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ABSTRACT: PURPOSE: To evaluate brain metabolite levels as in vivo indicators of disease progression in a widely studied mouse model of Niemann-Pick type C1 (NPC1) disease with quantitative (1) H magnetic resonance spectroscopy (MRS). MATERIALS AND METHODS: Single voxel MRS experiments were carried out in vivo in a mouse model of NPC1 disease and in control mice in two brain regions (central and posterior) at two timepoints (presymptomatic and endstage) to examine changes in metabolite levels in NPC1 disease. Concentrations of nine metabolites were quantified by fitting a simulated basis set of metabolite signals to the acquired spectra. RESULTS: The only differences found in brain metabolite levels between NPC1 disease model and control mice were increased myo-inositol and decreased taurine in the posterior region of the brain at the endstage of the disease. Metabolite changes reported in past clinical MRS studies of NPC disease were not found in the current study of the mouse model. CONCLUSIONS: The (1) H spectra obtained from NPC1 mice and control mice were very similar, even at endstages of the disease. Although differences in two metabolites associated with neurodegenerative diseases were found and could inform future studies of the disease model, it appears that MRS in this mouse model of NPC1 disease does not have the sensitivity desired for a biomarker. J. Magn. Reson. Imaging 2012;. © 2012 Wiley Periodicals, Inc.
Journal of Magnetic Resonance Imaging 11/2012; · 2.70 Impact Factor
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ABSTRACT: A new finite difference (FD) method for calculating the time evolution of complex transverse magnetization in diffusion-weighted magnetic resonance imaging and spectroscopy experiments is described that incorporates periodic boundary conditions. The new FD method relaxes restrictions on the allowable time step size employed in modeling which can significantly reduce computation time for simulations of large physical extent and allow for more complex, physiologically relevant, geometries to be simulated.
Physics in Medicine and Biology 02/2012; 57(4):N35-46. · 2.83 Impact Factor
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Robert A Maue,
Robert W Burgess,
Bing Wang,
Christine M Wooley,
Kevin L Seburn,
Marie T Vanier,
Maximillian A Rogers,
Catherine C Chang,
Ta-Yuan Chang,
Brent T Harris,
David J Graber,
Carlos A A Penatti,
Donna M Porter,
Benjamin S Szwergold,
Leslie P Henderson,
John W Totenhagen, Theodore P Trouard,
Ivan A Borbon,
Robert P Erickson
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ABSTRACT: We have identified a point mutation in Npc1 that creates a novel mouse model (Npc1(nmf164)) of Niemann-Pick type C1 (NPC) disease: a single nucleotide change (A to G at cDNA bp 3163) that results in an aspartate to glycine change at position 1005 (D1005G). This change is in the cysteine-rich luminal loop of the NPC1 protein and is highly similar to commonly occurring human mutations. Genetic and molecular biological analyses, including sequencing the Npc1(spm) allele and identifying a truncating mutation, confirm that the mutation in Npc1(nmf164) mice is distinct from those in other existing mouse models of NPC disease (Npc1(nih), Npc1(spm)). Analyses of lifespan, body and spleen weight, gait and other motor activities, as well as acoustic startle responses all reveal a more slowly developing phenotype in Npc1(nmf164) mutant mice than in mice with the null mutations (Npc1(nih), Npc1(spm)). Although Npc1 mRNA levels appear relatively normal, Npc1(nmf164) brain and liver display dramatic reductions in Npc1 protein, as well as abnormal cholesterol metabolism and altered glycolipid expression. Furthermore, histological analyses of liver, spleen, hippocampus, cortex and cerebellum reveal abnormal cholesterol accumulation, glial activation and Purkinje cell loss at a slower rate than in the Npc1(nih) mouse model. Magnetic resonance imaging studies also reveal significantly less demyelination/dysmyelination than in the null alleles. Thus, although prior mouse models may correspond to the severe infantile onset forms of NPC disease, Npc1(nmf164) mice offer many advantages as a model for the late-onset, more slowly progressing forms of NPC disease that comprise the large majority of human cases.
Human Molecular Genetics 11/2011; 21(4):730-50. · 7.64 Impact Factor
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ABSTRACT: To quantitatively and noninvasively assess neurological disease progression in a mouse model of Niemann-Pick type C (NPC) disease by measuring white matter status with magnetic resonance imaging (MRI) techniques of T2 mapping and diffusion tensor imaging (DTI).
