Automated ventricular mapping with multi-atlas fluid image alignment reveals genetic effects in Alzheimer's disease

We developed and validated a new method to create automated 3D parametric surface models of the lateral ventricles in brain MRI scans, providing an efficient approach to monitor degenerative disease in clinical studies and drug trials. First, we used a set of parameterized surfaces to represent the ventricles in four subjects' manually labeled brain MRI scans (atlases). We fluidly registered each atlas and mesh model to MRIs from 17 Alzheimer's disease (AD) patients and 13 age- and gender-matched healthy elderly control subjects, and 18 asymptomatic ApoE4-carriers and 18 age- and gender-matched non-carriers. We examined genotyped healthy subjects with the goal of detecting subtle effects of a gene that confers heightened risk for Alzheimer's disease. We averaged the meshes extracted for each 3D MR data set, and combined the automated segmentations with a radial mapping approach to localize ventricular shape differences in patients. Validation experiments comparing automated and expert manual segmentations showed that (1) the Hausdorff labeling error rapidly decreased, and (2) the power to detect disease- and gene-related alterations improved, as the number of atlases, N, was increased from 1 to 9. In surface-based statistical maps, we detected more widespread and intense anatomical deficits as we increased the number of atlases. We formulated a statistical stopping criterion to determine the optimal number of atlases to use. Healthy ApoE4-carriers and those with AD showed local ventricular abnormalities. This high-throughput method for morphometric studies further motivates the combination of genetic and neuroimaging strategies in predicting AD progression and treatment response. © 2007 Elsevier Inc. All rights reserved.

Automated 3D mapping & shape analysis of the lateral ventricles via fluid registration of multiple surface-based atlases

We developed and validated a new method to create automated 3D parametric surface models of the lateral ventricles, designed for monitoring degenerative disease effects in clinical neuroscience studies and drug trials. First we used a set of parameterized surfaces to represent the ventricles in a manually labeled set of 9 subjects' MRIs (atlases). We fluidly registered each of these atlases and mesh models to a set of MRIs from 12 Alzheimer's disease (AD) patients and 14 matched healthy elderly subjects, and we averaged the resulting meshes for each of these images. Validation experiments on expert segmentations showed that (1) the Hausdorff labeling error rapidly decreased, and (2) the power to detect disease-related alterations monotonically improved as the number of atlases, N, was increased from 1 to 9. We then combined the segmentations with a radial mapping approach to localize ventricular shape differences in patients. In surface-based statistical maps, we detected more widespread and intense anatomical deficits as we increased the number of atlases, and we formulated a statistical stopping criterion to determine the optimal value of N. Anterior horn anomalies in Alzheimer's patients were only detected with the multi-atlas segmentation, which clearly outperformed the standard single-atlas approach.

Reducing structural variation to determine the genetics of white matter integrity across hemispheres - a dti study of 100 twins

Studies of cerebral asymmetry can open doors to understanding the functional specialization of each brain hemisphere, and how this is altered in disease. Here we examined hemispheric asymmetries in fiber architecture using diffusion tensor imaging (DTI) in 100 subjects, using high-dimensional fluid warping to disentangle shape differences from measures sensitive to myelination. Confounding effects of purely structural asymmetries were reduced by using co-registered structural images to fluidly warp 3D maps of fiber characteristics (fractional and geodesic anisotropy) to a structurally symmetric minimal deformation template (MDT). We performed a quantitative genetic analysis on 100 subjects to determine whether the sources of the remaining signal asymmetries were primarily genetic or environmental. A twin design was used to identify the heritable features of fiber asymmetry in various regions of interest, to further assist in the discovery of genes influencing brain micro-architecture and brain lateralization. Genetic influences and left/right asymmetries were detected in the fiber architecture of the frontal lobes, with minor differences depending on the choice of registration template.

