RESUMEN
Malformations of cortical development (MCDs) represent a heterogeneous spectrum of disorders characterized by atypical development of the cerebral cortex. MCDs are most often diagnosed on the basis of imaging, although subtle lesions, such as focal cortical dysplasia, may only be revealed on neuropathology. Different subtypes have been defined, including lissencephaly, heterotopia, cobblestone malformation, polymicrogyria, and dysgyria. Many MCDs are of genetic origin, although acquired factors, such as congenital cytomegalovirus infections and twinning sequence, can lead to similar phenotypes. In this narrative review, we provide an overview of the diagnostic approach to MCDs, which is illustrated with clinical vignettes, on diagnostic pitfalls such as somatic mosaicism and consanguinity, and recognizable phenotypes on imaging, such as tubulinopathies, the lissencephaly spectrum, tuberous sclerosis complex, and FLNA-related periventricular nodular heterotopia.
Asunto(s)
Malformaciones del Desarrollo Cortical , Humanos , Malformaciones del Desarrollo Cortical/diagnóstico , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/genética , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Corteza Cerebral/anomalías , Lisencefalia/genética , Lisencefalia/diagnósticoRESUMEN
OBJECTIVE: To assess the longitudinal evolution of EEG findings in children with Zika related-microcephaly (ZRM) and to evaluate the associations of these patterns with the children's clinical and neuroimaging characteristics. METHODS: As part of the follow-up of the Microcephaly Epidemic Research Group Pediatric Cohort (MERG-PC) in Recife, Brazil, we performed serial EEG recordings in a subgroup of children with ZRM to evaluate changes in background rhythms and epileptiform activity (EA). Latent class analysis was used to identify patterns in the evolution of EA over time; clinical and neuroimaging findings were compared across the identified groups. RESULTS: Out of the 72 children with ZRM who were evaluated during 190 EEGs/videoEEGs, all participants presented with abnormal background activity, 37.5% presented with an alpha-theta rhythmic activity, and 25% presented with sleep spindles, which were less commonly observed in children with epilepsy. EA changed over time in 79.2% of children, and three distinct trajectories were identified: (i) multifocal EA over time, (ii) no discharges/focal EA evolving to focal/multifocal EA, and (iii) focal/multifocal EA evolving to epileptic encephalopathy patterns (e.g., hypsarrhythmia or continuous EA in sleep). The multifocal EA over time trajectory was associated with periventricular and thalamus/basal ganglia calcifications, brainstem and corpus callosum atrophy and had less focal epilepsy, whereas the children in the trajectory which evolved to epileptic encephalopathy patterns had more frequently focal epilepsy. SIGNIFICANCE: These findings suggest that, in most children with ZRM, trajectories of changes in EA can be identified and associated with neuroimaging and clinical features.
Asunto(s)
Electroencefalografía , Epilepsia , Microcefalia , Infección por el Virus Zika , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Edad de Inicio , Ritmo alfa , Investigación Biomédica , Corteza Cerebral/anomalías , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Epilepsias Parciales/diagnóstico por imagen , Epilepsias Parciales/etiología , Epilepsias Parciales/patología , Epilepsias Parciales/fisiopatología , Epilepsia/diagnóstico por imagen , Epilepsia/etiología , Epilepsia/patología , Epilepsia/fisiopatología , Movimientos Oculares , Estudios de Seguimiento , Análisis de Clases Latentes , Estudios Longitudinales , Microcefalia/diagnóstico por imagen , Microcefalia/etiología , Microcefalia/patología , Microcefalia/fisiopatología , Neuroimagen , Fases del Sueño , Ritmo Teta , Vigilia , Infección por el Virus Zika/complicaciones , Infección por el Virus Zika/diagnóstico por imagen , Infección por el Virus Zika/patología , Infección por el Virus Zika/fisiopatologíaRESUMEN
AIM: To assess the relationship of surface area of the cerebral cortex to intracranial volume (ICV) in syndromic craniosynostosis. METHOD: Records of 140 patients (64 males, 76 females; mean age 8y 6mo [SD 5y 6mo], range 1y 2mo-24y 2mo) with syndromic craniosynostosis were reviewed to include clinical and imaging data. Two hundred and three total magnetic resonance imaging (MRI) scans were evaluated in this study (148 patients with fibroblast growth factor receptor [FGFR], 19 patients with TWIST1, and 36 controls). MRIs were processed via FreeSurfer pipeline to determine total ICV and cortical surface area (CSA). Scaling coefficients were calculated from log-transformed data via mixed regression to account for multiple measurements, sex, syndrome, and age. Educational outcomes were reported by syndrome. RESULTS: Mean ICV was greater in patients