Altered expression of Alzheimer's disease-related genes in the cerebellum of autistic patients: a model for disrupted brain connectome and therapy.

Autism and Alzheimer's disease (AD) are, respectively, neurodevelopmental and degenerative diseases with an increasing epidemiological burden. The AD-associated amyloid-ß precursor protein-α has been shown to be elevated in severe autism, leading to the 'anabolic hypothesis' of its etiology. Here we performed a focused microarray analysis of genes belonging to NOTCH and WNT signaling cascades, as well as genes related to AD and apoptosis pathways in cerebellar samples from autistic individuals, to provide further evidence for pathological relevance of these cascades for autism. By using the limma package from R and false discovery rate, we demonstrated that 31% (116 out of 374) of the genes belonging to these pathways displayed significant changes in expression (corrected P-values <0.05), with mitochondria-related genes being the most downregulated. We also found upregulation of GRIN1, the channel-forming subunit of NMDA glutamate receptors, and MAP3K1, known activator of the JNK and ERK pathways with anti-apoptotic effect. Expression of PSEN2 (presinilin 2) and APBB1 (or F65) were significantly lower when compared with control samples. Based on these results, we propose a model of NMDA glutamate receptor-mediated ERK activation of α-secretase activity and mitochondrial adaptation to apoptosis that may explain the early brain overgrowth and disruption of synaptic plasticity and connectome in autism. Finally, systems pharmacology analyses of the model that integrates all these genes together (NOWADA) highlighted magnesium (Mg(2+)) and rapamycin as most efficient drugs to target this network model in silico. Their potential therapeutic application, in the context of autism, is therefore discussed.

Rat brain myo-inositol 3-phosphate synthase is a phosphoprotein.

The therapeutic effects of lithium in bipolar disorder are poorly understood. Lithium decreases free inositol levels by inhibiting inositol monophosphatase 1 and myo-inositol 3-phosphate synthase (IPS). In this study, we demonstrate for the first time that IPS can be phosphorylated. This was evident when purified rat IPS was dephosphorylated by lambda protein phosphatase and analyzed by phospho-specific ProQ-Diamond staining and Western blot analysis. These techniques demonstrated a mobility shift consistent with IPS being phosphorylated. Mass spectral analysis revealed that Serine-524 (S524), which resides in the hinge region derived from exon 11 of the gene, is the site for phosphorylation. Further, an antibody generated against a synthetic peptide of IPS containing monophosphorylated-S524, was able to discriminate the phosphorylated and non-phosphorylated forms of IPS. The phosphoprotein is found in the brain and testis, but not in the intestine. The intestinal IPS isoform lacks the peptide bearing S524, and hence, cannot be phosphorylated. Evidences suggest that IPS is monophosphorylated at S524 and that the removal of this phosphate does not alter its enzymatic activity. These observations suggest a novel function for IPS in brain and other tissues. Future studies should resolve the functional role of phospho-IPS in brain inositol signaling.

Potential teratogenic effects of ultrasound on corticogenesis: implications for autism.

The phenotypic expression of autism, according to the Triple Hit Hypothesis, is determined by three factors: a developmental time window of vulnerability, genetic susceptibility, and environmental stressors. In utero exposure to thalidomide, valproic acid, and maternal infections are examples of some of the teratogenic agents which increase the risk of developing autism and define a time window of vulnerability. An additional stressor to genetically susceptible individuals during this time window of vulnerability may be prenatal ultrasound. Ultrasound enhances the genesis and differentiation of progenitor cells by activating the nitric oxide (NO) pathway and related neurotrophins. The effects of this pathway activation, however, are determined by the stage of development of the target cells, local concentrations of NO, and the position of nuclei (basal versus apical), causing consequent proliferation at some stages while driving differentiation and migration at others. Ill-timed activation or overactivation of this pathway by ultrasound may extend proliferation, increasing total cell number, and/or may trigger precipitous migration, causing maldistribution of neurons amongst cortical lamina, ganglia, white matter, and germinal zones. The rising rates of autism coincident with the increased use of ultrasound in obstetrics and its teratogenic/toxic effects on the CNS demand further research regarding a putative correlation.

