Defective Reelin/Dab1 signaling pathways associated with disturbed hippocampus development of homozygous yotari mice.

Homozygous Dab1 yotari mutant mice, Dab1yot (yot/yot) mice, have an autosomal recessive mutation of Dab1 and show reeler-like phenotype including histological abnormality of the cerebellum, hippocampus, and cerebral cortex. We here show abnormal hippocampal development of yot/yot mice where granule cells and pyramidal cells fail to form orderly rows but are dispersed diffusely in vague multiplicative layers. Possibly due to the positioning failure of granule cells and pyramidal cells and insufficient synaptogenesis, axons of the granule cells did not extend purposefully to connect with neighboring regions in yot/yot mice. We found that both hippocampal granule cells and pyramidal cells of yot/yot mice expressed proteins reactive with the anti-Dab1 antibody. We found that Y198- phosphorylated Dab1 of yot/yot mice was greatly decreased. Accordingly the downstream molecule, Akt was hardly phosphorylated. Especially, synapse formation was defective and the distribution of neurons was scattered in hippocampus of yot/yot mice. Some of neural cell adhesion molecules and hippocampus associated transcription factors of the neurons were expressed aberrantly, suggesting that the Reelin-Dab1 signaling pathway seemed to be importantly involved in not only neural migration as having been shown previously but also neural maturation and/or synaptogenesis of the mice. It is interesting to clarify whether the defective neural maturation is a direct consequence of the dysfunctional Dab1, or alternatively secondarily due to the Reelin-Dab1 intracellular signaling pathways.

Incomplete hippocampal inversion and epilepsy: A systematic review and meta-analysis.

OBJECTIVE: Incomplete hippocampal inversion (IHI) is a relatively frequent radiological finding at visual inspection in both epilepsy and healthy controls, but its clinical significance is unclear. Here, we systematically retrieve and assess the association between epilepsy and IHI using a meta-analytic approach. Additionally, we estimate the prevalence of IHI in patients with malformation of cortical development (MCD). METHODS: We systematically searched two databases (Embase and PubMed) to identify potentially eligible studies from their inception to December 2019. For inclusion, studies were population-based, case-control, observational studies reporting on epilepsy and IHI. The risk of developing epilepsy in IHI (estimated with odds ratio [ORs]) and the frequency of IHI among patients with MCD are provided. RESULTS: We screened 3601 records and assessed eligibility of 2812 full-text articles. The final material included 13 studies involving 1630 subjects. Seven studies (1329 subjects: 952 epileptic and 377 nonepileptic) were included for the estimation of the risk of developing epilepsy in the presence of IHI. The estimated OR of active epilepsy in IHI was 1.699 (95% confidence interval = 0.880-3.281), with moderate heterogeneity across studies (I2  = 71%). Seven studies (591 patients) provided information about the frequency of IHI in MCD. Up to one third of patients with MCD (27.9%) presented coexistent IHI. SIGNIFICANCE: The present findings confirm that IHI is commonly observed in patients with MCD especially in periventricular nodular heterotopia or polymicrogyria. However, the estimated OR indicates overall weak increased odds of epilepsy in people with IHI, suggesting that the presence of isolated IHI cannot be considered a strong independent predictor for epilepsy development. Clear-cut neuroradiological criteria for IHI and advanced postprocessing analyses on structural magnetic resonance imaging scans are recommended to highlight differences between epileptogenic and nonepileptogenic IHI.

Anatomical, radiological and clinical features of mesial temporal lobe epilepsy: two illustrated cases reports / Aspectos anatômicos, radiológicos e clínicos da epilepsia do lobo temporal mesial: relato ilustrado de dois casos

Mesial temporal lobe epilepsy is the most commom form of focal epilepsy in adults. Its clinical features include focal seizure, dysmnestic symptoms ­ such as déjà vu or jamais vu ­ and autonomic or psychic aura. We reported two cases of mesial temporal lobe epilepsy with similar clinical features, but with entirely different etiologies. Mesial temporal sclerosis contributes up to 70% of all mesial temporal lobe epilepsy cases and MRI usually shows reduced hippocampal volume and increased signal intensity on T2-weighted imaging. Incomplete hippocampal inversion has uncertain relation with epilepsy and is characterized by an atypical verticalized and medially positioned anatomical pattern of the hippocampus and also a deep collateral sulcus.

