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PubMed2005

The International Infant Hydrocephalus Study: concept and rational.

INTRODUCTION: During the recent meetings of the International Study Group on Neuroendoscopy and the International Society for Pediatric Neurosurgery, the consensus view emerged that there is a need to assess the value and efficacy of neuroendoscopic procedures against shunting in a scientific manner, to resolve long-lasting debates on the subject. MATERIAL AND METHODS: A prospective randomized, controlled trial of endoscopic third ventriculostomy vs shunting in children presenting under the age of 2 years with pure aqueduct stenosis is been proposed and organized (the International Infant Hydrocephalus Study, IIHS). The participating surgeons must adhere to the philosophy of randomization and be suitably experienced in endoscopic techniques in infants. The primary outcome of the trial will be the overall health-related quality of life of these children at 5 years of age. Hence, the study is focusing on the effect of surgery on neurodevelopment, rather than the less important issue of shunt or stoma survival, that has been debated extensively with no conclusion so far. Intention-to-treat analysis will be performed according to the first surgery. Secondary outcomes such as complication and reoperation rate, total hospitalization time and cost, need for repeat imaging, and others will be analyzed as well. RESULTS: Pure aqueduct stenosis is relatively rare, making recruitment problematic, but has been chosen to avoid other confounding factors that could influence outcome. More than 25 centers worldwide have committed already to patient recruitment to the study. It is anticipated that recruitment will last for 2 years, aiming for 91 patients per arm. The study has started recruiting patients already in some countries. CONCLUSION: It is hoped that the trial will not only provide answers to unsettled debates on the value of neuroendoscopy but also create a network of collaborating pediatric neurosurgeons for future initiatives.

Cerebral Aqueduct↗

PubMed1996

Glial fibrillary acidic protein-immunoreactive astrocytosis in elderly patients with schizophrenia and dementia.

Clinical and neuropsychological studies of chronically institutionalized patients with schizophrenia indicate that severe cognitive impairment and functional disability in late life are very prevalent. The biological substrates for this dementia remain unknown. While subtle cytoarchitectural and morphometric abnormalities have been described in patients with schizophrenia and interpreted as reflecting aberrant neurodevelopment, postmaturational injury or neurodegeneration associated with gliosis remain as plausible explanations of at least some of the clinical manifestations of schizophrenia. We monitored astrocytosis and neurofibrillary tangle (NFT) formation in 21 elderly patients with schizophrenia (14 with concurrent dementia, 7 without), and in 12 normal and 5 Alzheimer's disease (AD) control cases. Astrocytes in ventromedial temporal, frontal, and calcarine cortices were immunohistochemically identified with monoclonal antibodies directed at glial fibrillary acidic protein (GFAP) and vimentin, and NFTs were labeled with an anti-tau antibody specific for paired helical filaments. There were no increases in GFAP- or vimentin-immunoreactive astrocyte counts, GFAP optical density, or NFT counts for the schizophrenic group as a whole compared to the non-neuropsychiatric group, while both groups differed from AD. When patients with schizophrenia were divided into demented and non-demented subtypes, those with dementia demonstrated significantly greater numbers of GFAP-positive astrocytes than those without dementia. These data may reflect an up-regulation of GFAP in normal astrocytes or the presence of reactive astrocytosis in a subgroup of schizophrenics. In the absence of any diagnostic neuropathological findings in this subgroup, the implications of these observations for the pathogenesis of schizophrenia remain to be determined.

Aged↗

PubMed1996

Recent advances in defining the neuropathology of schizophrenia.

