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PubMed1999

Cocaine adversely affects development of cortical embryonic neurons in vitro: immunocytochemical study of calcium-binding proteins.

Neurons of cerebral cortex from 15-16 day old embryos of white rats (Sprague-Dawley) were cultured in MEM enriched with 5% horse serum. On the 7th day after plating the cultures were divided into three experimental and one control groups (6-8 Petri dishes in each group). In group 1, cultures were grown without additives. In group 2, cocaine chloride was added at concentrations 0.3, 0.6 and 1 mg/ml of culture. In group 3, a monoclonal antibody against calcium-binding proteins, parvalbumin (APV) or calbindin (ACB) was added at a concentration 25 microl/ml. In group 4, a combination of cocaine +APV was added at a concentration 1 mg+25 microl/ml of culture media. On the 10th day cultures were immunostained using APV and ACB antibodies. In developing GABAergic neurons of group 2 cocaine produced cytotoxic effects that were expressed in drastic decrease in number of neurons and in degeneration of their processes. The lower concentrations of cocaine caused milder cytotoxity and their effects were reversible. The highest concentration of cocaine caused irreversible degeneration of neurons. Similar cytotoxity was caused by APV or ACB in group 3. The most severe cytotoxic effects were seen in group 4, where a mixture of cocaine and APV was used. Overall, it can be concluded that cocaine in higher concentrations directly affects development of GABAergic neurons in vitro.

Animals↗
PubMed2000

Is monochorionic twinning a risk factor for focal cortical dysgenesis?

OBJECTIVES: Various genetic and acquired factors have been proposed as being etiologically important in cortical dysgenesis. It has been suggested that fetal, developmental abnormalities may be induced by transient, circulatory instability in monochorionic twinning due to feto-fetal transfusions. We report the discordant occurrence of a malformation of cortical development in monozygotic, monochorionic twins, and discuss the findings and possible pathogenetic mechanisms. MATERIAL AND METHODS: The twins were females, 30 years of age, one of them suffering from uncontrolled localization-related epilepsy. Neurological deficits or mental retardation were not present. Genetic analysis, brain MRI, and a neuropsychological test battery were carried out. RESULTS: DNA analysis verified monozygocity. MRI showed a unilateral grey matter heterotopion and a contralateral temporal arachnoid cyst in the affected twin. Neuro-psychological assessment revealed no corresponding focal cognitive deficits, but an overall slightly lowered performance in the affected twin. CONCLUSION: Discordant affection of focal, cortical dysgenesis in monozygotic twins creates a particular opportunity to assess the consequences of such a disorder. The fact that only a mild generalized influence on cognitive functioning was demonstrated in this case, is possibly due to the plasticity of the fetal brain. According to current, obstetrical literature, the unique embryology of monochorionic twinning may predispose to vascular events in early fetal life. As ultrasound studies now indicate that a large proportion of pregnancies start out as twin products, we hypothesize that the "vanishing twin" syndrome and its potential hemodynamic hazard to the surviving fetus may be an etiological factor in malformations of cortical development, even in singletons.

Adult↗
PubMed1998

Increased contribution of NR2A subunit to synaptic NMDA receptors in developing rat cortical neurons.

