Selenium (Se) is a common metal and essential trace element (1) that plays critical roles in immune response, apoptosis, endoplasmic reticulum homeostasis, regulation of transcription factor, development of central nervous system (CNS) and redox homeostasis by selenoproteins (2–4). Se is essential to CNS and involves in a variety of functions, such as memory, cognition, coordination and motor performance (5). Se is associated with the pathology of neurological diseases, including epilepsy, Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS) (6, 7). Research has shown that low blood selenium level is associated with intractable epilepsy in children. Children with refractory epilepsy have a severe decrease in blood Se (8). Seizures can be controlled when children are supplemented with Se; after withdraw Se, seizures recurs and can only be controlled by re-supplementation with Se (9). Se deficiency is associated with progressive neurological damage and cognitive decline, which is detrimental to AD. In addition, excessive exposure to Se can also cause neurotoxicity. In Florida, an outbreak of selenium poisoning induced by nutritional supplements has been reported, and the disease is related to cognitive and memory and impairment in patients aged 15–57 years (10). Consequently, more research is needed to verify Se′s involvement in neurological disorders in humans.

In central and peripheral nervous system diseases related to axonal injury or degeneration, serum neurofilament light chain (sNfL) concentration is increased, which is a biomarker of nerve axonal injury (11). sNfL is a quantitative indicator of axonal injury, and its elevation may have prognostic value in a variety of neurological diseases. Huntington’s disease (HD), ALS, and traumatic brain injury (TBI) have all been linked to elevated sNfL levels (12–14). However, in multiple sclerosis (MS) and AD, higher sNfL levels are related to worse clinical outcomes and more severe neurological impairment (15, 16).

We collected data on blood Se and sNfL from participants in the National Health and Nutrition Examination Survey (NHANES, 2013–2014) in order to gain a better understanding of the relationship between these two variables. Assessing the relationship between blood Se concentration and sNfL in a US population was the main objective of this study.

We discovered an inverse relationship between blood Se and sNfL in a cross-sectional study involving 1,036 representative participants. These results show that higher blood Se concentration is associated with lower sNfL concentration, suggesting a potential protective effect of Se on neuronal injury. This is the first study to link blood Se to biomarkers of nerve injury in adults. Blood Se concentrations in US adults may also be concerning for neurological health if the correlations we found are causal. However, it is unknown whether sNfL reduction by increased blood Se concentration alleviates neurological disease.

In 1957, selenium was discovered to be a necessary trace element for mammals. Se primarily carries out a range of biological activities via 25 selenoproteins with selenocysteines in the active center. Mammals’ physiological processes, including immune response, thyroid hormone metabolism, antioxidant defense, and fertility, are influenced by selenium (21–23). Selenium is also essential for the brain. According to the study, epileptic patients’ blood Se levels were lower than those of healthy controls (24). Blood Se activity were significantly decreased in children with refractory epilepsy (8), when children with epilepsy are supplemented with Se, seizures can be controlled. In a study of epileptic mice, treatment with Nano-Se reversed PTZ-induced seizure behavior and seizure duration, oxidative damage, and neuronal loss (25). In addition, Se is closely related to cognitive function and movement disorders. A cross-sectional study conducted in rural China showed cognitive decline in 2,000 elderly people aged over 65 years with Se deficiency (26). Hippocampal neuron loss was significantly higher in Se deficient rats than in sufficient rats (27). Furthermore, mice given a diet low in selenium showed changes in hippocampal long-term potentiation, short-term plasticity, and synaptic transmission (28). Blood Se levels were found to be lower in PD patients than in non-PD patients in a cross-sectional study, suggesting that high blood Se levels may protect against PD (29). We discovered an inverse relationship between blood Se and sNfL in the current study, which is consistent with the findings of previously research and suggests that individuals with high blood Se levels may be less likely to have underlying neurological diseases.