with FGFR (1519cm3 , SD 269cm3 , p=0.016) than in patients with TWIST1 (1304cm3 , SD 145cm3 ) or controls (1405cm3 , SD 158cm3 ). CSA was related to ICV by a scaling law with an exponent of 0.68 (95% confidence interval [CI] 0.61-0.76) in patients with FGFR compared to 0.81 (95% CI 0.50-1.12) in patients with TWIST1 and 0.77 (95% CI 0.61-0.93) in controls. Lobar analysis revealed reduced scaling in the parietal (0.50, 95% CI 0.42-0.59) and occipital (0.67, 95% CI 0.54-0.80) lobes of patients with FGFR compared with controls. Modified learning environments were needed more often in patients with FGFR. INTERPRETATION: Despite adequate ICV in FGFR-mediated craniosynostosis, CSA development is reduced, indicating maldevelopment, particularly in parietal and occipital lobes. Modified education is also more common in patients with FGFR.
Asunto(s)
Corteza Cerebral/anomalías , Craneosinostosis/complicaciones , Malformaciones del Desarrollo Cortical/etiología , Adolescente , Corteza Cerebral/diagnóstico por imagen , Niño , Preescolar , Craneosinostosis/diagnóstico por imagen , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Adulto JovenRESUMEN
Background: Suicidal behaviours are a major source of mortality and morbidity among adolescents. Given the maturational changes that occur in cortical and subcortical structures during adolescence, we tested whether atypical brain structural measurements were associated with a history of suicide attempt. Methods: We assessed 3 groups of adolescents (n = 92; 79% female, mean age 15.9 years, range 11.6-18.1 years): patients with a depressive disorder and a history of suicide attempt (n = 28); patient controls, who had a depressive disorder but no history of suicide attempt (n = 34); and healthy controls (n = 30). We derived regional cortical thickness and surface area, and subcortical volumes, from T1-weighted anatomic MRI scans acquired at 3 T. Results: We found significant group differences in surface area in the prefrontal, temporal and parietal regions, as well as in the volume of several subcortical nuclei (pFDR ≤ 0.05), but not in cortical thickness. Post hoc analyses indicated that morphological alterations primarily differentiated patients with a history of suicide attempt from healthy controls, but not from patient controls. However, patients with a history of suicide attempt exhibited positive correlations between age and cortical thickness in the temporal cortices and right insula, and between age and right putamen volume (i.e., thicker regional cortex and larger subcortical volumes with age). These correlations were negative in both patient controls and healthy controls (i.e., thinner regional cortex and smaller subcortical volumes). Limitations: Sample sizes, cross-sectional findings and psychiatric heterogeneity were limitations of this study. Conclusion: Macroscopic structural differences in several brain regions differentiated adolescents with a history of suicide attempt from healthy controls, but not from patient controls. However, adolescents with a history of suicide attempt may present with atypical maturation of specific cortical and subcortical regions that might contribute to the risk of suicidal behaviour.
Asunto(s)
Corteza Cerebral/patología , Depresión/patología , Intento de Suicidio , Adolescente , Corteza Cerebral/anomalías , Corteza Cerebral/diagnóstico por imagen , Niño , Estudios Transversales , Femenino , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
Human AUTS2 mutations are linked to a syndrome of intellectual disability, autistic features, epilepsy, and other neurological and somatic disorders. Although it is known that this unique gene is highly expressed in developing cerebral cortex, the molecular and developmental functions of AUTS2 protein remain unclear. Using proteomics methods to identify AUTS2 binding partners in neonatal mouse cerebral cortex, we found that AUTS2 associates with multiple proteins that regulate RNA transcription, splicing, localization, and stability. Furthermore, AUTS2-containing protein complexes isolated from cortical tissue bound specific RNA transcripts in RNA immunoprecipitation and sequencing assays. Deletion of all major functional isoforms of AUTS2 (full-length and C-terminal) by conditional excision of exon 15 caused breathing abnormalities and neonatal lethality when Auts2 was inactivated throughout the developing brain. Mice with limited inactivation of Auts2 in cerebral cortex survived but displayed abnormalities of cerebral cortex structure and function, including dentate gyrus hypoplasia with agenesis of hilar mossy neurons, and abnormal spiking activity on EEG. Also, RNA transcripts that normally associate with AUTS2 were dysregulated in mutant mice. Together, these findings indicate that AUTS2 regulates RNA metabolism and is essential for development of cerebral cortex, as well as subcortical breathing centers.