1. Pharmacologically isolated miniature NMDA receptor-mediated excitatory postsynaptic currents (mN-EPSCs) were recorded in large visual cortical neurons in layer V of rat cortical slices. Haloperidol (100 microM) and CP101,606 (10 microM), two specific blockers of NMDA receptors comprising NR1/NR2B subunits, were tested on mN-EPSCs in rats at postnatal days 7 and 8 (P7-P8) and P13-P15. At both ages tested, no significant effects of these drugs were seen in the whole population of neurons, although in few neurons at both ages changes in amplitude were observed with haloperidol. Other dopamine receptor antagonists, spiperone and clozapine, failed to decrease mN-EPSCs in cortical neurons at P13-P15. 2. CP101,606 (10 microM) significantly decreased the amplitude of evoked N-EPSCs (eN-EPSCs) in visual cortical slices from rats at P3-P5, a developmental stage at which mRNA studies have indicated the virtual absence of NR2A mRNA. CP101,606 failed to significantly change evoked AMPA-mediated EPSCs at P5 and eN-EPSCs at P7-P8 and P13-P15. 3. NMDA receptor-mediated currents were also studied in somatic outside-out patches at P13-P15 with fast application of L-glutamate (1 mM). Haloperidol (50 microM) and CP101,606 (10 muM) blocked these currents in all patches tested. The effect of CP101,606 was concentration dependent. 4. We suggest that rather early in development synaptic receptors comprising NR1/NR2B subunits could be associated with other subunits so that blockade by haloperidol and CP101,606 is prevented. Moreover, the consistent blockade seen in outside out patches might be ascribed to the confinement of NR1/NR2B receptors to an extrasynaptic population.

Animals↗
PubMed2004

Neural progenitor cells do not differentiate prematurely in presenilin-1 null mutant mice.

Mice with a null mutation of the presenilin-1 (PS1-/-) gene die during late intrauterine life or shortly after birth and exhibit defects in cortical development. A previous report suggested that neurons differentiate prematurely in PS1-/- brain [M. Handler, X. Yang, J. Shen, Presenilin-1 regulates neuronal differentiation during neurogenesis, Development 127 (2000) 2593-2606]. Here we reexamined the issue of whether premature neuronal differentiation occurs in PS1-/- brain using fresh cell suspensions from embryonic E11.5 and E13.5 telencephalon where individual cell phenotypes can be easily determined with cell type specific markers. Immunostaining with seven neuronal specific markers (MAP2, beta-III tubulin, GABA, reelin, GluR2/3, calbindin, and calretinin) failed to reveal any evidence of premature neuronal differentiation in PS1-/- telencephalon. We also determined the fraction of cells expressing the neural progenitor marker nestin and found no evidence for premature depletion of neural progenitor cells in PS1-/- telencephalon. Moreover, based on MAP2 staining of tissue sections from E12.5 embryos the topography of newly generated neurons also appeared to be undisturbed in the telencephalon of PS1-/- embryos. These studies thus argue that premature neuronal differentiation is unlikely to be a core pathophysiological feature underlying the aberrant cortical development that occurs in PS1-/- brain.

Animals↗
PubMed2004

Structural abnormalities remote from the seizure focus: a study using T2 relaxometry at 3 T.

OBJECTIVE: To determine the extent and severity of mesial temporal and subcortical signal abnormalities in patients with partial epilepsy. METHODS: T2 relaxation time maps were acquired in 50 consecutive patients and 55 control subjects on a 3 T MRI scanner. Twenty-two patients had hippocampal sclerosis (HS), 16 had malformations of cortical development (MCD), and 12 had no obvious MR abnormalities (normal MR). The following eight regions were measured bilaterally: hippocampus, anterior temporal lobe (ATL) white matter, amygdala, frontal lobe white matter, caudate, putamen, pallidum, and thalamus. RESULTS: In patients with HS, increased T2 relaxation times were found in the ipsilateral hippocampus and ATL but not in subcortical nuclei. In patients with MCD, increased T2 relaxation times were found in the temporal lobe (hippocampus, ATL) and in subcortical areas (caudate, putamen, and pallidum); in patients with normal MR, increased T2 relaxation times were found in the hippocampus and putamen. The degree of abnormality did not correlate with the duration of epilepsy or the estimated seizure load. CONCLUSIONS: Mesial temporal structures show increased T2 relaxation times not only in patients with hippocampal sclerosis but also in patients with a seizure focus remote from the hippocampus. Patients with normal MR and focal malformations of cortical development have increased T2 relaxation times in subcortical structures. Therefore, abnormalities in T2 relaxation time can be found remote from the seizure focus. They cannot be simply attributed to secondary seizure effects.

