Biomedical subjects

Sheng-Kwei Song

Publications and source records attributed to Sheng-Kwei Song.

17 recordsLinked to original sources

PubMed2006

Differential sensitivity of in vivo and ex vivo diffusion tensor imaging to evolving optic nerve injury in mice with retinal ischemia.

Decreased axial (lambda(||)) and increased radial (lambda( perpendicular)) diffusivity have been shown to reflect axonal and myelin injury respectively. In the present study, evolving white matter injury within the optic nerves of mice with retinal ischemia was examined by in vivo and ex vivo measurements of lambda(||) and lambda( perpendicular). The results show that at 3 days after retinal ischemia, a 33% decrease in vivo and a 38% decrease ex vivo in lambda(||) without change in lambda( perpendicular) was observed in the injured optic nerve compared to the control, suggestive of axonal damage without myelin injury. At 14 days, both in vivo and ex vivo measured lambda( perpendicular) increased significantly to 220-240% of the control level in the injured optic nerve suggestive of myelin damage. In contrast, the axonal injury that was clearly detected in vivo as a significantly decreased lambda(||) (33% decrease) was not as clearly detected by ex vivo lambda(||) (17% decrease). The current findings suggest that ex vivo lambda( perpendicular) is comparable to in vivo lambda( perpendicular) in detecting myelin injury. However, the structural changes resulting from axonal damage causing the decreased in vivo lambda(||) may not be preserved ex vivo in the fixed tissues. Despite the accurate depiction of the pathology using lambda(||) and lambda( perpendicular) in vivo, the use of ex vivo lambda(||) to extrapolate the status of axonal injury in vivo would require further investigation.

Algorithms↗

PubMed2006

Noninvasive detection of cuprizone induced axonal damage and demyelination in the mouse corpus callosum.

Previously, we tested the prediction that axonal damage results in decreased axial diffusivity (lambda(parallel)) while demyelination leads to increased radial diffusivity (lambda(perpendicular)). Cuprizone treatment of C57BL/6 mice was a highly reproducible model of CNS white matter demyelination and remyelination affecting the corpus callosum (CC). In the present study, six C57BL/6 male mice were fed 0.2% cuprizone for 12 weeks followed by 12 weeks of recovery on normal chow. The control mice were fed normal chow and imaged in parallel. Biweekly in vivo DTI examinations showed transient decrease of lambda(parallel) in CC at 2-6 weeks of cuprizone treatment. Immunostaining for nonphosphorylated neurofilaments demonstrated corresponding axonal damage at 4 weeks of treatment. Significant demyelination was evident from loss of Luxol fast blue staining at 6-12 weeks of cuprizone ingestion and was paralleled by increased lambda(perpendicular) values, followed by partial normalization during the remyelination phase. The sensitivity of lambda(perpendicular) to detect demyelination may be modulated in the presence of axonal damage during the early stage of demyelination at 4 weeks of cuprizone treatment. Our results suggest that lambda(parallel) and lambda(perpendicular) may be useful in vivo surrogate markers of axonal and myelin damage in mouse CNS white matter.

Animals↗

PubMed2005

Detecting axon damage in spinal cord from a mouse model of multiple sclerosis.

In the current study, the feasibility and reproducibility of in vivo diffusion tensor imaging (DTI) of the spinal cord in normal mice are illustrated followed by its application to mice with experimental allergic encephalomyelitis (EAE) to detect and differentiate axon and myelin damage. Axial diffusivity, describing water movement along the axonal fiber tract, in all regions of spinal cord white matter from EAE-affected C57BL/6 mice was significantly decreased compared to normal mice, whereas there was no statistically significant change in radial diffusivity, describing water movement across the fiber tract. Furthermore, a direct comparison between DTI and histology from a single mouse demonstrated a decrease in axial diffusivity that was supported by widespread staining of antibody against beta-amyloid precursor protein. Regionally elevated radial diffusivity corresponded with locally diminished Luxol fast blue staining in the same tissue from the EAE mouse cord. Our findings suggest that axonal damage is more widespread than myelin damage in the spinal cord white matter of mice with EAE and that in vivo DTI may provide a sensitive and specific measure of white matter injury.

Animals↗

PubMed2005

Developmental changes in diffusion anisotropy coincide with immature oligodendrocyte progression and maturation of compound action potential.

