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PubMed2001

[Risk for schizophrenia and diagnostic image of cerebral membrane metabolism].

In recent years neurobiological research on the etiology of schizophrenia has became increasingly important. In terms of a vulnerability-stress model, structural and functional cerebral alterations in schizophrenics and subjects with a genetic risk for schizophrenia are presented together with hypotheses for disturbances of neurodevelopment or neurodegeneration developed from these implications. A detailed description follows of a neurobiochemical paradigm on the disturbance of metabolism of membrane-phospholipids. 31Phosphorous Magnetic Resonance Spectroscopy allows the detection of indicators of this possible endo-phenotype. The possibilities and limitations of this method are explained, as are findings up to the present. Finally, it is discussed that specific pre-, peri- and postnatal influences on the cerebral metabolism of lipids, and thus on cerebral development, may be related to structural and functional cerebral changes in schizophrenia.

Biomarkers↗

PubMed1989

Is there atypical handedness in schizophrenia?

Ninety-three schizophrenic patients and 105 normal controls were tested in a single session on an 8-item repeat-administration handedness test. The schizophrenic group, in contrast to the normal controls, showed a shift in the distribution away from right-handedness, which was due to an increase in the proportion of mixed-handers. Additional analyses revealed that the increase in mixed-handedness was largely due to an increase of within-item variability in the schizophrenic group, which we refer to as ambiguous handedness. Nearly 20% of the schizophrenic patients were inconsistent on 3 or more items compared with 3.8% of the normal controls. This increased incidence of atypical handedness is discussed within the context of disorders of attention and neurodevelopment.

Adult↗

PubMed2000

Sexual orientation and handedness in men and women: a meta-analysis.

Recent findings suggest that sexual orientation has an early neurodevelopmental basis. Handedness, a behavioral marker of early neurodevelopment, has been associated with sexual orientation in some studies but not in others. The authors conducted a meta-analysis of 20 studies that compared the rates of non-right-handedness in 6,987 homosexual (6,182 men and 805 women) and 16,423 heterosexual (14,808 men and 1,615 women) participants. Homosexual participants had 39% greater odds of being non-right-handed. The corresponding values for homosexual men (20 contrasts) and women (9 contrasts) were 34% and 91%, respectively. The results support the notion that sexual orientation in some men and women has an early neurodevelopmental basis, but the factors responsible for the handedness-sexual orientation association require elucidation. The authors discuss 3 possibilities: cerebral laterality and prenatal exposure to sex hormones, maternal immunological reactions to the fetus, and developmental instability.

Brain↗

PubMed1997

Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice.

Formation of the mammalian brain requires choreographed migration of neurons to generate highly ordered laminar structures such as those in the cortices of the forebrain and the cerebellum. These processes are severely disrupted by mutations in reelin which cause widespread misplacement of neurons and associated ataxia in reeler mice. Reelin is a large extracellular protein secreted by pioneer neurons that coordinates cell positioning during neurodevelopment. Two new autosomal recessive mouse mutations, scramble and yotari have been described that exhibit a phenotype identical to reeler. Here we report that scrambler and yotari arise from mutations in mdab1, a mouse gene related to the Drosophila gene disabled (dab). Both scrambler and yotari mice express mutated forms of mdab1 messenger RNA and little or no mDab1 protein. mDab1 is a phosphoprotein that appears to function as an intracellular adaptor in protein kinase pathways. Expression analysis indicates that mdab1 is expressed in neuronal populations exposed to Reelin. The similar phenotypes of reeler, scrambler, yotari and mdab1 null mice indicate that Reelin and mDab1 function as signalling molecules that regulate cell positioning in the developing brain.

Animals↗

PubMed2005

A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development.

