Ava Clark

Background: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition characterized by inattention, hyperactivity and impulsivity. ADHD is one of the most commonly diagnosed psychiatric conditions in children and adolescents.¹ Dopamine deficiency results from increased dopamine transporters (DAT-1) that reduce the available dopamine needed for reward and avoidance behaviors, leading to the symptoms of ADHD.² Early diagnosis of ADHD provides better outcomes for patients, including reduced functional impairments. However, diagnosis is challenging, as it is based on observation and reports, rather than biological bases.³ Clinical studies have identified microRNAs (miRNAs) that are differentially expressed in ADHD patients and could be used as a diagnostic panel for ADHD diagnosis.^3,4

Objectives: In this literature review, we explored the role of miRNAs in ADHD pathophysiology and the potential for miRNA biomarkers for ADHD diagnosis.

Search Methods: An online search was conducted using the PubMed database with the MeSH terms “Neurodevelopmental Disorders”[Majr] and “Brain/growth and development”[Majr] as well as the keywords “MicroRNA” and “miRNA”. Literature was selected from the timeframe of 2018-2025.

Results: miRNA biomarkers were identified in plasma white blood cell samples in patient populations using next-generation sequencing. Thirteen miRNAs were identified with differential expression in ADHD and control groups. A diagnostic panel constructed of these 13 miRNAs categorized group membership with a receiver-operator characteristic curve area under the curve (AUC) value of 0.94.³ This AUC value can be categorized as “excellent” (AUC ≥ 0.9).⁵ Further validation in a blinded study showed the panel performed with an accuracy of 85% and a sensitivity of 90%.³ A follow-up study using a panel of 12 of these miRNAs performed with a sensitivity of 96% and specificity of 94.2%.⁴ Not all miRNA biomarkers performed as well. In another study, assessing miRNA expression in serum using qPCR arrays, the diagnostic panel had “poor” performance with an AUC of 0.68 and a sensitivity of 67.5%.^5,6 miRNA expression may better reflect symptom severity. In a study assessing whole blood miRNA expression across six European cohorts, significant associations were found between elevated Conner’s hyperactivity scores and lower expression of 29 miRNAs as well as between higher Conner’s inattention scores and differential expression of three miRNAs.⁷ In vitro, two patient-identified miRNAs, miR-126-5p and miR-140-3p, increased differentiation and apoptosis of human cortical neuron (HCN-2) cells.⁴ Preclinically, miRNAs have been implicated as therapeutic targets. In an ADHD rat model of spontaneously hypertensive rats (SHR), miR-200b-3p antagomir reduced ADHD symptoms. Striatal injection of miR-200b-3p antagomir reduced striatal miR-200b-3p, inflammatory cytokines (e.g., TNF-α), and inattention, as measured with a Y-maze test. ⁸

Conclusions: When comparing clinical biomarker identification studies, multiple miRNAs were considered potential biomarkers in more than one study. miR-126-5p was a potential biomarker in two, miR-140-3p in three, and miR-101-3p in all four studies.^3,4,6,7 Preclinically-identified miR-200b-3p was not identified in the clinical biomarker studies but indicates that miRNAs can be therapeutically targeted to improve altered biology and behavior in ADHD.⁸ A weakness in the clinical studies was the lack of ethnically diverse study populations, which should be accounted for in subsequent research.^3,4,6 Overall, this literature implicates miRNAs in the pathophysiology of ADHD and reveals promise for miRNAs as both biomarkers and therapeutic targets for ADHD.^3,4,6-8

Works Cited:

1. Drechsler R, Brem S, Brandeis D, Grünblatt E, Berger G, Walitza S. ADHD: Current concepts and treatments in children and adolescents. Neuropediatrics. 2020;51(5):315-335. doi:10.1055/s-0040-1701658
2. Quintero J, Gutiérrez-Casares JR, Álamo C. Molecular characterisation of the mechanism of action of stimulant drugs lisdexamfetamine and methylphenidate on ADHD neurobiology: A review. Neurol Ther. 2022;11(4):1489-1517. doi:10.1007/s40120-022-00392-2
3. Wang LJ, Li SC, Lee MJ, et al. Blood-bourne microRNA biomarker evaluation in attention-deficit/hyperactivity disorder of Han Chinese individuals: an exploratory study. Front Psychiatry. 2018;9:227. doi:10.3389/fpsyt.2018.00227
4. Wang LJ, Kuo HC, Lee SY, et al. MicroRNAs serve as prediction and treatment-response biomarkers of attention-deficit/hyperactivity disorder and promote the differentiation of neuronal cells by repressing the apoptosis pathway. Transl Psychiatry. 2022;12(1):67. doi:10.1038/s41398-022-01832-1
5. Çorbacıoğlu ŞK, Aksel G. Receiver operating characteristic curve analysis in diagnostic accuracy studies: A guide to interpreting the area under the curve value. Turk J Emerg Med. 2023;23(4):195-198. doi:10.4103/tjem.tjem_182_23
6. Zadehbagheri F, Hosseini E, Bagheri-Hosseinabadi Z, Rekabdarkolaee HM, Sadeghi I. Profiling of miRNAs in serum of children with attention-deficit hyperactivity disorder shows significant alterations. J Psychiatr Res. 2019;109:185-192. doi:10.1016/j.jpsychires.2018.12.013
7. Dypås LB, Duale N, Olsen AK, et al. Blood miRNA levels associated with ADHD traits in children across six European birth cohorts. BMC Psychiatry. 2023;23(1):696. doi:10.1186/s12888-023-05199-5
8. Chang TM, Lin HL, Tzang CC, Liang JA, Hsu TC, Tzang BS. Unraveling the role of miR-200b-3p in attention-deficit/hyperactivity disorder (ADHD) and its therapeutic potential in spontaneously hypertensive rats (SHR). Biomedicines. 2024;12(1):144. doi:10.3390/biomedicines12010144