The search for the defining neuropathology of schizophrenia continues to be one of the highest priority areas of research into this severely debilitating and common neuropsychiatric disorder. While lesions that are diagnostic of the disorder have not yet been identified, recent efforts employing molecule-specific probes and quantitative methods of analysis have enumerated many potentially important findings in the brains of patients with schizophrenia that warrant confirmation and elucidation. In this review, the major findings of six broad areas of neuropathological investigation are summarized and discussed. While substantial controversy exists in all areas, in sum: (1) diagnostic neuropathological investigations find only assorted and nonspecific abnormalities in the brains of schizophrenics that are likely to be representative of lesions found in age-compatible control groups; (2) morphometric studies of gross structures generally confirm the clinical in vivo neuroimaging findings of enlarged ventricles, decreased size of ventromedial temporal lobe structures, and decreased parahippocampal cortical thickness; (3) morphometric microscopy studies find frequent alterations in neuron density and decreased neuron size in limbic, temporal, and frontal regions; (4) investigations of connectivity are at an early stage but describe abnormal dendritic spine densities in the cortex, various changes in synaptic vesicle protein expression in limbic, temporal, and frontal cortices, and alterations in glutamatergic, catecholaminergic, and intrinsic innervation in anterior cingulate cortex- together, these findings suggest a "miswiring" in the schizophrenic brain; (5) investigations of aberrant neurodevelopment in schizophrenia describe abnormalities in cortical cytoarchitecture and several developmentally regulated proteins in the hippocampal region suggesting abnormal neuronal migration, differentiation, and/or cell pruning; and (6) studies of neurodegeneration and neural injury find a general lack of neurodegenerative disease lesions or ongoing astrocytosis that would indicate post-maturational neural injury.

Brain↗

PubMed2026

Polygenic risk score for neurodevelopmental disorders and cognitive impairment at long-term follow-up of first-episode psychosis.

BACKGROUND: One of the most outstanding contributions to the understanding of the etiopathogenesis of schizophrenia spectrum disorders (SSD) was the neurodevelopmental hypothesis. SSD and neurodevelopmental disorders (NDD) share pathogenetic mechanisms and overlapping clinical and cognitive impairment features. METHODS: We investigated whether polygenic risk scores (PRSs) for NDD are associated with cognitive performance in patients with first-episode psychosis (FEP). The sample comprised 127 patients with FEP who were followed up for a mean of 20.9 years. Cognitive examination was performed using the MoCA test at follow-up. Pearson coefficient correlations and multiple regression analyses were performed to examine the contribution of the three PRSs for rare neurodevelopmental conditions (PRSNDD), attention-deficit hyperactivity disorder (PRSADHD) and autism spectrum disorder (PRSASD) to cognitive impairment after allowing for the effect of covariates. Furthermore, we examined the interconnections between the PRS for NDD and cognitive impairment using network analysis (NA), including core premorbid variables. RESULTS: PRSNDD showed significant associations with impairment on visuospatial/executive, attention, and language MoCA subtests, after allowing for the influence of covariates. PRSNDD and PRSADHD, but not PRSASD, were significantly associated with worse performance on the total MoCA score. Moreover, in the network analysis, the relationships between PRSs for NDD and cognitive impairment were highly interconnected with premorbid variables and PRSs for schizophrenia and educational attainment. CONCLUSIONS: These results provide evidence for a possible direct genetic effect on cognitive performance for the PRS of common genetic variations related to neurodevelopment and attention deficit hyperactivity disorder in patients with FEP.

Cognitive impairment↗

PubMed2000

Epidemiology of schizophrenia: the global burden of disease and disability.

Evidence from nearly a century of epidemiological research indicates that schizophrenia occurs in all populations with a prevalence in the range of 1.4 to 4.6 per 1000 and incidence rates in the range of 0.16-0.42 per 1000 population. Multi-centre studies conducted by the World Health Organization have highlighted important differences between 'Western' and 'Third World' populations as regards the course and outcome of the disorder, with a significantly better prognosis in the developing countries. The factors underlying the better outcome of schizophrenia in developing countries remain essentially unknown but are likely to involve interactions between genetic variation and specific aspects of the environment. These features place schizophrenia, along with diabetes, cancer and hypertension, into the group of genetically complex diseases which are characterised by polygenic transmission, locus heterogeneity and environmental contribution to causation. The emerging pattern of risk factors and antecedents of schizophrenia suggests multiple, mainly quantitative deviations from the average developmental trajectory, primarily in the areas of early neurodevelopment, cognitive ability and social behaviour. These deviations are compatible with the notion of non-specific background factors facilitating the operation of genetically determined causal pathways. Research likely to result in new insights should focus on the population distribution and behavioural effects of potential risk factors and markers suggested by biological and genetic research.