Quantitative T2 and DTI experiments were performed in vivo in NPC disease model and control mice at three timepoints to quantify differences and changes in white matter with measurements of T2 relaxation and DTI parameters. Histological staining for myelin content was also performed at two timepoints to compare with the MRI findings.
The results of the T2 and DTI measurements show significant differences in white matter areas of the brain in the NPC disease model compared to control mice at several timepoints, and were seen to change over time in both groups.
The findings of this study suggest that quantitative MRI measurements may be suitable in vivo biomarkers of disease status for future studies of NPC disease models. The changes in white matter measurements between timepoints in both control and NPC disease groups suggest that white matter structures continue to change and develop over time in the NPC model and can be tracked with MRI techniques.
Journal of Magnetic Resonance Imaging 11/2011; 35(3):528-36. · 2.70 Impact Factor
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ABSTRACT: This work reports results of experiments in hollow-fiber bioreactor C6 glioma cell cultures where the apparent diffusion coefficient (ADC) of intracellular water (iADC) was measured at diffusion times between 0.83 and 40 ms. The experiments were carried out before and after the onset of permanent ischemia. The changes in iADC following ischemia were dependent on the diffusion time employed in the experiment. An ischemia-induced decrease in the iADC was measured at short diffusion times, while at long diffusion times the iADC increased. Decreases in the iADC measured at short diffusion times are interpreted to be a result of a decrease in the intrinsic diffusivity of intracellular water due to energy failure. Increases in iADC measured at long diffusion times, are interpreted to result from cell swelling.
Magnetic Resonance in Medicine 03/2011; 66(3):859-67. · 2.96 Impact Factor
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Proceedings of the 8th IEEE International Symposium on Biomedical Imaging: From Nano to Macro, ISBI 2011, March 30 - April 2, 2011, Chicago, Illinois, USA; 01/2011
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ABSTRACT: A recent population-based genome-wide association study has revealed that the Niemann-Pick C1 (NPC1) gene is associated with early-onset and morbid adult obesity. Concurrently, our candidate gene-based mouse growth study performed using the BALB/cJ NPC1 mouse model (Npc1) with decreased Npc1 gene dosage independently supported these results by suggesting an Npc1 gene-diet interaction in relation to early-onset weight gain. To further investigate the Npc1 gene in relation to weight gain and metabolic features associated with insulin resistance, we interbred BALB/cJ Npc1(+/-) mice with wild-type C57BL/6J mice, the latter mouse strain commonly used to study aspects of diet-induced obesity and insulin resistance. This breeding produced a hybrid (BALB/cJ-C57BL/6J) Npc1(+/-) mouse model with increased susceptibility to weight gain and insulin resistance. The results from our study indicated that these Npc1(+/-) mice were susceptible to increased weight gain characterized by increased whole body and abdominal adiposity, adipocyte hypertrophy and hepatic steatosis in the absence of hyperphagia. Moreover, these Npc1(+/-) mice developed abnormal metabolic features characterized by impaired fasting glucose, glucose intolerance, hyperinsulinemia, hyperleptinemia and dyslipidemia marked by an increased concentration of cholesterol and triacylglycerol associated with low-density lipoprotein and high-density lipoprotein. The overall results are consistent with a unique Npc1 gene-diet interaction that promotes both weight gain and metabolic features associated with insulin resistance. Therefore, the NPC1 gene now represents a previously unrecognized gene involved in maintaining energy and metabolic homeostasis that will contribute to our understanding concerning the current global epidemic of obesity and type 2 diabetes mellitus.
Human Molecular Genetics 10/2010; 20(2):312-21. · 7.64 Impact Factor
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ABSTRACT: The apparent diffusion coefficient (ADC), as measured by diffusion-weighted MRI, has proven useful in the diagnosis and evaluation of ischemic stroke. The ADC of tissue water is reduced by 30-50% following ischemia and provides excellent contrast between normal and affected tissue. Despite its clinical utility, there is no consensus on the biophysical mechanism underlying the reduction in ADC. In this work, a numerical simulation of water diffusion is used to predict the effects of cellular tissue properties on experimentally measured ADC. The model indicates that the biophysical mechanisms responsible for changes in ADC postischemia depend upon the time over which diffusion is measured. At short diffusion times, the ADC is dependent upon the intrinsic intracellular diffusivity, while at longer, clinically relevant diffusion times, the ADC is highly dependent upon the cell volume fraction. The model also predicts that at clinically relevant diffusion times, the 30-50% drop in ADC after ischemia can be accounted for by cell swelling alone when intracellular T(2) is allowed to be shorter than extracellular T(2).