A epilepsia do lobo temporal mesial é a forma mais comum de epilepsia focal em adultos. Suas características clínicas incluem crises focais, sintomas dismnésicos - como déjà vu ou jamais vu - e aura autonômica ou psíquica. Relatamos dois casos de pacientes com epilepsia do lobo temporal mesial com manifestações clínicas semelhantes, mas com etiologias completamente diferentes. A esclerose mesial temporal contribui com até 70% de todos os casos de epilepsia do lobo temporal mesial e, geralmente, na ressonância magnética, apresenta atrofia do hipocampo e hipersinal na imagem ponderada em T2. A rotação incompleta do hipocampo possui uma relação incerta com a epilepsia e é caracterizada por alteração da estrutura interna do hipocampo, com um sulco colateral verticalizado e profundo.

Shared hippocampal abnormalities in sporadic temporal lobe epilepsy patients and their siblings.

OBJECTIVE: To examine the shared familial contribution to hippocampal and extrahippocampal morphological abnormalities in patients with sporadic temporal lobe epilepsy (TLE) and their unaffected siblings. METHODS: We collected clinical, electrophysiological, and T1-weighted magnetic resonance imaging (MRI) data of 18 sporadic patients with TLE without lesions other than hippocampal sclerosis (12 right, 6 left), their 18 unaffected full siblings, and 18 matched healthy volunteers. We compared between-group differences in cortical thickness and volumes of five subcortical areas (hippocampus, amygdala, thalamus, putamen, and pallidum). We determined the subregional extent of hippocampal abnormalities using surface shape analysis. All our imaging results were corrected for multiple comparisons using random field theory. RESULTS: We detected smaller hippocampal volumes in patients (right TLE: median right hippocampus 1.92 mL, interquartile range [IQR] 1.39-2.62, P < .001; left TLE: left hippocampus 2.05 mL, IQR 1.99-2.33, P = .01) and their unaffected siblings (right hippocampus 2.65 mL, IQR 2.32-2.80, P < .001; left hippocampus 2.39 mL, IQR 2.18-2.53, P < .001) compared to healthy controls (right hippocampus 2.94 mL, IQR 2.77-3.24; left hippocampus 2.71 mL, IQR 2.37-2.89). Surface shape analysis showed that patients with TLE had bilateral subregional atrophy in both hippocampi (right > left). Similar but less-pronounced subregional atrophy was detected in the right hippocampus of unaffected siblings. Patients with TLE had reduced cortical thickness in bilateral premotor/prefrontal cortices and the right precentral gyrus. Siblings did not show abnormalities in cortical or subcortical areas other than the hippocampus. SIGNIFICANCE: Our results demonstrate a shared vulnerability of the hippocampus in both patients with TLE and their unaffected siblings, pointing to a contribution of familial factors to hippocampal atrophy. This neuroimaging trait could represent an endophenotype of TLE, which might precede the onset of epilepsy in some individuals.

Activation of the G Protein-Coupled Estrogen Receptor (GPER) Increases Neurogenesis and Ameliorates Neuroinflammation in the Hippocampus of Male Spontaneously Hypertensive Rats.

It is known that spontaneously hypertensive rats (SHR) present a marked encephalopathy, targeting vulnerable regions such as the hippocampus. Abnormalities of the hippocampus of SHR include decreased neurogenesis in the dentate gyrus (DG), partial loss of neurons in the hilus of the DG, micro and astrogliosis and inflammation. It is also known that 17ß-estradiol (E2) exert neuroprotective effects and prevent hippocampal abnormalities of SHR. The effects of E2 may involve a variety of mechanisms, including intracellular receptors of the ERα and ERß subtypes or membrane-located receptors, such as the G protein-coupled estradiol receptor (GPER). We have now investigated the protective role of GPER in SHR employing its synthetic agonist G1. To accomplish this objective, 5 month-old male SHR received 150 µg/day of G1 during 2 weeks. At the end of this period, we analyzed neuronal progenitors by staining for doublecortin (DCX), and counted the number of glial fibrillary acidic protein (GFAP)-labeled astrocytes and Iba1-stained microglial cells by computerized image analysis. We found that G1 activation of GPER increased DCX+ cells in the DG and reduced GFAP+ astrogliosis and Iba1+ microgliosis in the CA1 region of hippocampus. We also found that the high expression of proinflammatory makers IL1ß and cyclooxygenase 2 (COX2) of SHR was decreased after G1 treatment, which correlated with a change of microglia phenotype from the activated to a resting morphology. Additionally, G1 treatment increased the anti-inflammatory factor TGFß in SHR hippocampus. Altogether, our results suggest that activation of GPER plays a neuroprotective role on the encephalopathy of SHR, an outcome resembling E2 effects but avoiding secondary effects of the natural hormone.