Genetics of anisotropy asymmetry: Registration and sample size effects

Brain asymmetry has been a topic of interest for neuroscientists for many years. The advent of diffusion tensor imaging (DTI) allows researchers to extend the study of asymmetry to a microscopic scale by examining fiber integrity differences across hemispheres rather than the macroscopic differences in shape or structure volumes. Even so, the power to detect these microarchitectural differences depends on the sample size and how the brain images are registered and how many subjects are studied. We fluidly registered 4 Tesla DTI scans from 180 healthy adult twins (45 identical and fraternal pairs) to a geometrically-centered population mean template. We computed voxelwise maps of significant asymmetries (left/right hemisphere differences) for common fiber anisotropy indices (FA, GA). Quantitative genetic models revealed that 47-62% of the variance in asymmetry was due to genetic differences in the population. We studied how these heritability estimates varied with the type of registration target (T1- or T2-weighted) and with sample size. All methods consistently found that genetic factors strongly determined the lateralization of fiber anisotropy, facilitating the quest for specific genes that might influence brain asymmetry and fiber integrity.

Genetics of path lengths in brain connectivity networks: HARDI-based maps in 457 adults

Brain connectivity analyses are increasingly popular for investigating organization. Many connectivity measures including path lengths are generally defined as the number of nodes traversed to connect a node in a graph to the others. Despite its name, path length is purely topological, and does not take into account the physical length of the connections. The distance of the trajectory may also be highly relevant, but is typically overlooked in connectivity analyses. Here we combined genotyping, anatomical MRI and HARDI to understand how our genes influence the cortical connections, using whole-brain tractography. We defined a new measure, based on Dijkstra's algorithm, to compute path lengths for tracts connecting pairs of cortical regions. We compiled these measures into matrices where elements represent the physical distance traveled along tracts. We then analyzed a large cohort of healthy twins and show that our path length measure is reliable, heritable, and influenced even in young adults by the Alzheimer's risk gene, CLU.

Heritability of white matter fiber tract shapes: A HARDI study of 198 twins

Genetic analysis of diffusion tensor images (DTI) shows great promise in revealing specific genetic variants that affect brain integrity and connectivity. Most genetic studies of DTI analyze voxel-based diffusivity indices in the image space (such as 3D maps of fractional anisotropy) and overlook tract geometry. Here we propose an automated workflow to cluster fibers using a white matter probabilistic atlas and perform genetic analysis on the shape characteristics of fiber tracts. We apply our approach to large study of 4-Tesla high angular resolution diffusion imaging (HARDI) data from 198 healthy, young adult twins (age: 20-30). Illustrative results show heritability for the shapes of several major tracts, as color-coded maps.

Comparison of fractional and geodesic anisotropy in diffusion tensor images of 90 monozygotic and dizygotic twins

We used diffusion tensor magnetic resonance imaging (DTI) to reveal the extent of genetic effects on brain fiber microstructure, based on tensor-derived measures, in 22 pairs of monozygotic (MZ) twins and 23 pairs of dizygotic (DZ) twins (90 scans). After Log-Euclidean denoising to remove rank-deficient tensors, DTI volumes were fluidly registered by high-dimensional mapping of co-registered MP-RAGE scans to a geometrically-centered mean neuroanatomical template. After tensor reorientation using the strain of the 3D fluid transformation, we computed two widely used scalar measures of fiber integrity: fractional anisotropy (FA), and geodesic anisotropy (GA), which measures the geodesic distance between tensors in the symmetric positive-definite tensor manifold. Spatial maps of intraclass correlations (r) between MZ and DZ twins were compared to compute maps of Falconer's heritability statistics, i.e. the proportion of population variance explainable by genetic differences among individuals. Cumulative distribution plots (CDF) of effect sizes showed that the manifold measure, GA, comparably the Euclidean measure, FA, in detecting genetic correlations. While maps were relatively noisy, the CDFs showed promise for detecting genetic influences on brain fiber integrity as the current sample expands.

