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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. 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. 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. 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.

The effective transverse relaxation rate (R 2 *) is sensitive to the microstructure of the human brain like the g-ratio which characterises the relative myelination of axons. However, the fibre-orientation dependence of R 2 * degrades its reproducibility and any microstructural derivative measure. To estimate its orientation-independent part (R 2,iso *) from single multi-echo gradient-recalled-echo (meGRE) measurements at arbitrary orientations, a second-order polynomial in time model (hereafter M2) can be used. Its linear time-dependent parameter, β 1 , can be biophysically related to R 2,iso * when neglecting the myelin water (MW) signal in the hollow cylinder fibre model (HCFM). Here, we examined the performance of M2 using experimental and simulated data with variable g-ratio and fibre dispersion. We found that the fitted β 1 can estimate R 2,iso * using meGRE with long maximum-echo time (TE max  ≈ 54 ms), but not accurately captures its microscopic dependence on the g-ratio (error 84%). We proposed a new heuristic expression for β 1 that reduced the error to 12% for ex vivo compartmental R 2 values. Using the new expression, we could estimate an MW fraction of 0.14 for fibres with negligible dispersion in a fixed human optic chiasm for the ex vivo compartmental R 2 values but not for the in vivo values. M2 and the HCFM-based simulations failed to explain the measured R 2 *-orientation-dependence around the magic angle for a typical in vivo meGRE protocol (with TE max  ≈ 18 ms). In conclusion, further validation and the development of movement-robust in vivo meGRE protocols with TE max  ≈ 54 ms are required before M2 can be used to estimate R 2,iso * in subjects.