anti-inflammatory medications for individuals with depression.
Keywords: IL-7, Depression, Gender, Serum, Plasma, Alzheimer’s disease
1. Introduction
Interleukin 7 (IL-7) a pro-inflammatory cytokine involved in B and T cell development and differentiation has been implicated as one of the inflammatory cytokines involved in the pathophysiology of depression. Simon et al. [1] using serum found the median level of IL-7 was significantly higher in Major Depression Disorder (MDD) patients compared to controls although subsequent analyses controlling for antidepressant history found no difference between antidepressant naive subjects with MDD and healthy controls. Lehto et al. [2] also using serum, found that MDD subjects had significantly lower levels of IL-7 than controls and those in the lowest tertile of IL-7 had a 3.4 times greater likelihood of having MDD. They hypothesized that the depression-tied impairment in T cell function may be related to lower serum levels of IL7 as a regulator of T cell homeostasis. Grosse et al. [3] in a study of T cell system dysregulation in major depression found decreased serum IL-7 levels in MDD patient. Dahl et al. [4] found that plasma levels of IL-7 were elevated in depressed individuals compared to controls. They also found that after 12 weeks of treatment these levels returned to normal levels in subjects who showed improvement in depressive symptoms. As our group has shown in the case of blood based markers of Alzheimer’s disease including IL-7 [5] the use of different blood fractions and different assay methodologies may be a factor contributing to the inconsistencies and may account for the differences found in the nature and direction of the relationship of IL-7 to depression. Recent reviews of cytokines and depression have failed to mention IL-7 as having a significant role in MDD [6–8].
IL-7 has been consistently shown to be a marker of Alzheimer’s disease in both serum and plasma [9–11]. Little research has looked at the biomarkers of depression in AD and the elderly. In previous work we have shown that serum biomarkers of depression in the elderly are impacted by gender and disease status [12–14]. It has also been shown that blood fraction (serum v. plasma) has a significant impact on biomarker disease relationships [15] and that the blood fraction utilized affects the link between biomarkers and AD [5]. The current study examined the link between IL-7 (serum and plasma) and depression scores by gender comparing a sample of Alzheimer’s patients with normal controls.
2. Materials and methods
2.1. Participants
The sample was drawn from the individuals enrolled in the Longitudinal Research Cohort of the Texas Alzheimer’s Research Care Consortium (TARCC) that had complete biomarker panels including IL-7 and had completed the Geriatric Depression Scale. TARCC is a longitudinal multi-site study of a cohort of AD patients and normal controls where each participant undergoes an annual evaluation that includes a medical examination, interview, neuropsychological testing, and blood draw. Serum (150 AD cases150 controls) and plasma (100 AD cases, 100 controls) levels of IL-7 were assayed. AD patients met consensus based diagnosis for probable AD based on NINCDS-ADRDA criteria and Controls were cognitively normal based on neuropsychological assessment. Institutional Review Board approval was received at all sites. Informed consent was obtained from all participants and/or legal representatives in the case of cognitive impairment.
2.2. Human serum sample collection
Samples were collected as follows: Serum—(1) non-fasting serum samples were collected into 10 mL tiger-top tubes; (2) samples were allowed to clot for 30 min at room temperature in a vertical position; (3) samples were centrifuged for 10 min at 1300 × g at room temperature within one hour of collection; (4) 1.0 mL aliquots were transferred into cryovial tubes; (5) Freezerworks™ barcode labels were affixed to each aliquot; (6) samples were placed into −80 °C freezers for storage until use. Plasma—(1) non-fasting blood was collected into 10 mL lavender-top (EDTA) tubes and gently inverted 10–12 times; (2) tubes were centrifuged at 1300 × g at room temperature for 10 min within one hour of collection; (3) 1 mL aliquots were transferred to cryovial tubes; (4) Freezerworks™ barcode labels were affixed; (5) tubes were placed in −80 °C freezers for storage.
2.3. Assays
Electrochemiluminescence (ECL). Plasma and serum samples were assayed in duplicate via a multiplex biomarker assay platform using ECL on the SECTOR Imager 2400A from MSD (available at http://www.mesoscale.com).
2.4. Methods and analyses
As part of the TARCC evaluation the 30-item Geriatric Depression Scale [16] is administered. All items are scored in the depressed direction with higher scores indicating increased depression. A score of 10 or higher was utilized to classify depression (yes/no). Correlation between serum and plasma was conducted using Pearson Correlations. Box-Cox transformation was applied to help normalize the distribution and increase the validity of measures of association. The links between serum and plasma levels of IL-7 and depression and gender were examined using correlations. Logistic regression was use to predict depression status (GDS ≥ 10 vs.GDS ≤ 9).
3. Results
The TARCC cohort is a primarily non-Hispanic white and relatively well-educated clinic based cohort. As shown in Table 1 the Control sample was significantly younger and achieved higher levels of education than the AD sample. The gender distribution for the two groups was basically the same.
Table 1.
Demographic Characteristics of Cohort.
| AD (N = 150) | Control (N = 150) | p-value | |
|---|---|---|---|
|
| |||
| Gender (Female) | 65% | 69% | 0.46 |
| Age in Years | 78.0 (8.2) | 70.6 (8.9) | <0.001 |
| 57–94 | 52–90 | ||
| Education in Years | 14.0 (3.4) | 15.6 (2.7) | <0.001 |
| 0–22 | 10–23 | ||
| Apoe4 Status (yes/no) | 61% | 26% | <0.001 |
| Hispanic | 5% | 5% | 0.61 |
| Non-Hispanic Whites | 95% | 95% | 0.46 |
| Mini-Mental Status Exam | 19.2 (6.1) | 29.4 (0.9) | <0.001 |
| 1–30 | 26–30 | ||
| CDR Sum of Boxes | 7.8 (4.4) | 0.0 (0.04) | <0.001 |
| 1–18 | 0–1 | ||
The correlation between serum and plasma for IL-7 was 0.34. In the total sample, serum (r2 = 0.16, p = 0.006) and plasma (r2 = −0.20, p = 0.007) IL-7 levels were significantly, but inversely, correlated with GDS-30 scores. When split by gender, serum IL-7 levels were significantly positively associated with GDS scores among men (r2 = 0.34, p = 0.001) (i.e. higher inflammation was associated with higher depression scores) whereas plasma IL-7 levels (r2 = −0.23, p = 0.008) were significantly negatively associated with GDS scores among women (i.e. higher inflammation was associated with lower depression scores).
