Human Brain White Matter Research Articles

Brain white matter development is associated with a human-specific haplotype increasing the synthesis of long chain fatty acids.

The genetic and molecular pathways driving human brain white matter (WM) development are only beginning to be discovered. Long chain polyunsaturated fatty acids (LC-PUFAs) have been implicated in myelination in animal models and humans. The biosynthesis of LC-PUFAs is regulated by the fatty acid desaturase (FADS) genes, of which a human-specific haplotype is strongly associated with ω-3 and ω-6 LC-PUFA concentrations in blood. To investigate the relationship between LC-PUFA synthesis and human brain WM development, we examined whether this FADS haplotype is associated with age-related WM differences across the life span in healthy individuals 9-86 years of age (n = 207). Diffusion tensor imaging was performed to measure fractional anisotropy (FA), a putative measure of myelination, of the cerebral WM tracts. FADS haplotype status was determined with a single nucleotide polymorphism (rs174583) that tags this haplotype. Overall, normal age-related WM differences were observed, including higher FA values in early adulthood compared with childhood, followed by lower FA values across older age ranges. However, individuals homozygous for the minor allele (associated with lower LC-PUFA concentrations) did not display these normal age-related WM differences (significant age × genotype interactions, p(corrected) < 0.05). These findings suggest that LC-PUFAs are involved in human brain WM development from childhood into adulthood. This haplotype and LC-PUFAs may play a role in myelin-related disorders of neurodevelopmental origin.

Association between in-scanner head motion with cerebral white matter microstructure: a multiband diffusion-weighted MRI study.

Diffusion-weighted Magnetic Resonance Imaging (DW-MRI) has emerged as the most popular neuroimaging technique used to depict the biological microstructural properties of human brain white matter. However, like other MRI techniques, traditional DW-MRI data remains subject to head motion artifacts during scanning. For example, previous studies have indicated that, with traditional DW-MRI data, head motion artifacts significantly affect the evaluation of diffusion metrics. Actually, DW-MRI data scanned with higher sampling rate are important for accurately evaluating diffusion metrics because it allows for full-brain coverage through the acquisition of multiple slices simultaneously and more gradient directions. Here, we employed a publicly available multiband DW-MRI dataset to investigate the association between motion and diffusion metrics with the standard pipeline, tract-based spatial statistics (TBSS). The diffusion metrics used in this study included not only the commonly used metrics (i.e., FA and MD) in DW-MRI studies, but also newly proposed inter-voxel metric, local diffusion homogeneity (LDH). We found that the motion effects in FA and MD seems to be mitigated to some extent, but the effect on MD still exists. Furthermore, the effect in LDH is much more pronounced. These results indicate that researchers shall be cautious when conducting data analysis and interpretation. Finally, the motion-diffusion association is discussed.

Cellular distribution of glucose and monocarboxylate transporters in human brain white matter and multiple sclerosis lesions

To ensure efficient energy supply to the high demanding brain, nutrients are transported into brain cells via specific glucose (GLUT) and monocarboxylate transporters (MCT). Mitochondrial dysfunction and altered glucose metabolism are thought to play an important role in the progression of neurodegenerative diseases, including multiple sclerosis (MS). Here, we investigated the cellular localization of key GLUT and MCT proteins in human brain tissue of non-neurological controls and MS patients. We show that in control brain tissue GLUT and MCT proteins were abundantly expressed in a variety of central nervous system cells, particularly in microglia and endothelial cells. In active MS lesions, GLUTs and MCTs were highly expressed in infiltrating leukocytes and reactive astrocytes. Astrocytes manifest increased MCT1 staining and maintain GLUT expression in inactive lesions, whereas demyelinated axons exhibit significantly reduced GLUT3 and MCT2 immunoreactivity in inactive lesions. Finally, we demonstrated that the co-transcription factor peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), an important protein involved in energy metabolism, is highly expressed in reactive astrocytes in active MS lesions. Overexpression of PGC-1α in astrocyte-like cells resulted in increased production of several GLUT and MCT proteins. In conclusion, we provide for the first time a comprehensive overview of key nutrient transporters in white matter brain samples. Moreover, our data demonstrate an altered expression of these nutrient transporters in MS brain tissue, including a marked reduction of axonal GLUT3 and MCT2 expression in chronic lesions, which may impede efficient nutrient supply to the hypoxic demyelinated axons thereby contributing to the ongoing neurodegeneration in MS.