Disruption of oligodendrocyte lineage progression is implicated in the white-matter injury that occurs in cerebral palsy. We have previously published a model in rabbits consistent with cerebral palsy. Little is known of normal white-matter development in perinatal rabbits. Using a multidimensional approach, we defined the relationship of oligodendrocyte lineage progression and functional maturation of axons to structural development of selected cerebral white-matter tracts as determined by diffusion tensor imaging (DTI). Immunohistochemical studies showed that late oligodendrocyte progenitors appear at gestational age 22 [embryonic day 22 (E22)], whereas immature oligodendrocytes appear at E25, and both increase rapidly with time (approximately 13 cells/mm2/d) until the onset of myelination. Myelination began at postnatal day 5 (P5) (E36) in the internal capsule (IC) and at P11 in the medial corpus callosum (CC), as determined by localization of sodium channels and myelin basic protein. DTI of the CC and IC showed that fractional anisotropy (FA) increased rapidly between E25 and P1 (E32) (11% per day) and plateaued (<5% per day) after the onset of myelination. Postnatal maturation of the compound action potential (CAP) showed a developmental pattern similar to FA, with a rapid rise between E29 and P5 (in the CC, 18% per day) and a slower rise from P5 to P11 (in the CC, <5% per day). The development of immature oligodendrocytes after E29 coincides with changes in FA and CAP area in both the CC and IC. These findings suggest that developmental expansion of immature oligodendrocytes during the premyelination period may be important in defining structural and functional maturation of the white matter.

Action Potentials↗

PubMed2005

Demyelination increases radial diffusivity in corpus callosum of mouse brain.

Myelin damage, as seen in multiple sclerosis (MS) and other demyelinating diseases, impairs axonal conduction and can also be associated with axonal degeneration. Accurate assessments of these conditions may be highly beneficial in evaluating and selecting therapeutic strategies for patient management. Recently, an analytical approach examining diffusion tensor imaging (DTI) derived parameters has been proposed to assess the extent of axonal damage, demyelination, or both. The current study uses the well-characterized cuprizone model of experimental demyelination and remyelination of corpus callosum in mouse brain to evaluate the ability of DTI parameters to detect the progression of myelin degeneration and regeneration. Our results demonstrate that the extent of increased radial diffusivity reflects the severity of demyelination in corpus callosum of mouse brain affected by cuprizone treatment. Subsequently, radial diffusivity decreases with the progression of remyelination. Furthermore, radial diffusivity changes were specific to the time course of changes in myelin integrity as distinct from axonal injury, which was detected by betaAPP immunostaining and shown to be most extensive prior to demyelination. Radial diffusivity offers a specific assessment of demyelination and remyelination, as distinct from acute axonal damage.

Algorithms↗

PubMed2005

Formalin fixation alters water diffusion coefficient magnitude but not anisotropy in infarcted brain.

This study was designed to determine whether formalin fixation alters diffusion parameters in the infarcted brain. Diffusion tensor images were obtained from anesthetized mice 1 hr after middle cerebral artery occlusion and repeated after formalin fixation of brains. In live animals, there was a significant decrease in the trace of the diffusion tensor (Tr(D)) in infarcted cortex and external capsule compared with contralateral brain areas, with no change in relative anisotropy (RA). After formalin fixation, Tr(D) was reduced 30-80%. However, the Tr(D) differential present in vivo between injured and healthy tissues was lost, with Tr(D) reduced to similar values in all tissues except for the edge of the cortical infarction, where it was lower than in surrounding tissues. RA values were unchanged after fixation. This study supports the preservation of diffusion anisotropy for both healthy and injured white matter in fixed mouse brain. However, the sensitivity of water diffusion in detecting tissue injury in vivo is not preserved in fixed tissues.

Animals↗

PubMed2005

MRI detection of early bone metastases in b16 mouse melanoma models.