La esquizofrenia como condición neurológica debida a un fallo en la lateralización del cerebro: observaciones macro y microscópicas / Chizophrenia as a neurological condition caused by a failure in the lateralisation of the brain: macro adn microcopic observations

Introducción. La esquizofrenia es una condición definida durante el desarrollo del cerebro. En esta enfermedad, parte de la sintomatología se asemeja a un trastorno afásico. Estudios recientes sugieren que las estructuras del cerebro que definen las funciones del lenguaje están lateralizadas de manera anormal en pacientes esquizofrénicos. Objetivos. Revisar la bibliografía médica buscando evidencia sobre posibles anormalidades en las asimetrías del cerebro en pacientes esquizofrénicos y discutir un nuevo concepto con respecto a la organización jerárquica de la corteza. Desarrollo. Al revisar la bibliografía hemos de tomar en consideración la limitación de cada técnica. Hasta el presente, los estudios de neuroimagen proporcionan datos más creíbles que aquellos que se derivan de series de autopsia. Sin embargo, ambos métodos, neuroimagen y estudios post mortem, presentan datos consistentes con la presencia de una minicolumnopatía en la esquizofrenia. Las minicolumnas definen conexiones corticocorticales que, a través del proceso evolutivo (encefalización), proporcionan la oportunidad de que áreas corticales homólogas adquieran su independencia. Esta nueva manera de pensar, derivada de conceptos sobre la modularidad cortical, ilumina posibles mecanismos que dan lugar a la dominancia cerebral y a cómo éstos pueden estar alterados en la esquizofrenia. Conclusiones. Aunque no hay hallazgos patognomónicos en la esquizofrenia, la mayoría de estudios sugieren la presencia de un fallo en la lateralización del cerebro. Si se comprueba esta conclusión, convendría reevaluar nuestras opiniones y empezar a considerar la esquizofrenia como un trastorno neurológico (AU)

Introduction. Schizophrenia is a neurodevelopmentally defined condition. Some of its salient symptomatology refers to language abnormalities that resemble an aphasic disorder. Recent studies suggest that brain structures that define language functions may be abnormally lateralized in schizophrenic patients. Aims. To review the medical literature for evidence of abnormalities of brain asymmetries in schizophrenic patients, and to discuss a new concept regarding the hierarchical organization of the cortex by interlinked minicolumns. Development. When reviewing the literature the limitation of applied techniques have to be taken into consideration. As of present, neuroimaging methods provide more credible data than those derived from autopsy series. Both neuroimaging and postmortem studies are consistent with the presence of a possible minicolumnopathy in schizophrenia. Minicolumns define a bias in corticocortical connections that throughout encephalization provide the opportunity for homologous cortical areas to become independent of each other. This new paradigm, derived from concepts of cortical modularity, sheds insights into the putative mechanisms of cerebral dominance and how they may be at fault in schizophrenia. Conclusions. Although there are no pathognomonic findings in schizophrenia a considerable majority of studies make reference to the possible presence of abnormal cerebral dominance. If proven, the cadre of articles would suggest reevaluating our views in order to consider schizophrenia as a neurological disorder (AU)

[Schizophrenia as a neurological condition caused by a failure in the lateralisation of the brain: macro and microscopic observations]. / La esquizofrenia como condición neurológica debida a un fallo en la lateralización del cerebro: observaciones macro y microscópicas.

INTRODUCTION: Schizophrenia is a neurodevelopmentally defined condition. Some of its salient symptomatology refers to language abnormalities that resemble an aphasic disorder. Recent studies suggest that brain structures that define language functions may be abnormally lateralized in schizophrenic patients. AIMS: To review the medical literature for evidence of abnormalities of brain asymmetries in schizophrenic patients, and to discuss a new concept regarding the hierarchical organization of the cortex by interlinked minicolumns. DEVELOPMENT: When reviewing the literature the limitation of applied techniques have to be taken into consideration. As of present, neuroimaging methods provide more credible data than those derived from autopsy series. Both neuroimaging and postmortem studies are consistent with the presence of a possible minicolumnopathy in schizophrenia. Minicolumns define a bias in corticocortical connections that throughout encephalization provide the opportunity for homologous cortical areas to become independent of each other. This new paradigm, derived from concepts of cortical modularity, sheds insights into the putative mechanisms of cerebral dominance and how they may be at fault in schizophrenia. CONCLUSIONS: Although there are no pathognomonic findings in schizophrenia a considerable majority of studies make reference to the possible presence of abnormal cerebral dominance. If proven, the cadre of articles would suggest reevaluating our views in order to consider schizophrenia as a neurological disorder.