Septo-optic Dysplasia : Assessment of Associated Findings with Special Attention to the Olfactory Sulci and Tracts.

PURPOSE: Septo-optic dysplasia is a congenital disorder consisting of optic nerve hypoplasia and absent septum pellucidum. While associated anomalies have been described, olfactory sulcus and bulb-tract hypoplasia have been scantily reported and was the focus of this study. METHODS: The picture archival and communications system and radiology information system (PACS-RIS) was searched over 15 years for patients with suspected septo-optic dysplasia (n = 41) and cerebral magnetic resonance imaging (MRI). Included patients had coronal (≤3 mm), axial (≤4 mm), and sagittal (≤4 mm) imaging reviewed by two staff neuroradiologists by consensus. Both olfactory sulcus and bulb-tract hypoplasia were ascribed a grade of 0 (normal) to 3 (complete hypoplasia). Other associated congenital anomalies were recorded, if present. Incidence of anomalies were compared to age-matched and gender-matched control patients. RESULTS: Out of 41 septo-optic dysplasia patients 33 were included (mean age = 120.7 months), with 8 excluded due to isolated septum pellucidum absence (n = 5), isolated bilateral optic hypoplasia (n = 2), or inadequate imaging (n = 1). An olfactory sulcus was hypoplastic on one or both sides in 14/33 (42.4%). Olfactory bulb hypoplasia was noted in one or both tracts in 15/33 (45.4%). A significant correlation was found between degree of olfactory sulcal and bulb-tract hypoplasia (ρ = 0.528, p = 0.0009). Other anomalies were: anterior falx dysplasia (n = 16, 48.5%), incomplete hippocampal inversion (n = 14, 42.4%), polymicrogyria (n = 11, 33.3%), callosal complete or partial agenesis (n = 10, 30.3%), schizencephaly (n = 8, 24.2%), ectopic posterior pituitary (n = 6, 18.2%), and nodular heterotopia (n = 4, 12.1%). Of the age-matched control patients 10/33 (30.3%) had at least mild anterior falx hypoplasia, and 1 control patient was noted to have unilateral incomplete hippocampal inversion (IHI); none of the age-matched control patients had olfactory sulcus or bulb-tract hypoplasia. CONCLUSION: Olfactory sulcus and bulb-tract hypoplasia are fairly common in septo-optic dysplasia and can be discordant between sides. Of the other associated anomalies, anterior falx dysplasia seems to be the most common.

Protein phosphatase 2ACα gene knock-out results in cortical atrophy through activating hippo cascade in neuronal progenitor cells.

Protein phosphatase 2ACα (PP2ACα), a vital member of the protein phosphatase family, has been studied primarily as a regulator for the development, growth and protein synthesis of a lot of cell types. Dysfunction of PP2ACα protein results in neurodegenerative disease; however, this finding has not been directly confirmed in the mouse model with PP2ACα gene knock-out. Therefore, in this study presented here, we generated the PP2ACα gene knock-out mouse model by the Cre-loxP targeting gene system, with the purpose to directly observe the regulatory role of PP2ACα gene in the development of mouse's cerebral cortex. We observe that knocking-out PP2ACα gene in the central nervous system (CNS) results in cortical neuronal shrinkage, synaptic plasticity impairments, and learning/memory deficits. Further study reveals that PP2ACα gene knock-out initiates Hippo cascade in cortical neuroprogenitor cells (NPCs), which blocks YAP translocation into the nuclei of NPCs. Notably, p73, directly targeted by Hippo cascade, can bind to the promoter of glutaminase2 (GLS2) that plays a dominant role in the enzymatic regulation of glutamate/glutamine cycle. Finally, we find that PP2ACα gene knock-out inhibits the glutamine synthesis through up-regulating the activity of phosphorylated-p73 in cortical NPCs. Taken together, it concludes that PP2ACα critically supports cortical neuronal growth and cognitive function via regulating the signaling transduction of Hippo-p73 cascade. And PP2ACα indirectly modulates the glutamine synthesis of cortical NPCs through targeting p73 that plays a direct transcriptional regulatory role in the gene expression of GLS2.