Adolescent↗
PubMed2006

Sonographic developmental milestones of the fetal cerebral cortex: a longitudinal study.

OBJECTIVE: To identify sonographic landmarks of normal fetal cortical development. METHODS: Serial ultrasound examinations were performed every 2 weeks from 18 weeks of gestation until term. In each session a detailed examination of the fetal brain was performed and the appearance of the main sulci and gyri was recorded. RESULTS: Twenty-two pregnant women volunteered to participate in the study. The fetal cortex followed an orderly pattern of development. By the time of the first ultrasound examination, at 18 weeks, the major fissures were present. The first sulci could be demonstrated as early as 18 weeks. Main landmarks, represented by the parieto-occipital fissure and the cingulate and calcarine sulci, were present between 22-24 weeks. The central sulcus was present in all cases by 28 weeks. By 30-32 weeks most of the main sulci could be demonstrated. CONCLUSIONS: Prenatal sonographic examinations can accurately demonstrate structures of the fetal cortex. Comparison of our results with those of both magnetic resonance imaging and other sonographic studies shows similarities in the order of appearance of the sulci and gyri, with only minor differences in the exact gestational age at which they are detected. Accurate knowledge of the ultrasound appearance of the fetal cortex at different stages of gestation is important in order to be able to diagnose in-utero malformations of cortical development.

Cerebral Cortex↗
PubMed2003

Magnetization transfer imaging in focal epilepsy.

OBJECTIVES: To test the hypothesis that magnetization transfer imaging (MTI), analyzed on a voxel-by-voxel basis, would identify areas of abnormal magnetization transfer ratio (MTR) in patients with focal epilepsy. METHODS: The authors used MTI maps and statistical parametric mapping (SPM) to objectively compare the cerebral structures of 15 patients with malformations of cortical development (MCD), 10 with partial seizures and acquired lesions, and 42 with partial seizures and normal conventional MRI with those of 30 control subjects. RESULTS: Significant reductions of MTR were identified in all 10 patients with acquired nonprogressive cerebral lesions and partial seizures. In all, the areas of decreased MTR concurred with abnormalities identified on visual inspection of conventional MRI. In 13 of the 15 patients with MCD, SPM detected regions of significantly reduced MTR, all of which corresponded to abnormalities identified on visual inspection of conventional MRI. In addition, in both groups, there were areas that were normal on conventional imaging that demonstrated abnormal MTR. There was a significant reduction of MTR in 15 of the 42 patients with cryptogenic focal epilepsy. In all of these, the areas of reduced MTR concurred with epileptiform EEG abnormality and clinical seizure semiology. CONCLUSIONS: Magnetization transfer imaging analyzed using statistical parametric mapping was sensitive in identifying malformations of cortical development and acquired cerebral lesions. Abnormalities of magnetization transfer ratio in individual MRI-negative patients suggest that minor structural disorganization exists in occult epileptogenic cerebral lesions.

Adolescent↗
PubMed2003

Single cell lineage analysis in human focal cortical dysplasia.

Focal cortical dysplasia (FCD) is a developmental malformation of the human cerebral cortex that is closely associated with epilepsy. Dysplastic, 'balloon' and heterotopic neurons that comprise FCD are heterogeneous cell populations that exhibit abnormal morphologies. A pivotal unanswered question is how these cell types are generated during cortical development. As a strategy to define the lineage relationships between cells in FCD, the size of a heterozygous trinucleotide (CAG) repeat sequence within the X-chromosome encoded androgen receptor (XAR) mRNA was determined by RT-PCR and direct sequencing in single, microdissected cells from six female patients with FCD compared with control cortex. As a consequence of X-chromosome inactivation, only one of the two XAR alleles is expressed in all somatic cells, and cell types derived from distinct progenitors will express XAR CAG repeat lengths of differing size. Disparate XAR CAG repeat lengths were detected with equal frequency in single dysplastic, 'balloon' and heterotopic neurons in FCD whereas the XAR CAG repeats lengths in control cortex were identical in 70-80% of closely apposed neurons. These results support a random X-inactivation pattern in FCD. We propose that dysplastic, 'balloon' and heterotopic neurons in FCD derive from a population of progenitor cells or post-mitotic neurons during cortical development.