The interaction between apparent diffusion coefficients and transverse relaxation rates of human brain metabolites and water studied by diffusion-weighted spectroscopy at 7 T

The dependence of apparent diffusion coefficients (ADCs) of molecules in biological tissues on an acquisition-specific timescale is a powerful mechanism for studying tissue microstructure. Unlike water, metabolites are confined mainly to intracellular compartments, thus providing higher specificity to tissue microstructure. Compartment-specific structural and chemical properties may also affect molecule transverse relaxation times (T₂). Here, we investigated the correlation between diffusion and relaxation for N-acetylaspartate, creatine and choline compounds in human brain white matter in vivo at 7 T, and compared them with those of water under the same experimental conditions. Data were acquired in a volume of interest in parietal white matter at two different diffusion times, Δ = 44 and 246 ms, using a matrix of three echo times (T(E)) and five diffusion weighting values (up to 4575 s/mm²). Significant differences in the dependence of the ADCs on T(E) were found between water and metabolites, as well as among the different metabolites. A significant decrease in water ADC as a function of TE was observed only at the longest diffusion time (p < 0.001), supporting the hypothesis that at least part of the restricted water pool can be associated with longer T₂, as suggested by previous studies in vitro. Metabolite data showed an increase of creatine (p < 0.05) and N-acetylaspartate (p < 0.05) ADCs with TE at Δ = 44 ms, and a decrease of creatine (p < 0.05) and N-acetylaspartate (p = 0.1) ADCs with TE at Δ = 246 ms. No dependence of choline ADC on TE was observed. The metabolite results suggest that diffusion and relaxation properties are dictated not only by metabolite distribution in different cell types, but also by other mechanisms, such as interactions with membranes, exchange between "free" and "bound" states or interactions with microsusceptibility gradients.

Mapping measures of microscopic diffusion anisotropy in human brain white matter in vivo with double‐wave‐vector diffusion‐weighted imaging

To demonstrate that rotationally invariant measures of the diffusion anisotropy on a microscopic scale can be mapped in human brain white matter in vivo. Echo-planar imaging experiments (resolution 3.0 × 3.0 × 3.0 mm(3) ) involving two diffusion-weighting periods (δ = 22 ms, Δ = 25 ms) in the same acquisition, so-called double-wave-vector or double-pulsed-field-gradient diffusion-weighting experiments, were performed on a 3 T whole-body magnetic resonance system with a long mixing time ( τm=45 ms) between the two diffusion weightings. The disturbing influences of background gradient fields, eddy currents, and the finite mixing time can be minimized using 84 direction combinations based on nine directions and their antipodes. In healthy volunteers, measures of the microscopic diffusion anisotropy ( IMA and MA indexes) could be mapped in white matter across the human brain. The measures were independent (i) of the absolute orientation of the head and of the diffusion directions and (ii) of the predominant fiber orientation. Compared to the fractional anisotropy derived from the conventional diffusion tensor, the double-wave-vector indexes exhibit a narrower distribution, which could reflect their independence of the fiber orientation distribution. Mapping measures of the microscopic diffusion anisotropy in human brain white matter is feasible in vivo and could help to characterize tissue microstructure in the healthy and pathological brain.

Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936

Apolipoprotein E (APOE) ε genotype has previously been significantly associated with cognitive, brain imaging, and Alzheimer's disease-related phenotypes (e.g., age of onset). In the TOMM40 gene, the rs10524523 (“523”) variable length poly-T repeat polymorphism has more recently been associated with similar ph/enotypes, although the allelic directions of these associations have varied between initial reports. Using diffusion magnetic resonance imaging tractography, the present study aimed to investigate whether there are independent effects of apolipoprotein E (APOE) and TOMM40 genotypes on human brain white matter integrity in a community-dwelling sample of older adults, the Lothian Birth Cohort 1936 (mean age = 72.70 years, standard deviation = 0.74, N approximately = 640–650; for most analyses). Some nominally significant effects were observed (i.e., covariate-adjusted differences between genotype groups at p < 0.05). For APOE, deleterious effects of ε4 “risk” allele presence (vs. absence) were found in the right ventral cingulum and left inferior longitudinal fasciculus. To test for biologically independent effects of the TOMM40 523 repeat, participants were stratified into APOE genotype subgroups, so that any significant effects could not be attributed to APOE variation. In participants with the APOE ε3/ε4 genotype, effects of TOMM40 523 status were found in the left uncinate fasciculus, left rostral cingulum, left ventral cingulum, and a general factor of white matter integrity. In all 4 of these tractography measures, carriers of the TOMM40 523 “short” allele showed lower white matter integrity when compared with carriers of the “long” and “very-long” alleles. Most of these effects survived correction for childhood intelligence test scores and vascular disease history, though only the effect of TOMM40 523 on the left ventral cingulum integrity survived correction for false discovery rate. The effects of APOE in this older population are more specific and restricted compared with those reported in previous studies, and the effects of TOMM40 on white matter integrity appear to be novel, although replication is required in large independent samples.

Reflection Coefficient Detection of Simulation Models for Microwave Imaging Simulation System

The study was conducted based on two objectives as framework. The first objective is to determine the point of microwave signal reflection while penetrating into the simulation models and, the second objective is to analyze the reflection pattern when the signal penetrate into the layers with different relative permittivity, εr. Thus, several microwave models were developed to make a close proximity of the in vivo human brain. The study proposed two different layers on two different characteristics models. The radii on the second layer and the corresponding antenna positions are the factors for both models. The radii for model 1 is 60 mm with an antenna position of 10 mm away, in contrast, model 2 is 10 mm larger in size with a closely adapted antenna without any gap. The layers of the models were developed with different combination of materials such as Oil, Sandy Soil, Brain, Glycerin and Water. Results show the combination of Glycerin + Brain and Brain + Sandy Soil are the best proximity of the in vivo human brain grey and white matter. The results could benefit subsequent studies for further enhancement and development of the models.

Microanisotropy imaging: quantification of microscopic diffusion anisotropy and orientational order parameter by diffusion MRI with magic-angle spinning of the q-vector

Diffusion tensor imaging (DTI) is the method of choice for non-invasive investigations of the structure of human brain white matter. The results are conventionally reported as maps of the fractional anisotropy (FA), which is a parameter related to microstructural features such as axon density, diameter, and myelination. The interpretation of FA in terms of microstructure becomes ambiguous when there is a distribution of axon orientations within the image voxel. In this paper, we propose a procedure for resolving this ambiguity by determining a new parameter, the microscopic fractional anisotropy (µFA), which corresponds to the FA without the confounding influence of orientation dispersion. In addition, we suggest a method for measuring the orientational order parameter (OP) for the anisotropic objects. The experimental protocol is capitalizing on a recently developed diffusion NMR pulse sequence based on magic-angle spinning of the q-vector. Proof-of-principle experiments are carried out on microimaging and clinical MRI equipment using lyotropic liquid crystals and plant tissues as model materials with high µFA and low FA on account of orientation dispersion. We expect the presented method to be especially fruitful in combination with DTI and high angular resolution acquisition protocols for neuroimaging studies of grey and white matter.

Crossing fibers detection with an analytical high order tensor decomposition.