T2 relaxometry improves detection of non-sclerotic epileptogenic hippocampus.

OBJECT: The use of T2 relaxometry was investigated to detect non-sclerotic epileptogenic abnormality of the hippocampus in presurgical evaluation of temporal lobe epilepsy (TLE). METHODS: This prospective study included 30 patients who underwent hippocampectomy as part of surgical treatment of refractory TLE. Ten patients had structural epileptogenic lesions in the extra-hippocampal temporal lobe. Twelve patients underwent intracranial electroencephalography (iEEG) study before surgery. Visual assessment of atrophy and increased T2 signal intensity, volumetry, and T2 relaxometry of hippocampus were performed pre-operatively using 3T magnetic resonance imaging, and compared with the neuropathological findings and iEEG findings. Magnetic resonance imaging of 30 age- and sex-matched healthy controls was used to establish normal values, which were defined as z score within 2. RESULTS: Visual assessment, volumetry, and T2 relaxometry detected hippocampal abnormalities on the surgical side in 16 (53%), 16 (53%), and 26 (87%) patients, respectively. Hippocampal volume loss was always associated with prolonged T2 relaxation time, and supported by histopathological diagnosis of HS in all cases except one. Hippocampal abnormality was detected only by T2 relaxometry in nine patients (30%). Pathological diagnosis of these cases included mild HS in one, microdysgenesis in one, and granule cell pathology in three. Four patients with normal hippocampal volume and T2 relaxation time had no HS or granule cell pathology. Prolonged T2 relaxation time was associated with medial temporal seizure onset in iEEG (p<0.05). CONCLUSIONS: T2 relaxometry improves the detection of non-sclerotic epileptogenic abnormality of the hippocampus.

Temporal lobe epilepsy in infants and children.

Clinical expression of temporal lobe seizures is different with a more diverse and more extensive etiology in infants and children than it is in adults. It is dominated by cortical dysplasia, low-grade tumors and perinatal damage. Hippocampal sclerosis, although less frequent, exists in children usually as a dual pathology associated with ipsilateral neocortical lesions. The clinical semiology of temporal seizures is more varied, and sometimes misleading. Motor features including tonic, clonic or myoclonic behaviors, and infantile spasms predominate in infants. Classical complex partial seizures with behavioral arrest and automatisms, as well as lateralizing signs are rare and occur mostly with onset after the age of two years. Interestingly, aura, emotional, and autonomic signs seem to be independent on the brain maturation process. Moreover, the neuropsychological profile varies according to age of onset and duration, lateralization of the focus and etiology. Quality of care benefits from individual cognitive assessment for memory and emotional processes.

ß-Catenin is required for maintaining hippocampal morphology during the perinatal period.

In mice, the compact hippocampal primordium is formed during the prenatal stage by early-generated neurons that migrate from the lateral ventricular zone. However, despite much being understood about the formation of the hippocampus, the molecular mechanisms that maintain the morphology of the hippocampal primordium after its formation remain to be characterized. ß-Catenin is a key factor of canonical Wnt signaling and also a component of adherens junctions. Previous embryonic deletion studies have demonstrated that ß-catenin is required for early development and generation of granule cells. However, whether ß-catenin is involved in the morphological maintenance of the hippocampus as a cell adhesion molecule is still unknown. Here, we report that perinatal deletion of ß-catenin in postmitotic neurons and some radial glial cells of hippocampus using CamKIIα-iCre; ß-cateninflox/flox conditional knockout mice, leads to disorganization of the radial glial scaffold and consequentially severe defects in hippocampal morphology. We demonstrate that ß-catenin is required for maintaining radial glial scaffold possibly via its well-known role in cell adhesion during the perinatal period. These findings provide essential advances into our understanding of the maintenance of the hippocampal primordium during the perinatal period.

