Globally, ADHD worth to be greatly considered in children as it can touch every aspect of the child's life activities and school presentation with subsequent educational and academic discrepancies (Nourredine et al. 2021). Based on the previous knowledge, this research is the foremost to investigate the causal association of ADHD with tissue dwelling and intestinal parasites along with various micronutrients and blood indices. We postulated that childhood parasitic infections may impact the neuropsychiatric development with special concern to gut-brain axis.
Compared with G2, children with ADHD significantly had higher odds of exposure to demographic risk factors for parasitic infectionsas contact with animals, contact with soil, and consumption of undercooked meat or unfiltered water. This result indicates that ADHD children carry higher potential to acquire parasitic infections which may either directly cause or even augment ADHD by its sequels (El-Beshbishi et al. 2018). The role of demographic risk factors in the development and spread of parasitic infection was well reported by Geneidy (2019). Furthermore, the levels of Hb, iron, zinc and copper showed statistically significant decrease in G1. These results are very logic coinciding with those of Marques, RC et al. (2020) who reported that Amazonian children were suffering from anemia and poor nutritional status as a chronic sequel of parasitic infections. The results of the present work are also confirmed by those obtained in Egyptian children by Mahmoud, AM et al. (2017) who indicated the causal relationship between intestinal parasitic infections and iron deficiency anemia. Therefore, several studies highlighted the parasitic infections as dangerous health problem owing to their impact on nutritional status and micronutrients level that leads to learning, physical, and mental disorders (Shalaby et al. 2017). On the other hand, parasitic infections significantly impact the brain activities by altering brainwave amplitudes triggering mental sluggishness, learning deficits, and ADHD but with unidentified mechanisms (Davoudi et al. 2020).
The statistically significant levels of seropositivity ofToxoplasma IgG in ADHD children in the present work can be interpreted by numerous behavioral studies which proved that latent toxoplasmosis may result in behavioral changes (Noori et al. 2020). At the same time, the behavioral changes of T. gondii-infected rodents such as rapid loss of concentration and elevated activity levels were clinical shown to bear resemblance to those manifested in ADHD patients (Nayeri et al. 2020). Moreover, latent toxoplasmosis has been associated with lethargy, impaired concentration, discrepancies in motor functions, and increased risk of injury which all described in patients with ADHD (Lam et al. 2020).
The mechanistic potentials by which T. gondii can manipulate brain functions include direct interactions with brain neurons which are the main target of Toxoplasma (Cabral et al. 2016). Experimental T. gondii infection resulted in neuro-inflammation and loss of brain parenchyma with subsequent neuro-psychiatric abnormalities (Hermes et al. 2008). Moreover, T. gondii was reported to interact with host genomics and proteomics throughout its life cycle, including human ADHD predisposing genes with a specific emphasis on the dopaminergic signaling and neurotransmitter pathways (Carter 2013). This can be interpreted by its direct enhancing impact on dopamine neurotransmitter release from neurons by emphasizing genes encoding tyrosine hydroxylase enzyme which is dopamine biosynthesis inhibitor (Volkow et al. 2009). In order to explain the hypothesis of the current work, the high prevalence of Toxoplasma IgG in ADHD children was interpreted by the finding that T. gondii cysts were mainly concentrated in the amygdala, nucleus accumbens, and hypothalamus which are dopamine-containing brain areas that control fear and movements with great emphasis on ADHD (Volkow et al. 2009; Lam et al. 2020). Furthermore, the antipsychotic dopamine receptor agonists, the mood stabilizers, or the selective dopamine reuptake inhibitor were reported to inhibit T. gondii multiplication as well as the associated behavioral disorder (Webster et al. 2006; Skallova et al. 2006). Similarly, L-tyrosine supplements, a crucial precursor for dopamine and norepinephrine, recorded positive results in ADHD patients (Wood et al. 1985).
In the present work, there was statistically significant level of seropositivity of anti-Toxocara IgG in ADHD group. The results herein coincide with experimental research which indicated that neurotoxocariasis leads to variable behavioral changes in infected animals(Othman et al. 2010). In addition, cohort studies indicated that neurotoxocariasis is one of the major causes of academic shortages as well as other psychological discrepancies depending on the intensity of parasite-induced pathology (Nicoletti 2020). Increased prevalence of anti-Toxocara IgG in ADHD group can be explained by Maiga, Y et al. (2007) and Lompo, LD et al. (2012) who revealed that Toxocara larvae release toxins that can cause direct neuronal damage. Furthermore, chronic Toxocara infection was found to augment expression of inflammatory cytokines such as TNF-mRNA with associated TNF-disturbances leading to sleep and cognitive impairment (Turrin and Plata 2000). The role of toxocariasis induced inflammatory mediators cannot be neglected in the affected brain circuits in experimental animals (Othman et al. 2010). This fact was also confirmed by Tonelli, LH et al. (2009) who indicated the role of inflammatory cytokines in prompting the behavioral and emotional neuroimmune mechanistic potentials that may activate the hypothalamus-pituitary-adrenal axis. Furthermore, inflammatory cytokines were found to amend the metabolism of norepinephrine and dopamine which were identified to be involved in ADHD pathogenesis (Chen et al. 2019). Taken together, the mechanisms by which toxocariasis can impact the pathogenesis of ADHD may involve inflammatory cytokines in parallel with brain neurotransmitters in experimental animals and perhaps in humans as well accounting for the behavioral and cognitive deficits (Othman et al. 2010).