Diffusion magnetic resonance imaging (dMRI) is the only technique to probe in vivo and noninvasively the fiber structure of human brain white matter. Detecting the crossing of neuronal fibers remains an exciting challenge with an important impact in tractography. In this work, we tackle this challenging problem and propose an original and efficient technique to extract all crossing fibers from diffusion signals. To this end, we start by estimating, from the dMRI signal, the so-called Cartesian tensor fiber orientation distribution (CT-FOD) function, whose maxima correspond exactly to the orientations of the fibers. The fourth order symmetric positive definite tensor that represents the CT-FOD is then analytically decomposed via the application of a new theoretical approach and this decomposition is used to accurately extract all the fibers orientations. Our proposed high order tensor decomposition based approach is minimal and allows recovering the whole crossing fibers without any a priori information on the total number of fibers. Various experiments performed on noisy synthetic data, on phantom diffusion, data and on human brain data validate our approach and clearly demonstrate that it is efficient, robust to noise and performs favorably in terms of angular resolution and accuracy when compared to some classical and state-of-the-art approaches.

A Scaffold for Efficiency in the Human Brain

The comprehensive relations between healthy adult human brain white matter (WM) microstructure and gray matter (GM) function, and their joint relations to cognitive performance, remain poorly understood. We investigated these associations in 27 younger and 28 older healthy adults by linking diffusion tensor imaging (DTI) with functional magnetic resonance imaging (fMRI) data collected during an n-back working memory task. We present a novel application of multivariate Partial Least Squares (PLS) analysis that permitted the simultaneous modeling of relations between WM integrity values from all major WM tracts and patterns of condition-related BOLD signal across all GM regions. Our results indicate that greater microstructural integrity of the major WM tracts was negatively related to condition-related blood oxygenation level-dependent (BOLD) signal in task-positive GM regions. This negative relationship suggests that better quality of structural connections allows for more efficient use of task-related GM processing resources. Individuals with more intact WM further showed greater BOLD signal increases in typical "task-negative" regions during fixation, and notably exhibited a balanced magnitude of BOLD response across task-positive and -negative states. Structure-function relations also predicted task performance, including accuracy and speed of responding. Finally, structure-function-behavior relations reflected individual differences over and above chronological age. Our findings provide evidence for the role of WM microstructure as a scaffold for the context-relevant utilization of GM regions.

White Matter Changes Associated with Antipsychotic Treatment in First-Episode Psychosis

Second-generation antipsychotics are utilized extensively in the treatment of psychotic disorders and other psychiatric conditions, but the effects of these medications on human brain white matter are not well understood. We thus investigated the effects of second-generation antipsychotics on white matter integrity using tract-based spatial statistics in patients experiencing a first episode of psychosis with little or no prior antipsychotic exposure, and how potential changes were associated with metabolic side effects. Thirty-five (26 men/9 women) patients experiencing a first episode of psychosis received diffusion tensor imaging (DTI) exams, clinical assessments, and provided fasting blood samples at the onset of antipsychotic treatment, and then again after 12 weeks of treatment with either risperidone or aripiprazole in a double-blind randomized clinical trial. In addition, 35 (26 men/9 women) healthy volunteers received DTI exams at a baseline time point and then after 12 weeks. Patients demonstrated significant (p<0.05; family-wise error corrected) fractional anisotropy reductions within the parietal and occipital white matter following antipsychotic treatment. Greater overall fractional anisotropy reduction was significantly correlated with greater increases in low-density lipoprotein. There were no significant fractional anisotropy increases among patients following treatment. Moreover, healthy volunteers did not demonstrate either significant increases or decreases in fractional anisotropy across a comparable 12-week interval. The use of antipsychotics may be associated with a subtle loss of white matter integrity that is related to greater side effects, thus raising potentially important considerations regarding risk/benefit in their usage. Limitations of the current study, however, include a prior history of substance use among patients and our inability to exclude the possibility of disease progression.