Cross-Cultural Comparison↗

PubMed2005

Dioxin effects on neonatal and infant thyroid function: routes of perinatal exposure, mechanisms of action and evidence from epidemiology studies.

OBJECTIVES: Animal experiments suggest that thyroid function alterations in newborns and infants may represent one of the most sensitive markers of toxicity from 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dioxin can be transferred from the mother to the offspring either in utero or through lactation. It has been suggested that thyroid-hormone alterations produced by dioxin in utero or shortly after birth may underlie long-term effects, such as cognitive-ability and neurodevelopment impairment. In the present review article, we appraise available evidence on the effects of perinatal exposure to dioxin on fetal and infant thyroid function. METHODS: We summarized the routes of perinatal dioxin exposure and research results on possible mechanisms of dioxin toxic effects on thyroid function. We performed a systematic review of epidemiology studies conducted on mother-child pairs exposed to background environmental levels to investigate dioxin effects on neonatal and infant thyroid function. RESULTS: Toxicological and mechanistic data indicate that dioxin may impair thyroid function in exposed newborns and infants. Investigations on background-exposed children have not consistently demonstrated an association between perinatal TCDD exposure and thyroid function, although some of the studies suggest that sub-clinical hypothyroidism may be induced by perinatal dioxin exposure within 3 months from birth. Between studies inconsistencies may be related to lab method differences, mixed exposures, and small sample size of the populations evaluated. CONCLUSION: Epidemiology studies have as yet failed to demonstrate an association between perinatal TCDD exposure and thyroid function alterations in human subjects, although suggestive evidence from animal and in-vitro experimental data is available.

Dioxins↗

PubMed2004

Nervous system development in normal and atresic chick embryo intestine: an immunohistochemical study.

Intestinal motility disorders are a common complication after surgery for neonatal intestinal atresia. Although intestinal atresia causes alterations in the enteric nervous system, especially in its inner structures (nervous fibers in the mucosa, submucous and deep muscular plexuses), how these alterations develop is unclear. The chick model is a useful research tool for investigating the ontogenesis of the enteric nervous system and the pathogenesis of congenital bowel diseases. More information is needed on the overlap between the developing enteric nervous system and intestinal atresia. Because vasoactive intestinal polypeptide and substance P are typical intestinal neuropeptides, and vasoactive intestinal polypeptide acts as a modulator in neurodevelopment and an inhibitor of smooth muscle cell proliferation, our aim in this study was to investigate the distribution of their immunoreactivity in the developing enteric nervous system of normal and experimental chick models. We studied gut specimens excised from normal chick embryos (aged 12-20 days) and experimental chick embryos (aged 15-20 days) that underwent surgical intervention on day 12 to induce intestinal atresia (atresic embryos) or simply to grasp the bowel loop (sham-operated embryos). In normal chick embryos we showed vasoactive intestinal polypeptide and substance P immunoreactivity from day 12 in the submucous and myenteric plexuses. The distribution of peptide immunoreactivity differed markedly in atresic and normal or sham-operated gut embryos. These differences especially affected the inner structures of the enteric nervous system of specimens proximal to atresia and were related to the severity of dilation. Because nerve structures in the gut wall mucosa and submucous and deep muscular plexuses play a role in motility control and stretch sensation in the intestinal wall, our findings in the chick embryo may help to explain how gut motility disorders develop after surgery for neonatal intestinal atresia.

Animals↗

PubMed2006

Clinical manifestations and neurodevelopmental outcome following an event of accidental intramuscular injection of atracurium in newborns.