Asunto(s)
Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/fisiología , Giro Dentado/crecimiento & desarrollo , Giro Dentado/metabolismo , ARN/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/fisiología , Animales , Animales Recién Nacidos , Corteza Cerebral/anomalías , Corteza Cerebral/metabolismo , Electroencefalografía , Exones/genética , Eliminación de Gen , Regulación de la Expresión Génica , Discapacidad Intelectual/genética , Ratones , Ratones Endogámicos C57BL , RNA-Seq , RespiraciónRESUMEN
The relationship between structural changes of the cerebral cortex revealed by Magnetic Resonance Imaging (MRI) and gene expression in the human fetal brain has not been explored. In this study, we aimed to test the hypothesis that relative regional thickness (a measure of cortical evolving organization) of fetal cortical compartments (cortical plate [CP] and subplate [SP]) is associated with expression levels of genes with known cortical phenotype. Mean regional SP/CP thickness ratios across age measured on in utero MRI of 25 healthy fetuses (20-33 gestational weeks [GWs]) were correlated with publicly available regional gene expression levels (23-24 GW fetuses). Larger SP/CP thickness ratios (more pronounced cortical evolving organization) was found in perisylvian regions. Furthermore, we found a significant association between SP/CP thickness ratio and expression levels of the FLNA gene (mutated in periventricular heterotopia, congenital heart disease, and vascular malformations). Further work is needed to identify early MRI biomarkers of gene expression that lead to abnormal cortical development.
Asunto(s)
Encéfalo/crecimiento & desarrollo , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/embriología , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/embriología , Adulto , Encéfalo/diagnóstico por imagen , Corteza Cerebral/anomalías , Femenino , Feto/diagnóstico por imagen , Feto/metabolismo , Filaminas/genética , Expresión Génica/genética , Expresión Génica/fisiología , Edad Gestacional , Cabeza , Humanos , Imagen por Resonancia Magnética , Red Nerviosa/metabolismo , Embarazo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , TranscriptomaRESUMEN
Neurodevelopmental disorders (NDDs) are a group of highly prevalent, clinically and genetically heterogeneous pediatric disorders comprising, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V), intellectual disability, developmental delay, autism spectrum disorders, and other neurological and cognitive disorders manifesting in the developmental age. To date, more than 1000 genes have been implicated in the etiopathogenesis of NNDs. Among them, AUTS2 (OMIM # 607270) encodes a protein involved in neural migration and neuritogenesis, and causes NNDs with different molecular mechanisms including copy number variations, single or multiple exonic deletion and single nucleotide variants. We describes a 9-year-old boy with global developmental delay, absent speech, minor craniofacial anomalies, hypoplasia of the cerebellar vermis and thinning of the corpus callosum, resulted carrier of the de novo AUTS2 c.1603_1626del deletion at whole exome sequencing (WES) predicted to cause the loss of eight amino acids [p.(His535_Thr542del)]. Notably, our patient is the first reported so far in medical literature carrying an in-frame deletion and the first in which absent language, hypoplasia of the cerebellar vermis and thinning of the corpus callosum has been observed thus useful to expand the molecular spectrum of AUTS2 pathogenic variants and to broaden our knowledge on the clinical phenotype associated.