Knowledge-based automated reconstruction of human brain white matter tracts using a path-finding approach with dynamic programming

It has been shown that the anatomy of major white matter tracts can be delineated using diffusion tensor imaging (DTI) data. Tract reconstruction, however, often suffers from a large number of false-negative results when a simple line propagation algorithm is used. This limits the application of this technique to only the core of prominent white matter tracts. By employing probabilistic path-generation algorithms, connectivity between a larger number of anatomical regions can be studied, but an increase in the number of false-positive results is inevitable. One of the causes of the inaccuracy is the complex axonal anatomy within a voxel; however, high-angular resolution (HAR) methods have been proposed to ameliorate this limitation. However, HAR data are relatively rare due to the long scan times required and the low signal-to-noise ratio. In this study, we tested a probabilistic path-finding method in which two anatomical regions with known connectivity were pre-defined and a path that maximized agreement with the DTI data was searched. To increase the accuracy of the trajectories, knowledge-based anatomical constraints were applied. The reconstruction protocols were tested using DTI data from 19 normal subjects to examine test–retest reproducibility and cross-subject variability. Fifty-two tracts were found to be reliably reconstructed using this approach, which can be viewed on our website.

Differential developmental trajectories of magnetic susceptibility in human brain gray and white matter over the lifespan

As indicated by several recent studies, magnetic susceptibility of the brain is influenced mainly by myelin in the white matter and by iron deposits in the deep nuclei. Myelination and iron deposition in the brain evolve both spatially and temporally. This evolution reflects an important characteristic of normal brain development and ageing. In this study, we assessed the changes of regional susceptibility in the human brain in vivo by examining the developmental and ageing process from 1 to 83 years of age. The evolution of magnetic susceptibility over this lifespan was found to display differential trajectories between the gray and the white matter. In both cortical and subcortical white matter, an initial decrease followed by a subsequent increase in magnetic susceptibility was observed, which could be fitted by a Poisson curve. In the gray matter, including the cortical gray matter and the iron-rich deep nuclei, magnetic susceptibility displayed a monotonic increase that can be described by an exponential growth. The rate of change varied according to functional and anatomical regions of the brain. For the brain nuclei, the age-related changes of susceptibility were in good agreement with the findings from R2* measurement. Our results suggest that magnetic susceptibility may provide valuable information regarding the spatial and temporal patterns of brain myelination and iron deposition during brain maturation and ageing.

Increased global and local efficiency of human brain anatomical networks detected with FLAIR-DTI compared to non-FLAIR-DTI.

Diffusion-weighted MRI (DW-MRI), the only non-invasive technique for probing human brain white matter structures in vivo, has been widely used in both fundamental studies and clinical applications. Many studies have utilized diffusion tensor imaging (DTI) and tractography approaches to explore the topological properties of human brain anatomical networks by using the single tensor model, the basic model to quantify DTI indices and tractography. However, the conventional DTI technique does not take into account contamination by the cerebrospinal fluid (CSF), which has been known to affect the estimated DTI measures and tractography in the single tensor model. Previous studies have shown that the Fluid-Attenuated Inversion Recovery (FLAIR) technique can suppress the contribution of the CSF to the DW-MRI signal. We acquired DTI datasets from twenty-two subjects using both FLAIR-DTI and conventional DTI (non-FLAIR-DTI) techniques, constructed brain anatomical networks using deterministic tractography, and compared the topological properties of the anatomical networks derived from the two types of DTI techniques. Although the brain anatomical networks derived from both types of DTI datasets showed small-world properties, we found that the brain anatomical networks derived from the FLAIR-DTI showed significantly increased global and local network efficiency compared with those derived from the conventional DTI. The increases in the network regional topological properties derived from the FLAIR-DTI technique were observed in CSF-filled regions, including the postcentral gyrus, periventricular regions, inferior frontal and temporal gyri, and regions in the visual cortex. Because brain anatomical networks derived from conventional DTI datasets with tractography have been widely used in many studies, our findings may have important implications for studying human brain anatomical networks derived from DW-MRI data and tractography.