Adult↗
PubMedDate not supplied

Proton MR spectroscopy of polymicrogyria and heterotopia.

BACKGROUND AND PURPOSE: Proton MR spectroscopy of the brain allows noninvasive in vivo assessment of metabolites, which may be useful in understanding the biology of malformations of cortical development. The aim of this study was to determine the MR spectroscopic characteristics of polymicrogyria and heterotopia compared with those of normal frontal lobe white matter. METHODS: We recruited 22 patients with radiographic findings characteristic of polymicrogyria, nine patients with radiographic findings characteristic of heterotopia, and 10 control subjects into the study. The MR imaging technique consisted of high-spatial-resolution axial dual-echo and gradient-echo 3D volume imaging. A single-voxel point-resolved technique (1600/135 [TR/TE]) was used to acquire spectra from the region of neocortical malformation and from frontal lobe white matter in control subjects. The differences in N-acetyl moieties (NA)/creatine (Cr), NA/choline (Cho), and Cho/Cr ratios among patients with heterotopia, those with polymicrogyria, and control subjects were compared by using the Kruskal-Wallis test followed by the Mann-Whitney U (Wilcoxon) test. RESULTS: No statistically significant differences were noted in the NA/Cr, NA/Cho, and Cho/Cr ratios between the polymicrogyria group and controls, the heterotopia group and controls, or the polymicrogyria and heterotopia groups. CONCLUSION: Both heterotopia and polymicrogyria are malformations of cortical development that occur at a relatively late stage of brain development. The neurons and glia in these lesions are mature, and the metabolites appear to be similar to those of normal adult frontal white matter.

Adolescent↗
PubMed2001

Mental retardation in pediatric candidates for epilepsy surgery: the role of early seizure onset.

PURPOSE: We sought to determine whether early age at seizure onset is a risk factor for mental retardation, independent of etiology. Assessment of risk for mental retardation with continued uncontrolled seizures plays a role in considerations of timing for epilepsy surgery. Previous studies have indicated that onset of seizures in the first years of life may be a risk factor for mental retardation, but the etiologies of the epilepsies were not included in the analyses. METHODS: Intellectual function was assessed at ages 2-20 years during presurgical evaluation in 100 patients with intractable epilepsy due to focal lesions limited to part of one lobe of the brain. Mental retardation (MR) was defined as Full-Scale Intelligence Quotient (FSIQ) < or =70. The age at seizure onset and the seizure frequency were obtained retrospectively. RESULTS: Younger ages at seizure onset were associated with lower FSIQ scores, and mean FSIQ was also significantly lower for patients with onset of epilepsy at < or =24 months of age (74.0 +/- 21.5) versus that in patients with onset of epilepsy later in life (87.8 +/- 18.8; p = 0.005). The frequency of patients with MR was significantly higher for patients with seizure onset at < or =24 months of age (15 of 33, 46%) than for patients with seizure onset later in life (eight of 67, 12%; p < 0.001). This difference persisted within etiologic subgroups. For patients with focal malformation of cortical development, MR was seen in eight (50%) of 16 patients with seizure onset at < or =24 months versus two (10%) of 20 patients with seizure onset at >24 months (p < 0.001); for patients with tumor, MR was seen in four (50%) of eight patients with seizure onset at < or =24 months versus four (13%) of 30 patients with seizure onset at >24 months (p = 0.003); and for patients with hippocampal sclerosis, MR was seen in two (28%) of seven patients with seizure onset at < or =24 months versus none of 30 patients with seizure onset at >24 months (NS). Within the subgroup with daily seizures, MR was present in 13 (65%) of 20 patients with seizure onset at < or =24 months versus five (17%) of 29 patients with seizure onset later in life (p = 0.001). CONCLUSIONS: These results indicate that onset of intractable epilepsy within the first 24 months of life is a significant risk factor for MR, especially if seizures occur daily. The risk based on early age at seizure onset appeared independent of etiology and persisted within subgroups of patients with focal malformation of cortical development, tumor, or hippocampal sclerosis. Prospective studies will be important to clarify whether early surgical intervention may reduce the risk for subsequent MR in carefully selected infants.

