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1.  Diffusion tensor imaging detects treatment effects of FTY720 in experimental autoimmune encephalomyelitis mice 
NMR in biomedicine  2013;26(12):10.1002/nbm.3012.
Fingolimod (FTY720) is an orally available sphingosine-1-phosphate (S1P) receptor modulator reducing relapse frequency in relapse-remitting multiple sclerosis (RRMS) patients. In addition to immunosuppression, neuronal protection of FTY720 has also been suggested but remains controversial. Axial and radial diffusivities derived from in vivo diffusion tensor imaging (DTI) were employed as non-invasive biomarkers of axonal injury and demyelination to assess axonal protection of FTY720 in experimental autoimmune encephalomyelitis (EAE) mice. EAE was induced through active immunization of C57BL/6 mice using myelin oligodendrocyte glycoprotein peptide 35 – 55 (MOG35–55). We evaluated both prophylactic and therapeutic treatment effect of FTY720 at doses of 3 and 10 mg/kg on these EAE mice by daily clinical scoring and end-point in vivo DTI. Prophylactic administration of FTY720 suppressed the disease onset and prevented axon and myelin damage as compared with EAE mice without treatment. Therapeutic treatment of FTY720 did not prevent EAE onset but reduced the disease severity improving axial and radial diffusivity toward the control values without a statistical significance. Consistent with previous findings, in vivo DTI-derived axial and radial diffusivity correlated with clinical scores in EAE mice. Results support the use of in vivo DTI as an effective outcome measure for preclinical drug development.
doi:10.1002/nbm.3012
PMCID: PMC3838438  PMID: 23939596
diffusion tensor imaging; axial diffusivity; radial diffusivity; axonal injury; demyelination; experimental autoimmune encephalomyelitis; multiple sclerosis; FTY720
2.  The impact of myelination on axon sparing and locomotor function recovery in spinal cord injury assessed using diffusion tensor imaging 
NMR in biomedicine  2013;26(11):1484-1495.
The dysmyelinated axons of shiverer mice exhibit impaired conduction characteristics similar to early postnatal axons before myelination, while the patterns of neuronal activity and connectivity are relatively comparable to those of wild-type myelinated axons. This unique dysmyelination pattern is exploited in the present study to determine the role of compact myelin on the loss and recovery of function following traumatic spinal cord injury (SCI). We applied in vivo diffusion tensor imaging (DTI) and post-mortem immunohistochemistry analysis to examine changes in myelin and axonal integrity and evaluated these changes in concert with analysis of locomotor function from 1 to 4 weeks following a mid-thoracic contusion injury in homozygous shiverer and heterozygous littermate mice. The DTI biomarkers, axial and radial diffusivities, are noninvasive indicators of axon and myelin integrity in response to SCI of both myelinated and dysmyelinated spinal cord. We show that myelin is critical for normal hind limb function in open field locomotion. However, when the functional outcome is limited during chronic SCI, the extent of recovery is associated with residual axonal integrity and independent of the extent of intact myelin at the lesion epicenter.
doi:10.1002/nbm.2981
PMCID: PMC3800477  PMID: 23775778
diffusion tensor imaging; myelin; dysmyelination; white matter; spinal cord injury
3.  Quantification of increased cellularity during inflammatory demyelination 
Brain  2011;134(12):3587-3598.