Direct mapping of hippocampal surfaces with intrinsic shape context

We propose in this paper a new method for the mapping of hippocampal (HC) surfaces to establish correspondences between points on HC surfaces and enable localized HC shape analysis. A novel geometric feature, the intrinsic shape context, is defined to capture the global characteristics of the HC shapes. Based on this intrinsic feature, an automatic algorithm is developed to detect a set of landmark curves that are stable across population. The direct map between a source and target HC surface is then solved as the minimizer of a harmonic energy function defined on the source surface with landmark constraints. For numerical solutions, we compute the map with the approach of solving partial differential equations on implicit surfaces. The direct mapping method has the following properties: (1) it has the advantage of being automatic; (2) it is invariant to the pose of HC shapes. In our experiments, we apply the direct mapping method to study temporal changes of HC asymmetry in Alzheimer's disease (AD) using HC surfaces from 12 AD patients and 14 normal controls. Our results show that the AD group has a different trend in temporal changes of HC asymmetry than the group of normal controls. We also demonstrate the flexibility of the direct mapping method by applying it to construct spherical maps of HC surfaces. Spherical harmonics (SPHARM) analysis is then applied and it confirms our results on temporal changes of HC asymmetry in AD.

Mapping cortical change in Alzheimer's disease, brain development, and schizophrenia

This paper describes algorithms that can identify patterns of brain structure and function associated with Alzheimer's disease, schizophrenia, normal aging, and abnormal brain development based on imaging data collected in large human populations. Extraordinary information can be discovered with these techniques: dynamic brain maps reveal how the brain grows in childhood, how it changes in disease, and how it responds to medication. Genetic brain maps can reveal genetic influences on brain structure, shedding light on the nature-nurture debate, and the mechanisms underlying inherited neurobehavioral disorders. Recently, we created time-lapse movies of brain structure for a variety of diseases. These identify complex, shifting patterns of brain structural deficits, revealing where, and at what rate, the path of brain deterioration in illness deviates from normal. Statistical criteria can then identify situations in which these changes are abnormally accelerated, or when medication or other interventions slow them. In this paper, we focus on describing our approaches to map structural changes in the cortex. These methods have already been used to reveal the profile of brain anomalies in studies of dementia, epilepsy, depression, childhood- and adult-onset schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder, fetal alcohol syndrome, Tourette syndrome, Williams syndrome, and in methamphetamine abusers. Specifically, we describe an image analysis pipeline known as cortical pattern matching that helps compare and pool cortical data over time and across subjects. Statistics are then defined to identify brain structural differences between groups, including localized alterations in cortical thickness, gray matter density (GMD), and asymmetries in cortical organization. Subtle features, not seen in individual brain scans, often emerge when population-based brain data are averaged in this way. Illustrative examples are presented to show the profound effects of development and various diseases on the human cortex. Dynamically spreading waves of gray matter loss are tracked in dementia and schizophrenia, and these sequences are related to normally occurring changes in healthy subjects of various ages.

A new regulatory variant in the interleukin-6 receptor gene associates with asthma risk

The main genetic determinant of soluble interleukin 6 receptor (sIL-6R) levels is the missense variant rs2228145 that maps to the cleavage site of IL-6R. For each Ala allele, sIL-6R serum levels increase by ∼20 ng ml -1 and asthma risk by 1.09-fold. However, this variant does not explain the total heritability for sIL-6R levels. Additional independent variants in IL6R may therefore contribute to variation in sIL-6R levels and influence asthma risk. We imputed 471 variants in IL6R and tested these for association with sIL-6R serum levels in 360 individuals. An intronic variant (rs12083537) was associated with sIL-6R levels independently of rs4129267 (P=0.0005), a proxy single-nucleotide polymorphism for rs2228145. A significant and consistent association for rs12083537 was observed in a replication panel of 354 individuals (P=0.033). Each rs12083537:A allele increased sIL-6R serum levels by 2.4 ng ml -1. Analysis of mRNA levels in two cohorts did not identify significant associations between rs12083537 and IL6R transcription levels. On the other hand, results from 16 705 asthmatics and 30 809 controls showed that the rs12083537:A allele increased asthma risk by 1.04-fold (P=0.0419). Genetic risk scores based on IL6R regulatory variants may prove useful in explaining variation in clinical response to tocilizumab, an anti-IL-6R monoclonal antibody.

