Genetic determinants of cortical structure (thickness, surface area and volumes) among disease free adults in the CHARGE Consortium

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease

Efeitos da fratura do arco zigomático no crescimento facial em ratos jovens Effect of zygomatic arch fracture on facial growth in young rats<A NAME="home"></A>

Os efeitos da fratura unilateral do arco zigomático no crescimento facial foram avaliados através de mensurações cefalométricas. Fratura com desvio medial no lado direito foi realizada em ratos com um mês de idade. Os animais foram sacrificados com três meses de idade e sua mandíbula foi desarticulada. O crânio foi submetido à tomada radiográfica axial e as hemimandíbulas à norma lateral. As mensurações foram realizadas através de um sistema de computador. Foi verificada diferença significante a menor para a altura do corpo e do ramo da mandíbula. Não houve diferença significante para a profundidade da fossa infratemporal, bem como para as diversas mensurações na maxila e para o comprimento mandibular. A tendência de retorno do arco zigomático com desvio à sua posição original foi confirmada.<br>The effect of unilateral zygomatic arch fracture on facial growth was analysed by means of cephalometric measurements. Medially displaced fracture of the right side was achieved in one month old rats. Reaching three months the animals were sacrified, and their mandibles disarticulated. The skull was submitted to axial radiographic incidence and the hemimandibles to a lateral radiographic incidence. The measurements were made through a computer system. Significant differences were verified with a decrease in body height and ramus of the mandible. There was no significant difference in infratemporal fossae depth, as well as in diverse measurements in maxilla and in mandibular lenght. The tendency of the fractured arch to return to its original position was confirmed

Radioisotopic evaluation of bone repair after experimental surgical trauma Avaliação radiofarmacológica do reparo ósseo após trauma cirúrgico padronizado

BACKGROUND: Scientific approach of the bone reaction after surgical procedures provides valuable information on methods and techniques. The purpose of this study was to follow this process using a radioisotope marker of bone remodelling. MATERIAL AND METHODS: Two bone cavities were created (one for every tibia) in adult Wistar male rats using a 0.5 mm spherical burr; left tibial cavities were filled with bovine freeze-dried bone; the right ones were left unfilled for control. Scintigrams were done with sodium methylene diphosphonate (MDP) labelled with radioactive pertechnetate (99mTcO4-) to evaluate the inflammatory response and the local osteoblastic activity. The evolution of bone repair was additionally evaluated by light microscopy. RESULTS: Our results have shown that the highest bone activity was recorded between the 7th and the 14th day after surgery. The morphological analysis confirmed the results obtained with radioisotope analysis and did not reveal significant differences regarding the evolution of bone repair between the filled and the unfilled defects. CONCLUSION: We confirmed that 99mTc -MDP is a valuable tool to study bone repair, as it was able to show subtle alterations of bone activity even in lesions as small as those created herein (0.5 mm wide, 0.5 mm deep).<br>Este trabalho objetivou estudar a evolução temporal do processo de reparo ósseo em tíbia de rato, após trauma cirúrgico padronizado. A incorporação do radiofármaco 99mTc-MDP na região afetada foi tomada como medida indireta da intensidade de reação tecidual; foi feito também acompanhamento histológico do processo de reparo. Foram realizadas cirurgias nas duas tíbias de 72 animais divididos em 2 grupos, sendo sacrificados em diferentes dias pós-operatórios (1, 3, 7, 14, 21 e 28 dias p.o.). As cavidades criadas nas tíbias esquerdas foram preenchidas com osso liofilizado bovino, e as direitas serviram como controle (não preenchidas). Grupos paralelos de animais foram injetados com 99mTc para avaliar a influência do fluxo sangüíneo regional nos resultados. Duas horas após a injeção dos radiofármacos os animais foram sacrificados, a radiatividade foi contada tanto nos fragmentos das tíbias contendo os defeitos cirúrgicos como em fragmentos intactos de fêmur e de tíbias, como controle. Os resultados indicam que a maior atividade do tecido ósseo ocorreu entre 7 e 14 dias p.o. O emprego do radiofármaco mostrou ser de valor na avaliação do reparo dada sua sensibilidade. Não houve efeito significativo da presença de osso liofilizado sobre a evolução do reparo ósseo