Multiple sclerosis is characterized by inflammatory demyelination and irreversible axonal injury leading to permanent neurological disabilities. Diffusion tensor imaging demonstrates an improved capability over standard magnetic resonance imaging to differentiate axon from myelin pathologies. However, the increased cellularity and vasogenic oedema associated with inflammation cannot be detected or separated from axon/myelin injury by diffusion tensor imaging, limiting its clinical applications. A novel diffusion basis spectrum imaging, capable of characterizing water diffusion properties associated with axon/myelin injury and inflammation, was developed to quantitatively reveal white matter pathologies in central nervous system disorders. Tissue phantoms made of normal fixed mouse trigeminal nerves juxtaposed with and without gel were employed to demonstrate the feasibility of diffusion basis spectrum imaging to quantify baseline cellularity in the absence and presence of vasogenic oedema. Following the phantom studies, in vivo diffusion basis spectrum imaging and diffusion tensor imaging with immunohistochemistry validation were performed on the corpus callosum of cuprizone treated mice. Results demonstrate that in vivo diffusion basis spectrum imaging can effectively separate the confounding effects of increased cellularity and/or grey matter contamination, allowing successful detection of immunohistochemistry confirmed axonal injury and/or demyelination in middle and rostral corpus callosum that were missed by diffusion tensor imaging. In addition, diffusion basis spectrum imaging-derived cellularity strongly correlated with numbers of cell nuclei determined using immunohistochemistry. Our findings suggest that diffusion basis spectrum imaging has great potential to provide non-invasive biomarkers for neuroinflammation, axonal injury and demyelination coexisting in multiple sclerosis.
doi:10.1093/brain/awr307
PMCID: PMC3235568  PMID: 22171354
magnetic resonance imaging; diffusion tensor imaging; multiple tensor model; white matter injury; inflammation
4.  Cell Swelling Contributes to Thickening of Low-Dose N-methyl-D-Aspartate–Induced Retinal Edema 
Purpose.
The contribution of cell swelling versus vascular leakage in retinal edema remains largely undefined. The objective of this study was to use in vivo magnetic resonance imaging (MRI) to assess retinal cell swelling in the edematous mouse retina.
Methods.
Inner retinal edema was induced by intravitreal injection of 2.5 nmol N-methyl-D-aspartate (NMDA). To assess retinal cell swelling, diffusion MRI was performed at baseline, 3-hours, 1 day, 3 days, and 7 days (n ≥ 5 at each time point) after NMDA injection. To detect retinal vascular leakage, gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) enhanced MRI was performed at baseline, 3 hours and 1 day (n = 5 for each group) after NMDA injection. Upon the completion of MRI, mouse eyes were enucleated, cryosectioned, and stained for assessing retinal layer thickness and cell death.
Results.
Inner retinal cell swelling was hyperintense on diffusion-weighted images at 3 hours and 1 day after NMDA injection. The thickened inner retina was also seen in anatomic MRI and histology. Quantitatively, inner retinal apparent diffusion coefficient (ADC) decreased approximately 20% at 3 hours and 1 day after NMDA injection (P < 0.05 compared with baseline), suggesting cell swelling. Systematic injection of paramagnetic Gd-DTPA did not alter vitreous longitudinal relaxation time (T1) at baseline or at 3 hours after NMDA injection. In contrast, vitreous T1 in mice decreased 16 ± 6% (P < 0.05), reflecting retinal vascular leakage at 1 day after NMDA injection.
Conclusions.
Noninvasive diffusion MRI was performed to detect retinal cell swelling in vivo. Our results demonstrated that retinal cell swelling could directly lead to retinal thickening independent of vascular leakage.
Noninvasive magnetic resonance imaging was performed to detect retinal cell swelling in vivo. Our results demonstrated cell swelling could directly contribute to edematous retinal thickening independent of retinal vascular leakage.
doi:10.1167/iovs.11-8827
PMCID: PMC3367403  PMID: 22467578
5.  Diffusion Tensor Imaging Detected Optic Nerve Injury Correlates with Decreased Compound Action Potentials after Murine Retinal Ischemia 
Decreased diffusion anisotropy correlated with decreased compound action potential. Decreased axial diffusivity correlated with histology determined axonal injury. Increased radial diffusivity correlated with histology determined myelin damage.
Purpose.
This study evaluated the function of mouse optic nerves after transient retinal ischemia using in vitro electrophysiologic recordings of compound action potentials (CAPs) correlated with diffusion tensor imaging (DTI) injury markers with confirmation by immunohistochemistry-determined pathology.
Methods.
Retinal ischemia was induced in 7- to 8-week-old female C57BL/6 mice by elevating intraocular pressure to 110 mm Hg for 60 minutes. At 3 and 7 days after retinal ischemia, optic nerves were removed for CAP measurements. The CAP amplitude was recorded using suction electrodes in isolated control and injured optic nerves followed by ex vivo DTI evaluation. After DTI, optic nerves were embedded in paraffin and cut for immunohistochemical analyses.