Mapping the regulatory sequences controlling 93 breast cancer-associated miRNA genes leads to the identification of two functional promoters of the Hsa-mir-200b cluster, methylation of which is associated with metastasis or hormone receptor status in advanced breast cancer

MicroRNAs (miRNAs) are small non-coding RNAs of 20 nt in length that are capable of modulating gene expression post-transcriptionally. Although miRNAs have been implicated in cancer, including breast cancer, the regulation of miRNA transcription and the role of defects in this process in cancer is not well understood. In this study we have mapped the promoters of 93 breast cancer-associated miRNAs, and then looked for associations between DNA methylation of 15 of these promoters and miRNA expression in breast cancer cells. The miRNA promoters with clearest association between DNA methylation and expression included a previously described and a novel promoter of the Hsa-mir-200b cluster. The novel promoter of the Hsa-mir-200b cluster, denoted P2, is located 2 kb upstream of the 5′ stemloop and maps within a CpG island. P2 has comparable promoter activity to the previously reported promoter (P1), and is able to drive the expression of miR-200b in its endogenous genomic context. DNA methylation of both P1 and P2 was inversely associated with miR-200b expression in eight out of nine breast cancer cell lines, and in vitro methylation of both promoters repressed their activity in reporter assays. In clinical samples, P1 and P2 were differentially methylated with methylation inversely associated with miR-200b expression. P1 was hypermethylated in metastatic lymph nodes compared with matched primary breast tumours whereas P2 hypermethylation was associated with loss of either oestrogen receptor or progesterone receptor. Hypomethylation of P2 was associated with gain of HER2 and androgen receptor expression. These data suggest an association between miR-200b regulation and breast cancer subtype and a potential use of DNA methylation of miRNA promoters as a component of a suite of breast cancer biomarkers.

Energetics of rare earth manganese perovskites A1-xA ' xMnO3 (A = La, Nd, Y and A ' = Sr, La) systems

High temperature reaction calorimetry using molten lead berate as solvent has been used to study the thermochemistry of NdMnO3, YMnO3, La1-xSrxMnO3 (with 0 < x < 0.5), and Ln(0.5)Ca(0.5)MnO(3) (with Ln = La, Nd, Y), The enthalpies of formation of these multicomponent oxides from their binary constituents have been calculated from the measured enthalpy of drop solution, The energetic stability of the perovskite depends on the size of the A cation, The enthalpy of formation of YMnO3 (smallest A cation) is more endothermic than those of NdMnO3 and LaMnO3. The energetics of the perovskite also depends on the oxidation state of the B site's ions. In the La1-xSrxMnO3 system, the energetic stability of the structure increases with the Mn4+/Mn3+ ratio, The new values of the enthalpies of oxidations, with reliable standard entropies, were used to plot the phase stability diagram of the lanthanum-manganese-oxygen system in the temperature range 300-1100 K, The LaMnO3/MnO phase boundary evaluated in this study agrees with the one published by Atsumi et nl. calculated from thermogravimetric and conductivity measurements.

Validation of processing maps for 304L stainless steel using hot forging, rolling and extrusion

The development of a microstructure in 304L stainless steel during industrial hot-forming operations, including press forging (mean strain rate of 0.15 s(-1)), rolling/extrusion (2-5 s(-1)), and hammer forging (100 s(-1)) at different temperatures in the range 600-1200 degrees C, was studied with a view to validating the predictions of the processing map. The results have shown that excellent correlation exists between the regimes exhibited by the map and the product microstructures. 304L stainless steel exhibits instability bands when hammer forged at temperatures below 1100 degrees C, rolled/extruded below 1000 degrees C, or press forged below 800 degrees C. All of these conditions must be avoided in mechanical processing of the material. On the other hand, ideally, the material may be rolled, extruded, or press forged at 1200 degrees C to obtain a defect-free microstructure.