Bone metastasis causes significant morbidity in cancer patients, including bone pain, pathologic fractures, nerve compression syndrome, and hypercalcemia. Animal models are utilized to study the pathogenesis of skeletal metastases and to evaluate potential therapeutic agents. Previously published methods for imaging bone metastasis in rodent models have focused on identifying advanced stage metastasis using simple X-rays. Here we report MRI as a method for detecting early bone metastases in mouse models in vivo. B16 mouse melanoma cells were injected into the left cardiac ventricle of C57BL/6 mice and magnetic resonance (MR) images were obtained of the left leg following the development of metastatic disease, when tumor associated bone destruction was histologically present but not visible by X-ray. T1 and T2 relaxation times of bone marrow were measured in healthy control mice and B16 melanoma tumor-bearing mice. Mean T2 values for normal marrow were 28 ms (SD 5) and for diseased bone marrow were 41 ms (SD 3). T2 relaxation time of diseased bone marrow is significantly longer than that of normal bone marrow (P < 0.0001) and can be used as a marker of early bone metastases. These studies demonstrate that MR imaging can detect bone marrow metastases in small animals prior to development of cortical bone loss identified by X-ray.

Animals↗

PubMed2005

Detection of age-dependent brain injury in a mouse model of brain amyloidosis associated with Alzheimer's disease using magnetic resonance diffusion tensor imaging.

Using magnetic resonance diffusion tensor imaging (DTI), the present study investigates changes in both gray and white matter in the APPsw transgenic mouse (Tg2576), a model of beta-amyloid plaque deposition associated with Alzheimer's disease (AD). DTI analyses were performed in cross-sectional groups of transgene-positive and -negative mice at 8, 12, 16, and 18 months of age to assess the magnitude of water diffusion in gray matter (i.e., Tr(D)) and changes in diffusion in white matter that may be indicative of axonal degeneration (i.e., reduced water diffusion parallel to axonal tracts, lambda(||)) and myelin degradation (i.e., increased water diffusion perpendicular to axonal tracts, lambda(perpendicular)). No appreciable changes in gray or white matter were observed between the APPsw and the age-matched control mice at 8 months of age. Reduced Tr(D) and lambda(||) were observed in gray and white matter, respectively, for the APPsw mice at ages greater than 8 months, which coincides with the time period when appreciable amyloid plaque accumulation was confirmed by ex vivo histopathological studies. The decreases in lambda(||) suggest the presence of axonal injury in multiple white matter tracts of APPsw mice. Unlike lambda(||), lambda(perpendicular) was unaltered between control and APPsw mice in most white matter tracts. However, in the corpus collosum (CC), lambda(perpendicular) increased at 16 and 18 months of age, suggesting the possibility of myelin damage in the CC at these later ages. This work demonstrates the potential for DTI as a noninvasive modality to detect evolving pathology associated with changes in tissue water diffusion properties in brain tissues.

Aging↗

PubMed2005

Regional ventricular wall thickening reflects changes in cardiac fiber and sheet structure during contraction: quantification with diffusion tensor MRI.

Dynamic changes of myocardial fiber and sheet structure are key determinants of regional ventricular function. However, quantitative characterization of the contraction-related changes in fiber and sheet structure has not been reported. The objective of this study was to quantify cardiac fiber and sheet structure at selected phases of the cardiac cycle. Diffusion tensor MRI was performed on isolated, perfused Sprague-Dawley rat hearts arrested or fixed in three states as follows: 1) potassium arrested (PA), which represents end diastole; 2) barium-induced contracture with volume (BV+), which represents isovolumic contraction or early systole; and 3) barium-induced contracture without volume (BV-), which represents end systole. Myocardial fiber orientations at the base, midventricle, and apex were determined from the primary eigenvectors of the diffusion tensor. Sheet structure was determined from the secondary and tertiary eigenvectors at the same locations. We observed that the transmural distribution of the myofiber helix angle remained unchanged as contraction proceeded from PA to BV+, but endocardial and epicardial fibers became more longitudinally orientated in the BV- group. Although sheet structure exhibited significant regional variations, changes in sheet structure during myocardial contraction were relatively uniform across regions. The magnitude of the sheet angle, which is an index of local sheet slope, decreased by 23 and 44% in BV+ and BV- groups, respectively, which suggests more radial orientation of the sheet. In summary, we have shown for the first time that geometric changes in both sheet and fiber orientation provide a substantial mechanism for radial wall thickening independent of active components due to myofiber shortening. Our results provide direct evidence that sheet reorientation is a primary determinant of myocardial wall thickening.

Animals↗

PubMed2004

Diffusion tensor imaging detects age-dependent white matter changes in a transgenic mouse model with amyloid deposition.