Disrupted-In-Schizophrenia-1 (DISC1), originally identified at the breakpoint of a chromosomal translocation that is linked to a rare familial schizophrenia, has been genetically implicated in schizophrenia in other populations. Schizophrenia involves subtle cytoarchitectural abnormalities that arise during neurodevelopment, but the underlying molecular mechanisms are unclear. Here, we demonstrate that DISC1 is a component of the microtubule-associated dynein motor complex and is essential for maintaining the complex at the centrosome, hence contributing to normal microtubular dynamics. Carboxy-terminal-truncated mutant DISC1 (mutDISC1), which results from a chromosomal translocation, functions in a dominant-negative manner by redistributing wild-type DISC1 through self-association and by dissociating the DISC1-dynein complex from the centrosome. Consequently, either depletion of endogenous DISC1 or expression of mutDISC1 impairs neurite outgrowth in vitro and proper development of the cerebral cortex in vivo. These results indicate that DISC1 is involved in cerebral cortex development, and suggest that loss of DISC1 function may underlie neurodevelopmental dysfunction in schizophrenia.

Animals↗

PubMed1995

The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation.

A major challenge for human genetics is to identify new causes of mental retardation, which, although present in about 3% of individuals, is unexplained in more than half of all cases. We have developed a strategy to screen for the abnormal inheritance of subtelomeric DNA polymorphisms in individuals with mental retardation and have detected three abnormalities in 99 patients with normal routine karyotypes. Pulsed-field gel electrophoresis and reverse chromosome painting showed that one case arose from an interstitial or terminal deletion and two from the de novo inheritance of derivative translocation chromosomes. At least 6% of unexplained mental retardation is accounted for by these relatively small chromosomal abnormalities, which will be an important resource in the characterization of the genetic basis of neurodevelopment.

Adult↗

PubMed2006

Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia.

Recent molecular genetics studies implicate neuregulin 1 (NRG1) and its receptor erbB in the pathophysiology of schizophrenia. Among NRG1 receptors, erbB4 is of particular interest because of its crucial roles in neurodevelopment and in the modulation of N-methyl-D-aspartate (NMDA) receptor signaling. Here, using a new postmortem tissue-stimulation approach, we show a marked increase in NRG1-induced activation of erbB4 in the prefrontal cortex in schizophrenia. Levels of NRG1 and erbB4, however, did not differ between schizophrenia and control groups. To evaluate possible causes for this hyperactivation of erbB4 signaling, we examined the association of erbB4 with PSD-95 (postsynaptic density protein of 95 kDa), as this association has been shown to facilitate activation of erbB4. Schizophrenia subjects showed substantial increases in erbB4-PSD-95 interactions. We found that NRG1 stimulation suppresses NMDA receptor activation in the human prefrontal cortex, as previously reported in the rodent cortex. NRG1-induced suppression of NMDA receptor activation was more pronounced in schizophrenia subjects than in controls, consistent with enhanced NRG1-erbB4 signaling seen in this illness. Therefore, these findings suggest that enhanced NRG1 signaling may contribute to NMDA hypofunction in schizophrenia.

Animals↗

PubMed1993

Schizophrenia: a neurodevelopmental perspective.

The role of aberrant neurodevelopment in the etiology of schizophrenia is reviewed in light of recent neuropathologic, neurochemical, and neuroimaging evidence of cerebral abnormalities in schizophrenic patients. There may exist some genetic defect in the control of brain development. Clinical epidemiologic surveys highlight the importance of obstetric complications, and prenatal exposure to influenza epidemics in contributing to these abnormalities. It is suggested that such environmental hazards and aberrations in the control of early brain development produce the neuronal phenotype that manifests as schizophrenia with early age of onset of symptoms associated with soft neurologic signs and is more common in young males.

Brain Chemistry↗

PubMed2026

Individualized antisense oligonucleotides for SCN2A-related developmental epileptic encephalopathy.

SCN2A variants are among the most common genetic causes of developmental and epileptic encephalopathies (DEEs), which can present with uncontrolled seizures at birth and account for 1-2% of all epileptic encephalopathies. A substantial fraction of causal variants are gain-of-function or mixed-function variants associated with increased channel open probability or greater sodium current flux. Here two parallel n = 1 clinical studies were conducted in two patients (9-year-old and 14-year-old boys) with SCN2A-related DEE. Individualized allele-selective antisense oligonucleotides (ASOs) were designed to target heterozygous intronic single-nucleotide polymorphisms (SNPs) for decreased expression of mutant SCN2A transcript while preserving the wild-type copy. Primary endpoints included quantitative change from baseline in seizure frequency and neurodevelopment, including motor scores. Efficacy measures were also individualized to each patient's phenotype, including refractory seizures, developmental delay, autism spectrum disorder, choreoathetosis and gastrointestinal dysfunction. Patients experienced a reduction in seizure frequency (26% and 90% in the two patients, respectively), decreased use of concomitant medications and improvement in neurodevelopmental skills. Both ASOs were well tolerated, with no ASO-related serious adverse events. Continued long-term follow-up of these preliminary positive safety and efficacy findings is needed to confirm the disease-modifying potential of these ASOs. Haplotype phasing in a separate cohort of infants with SCN2A-related disorder (SCN2A-RD), diagnosed by rapid whole-genome sequencing, identified 16% of patients with compatible SNPs. These data provide a pathway from n = 1 to n of more patients with SCN2A-RD and other monogenic disorders. ClinicalTrials.gov registration: NCT06314490 .