The structural proteins that make up the cytoskeleton of nerve cells include neurofilaments, which are made up of light, medium, and heavy chains (30). The amount of NfL released into the extracellular space is correlated with damage to nerve axons. In neurodegenerative diseases that cause damage to neurons, axons break down and release NfL, which eventually finds its way into the peripheral blood and cerebrospinal fluid (31). In clinical practice, sNfL has become a biomarker for a variety of neurological diseases (32). According to a sizable longitudinal cohort study, sNfL levels increased with age and time in PD patients and were associated with the severity of the disease (33). Elevated sNfL levels have been found in neurological diseases such as TBI, HD, and ALS (12–14). However, worse clinical outcomes in multiple sclerosis and AD and more severe neurological impairment are generally associated with higher sNfL levels (15, 16). Furthermore, it was found that hospitalized stroke patients had higher sNfL levels, and there was a positive correlation between sNfL levels and cerebral infarction (34). In individuals with mild ischemic stroke, there is a higher chance of early neurological deterioration when there is an increase in sNfL levels (35), which can also predict adverse clinical outcomes at 90 days after ischemic stroke (36). The results of our subgroup analyses suggest that blood Se does not affect sNfL levels in participants with a history of stroke. However, whether blood Se levels have an effect on subsequent stroke occurrence requires further epidemiological studies.

Serum NfL levels were discovered to have a strong, positive correlation with age. In individuals younger than 35 years, sNfL levels are relatively stable, but begin to increase nonlinearly with age. After controlling for age, gender was also associated with serum NfL levels, with a mean sNfL level of 17.99 pg./mL in males and 15.78 pg./mL in females (37). In our study, we found that the decrease in sNfL was more pronounced in men and in participants younger than 60 years of age with increasing blood Se levels. It is well known that obesity, smoking, and alcohol consumption are risk factors for vascular events. In a study of the relationship between morbid obesity and circulating NfL, absolute circulating NfL concentrations were found to be lower in morbidly obese subjects than in lean individual participants (38). According to Zhu et al. (39), there is a strong positive correlation between sNfL levels and serum cotinine, which raises the possibility that smoking is a contributing factor to neurological impairment. The high level of sNfL in alcohol dependent individuals suggests that sNfL can be used as a biomarker to evaluate alcohol-induced brain damage (40). Our results showed that sNfL levels were significantly decreased in participants with a history of smoking and drinking as the blood Se concentration increased. Selenium may have a protective effect on nervous system injury induced by smoking and drinking.

It is important to note that excessive Se exposure can also cause neurotoxicity, including memory and cognitive impairment. High doses of Se induce prooxidative effects and toxicity (41). Zeng et al. (29) found a nonlinear connection between blood selenium levels and PD, with high selenium levels significantly lowering the probability of PD development compared to low selenium levels. Around 2.4 μmol/L was the inflection point, after which the rate of risk reduction dramatically dropped as selenium levels rose. Consequently, we carried out a threshold effect analysis, and the findings showed that the inflection point was present at 2.22. When the Log blood Se exceeded 2.22, the sNfL level maintained a relatively stable level in the population. It is suggested that the neuroprotective effect is diminished and even neurotoxicity may occur when blood selenium levels surpass a particular threshold. This study provides a basis for dietary Se intake and maintenance of blood Se level in the American population in the future.

There are certain restrictions on our study. Firstly, the design of the cross-sectional analysis prevented us from establishing a causal relationship between blood Se and sNfL. Longitudinal studies would be necessary to confirm the link. Second, it was not possible to screen out all patients with neurological diseases related to axonal injury or subclinical neurological diseases. Finally, this study only collected blood samples from participants at a single time point and could not dynamically analyze changes in sNfL.

In conclusion, our study showed that a negative association between blood Se and sNfL, which is affected by gender, age, BMI, smoking, and drinking. When the blood Se concentration reaches a certain level, the sNfL level in the population is maintained at a relatively stable level even with the increase of blood Se concentration.