Brain iron load and neuroaxonal vulnerability in adult attention-deficit hyperactivity disorder

Abstract

Aim: Adult attention deficit hyperactivity disorder (ADHD) may be associated with an increased risk of dementia in old age. Here, we investigated the liability for neurodegenerative brain disease in adult ADHD, possibly reflected by increased brain iron content and associated neuroaxonal vulnerability.

Methods: Thirty-two adults with ADHD (35 ± 10 years) and 29 age- and sex-matched controls (32 ± 12 years) underwent magnetic resonance imaging (MRI), standardized psychometric testing and assessment of lifestyle factors. Quantitative susceptibility mapping (QSM) was used to assess magnetic abnormalities indicating local alterations of iron deposition in the brain. By calculating QSM-maps, local iron deposition was tested for statistically significant differences between ADHD and healthy controls. Plasma neurofilament light chain (NfL) levels were measured as an indicator of neuroaxonal integrity by using a fourth-generation ELLA immunoassay.

Results: Brain iron content differed in persons with ADHD, with strongest effects observable in the right precentral cortex (healthy controls: 0.0033 ± 0.0017ppm; ADHD: 0.0048 ± 0.0016ppm; t(59) = 3.56, P < 0.001). Moreover, right precentral cortex iron in persons with ADHD was associated with increased blood NfL levels (F(1.57) = 13.2, P = 0.001, r² = 0.19).

Conclusion: Our results indicate altered regional iron content in the brains of adults with ADHD. The observed association between increased precentral magnetic susceptibility and increased NfL suggests a connection between local excess of brain iron and neuroaxonal damage in ADHD. Given the limited sample size of the current study and the naturalistic medication plan, further longitudinal studies are needed to establish whether altered brain iron distribution in adults with ADHD may be associated with an increased risk of dementia at old age.

Keywords: ADHD; MRI; NfL; dementia; iron.

Fig. 1

Example of the segmented ROI positions based on Freesurfer aseg‐atlas.

Fig. 2

(a and b) Quantitative susceptibility maps for (a) a healthy control (42‐year‐old female) and (b) a subject with ADHD (26‐year‐old female). Increased susceptibility values are visible in iron‐rich deep gray matter structures, such as the caudate nucleus, precuneus and caudal anterior cingulate on ADHD population.

Fig. 3

(a and b) Magnetic susceptibility values (in ppm) of the controls (white) and ADHD patients (black). Error bars represent standard error of mean (SEM). Statistically significant differences in QSM values between the controls and ADHD group were detected bilaterally in the precentral area, cerebral white matter, caudal anterior cingulate cortex, and precuneus; at left nucleus accumbens, pars opercularis, caudate, rostral anterior and isthmus cingulate cortex, right inferior parietal cortex, and parahippocampus. *(P < 0.05), **(P < 0.01), ***(P < 0.001) indicate statistically significant difference of QSM values between the control and ADHD groups.

Fig. 4

Scatterplot of QSM values of the right precentral cortex (ppm) and serum NfL (pg/mL) for healthy controls and ADHD patients. The statistical relationship is visualized by least‐squares regression lines for each group, difference of slopes = (F(1.57) = 13.2, P = 0.001).