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John G Sled

Publications and source records attributed to John G Sled.

17 recordsLinked to original sources
PubMed2006

Anatomical phenotyping in the brain and skull of a mutant mouse by magnetic resonance imaging and computed tomography.

Since genetically modified mice have become more common in biomedical research as models of human disease, a need has also grown for efficient and quantitative methods to assess mouse phenotype. One powerful means of phenotyping is characterization of anatomy in mutant vs. normal populations. Anatomical phenotyping requires visualization of structures in situ, quantification of complex shape differences between mouse populations, and detection of subtle or diffuse abnormalities during high-throughput survey work. These aims can be achieved with imaging techniques adapted from clinical radiology, such as magnetic resonance imaging and computed tomography. These imaging technologies provide an excellent nondestructive method for visualization of anatomy in live individuals or specimens. The computer-based analysis of these images then allows thorough anatomical characterizations. We present an automated method for analyzing multiple-image data sets. This method uses image registration to identify corresponding anatomy between control and mutant groups. Within- and between-group shape differences are used to map regions of significantly differing anatomy. These regions are highlighted and represented quantitatively by displacements and volume changes. This methodology is demonstrated for a partially characterized mouse mutation generated by N-ethyl-N-nitrosourea mutagenesis that is a putative model of the human syndrome oculodentodigital dysplasia, caused by point mutations in the gene encoding connexin 43.

Animals↗
PubMed2006

Presentation of 3D isotropic imaging data for optimal viewing.

Three-dimensional (3D) isotropically sampled data facilitates retrospective viewing of arbitrarily aligned image planes and simplifies automated computer analysis of 3D structures. However, compared to acquisitions that employ thick slices, MRI acquisitions with isotropic sampling have a lower signal-to-noise ratio (SNR). A rater study was performed to examine viewer preference for the trade-off between SNR and the partial-volume effect of through-plane averaging. A robust preference for a 5:1 ratio in through-plane to in-plane was found for a typical SNR of 11.

Algorithms↗
PubMed2006

Embryonic and neonatal phenotyping of genetically engineered mice.

Considerable progress has been made in adapting existing and developing new technologies to enable increasingly detailed phenotypic information to be obtained in embryonic and newborn mice. Sophisticated methods for imaging mouse embryos and newborns are available and include ultrasound and magnetic resonance imaging (MRI) for in vivo imaging, and MRI, vascular corrosion casts, micro-computed tomography, and optical projection tomography (OPT) for postmortem imaging. In addition, Doppler and M-mode ultrasound are useful noninvasive tools to monitor cardiac and vascular hemodynamics in vivo in embryos and newborns. The developmental stage of the animals being phenotyped is an important consideration when selecting the appropriate technique for anesthesia or euthanasia and for labeling animals in longitudinal studies. Study design also needs to control for possible differences between inter- and intralitter variability, and for possible long-term developmental effects caused by anesthesia and/or procedures. Noninvasive or minimally invasive intravenous or intracardiac injections or blood sampling, and arterial pressure and electrocardiography (ECG) measurements are feasible in newborns. Whereas microinjection techniques are available for embryos as young as 6.5 days of gestation, further advances are required to enable minimally invasive fluid or tissue samples, or blood pressure or ECG measurements, to be obtained from mouse embryos in utero. The growing repertoire of techniques available for phenotyping mouse embryos and newborns promises to accelerate knowledge gained from studies using genetically engineered mice to understand molecular regulation of morphogenesis and the etiology of congenital diseases.

Animals↗
PubMed2005

Correction of artefacts in optical projection tomography.