Von Economo neurons are present in the dorsolateral (dysgranular) prefrontal cortex of humans.

Von Economo neurons (VENs), also known as spindle cells, have been described in layer V of the anterior cingulate (BA 24) and frontoinsular cortex (FI) of humans and other great apes. In the present study we used immunohistochemistry against two specific neuronal markers (NeuN and MAP2) in order to establish the presence of these cell types in Brodmann area 9 (BA 9) of the human prefrontal cortex. We evaluated tissue samples of eight human postmortem brains (age range 26-50) from BAs 9, 24, 4, 46, 45, 10 and 17. We identified a group of cells with similar morphology to that previously described for VENs in all specimens of BA 9 examined, albeit less frequently than in BA 24. This is the first description of this cell type in a human brain area with well developed granular layers (BA 9).

Deciphering the lithium transcriptome: microarray profiling of lithium-modulated gene expression in human neuronal cells.

The mechanisms underlying lithium's therapeutic efficacy in the chronic treatment of bipolar disorder are not clearly understood. Useful insights can be obtained by identifying genes that are differentially regulated during chronic lithium treatment. Toward this end, we have used microarray technology to identify mRNAs that are differentially expressed in a human neuronal cell line that has been continuously maintained in therapeutic levels of lithium for 33 days. Significantly, unlike other transcriptomes where predominantly rodent cells were used and a limited number of genes probed, we have used human cells probed with more extensive 44,000 gene microarrays. A total of 671 differentially regulated transcripts, after correcting for false discovery rates, were identified, of which 347 and 324, respectively, were found to be up- and downregulated. Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, was the most upregulated while tribbles homolog 3 (TRB3), a pro-apoptotic protein, was the most downregulated, implying a beneficial effect of lithium on neuronal cells. Several of the most highly regulated genes are novel, uncharacterized and encode proteins of unknown function. Differentially expressed genes associated with phosphoinositide metabolism include those encoding phosphatidyl inositol 4-phosphate 5-kinase type II alpha (PIP5K2A), WD repeat domain, phosphoinositide interacting 1 protein (WIPI49), tribbles homolog 3 (TRB3) and sorting nexin 14 (SNX14). A protein interactome using some of the saliently regulated genes identified protein kinase C (PKC) as a major target for lithium action while a global analysis of all 671 differentially expressed genes identified the mitogen-activated protein kinase pathway as the most regulated. The list of highly regulated genes, besides encoding putative targets for antimanic agents, should prove useful in defining novel pathways, or to better understand the mechanisms, underlying the mood stabilization process.

Minicolumnar structure in Heschl's gyrus and planum temporale: Asymmetries in relation to sex and callosal fiber number.

AIM: To investigate the cytoarchitectural basis of asymmetries in human auditory cortex. Minicolumn spacing and number, and regional cortical volume and surface area were measured in the primary auditory region (Heschl's gyrus, HG) and posterior auditory association region (planum temporale, PT) in 17 neurologically normal adults (10 female, seven male). PT surface area, minicolumn spacing and minicolumn number were greater in the left hemisphere. HG surface area was larger in the left hemisphere. Asymmetries of minicolumn number in primary and association auditory regions correlated with axonal fiber numbers in the subregions of the corpus callosum through which they project. PT minicolumn number was more asymmetrical in men than women but total number was similar in the two sexes. We conclude that asymmetry of the surface area of the PT is a function of minicolumn spacing. Fewer callosal projections between the plana are found when the minicolumn spacing is more asymmetrical.

Rett syndrome as a minicolumnopathy.

