Quantitative MRI susceptibility mapping reveals cortical signatures of changes in iron, calcium and zinc in malformations of cortical development in children with drug-resistant epilepsy

Abstract

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 its 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 (χ) and R2* maps were calculated for 40 paediatric patients with suspected FCD (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* were performed within lesions, using a surface-based approach with comparison to homologous regions, and globally 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 and confirmed FCDIIb 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 2-3mm 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, and decreased iron in the brain region exhibiting low χ and high R2*. QSM revealed expected age-related changes in the striatum nuclei, substantia nigra, sub-thalamic and red nucleus, but these changes were not altered in epilepsy. 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. Theses findings suggests that the measurements of cortical χ measurements could be used to detect and delineate epilepsy lesions.

Widespread, depth-dependent cortical microstructure alterations in paediatric focal epilepsy

“…Accordingly, in this study the detected alterations were not specific to (or driven by) the focal cortical lesions of patients, as demonstrated by the observed heterogeneity of qMRI profiles within the investigated FCDs. Interestingly, the detected heterogeneity of qMRI cortical signatures in patients’ lesions supports previous evidence that qMRI changes may be specific to different FCD subtypes (Lorio et al, 2020, 2021).…”

“…Overall, our findings indicate the presence of widespread, depth-mediated qT1 and qT2 increases in a heterogeneous sample of children with focal epilepsy. Additionally, they demonstrate significant alterations in patients’ intracortical organization (Lorio et al, 2021), as shown by a “surface-out” gradient of increased qT1 and qT2 values driven from the WM/GM border in patients. Consistent with previous evidence (Ahmad et al, 2020; Bernhardt et al, 2018; Hattingen et al, 2018), the observed cortical changes were robust to potential confounders, including age-variation and differences in vertex-wise cortical thickness and curvature, suggesting that they represent a different underlying pathophysiological mechanism.…”

“…The relationship of qT1 and qT2 changes to clinical parameters including age of onset, disease duration and number of seizures per year was also assessed. As a post-hoc analysis, based on previous evidence that quantitative diffusion and susceptibility imaging can detect cortical signatures of malformations of cortical development (Lorio et al, 2020, 2021), we assessed whether any changes seen in group differences were specific to (and therefore driven by) the focal cortical lesions of individual patients.…”

New 3D phase-unwrapping method based on voxel clustering and local polynomial modeling: application to quantitative susceptibility mapping

“…Error at any step is likely to be introduced, even propagated and accumulated in the following process. Researchers have proposed many algorithms for addressing the challenges in these steps over the past years, and these have been successfully applied to measure iron in brain tissue, distinguish between hemorrhage and calcification, measure the cerebral metabolic rate for oxygen and liver iron deposition, and reveal the cortical development in children with drugresistant epilepsy (3,(6)(7)(8).…”