Asunto(s)
Trastorno Dismórfico Corporal/genética , Proteínas del Citoesqueleto/genética , Discapacidades del Desarrollo/genética , Predisposición Genética a la Enfermedad , Discapacidad Intelectual/genética , Factores de Transcripción/genética , Trastorno Dismórfico Corporal/patología , Corteza Cerebral/anomalías , Corteza Cerebral/patología , Niño , Discapacidades del Desarrollo/patología , Exones , Humanos , Discapacidad Intelectual/patología , Masculino , Fenotipo , Eliminación de Secuencia/genética , Trastornos del Habla/genética , Trastornos del Habla/patología , Secuenciación del ExomaAsunto(s)
Adenilosuccinato Liasa/deficiencia , Adenilosuccinato Liasa/genética , Agenesia del Cuerpo Calloso/fisiopatología , Trastorno Autístico/genética , Discapacidades del Desarrollo/fisiopatología , Epilepsia/fisiopatología , Lisencefalia/fisiopatología , Hipotonía Muscular/fisiopatología , Errores Innatos del Metabolismo de la Purina-Pirimidina/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/fisiopatología , Agenesia del Cuerpo Calloso/diagnóstico por imagen , Trastorno Autístico/diagnóstico , Trastorno Autístico/fisiopatología , Vermis Cerebeloso/anomalías , Vermis Cerebeloso/diagnóstico por imagen , Corteza Cerebral/anomalías , Corteza Cerebral/diagnóstico por imagen , Electroencefalografía , Heterocigoto , Humanos , Recién Nacido , Lisencefalia/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Mutación , Tamaño de los Órganos , Errores Innatos del Metabolismo de la Purina-Pirimidina/diagnóstico , Errores Innatos del Metabolismo de la Purina-Pirimidina/fisiopatología , Secuenciación del ExomaRESUMEN
The cerebral cortex is an intricate structure that controls human features such as language and cognition. Cortical functions rely on specialized neurons that emerge during development from complex molecular and cellular interactions. Neurodevelopmental disorders occur when one or several of these steps is incorrectly executed. Although a number of causal genes and disease phenotypes have been identified, the sequence of events linking molecular disruption to clinical expression mostly remains obscure. Here, focusing on human malformations of cortical development, we illustrate how complex interactions at the genetic, cellular, and circuit levels together contribute to diversity and variability in disease phenotypes. Using specific examples and an online resource, we propose that a multilevel assessment of disease processes is key to identifying points of vulnerability and developing new therapeutic strategies.
Asunto(s)
Corteza Cerebral/anomalías , Trastornos Mentales/metabolismo , Enfermedades del Sistema Nervioso/metabolismo , Neurogénesis/fisiología , Neuronas/fisiología , Animales , Conducta , Movimiento Celular/genética , Movimiento Celular/fisiología , Corteza Cerebral/metabolismo , Corteza Cerebral/ultraestructura , Regulación del Desarrollo de la Expresión Génica , Humanos , Trastornos Mentales/genética , Ratones , Enfermedades del Sistema Nervioso/genética , Vías Nerviosas/anomalías , Vías Nerviosas/metabolismo , Vías Nerviosas/ultraestructura , Neurogénesis/genética , Neuronas/citología , Especificidad de Órganos/genética , Especificidad de Órganos/fisiologíaRESUMEN
To illustrate the prenatal cerebral imaging features associated with tubulinopathy, we report on five affected fetuses from unrelated families, with a de-novo heterozygous variant in a tubulin gene (TUBA1A, TUBB2B or TUBB3). We identified two distinct prenatal imaging patterns related to tubulinopathy: a severe form, characterized by enlarged germinal matrices, microlissencephaly and a kinked brainstem; and a mild form which has not been reported previously in the prenatal literature. The latter form is associated with non-specific features, including an asymmetric brainstem, corpus callosal dysgenesis, a lack of Sylvian fissure operculization and distortion of the anterior part of the interhemispheric fissure with subsequent impacted medial borders of the frontal lobes, the combination of which, in the absence of additional extracerebral anomalies, is highly suggestive of tubulinopathy. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.