OBJECTIVE: Rett syndrome is a progressive neurological disorder affecting primarily females. It is characterized by the early regression of acquired language, cognitive functions, social skills, and purposeful hand function. Patients with Rett syndrome are often misdiagnosed as autistic. Recent reports of minicolumnar abnormalities in the brains of autistic and Asperger's syndrome prompted us to search for similar pathology in Rett syndrome. MATERIAL: The patient population consisted of 5 Rett syndrome patients (mean age = 14.4 +/- 4.0 years) and 17 controls (mean age = 14.6 +/- 9.5 years). Tissue was celloidin embedded, sectioned at 35 um and Nissl stained. Images (100x) were taken from Brodmann's areas 9, 21, and 22 from layer III of the left hemisphere. METHOD: Columnar width measurements for these images were obtained with computerized image analysis using previously published algorithms. Each area was analyzed separately with univariate ANOVA, including diagnosis as a fixed factor and age (linear and quadratic terms), and sex as covariates. RESULTS: Diagnosis dependent effects were statistically significant only in area 21 (p = 0.009) even when taking into account a Bonferroni correction for the multiple comparisons. CONCLUSION: Both the regional nature of the changes as well as differences in mean cell spacing differentiates the abnormal minicolumnar morphometry of Rett syndrome from that of autism.

Lateralization of minicolumns in human planum temporale is absent in nonhuman primate cortex.

Gross analyses of large brain areas, as in MRI studies of macroanatomical structures, average subtle alterations in small regions, inadvertently missing significant anomalies. We developed a computerized imaging program to microscopically examine minicolumns and used it to study Nissl-stained slides of normal human, chimpanzee, and rhesus monkey brains in a region of the planum temporale. With this method, we measured the width of cell columns, the peripheral neuropil space, the spacing density of neurons within columns, and the Gray Level index per minicolumn. Only human brain tissue revealed robust asymmetry in two aspects of minicolumn morphology: wider columns and more neuropil space on the left side. This asymmetry was absent in chimpanzee and rhesus monkey brains.

Senile plaques exert no mass lesion effect on surrounding neurons.

Since the turn of the century studies have suggested that clinical deterioration in Alzheimer's disease (AD) is accompanied by a gradual increase in both the size and numbers of senile plaques (SP's). Our study investigated the 'mass effect' of SP's on the morphometry of adjacent neurons. For this purpose, we used a computerized image analysis system to study pyramidal cells from the hippocampus of ten AD patients, ten demented schizophrenic (SC) patients and ten cognitively impaired non-AD/non-SC control patients with. We examined cell shape, area and disarray and quantitated the number of SP's and neurofibrillary tangles (NFT's) in the CA1 subfield of the hippocampus. Our results indicated no significant differences between groups for measurements of neuronal shape, size, or disarray. Contrary to earlier reports, our results noted no evidence of pyramidal cell disarray in schizophrenic patients. Our results suggest that SP's incorporate, rather than displace, their surrounding neuropil.

Morphological differences between minicolumns in human and nonhuman primate cortex.

Our study performed a quantitative investigation of minicolumns in the planum temporale (PT) of human, chimpanzee, and rhesus monkey brains. This analysis distinguished minicolumns in the human cortex from those of the other nonhuman primates. Human cell columns are larger, contain more neuropil space, and pack more cells into the core area of the column than those of the other primates tested. Because the minicolumn is a basic anatomical and functional unit of the cortex, this strong evidence showed reorganization in this area of the human brain. The relationship between the minicolumn and cortical volume is also discussed.

Quantitative analysis of cell columns in the cerebral cortex.

We present a quantified imaging method that describes the cell column in mammalian cortex. The minicolumn is an ideal template with which to examine cortical organization because it is a basic unit of function, complete in itself, which interacts with adjacent and distance columns to form more complex levels of organization. The subtle details of columnar anatomy should reflect physiological changes that have occurred in evolution as well as those that might be caused by pathologies in the brain. In this semiautomatic method, images of Nissl-stained tissue are digitized or scanned into a computer imaging system. The software detects the presence of cell columns and describes details of their morphology and of the surrounding space. Columns are detected automatically on the basis of cell-poor and cell-rich areas using a Gaussian distribution. A line is fit to the cell centers by least squares analysis. The line becomes the center of the column from which the precise location of every cell can be measured. On this basis several algorithms describe the distribution of cells from the center line and in relation to the available surrounding space. Other algorithms use cluster analyses to determine the spatial orientation of every column.