Cortical hypoplasia and ventriculomegaly of p73-deficient mice: Developmental and adult analysis.

Trp73, a member of the p53 gene family, plays a crucial role in neural development. We describe two main phenotypic variants of p73 deficiency in the brain, a severe one characterized by massive apoptosis in the cortex leading to early postnatal death and a milder, non-/low-apoptosis one in which 50% of pups may reach adulthood using an intensive-care breeding protocol. Both variants display the core triad of p73 deficiency: cortical hypoplasia, hippocampal malformations, and ventriculomegaly. We studied the development of the neocortex in p73 KO mice from early embryonic life into advanced age (25 months). Already at E14.5, the incipient cortical plate of the p73 KO brains showed a reduced width. Examination of adult neocortex revealed a generalized, nonprogressive reduction by 10-20%. Area-specific architectonic landmarks and lamination were preserved in all cortical areas. The surviving adult animals had moderate ventricular distension, whereas pups of the early lethal phenotypic variant showed severe ventriculomegaly. Ependymal cells of wild-type ventricles strongly express p73 and are particularly vulnerable to p73 deficiency. Ependymal denudation by apoptosis and reduction of ependymal cilia were already evident in young mice, with complete absence of cilia in older animals. Loss of p73 function in the ependyma may thus be one determining factor for chronic hydrocephalus, which leads to atrophy of subcortical structures (striatum, septum, amygdala). p73 Is thus involved in a variety of CNS activities ranging from embryonic regulation of brain size to the control of cerebrospinal fluid homeostasis in the adult brain via maintenance of the ependyma.

The selective glucocorticoid receptor modulator CORT108297 restores faulty hippocampal parameters in Wobbler and corticosterone-treated mice.

Mutant Wobbler mice are models for human amyotrophic lateral sclerosis (ALS). In addition to spinal cord degeneration, Wobbler mice show high levels of blood corticosterone, hyperactivity of the hypothalamic-pituitary-adrenal axis and abnormalities of the hippocampus. Hypersecretion of glucocorticoids increase hippocampus vulnerability, a process linked to an enriched content of glucocorticoid receptors (GR). Hence, we studied if a selective GR antagonist (CORT108297) with null affinity for other steroid receptors restored faulty hippocampus parameters of Wobbler mice. Three months old genotyped Wobbler mice received s.c. vehicle or CORT108297 during 4 days. We compared the response of doublecortin (DCX)+ neuroblasts in the subgranular layer of the dentate gyrus (DG), NeuN+ cells in the hilus of the DG, glial fibrillary acidic protein (GFAP)+ astrocytes and the phenotype of Iba1+ microglia in CORT108297-treated and vehicle-treated Wobblers. The number of DCX+ cells in Wobblers was lower than in control mice, whereas CORT108297 restored this parameter. After CORT108297 treatment, Wobblers showed diminished astrogliosis, and changed the phenotype of Iba1+ microglia from an activated to a quiescent form. These changes occurred without alterations in the hypercorticosteronemia or the number of NeuN+ cells of the Wobblers. In a separate experiment employing control NFR/NFR mice, treatment with corticosterone for 5 days reduced DCX+ neuroblasts and induced astrocyte hypertrophy, whereas treatment with CORT108297 antagonized these effects. Normalization of neuronal progenitors, astrogliosis and microglial phenotype by CORT108297 indicates the usefulness of this antagonist to normalize hippocampus parameters of Wobbler mice. Thus, CORT108297 opens new therapeutic options for the brain abnormalities of ALS patients and hyperadrenocorticisms.

Bilateral hippocampal malformation and concurrent granulomatous meningoencephalitis in a dog with refractory epilepsy.

A 5-year-old dog was referred with a history of anorexia and apathy for 3 weeks and acute status epilepticus. Ten weeks later the animal was humanely destroyed due to refractory epilepsy despite anti-epileptic medical treatment. Microscopical examination of the brain revealed bilateral malformation of the dentate gyrus with abnormal gyration. Cornu ammonis segments comprised of sparse pyramidal cells accompanied by marked gliosis. Additionally, there was severe generalized disseminated granulomatous meningoencephalitis, mainly localized to the white matter of the cerebral hemispheres. This is the first description of bilateral hippocampal malformation in a dog.