Asunto(s)
Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/embriología , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/embriología , Ultrasonografía Prenatal , Tronco Encefálico/anomalías , Tronco Encefálico/diagnóstico por imagen , Tronco Encefálico/embriología , Corteza Cerebral/anomalías , Femenino , Feto/anomalías , Feto/diagnóstico por imagen , Feto/embriología , Variación Genética , Humanos , Malformaciones del Desarrollo Cortical/genética , Ilustración Médica , Microcefalia/diagnóstico por imagen , Microcefalia/embriología , Embarazo , Tubulina (Proteína)/genéticaRESUMEN
Genetic studies identified multiple mutations associated with malformations of cortical development (MCD) in humans. When analyzing the underlying mechanisms in non-human experimental models it became increasingly evident, that these mutations accumulate in genes, which functions evolutionary progressed from rodents to humans resulting in an incomplete reflection of the molecular and cellular alterations in these models. Human brain organoids derived from human pluripotent stem cells resemble early aspects of human brain development to a remarkable extent making them an attractive model to investigate MCD. Here we review how human brain organoids enable the generation of fundamental new insight about the underlying pathomechanisms of MCD. We show how phenotypic features of these diseases are reflected in human brain organoids and discuss challenges and future considerations but also limitations for the use of human brain organoids to model human brain development and associated disorders.
Asunto(s)
Corteza Cerebral/metabolismo , Lisencefalia/genética , Megalencefalia/genética , Microcefalia/genética , Proteínas del Tejido Nervioso/genética , Organoides/metabolismo , Heterotopia Nodular Periventricular/genética , Diferenciación Celular , Corteza Cerebral/anomalías , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/fisiopatología , Células Ependimogliales/citología , Células Ependimogliales/metabolismo , Regulación de la Expresión Génica , Humanos , Lisencefalia/metabolismo , Lisencefalia/patología , Lisencefalia/fisiopatología , Megalencefalia/metabolismo , Megalencefalia/patología , Megalencefalia/fisiopatología , Microcefalia/metabolismo , Microcefalia/patología , Microcefalia/fisiopatología , Modelos Biológicos , Mutación , Proteínas del Tejido Nervioso/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Neurogénesis/genética , Neuronas/citología , Neuronas/metabolismo , Organoides/patología , Heterotopia Nodular Periventricular/metabolismo , Heterotopia Nodular Periventricular/patología , Heterotopia Nodular Periventricular/fisiopatología , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Cultivo Primario de CélulasRESUMEN
The way in which aberrant neural circuits contribute to epilepsy remains unclear. To elucidate this question, we dissected the circuit mechanisms underlying epileptogenesis using a mouse model of focal cortical malformation with spontaneous epileptiform discharges. We found that spontaneous spike-wave discharges and optogenetically induced hyperexcitable bursts in vivo were present in a cortical region distal to (>0.7 mm) freeze-lesion-induced microgyrus, instead of near the microgyrus. ChR2-assisted circuit mapping revealed ectopic inter-laminar excitatory input from infragranular layers to layers 2/3 pyramidal neurons as the key component of hyperexcitable circuitry. This hyperactivity disrupted the balance between excitation and inhibition and was more prominent in the cortical region distal to the microgyrus. Consistently, the inhibition from both parvalbumin-positive interneurons (PV) and somatostatin-positive interneurons (SOM) to pyramidal neurons were altered in a layer- and site-specific fashion. Finally, closed-loop optogenetic stimulation of SOM, but not PV, terminated spontaneous spike-wave discharges. Together, these results demonstrate the occurrence of highly site- and cell-type-specific synaptic reorganization underlying epileptic cortical circuits and provide new insights into potential treatment strategies.
