Elevated serum neurofilament levels in young first-episode and medication-naïve major depressive disorder patients with alterative white matter integrity

Highlights

• Serum neurofilament (NF) levels were significantly higher in major depressive disorder (MDD) patients than that in healthy controls.

• Fractional anisotropy (FA) of six brain WM tracts in patients with MDD were identified to be lower than that in HCs after family-error wise correction for multiple comparisons using tract-based spatial statistics (TBSS).

• Negative associations between serum NF levels and impaired WM integrity, which might contribute to the understanding of pathophysiological mechanism of MDD.

Abstract

The mechanism of white matter (WM) microstructure alteration in major depressive disorder (MDD) is unknown. Serum neurofilament (NF) levels have been identified as promising biomarkers for axonal damage and degeneration in neurological disorders. Furthermore, elevated plasma NF levels were also reported in depressive patients with treatment resistance. The current study investigated the serum NF levels of first-episode, medication-naïve patients with different severities of MDD and assessed their relationships with WM integrity. Diffusion tensor images and serum NF levels of 82 MDD patients and 72 age- and sex-matched healthy controls (HCs) were taken. We found that serum NF levels were significantly higher in patients with MDD than those in HCs. Fractional anisotropy (FA) of six brain WM tracts (the body and genu of the corpus callosum, left superior and posterior corona radiata, and bilateral anterior corona radiata) in patients with MDD were lower than those in the HCs after family-wise error-correction for multiple comparisons. Negative correlations between serum NF levels in the severe group of MDD and the decreased FA of the left anterior corona radiata were found in MDD, which might contribute to an understanding of the pathophysiological mechanism of MDD.

Introduction

Major depressive disorder (MDD) is a chronic and disabling affective disease characterised by persistent low mood and anhedonia, disturbances in sleep and appetite, feelings of worthlessness and hopelessness, and suicidal thoughts and tendencies. The lifetime and 12-month prevalence of MDD are 3.4% and 2.1% in China (Huang et al., 2019), and 6% (Kessler and Bromet, 2013) and 15–18% (Bromet et al., 2011) worldwide, respectively. However, the pathophysiology of MDD is not completely understood. Neuroimaging and proteomics research has aimed to discover changes in brain microstructure and potential related serum biomarkers in MDD (Liao et al., 2013) (Lee et al., 2016).

Diffusion tensor imaging (DTI) is a noninvasive imaging technique used to evaluate the microstructure of the white matter (WM) tract in the brain in vivo based on the diffusion characteristics of water (Taylor et al., 2004). Tract-based spatial statistics (TBSS) via a mean fractional anisotropy (FA) skeleton for normalisation allows reliable statistical analysis of the centre and main part of the WM tract. FA reduction sensitively reflects WM fibre disruption, for which degeneration is widely used (Beaulieu, 2002). Several meta-analyses of DTI studies in MDD identified lower FA values in the anterior corona radiata (ACR), the genu of the corpus callosum (gCC) (Chen et al., 2016), and the body of the corpus callosum (bCC)(Chen et al., 2017). These WM tracts are composed of large-calibre myelinated axons that are rich in neurofilaments (NFs). NFs are unique intermediated filaments that play essential roles in neuronal cytoskeleton maintenance, myelinated axon calibre increase, and nerve conduction (Hoffman et al., 1984; Nixon and Sihag, 1991). NFs are composed of four subunits with different domain structures and functions, termed neurofilament light (NF-L), neurofilament middle (NF-M), neurofilament heavy (NF-H) chains, and alpha-internexin.

Demyelination and partial loss of axons and myelin sheaths are thought to be important underlying mechanisms of WM pathology in MDD (Nixon and Sihag, 1991; Sjo¨ gren et al., 2001). NF proteins may be released into extracellular(Guedes et al., 2020; Khalil et al., 2020) and cerebrospinal fluid (CSF) and blood after neuronal death or axonal injury and loss; therefore, CSF, especially serum NF levels (Petzold, 2005; Yuan et al., 2017) (Kuhle et al., 2017; Sjo¨ gren et al., 2001) are promising presymptomatic biomarkers for large myelinated axonal damage and degeneration in multiple sclerosis (MS) and neurodegenerative disorders(Wang et al., 2019). Furthermore, serum NF levels may be associated with the severity of these diseases at different stages, outcomes (Kuhle et al., 2019; Saraste et al., 2021), and discrimination of frontotemporal lobar degeneration spectrum disorders from late-onset primary psychiatric disorders (Katisko et al., 2020).

MS is an autoimmune disease characterised by multiple and scattered demyelinating WM lesions in the central nervous system and is often associated with depression. Both clinical and animal experimental studies have identified common characteristics between MS and MDD; especially in the early stages, the pathogeneses are closely related to inflammation-dependant mediated synaptic changes. Numerous studies have demonstrated the potent effects of elevated inflammatory indicators on abnormal serotonin and glutamate metabolism(Bruno et al., 2020), overstimulation of HPA and microglial cells (Malhi and Mann, 2018) that may induce pathological synaptic pruning, and brain structural and functional changes related to emotional and behavioural disorders such as MDD (Rosenblat et al., 2014). The hyperactivity of inflammation-related factors and an imbalance between monoamine and glutamate are involved in depressive symptoms in the early phase of MS even before clinical onset, while an imbalance between glutamate and GABA energy leads to excitatory toxic damage in the long term (Bruno et al., 2020).

Correlations based on different forms between NF pathology and the presence of WM changes in psychiatric diseases has also been observed. English et al. reported reduced NF-L and NF-H expression in schizophrenia and bipolar disorder and increased NF-M expression in bipolar disorder in dorsal lateral prefrontal deep WM tissue (English et al., 2009). Higher CSF NF-L levels were observed in elderly women with depression (Gudmundsson et al., 2010) and adult bipolar disorder (Jakobsson et al., 2014) (Isgren et al., 2017).

The detection of changes in NF level in brain tissue and CSF may be more direct and accurate; however, the invasiveness of specimen collection limits its clinical usefulness. Peripheral blood samples, as an important indicator of pathological changes, are more widely used because of their noninvasiveness and cost-effectiveness. Additionally, data on blood NF levels in patients with MDD, those who are medication-naïve and with early-stage disease, are lacking, although a recent study reported a correlation between elevated plasma NF-L levels and treatment resistance in major depression (Spanier et al., 2019).

To our knowledge, no study has simultaneously explored serum NF levels and their association with WM microstructure based on relatively large numbers of samples from first-episode and medication-naïve patients with MDD. Furthermore, the present study also explored the associations of NF levels for different depression severities with WM changes. Therefore, we performed this study to assess the combination of serum NF levels and TBSS focusing on the fibre backbone of the WM to investigate whether serum NF levels (1) were higher in MDD than in healthy controls (HCs), (2) differed amongst patients with different severities of depression grouped by rating scale, and (3) were associated with clinical status and WM integrity in MDD.