A new imaging technique called optical projection tomography (OPT), essentially an optical version of x-ray computed tomography (CT), provides molecular specificity, cellular resolution and larger specimen coverage ( approximately 1 cubic centimetre) than was previously possible with other imaging techniques. It is ideally suited to gene expression studies in small animals. Reconstructed OPT images demonstrate several artefacts which reduce the overall image quality. In this paper, we describe methods to prevent smear artefacts due to illumination intensity fluctuation, ring artefacts due to CCD pixel sensitivity variation and a new 'detector edge' artefact caused by non-zero background signal. We also present an automated method to align the position of the rotational axis during image reconstruction. Finally, we propose a method to eliminate bowl artefacts due to projection truncation using a lower resolution OPT scan of the same specimen. This solution also provides OPT with the ability to obtain a high-resolution reconstruction from a region of interest of a specimen that is larger than the field of view. Implementation of these corrections and modifications increases the accuracy of the OPT imaging technique and extends its capabilities to obtain higher resolution data from within a whole specimen.

Algorithms↗
PubMed2005

Axonal injury in the cerebral normal-appearing white matter of patients with multiple sclerosis is related to concurrent demyelination in lesions but not to concurrent demyelination in normal-appearing white matter.

We assessed axonal injury and demyelination in the cerebral normal-appearing white matter (NAWM) of MS patients in a pilot study using proton magnetic resonance spectroscopic imaging and quantitative magnetization transfer (MT) imaging. Resonance intensities of N-acetylaspartate (NAA) relative to creatine (Cr) were measured in a large central brain volume. NAA/Cr in NAWM was estimated by regression of the NAA/Cr in each voxel against white matter fraction and extrapolation to a white matter fraction of 1. The fractional size of the semi-solid pool (F) was obtained from the binary spin bath model of MT by computing the model parameters from multiple MT-weighted and relaxometry acquisitions. F in NAWM was significantly smaller in the patients [0.109 (0.009)] relative to controls [0.123 (0.007), P = 0.011], but did not differ between RR [0.1085] and SP [0.1087] patients [P > 0.99]. NAA/Cr and F in the NAWM were not correlated (r = 0.16, P > 0.7), mainly due to a lack of variation in F among patients. This may indicate a floor to the extent of myelin pathology that can occur in NAWM before a lesion appears, or that axonal damage is not strictly related to demyelination. The correlation between NAWM NAA/Cr and T2w lesion volume was not significant (P > 0.1). However, dividing the lesion volumes by the mean F in T2w lesions resulted in a quantity that correlated well with NAWM NAA/Cr (r = -0.78, P = 0.038), possibly reflecting the association of Wallerian degeneration in the NAWM with axonal transection associated with demyelination within lesions.

Adult↗
PubMed2005

Neuroanatomical differences between mouse strains as shown by high-resolution 3D MRI.

The search for new mouse models of human disease requires a sensitive metric to make three-dimensional (3D) anatomical comparisons in a rapid and quantifiable manner. This is especially true in the brain, where changes in complex shapes such as the hippocampus and ventricles are difficult to assess with 2D histology. Here, we report that the 3D neuroanatomy of three strains of mice (129S1/SvImJ, C57/Bl6, and CD1) is significantly different from one another. Using image co-registration, we 'morphed' together nine brains of each strain scanned by magnetic resonance imaging at (60 microm)3 resolution to synthesize an average image. We applied three methods of comparison. First, we used visual inspection and graphically examined the standard deviation of the variability in each strain. Second, we annotated 42 neural structures and compared their volumes across the strains. Third, we assessed significant local deviations in volume and displacement between the two inbred strains, independent of prior anatomical knowledge.

Algorithms↗
PubMed2005

The role of edema and demyelination in chronic T1 black holes: a quantitative magnetization transfer study.