Increasing evidence demonstrates that there is marked damage and dysfunction not only in the gray matter but also in the white matter in Alzheimer's disease (AD). In this study, transgenic mice overexpressing beta-amyloid precursor protein (APP) under control of the platelet-derived growth factor promoter (PDAPP mice) were examined using diffusion tensor magnetic resonance imaging (DTI) to evaluate the extent of white matter injury before and following the development of AD-like pathology. The profile of DTI parameters was significantly different in old PDAPP mice compared to that of old control mice following the development of AD-like pathology. No difference in DTI parameters was observed between the young PDAPP and control mice. Our results suggest that as amyloid beta (Abeta) deposition and levels increase over time in PDAPP mice, these changes lead to primary or secondary white matter injury that can be detected by DTI.

Aging↗

PubMed2003

Remodeling of cardiac fiber structure after infarction in rats quantified with diffusion tensor MRI.

Structural remodeling of myocardium after infarction plays a critical role in functional adaptation. Diffusion tensor magnetic resonance imaging (DTMRI) provides a means for rapid and nondestructive characterization of the three-dimensional fiber architecture of cardiac tissues. In this study, microscopic structural changes caused by MI were evaluated in Fischer 344 rats 4 wk after infarct surgery. DTMRI studies were performed on 15 excised, formalin-fixed rat hearts of both infarct (left anterior descending coronary artery occlusion, n = 8) and control (sham, n = 7) rats. Infarct myocardium exhibited increased water diffusivity (41% increase in trace values) and decreased diffusion anisotropy (37% decrease in relative anisotropy index). The reduced diffusion anisotropy correlated negatively with microscopic fiber disarray determined by histological analysis (R = 0.81). Transmural courses of fiber orientation angles in infarct zones were similar to those of normal myocardium. However, regional angular deviation of the diffusion tensor increased significantly in the infarct myocardium and correlated strongly with microscopic fiber disarray (R = 0.86). These results suggest that DTMRI may provide a valuable tool for defining structural remodeling in diseased myocardium at the cellular and tissue level.

Animals↗

PubMed2003

Directional correlation characterization and classification of white matter tracts.

To study the architectural characteristics of white matter (WM) tracts, the directional correlation (DC), defined as the inner product of the major eigenvector of adjacent pixels, was used as a quantitative index to investigate directional similarity in WM tracts. A region-growing algorithm was employed to propagate an area from a seed point as a function of the DC threshold (DCt) to critically evaluate the directional properties of WM tracts. As the DCt was increased, more pixels were excluded from the propagated region as their DC fell below the DCt, and neighboring WM tracts could be distinguished as the area decreased. Taking the DC into account, a systematic classification routine for WM tracts was devised and tested on a mouse brain in vivo. The results show that individual WM tracts possess a high degree of directional similarity, and, by careful choice of the DCt value, the proposed classification algorithm can recognize all possible WM tracts in a given data set.

Animals↗

PubMed2003

Improved molecular imaging contrast agent for detection of human thrombus.

Molecular imaging of microthrombus within fissures of unstable atherosclerotic plaques requires sensitive detection with a thrombus-specific agent. Effective molecular imaging has been previously demonstrated with fibrin-targeted Gd-DTPA-bis-oleate (BOA) nanoparticles. In this study, the relaxivity of an improved fibrin-targeted paramagnetic formulation, Gd-DTPA-phosphatidylethanolamine (PE), was compared with Gd-DTPA-BOA at 0.05-4.7 T. Ion- and particle-based r(1) relaxivities (1.5 T) for Gd-DTPA-PE (33.7 (s*mM)(-1) and 2.48 x 10(6) (s*mM)(-1), respectively) were about twofold higher than for Gd-DTPA-BOA, perhaps due to faster water exchange with surface gadolinium. Gd-DTPA-PE nanoparticles bound to thrombus surfaces via anti-fibrin antibodies (1H10) induced 72% +/- 5% higher change in R(1) values at 1.5 T (deltaR(1) = 0.77 +/- 0.02 1/s) relative to Gd-DTPA-BOA (deltaR(1) = 0.45 +/- 0.02 1/s). These studies demonstrate marked improvement in a fibrin-specific molecular imaging agent that might allow sensitive, early detection of vascular microthrombi, the antecedent to stroke and heart attack.

Contrast Media↗

PubMed2003

Relative indices of water diffusion anisotropy are equivalent in live and formalin-fixed mouse brains.