Bilateral posterior periventricular nodular heterotopia: a recognizable cortical malformation with a spectrum of associated brain abnormalities.

BACKGROUND AND PURPOSE: Bilateral posterior PNH is a distinctive complex malformation with imaging features distinguishing it from classic bilateral PNH associated with FLNA mutations. The purpose of this study was to define the imaging features of posterior bilateral periventricular nodular heterotopia and to determine whether associated brain malformations suggest specific subcategories. MATERIALS AND METHODS: We identified a cohort of 50 patients (31 females; mean age, 13 years) with bilateral posterior PNH and systematically reviewed and documented associated MR imaging abnormalities. Patients were negative for mutations of FLNA. RESULTS: Nodules were often noncontiguous (n = 28) and asymmetric (n = 31). All except 1 patient showed associated developmental brain abnormalities involving a spectrum of posterior structures. A range of posterior fossa abnormalities affected the cerebellum, including cerebellar malformations and posterior fossa cysts (n = 38). Corpus callosum abnormalities (n = 40) ranged from mild dysplasia to agenesis. Posterior white matter volume was decreased (n = 22), and colpocephaly was frequent (n = 26). Most (n = 40) had associated cortical abnormalities ranging from minor to major (polymicrogyria), typically located in the cortex overlying the PNH. Abnormal Sylvian fissure morphology was common (n = 27), and hippocampal abnormalities were frequent (n = 37). Four family cases were identified-2 with concordant malformation patterns and 2 with discordant malformation patterns. CONCLUSIONS: The associations of bilateral posterior PNH encompass a range of abnormalities involving brain structures inferior to the Sylvian fissures. We were unable to identify specific subgroups and therefore conceptualize bilateral posterior PNH as a continuum of infrasylvian malformations involving the posterior cerebral and hindbrain structures.

Intracranial evaluation of the epileptogenic zone in regional infrasylvian polymicrogyria.

PURPOSE: To define the relationship between the epileptogenic zone and the polymicrogyric area using intracranial electroencephalography (EEG) recordings in patients with structural epilepsy associated with regional infrasylvian polymicrogyria (PMG). METHODS: We retrospectively reviewed the medical charts, scalp, and intracranial video-EEG recordings, neuroimaging findings, and neuropsychological evaluations of four patients with refractory temporal lobe epilepsy related to PMG who consequently underwent resective surgery. KEY FINDINGS: High-resolution magnetic resonance imaging (MRI) revealed temporal lobe PMG in all cases, accompanied by hippocampal malrotation and closed lip schizencephaly in 3/4 cases, respectively. In intracranial recordings, interictal spike activity was localized within the PMG in only 2/4 and within the amygdala, hippocampus, and entorhinal cortex in all cases. In the first patient, two epileptogenic networks coexisted: the prevailing network initially involved the mesial temporal structures with spread to the anterior PMG; the secondary network successively involved the anterior part of the PMG and later the mesial temporal structures. In the second patient, the epileptogenic network was limited to the mesial temporal structures, fully sparing the PMG. In the third patient, the epileptogenic network first involved the mesial temporal structures and later the PMG. Conversely, in the last case, part of the PMG harbored an epileptogenic network that propagated to the mesial temporal structures. Consistent with these findings a favorable outcome (Engel class I in three of four patients; Engel class II in one of four) at last follow-up was obtained by a resection involving parts of the PMG cortex in three of four and anteromesial temporal lobe structures in another three of four cases. SIGNIFICANCE: Infrasylvian PMG displays a heterogeneous epileptogenicity and is occasionally and partially involved in the epileptogenic zone that commonly includes the mesial temporal structures. Our results highlight the intricate interrelations between the MRI-detectable lesion and the epileptogenic zone as delineated by intracranial recordings. Seizure freedom can be accomplished as a result of a meticulous intracranial study guiding a tailored resection that may spare part of the PMG.

Progesterone attenuates several hippocampal abnormalities of the Wobbler mouse.

