Association of Serum Neurofilament Light Chain with Depressive Symptoms: a population-based study

Abstract

Background

Neurofilament light chain proteins (NfL) are widely accepted biomarkers of neuronal injury, and depressive symptoms are related to neuronal injury. Nevertheless, evidences of the association between NfL and depressive symptoms are still limited. This is the first population-based study to examine the association between NfL and depressive symptoms in general population.

Methods

We included 1907 participants with measurement of serum NfL from the 2013–2014 U.S. National Health and Nutrition Examination Survey. Depressive symptoms were measured by the 9-item Patient Health Questionnaire. Logistic regression models were conducted to examine associations between serum NfL levels and depressive symptoms. Restricted cubic spline regressions were applied to estimate the possible nonlinear relationships between them.

Results

Increased serum NfL were associated with higher risk of depressive symptoms after adjusted for confounder factors (per SD: odds ratios [OR] = 1.16, 95% confidence intervals [CI]: 1.02–1.34). Individuals with higher serum NfL (> 21.8 pg/ml, the upper 20% quantile) had a higher likelihood of depressive symptoms compared to normal counterparts (OR = 1.50, 95% CI: 1.01–2.22), and sensitivity analysis using different grouping criteria provided similar results. Furthermore, restricted cubic spline regression analysis demonstrated that a near-linear association occurred between serum NfL and the risk of depressive symptoms (P-nonlinear = 0.681, P-overall < 0.001).

Conclusions

This study found linear association between serum NfL levels and depressive symptoms in general population. Our findings support that serum NfL levels may be a novel biomarker for depressive symptoms, further studies are needed to validate our findings underlying this association.

Introduction

Depression is a common mental disorder that affects over 322 million people in the general population, the number of persons with depressive disorders account for 4.4% and is still going up in the world(WHO, 2017). The Global Burden of Disease Study reported that depressive disorders are the leading cause of mental health-related disability burden worldwide(GBD.2019.Diseases.and.Injuries.Collaborators, 2022), and associated with all-cause and cardiovascular disease mortality among adults(Cuijpers et al., 2014; Leone et al., 2021; Meng et al., 2020). Additionally, depressive symptoms are related to many cytoarchitectural changes and injury in neurons(Banasr, Sanacora, & Esterlis, 2021; Csabai, Wiborg, & Czéh, 2018; Holmes et al., 2019; Williams et al., 2019).

Recently, neurofilament light chain proteins (NfL), a neuron-specific component of the axonal cytoskeleton, has been proposed as a potential indicator of neuronal damage(Khalil et al., 2018). It has been reported to associated with many neurological disorders, such as multiple sclerosis, dementia, stroke, Parkinson disease (PD) and traumatic brain injury(Gaetani et al., 2019; Khalil et al., 2018). Meanwhile, previous preliminary studies also investigated the association of serum NfL with depressive disorder and reported conflicting findings(Travica, Berk, & Marx, 2022). Several studies found that there were no significant associations between NfL and depressive symptoms(Besse et al., 2020; Isgren et al., 2017; Tauil et al., 2021), while increased evidences suggested significantly higher NfL levels in patients with major depression among case-control studies(Bavato et al., 2021; Chen et al., 2022). Furthermore, prospective studies also reported that elevated levels of NfL were associated with higher risk of depressive symptoms among specific populations, such as patients with ischemic stroke(Zhao et al., 2020), PD(Yin et al., 2022), and veterans with history of mild traumatic brain injury(Guedes et al., 2020). However, due to either the restricted sample size and settings, or specific populations, the relationship between NfL and depression was still controversial. Therefore, the association of NfL with depression remains to be further investigated.

In this study, we aimed to investigate the association of serum NfL with depressive symptoms in general population. We first hypothesized that serum NfL is a novel biomarker for depressive symptoms, and elevated levels of serum NfL would be associated with higher risk of depressive symptoms in general population, and then determined the cross-sectional association between serum NfL and depressive symptoms in the 2013–2014 National Health and Nutrition Examination Survey (NHANES).

