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Objective Malformations of cortical development (MCD), including focal cortical dysplasia (FCD), are the most common cause of drug-resistant focal epilepsy in children. Histopathological lesion characterisation demonstrates abnormal cell types and lamination, alterations in myelin (typically co-localised with iron), and sometimes calcification. Quantitative susceptibility mapping (QSM) is an emerging MRI technique that measures tissue magnetic susceptibility (χ) reflecting it's mineral composition. We used QSM to investigate abnormal tissue composition in a group of children with focal epilepsy with comparison to effective transverse relaxation rate (R2*) and Synchrotron radiation X-ray fluorescence (SRXRF) elemental maps. Our primary hypothesis was that reductions in χ would be found in FCD lesions, resulting from alterations in their iron and calcium content. We also evaluated deep grey matter nuclei for changes in χ with age. Methods QSM and R2* maps were calculated for 40 paediatric patients with suspected MCD (18 histologically confirmed) and 17 age-matched controls. Patients’ sub-groups were defined based on concordant electro-clinical or histopathology data. Quantitative investigation of QSM and R2* was performed within lesions, using a surface-based approach with comparison to homologous regions, and within deep brain regions using a voxel-based approach with regional values modelled with age and epilepsy as covariates. Synchrotron radiation X-ray fluorescence (SRXRF) was performed on brain tissue resected from 4 patients to map changes in iron, calcium and zinc and relate them to MRI parameters. Results Compared to fluid‐attenuated inversion recovery (FLAIR) or T1‐weighted imaging, QSM improved lesion conspicuity in 5% of patients. In patients with well-localised lesions, quantitative profiling demonstrated decreased χ, but not R2*, across cortical depth with respect to the homologous regions. Contra-lateral homologous regions additionally exhibited increased χ at 2–3 mm cortical depth that was absent in lesions. The iron decrease measured by the SRXRF in FCDIIb lesions was in agreement with myelin reduction observed by Luxol Fast Blue histochemical staining. SRXRF analysis in two FCDIIb tissue samples showed increased zinc and calcium in one patient, and decreased iron in the brain region exhibiting low χ and high R2* in both patients. QSM revealed expected age-related changes in the striatum nuclei, substantia nigra, sub-thalamic and red nucleus. Conclusion QSM non-invasively revealed cortical/sub-cortical tissue alterations in MCD lesions and in particular that χ changes in FCDIIb lesions were consistent with reduced iron, co-localised with low myelin and increased calcium and zinc content. These findings suggest that measurements of cortical χ could be used to characterise tissue properties non-invasively in epilepsy lesions.

Alzheimer's disease is connected to a number of other neurodegenerative conditions, known collectively as ‘tauopathies’, by the presence of aggregated tau protein in the brain. Neuroinflammation and oxidative stress in AD are associated with tau pathology and both the breakdown of axonal sheaths in white matter tracts and excess iron accumulation grey matter brain regions. Despite the identification of myelin and iron concentration as major sources of contrast in quantitative susceptibility maps of the brain, the sensitivity of this technique to tau pathology has yet to be explored. In this study, we perform Quantitative Susceptibility Mapping (QSM) and T2* mapping in the rTg4510, a mouse model of tauopathy, both in vivo and ex vivo. Significant correlations were observed between histological measures of myelin content and both mean regional magnetic susceptibility and T2* values. These results suggest that magnetic susceptibility is sensitive to tissue myelin concentrations across different regions of the brain. Differences in magnetic susceptibility were detected in the corpus callosum, striatum, hippocampus and thalamus of the rTg4510 mice relative to wild type controls. The concentration of neurofibrillary tangles was found to be low to intermediate in these brain regions indicating that QSM may be a useful biomarker for early stage detection of tau pathology in neurodegenerative diseases., Highlights • The rTg4510 is a mouse model of tauopathy. • We applied QSM and T2* Mapping MRI techniques to the rTg4510 in vivo and ex vivo. • QSM demonstrated sensitivity to regions of low and intermediate tau burden. • QSM may hold potential as a non-invasive early biomarker of tau pathology.

T2*-weighted gradient-echo MRI images at high field (≥ 7 T) have shown rich image contrast within and between brain regions. The source for these contrast variations has been primarily attributed to tissue magnetic susceptibility differences. In this study, the contribution of myelin to both T2* and frequency contrasts is investigated using a mouse model of demyelination based on a cuprizone diet. The demyelinated brains showed significantly increased T2* in white matter and a substantial reduction in gray-white matter frequency contrast, suggesting that myelin is a primary source for these contrasts. Comparison of in-vivo and in-vitro data showed that, although tissue T2* values were reduced by formalin fixation, gray-white matter frequency contrast was relatively unaffected and fixation had a negligible effect on cuprizone-induced changes in T2* and frequency contrasts.

The authors regret that the following corrections were left off the original manuscripts: 1. Page 1263, Eq. (1) should be: y 1⁄4 14:62 1− exp −0:04x ð Þ f g þ 4:6 2. Page 1263, right column, in the paragraph that starts with: “Fig. 7A shows the relationship between...”, the sentence “The best-fit lines to the data are given by:...” should be written as: The best fit lines to the data are given by: y=0.058x+10.75 (at 1.5 T), y=0.120x+14.12 (at 3 T) and y=0.319x+19.79 (at 7 T), where x is the iron concentration in ppm and y is the R2⁎ in Hz. 3. Page 1264, Fig. 7(A). The three fitted equations should be: y 1⁄4 0:319xþ 19:79 y 1⁄4 0:120xþ 14:12 y 1⁄4 0:058xþ 10:75 4. Page 1266, Acknowledgments should be: We thank Dr. Matusuda Kant, M.D., Ph.D. and Suan Fulton The authors would like to apologise for any inconvenience caused.

Quantitative susceptibility mapping (QSM) is a promising non-invasive method for obtaining information relating to oxygen metabolism. However, the optimal acquisition sequence and QSM reconstruction method for reliable venous susceptibility measurements are unknown. Full flow compensation is generally recommended to correct for the influence of venous blood flow, although the effect of flow compensation on the accuracy of venous susceptibility values has not been systematically evaluated. In this study, we investigated the effect of different acquisition sequences, including different flow compensation schemes, and different QSM reconstruction methods on venous susceptibilities. Ten healthy subjects were scanned with five or six distinct QSM sequence designs using monopolar readout gradients and different flow compensation schemes. All data sets were processed using six different QSM pipelines and venous blood susceptibility was evaluated in whole-brain segmentations of the venous vasculature and single veins. The quality of vein segmentations and the accuracy of venous susceptibility values were analyzed and compared between all combinations of sequences and reconstruction methods. The influence of the QSM reconstruction method on average venous susceptibility values was found to be 2.7–11.6 times greater than the influence of the acquisition sequence, including flow compensation. The majority of the investigated QSM reconstruction methods tended to underestimate venous susceptibility values in the vein segmentations that were obtained. In summary, we found that multi-echo gradient-echo acquisition sequences without full flow compensation yielded venous susceptibility values comparable to sequences with full flow compensation. However, the QSM reconstruction method had a great influence on susceptibility values and thus needs to be selected carefully for accurate venous QSM.