Much progress has been made in the last 10 years in understanding the neural correlates of attention-deficit/hyperactivity disorder (ADHD), yet there remains no established, clinically useful biomarker of ADHD [1]. Along with findings of aberrant brain volumes, cortical thickness, tissue microstructure, neural activation and neurotransmitter levels [1], recent findings of atypical brain iron levels have added another promising avenue to examine.

Serum iron & ADHD: a long history

The interest in studying the role of iron in ADHD is not a new concept with some of the earliest studies conducted nearly 20 years ago [2]. These studies specifically focused on the relationship between serum iron levels and ADHD symptoms. Guided by epidemiological evidence that low serum iron levels in iron-deficient infants, children and adolescents are strongly correlated with cognitive deficits similar to ADHD symptoms (e.g., reduced attention, motivation, working memory, motor control) [3], several groups examined whether serum iron measures could serve as ADHD biomarkers. Despite some encouraging early findings [2], a recent large case-controlled study of over 100 medication-naive ADHD children found no differences in serum iron measures when compared with typically developing controls (TDC) [4]. Indeed in our own recent study, we too were unable to distinguish ADHD patients from TDC using serum iron measures [5]. Together, these findings suggest that serum iron measures do not provide reliable biomarkers for ADHD.

Brain iron & ADHD: a brief history

The relationship between peripheral serum iron and brain iron is complex and indirect [6], and it is important to emphasize that normal peripheral serum iron measures do not exclude the possibility of abnormal brain iron levels in ADHD. In fact, animal studies have reported the association of low brain iron with disrupted neural processes implicated in ADHD, including dopaminergic abnormalities (e.g., reduced dopamine [DA] transporters, decreased intracellular DA, increased extracellular DA, reduced DA receptors) [7,8]. Specifically, a fundamental relationship between brain iron and DA metabolism has been demonstrated through iron's role as a required cofactor for catecholamine synthesis and its regulatory inhibitory feedback [9,10]. This functional overlap may explain why high concentrations of both brain iron and DA are co-localized to the same basal ganglia regions [8,11], why aberrant dopaminergic features were found only in brain regions with atypical brain iron levels and were associated with ADHD-like deficits [7,8] which improved after psychostimulant treatment [12]. Evidence linking atypical brain iron levels with the dopaminergic system have also been observed in restless leg syndrome [13], a sensorimotor disorder that is highly comorbid with ADHD [2]. However, despite these connections, it is still unknown how the functional units of the dopaminergic system and brain iron homeostasis all relate to one another, let alone how each component adapts to disease or modulation by psychostimulants.

MRI: a noninvasive method for assessing brain iron

The brain has high concentrations of tissue iron relative to most other organs, particularly in deep gray matter regions such as the basal ganglia [11]. In contrast to the radioactive tracers required to measure DA biomarkers in molecular imaging, brain iron can be assessed noninvasively using MRI [14]. This is due to the strong magnetic properties of iron that can significantly affect MRI signal decay. Thus, brain iron may be regarded as a noninvasive, endogenous contrast agent [14]. The most conventional MRI methods used to assess brain iron are the transverse relaxation rates known commonly as R2, R2* and R2’. Unfortunately, the specificity of these relaxation rate measures for iron is less than adequate because these measures are also affected by other biophysical influences unrelated to iron [14]. Fortunately, the recent development of more advanced MRI methods, such as quantitative susceptibility mapping and magnetic field correlation (MFC) imaging, address these limitations and provide measurements with sensitivity and improved specificity for iron [14]. Although these advanced methods are still ‘works in progress’ and require further optimization, their clinical feasibility has been encouraging [5,15,16].