Magnetic Resonance in Medicine 09/2009; 62(6):1414-22. · 2.96 Impact Factor
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ABSTRACT: Diffusion-weighted MRI is commonly used in the diagnosis and evaluation of ischemic stroke because of the rapid decrease observed in the apparent diffusion coefficient (ADC) of tissue water following ischemia. Although this observation has been clinically useful for many years, the biophysical mechanisms underlying the reduction of tissue ADC are still unknown. To help elucidate these mechanisms, we have employed a novel three-dimensional (3D) hollow-fiber bioreactor (HFBR) perfused cell culture system that enables cells to be grown to high density and studied via MRI and MRS. By infusing contrast media into the HFBR, signals from intracellular water and extracellular water are spectroscopically resolved and can be investigated individually. Diffusion measurements carried out on C6 glioma HFBR cell cultures indicate that ischemia-induced cellular swelling results in an increase in the ADC of intracellular water from 0.35 microm(2)/ms to approximately 0.5 microm(2)/ms (diffusion time = 25 ms).
Magnetic Resonance in Medicine 09/2008; 60(2):258-64. · 2.96 Impact Factor
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ABSTRACT: In order to investigate the properties of water motion within and around brain tumors as a function of tumor growth, longitudinal diffusion tensor imaging (DTI) was carried out in a rat brain glioma (C6) model. As tumors grew in size, significant anisotropy of water diffusion was seen both within and around the tumor. The tissue water surrounding the tumor exhibited high planar anisotropy, as opposed to the linear anisotropy normally seen in white matter, indicating that cells were experiencing stress in a direction normal to the tumor border. When tumors were sufficiently large, significant anisotropy was also seen within the tumor because of longer-range organization of cancer cells within the tumor borders. These findings have important implications for diffusion-weighted MRI experiments examining tumor growth and response to therapy.
NMR in Biomedicine 06/2008; 21(8):799-808. · 3.21 Impact Factor
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ABSTRACT: To noninvasively evaluate the early effects of Niemann-Pick type C (NPC) disease, diffusion tensor imaging (DTI) was carried out in the brains of very young (23-day-old) mice. The diffusion of water in white matter tracts of Npc1(-/-) mice at this young age was already abnormal, exhibiting decreased anisotropy, as quantified by fractional anisotropy (FA), compared with their wild-type littermates, the controls. Postmortem histological staining revealed myelin deficiencies in Npc1(-/-) mice, consistent with the reduction in FA measured in vivo. Beneficial effects of treatment with allopregnanolone and/or 2 hydroxypropyl-beta-cyclodextrin was also detectable at this age by FA, which correlated with increased myelination as seen by histology. This is the earliest detection of a therapeutic effect in Npc1(-/-) mice.
Journal of Neuroscience Research 06/2008; 86(12):2802-7. · 2.74 Impact Factor
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ABSTRACT: Caffeine ingestion results in increased brain cell metabolism (Nehlig et al. [1992] Brain Res Brain Res Rev 17:139-170) and decreased cerebral blood flow (Field et al. [2003] Radiology 227:129-135; Mulderink et al. [2002] Neuroimage 15:37-44). The current study investigated the effect of caffeine in a word stem completion task using only novel word stems (no repeated stimuli). Resting perfusion was measured with arterial spin labeled perfusion MRI, along with blood oxygenation level-dependent (BOLD) signal before and after ingestion of regular coffee, decaffeinated coffee, and water. Based on previous research (Laurienti et al. [2002] Neuroimage 17:751-757; Mulderink et al. [2002] Neuroimage 15:37-44), we hypothesized that caffeine would result in increased BOLD signal intensity and extent of BOLD activation. As expected, caffeine resulted in a significant decrease in cerebral perfusion. However, both the control and caffeine groups showed an increase in BOLD signal amplitude across two sets of novel word stems. Additionally, the control group showed a 50% reduction in the extent of BOLD activation, while the caffeine group showed no change in activation extent. Neither group showed changes in BOLD baseline signal over time, which had been suggested to mediate caffeine-related BOLD signal changes. The results suggest that caffeine may attenuate general task practice effects that have been described in recent functional MRI studies of word stem completion (Buckner et al. [2000] Brain 123:620-640).