Asunto(s)
Corteza Cerebral/anomalías , Epilepsia/fisiopatología , Red Nerviosa/fisiopatología , Potenciales de Acción/fisiología , Animales , Corteza Cerebral/fisiopatología , Modelos Animales de Enfermedad , Epilepsia/terapia , Canales Epiteliales de Sodio/genética , Femenino , Humanos , Interneuronas/metabolismo , Masculino , Ratones Transgénicos , Microelectrodos , Optogenética , Parvalbúminas/metabolismo , Células Piramidales/metabolismo , Somatostatina/metabolismo , Técnicas EstereotáxicasRESUMEN
In mammalian cell lines, the endosomal sorting complex required for transport (ESCRT)-III mediates abscission, the process that physically separates daughter cells and completes cell division. Cep55 protein is regarded as the master regulator of abscission, because it recruits ESCRT-III to the midbody (MB), the site of abscission. However, the importance of this mechanism in a mammalian organism has never been tested. Here we show that Cep55 is dispensable for mouse embryonic development and adult tissue homeostasis. Cep55-knockout offspring show microcephaly and primary neural progenitors require Cep55 and ESCRT for survival and abscission. However, Cep55 is dispensable for cell division in embryonic or adult tissues. In vitro, division of primary fibroblasts occurs without Cep55 and ESCRT-III at the midbody and is not affected by ESCRT depletion. Our work defines Cep55 as an abscission regulator only in specific tissue contexts and necessitates the re-evaluation of an alternative ESCRT-independent cell division mechanism.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Citocinesis , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Animales , Animales Recién Nacidos , Apoptosis , Proteínas de Ciclo Celular/deficiencia , Proteínas de Ciclo Celular/genética , Células Cultivadas , Corteza Cerebral/anomalías , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Fibroblastos/metabolismo , Eliminación de Gen , Genotipo , Riñón/anomalías , Ratones Endogámicos C57BL , Ratones Noqueados , Microcefalia/patología , MitosisRESUMEN
De novo germline mutations in the RNA helicase DDX3X account for 1%-3% of unexplained intellectual disability (ID) cases in females and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here, we use human and mouse genetics and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n = 107), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuron generation. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity, induce ectopic RNA-protein granules in neural progenitors and neurons, and impair translation. Together, these results uncover key mechanisms underlying DDX3X syndrome and highlight aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.
Asunto(s)
Corteza Cerebral/metabolismo , ARN Helicasas DEAD-box/genética , Mutación Missense , Trastornos del Neurodesarrollo/genética , Neurogénesis , Animales , Línea Celular Tumoral , Células Cultivadas , Corteza Cerebral/anomalías , Corteza Cerebral/embriología , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Trastornos del Neurodesarrollo/patología , ARN/metabolismoRESUMEN
Down Syndrome (DS) is the most frequent genetic cause of intellectual disability with a wide spectrum of neurodevelopmental outcomes. At present, the relationship between structural brain morphology and the spectrum of cognitive phenotypes in DS, is not well understood. This study aimed to quantify the development of the fetal and neonatal brain in DS participants, with and without a congenital cardiac defect compared with a control population using dedicated, optimised and motion-corrected in vivo magnetic resonance imaging (MRI). We detected deviations in development and altered regional brain growth in the fetus with DS from 21 weeks' gestation, when compared to age-matched controls. Reduced cerebellar volume was apparent in the second trimester with significant alteration in cortical growth becoming evident during the third trimester. Developmental abnormalities in the cortex and cerebellum are likely substrates for later neurocognitive impairment, and ongoing studies will allow us to confirm the role of antenatal MRI as an early biomarker for subsequent cognitive ability in DS. In the era of rapidly developing technologies, we believe that the results of this study will assist counselling for prospective parents.
Asunto(s)
Cerebelo , Corteza Cerebral , Síndrome de Down/diagnóstico por imagen , Desarrollo Fetal , Feto , Cardiopatías Congénitas , Biomarcadores , Cerebelo/anomalías , Cerebelo/diagnóstico por imagen , Cerebelo/crecimiento & desarrollo , Corteza Cerebral/anomalías , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/crecimiento & desarrollo , Comorbilidad , Síndrome de Down/epidemiología , Síndrome de Down/patología , Femenino , Desarrollo Fetal/fisiología , Feto/anomalías , Feto/diagnóstico por imagen , Edad Gestacional , Cardiopatías Congénitas/epidemiología , Humanos , Recién Nacido , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Embarazo , Diagnóstico PrenatalRESUMEN
The development and organisation of the human brain start in the embryonic stage and is a highly complex orchestrated process. It depends on series of cellular mechanisms that are precisely regulated by multiple proteins, signalling pathways and non-protein-coding genes. A crucial process during cerebral cortex development is the migration of nascent neuronal cells to their appropriate positions and their associated differentiation into layer-specific neurons. Neuronal migration defects (NMD) comprise a heterogeneous group of neurodevelopmental disorders including monogenetic disorders and residual syndromes due to damaging factors during prenatal development like infections, maternal diabetes mellitus or phenylketonuria, trauma, and drug use. Multifactorial causes are also possible. Classification into lissencephaly, polymicrogyria, schizencephaly, and neuronal heterotopia is based on the visible morphologic cortex anomalies. Characteristic clinical features of NMDs are severe psychomotor developmental delay, severe intellectual disability, intractable epilepsy, and dysmorphisms. Neurometabolic disorders only form a small subgroup within the large group of NMDs. The prototypes are peroxisomal biogenesis disorders, peroxisomal ß-oxidation defects and congenital disorders of O-glycosylation. The rapid evolution of biotechnology has resulted in an ongoing identification of metabolic and non-metabolic disease genes for NMDs. Nevertheless, we are far away from understanding the specific role of cortical genes and metabolites on spatial and temporal regulation of human cortex development and associated malformations. This limited understanding of the pathogenesis hinders the attempt for therapeutic approaches. In this article, we provide an overview of the most important cortical malformations and potential underlying neurometabolic disorders.