In the current work, no helminthic eggs were detected in direct stool examination though; Schistosoma CCA was detected in G1 but with no statistical significance. Regarding schistosomiasis as the second most common parasitic infection in the world and one of the most imperative causes of anemia (Mnkugwe et al. 2020), it was logic to interpret the existence of schistosomiasis in ADHD group. Urinary and gastrointestinal schistosomiasis can predispose to iron deficiency anemia either by direct blood loss in urine and stool or by associated schistosomal hypersplenism (Adam et al. 2021). On the other hand, Schistosoma infection was reported to be highly associated with learning and memory deficits due to cognitive dysfunction by different mechanisms either directly through eggs deposition in the brain, or indirectly, via infection associated iron-deficiency and malnutrition (Ezeamama et al. 2018). On the other hand, the role of other helminthic infections in triggering neurotransmitters changes was highlighted in several researches (Brahem et al. 2006; Ismail et al. 2007). Therefore, according to the previously mentioned mechanisms, future research is needed to explore the cross talk between helminthic infections and neurodevelopmental disorders including ADHD.
There is no doubt that intestinal parasitic infections among school children can significantly trigger iron deficiency anemia, physical and mental retardation (Marques et al. 2020). This systemic impact may be linked to significant reduction of Hb levels in children as parasites require iron, carbohydrates, lipids, minerals and vitamins to gain energy for their life cycles, growth and multiplication (Teja et al. 2020). According to Mahmoud, AM et al. (2017), G. lamblia and C. parvum associated diarrheaas well as E. histolytica associated dysentery was recorded to predispose to iron deficiency anemia among Egyptian school children. The mechanical damage of the intestinal epithelium by the ventral suckers of G. lamblia, toxic injury with subsequent increase of the intestinal permeability, and malabsorption are the main causes of anemia in giardiasis (Hussein et al. 2016). The results of the current study agree with Shalaby, NM et al. (2017) who reported the suppressor impact of G. lamblia, C. parvum and E. histolytica infection on Zn, iron, and Cu serum levels due to their malabsorption. In the present study, G. lamblia was highly correlated to decreased Zn levels. This result can be interpreted by the supposition that the mucosal lesions triggered by the sucking discs of G. lamblia may significantly impair the intestinal Zn absorption. Moreover, these parasitic infections shift zinc to the liver with significant decrease of its level in serum (Mahmoud et al. 2017).
Protozoal diarrhea is one of the foremost causes of anemia and dehydration as well as loss of minerals. Furthermore, their treatment with anti-protozoal drugs had amended the micronutrient serum levels (Wiser 2021). On the other hand, Zn serum level can be easily dropped especially in children because of their higher growth demands as it cannot be stored in the body (Skalny et al. 2020). Zinc is well-thought to be crucial in the metabolism of nucleic acids and the protein synthesis, therefore its deficiency delay the growth process in children (Zhu et al. 2021). Evidence of mineral deficiencies in children suffering from ADHD such as zinc, iron, calcium, magnesium, and selenium was proved by Viktorinova, A et al. (2009) as decreased Zn and iron levels might be allied with substantial dampening of dopaminergic transmission exacerbating anxiety and behavioral disorders (Oner et al. 2010; Ajsuvakova et al. 2020). On the other hand, zinc supplementation in children reported reduced ADHD manifestations (Noorazar et al. 2020).
Regarding the results of the present work, the mean±SD of the levels of Hb, iron, zinc, copper, and eosinophils percentages showed statistically significant differences between G1 and G2 which highlight various ADHD associated comorbidities. Decreased levels of Hb and iron in the present study in ADHD group highly coincides with (Rodríguez et al. 2021) who correlated low levels of serum iron in children as a risk for cognitive, behavioral, and learning problems. Likewise, iron deficiency may interfere with oxygen supply of the brain altering the cognitive ability hence the development of ADHD (Robberecht et al. 2020). As iron deficiency anemia is the most dominant form of anemia it was proved to be a potential risk factor for hyperactivity (Oner et al. 2012) and neurological discrepancies including ADHD (Bener et al. 2014). Moreover, decreased iron stores were also supposed to dampen the psychostimulants efficacy in children with ADHD (Cortese et al. 2012). Regarding iron as a cofactor of tyrosine hydroxylase and tryptophan hydroxylase biosynthesis, its depletion can alter neurotransmitters such as dopamine (Erikson et al. 2000).