Robust estimation of fractal measures for characterizing the structural complexity of the human brain: Optimization and reproducibility

High-resolution isotropic three-dimensional reconstructions of human brain gray and white matter structures can be characterized to quantify aspects of their shape, volume and topological complexity. In particular, methods based on fractal analysis have been applied in neuroimaging studies to quantify the structural complexity of the brain in both healthy and impaired conditions. The usefulness of such measures for characterizing individual differences in brain structure critically depends on their within-subject reproducibility in order to allow the robust detection of between-subject differences. This study analyzes key analytic parameters of three fractal-based methods that rely on the box-counting algorithm with the aim to maximize within-subject reproducibility of the fractal characterizations of different brain objects, including the pial surface, the cortical ribbon volume, the white matter volume and the gray matter/white matter boundary. Two separate datasets originating from different imaging centers were analyzed, comprising 50 subjects with three and 24 subjects with four successive scanning sessions per subject, respectively. The reproducibility of fractal measures was statistically assessed by computing their intra-class correlations. Results reveal differences between different fractal estimators and allow the identification of several parameters that are critical for high reproducibility. Highest reproducibility with intra-class correlations in the range of 0.9–0.95 is achieved with the correlation dimension. Further analyses of the fractal dimensions of parcellated cortical and subcortical gray matter regions suggest robustly estimated and region-specific patterns of individual variability. These results are valuable for defining appropriate parameter configurations when studying changes in fractal descriptors of human brain structure, for instance in studies of neurological diseases that do not allow repeated measurements or for disease-course longitudinal studies.

Myelin water mapping by spatially regularized longitudinal relaxographic imaging at high magnetic fields

Magnetic resonance T1 -weighted images are routinely used for human brain segmentation, brain parcellation, and clinical diagnosis of demyelinating diseases. Myelin is thought to influence the longitudinal relaxation commonly described by a mono-exponential recovery, although reports of bi-exponential longitudinal relaxation have been published. The purpose of this work was to investigate if a myelin water T1 contribution could be separated in geometrically sampled Look-Locker trains of low flip angle gradient echoes. T1 relaxograms from normal human brain were computed by a spatially regularized inverse Laplace transform after estimating the apparent inversion efficiency. With sufficiently long inversion-time sampling (ca. 5 × T1 of cerebrospinal fluid), the T1 relaxogram revealed a short-T1 peak (106-225 ms). The apparent fraction of this water component increased in human brain white matter from 8.3% at 3 T, to 11.3% at 4 T and 15.0% at 7 T. The T2 * of the short-T1 peak at 3 T was shorter, 27.9 ± 13.0 ms, than that of the long-T1 peak, 51.3 ± 5.6 ms. The short-T1 fraction is interpreted as the water resident in myelin. Its detection is facilitated by longer T1 of axoplasmic water at higher magnetic field.

Tracking cerebral white matter changes across the lifespan: insights from diffusion tensor imaging studies

Delineating the normal development of brain white matter (WM) over the human lifespan is crucial to improved understanding of underlying WM pathology in neuropsychiatric and neurological conditions. We review the extant literature concerning diffusion tensor imaging studies of brain WM development in healthy individuals available until October 2012, summarise trends of normal development of human brain WM and suggest possible future research directions. Temporally, brain WM maturation follows a curvilinear pattern with an increase in fractional anisotropy (FA) from newborn to adolescence, decelerating in adulthood till a plateau around mid-adulthood, and a more rapid decrease of FA from old age onwards. Spatially, brain WM tracts develop from central to peripheral regions, with evidence of anterior-to-posterior maturation in commissural and projection fibres. The corpus callosum and fornix develop first and decline earlier, whilst fronto-temporal WM tracts like cingulum and uncinate fasciculus have protracted maturation and decline later. Prefrontal WM is most vulnerable with greater age-related FA reduction compared with posterior WM. Future large scale studies adopting longitudinal design will better clarify human brain WM changes over time.

Differences of inter-tract correlations between neonates and children around puberty: a study based on microstructural measurements with DTI