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Corteza Cerebral/anomalías , Corteza Cerebral/crecimiento & desarrollo , Malformaciones del Desarrollo Cortical del Grupo II/genética , Errores Innatos del Metabolismo/genética , Corteza Cerebral/patología , Humanos , Imagen por Resonancia Magnética , Malformaciones del Desarrollo Cortical del Grupo II/clasificación , Mutación , Neuronas/fisiologíaRESUMEN
Very preterm (VPT) infants are at high-risk for neurodevelopmental impairments, however there are few validated biomarkers at term-equivalent age that accurately measure abnormal brain development and predict future impairments. Our objectives were to quantify and contrast cortical features between full-term and VPT infants at term and to associate two key antecedent risk factors, bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP), with cortical maturational changes in VPT infants. We prospectively enrolled a population-based cohort of 110 VPT infants (gestational age ≤31 weeks) and 51 healthy full-term infants (gestational age 38-42 weeks). Structural brain MRI was performed at term. 94 VPT infants and 46 full-term infants with high-quality T2-weighted MRI were analyzed. As compared to full-term infants, VPT infants exhibited significant global cortical maturational abnormalities, including reduced surface area (-5.9%) and gyrification (-6.7%) and increased curvature (5.9%). In multivariable regression controlled for important covariates, BPD was significantly negatively correlated with lobar and global cortical surface area and ROP was significantly negatively correlated with lobar and global sulcal depth in VPT infants. Our cohort of VPT infants exhibited widespread cortical maturation abnormalities by term-equivalent age that were in part anteceded by two of the most potent neonatal diseases, BPD and ROP.
Asunto(s)
Displasia Broncopulmonar/complicaciones , Corteza Cerebral/anomalías , Trastornos del Neurodesarrollo/etiología , Retinopatía de la Prematuridad/complicaciones , Displasia Broncopulmonar/diagnóstico por imagen , Estudios de Casos y Controles , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/crecimiento & desarrollo , Estudios de Cohortes , Femenino , Humanos , Lactante , Recien Nacido Extremadamente Prematuro , Recien Nacido Prematuro , Imagen por Resonancia Magnética , Masculino , Análisis Multivariante , Trastornos del Neurodesarrollo/diagnóstico por imagen , Estudios Prospectivos , Retinopatía de la Prematuridad/diagnóstico por imagen , Factores de RiesgoRESUMEN
Polymorphic variants of the gene encoding for metabotropic glutamate receptor 3 (mGlu3) are linked to schizophrenia. Because abnormalities of cortical GABAergic interneurons lie at the core of the pathophysiology of schizophrenia, we examined whether mGlu3 receptors influence the developmental trajectory of cortical GABAergic transmission in the postnatal life. mGlu3-/- mice showed robust changes in the expression of interneuron-related genes in the prefrontal cortex (PFC), including large reductions in the expression of parvalbumin (PV) and the GluN1 subunit of NMDA receptors. The number of cortical cells enwrapped by perineuronal nets was increased in mGlu3-/- mice, suggesting that mGlu3 receptors shape the temporal window of plasticity of PV+ interneurons. Electrophysiological measurements of GABAA receptor-mediated responses revealed a more depolarized reversal potential of GABA currents in the somata of PFC pyramidal neurons in mGlu3-/- mice at postnatal d 9 associated with a reduced expression of the K+/Cl- symporter. Finally, adult mGlu3-/- mice showed lower power in electroencephalographic rhythms at 1-45 Hz in quiet wakefulness as compared with their wild-type counterparts. These findings suggest that mGlu3 receptors have a strong impact on the development of cortical GABAergic transmission and cortical neural synchronization mechanisms corroborating the concept that genetic variants of mGlu3 receptors may predispose to psychiatric disorders.-Imbriglio, T., Verhaeghe, R., Martinello, K., Pascarelli, M. T., Chece, G., Bucci, D., Notartomaso, S., Quattromani, M., Mascio, G., Scalabrì, F., Simeone, A., Maccari, S., Del Percio, C., Wieloch, T., Fucile, S., Babiloni, C., Battaglia, G., Limatola, C., Nicoletti, F., Cannella, M. Developmental abnormalities in cortical GABAergic system in mice lacking mGlu3 metabotropic glutamate receptors.