A logistic regression model predicting depression status among the entire cohort (GDS30 > = 10) including age, gender, education, plasma and serum IL-7 levels, found both blood fractions significantly associated with depression status but in opposite directions. Specifically, plasma IL-7 was significantly negatively associated with depression status (OR = 0.01, 95% CI 0.00–0.47) whereas serum IL-7 was significantly positively associated with depression status (OR = 3.01, 95% CI 1.02–9.31).
Preliminary analyses suggest that diagnosis (AD versus control) also impacted the relation between GDS scores and IL-7. Plasma IL-7 levels were significantly negatively associated with GDS scores among women diagnosed with AD whereas serum IL-7 was significantly negatively associated with GDS scores among female normal controls. No significant relationships were found for males by diagnosis.
4. Discussion
The findings of previous research on the relationship of IL-7 to depression have been mixed. Previous work by our group [5] has shown that the relationship of specific blood-based biomarkers to disease state is dependent on the blood fraction being investigated.
5. Conclusion
Here we demonstrate that IL-7 levels were weakly correlated across blood fractions, which suggests that the nature of the IL-7 depression link may depend on the blood fraction utilized. Our results confirm prior work that IL-7 is significantly associated with depression scores; however, we found that the IL-7 depression link varies both by blood fraction and gender. This finding makes interpreting results and comparing across studies difficult and may account for the inconsistencies in the extant literature. Additionally, it appears that having the diagnosis of AD may impact the nature of the IL-7 depression relationship, but only for females.
5.1. Future considerations
The TARCC data reported in this study is from a sample that is made up almost exclusively of non-Hispanic whites. The nature of the IL-7 depression relationship may be further affected by ethnic and racial variables. The sample is relatively small and research on large, more diverse samples would be useful. We used scores on the GDS as our definition of depression and the use of more stringent diagnostic criteria may be necessary to further clarify the relationship.
5.2. Concluding remarks
It is clear from our findings that future work examining blood-based markers of depression must consider gender as well as blood fraction in analyses. The current findings suggest that gender should be considered in trial design if IL-7 is considered as a therapeutic agent for depression or AD.
HIGHLIGHTS.
Interleukin 7 (IL-7) is involved in B and T cell development and differentiation. Recent work suggests IL-7 may be altered in depression; however, we have previously shown that gender and blood fraction oftentimes impacts putative biomarker relationships among those with and without Alzheimer’s disease (AD). The current study examined the impact of blood fraction (serum versus plasma) and gender on the IL7 depression link in a sample of elders with and without AD. Non-fasting serum (150 AD cases 150 controls) and plasma (100 AD cases, 100 controls) IL-7 levels were assayed via electrochemiluminescence. In the total sample, serum (r2 = 0.16, p = 0.006) and plasma (r2 = −0.20, p = 0.007) IL-7 levels were significantly, but inversely, correlated with GDS-30 scores. When split by gender, serum IL-7 levels were significantly positively associated with GDS scores among men (r2 = 0.34, p = 0.001) whereas plasma IL-7 levels (r2 = −0.23, p = 0.008) were significantly negatively associated with GDS scores among women. Our findings support a significant link between IL-7 and depression; however, we further highlight the importance of blood fraction and gender when examining this relationship.
Acknowledgments
Research reported in this publication was supported by the National Institute on Aging under award number AG039389. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This study was supported in part if necessary by funding provided to the Texas Alzheimer’s Research and Care Consortium (TARCC) by the state of Texas, through the Texas Council on Alzheimer’s Disease and Related Disorders.
Texas Alzheimer’s Research and Care Consortium List of Investigators:
Investigators from the Texas Alzheimer’s Research and Care Consortium: Baylor College of Medicine: Rachelle Doody MD, PhD, Valory Pavlik PhD, Paul Massman PhD, Eveleen Darby MA/MS, Monica Rodriguear MA, Aisha Khaleeq MD; Texas Tech University Health Sciences Center: John C. DeToledo, MD, Henrick Wilms MD, PhD, Kim Johnson PhD, Victoria Perez, Michelle Hernandez; University of North Texas Health Science Center: Thomas Fairchild PhD, Janice Knebl DO, Robert C. Barber PhD, Douglas Mains DrPH, Lisa Alvarez, Adriana Gamboa; University of Texas Southwestern Medical Center: Perrie Adams PhD, Munro Cullum PhD, Roger Rosenberg MD, Benjamin Williams MD, PhD, Mary Quiceno MD, Joan Reisch PhD, Linda S. Hynan PhD, Ryan Huebinger PhD, Janet Smith BS, Barb Davis MA, Trung Nguyen MD, PhD; University of Texas Health Science Center – San Antonio: Donald Royall MD, Raymond Palmer PhD, Marsha Polk; Texas A&M University Health Science Center: Farida Sohrabji PhD, Steve Balsis PhD, Rajesh Miranda, PhD; University of North Carolina: Kirk C. Wilhelmsen MD, PhD, Jeffrey L. Tilson PhD, Scott Chasse, PhD.
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