This study is the first to investigate the association between BDNF levels and preschool children’s cognitive development in healthy subjects. We found that serum BDNF level was negatively associated with both full-scale and verbal IQ scores and that plasma BDNF level was negatively associated with CBCL attention and behavior problem scores.

BDNF is an important factor in neuro-development [3, 4]. Our results show that BDNF may play a role in intelligence, attention and clinical symptoms of preschool children with neuro-developmental disorders such as intellectual disability and ADHD. Higher peripheral BDNF concentration could be a biomarker of these states.

There are some reports of an association between BDNF and intellectual disability and of a general inverse correlation with intelligence in children [23–25]. Nelson et al. [23] reported elevated peripheral blood BDNF levels in neonates with intellectual disabilities than in controls. They suggested that BDNF dysregulation may play a role in the development of intellectual disability and that BDNF levels may be an early biomarker for identification of intellectual disability [23]. Miyazaki et al. [24] also found that children and adolescents (mean age: 11.0 ± 5.9 years), diagnosed with an intellectual disability, had higher blood BDNF levels than controls. They concluded that elevated BDNF levels may reflect an abnormal state in prenatal or early postnatal neuronal development [24]. However, Taurines et al. [25] found no correlation between altered peripheral BDNF mRNA expression and BDNF protein concentrations in blood of children and adolescents with autism spectrum disorder.

Research has been conducted on cognitive function of BDNF over-expressed transgenic mice [10, 43]. Croll et al. [43] found that BDNF over-expressed transgenic mice show significant impairment in learning (passive avoidance) and increase locomotor activities (maze arm entries) and hyper-excitability in the CA3 area of the hippocampus. They suggested that excess BDNF may interfere with normal learning and memory, and this result is due to too much excitability in the learning circuit or too much plasticity leading to synaptic refinement [43]. Cunha et al. [10] also described that overexpression of BDNF in the forebrain may reduce learning and memory formation in mice. They proposed that the physiological amount of BDNF is helpful in learning and memory, but an increased or decreased level of BDNF induces inhibitory and excitatory neurotransmission in the brain, causing loss of synaptic refinement and impairment of learning and memory [5].

Some researchers found a relationship between a polymorphism of the BDNF gene and cognitive functions in humans [44–46]. Egan et al. [44] reported that the Val66Met polymorphism of the BDNF gene, valine (Val) to methionine (Met) substitution at codon 66, is related to poor episodic memory, abnormal hippocampal activation, abnormal intracellular trafficking and dysregulation of BDNF secretion in humans. fMRI research of the Val66Met polymorphism of the BDNF gene also described that the Val66Met polymorphism impacts memory related brain activity in the healthy humans. Additionally, the Met allele of the BDNF Val66Met polymorphism is related to increased serum BDNF levels in adults [46]. Therefore, we need additional research about single nucleotide polymorphisms of the BDNF gene in children with higher serum levels of BDNF such as those in this study.

There are some controversial results about the relationship between BDNF and ADHD [20, 22, 47]. Shim et al. [22] found that children (mean age: 8.8 ± 2.3 years), who are diagnosed with ADHD, have higher plasma BDNF levels than control children, and the severity of inattention problems have a positive correlation with plasma BDNF levels. They suggested that increased BDNF levels possibly reflect a compensatory mechanism in the response of abnormal and late brain maturation [22]. However, Scassellati et al. [47] found no difference in serum BDNF level between ADHD children (mean age: 8.8 ± 2.3 years) and control children. Corominas-Roso et al. [20] reported that adults with ADHD (mean age: 33.43 ± 8.99 years) have lower BDNF levels than control adults. They suggested that low BDNF levels may contribute to the neurodevelopmental deficit in ADHD [20]. A study have reported that the serum BDNF level increases over the first several years and, then decreases after reaching adult levels in humans [26]. Therefore, more research is needed on the association between peripheral BDNF concentration and neuro developmental disorders in human development.

Animal studies have also reported controversial results about the relationship of BDNF with inattention and hyperactivity [43, 48–50]. Young adult transgenic mice, which over-express BDNF, have a tendency to spend more time being mobile [43], but BDNF knockout adult mice demonstrate more impulsive behavior, hyperactivity and learning deficiency [48–50].

Some studies have reported on the association between the BDNF gene and ADHD [51–53]. Of these studies, a cohort study on the association between the Val66Met polymorphism of BDNF and children with ADHD found that the Met allele is associated with ADHD symptoms, such as hyperactivity-impulsivity [53]. Another study found that the Valine allele of the Val66Met polymorphism of the BDNF gene is associated with the pathogenesis of ADHD [52]. Thus, additional studies are needed on the association between peripheral BDNF concentration and single nucleotide polymorphisms of the BDNF gene in children with ADHD.

Our study used serum and plasma levels of BDNF to investigate the relationships among peripheral blood BDNF level and childhood IQ and neurobehavior. In this study, serum BDNF level was related to VIQ and FIQ. However, plasma BDNF was not associated with VIQ and FIQ. Plasma BDNF levels were related to externalizing problems and attention problems according to the CBCL, but not with serum BDNF levels. Many other studies have assessed the relationship between the serum or plasma level of BDNF and neuropsychiatric or developmental disorders [16, 19, 20, 22, 24]. However, there is still no standard method to measure peripheral BDNF levels. Additionally, the relationship between serum and plasma BDNF levels has not established. Yoshimura et al. [54] reported that plasma and serum levels of BDNF are positively correlated in healthy volunteers. However, Bocchio-Chiavetto et al. [55] found no correlation between plasma and serum levels of BDNF in major depressive patients in a meta-analysis. Some researchers have suggested that plasma BDNF is a reliable indicator of brain BDNF levels because of the little influence of the BDNF that is stored in platelets [22, 56]. Other researchers have suggested that serum BDNF is a valid marker of brain BDNF because serum BDNF reflects the BDNF accumulated by platelets during illness or treatment periods [57]. Accordingly, we used two indicators, serum and plasma BDNF. Therefore, to use BDNF as a biomarker, a standardized method of measurement of BDNF and the source of peripheral BDNF is needed.

This study has some limitations that must be considered. First, we did not assess our subjects with structured interviews to rule out psychiatric illnesses. However, we assessed their intelligence and psychiatric history using a standardized intelligence scale and questionnaire. Second, we assessed the correlation between peripheral blood BDNF and intelligence and psychiatric problems in the same group. Therefore, we could not compare the absolute peripheral BDNF level of patients with ADHD or other DSM-5 neurodevelopmental disorders. Third, this study was a cross-sectional study. In BDNF over-expressing mice, memory retention was impaired in younger animals, but not in older ones [10]. Thus, a long-term follow up study on blood BDNF levels and psychopathologies is needed. Last, we included 28 preschool children, and higher number of subjects would increase statistical power.