UNLABELLED: Pediatric populations are at risk for medication errors that may be associated with mortality and disability. The purpose of this study was to describe the clinical manifestations of seven newborns following an event of accidental intramuscular injection of atracurium and to assess the impact on neurodevelopmental outcome. This study enrolled seven newborns who were accidentally administered 10 mg of atracurium, equivalent to 2.6-3.3 mg/kg, in a local perinatal clinic. Accident reports and hospital records were reviewed to obtain the history and medical data for the event. The survivors were prospectively examined for their growth, health and neurodevelopment until 24 months of age. All newborns showed immediate apnea and cyanosis requiring resuscitation after atracurium injection and presented with respiratory failure and flaccid paralysis on arrival for emergency medical services. One newborn was asystolic despite resuscitation and died of multiple organ failure. Of the five survivors available for follow-up, all achieved favorable growth outcomes. However, four showed mild to significant delay in development; and two manifested mild hypomyelination of cerebral white matter on the brain magnetic resonance imaging. CONCLUSION: Newborns accidentally injected with high doses of atracurium are at risk of death and neurodevelopmental delay. The serious clinical manifestations, developmental delay and cerebral hypomyelination were most likely due to insufficient immediate respiratory assistance following atracurium injection.

Atracurium↗

PubMed2005

Evaluation of the Glucometer Elite XL device for screening for neonatal hypoglycaemia.

UNLABELLED: To prevent persistent neurodevelopment and physical growth deficits in neonatal care, it is mandatory to determine blood glucose levels as quickly and precisely as possible, preferably using micro-methods. However, most commercially available instruments have not been validated and approved for this purpose. The aim of this study was to validate the Glucometer Elite XL, a newly developed device for point-of-care testing (POCT). In samples from 869 newborn infants, glucose levels were simultaneously measured by the Glucometer Elite XL in whole blood and by an accepted clinical laboratory method in haemolysed blood using the ECA 2000 device. An acceptable method agreement was found between the POCT and the ECA 2000 method (mean difference 0.013 mmol/l, SD 0.69). As determined by regression analysis (Passing-Bablok), the slope was 1.086 with a y-intercept of -0.4 mmol/l ( r =0.959, P <0.05). The differences between measurement pairs of both assays versus the haematocrit were negligible. With a cut-off for hypoglycaemia at 2.6 mmol/l glucose in haemolysed blood, the sensitivity of the POCT device was 0.63 and specificity was 0.98. Raising the cut-off of the Glucometer Elite XL to 3.2 mmol/l, the sensitivity and specificity incremented to 1.0 and 0.89, respectively. CONCLUSION: The Glucometer Elite XL instrument can be recommended for point-of-care blood glucose measurement in newborn infants if its character as a screening method is taken into account. To compensate deviating results, we advise to shift its cut-off for hypoglycaemia recognition to a safe threshold of 3.2 mmol/l. However, hypoglycaemia has to be confirmed by a valid glucose measurement in the clinical laboratory.

Blood Chemical Analysis↗

PubMed1999

Cerebral blood flow and neurological outcome in the preterm infant.

UNLABELLED: Cerebral blood flow (CBF) studies have provided some insight into pathophysiological mechanisms of cerebral damage in newborn children; their value in predicting brain damage, however, remains elusive. The purpose of our study was to evaluate the role of CBF measurements in predicting developmental outcome in preterm neonates at 18 months. Preterm babies with a gestational age of less than 34 weeks and a birth weight of less than 1500 g (n = 71) were enrolled in the study. CBF was measured by the noninvasive intravenous 133Xe method on three different occasions. We classified our measurements into three groups: depending on the time when performed group 1: between 2 and 36 h (n = 52); group 2: between 36 and 108 h (n = 44); group 3: between 108 and 240 h (n = 41). At the age of 18 months neurodevelopment testing was performed according to the Bayley mental and motor scales. Surviving infants had a higher mean CBF over the three groups than non surviving children (15.2 +/- 3.5 ml/100 g brain tissue/min vs 13.0 +/- 2.1 ml/100 g brain tissue/min, P < 0.05). There was no correlation of CBF with mental or motor development in our study population in either of the three groups. CONCLUSION: In preterm infants basal CBF is higher in surviving than in non surviving infants, but there is no correlation of resting CBF and later neurological outcome.

Aging↗

PubMed2005

Brain SPECT imaging in children and adolescents with obsessive-compulsive disorder.

