Evidence-Based Reviews

What does molecular imaging reveal about the causes of ADHD and the potential for better management?

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References

D2 receptors are present in presynaptic and postsynaptic neurons47 in the neocor­tex, substantia nigra, nucleus accumbens, and olfactory tubercle, as well as in other structures.48 Presynaptic D2 receptors act as autoregulators, inhibiting dopaminergic synthesis, firing rate, and release.49

Using C-11 raclopride PET imaging, Lou et al50 reported high D2/3 receptor availabil­ity in adolescents who had a history of peri­natal cerebral ischemia. They found that this availability is associated with an increase in the severity of ADHD symptoms. They pro­posed that the increase in “empty” receptor density might have been caused by perinatal ischemia-induced presynaptic dopaminer­gic neuronal loss or an increase in presynap­tic dopamine reuptake (Figure 550). Either mechanism could result in up-regulation in postsynaptic D2/3 receptors.

Volkow et al51 reported that D2 receptor density correlated with methylphenidate-induced changes in rCBF in frontal and tem­poral lobes in humans. They postulated that the variable therapeutic effects of methyl­phenidate seen in ADHD patients might be related to variations in baseline D2 receptor availability.

Lou et al50 reported elevated D2 recep­tor density, demonstrated using carbon-11 raclopride, in children with ADHD, com­pared with normal adults.

Further support for a relationship between D2-receptor density and symptom­atic improvement with methylphenidate in ADHD was presented by Ilgin et al52 using iodine-123 iodobenzamide SPECT. They found elevated D2 receptor levels in 9 drug-naïve children with ADHD, which is 20% to 60% above what is seen in unaffected chil­dren. They noted that these patients showed improvement in hyperactivity when treated with methylphenidate.

In a similar study of 20 drug-naïve adults, Volkow et al53 found that durable symptom­atic improvement with methylphenidate therapy was associated with increased D2 receptor availability.


Summing up

Striatal DaT is the most likely synaptic tar­get for stratifying patients with ADHD, now that a dopamine transporter imaging agent is available commercially. Stratification might allow for refinement in the diagnostic categorization of ADHD, with introduction of stimulant-responsive and stimulant-unresponsive subtypes that are based on DaT imaging findings.


Bottom Line

Given recent advances showing molecular alterations in the dopaminergic-frontostriatal pathway as central to attention-deficit/hyperactivity disorder, molecular imaging might be useful as an objective study for diagnosis.

Related Resources
• Schweitzer JB, Lee DO, Hanford RB, et al. A positron emis­sion tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predict­ing treatment response. Neuropsychopharmacology. 2003;28(5):967-973.
• Raz A. Brain imaging data of ADHD. Psychiatric Times. http://www.psychiatrictimes.com/adhd/brain-imaging-data-adhd.


Drug Brand Names

Iodine-123 ioflupane • Methylphenidate • Ritalin DaTscan


Acknowledgment

Kylee M. L. Unsdorfer, a medical student at Northeast Ohio Medical University, helped prepare the manuscript of this article.


Disclosures

Dr. Thacker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Binkovitz received 4 doses of ioflupane I123I (DaTscan) from General Electric for investigator-initiated research, used for animal imaging in 2012.

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