Results.
Consistent with previous in vivo DTI measurements, a 25% decrease in axial diffusivity with normal radial diffusivity was seen at 3 days after retinal ischemia, suggesting axonal injury without myelin damage. At 7 days, there was no additional change in axial diffusivity compared with that at 3 days, but radial diffusivity significantly increased by 50%, suggestive of significant myelin damage due to sustained axonal injury. The relative anisotropy (RA) progressively decreased after retinal ischemia when compared with that of the controls. The CAP amplitude in injured nerves also progressively decreased after retinal ischemia, which correlated with the reduced RA (r = 0.80).
Conclusions.
This study suggests that CAP amplitude reflects both axonal and myelin integrity and RA is an optimal parameter for functional assessment compared with axial or radial diffusivity alone in murine optic nerves after retinal ischemia.
doi:10.1167/iovs.11-7908
PMCID: PMC3292354  PMID: 22159023
6.  Diffusion Tensor Imaging Detects Retinal Ganglion Cell Axon Damage in the Mouse Model of Optic Nerve Crush 
The authors assessed crush-injured retinal ganglion cell axons using in vivo diffusion tensor imaging.
Purpose.
Diffusion tensor imaging (DTI) measures the random motion of water molecules reflecting central nervous system tissue integrity and pathology. Glaucoma damages retinal ganglion cells (RGCs) and their axons. The authors hypothesized that DTI-derived axonal and myelin injury biomarkers may be used to detect early axonal damage and may be correlated with RGC loss in the mouse model of optic nerve crush (ONC).
Methods.
The progression of RGC axon degeneration was quantitatively assessed with DTI in vivo, corroborated with axon/myelin immunohistochemical staining and retrograde fluorogold labeling in mice after ONC.
Results.
Decreased axial diffusivity (λ‖) and relative anisotropy (RA) of damaged axons were observed from 6 hours to 14 days, reflecting axonal injury. DTI detected axonal injury at 6 hours after ONC when SMI-31 did not detect axonal abnormality. Both decreased λ‖, and SMI-31 identified axon damage at 3 days after ONC. Decreased λ‖ correlated with reduced SMI-31–positive axon counts from 3 days after ONC. In contrast, the increased λ⊥ was seen only in the distal segment of optic nerve whereas decreased myelin basic protein-positive axon counts were seen in all segments 3 days after ONC. The number of retrograde-labeled RGCs did not decline significantly until 7 days after ONC. There was a significant correlation between RGC loss and optic nerve axon damage.
Conclusions.
The authors demonstrated that in vivo DTI detected axonal injury earlier than SMI-31. Results suggest that in vivo DTI of optic nerve injury may be used as a noninvasive tool for assessing the pathogenesis of RGC axonal injury.
doi:10.1167/iovs.11-7619
PMCID: PMC3175987  PMID: 21810979
7.  Magnetic Resonance Diffusion Characteristics of Histologically Defined Prostate Cancer in Humans 
The contrast provided by diffusion-sensitive magnetic resonance offers the promise of improved tumor localization in organ-confined human prostate cancer (PCa). Diffusion tensor imaging (DTI) measurements of PCa were performed in vivo, in patients undergoing radical prostatectomy, and later, ex vivo, in the same patients’ prostatectomy specimens. The imaging data were coregistered to histological sections of the prostatectomy specimens, thereby enabling unambiguous characterization of diffusion parameters in cancerous and benign tissues. Increased cellularity, and hence decreased luminal spaces, in peripheral zone PCa led to approximately 40% and 50% apparent diffusion policy (ADC) decrease compared with benign peripheral zone tissues in vivo and ex vivo, respectively. In contrast, no significant diffusion anisotropy differences were observed between the cancerous and noncancerous peripheral zone tissues. However, the dense fibromuscular tissues in prostate, such as stromal tissues in benign prostatic hyperplasia in central gland, exhibited high diffusion anisotropy. A tissue classification method is proposed to combine DTI and T2-weighted image contrasts that may provide improved specificity of PCa detection over T2-weighted imaging alone. PCa identified in volume rendered MR images qualitatively correlates well with histologically determined PCa foci.
doi:10.1002/mrm.21896
PMCID: PMC3080096  PMID: 19215051
prostate carcinoma (PCa); diffusion tensor imaging (DTI); apparent diffusion coefficient (ADC); fractional anisotropy (FA)
8.  Diffusion Tensor Imaging at 3 Hours after Traumatic Spinal Cord Injury Predicts Long-Term Locomotor Recovery 
Journal of Neurotrauma  2010;27(3):587-598.