Human Brain Mapping 08/2007; 28(7):654-62. · 5.88 Impact Factor
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ABSTRACT: DOTA-based complexes of gadolinium (Gd) bearing a thiol moiety on a propyl or hexyl arm were synthesized. It was hypothesized that these complexes would form reversible covalent linkages with human serum albumin (HSA), which contains a reactive thiol at cysteine-34. The binding constant of the hexyl complex to HSA was measured to be 64 mM(-1) and decreased to 17, 6.1, and 3.6 mM(-1) in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The binding constant of the propyl complex to HSA was significantly lower (5.0 mM(-1)) and decreased to 2.0, 1.5, and 0.87 mM(-1) in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The longitudinal water-proton relaxivities of the hexyl and propyl complexes at 37 degrees C and 4.7 T were 2.3 and 2.9 mM(-1) s(-1), respectively, in saline. The relaxivities of the HSA-bound forms of the hexyl and propyl complexes were calculated to be 5.3 and 4.5 mM(-1) s(-1), respectively. The in vivo pharmacokinetics of both thiol complexes were altered by a chase of homocysteine but not saline, while the washout of GdDTPA was unaffected by either chase. Such redox-sensitive reversible binding of Gd complexes to plasma albumin can be exploited for imaging tissue redox and the blood-pool by MRI.
Magnetic Resonance in Medicine 07/2006; 55(6):1272-80. · 2.96 Impact Factor
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Iram Ahmad,
Silvia Lope-Piedrafita,
Xiaoning Bi,
Chad Hicks,
Yueqin Yao,
Clara Yu,
Elizabeth Chaitkin,
Christine M Howison,
Lyndon Weberg, Theodore P Trouard,
Robert P Erickson
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ABSTRACT: Niemann-Pick C disease (NPC) is an irreversible neurodegenerative disorder without current treatment. It is thought to result from deficient intracellular cholesterol and/or ganglioside trafficking. We have investigated the effects of allopregnanolone treatments on survival, weight loss, motor function, magnetic resonance imaging (MRI), and neuropathology in the mouse model of NPC (Npc1(-/-) mice). We confirmed previous results showing that a single injection of 250 microg of allopregnanolone on postnatal day 7 significantly extended the life span of Npc1(-/-) mice. This caused a marked difference in the weight curves of the treated mice but no statistical difference in the Rota-Rod performance. T2-weighted MRI and diffusion tensor imaging (DTI) of treated mice showed values of signal intensity and fractional anisotropy closer to those of wild-type mice than those of untreated Npc1(-/-) mice. Neuropathology showed that day-7 treatment markedly suppressed astrocyte reaction and significantly reduced microglial activation. Furthermore, the steroid treatment also increased myelination in brains of Npc1(-/-) mice. Similar effects of allopregnanolone treatment were observed in Npc1(-/-), mdr1a(-/-) double-mutant mice, which have a deficient blood-brain barrier, resulting in increased steroid uptake. The effects on survival and weight loss of a single injection on day 7 followed by injections every 2 weeks were also evaluated in Npc1(-/-) mice, and the beneficial effects were found to be greater than with the single injection at day 7. We conclude that allopregnanolone treatment significantly ameliorates several symptoms of NPC in Npc1(-/-) mice, presumably by effects on myelination or neuronal connectivity.
Journal of Neuroscience Research 01/2006; 82(6):811-21. · 2.74 Impact Factor
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ABSTRACT: Niemann-Pick Type C disease is a homozygous recessive disorder resulting in errant intracellular cholesterol metabolism and the accumulation of intracellular unesterified cholesterol and sphingolipids. Although no current effective treatment exists for Niemann-Pick Type C disease, a number of therapies are under development in animal models. As therapies are brought into clinical trials, it will be extremely helpful to have a reliable means to track the progression of the disease and to monitor its response to therapy. In this effort, diffusion tensor imaging has been applied to investigate the white matter in a Niemann-Pick Type C patient, and the results compared to those from age-matched control subjects. Diffusion tensor imaging enables quantitative measurement of water diffusion in white matter, which is sensitive to the architecture and integrity of the tissue. Compared with control subjects, significant reductions in fractional anisotropy values were observed in regions of white matter, most prominently in the corpus callosum. The results from this case study suggest that diffusion tensor imaging may allow progression of the disease to be quantitatively measured and may be able to play a role as a surrogate marker in clinical trials.
