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In vivo MRI Successfully Reveals the Malformation of Cortical Development in Infant Rats.

ABSTRACT: Objective: Malformations of cortical development (MCDs) are major causes of intractable epilepsies. To characterize the early neuroimaging findings of MCDs, we tried to identify the MRI features consistent with pathological findings in an infant rat MCD model, prenatally exposed to methylazoxymethanol (MAM), by using newly developed MRI techniques. Methods: At gestational day 15, two doses of MAM (15 mg/kg intraperitoneally) or normal saline were injected into pregnant rats. The offspring underwent in vivo MRI, including glutamate chemical exchange saturation transfer (GluCEST), 1H-MR spectroscopy, and diffusion tensor imaging, at postnatal day (P) 15 using a 7T small-animal imaging system. Another set of prenatally MAM-exposed rats were sacrificed for histological staining. Results: At P15, the retrosplenial cortex (RSC) of rats with MCDs showed decreased neuronal nuclei, parvalbumin, and reelin expressions. Moreover, dendritic arborization of pyramidal cells in the RSC significantly decreased in infant rats with MCDs. In vivo MRI showed significantly decreased GluCEST (%) in the RSC of rats with MCDs (p = 0.000) and a significant correlation between GluCEST (%) and RSC thickness (r = 0.685, p = 0.003). The rats with MCDs showed reduced glutamate (p = 0.002), N-acetylaspartate (p = 0.002), and macromolecule and lipid levels (p = 0.027) and significantly reduced fractional anisotropy values in the RSC. Conclusion: In vivo MRI revealed reduced neuronal population and dendritic arborization in the RSC of infant rats with MCDs during the early postnatal period. These pathological changes of the cortex could serve as clinical imaging biomarkers of MCDs in infants.

SUBMITTER: Lee M

PROVIDER: S-EPMC7251149 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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In vivo MRI Successfully Reveals the Malformation of Cortical Development in Infant Rats.

Lee Minyoung M Kim Eun-Jin EJ Woo Dong-Cheol DC Shim Woo-Hyun WH Yum Mi-Sun MS

Frontiers in neuroscience 20200520

Objective: Malformations of cortical development (MCDs) are major causes of intractable epilepsies. To characterize the early neuroimaging findings of MCDs, we tried to identify the MRI features consistent with pathological findings in an infant rat MCD model, prenatally exposed to methylazoxymethanol (MAM), by using newly developed MRI techniques. Methods: At gestational day 15, two doses of MAM (15 mg/kg intraperitoneally) or normal saline were injected into pregnant rats. The of ...[more]

PMID: 32508585

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Project description:OBJECTIVE:To evaluate Sylvian fissure development by assessing Sylvian fissure angles in fetuses with malformation of cortical development (MCD). METHODS:This was a retrospective study of 22 fetuses with MCD. Cases with a stored three-dimensional (3D) brain volume acquired at 18?+?0 to 30?+?6?weeks of gestation at an ultrasound-based research clinic between January 2010 and December 2017 were identified through a database. Of the 22 fetuses, seven had an extracranial abnormality, such as cardiac, renal, gastrointestinal and/or digital anomalies, and five had a minor abnormality such as micrognathia, low-set ears and/or single umbilical artery. To confirm the final clinical diagnosis of brain abnormality, postmortem histological findings or prenatal or postnatal magnetic resonance images were used. For measurement of Sylvian fissure angle, an anterior coronal plane of the fetal brain on transvaginal 3D volume multiplanar imaging was visualized as a single image from the three orthogonal views. The right and left Sylvian fissure angles were measured between a horizontal reference line (0°) and a line drawn along the upper side of the respective Sylvian fissure. The Sylvian fissure angle on both sides was plotted on the graphs of the reference ranges for gestational age in weeks. RESULTS:In 21 (95.5%; 95% CI, 86.8-100.0%) of 22 fetuses with MCD, the Sylvian fissure angle on one or both sides was larger than the 90th percentile of the normal reference. There was one case with apparent focal MCD in the parietal lobe, but the Sylvian fissure angles were normal. A case with apparent unilateral cortical dysplasia and one with apparent unilateral schizencephaly had conspicuous discrepancies between the left and right Sylvian fissure angles. Abnormal genetic test results were obtained in six cases, including four cases with a mutation in a single gene. CONCLUSIONS:This study has shown that the Sylvian fissures, as defined by the Sylvian fissure angle, have delayed development in most MCD cases prior to the diagnosis of the condition. The Sylvian fissure angle may potentially be a strong indicator for the subsequent development of cortical malformation, before the time point at which the gyri and sulci become obvious on the fetal brain surface. Further research is required to validate these findings. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Project description:ObjectiveMalformations 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.MethodsQSM 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.ResultsCompared 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.ConclusionQSM 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.

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In vivo MRI Successfully Reveals the Malformation of Cortical Development in Infant Rats.

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<i>In vivo</i> MRI Successfully Reveals the Malformation of Cortical Development in Infant Rats.

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