Computer analysis of magnetic resonance imaging of the brain in children and adolescents after treatment of diabetic ketoacidosis.

Cerebral vascular accidents are one of the causes of morbidity and mortality in children with diabetic ketoacidosis. We investigated the possible occurrence of asymptomatic cerebrovascular infarcts and the course of subclinical brain edema in six patients. Neurologic examinations and computer analysis of magnetic resonance imaging were performed immediately after, and again at 14 days after, correction of DKA. None of the patients had clinical evidence of a neurologic deficit. Neither radiologic evaluation nor computer analysis of MRI identified changes indicating asymptomatic ischemic events. However, a computer analysis of the MRI identified a significant increase of the total ventricle area between Day one and Day 14. Our study does not establish whether this change is a return to the baseline prior to DKA or a new baseline, representing an early manifestation of diabetic encephalopathy.

Planum temporale asymmetry reversal in schizophrenia: replication and relationship to gray matter abnormalities.

OBJECTIVE: The planum temporale, the posterior superior surface of the superior temporal gyrus, is a highly lateralized brain structure involved with language. In schizophrenic patients the authors previously found consistent reversal of the normal left-larger-than-right asymmetry of planum temporale surface area. The original subjects plus new patients and comparison subjects participated in this effort to replicate and extend the prior study. METHOD: High-resolution magnetic resonance imaging of 28 schizophrenic patients and 32 group-matched normal subjects was performed. The authors measured planum temporale surface area, gray matter volume underlying the planum temporale, and gray matter thickness. Asymmetry indices for areas and volumes were calculated. RESULTS: Overall gray matter and total brain volume were not significantly smaller in the patients than in the comparison subjects. As previously reported, there was striking reversal of the normal asymmetry for planum temporale surface area in the male and female schizophrenic subjects. Bilaterally, gray matter volume beneath the planum temporale was smaller in the schizophrenic patients, and the gray matter thickness of the right planum temporale was only 50% of the comparison value. Volume of planum temporale gray matter did not show significant asymmetry in either group. CONCLUSIONS: This study extends the finding of reversed planum temporale surface area asymmetry in schizophrenic patients and clarifies its relationship to underlying gray matter volume. Although right planum temporale surface area is larger than normal in schizophrenia, gray matter volume is less than the comparison value; thus, gray matter thickness is substantially less than normal.

The temporolimbic system theory of paranoid schizophrenia.

The hippocampus serves as a funnel for heavily processed sensory information that has converged at the entorhinal cortex. Lesions of the hippocampus do not alter incoming sensory or motor information but, rather, alter their integration with our baggage of emotional experiences and social values. According to Bogerts, such a lesion would be ideally situated to result in laboriously processed sensory information that is out of context to our outside environment. In this regard, Bogerts describes the pathological findings of a patient with a gross delusional disorder. The salient finding at autopsy was a developmental lesion in the left posterior parahippocampal gyrus. Although a number of lesions have been described in the brains of patients with schizophrenia, Bogerts believes that those in the limbic system appear critical to the expression of paranoid symptoms.

Functional and anatomical aspects of prefrontal pathology in schizophrenia.

Neuropathology is a field that correlates autopsy findings to clinical symptomatology. Since the brain has an inordinate number of parceled regions, each having a different function, it makes more sense to work in an inverse fashion and use clinical findings to establish pathological correlations. In this regard, a lesion in the prefrontal lobes can explain some of the salient findings in schizophrenia, for example, scrambled language, disordered thinking, and abnormal behavior. Recent quantitative cytoarchitectural observations by Goldman-Rakic and Selemon sustain such a correlation. By using a computerized image analysis system, these authors have described an abnormally high neuronal density and reduced cortical thickness in many of their patients with schizophrenia. The importance of these findings is discussed in terms of the recent schizophrenia literature.