Letter to the Editor: Brain iron mapping using MRI relaxation rate or R2* revisited

Dear Editor, We read with interest a recent article published in this journal [Péran et al., 2009] in which in vivo volume-based transverse relaxation rate or R2* 1⁄4 1/T2* measurements of brain caudate, putamen, and globus pallidus were found to strongly correlate with iron content based on the measurements reported in a 1958 postmortem study [Hallgren and Sourander, 1958]. The paper [Péran et al., 2009] and topic of quantitative iron mapping of the human brain in vivo using magnetic resonance imaging methods are timely and important for the interpretation of normative or patient data [Aquino et al., 2009; Bartzokis et al., 2007; Haacke et al., 2010; Harder et al., 2008; Hasan et al., 2010; House et al., 2008; Kumar et al., 2010; Pfefferbaum et al., 2009; Rodrigue et al., 2011]. According to the data presented in Péran et al., [2009], R2* 1⁄4 11.31 þ 1.142 * [Iron] (r 1⁄4 0.9623). Such relationship between R2* and Iron content at 3.0 T is analogous to that previously reported by Gillman et al. [1999] (R2* 1⁄4 14.9 þ 1.11 * [Iron]) using seven different regions-of-interest that included putamen, caudate, globus pallidus, substantia nigra, red nucleus, prefrontal cortex, and frontal white matter. A statistically significant relationship between R2* and Iron content at 3.0 T has also been reported using in vivo data [Yao et al., 2009] and more recently using postmortem measurements at 3.0 T [Langkammer et al., 2010] and 1.5 T [Rodrigue et al., 2011]. Despite apparent consistency with published reports [Haacke et al., 2005] at different magnetic fields (B0), there are several issues that need to be clarified. First, there are some inconsistencies between Table I and Figure 2. Table I indicates that the caudate nuclei volumes were smaller, as expected, than those of the putamen; but Figure 2 shows that the caudate volumes were larger. Second, as clearly tabulated in Table I, the volume-based thalamus bilateral R2* measurements were not significantly different from those of the caudate nuclei. This observation is surprising if one were to assume—as implied by Péran et al. [2009]—that R2* reflects primarily iron, as the iron content of the thalamus is expected to be 50% that of the caudate (see also Fig. 7 in [Drayer, 1988]; see Table I in [Hallgren and Sourander, 1958]). Thus, the interpretation model that R2* is linearly related to iron should be approached with caution. A closer look at the procedure adopted by Péran et al. [2009] and the tabulated thalamic volumes indicates that the segmented thalami included both white and gray matter. Thus, any contamination with white matter must be incorporated in the model as white matter R2* measurements are high reflecting myelination or macromolecular content [Drayer, 1988; Gilamn et al., 2001; Mitsumori et al., 2009] and do not relate to iron directly [Li et al., 2009]. Third, Péran et al., [2009] stated that ‘‘We chose to use thalamus as a control structure since this subcortical region did not demonstrate age-related iron increase [Hallgren and Sourander, 1958]. ’’ This statement contradicts what has actually been reported by Hallgren and Sourander [1958] in which the thalamus iron content exhibited a peaking at age 35 years (see Fig. 8 in [Hallgren and Souranders, 1958]). The only structure that