The human brain development is a complicated yet well-organized process. Metrics derived from diffusion tensor imaging (DTI), including fractional anisotropy (FA), radial (RD), axial (AxD), and mean diffusivity (MD), have been used to noninvasively access the microstructural development of human brain white matter (WM). At birth, most of the major WM tracts are apparent but in a relatively disorganized pattern. Brain maturation is a process of establishing an organized pattern of these major WM tracts. However, how the linkage pattern of major WM tracts changes during development remains unclear. In this study, DTI data of 26 neonates and 28 children around puberty were acquired. 10 major WM tracts, representing four major tract groups involved in distinctive brain functions, were traced with DTI tractography for all 54 subjects. With the 10 by 10 correlation matrices constructed with Spearman's pairwise inter-tract correlations and based on tract-level measurements of FA, RD, AxD, and MD of both age groups, we assessed if the inter-tract correlations become stronger from birth to puberty. In addition, hierarchical clustering was performed based on the pairwise correlations of WM tracts to reveal the clustering pattern for each age group and pattern shift from birth to puberty. Stronger and enhanced microstructural inter-tract correlations were found during development from birth to puberty. The linkage patterns of two age groups differ due to brain development. These changes of microstructural correlations from birth to puberty suggest inhomogeneous but organized myelination processes which cause the reshuffled inter-tract correlation pattern and make homologous tracts tightly clustered. It opens a new window to study WM tract development and can be potentially used to investigate atypical brain development due to neurological or psychiatric disorders.

Quantitative tract-based white matter development from birth to age 2 years

Few large-scale studies have been done to characterize the normal human brain white matter growth in the first years of life. We investigated white matter maturation patterns in major fiber pathways in a large cohort of healthy young children from birth to age two using diffusion parameters fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (RD). Ten fiber pathways, including commissural, association and projection tracts, were examined with tract-based analysis, providing more detailed and continuous spatial developmental patterns compared to conventional ROI based methods. All DTI data sets were transformed to a population specific atlas with a group-wise longitudinal large deformation diffeomorphic registration approach. Diffusion measurements were analyzed along the major fiber tracts obtained in the atlas space. All fiber bundles show increasing FA values and decreasing radial and axial diffusivities during development in the first 2years of life. The changing rates of the diffusion indices are faster in the first year than the second year for all tracts. RD and FA show larger percentage changes in the first and second years than AD. The gender effects on the diffusion measures are small. Along different spatial locations of fiber tracts, maturation does not always follow the same speed. Temporal and spatial diffusion changes near cortical regions are in general smaller than changes in central regions. Overall developmental patterns revealed in our study confirm the general rules of white matter maturation. This work shows a promising framework to study and analyze white matter maturation in a tract-based fashion. Compared to most previous studies that are ROI-based, our approach has the potential to discover localized development patterns associated with fiber tracts of interest.

KIAA1797/FOCAD encodes a novel focal adhesion protein with tumour suppressor function in gliomas

In a strategy to identify novel genes involved in glioma pathogenesis by molecular characterization of chromosomal translocation breakpoints, we identified the KIAA1797 gene, encoding a protein with an as yet undefined function, to be disrupted by a 7;9 translocation in a primary glioblastoma culture. Array-based comparative genomic hybridization detected deletions involving KIAA1797 in around half of glioblastoma cell lines and glioblastomas investigated. Quantification of messenger RNA levels in human tissues demonstrated highest KIAA1797 expression in brain, reduced levels in all glioblastoma cell lines and most glioblastomas and similar levels in glial and neuronal cells by analysis of different hippocampal regions from murine brain. Antibodies against KIAA1797 were generated and showed similar protein levels in cortex and subcortical white matter of human brain, while levels were significantly reduced in glioblastomas with KIAA1797 deletion. By immunofluorescence of astrocytoma cells, KIAA1797 co-localized with vinculin in focal adhesions. Physical interaction between KIAA1797 and vinculin was demonstrated via co-immunoprecipitation. Functional in vitro assays demonstrated a significant decrease in colony formation, migration and invasion capacity of LN18 and U87MG glioma cells carrying a homozygous KIAA1797 deletion ectopically expressing KIAA1797 compared with mock-transduced cells. In an in vivo orthotopic xenograft mouse model, U87MG tumour lesions expressing KIAA1797 had a significantly reduced volume compared to tumours not expressing KIAA1797. In summary, the frequently deleted KIAA1797 gene encodes a novel focal adhesion complex protein with tumour suppressor function in gliomas, which we name 'focadhesin'. Since KIAA1797 genetic variation has been implicated in Alzheimer's disease, our data are also relevant for neurodegeneration.