Formalin fixation of tissue is a common laboratory practice. A direct comparison of diffusion tensor imaging (DTI) parameters from mouse brains before (in vivo) and after (ex vivo) formalin fixation is reported herein. Five diffusion indices were examined in a cohort of seven mice: relative anisotropy (RA), directional correlation (DC), trace (Tr(D)), trace-normalized axial diffusivity (D(axially)), and radial diffusivity (D(radially)). Seven regions of interest (ROIs), including five in white matter and two in gray matter, were selected for examination. Consistent with previous findings, a significant decrease of Tr(D) was observed for all ROIs after fixation. However, water diffusion anisotropy, as defined by the indices RA, DC, D(axially), and D(radially), remained unchanged after fixation. Thus, fixation does not appear to alter diffusion anisotropy in the mouse brain. This finding supports the utility of diffusion anisotropy analysis of fixed tissue. The combination of DTI measurements and standard histology may shed light on the microstructural determinants of diffusion anisotropy in normal and disease states.

Animals↗

PubMed2003

Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia.

Both axon and myelin degeneration have significant impact on the long-term disability of patients with white matter disorder. However, the clinical manifestations of the neurological dysfunction caused by white matter disorders are not sufficient to determine the origin of neurological deficits. A noninvasive biological marker capable of detecting and differentiating axon and myelin degeneration would be a significant addition to currently available tools. Directional diffusivities derived from diffusion tensor imaging (DTI) have been previously proposed by this group as potential biological markers to detect and differentiate axon and myelin degeneration. To further test the hypothesis that axial (lambdaparallel) and radial (lambdaperpendicular) diffusivities reflect axon and myelin pathologies, respectively, the optic nerve was examined serially using DTI in a mouse model of retinal ischemia. A significant decrease of lambdaparallel, the putative DTI axonal marker, was observed 3 days after ischemia without concurrently detectable changes in lambdaperpendicular, the putative myelin marker. This result is consistent with histological findings of significant axonal degeneration with no detectable demyelination at 3 days after ischemia. The elevation of lambdaperpendicular observed 5 days after ischemia is consistent with histological findings of myelin degeneration at this time. These results support the hypothesis that lambdaparallel and lambdaperpendicular hold promise as specific markers of axonal and myelin injury, respectively, and, further, that the coexistence of axonal and myelin degeneration does not confound this utility.

Animals↗

PubMed2002

Improved magnetic resonance imaging detection of prostate cancer in a transgenic mouse model.

Transgenic mouse models of prostate cancer provide an opportunity to conduct genetic tests of the molecular mechanisms underlying initiation and progression of tumorigenesis. They also allow assessment of the effects of various pharmacological interventions. However, one limitation that has impeded full exploitation of these models is the lack of in vivo imaging procedures of sufficient sensitivity and resolution to detect and follow tumors at early stages of growth. We have addressed this problem through the use of diffusion-weighted magnetic resonance imaging (DWI). A transgenic mouse model (CR2-TAg) of prostate cancer was used to show that DWI can detect tumors <1 mm in diameter. Markedly enhanced DWI contrast results from a 2-fold difference in apparent diffusion coefficient between benign and malignant prostatic tissue (P < 0.00001). Clinical application of DWI may offer advantages over current T2-weighted magnetic resonance imaging methods.

Animals↗

PubMed2002

Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water.

Myelin loss and axonal damage are both observed in white matter injuries. Each may have significant impact on the long-term disability of patients. Currently, there does not exist a noninvasive biological marker that enables differentiation between myelin and axonal injury. We describe herein the use of magnetic resonance diffusion tensor imaging (DTI) to quantify the effect of dysmyelination on water directional diffusivities in brains of shiverer mice in vivo. The principal diffusion eigenvalues of eight axonal fiber tracts that can be identified with certainty on DTI maps were measured. The water diffusivity perpendicular to axonal fiber tracts, lambda(perpendicular), was significantly higher in shiverer mice compared with age-matched controls, reflecting the lack of myelin and the increased freedom of cross-fiber diffusion in white matter. The water diffusivity parallel to axonal fiber tracts, lambda(parallel), was not different, which is consistent with the presence of intact axons. It is clear that dysmyelination alone does not impact lambda(parallel). The presence of intact axons in the setting of incomplete myelination was confirmed by electron microscopy. Although further validation is still needed, our finding suggests that changes in lambda(perpendicular) and lambda(parallel) may potentially be used to differentiate myelin loss versus axonal injury.

Animals↗