Materials And Methods

Depressive Symptoms

Depressive symptoms were assessed by the 9-item Patient Health Questionnaire (PHQ-9) among participants aged 20 years or older (Kroenke, Spitzer, & Williams, 2001; Spitzer, Kroenke, & Williams, 1999), which assesses frequencies at certain symptoms experienced in the last two weeks, ranging from 0 (‘not at all’) to 3 (‘nearly every day’). These questionnaires were self-administered, and the total scores ranged from 0 to 27. A cut-off score of 10 or above was used to define probable cases of depressive symptoms, with a sensitivity of 88% and a specificity of 88%(Kroenke et al., 2001).

Serum Neurofilament Light Chain Proteins

The NfL would release into the cerebrospinal fluid (CSF) after axonal injury and then into the peripheral blood(Khalil et al., 2018). Serum NfL was measured by a novel, high throughput, automated platform (Attelica) developed by Siemens Healthineers. A full description of the assay′s development and validation has been reported elsewhere(Lee et al., 2022). Briefly, the light reagent uses a monoclonal anti-NfL antibody labeled with a proprietary acridinium ester for chemiluminescent detection(Lee et al., 2022). In NHANES, serum NfL was measured in participants aged 20 years or older. In this analyses, serum NfL were evaluated as both continuous and categorized variables. Due to serum NfL exhibited a nonnormal distribution, serum NfL was log-transformed prior to performing analyses. Additionally, the serum NfL levels were dichotomized as high (upper 20% quantile ≥ 21.8 pg/ml vs lower 80% quantile < 21.8 pg/ml) and normal groups. Especially, in order to obtain robust results, we used different cut-off level to define high serum NfL. In brief, high serum NfL was defined as the upper 25% (≥ 19.3 pg/ml), 10% (≥ 30.2 pg/ml) and 5% (≥ 40.4 pg/ml) quantiles of serum NfL in sensitivity analyses, respectively.

Covariates

Covariates included sociodemographic information, lifestyle behaviors and clinical characteristics. In detail, sociodemographic information included age, gender, marital status (married or living with partners vs. single), education (less than college vs. college or more), and race/ethnicity (Mexican Hispanic, other Hispanic, Non-Hispanic White, Non-Hispanic black and other race). Lifestyles included smoking status (never, former, and current smokers), alcohol consumption, physical activity (PA) and body mass index. PA was assessed by a questionnaire, which included the frequency (time per week), duration (minutes per time) and intensity (vigorous or moderate) of PA in one typical week. The vigorous intensity of PA was doubled and added to minutes of the moderate intensity(Divney et al., 2019). According to the 2018 PA Guidelines, which recommend that adults should engage in at least 150–300 minutes per week of moderate-intensity PA, 75–150 min/week of vigorous-intensity PA, or an equivalent combination(Piercy et al., 2018). Meanwhile, the participants were also categorized into two groups: 1) participants who met the 2018 PA Guidelines (≥ 150 min/week) and 2) participants who did not meet the 2018 PA Guidelines (< 150 min/week). Clinical characteristics included cardiovascular disease (CVD), diabetes, cancer, and arthritis. CVD included angina angina/angina pectoris, heart attack, coronary heart disease and stroke. Especially, aforementioned diseases were defined as being told by a doctor or health professional that they have the disease. Additionally, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were also measured.

Results

In this study, we included 1907 participants (48.40% males and 51.60% females) from the 2013–2014 NHANES (Table 1). The mean age was 47.12 (15.49) years. Of these participants, 894 (46.88%) and 1013 (53.12%) participants were middle (aged 45–64 years) and older adults (aged ≥ 65 years), respectively. Overall, 179 (9.39%) participants were defined as having depressive symptoms. The more detail characteristics were presented in Table 1.

Table 2 shows the results of logistic regression analyses between NfL and risk of depressive symptoms. When examining serum NfL as continuous variable, higher levels of logNfL were associated greater risk of depressive symptom in unadjusted model (OR = 3.04, 95% CI = 1.84-5.00), and the association persisted after considering potential confounder factors (OR = 2.09, 95% CI = 1.09–3.96). In further analyses, per SD increase of serum NfL were associated with higher risk of depressive symptom in both unadjusted (OR = 1.25, 95% CI = 1.11–1.43) and adjusted model (OR = 1.16, 95% CI = 1.02–1.34). For categorical variable (Table 2), when dichotomized serum NfL as high (upper 20% quantile) and normal (lower 80% quantile) groups, high serum NfL groups were also associated with higher risk of depressive symptom both in unadjusted (OR = 1.96, 95% CI = 1.39–2.73) and adjusted model (OR = 1.50, 95% CI = 1.01–2.22). Sensitivity analysis using different grouping criteria provided similar results after adjusted for potential confounder factors (upper 25% vs lower 75% quantile: OR = 1.47, 95% CI = 1.00-2.15; upper 10% vs lower 90% quantile: OR = 1.66, 95% CI = 1.02–2.64; upper 5% vs lower 95% quantile: OR = 2.38, 95% CI = 1.30–4.21).

