Brain iron levels in children with attention-deficit/hyperactivity disorder (ADHD): MRI study

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common childhood psychiatric disorders, estimated to affect about 5% of school-aged children worldwide. According to the Diagnostic and Statistical Manual of Mental Disorders-4th edition-Text Revision (DSM-IV-TR), ADHD is defined by a persistent and age-inappropriate pattern of inattention, hyperactivity-impulsivity or both. The exact etiopathogenesis underlying ADHD is not completely understood. It is likely that ADHD is an heterogeneous syndromic entity with a multifactorial etiopathogenesis, including genetic and environmental factors. Several lines of evidence, reviewed in detail in the first part of the thesis, suggest that iron deficiency (ID) might be involved in the etiopathogenesis of ADHD. First, iron is a co-factor of enzymes necessary for the synthesis and catabolism of the aminergic neurotransmitters (dopamine, serotonin, and noradrenaline), which have been shown to be involved in the pathophysiology of ADHD. Second, iron deficiency is associated with a decrease in dopamine D2 receptors, as well as of dopamine transporter in basal ganglia (in particular in the striatum), which have been implicated in ADHD pathogenesis. Third, there is a large body of research showing that ID with or without anemia in childhood is associated with cognitive and behavioral impairments, including poor attention and hyperactivity. Fourth, ID in basal ganglia is also increasingly recognized as a central factor in the pathophysiology of Restless Legs Syndrome, which may be co-morbid with ADHD, thus suggesting possible common pathophysiologic pathways in which iron deficiency may play a role. Finally, overweight, which is more common in children with ADHD than controls, has been associated with iron deficiency. Rationale: To date, available studies on ID in ADHD are based on the measure of serum ferritin, a peripheral marker of ID. However, how well peripheral iron indices correlate with central (i.e. brain) iron content is still unclear. Since it is central iron that may impact on brain function, there is a need to assess brain iron levels in children with ADHD. No published study has assessed brain iron levels in children with ADHD by means of Magnetic Resonance Imaging (MRI). Aims: The aims of the study, presented in the second part of the thesis, are the following: Primary: To compare brain iron levels, estimated by means of MRI, in a sample of children with ADHD, in a group of children with other psychiatric disorders (different from ADHD), and in a group of healthy controls. Iron levels were estimated in four regions which have been shown to contain iron: thalamus, putamen, pallidum, and caudate. Secondary: To assess the relationship between serum ferritin levels and estimated brain iron levels in the three study groups. Methods: Subjects: Patients (6-14 years) with ADHD, as well as those with other psychiatric disorders, were recruited from the Child and Adolescent Psychopathology Unit of the Hospital Robert Debré in Paris (2006-2008). Healthy controls were recruited from relatives of hospital employees. Non-inclusion criteria were the presence of one or more neurologic disorders, a previous or ongoing iron supplementation, anemia, and the current use of any drug that could significantly affect cognitive function. Procedures: Psychiatric evaluation: The diagnosis of ADHD, as well as of other psychiatric disorders, was made according to DSM-IV-TR criteria and was confirmed by the semi-structured interview Kiddie-SADS-PL. The Kiddie-SADS-PL confirmed the absence of any relevant psychiatric disorder in the control group. Assessment of peripheral iron status: A complete blood count and measurement of serum ferritin levels, as well as of serum iron and hemoglobin (Tinaquant and Ferrozine method) were obtained. MRI measurements: Estimation of brain iron was obtained on the basis of T2*. The inverse of T2* (R2*) are directly correlated with iron stores. MRI examinations were performed on a 1.5 T Philips Unit. Statistical analysis: T2* were compared in the three study groups using one-way ANOVA analysis with Bonferroni multiple comparison procedure. The correlation between serum ferritin levels and estimated brain iron levels in the four regions was assessed by means of the Spearman correlation. All statistical analyses were performed using SPSS v. 15.0 (SPSS, Inc., Chicago, IL, USA). Results: Data from eighteen children with ADHD, nine patients with other psychopathologies (Anxiety Disorders, Mood Disorders, Obsessive Compulsive Disorder, and Early Schizophrenia), and nine healthy controls were used for the statistical analysis. According to the power analysis, this sample size allowed for a detection of a difference of 2 points in T2* with a power of about 85%. It was found that T2* were significantly higher (meaning that iron levels were significantly lower) in thalamus, both in right (p= 0.015) and in left thalamus (p= 0.010) in children with ADHD compared to healthy controls. No other significant differences were found for the other regions of interest. Children with ADHD had serum ferritin levels significantly lower than children with other psychiatric disorders (p =0.006) and healthy controls (p=0.001). Serum ferritin levels were inversely correlated with T2*, but the correlations were not significant in any regions of interest (p> 0.005). Discussion: This is the first study to assess brain iron levels in children with ADHD. MRI data suggest that low iron levels in thalamus might impair its functioning in children with ADHD. Although the thalamus has been scarcely investigated in ADHD, it is presumed to be a very critical brain region subserving normal attention processes. Iron deficiency might negatively impact thalamic functioning also in other psychiatric disorders, but further studies are needed to assess to what extent iron deficiency is specific of ADHD or can be found in other psychiatric disorders. Serum ferritin levels inversely increased with T2*, but the correlation was not significant. Although low peripheral iron levels may negatively impact on brain iron, our results suggest that serum ferritin levels might be only a proxy for brain iron but can not estimate it accurately. Conclusions and future perspectives: This study provides a significant contribution to our understanding of the pathophysiology of ADHD, suggesting that brain iron deficiency might contribute to the pathophysiology of ADHD (and perhaps of other childhood psychiatric disorders) via its impact on thalamic functioning, which is part of neuronal circuits serving attention and alertness. Further studies, with novel MRI approaches to better estimate brain iron, are needed to confirm our results. This body of research might contribute to advance our knowledge on the etiopathogenesis and pathophysiologic pathways underlying the cluster of ADHD symptoms. The approach which underlies the rationale of these studies is an innovative one in the field of ADHD, and, in general, in child psychiatry, moving from the description of syndromes to pathophysiologybased disorders.