Abstract
Accurate diagnosis of spinal cord injury (SCI) severity must be achieved before highly aggressive experimental therapies can be tested responsibly in the early phases after trauma. These studies demonstrate for the first time that axial diffusivity (λ||), derived from diffusion tensor imaging (DTI) within 3 h after SCI, accurately predicts long-term locomotor behavioral recovery in mice. Female C57BL/6 mice underwent sham laminectomy or graded contusive spinal cord injuries at the T9 vertebral level (5 groups, n = 8 for each group). In-vivo DTI examinations were performed immediately after SCI. Longitudinal measurements of hindlimb locomotor recovery were obtained using the Basso mouse scale (BMS). Injured and spared regions of ventrolateral white matter (VLWM) were reliably separated in the hyperacute phase by threshold segmentation. Measurements of λ|| were compared with histology in the hyperacute phase and 14 days after injury. The spared normal VLWM determined by hyperacute λ|| and 14-day histology correlated well (r = 0.95). A strong correlation between hindlimb locomotor function recovery and λ||-determined spared normal VLWM was also observed. The odds of significant locomotor recovery increased by 18% with each 1% increase in normal VLWM measured in the hyperacute phase (odds ratio = 1.18, p = 0.037). The capability of measuring subclinical changes in spinal cord physiology and murine genetic advantages offer an early window into the basic mechanisms of SCI that was not previously possible. Although significant obstacles must still be overcome to derive similar data in human patients, the path to clinical translation is foreseeable and achievable.
doi:10.1089/neu.2009.1063
PMCID: PMC2867549  PMID: 20001686
axial diffusion; diffusion tensor imaging; hyperacute; magnetic resonance imaging; recovery; spinal cord injury
9.  Full Tensor Diffusion Imaging Is Not Required To Assess the White-Matter Integrity in Mouse Contusion Spinal Cord Injury 
Journal of Neurotrauma  2010;27(1):253-262.
Abstract
In vivo diffusion tensor imaging (DTI) derived indices have been demonstrated to quantify accurately white-matter injury after contusion spinal cord injury (SCI) in rodents. In general, a full diffusion tensor analysis requires the acquisition of diffusion-weighted images (DWI) along at least six independent directions of diffusion-sensitizing gradients. Thus, DTI measurements of the rodent central nervous system are time consuming. In this study, diffusion indices derived using the two-direction DWI (parallel and perpendicular to axonal tracts) were compared with those obtained using six-direction DTI in a mouse model of SCI. It was hypothesized that the mouse spinal cord ventral-lateral white-matter (VLWM) tracts, T8–T10 in this study, aligned with the main magnet axis (z) allowing the apparent diffusion coefficient parallel and perpendicular to the axis of the spine to be derived with diffusion-weighting gradients in the z and y axes of the magnet coordinate respectively. Compared with six-direction full tensor DTI, two-direction DWI provided comparable diffusion indices in mouse spinal cords. The measured extent of spared white matter after injury, estimated by anisotropy indices, using both six-direction DTI and two-direction DWI were in close agreement and correlated well with histological staining and behavioral assessment. The results suggest that the two-direction DWI derived indices may be used, with significantly reduced imaging time, to estimate accurately spared white matter in mouse SCI.
doi:10.1089/neu.2009.1026
PMCID: PMC2824236  PMID: 19715399
assessment tools; biomarkers; in vivo studies; MRI; traumatic spinal cord injury
10.  Impact Speed Does Not Determine Severity of Spinal Cord Injury in Mice with Fixed Impact Displacement 
Journal of Neurotrauma  2009;26(8):1395-1404.