It is now recognised that progesterone plays a protective role for diseases of the central nervous system. In the Wobbler mouse, a model of motoneurone degeneration, progesterone treatment prevents spinal cord neuropathology and clinical progression of the disease. However, neuropathological and functional abnormalities have also been discovered in the brain of Wobbler mice and patients with amyotrophic lateral sclerosis. The present study examined the hippocampus of control and afflicted Wobbler mice and the changes in response to progesterone treatment. Mice received either a single progesterone implant (20 mg for 18 days). We found that the hippocampal pathology of the untreated Wobblers involved a decreased expression of brain-derived neurotrophic factor (BDNF) mRNA, decreased astrogliosis in the stratum lucidum, stratum radiatum and stratum lacunosum-moleculare, decreased doublecortin (DCX)-positive neuroblasts in the subgranular zone of the dentate gyrus and a decreased density of GABA immunoreactive hippocampal interneurones and granule cells of the dentate gyrus. Although progesterone did not change the normal parameters of control mice, it attenuated several hippocampal abnormalities in Wobblers. Thus, progesterone increased hippocampal BDNF mRNA expression, decreased glial fibrillary acidic protein-positive astrocytes and increased the number of GABAergic interneurones and granule cells. The number of DCX expressing neuroblasts and immature neurones remained impaired in both progesterone-treated and untreated Wobblers. In conclusion, progesterone treatment exerted beneficial effects on some aspects of hippocampal neuropathology, suggesting its neuroprotective role in the brain, in agreement with previous data obtained in the spinal cord of Wobbler mice.

Gamma radiation-induced impairment of hippocampal neurogenesis, comparison of single and fractionated dose regimens / Deterioro de la neurogénesis en el hipocampo inducida por radiación gamma, comparación de los regímenes de dosis única y fraccionada

Radiation therapy of the brain is associated with many consequences, including cognitive disorders. Pathogenesis of radiation induced cognitive disorder is not clear, but reduction of neurogenesis in hippocampus may be an underlying reason. 24 adult male rats entered to study. Radiation absorbed dose to midbrain was 10 Gy, delivered by routine cobalt radiotherapy machine which its output was measured 115.24 cGy/min. The rats were divided in four groups of sixes, including groups of control, single fraction 10 Gy, fractionated 10 Gy and finally anaesthesia sham group. Number of pyramidal nerve cells was counted in two regions of hippocampus formation (CA1 and CA3). The radiation could reduce the number of cells in two regions of hippocampus significantly (p=0.000). It seems fractionated 10 Gy irradiation to more efficient than single fraction, while role of anaesthesia drug should be cautiously assessed. Moreover the rate of neurogenesis reduction was determined the same in these regions of hippocampus meaning the same radiosensitivity of cells.

La terapia de radiación cerebral está asociada con muchas consecuencias, incluyendo los trastornos cognitivos. La patogénesis del trastorno cognitivo inducido por la radiación no está claro, pero la reducción de la neurogénesis en el hipocampo puede ser una razón subyacente. Fueron etudiadas 24 ratas macho adultas. La dosis de radiación absorbida en el mesencéfalo fue de 10 Gy, proveniente de una máquina de radioterapia de cobalto con una salida de 115,24 cGy/min. Las ratas fueron divididas en cuatro grupos de seis ratas cada uno, incluyendo un grupo control, fracción única de 10 Gy, fraccionada de 10 Gy y finalmente el grupo de anestesia simulado. El número de células nerviosas piramidales se contó en dos regiones de la formación del hipocampo (CA1 y CA3). La radiación podría reducir significativamente (p = 0,000) el número de células en dos regiones del hipocampo . Al parecer, la radiacioón fraccionada de 10 Gy es más eficiente que la fracción única, mientras que el rol de la anestesia debe ser cuidadosamente evaluado. Por otra parte la tasa de reducción de la neurogénesis fue observada en las mismas regiones del hipocampo es decir, con la misma radiosensibilidad de las células.

Cerebral abnormalities in infants with myelomeningocele.