Pediatric Neurology 12/2005; 33(5):325-30. · 1.52 Impact Factor
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ABSTRACT: Radially acquired fast spin-echo data can be processed to obtain T2-weighted images and a T2 map from a single k-space data set. The general approach is to use data at a specific TE (or narrow TE range) in the center of k-space and data at other TE values in the outer part of k-space. With this method high-resolution T2-weighted images and T2 maps are obtained in a time efficient manner. The mixing of TE data, however, introduces errors in the T2-weighted images and T2 maps that affect the accuracy of the T2 estimates. In this work, various k-space data processing methods for reconstructing T2-weighted images and T2 maps from a single radial fast spin-echo k-space data set are analyzed in terms of the accuracy of T2 estimates. The analysis is focused on the effect of image artifacts, object dependency, and noise on the T2 estimates. Results are presented in computer-generated phantoms and in vivo.
Magnetic Resonance in Medicine 10/2005; 54(3):549-59. · 2.96 Impact Factor
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ABSTRACT: The complexity of biologic tissues, with multiple compartments each with its own diffusion and relaxation properties, requires complex formalisms to model water signal in most magnetic resonance imaging or magnetic resonance spectroscopy experiments. In this article, we describe a magnetic susceptibility-induced shift in the resonance frequency of extracellular water by the introduction of a gadolinium contrast agent to medium perfusing a hollow fiber bioreactor. The frequency shift of the extracellular water (+185 Hz at 9.4 T) uncovers the intracellular water and allows direct measurement of motional and relaxation properties of the intracellular space. The proposed method provides a unique tool for understanding the mechanisms underlining diffusion and relaxation in the intracellular space.
Magnetic Resonance in Medicine 08/2005; 54(1):79-86. · 2.96 Impact Factor
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ABSTRACT: Radial fast spin-echo (radial-FSE) methods enable multishot diffusion-weighted MRI (DWMRI) to be carried out without significant artifacts due to motion and/or susceptibility and can be used to generate DWMRI images with high spatial resolution. In this work, a novel method that allows isotropic diffusion weighting to be obtained in a single radial k-space data set is presented. This is accomplished by altering the direction of diffusion weighting gradients between groups of TR periods, which yield sets of radial lines that possess diffusion weighting sensitive to motion in different directions. By altering the diffusion weighting directions and controlling the view ordering appropriately within the sequence, an effectively isotropic diffusion-weighted image can be obtained within one radial-FSE scan. The order in which radial lines are acquired can also be controlled to yield data sets without significant artifacts due to motion, T(2) decay, and/or diffusion anisotropy.
Magnetic Resonance in Medicine 07/2005; 53(6):1347-54. · 2.96 Impact Factor
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ABSTRACT: RAD-GRASE is an MRI sequence that combines radial (RAD) k-space scanning with the gradient and spin-echo (GRASE) technique. RAD-GRASE has the advantages of all radial data acquisition methods in that it can reduce motion sensitivity and correct motion-induced data errors, which can be exploited to achieve high-resolution diffusion-weighted imaging (DWI). One can obtain different types of image contrast, including DWI, T(1), T(2), and T(2)*, in RAD-GRASE by controlling the magnetization preparation and sequence timing. Moreover, because there is oversampling of the low spatial frequencies inherent to radial sequences, partial data reconstruction can be used to achieve multiple forms of image contrast from a single acquired data set, and to generate parametric image maps of equilibrium magnetization, T(2), and T(2) (dagger). The RAD-GRASE technique can also be used to achieve fat-suppressed and/or separated fat and water images by choosing the appropriate timing parameters.
Magnetic Resonance in Medicine 07/2005; 53(6):1363-71. · 2.96 Impact Factor
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ABSTRACT: Radial MRI sequences are frequently used to obtain images with reduced sensitivity to motion. To decrease imaging time, multiple spin-echo acquisitions can be incorporated into radial sequences. In this case, different radial lines of Fourier data have different TE times and the resulting images can contain streaking artifacts due to T(2) decay. The streaking is not only dependent on the T(2) of the object and the timing of the data acquisition, but also on the order in which radial lines are collected (view order). The view ordering can easily be controlled to minimize artifacts due to T(2) decay as well as motion. Four view-ordering techniques are presented and evaluated for the radial FSE sequence.
Magnetic Resonance in Medicine 05/2004; 51(4):768-74. · 2.96 Impact Factor