Huellas de Eros y Thánatos en la narrativa de Diamela Eltit : La palabra en movimiento en el juego entre tropos, metáforas y deconstrucciones lingüísticas

Väitöskirja analysoi espanjan kielen dekonstruktioita ruumiin metaforista ja troopeista koostuvassa aineistossa chileläisen kirjailijan Diamela Eltitin (1949 -) neljässä romaanissa: Lumpérica (1983), Vaca sagrada (1991), El infarto del alma (1994) ja Los trabajadores de la muerte (1998). Näkökulma on kielen muutoksessa Eltitin proosassa 1980- ja 1990-luvuilla alkaen kokeellisesta huippuvaiheesta 1983, jolloin hän julkaisi esikoisromaaninsa Lumpérica. Tutkimus korostaa Eltitin romaanien historiallista arvoa, kirjallisuuden tapaa murtaa kielen rakenteita ja sitä miten tämä murros kytkeytyy taideteoreettiseen muutokseen kulttuuridiskursseissa. Tutkimus tarkastelee Eltitin kehityskaarta kenraali Augusto Pinochetin sotilasvallankaappauksesta 1973 halki sotilashallituksen kauden (1973-1990) aina kansalaisyhteiskunnan vahvistumiseen ja vuoteen 1998. Tutkimus analysoi ruumiin troopeista ja metaforista koostuvaa tutkimusaineistoa lingvistiikan, kirjallisuustieteen, historian ja sukupuolen tutkimuksen monitieteisessä viitekehyksessä. Sen vuoksi väitöskirja liittyy espanjalaisen filologian, yleisen kirjallisuustieteen, Latinalaisen Amerikan tutkimuksen ja naistutkimuksen oppiaineisiin. Kolme tärkeintä oppiteoreettista runkoa ovat lingvistinen strukturalismi, dekonstruktio ja feministiset kirjallisuusteoriat. Dekonstruktiivinen lähestymistapa tekstiin korostaa kielen merkityksen muodostumisen filosofista perustaa. Se pyrkii selvittämään, miten merkitys muodostuu kirjoittajan, tekstin ja lukijan välillä. Tekstikritiikki koostuu semanttisesta ja dekonstruktiivisesta tekstianalyysistä, jonka metodologisen mallin perusta on tanskalaisen kielitieteilijän Louis Hjelmslevin (1899-1965) kielitieteellinen malli. Väitös ei käytä mallia suoraan, vaan soveltaa sitä kaunokirjallisuuden tutkimukseen. Oppiteoreettisen viitekehyksen osalta tutkimus sijoittuu strukturalismin ja poststrukturalismin murrokseen. Tutkimus korostaa Eltitin radikaalia muotokieltä ja teatraalisuutta, hänen kielensä visuaalisuutta ja ruumiin metaforien eroottista jännitettä, mikä ilmenee mm. falloksen metaforaksi tulkitun hehkuvan valon kuvissa romaanissa Lumpérica. Vanhat kreikkalaiset myytit Éros ja Thánatos kasvavat esille länsimaisen taidehistorian perinteestä ja kontekstualisoituvat uusiksi kielikuviksi Chilen kirjallisessa maaperässä. Ne muodostavat Eltitin taiteellisen tuotannon pysyvän aihepiirin ja luovat teoksiin synkkää ja karua virettä sekä tummia ja eroottisia sävyjä. Tutkimus osoittaa, että Eltit dekonstruoi kieltä, mutta dekonstruktiot eivät ole jatkuvia eivätkä samanlaisia kaikissa romaaneissa. Kielellisten dekonstruktioiden variaatio on laaja eikä Eltit murra kielen syntaktisia ja morfologisia rakenteita kaikissa teksteissään. Tutkimuksen perusteella väitän, että Eltitin kirjoituksesta puhuttaessa useat tutkijat käyttävät epämääräisesti dekonstruktio-termiä. Useiden tutkijoiden toteamus dekonstruktiosta Diamela Eltitin kirjallisessa tuotannossa pysyvänä piirteenä on epätäsmällinen. Sen sijaan dekonstruktiivinen kirjoitus tarkoittaa Eltitillä laajasti vaihtelevaa lähestymistapaa kieleen, mikä ilmenee kehityslinjana hänen tuotannossaan ja eri tavoin jokaisessa teoksessa.