Abstract
The speed of three leading rodent SCI impacting devices—0.1 m/s (Infinite Horizon), 0.2 m/s (Ohio State University), and 0.4 m/s (New York University)—were investigated using a custom-fabricated impactor to determine its effect on mouse spinal cord injury severity. The spared white matter was examined at 7 and 21 days post-injury with in vivo diffusion tensor imaging (DTI) and post-mortem histology, respectively. The neurological outcome of the injured mice was longitudinally evaluated using the Basso mouse scale. In vivo DTI derived diffusion anisotropy maps provided excellent gray-white matter contrast enabling objective and noninvasive quantification of normal appearing white matter. In vivo DTI estimated spared white matter content correlated well with those determined using post-mortem histology. No significant difference in BMS was observed among injury groups of various impact speeds. The present results suggest that injury severity can be reproduced using speeds from 0.1 to 0.4 m/s at the fixed impact displacement.
doi:10.1089/neu.2008.0728
PMCID: PMC2850293  PMID: 19257804
BMS; contusion SCI; diffusion tensor imaging; impact speed; spared white matter
11.  Impact speed does not determine severity of spinal cord injury in mice with fixed impact displacement 
Journal of neurotrauma  2009;26(8):10.1089/neu.2008-0728.
The speed of three leading rodent SCI impacting devices: 0.1 m/s (Infinite Horizon), 0.2 m/s (Ohio State Univerity), and 0.4 m/s (New York University) were investigated using a custom-fabricated impactor to determine its effect on mouse spinal cord injury severity. The spared white matter was examined at 7 and 21 days post injury with in vivo diffusion tensor imaging (DTI) and postmortem histology respectively. The neurological outcome of the injured mice was longitudinally evaluated using the Basso Mouse Scale. In vivo DTI derived diffusion anisotropy maps provided excellent gray-white matter contrast enabling objective and noninvasive quantification of normal appearing white matter. In vivo DTI estimated spared white matter content correlated well with those determined using postmortem histology. No significant difference in BMS was observed among injury groups of various impact speeds. The present results suggest that injury severity can be reproduced using speeds from 0.1 – 0.4 m/s at the fixed impact displacement.
doi:10.1089/neu.2008-0728
PMCID: PMC2850293  PMID: 19257804
Contusion SCI; Impact speed; BMS; Diffusion tensor imaging; Spared white matter
12.  Diffusion tensor imaging detects axonal injury and demyelination in the spinal cord and brain of a murine model of globoid cell leukodystrophy 
NMR in biomedicine  2009;22(10):1100-1106.
Globoid cell leukodystrophy is an inherited neurodegenerative disorder caused by a deficiency of the lysosomal enzyme galactosylceramidase. In both human patients and the authentic murine Twitcher model, pathological findings include demyelination as well as axonal damage in both the central and peripheral nervous system. Diffusion tensor imaging (DTI) has emerged as a powerful noninvasive technique that is sensitive to these white matter disease processes. Increases in radial diffusivity (λ⊥) and decreases in axial diffusivity (λ||) correlate with histopathological evidence of demyelination and axonal damage, respectively. Compared to age-matched, normal littermates, DTI of optic nerve and trigeminal nerve in end-stage Twitcher mice displayed a statistically significant increase in λ⊥ and decrease in λ|| consistent with previously characterized demyelination and axonal damage in these regions. In the Twitcher spinal cord, a statistically significant decrease in λ|| was identified in both the dorsal and ventrolateral white matter relative to normal controls. These results were consistent with immunofluorescent evidence of axonal damage in these areas as detected by staining for nonphosphorylated neurofilaments (SMI32). Increase in λ⊥ in Twitcher spinal cord white matter relative to normal controls reached statistical significance in the dorsal columns and approached statistical significance in the ventrolateral region. Reduced levels of myelin basic protein were detected by immunofluorescent staining in both these white matter regions in the Twitcher spinal cord. Fractional anisotropy, a nonspecific but sensitive indicator of white matter disease, was significantly reduced in optic nerve, trigeminal nerve, and throughout the spinal cord white matter of Twitcher mice relative to normal controls. This first reported application of spinal cord DTI in the setting of GLD holds potential as a noninvasive, quantitative assay of therapeutic efficacy in future treatment studies.