MRI assessment of brain iron: a potential biomarker of ADHD

Consistent with the only ADHD MRI study of brain iron [17], our own recent report [5] demonstrated that medication-naive ADHD patients had significantly lower MRI-based indices of brain iron in striatal and thalamic regions compared with either TDC or psychostimulant-medicated ADHD patients. Interestingly, psychostimulant-medicated ADHD patients and TDC did not differ statistically in any MRI-based brain iron index. These findings implicate reduced brain iron in ADHD pathophysiology – prior to medication – which appears to normalize with psychostimulant treatment. Moreover, unlike other neural correlates of ADHD [18], these brain iron findings were not confounded by ADHD comorbidity. Considering that psychostimulants reduce ADHD symptoms predominantly by increasing striatal DA [19,20] and that our results parallel prior molecular imaging findings of reduced striatal DA biomarkers in medication-naive ADHD patients and greater DA biomarkers in those treated with psychostimulants [21], it is possible that MRI-based indices of brain iron levels may indirectly reflect the disrupted dopaminergic pathway in ADHD [19,20]. However, there remains a need for validation studies in both animals and humans using multimodal MRI and molecular imaging approaches to examine correlations within the inter-related systems. Nonetheless, given that brain iron is fundamentally linked to the dopaminergic system, it is highly possible that brain iron homeostasis may also be disrupted in ADHD.

What are the harms of misdiagnosis?

Preventing the misdiagnosis of any disorder is as important as making a correct diagnosis. In the case of ADHD, making the correct diagnosis is particularly important since the first line of treatment usually involves prescribing psychostimulants that are Schedule II Controlled Substances due to their ‘high potential for abuse’ [22]. Although psychostimulants are successful in reducing inattentive and hyperactive/impulsive symptoms in up to 70% of ADHD cases [23], reported side effects for nonresponsive cases have been as severe as addiction or psychosis [22,24]. Along with the 42% increase in the rate of ADHD diagnosis within the past decade, rates of children and adolescents taking psychostimulants have also skyrocketed (28% increase between 2007 and 2011) [25]. While some have argued that improved public education and awareness have resulted in more patients seeking and obtaining medical treatment for ADHD, others have raised concerns that these statistics reflect a societal trend of liberally overdiagnosing ADHD. Indeed, reports of healthcare providers making the ADHD diagnosis without conducting a comprehensive battery of behavioral assessments and/or prescribing ADHD medications for non-ADHD symptoms (e.g., improve grades) are common [26]. Thus, while psychostimulants are effective when ADHD is properly diagnosed and may even be protective against substance use disorders in ADHD [27], the danger of prescribing psychostimulants to children and adolescents who are misdiagnosed with ADHD should not be underestimated. These risks underscore the need to identify ADHD biomarkers that may help to inform more accurate diagnosis.

Where do we go from here?

Several factors make brain iron an attractive ADHD biomarker candidate. Foremost, brain iron has a fundamental relationship to the dopaminergic system [7–10], which is known to be disrupted in ADHD and is a target of psychostimulant treatment [19,20]. Moreover, the ability to noninvasively assess brain iron levels in humans using MRI is a promising development in the study of ADHD, as it bypasses the use of radiation that is required for DA biomarkers [14]. Unfortunately, there remains a paucity of in vivo imaging studies examining brain iron in the disorder. To date there have been only two cross-sectional studies using relaxation rates and MFC measures [5,17]; this is simply not enough to confirm or dispute the potential of brain iron as a biomarker for ADHD. Although both studies support low brain iron as a biomarker for ADHD prior to medication, additional longitudinal studies examining brain iron levels pre- and postpsychostimulant medication are needed to corroborate these preliminary findings. Furthermore, future studies should utilize advanced MRI methods to ensure that negative results reflect biology rather than the limitations of the imaging tools. These studies must also account for several clinical demographics, including ADHD comorbidity and medication history, as these facets have been shown to affect the neural correlates of ADHD along with clinical symptoms and outcomes [1,5,18,28]. Although much more work is needed to validate the potential of brain iron as an ADHD biomarker, these promising preliminary findings coupled with the clinical feasibility of noninvasively assessing brain iron with MRI warrants moving forward in this line of research.