Tobacco smoking stands as a major public health concern, contributing to the deaths of over 5.4 million individuals annually[1], with the potential for this number to rise to approximately nine million by 2030 as per the World Health Organization (WHO)[2]. Extensive research has demonstrated that smoking is a significant risk factor for a multitude of diseases, including lung cancer, ischemic heart disease, chronic obstructive pulmonary disease, and various other forms of cancer[3]. In addition to these well-documented health implications, chronic exposure to smoking has been linked to respiratory tract infections, asthma in infants, diminished immune cell activity, and heightened allergic responses[4]. Furthermore, epidemiological studies have associated smoking with a range of neurological disorders, such as Parkinson’s disease, Alzheimer’s disease, stroke, multiple sclerosis, silent cerebral infarction, and sleep disorders[3, 5, 6]. Notably, habitual smokers are at a twofold higher risk of developing Alzheimer’s disease[7]. Similarly, a strong positive dose-dependent association has been observed between ischemic stroke and smoking[8], and smoking even one cigarette daily increases the risk of developing a stroke[9]. Furthermore, smoking has been identified as a risk factor for multiple sclerosis[10] and has been linked to sleep apnea, sleep-disordered breathing, insomnia, and poor sleep quality[11]. However, despite the numerous adverse effects of smoking, an inverse relationship has been found between smoking and the incidence and mortality of Parkinson’s disease[12].
In contrast to the complex effects of smoking, nicotine, the principal psychoactive chemical in tobacco smoke, has demonstrated distinct effects. Studies have highlighted the pivotal role of nicotine as an agonist of nicotinic acetylcholine receptors (nAChRs) in both the central and peripheral nervous systems[13]. Given the widespread presence of nAChRs throughout the brain and the significance of the central cholinergic system in cognitive function restoration, nicotine, and its analogs have shown promise in inducing cognitive improvement[14]. Nicotine has been found to influence various cognitive functions, including attention, learning, and memory[15], and has been shown to improve cognitive impairment in disease-induced cognitive disorders, such as Alzheimer’s disease, Parkinson’s disease, age-associated memory impairment, schizophrenia, stroke, autism spectrum disorder, and attention deficit hyperactivity disorder[16]. Moreover, nicotine has been associated with a reduced risk of Parkinson’s disease[17] and has exhibited potential for the treatment of this condition[18]. Additionally, nicotine has been linked to improvements in attention, working memory, fear memory, spatial memory, and enhanced social interaction in non-smoking adults[14]. However, it is noteworthy that paradoxical effects have been reported, potentially due to its inverted U-shaped dose-response effects, with small doses of nicotine leading to improved cognition, while heavy smoking, both chronically and acutely, results in cognitive impairment[19]. Furthermore, high-dose nicotine treatment has been linked to phenotypes of spatial memory impairment, anxiety, depression, and cognitive impairment in animals[20, 21].
Neurofilament light chain (NfL) has emerged as a promising biomarker for various neurological diseases. Neurofilaments, comprising light, medium, and heavy chains, are neuron-specific type IV intermediate filament heteropolymers that play a crucial role in the neural cytoskeleton[22]. Following neuro-axonal damage, they are released into the extracellular space and have been proposed as potential biomarkers for neuro-axonal injury in neurological diseases[22, 23]. Notably, elevated levels of NfL have been associated with several neurological disorders, including multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, stroke, Huntington’s disease, motor neuron disease, and traumatic brain injury[24-27]. Additionally, NfL levels have been linked to disease severity, aging, and body mass index[28, 29]. Despite the substantial evidence regarding the associations between smoking and neurological diseases, there is a notable gap in research investigating the associations between nicotine in body fluids and serum neurofilament light chain (sNfL). This study aims to explore the effect of nicotine concentration in body fluids (serum and urine) on sNfL levels, and specifically, whether sNfL decreases with increasing nicotine at lower nicotine concentrations. Given the extremely short elimination half-life of nicotine, cotinine and trans-3’-hydroxycotinine (hydroxycotinine) are being considered as preferred biomarkers due to their higher concentrations and significantly longer elimination half-lives[30]. The estimated elimination half-life of cotinine is approximately 15-20 hours, whereas the half-life of nicotine is only 0.5-3 hours. Similarly, the half-life of hydroxycotinine is about 5-6 hours, but when generated from cotinine, its elimination half-life becomes similar to that of cotinine[30].
To this end, this study aims to utilize cotinine and hydroxycotinine to investigate the associations with sNfL in a nationwide population in the US.