doi:10.1002/nbm.1420
PMCID: PMC2910583  PMID: 19650072
globoid cell leukodystrophy; Twitcher mouse; diffusion tensor imaging; radial diffusivity; axial diffusivity; axonal damage; demyelination; spinal cord
13.  Full tensor diffusion imaging is not required to assess the white matter integrity in mouse contusion spinal cord injury 
Journal of neurotrauma  2010;27(1):253-262.
In vivo diffusion tensor imaging (DTI) derived indices have been demonstrated to accurately quantify white matter injury after contusion spinal cord injury (SCI) in rodents. In general, a full diffusion tensor requires the acquisition of diffusion weighted images (DWI) along at least six independent directions of diffusion sensitizing gradients. Thus, DTI measurements of rodent central nervous system are time consuming. In this study, diffusion indices derived using the two-direction DWI (parallel and perpendicular to axonal tracts) were compared with those obtained using six-direction DTI in a mouse model of SCI. It was hypothesized that the mouse spinal cord ventral-lateral white matter (VLWM) tracts, T8 – 10 in this study, aligned with the main magnet axis (z) allowing the apparent diffusion coefficient parallel and perpendicular to the axis of the spine to be derived with diffusion weighting gradients in the z and y axes of the magnet coordinate respectively. Compared with six-direction full tensor DTI, two-direction DWI provided comparable diffusion indices in mouse spinal cords. The measured extent of spared white matter after injury, estimated by anisotropy indices, using both six-direction DTI and two-direction DWI were in close agreement and correlated well with histological staining and behavior assessment. The results suggest that the two-direction DWI derived indices may be used, with significantly reduced imaging time, to accurately estimate spared white matter in mouse SCI.
doi:10.1089/neu.2009.1026
PMCID: PMC2824236  PMID: 19715399
Assessment Tools; Biomarkers; In vivo studies; MRI; Traumatic spinal cord injury
14.  Diffusion Tensor Imaging of Mouse Brain Stem and Cervical Spinal Cord 
Journal of neuroscience methods  2008;176(2):186-191.
In vivo diffusion tensor imaging measurements of the mouse brain stem and cervical spinal cord are presented. Utilizing actively decoupled transmit/receive coils, high resolution diffusion images (117 × 59 × 500 μm3) were acquired at 4.7 T within an hour. Both brain stem and cervical spine displayed clear gray-white matter contrast. The cervical spinal cord white matter showed similar tissue characteristics as seen in the thoracic cord. The coherent fiber orientation in the white matter was observed in both the brain stem and the cervical spinal cord. The results may serve as a reference for future inter-lab comparison in mouse brain stem and cervical spine diffusion measurements.
doi:10.1016/j.jneumeth.2008.09.005
PMCID: PMC2637387  PMID: 18834905
Diffusion tensor imaging; Mice; Brain stem; Cervical spinal cord; Axial and radial diffusivity; Diffusion anisotropy
15.  Axial Diffusivity is the Primary Correlate of Axonal Injury in the EAE Spinal Cord: A Quantitative Pixelwise Analysis 
The dissociation between MRI and permanent disability in Multiple Sclerosis (MS), termed the clinicoradiological paradox, can largely be attributed to the lack of specificity of conventional, relaxivity-based MRI measurements in detecting axonal damage, the primary pathological correlate of long-term impairment in MS. Diffusion tensor imaging (DTI) has shown promise in specifically detecting axonal damage and demyelination in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). In order to quantify the specificity of DTI in detecting axonal injury, in vivo DTI maps from the spinal cords of mice with EAE and quantitative histological maps were both registered to a common space. A pixelwise correlation analysis between DTI parameters, histological metrics, and EAE scores revealed a significant correlation between the water diffusion parallel to the white matter fibers, or axial diffusivity, and EAE score. Furthermore, axial diffusivity was the primary correlate of quantitative staining for neurofilaments (SMI31), markers of axonal integrity. Both axial diffusivity and neurofilament staining were decreased throughout the entire white matter, not solely within the demyelinated lesions seen in EAE. In contrast, although anisotropy was significantly correlated with EAE score, it was not correlated with axonal damage. The results demonstrate a strong, quantitative relationship between axial diffusivity and axonal damage and show that anisotropy is not specific for axonal damage following inflammatory demyelination.
