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

Lorio, Sara; Sedlacik, Jan; So, Po‐Wah; Parkes, Harold G.; Gunny, Roxana; Löbel, Ulrike; Li, Yao‐Feng; Ogunbiyi, Olumide; Mistry, Talisa; Dixon, Emma; Adler, Sophie; Cross, J. Helen; Baldeweg, Torsten; Jacques, Thomas S.; Shmueli, Karin; Carmichael, David W.

doi:10.1016/j.neuroimage.2021.118102

Cited by 12 publications

(9 citation statements)

References 102 publications

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“…Overall, our findings indicate the presence of consistent, widespread, depth-mediated qT1 and qT2 increases in children with focal epilepsy. Additionally, they reveal significant alterations in patients’ intracortical organization 39 , demonstrated by a radial gradient of increased qT1 and qT2 values driven from the WM/GM border in patients. Consistent with previous evidence 21,25,40 , the observed cortical changes were robust to potential confounders, including age-at-scan and brain morphology, suggesting that they represent a different underlying pathophysiological mechanism.…”

Section: Discussionmentioning

confidence: 96%

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

Casella

Vecchiato

Cromb

et al. 2022

Preprint

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Our current understanding of focal epilepsy is evolving as increasing evidence suggests that tissue abnormalities may extend beyond the focus. In adults, widespread structural changes remote from the epileptic focus have been demonstrated with MRI, predominantly using morphological markers. However, the underlying pathophysiology of these changes is unclear, and it is not known whether these result from ongoing disease processes or treatment-related side-effects, or whether they emerge earlier. Few studies have focused on children, who typically have shorter disease duration. Fewer still have utilised quantitative MRI, which may provide a more sensitive and interpretable measure of tissue microstructural changes. In this study, we aimed to determine if there were common spatial modes of changes in cortical architecture in children with drug-resistant focal epilepsy, and secondarily if changes were related to disease severity. To assess cortical microstructure, quantitative T1 and T2 relaxometry (qT1 and qT2) was measured in 89 children - 43 with drug-resistant focal epilepsy [age-range=4-18 years] and 46 healthy controls [age-range=2-18 years]. We assessed depth-dependent qT1 and qT2 values across the cortex, as well as their gradient of change across cortical depths. As a post-hoc analysis, we determined whether global changes seen in group analyses were driven by focal pathologies in individual patients. Finally, we trained a classifier using qT1 and qT2 gradient maps from patients with radiologically-defined abnormalities (MRI-positive) and healthy controls, and tested if this could classify patients without reported radiological abnormalities (MRI-negative). We detected depth-dependent qT1 and qT2 increases in widespread cortical areas, likely representing loss of structure such as altered cortical stratification, gliosis, myelin and iron alterations, oedema-associated increases in free-water, or a combination of these. Changes did not correlate with disease severity measures, suggesting they may appear during cerebral development and represent antecedent neurobiological alterations. Using a classifier trained with MRI-positive patients and controls, sensitivity was 62% at 100% specificity on held-out MRI-negative patients and controls. Our findings suggest the presence of a potential imaging endophenotype of focal epilepsy, detectable irrespective of radiologically-identified abnormalities, and possibly evident at a pre-symptomatic disease stage.

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Section: Discussionmentioning

confidence: 96%

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

Casella

Vecchiato

Cromb

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…24 Our findings indicate the presence of consistent, widespread, depth-mediated qT1 and qT2 increases in pediatric focal epilepsy. Additionally, they reveal significant alterations in patients' intracortical organization, 44 demonstrated by a radial gradient of increased qT1 and qT2 values driven from the WM/GM border. Consistent with previous evidence, 21,26,45 cortical changes were robust to potential confounders, including age at scan and brain morphology (Figure S2), suggesting that they represent a different underlying pathophysiological mechanism.…”

Section: Discussionmentioning

confidence: 97%

Widespread, depth‐dependent cortical microstructure alterations in pediatric focal epilepsy