OBJECTIVE: To evaluate the patterns of regional cerebral blood flow (rCBF) in cortical and subcortical regions by Brain SPECT imaging, in children and adolescents with obsessive-compulsive disorder (OCD) before and after treatment. METHOD: Fourteen OCD patients (6 to 17 years old) underwent brain SPECT; ten of those subjects were reexamined after successful treatment. rCBF ratios were correlated with clinical parameters on the 14 patients in symptomatic state, and we compared rCBF ratios of the ten patients before and after treatment. RESULTS: There was no statistically significant difference in average ratios of rCBF before and after treatment. There were significant clinical correlations between current age and age of onset of OCD and rCBF in the bilateral superior frontal, and bilateral parietal cortical regions. CONCLUSIONS: Further investigations on abnormal neurodevelopment of cortical-subcortical circuits possibly involved in symptomatology of paediatric OCD are warranted.

Adolescent↗

PubMed2005

Modulation of phospholipase A2 activity in primary cultures of rat cortical neurons.

In neurons, phospholipase A2 (PLA2) plays a central role in the regulation of membrane phospholipid metabolism. We have addressed the pharmacological modulation of PLA2 in primary cultures of rat cortical neurons. Inhibition curves were obtained in 4 day-in-culture neurons treated for 30 minutes with either the dual PLA2 inhibitor methyl arachidonyl fluorophosphonate (MAFP), or the iPLA2 inhibitor bromoenol lactone (BEL). Full inhibition was achieved with 100 and 250 microM of MAFP, or 10 and 20 microM of BEL. Conversely, a dose-dependent activation of PLA2 was obtained with 10-20 microg/ml of melitin. PLA2 inhibition with MAFP or BEL was not acutely toxic for cultured neurons. However, sustained inhibition of the enzyme precluded the development of neurites, and resulted in long-term loss of neuronal viability. We present a model of pharmacological challenge of PLA2 in vitro, which can be further used to address the involvement of the enzyme in neurodevelopment and neurodegeneration models.

Animals↗

PubMed2006

Possible association between nonsynonymous polymorphisms of the anaplastic lymphoma kinase (ALK) gene and schizophrenia in a Japanese population.

We examined, for the first time, the possible association between schizophrenia and the anaplastic lymphoma kinase (ALK) gene which plays an important role in neurodevelopment. When two nonsynonymous polymorphisms (Arg1491Lys and Glu1529Asp) were examined, there were significant differences in genotype and allele distributions between patients and controls. Individuals homozygous for the minor allele (1491Lys-1529Asp) were more common in patients than in controls (p = 0.0064, odds ratio 2.4, 95% CI 1.3-4.6). These results suggest that genetic variations of the ALK gene might confer susceptibility to schizophrenia.

Alleles↗

PubMed2006

Polymorphic GGC repeat differentially regulates human reelin gene expression levels.

The human gene encoding Reelin (RELN), a pivotal protein in neurodevelopment, includes a polymorphic GGC repeat in its 5' untranslated region (UTR). CHO cells transfected with constructs encompassing the RELN 5'UTR with 4-to-13 GGC repeats upstream of the luciferase reporter gene show declining luciferase activity with increasing GGC repeat number (P < 0.005), as predicted by computer-based simulations. Conversely, RELN 5'UTR sequences boost reporter gene expression above control levels in neuronal SN56 and N2A cell lines, but 12- and 13-repeat alleles still yield 50-60% less luciferase activity compared to the more common 8- and 10-repeat alleles (P < 0.0001). RELN "long" GGC alleles significantly blunt gene expression and may, through this effect, confer vulnerability to human disorders, such as schizophrenia and autism.

5' Untranslated Regions↗

PubMed2006

The role of phospholipase A2 in neuronal homeostasis and memory formation: implications for the pathogenesis of Alzheimer's disease.