PURPOSE: To use quantitative magnetization transfer imaging (qMTI) in an investigation of T1-weighted hypointensity observed in clinical magnetic resonance imaging (MRI) scans of multiple sclerosis (MS) patients, which has previously been proposed as a more specific indicator of tissue damage than the more commonly detected T2 hyperintensity. MATERIALS AND METHODS: A cross-sectional study of 10 MS patients was performed using qMTI. A total of 60 MTI measurements were collected in each patient at a resolution of 2 x 2 x 7 mm, over a range of saturation pulses. The observed T1 and T2 were also measured. qMT model parameters were estimated using a voxel-by-voxel fit. RESULTS: A total of 65 T2-hyperintense lesions were identified; 53 were also T1 hypointense. In these black holes, the qMTI-derived semisolid pool fraction F correlated negatively with T(1,obs) (r2 = 0.76; P < 0.0001). The water pool absolute size (PDf) showed a weaker correlation with T(1,obs) (positive, r2 = 0.53; P < 0.0001). The magnetization transfer ratio (MTR) showed a similarly strong correlation with F and a weaker correlation with PDf (r2 = 0.18; P < 0.04). CONCLUSION: T1 increases in chronic black holes strongly correlated with the decline in semisolid pool size, and somewhat less to the confounding effect of edema. MTR was less sensitive than T(1,obs) to liquid pool changes associated with edema.

Adult↗
PubMed2005

Fast spin-echo for multiple mouse magnetic resonance phenotyping.

High-resolution magnetic resonance imaging is emerging as a powerful tool for phenotyping mice in biologic studies of genetic expression, development, and disease progression. In several applications, notably random mutagenesis trials, large cohorts of mice must be examined for abnormalities that may occur in any part of the body. In the aim of establishing a protocol for imaging multiple mice simultaneously in a standardized high-throughput fashion, this study investigates variations of a three-dimensional fast spin-echo sequence that implements driven equilibrium, modified refocusing, and partial excitation pulses. Sequence variations are compared by simulated and experimental measurements in phantoms and mice. Results indicate that when using a short repetition time (TR<or=T1) a sequence employing a partial excitation tip angle provides both improved signal and good T2 contrast compared with standard fast spin-echo imaging. This sequence is used to simultaneously acquire four live mouse head images at 100 microm isotropic resolution with a scan time under 3 h at 7 T.

Animals↗
PubMed2005

Magnetic resonance imaging for detection and analysis of mouse phenotypes.

With the enormous and growing number of experimental and genetic mouse models of human disease, there is a need for efficient means of characterizing abnormalities in mouse anatomy and physiology. Adaptation of magnetic resonance imaging (MRI) to the scale of the mouse promises to address this challenge and make major contributions to biomedical research by non-invasive assessment in the mouse. MRI is already emerging as an enabling technology providing informative and meaningful measures in a range of mouse models. In this review, recent progress in both in vivo and post mortem imaging is reported. Challenges unique to mouse MRI are also identified. In particular, the needs for high-throughput imaging and comparative anatomical analyses in large biological studies are described and current efforts at handling these issues are presented.

Animals↗
PubMed2005

A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia.

Oculodentodigital dysplasia (ODDD) is an autosomal dominant disorder characterized by pleiotropic developmental anomalies of the limbs, teeth, face and eyes that was shown recently to be caused by mutations in the gap junction protein alpha 1 gene (GJA1), encoding connexin 43 (Cx43). In the course of performing an N-ethyl-N-nitrosourea mutagenesis screen, we identified a dominant mouse mutation that exhibits many classic symptoms of ODDD, including syndactyly, enamel hypoplasia, craniofacial anomalies and cardiac dysfunction. Positional cloning revealed that these mice carry a point mutation in Gja1 leading to the substitution of a highly conserved amino acid (G60S) in Cx43. In vivo and in vitro studies revealed that the mutant Cx43 protein acts in a dominant-negative fashion to disrupt gap junction assembly and function. In addition to the classic features of ODDD, these mutant mice also showed decreased bone mass and mechanical strength, as well as altered hematopoietic stem cell and progenitor populations. Thus, these mice represent an experimental model with which to explore the clinical manifestations of ODDD and to evaluate potential intervention strategies.

Abnormalities, Multiple↗
PubMed2004

Angiopoietin-1 causes reversible degradation of the portal microcirculation in mice: implications for treatment of liver disease.