Adolescent↗
PubMed2004

Clinicopathologic findings in patients with infantile hemiparesis and epilepsy.

Infantile hemiparesis may be associated with significant morbidity and may have a profound impact on a child's physical and social development. There are little published data evaluating the clinicopathologic features of patients with infantile hemiparesis. The present study retrospectively examines these clinicopathologic features in a surgical series of 21 patients with infantile hemiparesis. The study group was comprised of 21 patients, 13 females and 8 males, ranging in age from 5 to 41 years (mean, 20 years) at the time of surgery. Hemiparesis involved the right side in 16 patients and the left side in 5 patients. Imaging studies identified porencephaly in 8 patients (38%), encephalomalacia in 5 patients (24%), focal cerebral atrophy in 9 patients (43%), ventricular dilatation in 6 patients (29%), and white matter hyperintensities in 4 patients (19%). Concomitant neurologic diseases included medically intractable epilepsy in all 21 patients and visual field defects in 11 patients (52%). Significant perinatal history included prematurity in 7 patients (33%) and cesarean section, forceps delivery, placental abruption, fetal distress, and prolonged rupture of membranes each in 1 patient (5%). The remainder of the patients had an uncomplicated perinatal course (43%). Twelve patients underwent functional hemispherectomy (57%), 8 patients underwent lobectomy (38%) and 1 patient underwent "cyst" resection (5%). Histological evaluation demonstrated lesional (corresponding to radiographic findings) tissue in 15 of the 21 cases (71%). Infarction, malformations due to abnormalities of cortical development (cortical dysplasia) and gliosis with microcalcifications were each found in 6 patients (29%). Infarction and a geographically distinct area of cortical dysplasia were found to coexist in 1 case. Histopathologic findings in the 6 cases in which excised tissue was considered nonlesional included gliosis in all 6 of the cases, hippocampal sclerosis in 2 cases (10%), and neuronal heterotopia in 2 cases (10%). An osteoma was identified in 1 patient. The most common pathological findings observed in our series were infarction and cortical dysplasia, although radiographically, infarct-related changes were the most evident. Hippocampal sclerosis was encountered in 2 patients, suggesting that a subset of cortical dysplasias and hippocampal sclerosis may be caused by an in utero ischemic event.

Adolescent↗
PubMed1997

DAX1 gene expression upregulated by steroidogenic factor 1 in an adrenocortical carcinoma cell line.

Two nuclear hormone receptor superfamily members, DAX1 and SF1, are required for normal adrenal cortical development. Mutations in DAX1 are responsible for X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism. Steroidogenic Factor 1 (SF1) regulates the expression of a number of steroidogenic genes and a putative SF1 response element (SF1-RE) in the DAX1 promoter which binds SF1 specifically. Therefore, we examined deletions in the DAX1 promoter driving expression of beta-galactosidase, with and without coexpression of SF1, in the human adrenocortical carcinoma cell line NCI-H295. We defined the DAX initiation start site and localized the putative SF1-RE at -135 to -143 bp. Loss of the putative SF1-RE region or specific removal of the 9-bp SF1 site resulted in decreased transcriptional activity by 2.3-to 2.5-fold. When cotransfected with 1550 bp of the DAX1 promoter, an SF1-containing expression vector increased the transcriptional activity of the DAX1 promoter by 4-fold. No significant change above baseline occurred when the cells were cotransfected with the 1541-bp fragment containing the entire 1550-bp promoter region minus the 9-bp SF1-RE. We conclude that the SF1-RE is an enhancer element within the DAX1 promoter and speculate that SF1 may be a transcription factor that acts, at least in part, through DAX1 for normal adrenal cortical development.

