MR imaging for the quantitative assessment of brain iron in aceruloplasminemia: A postmortem validation study

Abstract

Aims: Non-invasive measures of brain iron content would be of great benefit in neurodegeneration with brain iron accumulation (NBIA) to serve as a biomarker for disease progression and evaluation of iron chelation therapy. Although magnetic resonance imaging (MRI) provides several quantitative measures of brain iron content, none of these have been validated for patients with a severely increased cerebral iron burden. We aimed to validate R₂* as a quantitative measure of brain iron content in aceruloplasminemia, the most severely iron-loaded NBIA phenotype.

Methods: Tissue samples from 50 gray- and white matter regions of a postmortem aceruloplasminemia brain and control subject were scanned at 1.5 T to obtain R₂^*, and biochemically analyzed with inductively coupled plasma mass spectrometry. For gray matter samples of the aceruloplasminemia brain, sample R₂* values were compared with postmortem in situ MRI data that had been obtained from the same subject at 3 T - in situ R₂*. Relationships between R₂* and tissue iron concentration were determined by linear regression analyses.

Results: Median iron concentrations throughout the whole aceruloplasminemia brain were 10 to 15 times higher than in the control subject, and R₂* was linearly associated with iron concentration. For gray matter samples of the aceruloplasminemia subject with an iron concentration up to 1000 mg/kg, 91% of variation in R₂* could be explained by iron, and in situ R₂* at 3 T and sample R₂* at 1.5 T were highly correlated. For white matter regions of the aceruloplasminemia brain, 85% of variation in R₂* could be explained by iron.

Conclusions: R₂* is highly sensitive to variations in iron concentration in the severely iron-loaded brain, and might be used as a non-invasive measure of brain iron content in aceruloplasminemia and potentially other NBIA disorders.

Keywords: Aceruloplasminemia; Ferritin; Iron; Neurodegeneration with brain iron accumulation (NBIA); Postmortem MRI; Susceptibility; Transverse relaxation rate (R(2)*).