Adolescent↗

PubMed2026

Sex-specific biological aging clocks across organs and omics.

Sex differentially shapes aging, neurodevelopment and neurodegenerative diseases such as Alzheimer's disease (AD). However, most biological aging clocks (artificial intelligence-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance.Here we developed 38 sex-specific biological aging clocks across 15 organ systems. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references and then reveal marked divergence between female and male clocks. Key genetic parameters and Mendelian randomization results indicate that organ-specific aging liability and its relationships to cardiometabolic, endocrine and mental traits are configured differently in females and males. Proteomic analyses identify distinct, organ-resolved synaptic, immune, vascular and metabolic networks that differentially track female and male biological aging. In longitudinal survival analyses, sex-specific clocks predict whole-body systemic diseases and all-cause mortality in a sex-dependent and organ-dependent manner. Further analyses reveal sex-dependent associations between the brain aging clock and cognitive decline trajectory during a preclinical AD clinical trial. Sex-stratified clocks may offer distinct value by defining biological age against sex-appropriate normative references and revealing sex-dependent genetic, molecular and clinical signatures that pooled models may obscure. Meanwhile, sex-pooled and sex-interaction approaches remain valuable, as human aging and disease also share fundamental biological similarities between females and males. Together, these findings reveal sex-specific biological aging signatures in aging, AD and systemic health, highlighting the need for explicitly sex-stratified modeling approaches.

Journal Article↗

PubMed2026

Prenatal cell-free DNA methylome detects association with autism and maternal obesity.

Early identification of autism spectrum disorder (ASD) remains a critical challenge, particularly in utero when non-genetic factors such as maternal obesity (MO) are implicated. Here, we report results of whole-genome bisulfite sequencing of cell-free DNA (cfDNA) from third-trimester maternal plasma in a high-likelihood ASD pregnancy cohort associated with child (3 y) ASD diagnosis and/or MO. Differentially methylated regions (DMRs) between ASD and control cfDNA are strongly enriched for synaptic functions and genes previously implicated in ASD. These cfDNA ASD DMRs recapitulate those observed in ASD placenta and postmortem cortex and significantly overlap with MO DMRs. Our findings establish cfDNA methylation derived from maternal blood as a minimally invasive window into fetal brain ASD etiology, providing a framework for future mechanistic and early intervention studies. Future studies could investigate additional prenatal environmental exposures interacting with genetics during neurodevelopment.

Journal Article↗

PubMed2003

Postnatal brain development and neural cell differentiation modulate mitochondrial Bax and BH3 peptide-induced cytochrome c release.

Bax mediates cytochrome c release and apoptosis during neurodevelopment. Brain mitochondria that were isolated from 8-day, 17-day, and adult rats displayed decreasing levels of mitochondrial Bax. The amount of cytochrome c released from brain mitochondria by a peptide containing the BH3 cell death domain decreased with increasing age. However, approximately 60% of cytochrome c in adult brain mitochondria could be released by the BH3 peptide in the presence of exogenous human recombinant Bax. Mitochondrial Bax was downregulated in PC12S neural cells differentiated with nerve growth factor, and mitochondria isolated from these cells demonstrated decreased sensitivity to BH3-peptide-induced cytochrome c release. These results demonstrate that immature brain mitochondria and mitochondria from undifferentiated neural cells are particularly sensitive to cytochrome c release mediated by endogenous Bax and a BH3 death domain peptide. Postnatal developmental changes in mitochondrial Bax levels may contribute to the increased susceptibility of neurons to pathological apoptosis in immature animals.