Adrenocortical Carcinoma↗
PubMed2005

Whole-brain T2 mapping demonstrates occult abnormalities in focal epilepsy.

OBJECTIVES: To examine the cerebral structure of 14 patients with partial seizures and acquired lesions, 20 patients with malformations of cortical development (MCDs), and 45 patients with partial seizures and normal conventional MRI using whole-brain T2 mapping and statistical parametric mapping (SPM). METHODS: T2 maps were calculated, and individual patients were compared with a group of 30 control subjects using SPM. RESULTS: T2 mapping and objective voxel-by-voxel statistical comparison identified regions of increased T2 signal in all 14 patients with acquired nonprogressive cerebral lesions and partial seizures. In all of these, the areas of increased T2 signal concurred with abnormalities identified on visual inspection of conventional MRI. In 18 of 20 patients with MCDs, SPM detected regions of increased T2 signal, all of which corresponded to abnormalities identified on visual inspection of conventional MRI. In addition, in both groups, there were areas that were normal on conventional imaging, which demonstrated abnormal T2 signal. Voxel-by-voxel statistical analysis identified increased T2 signal in 23 of the 45 patients with cryptogenic focal epilepsy. In 20 of these, the areas of increased T2 signal concurred with epileptiform EEG abnormality and clinical seizure semiology. Group analysis of MRI-negative patients with electroclinical seizure onset localizing to the left and right temporal and left and right frontal regions revealed increased T2 signal within the white matter of each respective lobe. CONCLUSIONS: T2 mapping analyzed using statistical parametric mapping was sensitive in patients with malformations of cortical development and acquired cerebral damage. Increased T2 signal in individual and grouped MRI-negative patients suggests that minor structural abnormalities exist in occult epileptogenic cerebral lesions.

Adult↗
PubMed2002

Filamin A and Filamin B are co-expressed within neurons during periods of neuronal migration and can physically interact.

Mutations in the X-linked gene Filamin A (FLNA) lead to the human neurological disorder, periventricular heterotopia (PH). Although PH is characterized by a failure in neuronal migration into the cerebral cortex with consequent formation of nodules in the ventricular and subventricular zones, many neurons appear to migrate normally, even in males, suggesting compensatory mechanisms. Here we characterize expression patterns for FlnA and a highly homologous protein Filamin B (FlnB) within the nervous system, in order to better understand their potential roles in cortical development. FlnA mRNA was widely expressed in all cortical layers while FlnB mRNA was most highly expressed in the ventricular and subventricular zones during development. In adulthood, widespread but reduced expression of FlnA and FlnB persisted throughout the cerebral cortex. FlnA and FlnB proteins were highly expressed in both the leading processes and somata of migratory neurons during corticogenesis. Postnatally, FlnA immunoreactivity was largely localized to the cell body with FlnB in the soma and neuropil during neuronal differentiation. In adulthood, diminished expression of both proteins localized to the cell soma and nucleus. Moreover, the putative FLNB homodimerization domain strongly interacted with itself or the corresponding homologous region of FLNA by yeast two-hybrid interaction, the two proteins co-localized within neuronal precursors by immunocytochemistry and the existence of FLNA-FLNB heterodimers could be detected by co-immunoprecipitation. These results suggest that FLNA and FLNB may form both homodimers and heterodimers and that their interaction could potentially compensate for the loss of FLNA function during cortical development within PH individuals.

Animals↗