BACKGROUND AND PURPOSE: We evaluated brain abnormalities associated with myelomeningocele in infants. MATERIAL AND METHODS: Between June 1995 and June 2008, 42 patients with myelomeningocele were treated in our hospital. Only 24 patients (13 males, 11 females, mean age 1.5 months, range 1 day - 11 months) were evaluated by both spinal and brain magnetic resonance imaging (MRI) and were enrolled in the study. RESULTS: Brain MRI revealed: hydrocephalus in 21 (87.5%) patients, all of whom required immediate shunting. Total agenesis of the corpus callosum was observed in 2 (8.3%) patients, partial agenesis was seen in 4 (17%) patients and 8 (34%) patients had dysplasia of the corpus callosum. Absence of the septum pellucidum was observed in 2 (8%) patients. Widening of the interhemispheric fissure and colpocephaly were noted in 10 (41%) and in 3 (12%) patients, respectively. Abnormal white matter maturation was observed in 2 (8%) patients. Small posterior fossa was observed in 18 (74%) patients, Chiari malformation in 16 (67%) patients, cerebellar and brain stem hypoplasia in 3 (12%) and 7 (30%) patients, respectively. CONCLUSIONS: MRI examination of the myelomeningocele site is not sufficient. Clinicians should consider obtaining imaging studies of the entire neuraxis in patients with myelomeningocele.

Hippocampal abnormalities in malformations of cortical development: MRI study.

OBJECTIVES: Hippocampal abnormalities may coexist with malformations of cortical development (MCD). This cross-sectional MRI study aimed at categorizing hippocampal abnormalities in a large group of MCD and comparing MCD patients with (group W) and without (group W/O) hippocampal abnormalities. METHODS: Hippocampal anatomy, rotation, size, internal structure, and MRI signal alterations were assessed visually by 3 independent raters in patients with MCD and epilepsy. Four types of hippocampal abnormalities were examined in 220 patients (116 women, mean age 31 +/- 16.6, range 2-76 years): partially infolded/hypoplastic hippocampus (HH), hippocampal sclerosis (HS), malrotated hippocampus (MH), and enlarged hippocampus (EH). The commonest MCD in the cohort were focal cortical dysplasia (27%), polymicrogyria (PMG) (21%), developmental tumors (15%), and periventricular nodular heterotopia (PNH) (14%). RESULTS: Hippocampal abnormalities were seen in 69/220 (31%) patients: HH in 34/69 (49%); HS in 18/69 (26%); MH in 15/69 (22%); and EH in 2/69 (3%). PNH (21/30 [70%]) and PMG (22/47 [47%]) were most commonly associated with hippocampal abnormalities. Compared to the W/O group, patients in the W group had a higher rate of learning disability (W 41/69 [59%] vs W/O 56/151 [37%]; p = 0.003) and delayed developmental milestones (W 36/69 [52%] vs W/O 53/151 [35%]; p = 0.025); groups did not differ otherwise with regard to clinical presentation. HH was associated with symptomatic generalized epilepsies (11/34 [32%]) and high rate of learning disability (27/34 [79%]), neurologic deficits (25/34 [73%]), and delayed developmental milestones (23/34 [68%]). CONCLUSIONS: About a third of patients with malformations of cortical development had hippocampal abnormalities. Patients with hypoplastic hippocampus had the most severe clinical phenotype.

Hippocampal abnormalities in an MR imaging series of patients with tuberous sclerosis.

BACKGROUND AND PURPOSE: Hippocampal abnormalities are known as highly epileptogenic precursor lesions in the general population, primarily manifesting as MTS. The purpose of this study was to evaluate the occurrence of hippocampal abnormalities on MR imaging in patients with TS to explore the possible underlying mechanisms of the abnormalities and to identify the relationship between an abnormal HF and epilepsy. MATERIALS AND METHODS: We studied MR images and clinical data from 31 patients with TS. The MR imaging protocol was identical for all patients and included tilted coronal images of their temporal lobes. The diagnosis of TSC was made according to established criteria. The HFs of the patients were evaluated from coronal images according to size, morphology, and signal intensity. The data were submitted to statistical analysis, and P values < or = .05 were considered significant. RESULTS: We found HF abnormalities in 5 patients. Four had typical MTS, and 1 had HIMAL. We found a positive correlation between childhood febrile seizures and MTS in patients with TS. We also confirmed that patients with altered hippocampi had a tendency to exhibit more cortical tubers. CONCLUSIONS: Analysis of this series of patients demonstrated the presence of HF abnormalities, mainly MTS in patients with TS. We also found that the occurrence of febrile seizures during the first year of life appears to be one of the determining factors for MTS development in these patients.