Animals↗

PubMed1997

Effect of increasing breast milk docosahexaenoic acid on plasma and erythrocyte phospholipid fatty acids and neural indices of exclusively breast fed infants.

OBJECTIVES: To determine the effect of increasing docosahexaenoic acid (DHA, 22:6 n-3) in breast milk on infant fatty acid profiles. A secondary aim was to examine aspects of neural development. DESIGN AND SETTING: Double blind, placebo controlled study of infants recruited from postnatal wards at Flinders Medical Centre. SUBJECTS: Fifty-two healthy term infants who were breast fed for at least 12 weeks and were from middle class families. INTERVENTION: Breast milk with DHA concentrations that ranged from 0.1-1.7% of total fatty acids. This was achieved by supplementation of the maternal diet for the first 12 weeks post partum. RESULTS: Breast milk with DHA was related to infant plasma (r = 0.89, P < 0.001) and erythrocyte (r = 88, P < 0.001) phospholipids in a saturable curvilinear manner so that breast milk DHA above 0.8% of total fatty acids resulted in little further increase in infant plasma or erythrocyte DHA levels. The rise in plasma and erythrocyte DHA was approximated by a fall in total n-6 polyunsaturated fatty acids. We could detect no relationship between visual evoked potential acuity (measured at 12 and 16 weeks) of infants by either the dietary grouping or the DHA status of individuals. A stepwise multiple regression showed that infant erythrocyte DHA at 12 weeks and home stimulation were the only independent factors associated with Bayley's MDI at 1 y (adjusted model r2 = 0.18, P < 0.005); while at 2 y gender and social score of the spouse were the only significant predictors of Bayley's MDI (adjusted model r2 = 0.22, P < 0.005). CONCLUSIONS: Increasing breast milk DHA levels caused a dose dependent saturable increase in infant plasma and erythrocyte phospholipid DHA. There were no long-term effects of infant DHA status on indices of neurodevelopment.

Breast Feeding↗

PubMed2006

Influence of serotonin receptor 2A His452Tyr polymorphism on brain temporal structures: a volumetric MR study.

Serotonin (5-HT) receptors 2A are expressed in brain regions involved in memory and learning processes. Recently, a functional single nucleotide polymorphism in the 5-HT2A receptor gene leading to an amino-acid substitution at residue 452 (His452Tyr) has been involved in memory performance, persons with the rare 452Tyr allele showing poorer memory performance compared to His452His subjects. To investigate a putative structural effect of this polymorphism on temporal areas typically involved in memory processes, we performed voxel-based morphometry (VBM) and region-of-interest (ROI) volumetric analysis on high-resolution magnetic resonance images in 15 carriers and 61 noncarriers of the 452Tyr allele. ROI volumetric analysis showed a significant reduction of the fractional volume of the temporal white matter in 452Tyr carriers (0.67+/-0.07 vs 0.73+/-0.08; P=0.007). VBM confirmed this finding and in addition showed reduced grey matter in the left hippocampus, left inferior temporal gyrus, and bilaterally in the middle and superior temporal gyrus. A possible effect on synaptic plasticity or neurodevelopment might explain the influence of the His452Tyr polymorphism on temporal brain structures, and this might be the basis for poorer memory performance in 452Tyr carriers. These findings should be considered preliminary and future replication is needed.

Adult↗

PubMed2005

Neurobehavioral assessment predicts differential outcome between VLBW and ELBW preterm infants.

OBJECTIVE: To evaluate the impact of birth weight on development of very low birth weight (VLBW) infants using the Neurobehavioral Assessment of the Preterm Infant (NAPI) before hospital discharge, and to show the relation to follow-up outcomes at 12, 18 and 30 months of age. STUDY DESIGN: In total, 113 preterm infants were assessed with the NAPI at 36 weeks postmenstrual age. Later, neurodevelopment was examined using the Bayley Infant Neurodevelopmental Screener (BINS) at 12 months and the Bayley Scales of Infant Development, at 18 and 30 months. The cohort was divided into two groups, based on birth weight, extremely low birth weight (ELBW) (<1000 g) and VLBW (1000 to 1500 g). RESULTS: ELBW infants showed significantly lower NAPI scores compared with VLBW infants at 36 weeks. The predischarge NAPI scores correlated with the 12, 18 and 30 months scores when the ELBW infants continue to have lower performance than the VLBW infants. In all, 14 infants developed cerebral palsy. These infants had significantly lower NAPI, BINS and Bayley scores compared with all other preterm infants. CONCLUSION: NAPI before discharge provides clinically meaningful information related to later neurodevelopmental outcome.