Asunto(s)
Corteza Cerebral/anomalías , Embrión de Mamíferos/anomalías , Neuronas GABAérgicas/fisiología , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Biomarcadores , Corteza Cerebral/metabolismo , Femenino , Regulación de la Expresión Génica , Genes Homeobox , Inmunohistoquímica , Masculino , Ratones , Ratones Noqueados , ARN Mensajero , Receptores de Glutamato Metabotrópico/genéticaRESUMEN
AIMS: Although hypertension (HTN) is the high comorbidity of Type 2 diabetes mellitus (T2DM) and known to be a vascular risk factor for brain damage, the effects of HTN on brain function in T2DM patients are not well understood. Present study was performed to investigate whether HTN might accelerate the Cerebral cortical thickness (CT) alterations in patients with T2DM. METHODS: We enrolled 35 participants with only T2DM, 25 T2DM patients with HTN (HT2DM) and 28 healthy controls (HCs). The cognitive function was assessed and brain image data was collected then the CT was calculated for each participant. Partial correlations between the CT of each brain region and standard laboratory testing data and neuropsychological scale scores were also analyzed. Multivariable regression analysis was performed to evaluated the vascular risk factors and brain regions with different CT in HT2DM patients. RESULTS: Cognitive impairment is associated with thinning of the cerebral cortical thickness reduction in T2DM patients. CT thinning in the left inferior parietal lobe, left posterior cingulate and right precuneus were observed in HT2DM group relative to only T2DM group. Furthermore, the CT decreasing in the right precuneus was negatively correlated with duration of HTN. CONCLUSION: The current study revealed that coexistent HTN may accelerate the CT reduction in T2DM patients.
Asunto(s)
Corteza Cerebral/anomalías , Diabetes Mellitus Tipo 2/complicaciones , Hipertensión/complicaciones , Imagen por Resonancia Magnética/métodos , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
TAF1/MRSX33 intellectual disability syndrome is an X-linked disorder caused by loss-of-function mutations in the TAF1 gene. How these mutations cause dysmorphology, hypotonia, intellectual and motor defects is unknown. Mouse models which have embryonically targeted TAF1 have failed, possibly due to TAF1 being essential for viability, preferentially expressed in early brain development, and intolerant of mutation. Novel animal models are valuable tools for understanding neuronal pathology. Here, we report the development and characterization of a novel animal model for TAF1 ID syndrome in which the TAF1 gene is deleted in embryonic rats using clustered regularly interspaced short palindromic repeats (CRISPR) associated protein 9 (Cas9) technology and somatic brain transgenesis mediated by lentiviral transduction. Rat pups, post-natal day 3, were subjected to intracerebroventricular (ICV) injection of either gRNA-control or gRNA-TAF1 vectors. Rats were subjected to a battery of behavioral tests followed by histopathological analyses of brains at post-natal day 14 and day 35. TAF1-edited rats exhibited behavioral deficits at both the neonatal and juvenile stages of development. Deletion of TAF1 lead to a hypoplasia and loss of the Purkinje cells. We also observed a decreased in GFAP positive astrocytes and an increase in Iba1 positive microglia within the granular layer of the cerebellum in TAF1-edited animals. Immunostaining revealed a reduction in the expression of the CaV3.1â¯T-type calcium channel. Abnormal motor symptoms in TAF1-edited rats were associated with irregular cerebellar output caused by changes in the intrinsic activity of the Purkinje cells due to loss of pre-synaptic CaV3.1. This animal model provides a powerful new tool for studies of neuronal dysfunction in conditions associated with TAF1 abnormalities and should prove useful for developing therapeutic strategies to treat TAF1 ID syndrome.