In many different liver diseases, such as cirrhosis, degradation of the microcirculation, including obliteration of small portal or hepatic veins contributes to disease-associated portal hypertension. The present study demonstrates the importance of angiogenesis in the establishment of arteriovenous shunts and the accompanying changes to the venous bed. One aspect of angiogenesis involves the branching of new vessels from pre-existing ones, and the molecular mechanisms controlling it are complex and involve a coordinated effort between specific endothelial growth factors and their receptors, including the angiopoietins. We modulated the hepatic vasculature in mice by conditionally expressing angiopoietin-1 in hepatocytes. In mice exposed to angiopoietin-1 during development, arterial sprouting, enlarged arteries, marked loss of portal vein radicles, hepatic vein dilation, and suggestion of arteriovenous shunting were observed. Most importantly, these phenotypic changes were completely reversed within 14 days of turning off transgene expression. Expression of excess angiopoietin-1 beginning in adulthood did not fully recapitulate the phenotype, but did result in enlarged vessels. Our findings suggest that controlling excessive angiogenesis during liver disease may promote the restoration of the portal vein circuit and aid in the resolution of disease-associated portal hypertension.

Angiopoietin-1↗
PubMed2004

MicroCT scanner performance and considerations for vascular specimen imaging.

Obtaining three-dimensional geometrical data of vascular systems is of major importance to a number of research areas in medicine and biology. Examples are the characterization of tumor vasculature, modeling blood flow, or genetic effects on vascular development. The performance of the General Electric Medical Systems MS8 microCT scanner is examined in the context of these applications. The system is designed to acquire high-resolution images of specimens up to 5 cm in diameter. A maximum resolution of 38 lp/mm at the 10% modulation transfer function level or 22 microm full width at half maximum of the plane spread function can be achieved with 8.5 microm voxels and a 17 mm field of view. Three different contrast agents are discussed and applied for imaging of small animal vasculature: corrosion casting material Batson's No. 17 with an added lead pigment, silicon rubber MICROFIL MV122, and a suspension of barium sulfate (Baritop) in gelatin. Contrast for all of these agents was highly variable in different vessels as well as within the same vessel. Imaging of PMMA tubing filled with MICROFIL shows that even vessels below 20 microm in diameter are detectable and that diameter estimation of vessels based on thresholding is possible with a precision of 2-3 pixels.

Angiography↗
PubMed2003

Quantitative T2 in the occipital lobe: the role of the CPMG refocusing rate.

PURPOSE: To investigate the dependence of occipital gray and white matter T(2) on the Carr-Purcell-Meiboom-Gill (CPMG) refocusing interval, thereby testing the basis of a novel functional magnetic resonance imaging (fMRI) method for blood volume quantification, and addressing recent questions surrounding T(2) contrast in the occipital lobe. MATERIALS AND METHODS: A CPMG sequence with 1 x 1 x 5 mm(3) resolution was used to quantify T(2) in a single axial slice at the midlevel of the occipital lobe in 23 healthy adult volunteers. Refocusing intervals of 8, 11, and 22 msec were compared. A Bayesian classifier was used to classify a 1 x 1 x 1 mm(3) T(1)-weighted three-dimensional data set into gray matter, white matter, and cerebrospinal fluid, with an average 95% a posteriori probability used as the threshold for inclusion into a tissue-specific region of interest (ROI). RESULTS: The usual T(2) contrast between the gray and white matter (i.e., T(2GM) > T(2WM)) was observed, with a highly significant effect of tissue type on the estimated T(2) (P < 10(-5)). The observed T(2) gradually decreased with increasing refocusing interval, for a decrease of 3.3 +/- 1.5 msec in gray matter and 3.0 +/- 1.5 msec in white matter between the 8 and 22 msec refocusing interval acquisitions. CONCLUSION: The observed T(2) shortening is consistent with the effect of the dramatic decrease in T(2) of partly deoxygenated blood on this range of refocusing rates.