Casella,

Vecchiato,

Cromb

et al. 2023

Epilepsia

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ObjectiveTissue abnormalities in focal epilepsy may extend beyond the presumed focus. The underlying pathophysiology of these broader changes is unclear, and it is not known whether they result from ongoing disease processes or treatment‐related side effects, or whether they emerge earlier. Few studies have focused on the period of onset for most focal epilepsies, childhood. Fewer still have utilized quantitative magnetic resonance imaging (MRI), which may provide a more sensitive and interpretable measure of tissue microstructural change. Here, we aimed to determine common spatial modes of changes in cortical architecture in children with heterogeneous drug‐resistant focal epilepsy and, secondarily, whether changes were related to disease severity.MethodsTo assess cortical microstructure, quantitative T1 and T2 relaxometry (qT1 and qT2) was measured in 43 children with drug‐resistant focal epilepsy (age range = 4–18 years) and 46 typically developing children (age range = 2–18 years). We assessed depth‐dependent qT1 and qT2 values across the neocortex, as well as their gradient of change across cortical depths. We also determined whether global changes seen in group analyses were driven by focal pathologies in individual patients. Finally, as a proof‐of‐concept, we trained a classifier using qT1 and qT2 gradient maps from patients with radiologically defined abnormalities (MRI positive) and healthy controls, and tested whether this could classify patients without reported radiological abnormalities (MRI negative).ResultsWe uncovered depth‐dependent qT1 and qT2 increases in widespread cortical areas in patients, likely representing microstructural alterations in myelin or gliosis. Changes did not correlate with disease severity measures, suggesting they may represent antecedent neurobiological alterations. Using a classifier trained with MRI‐positive patients and controls, sensitivity was 71.4% at 89.4% specificity on held‐out MRI‐negative patients.SignificanceThese findings suggest the presence of a potential imaging endophenotype of focal epilepsy, detectable irrespective of radiologically identified abnormalities.

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“…Because iron co-localizes with myelin, reduced iron content caused by demyelination will cause T2 increase. 39 Last but not least, gliosis was histologically confirmed to increase both T1 and T2. 40 Overall, the increased MRF signals in both GM and WM could be explained by the myriad of pathophysiological changes underlying the FCD lesions.…”

Section: Mrf T1 and T2 Valuesmentioning

confidence: 93%

Combining magnetic resonance fingerprinting with voxel‐based morphometric analysis to reduce false positives for focal cortical dysplasia detection

Ding,

Hu,

et al. 2024

Epilepsia

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ObjectiveWe aim to improve focal cortical dysplasia (FCD) detection by combining high‐resolution, three‐dimensional (3D) magnetic resonance fingerprinting (MRF) with voxel‐based morphometric magnetic resonance imaging (MRI) analysis.MethodsWe included 37 patients with pharmacoresistant focal epilepsy and FCD (10 IIa, 15 IIb, 10 mild Malformation of Cortical Development [mMCD], and 2 mMCD with oligodendroglial hyperplasia and epilepsy [MOGHE]). Fifty‐nine healthy controls (HCs) were also included. 3D lesion labels were manually created. Whole‐brain MRF scans were obtained with 1 mm3 isotropic resolution, from which quantitative T1 and T2 maps were reconstructed. Voxel‐based MRI postprocessing, implemented with the morphometric analysis program (MAP18), was performed for FCD detection using clinical T1w images, outputting clusters with voxel‐wise lesion probabilities. Average MRF T1 and T2 were calculated in each cluster from MAP18 output for gray matter (GM) and white matter (WM) separately. Normalized MRF T1 and T2 were calculated by z‐scores using HCs. Clusters that overlapped with the lesion labels were considered true positives (TPs); clusters with no overlap were considered false positives (FPs). Two‐sample t‐tests were performed to compare MRF measures between TP/FP clusters. A neural network model was trained using MRF values and cluster volume to distinguish TP/FP clusters. Ten‐fold cross‐validation was used to evaluate model performance at the cluster level. Leave‐one‐patient‐out cross‐validation was used to evaluate performance at the patient level.ResultsMRF metrics were significantly higher in TP than FP clusters, including GM T1, normalized WM T1, and normalized WM T2. The neural network model with normalized MRF measures and cluster volume as input achieved mean area under the curve (AUC) of .83, sensitivity of 82.1%, and specificity of 71.7%. This model showed superior performance over direct thresholding of MAP18 FCD probability map at both the cluster and patient levels, eliminating ≥75% FP clusters in 30% of patients and ≥50% of FP clusters in 91% of patients.SignificanceThis pilot study suggests the efficacy of MRF for reducing FPs in FCD detection, due to its quantitative values reflecting in vivo pathological changes. © 2024 International League Against Epilepsy.

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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

Cited by 12 publications

References 102 publications

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

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

Widespread, depth‐dependent cortical microstructure alterations in pediatric focal epilepsy

Combining magnetic resonance fingerprinting with voxel‐based morphometric analysis to reduce false positives for focal cortical dysplasia detection

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