doi:10.1523/JNEUROSCI.4605-08.2009
PMCID: PMC2673458  PMID: 19261876
Diffusion tensor imaging; axial diffusivity; radial diffusivity; spinal cord; experimental autoimmune encephalomyelitis; axonal damage; demyelination; white matter
16.  Evolving Wallerian Degeneration after Transient Retinal Ischemia in Mice Characterized by Diffusion Tensor Imaging 
NeuroImage  2007;40(1):1-10.
Wallerian degeneration plays a significant role in many central nervous system (CNS) diseases. Tracking the progression of Wallerian degeneration may provide better understanding of the evolution of many CNS diseases. In this study, a 28-day longitudinal in vivo DTI of optic nerve (ON) and optic tract (OT) was conducted to evaluate the temporal and spatial evolution of Wallerian degeneration resulting from the transient retinal ischemia. At 3 − 28 days after ischemia, ipsilateral ON and contralateral OT showed significant reduction in axial diffusivity (32 − 40% and 21 − 29% respectively) suggestive of axonal damage. Both ON and OT showed significant increase in radial diffusivity, 200 − 290% and 58 − 65% in ON and OT respectively, at 9 − 28 days suggestive of myelin damage. Immuohistochmistry of phosphorylated neurofilament (pNF) and myelin basic protein (MBP) was performed to assess axonal and myelin integrities validating the DTI findings. Both DTI and immunohistochemistry detected that transient retinal ischemia caused more severe damage to ON than to OT. The current results suggest that axial and radial diffusivities are capable of reflecting the severity of axonal and myelin damage in mice as assessed using immunohistochemistry.
doi:10.1016/j.neuroimage.2007.11.049
PMCID: PMC2276530  PMID: 18187343
17.  Axonal injury detected by in vivo DTI correlates with neurological disability in a mouse model of Multiple Sclerosis 
NMR in biomedicine  2008;21(6):589-597.
Recent studies have suggested that axonal damage, and not demyelination, is the primary cause of long-term neurological impairment in Multiple Sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). The axial and radial diffusivities derived from diffusion tensor imaging (DTI) have shown promise as noninvasive surrogate markers of axonal damage, and demyelination, respectively. In the current study, in vivo DTI of the spinal cords from mice with chronic EAE was performed to determine if axial diffusivity correlated with neurological disability in EAE assessed by the commonly used clinical scoring system. Axial diffusivity in the ventrolateral white matter had a significant negative correlation with EAE clinical score and was significantly lower in mice with severe EAE than mice with moderate EAE. Furthermore, the greater decreases in axial diffusivity were associated with greater amounts of axonal damage as confirmed by quantitative staining for non-phosphorylated neurofilaments (SMI-32). Radial diffusivity and relative anisotropy could not distinguish between the groups of mice with moderate EAE and those with severe EAE. The results further the notion that axial diffusivity is a noninvasive marker of axonal damage in white matter and could provide the necessary link between pathology and neurological disability.
doi:10.1002/nbm.1229
PMCID: PMC2602834  PMID: 18041806
Diffusion tensor imaging; axial diffusivity; radial diffusivity; spinal cord; experimental autoimmune encephalomyelitis; axonal damage; demyelination; white matter
18.  Assessing Optic Nerve Pathology with Diffusion MRI: from Mouse to Human 
NMR in biomedicine  2008;21(9):928-940.