Birth Weight↗

PubMed2000

Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia.

Schizophrenia is a heterogeneous disease involving genetic and environmental factors. The frequency of structural brain abnormalities or physical anomalies supports a neurodevelopmental etiology, especially in early onset schizophrenia. Brain-Derived-Neurotrophic-Factor (BDNF) is involved in the neurodevelopment of dopaminergic (DA)-related systems and interacts with the meso-limbic DA systems, involved in the therapeutic response to antipsychotic drugs and substance abuse. In addition, BDNF promotes and maintains dopamine D3 receptor (DRD3) expression. In a French Caucasian population, we found no statistical difference in allele or genotype distribution of the BDNF gene dinucleotide repeat polymorphism (166-174 bp) between the whole group of schizophrenic patients and controls. By contrast, an excess of the 172-176 bp alleles was found in patients with late onset, in neuroleptic-responding patients and in non-substance-abusing patients. BDNF gene variants thus appear to be associated with developmental features of schizophrenia. In addition, this association with good treatment responding was independent from the association found with the DRD3 Ball gene polymorphism in the same population. These results suggest an independent contribution of each gene to a treatment-sensitive form of schizophrenia.

Adult↗

PubMed2001

Role of the serotonin transporter gene in the behavioral expression of autism.

The promoter polymorphism of the serotonin transporter gene (HTT, locus SLC6A4) is of special interest in autism given the well-replicated platelet hyperserotonemia of autism, treatment effects of serotonin reuptake inhibitors, and the role of serotonin in limbic functioning and neurodevelopment. Parent-offspring transmission of the long (l) and short (s) alleles of the deletion/insertion polymorphism in the HTT promoter region was examined in families of 71 children with autism using the transmission test for linkage disequilibrium (TDT). Transmission of HTT promoter alleles did not differ between probands with autism and their unaffected siblings. However, allelic transmission in probands was dependent upon severity of impairments in the social and communication domains, with greater s allele transmission in severely impaired individuals and greater l transmission in mild/moderately impaired individuals. This relationship between HTT promoter alleles and severity of autistic impairment was also seen when ratings of social and communication behaviors were compared across genotypes. The data indicate that HTT promoter alleles by themselves do not convey risk for autism, but, rather, modify the severity of autistic behaviors in the social and communication domains. The results require replication and, given the size of the groups and subgroups examined, must be considered still preliminary. The results suggest that future research on the genetics of autism should carefully assess each of the major behavioral domains and seriously consider the possible role of modifying loci.

Adolescent↗

PubMed2003

Linkage of schizophrenia with chromosome 1q loci in Taiwanese families.

A positive linkage of schizophrenia with chromosome 1q loci has been reported in Caucasian patients. This study was designed to evaluate the linkage of schizophrenia with markers of the 1q22-44 region in 52 Taiwanese families with at least two affected siblings. In the region 1q22-31 (17.8 cM), marker D1S1679 had a maximal proportion (0.57, P=0.03) of shared identity by descent (IBD) under a narrow phenotype (DSM-IV schizophrenia only). In the region 1q42-44 (26.8 cM), the marker D1S251, located near the breakpoint of a balanced translocation t (1;11) (q42.1;q14.3) segregated with schizophrenia, and also near the neurodevelopment-related 'Disrupted in Schizophrenia 1' gene, had a maximum NPL score of 1.73 (P=0.03) under the narrow phenotype model and 2.18 (P=0.01) under the broad phenotype model comprised of schizophrenia, schizoaffective disorder, and other nonaffective psychotic disorders as defined by DSM-IV criteria. The marker D1S2836 also had a maximal proportion (0.57, P=0.05) of shared IBD under the broad model. These findings may provide guidance for positional cloning studies on candidate genes in the 1q22-31 and 1q41-44 regions.

Asian People↗