Phospholipase A(2) (PLA(2)) is a key enzyme in cerebral phospholipid metabolism. Preliminary post-mortem studies have shown that PLA(2) activity is decreased in frontal and parietal areas of the AD brain, which is in accordance with recent (31)P-Magnetic Resonance Spectroscopy evidence of reduced phospholipid turnover in the pre-frontal cortex of moderately demented AD patients. Such abnormality may also be observed in peripheral cells, and reduced PLA(2) activity in platelet membranes of AD patients, and correlates with the severity of dementia. In rat hippocampal slices, PLA(2) has been implicated in mechanisms of synaptic plasticity. In adult rats, the stereotaxic injection of PLA(2) inhibitors in the CA1 area of hippocampus impaired, in a dose-dependent manner, the formation of short- and long-term memory. Additionally, such inhibition resulted in a reduction of the fluidity of hippocampal membranes. In primary cultures of cortical and hippocampal neurons, the inhibition of PLA(2) precluded neurite outgrowth, and the sustained inhibition of the enzyme in mature cultures lead to loss of viability. Taken together, these findings reinforce the involvement of PLA(2) enzymes in neurodevelopment and neurodegeneration processes, and further suggest that reduced PLA(2) activity, probably reducing membrane phospholipids breakdown, may contribute to the memory impairment in AD.

Alzheimer Disease↗

PubMed2002

Hippocampal neurons in schizophrenia.

The hippocampus is crucial for normal brain function, especially for the encoding and retrieval of multimodal sensory information. Neuropsychiatric disorders such as temporal lobe epilepsy, amnesia, and the dementias are associated with structural and functional abnormalities of specific hippocampal neurons. More recently we have also found evidence for a role of the hippocampus in the pathophysiology of schizophrenia. The most consistent finding is a subtle, yet significant volume difference in schizophrenia. Here we review the cellular and molecular basis of smaller hippocampal volume in schizophrenia. In contrast to neurodegenerative disorders, total hippocampal cell number is not markedly decreased in schizophrenia. However, the intriguing finding of a selective loss of hippocampal interneurons deserves further study. Two neurotransmitter receptors, the GABAA and AMPA/kainate glutamate receptors, appear to be abnormal, whereas changes of the NMDA glutamate receptor are less robust. The expression of several genes, including those related to the GABAergic system, neurodevelopment, and synaptic function, is decreased in schizophrenia. Taken together, recent studies of hippocampal cell number, protein expression, and gene regulation point towards an abnormality of hippocampal architecture in schizophrenia.

Glutamic Acid↗

PubMed2004

Binge alcohol consumption by non-alcohol-dependent women during pregnancy affects child behaviour, but not general intellectual functioning; a prospective controlled study.

Effects of binge ethanol consumption during early gestation on child neurodevelopment have not been elucidated. To study whether binge drinking affects cognitive abilities and behavior of exposed children, a prospective observational study comparing 51 children exposed to binge drinking during the first trimester of pregnancy to 51 children not exposed to any teratogens was conducted. The children's physical development, intelligence, language abilities and behavior were assessed. Temperament test results showed that children exposed in utero to maternal binge drinking displayed a greater degree of disinhibited behavior and that this behavior was associated with early drinking variables. Although binge alcohol drinking by non-alcohol-dependent women during the first trimester of pregnancy does not appear to affect intelligence or cognitive and language development of young children, binge drinking in pregnancy does increase the likelihood of certain behavioral characteristics that might predispose these children to later behavioral dysfunction.

Adult↗

PubMed2007

Consequences of prenatal toxin exposure for mental health in children and adolescents: a systematic review.

Drug use during pregnancy is common and the developing foetus may be exposed to a range of environmental toxins that have long-term consequences for neurodevelopment. We conducted a systematic review of the literature to explore the results of longitudinal cohort studies that have examined this question. Out of 2,977 abstracts identified, 7 previous systematic reviews and 95 original articles met further selection criteria. These mostly addressed the neurodevelopmental effects of exposure to lead, polychlorinated biphenyls, mercury, cocaine, alcohol, marijuana, cigarettes and antidepressants. Radiation, opiates, steroids, amphetamines and caffeine have received much less attention. Findings are difficult to interpret because risk factors tend to cluster together and interact. However, some findings are consistent. Lead and PCB's have a general effect on brain development, whilst marijuana and alcohol appear to have long-term effects specifically on attentional skills. The effects of alcohol increase with maternal age and binge drinking is more important than average intake. The effects of cocaine diminish with age and are largely mediated through psychosocial factors, whilst the relation between smoking and later delinquency is largely mediated by genetically inherited factors. Exposure to toxins during pregnancy may constitute an important but relatively unacknowledged cause of child psychiatric morbidity.

Adolescent↗