Furthermore, we conducted stratified analysis across various strata defined by age, gender, educational status, body mass index, race, marital status, smoking status, alcohol consumption, and physical activity using multivariable Model 3 (Table 3). We found significant associations of logNfL with depressive symptoms in each stratum, and the interaction tests comparing the ORs across the strata were not significant (P-value > 0.05), suggesting that increased logNfL was associated with a higher risk of depressive symptoms, regardless of age, gender, educational status, body mass index, race, marital status, smoking status, alcohol consumption, and physical activity. Additionally, to visualize the potential dose-response relationship, multivariable restricted cubic spline regression was performed to predict the ORs for depressive symptoms between the 5th and 95th percentiles of the logNfL (Fig. 1). Interestingly, the association of serum NfL with the risk of depressive symptoms was nearly linear (P-overall < 0.001, P-nonlinear = 0.681).

Discussion

In this cross-sectional design of the 2013–2014 NHANES, we found that elevated levels of serum NfL were robustly and independently associated with higher risk of depressive symptoms in general population. Additionally, these associations were nearly linear. In summary, our findings support the hypothesis that serum NfL is a novel biomarker for depressive symptoms.

Previous studies have release the conflicting relationship between levels of NfL and depression(Travica et al., 2022). Several studies reported that there were no significant associations of NfL with depression(Besse et al., 2020; Isgren et al., 2017; Tauil et al., 2021). For example, Besse et.al recruited 15 patients with major depressive disorder receiving electroconvulsive therapy and 15 sex- and age-matched healthy controls, and found that serum NfL concentrations did not differ between patients and healthy controls (patients: 16.04 pg/ml, control: 15.57 pg/ml, P-value > 0.05)(Besse et al., 2020). Tauil et.al also did not found significant association between level of NfL in the cerebrospinal fluid (CSF) and depressive score (r = -0.20, P-value = 0.38), which included 10 controls, 14 untreated patients with relapse remitting multiple sclerosis (RRMS) and 16 RRMS patients treated with fingolimod(Tauil et al., 2021). Isgren et.al recruited 77 patients with bipolar disorder, and found that baseline CSF NfL was associated with depressive episodes at 6–7 years follow-up (OR = 1.19, 95% CI: 0.44–3.18)(Isgren et al., 2017). In these case-control studies, researchers did not find significant relationships between NfL and depressive symptoms.

In contrast, other studies demonstrated significant relationships between NfL and depression(Bavato et al., 2021; Chen et al., 2022; Guedes et al., 2020; Yin et al., 2022; Zhao et al., 2020). Chen et.al enrolled 40 patients with major depressive disorder, and 40 age- and sex-matched healthy controls, they found that patients with major depressive disorder exhibited significantly higher plasma NfL levels than controls (28.76 ± 22.53 vs 16.65 ± 8.07, P-value = 0.007)(Chen et al., 2022). Similarly, Bavato et.al included 41 patients with major depressive disorders and 485 healthy controls, and reported patients showed elevated serum levels of NfL than healthy controls(Bavato et al., 2021). Additionally, prospective studies also released that elevated levels of NfL were associated higher risk of depressive symptoms among several specific populations, such as patients with ischemic stroke(Zhao et al., 2020), PD(Yin et al., 2022), and veterans with history of mild traumatic brain injury(Guedes et al., 2020). In detail, Zhao et.al included 236 ischemic stroke cases in a single-center prospective cohort, and 55 patients were defined as post-stroke depression during 3-month follow-up period(Zhao et al., 2020). They showed that per IQR increase of serum NfL, the OR of incident depression was 2.65 (95% CI: 1.59–4.04) after adjusted potential confounder factors(Zhao et al., 2020). Yin et.al conducted a prospectively study with enrolling 116 patients with PD, and found plasma NfL levels were higher in patients with depression than in those without these symptoms (PD with no depression: 16.2 ± 5.9, PD with moderate depression 32.1 ± 20.5, PD with severe depression 31.2 ± 19.7) with all P-value less than 0.01(Yin et al., 2022). In addition, Guedes et.al enrolled 45 controls and 150 veterans with history of mild traumatic brain injury, they found that increase plasma levels of NfL were associated with higher depressive score (r = 0.204, P-value = 0.016)(Guedes et al., 2020). In summary, these studies demonstrated a significant association between NfL and depression, which was consistent with our findings.