Adult↗
PubMed2002

Regional magnetization transfer ratio changes in mild cognitive impairment.

Reduction in temporal lobe volume is consistently found in dementia of Alzheimer's type (DAT). However, due to the lack of a consistent association between brain volume and cognitive decline in mild cognitive impairment (MCI), volumetric measures are not a reliable predictor for the progression of the disease. In our study, we hypothesized that changes in the magnetization transfer ratio (MTR) may reflect underlying brain pathology in the absence of quantifiable volumetric changes. Such a measure may be used as a predictor for abnormal cognitive decline in elderly subjects. The study was carried out on 15 normal elderly controls, 11 subjects with DAT, and 12 subjects with MCI. We used MTRs with magnetic resonance imaging (MRI) to detect tissue changes in the four lobes of each hemisphere, and compared that to the volumetric changes in the same regions. Our results indicate that the MTR of both temporal lobes is significantly reduced in subjects with MCI in the absence of significant volumetric changes. In comparison, DAT subjects have significantly reduced temporal lobe volumes and MTR. We conclude that changes in MTR have the potential to mark the progression of MCI to DAT, before volumetric changes are detected on conventional MRI scans.

Aged↗
PubMed2002

Magnetization transfer ratio in mild cognitive impairment and dementia of Alzheimer's type.

Almost half of the elderly subjects that are diagnosed with mild cognitive impairment (MCI) go on to develop dementia of Alzheimer's type (DAT) over a 5-year follow-up. MCI and DAT subjects show regional decreases in the volume of brain structures, which correlate with the cognitive decline among these groups. Volumetric changes are found more consistently in the DAT group than in the MCI group. Since not all MCI subjects demonstrate volumetric decline, we propose that the underlying changes in the structural integrity of the brain, measured using magnetization transfer ratio (MTR), may be used as an additional predictor for abnormal cognitive decline in the elderly. Magnetic resonance (MR) images were obtained in 15 DAT, MCI, and elderly control subjects. Using automatic tissue classification, the brain region of each MR volume was segmented into gray matter and white matter. Mean and standard error of the mean MTR measured within the gray matter was found to be significantly lower in the MCI (30.77 +/-0.29; P = 0.037) and the DAT (29.37 +/-0.41; P = 0.000) group compared to the control group (32.11 +/-0.20). The MTR of white matter was significantly lower only in the DAT group. The gray matter volume was significantly lower (P = 0.000) in the DAT (387.29 +/-26.04 cm(3)) group compared to controls (532.93 +/-20.53 cm(3)) and MCI (464.64 +/-16.93 cm(3)). No significant differences were found in the white matter volume between the three groups. We conclude that changes in MTR are measurable even in the absence of detectable volumetric changes in gray and white matter in the MCI group. Furthermore, MTR changes may present a novel MRI measure for the early diagnosis of dementia of Alzheimer's type.

Aged↗
PubMedDate not supplied

High-resolution longitudinal screening with magnetic resonance imaging in a murine brain cancer model.

One of the main limitations of intracranial models of diseases is our present inability to monitor and evaluate the intracranial compartment noninvasively over time. Therefore, there is a growing need for imaging modalities that provide thorough neuropathological evaluations of xenograft and transgenic models of intracranial pathology. In this study, we have established protocols for multiple-mouse magnetic resonance imaging (MRI) to follow the growth and behavior of intracranial xenografts of gliomas longitudinally. We successfully obtained weekly images on 16 mice for a total of 5 weeks on a 7-T multiple-mouse MRI. T2- and T1-weighted imaging with gadolinium enhancement of vascularity was used to detect tumor margins, tumor size, and growth. These experiments, using 3D whole brain images obtained in four mice at once, demonstrate the feasibility of obtaining repeat radiological images in intracranial tumor models and suggest that MRI should be incorporated as a research modality for the investigation of intracranial pathobiology.

Angiopoietin-1↗