Taken together, these studies were all case-control settings with small sample size, findings of the conflicting relationship between NfL levels and depression would be misinterpret due to either the restricted sample size, or settings, or specific populations. While, we investigated the association in a population-based cohort study with larger sample size, our findings would provide more compelling evidence that elevated levels of serum NfL were associated with higher risk of depressive symptoms in general population.

The mechanisms that increased levels of serum NfL were associated with depressive symptoms were not entirely understood. The possible mechanisms maybe proposed based on published literatures. NfL is a neuron-specific component of the axonal cytoskeleton, and released into the CSF and peripheral blood after neuroaxonal injury caused by neuroinflammatory, neurodegenerative, traumatic, or vascular injuries(Khalil et al., 2018). The levels of NfL can be quantified in serum and plasma(Ashton et al., 2021; Gisslén et al., 2016; Kuhle et al., 2016; Simrén, Ashton, Blennow, & Zetterberg, 2021). Depressive disorder is closely related to immunological and inflammatory dysfunctions(Beurel, Toups, & Nemeroff, 2020; Kappelmann et al., 2021; Miller & Raison, 2016), whereby activated neuroimmune and related oxidative pathways would induce damage in neurons, leading to the depressive symptoms(Hodes, Kana, Menard, Merad, & Russo, 2015; Wang et al., 2019; Wohleb, Franklin, Iwata, & Duman, 2016). In brief, serum NfL was a marker of axonal injury, and depression would lead to damage in neurons via immunological and inflammatory dysfunctions.

Our study has several strengths. The study was conducted based on the NHANES, which is a nationally representative cross-sectional survey of civilian, noninstitutionalized persons. This population-based study could generalize our findings to general population, regardless of age, gender, educational status, body mass index, race, marital status, smoking status, alcohol consumption, and physical activity. Secondly, until now, this is the first and largest study conducted among general rather than specific population. Hence, our findings of the relationship between NfL and depressive symptoms could be more reliable and robust. Additionally, to our knowledge, this study first reported a nonlinear association between serum NfL and depressive symptoms.

However, several limitations also presented in our study. First, the NHANES data are cross-sectional, and causal relationship between serum NfL and depressive symptoms was not investigated. Therefore, it would be interesting for future research to get more insight on the role of serum NfL on depressive symptoms to validate our findings in longitudinal and Mendelian randomization studies. Second, depressive symptoms were assessed by the PHQ-9, which is a self-report questionnaire. The accurate assessment of depression by clinical diagnosis is needed in further studies. Last, we just included participants from the USA, whether our findings may be generalized to other population would need further investigation.

Conclusions

In conclusion, serum NfL, a neuronal marker of neuronal injury, was robustly and independently associated with depressive symptoms in general population. Additionally, these associations were nearly linear. Our findings support the hypothesis that serum NfL is a novel biomarker for depressive symptoms. Longitudinal studies and objective measurements of depression are needed to validate our findings in the future.

Declarations

Acknowledgements

The data and samples used for this research were obtained from the U.S. NHANES. We would like to thank the U.S. Centers for Disease Control and Prevention.

Conflict of interest

The authors declare that they have no relevant financial interests.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82000070), the National Natural Science Foundation of China-Youth Science Fund (3210040426, 32200536) and the Shanghai Rising-Star Program (21QB1400900).

Compliance with ethical standards

The data in our study were publicly available and used in a secondary analysis; thus, no additional ethical review was necessary.

Author Contributions

Zhang H and Jiang S designed and conducted the research. He F, Li Y, Hao M and Hu Z analyzed the data and performed the statistical analyses, Zhang H wrote the paper, Zhang H and Jiang S had primary responsibility for the final content, and all authors read and approved the final manuscript.

Data available

The datasets analyzed in the study are publicly available at https://www.cdc.gov/nchs/nhanes/index.htm. The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

Sponsor’s Role

None.

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