Optic nerve is often affected in patients with glaucoma and multiple sclerosis (MS). Conventional MRI can detect nerve damage but it does not accurately assess the underlying pathologies. Mean diffusivity and diffusion anisotropy indices derived from diffusion tensor imaging (DTI) have been shown to be sensitive to a variety of central nervous system (CNS) white matter pathologies. Despite being sensitive, the lack of specificity limits the ability of these measures to differentiate the underlying pathology in CNS white matter tissues. Directional (axial and radial) diffusivities, measuring water diffusion parallel and perpendicular to the axonal tracts, have been shown to be specific to axonal and myelin damages in mouse models of optic nerve injury, including retinal ischemia and experimental autoimmune encephalomyelitis (EAE). The progression of Wallerian degeneration has also been detected using directional diffusivities after retinal ischemia. However, translating these findings to human optic nerve is technically challenging. The current status of human optic nerve diffusion MRI, including the imaging sequences and protocols, are summarized herein. Despite lacking a consensus of the optimal sequence or protocol among different groups, increased mean diffusivity and decreased diffusion anisotropy has been observed in injured optic nerve from chronic optic neuritis patients. Decreased λ∥, correlating with visual function and recovery, was observed recently in acute optic neuritis patients in a pilot study, suggesting the specificity of λ∥ to axonal injury. From different mouse models of optic nerve injuries to the emerging studies on optic neuritis patients, directional diffusivities demonstrate great potential to be specific biomarkers for axonal and myelin injury.
doi:10.1002/nbm.1307
PMCID: PMC2603138  PMID: 18756587
19.  Oligodendrocyte Lineage and Subventricular Zone Response to Traumatic Axonal Injury in the Corpus Callosum 
Traumatic brain injury frequently causes traumatic axonal injury (TAI) in white matter tracts. Experimental TAI in the corpus callosum of adult mice was used to examine the effects on oligodendrocyte lineage cells and myelin in conjunction with neuroimaging. The injury targeted the corpus callosum over the subventricular zone, a source of neural stem/progenitor cells. TAI was produced in the rostral body of the corpus callosum by impact onto the skull at bregma. During the first week post-injury, magnetic resonance diffusion tensor imaging showed that axial diffusivity decreased in the corpus callosum and that corresponding regions exhibited significant axon damage accompanied by hypertrophic microglia and reactive astrocytes. Oligodendrocyte progenitor proliferation increased in the subventricular zone and corpus callosum. Oligodendrocytes in the corpus callosum shifted toward upregulation of myelin gene transcription. Plp/CreERT:R26IAP reporter mice showed normal reporter labeling of myelin sheaths 0 to 2 days post-injury but labeling was increased between 2 to 7 days post-injury. Electron microscopy revealed axon degeneration, demyelination and redundant myelin figures. These findings expand the cell types and responses to white matter injuries that inform diffusion tensor imaging evaluation and identify pivotal white matter changes following TAI that may affect axon vulnerability vs. recovery following brain injury.
doi:10.1097/NEN.0000000000000009
PMCID: PMC4130339  PMID: 24226267
Traumatic brain injury; Axonal damage; Corpus callosum; Diffusion tensor imaging; Oligodendrocyte progenitor; Redundant myelin; Regeneration
20.  Improved in vivo diffusion tensor imaging of human cervical spinal cord 
NeuroImage  2012;67:64-76.
We describe a cardiac gated high in-plane resolution axial human cervical spinal cord diffusion tensor imaging (DTI) protocol. Multiple steps were taken to optimize both image acquisition and image processing. The former includes slice-by-slice cardiac triggering and individually tiltable slices. The latter includes (i) iterative 2D retrospective motion correction, (ii) image intensity outlier detection to minimize the influence of physiological noise, (iii) a non-linear DTI estimation procedure incorporating non-negative eigenvalue priors, and (iv) tract-specific region-of-interest (ROI) identification based on an objective geometry reference. Using these strategies in combination, radial diffusivity (λ⊥) was reproducibly measured in white matter (WM) tracts (adjusted mean [95% confidence interval]=0.25 [0.22, 0.29]µm2/ms), lower than previously reported λ⊥ values in the in vivo human spinal cord DTI literature. Radial diffusivity and fractional anisotropy (FA) measured in WM varied from rostral to caudal as did mean translational motion, likely reflecting respiratory motion effect. Given the considerable sensitivity of DTI measurements to motion artifact, we believe outlier detection is indispensable in spinal cord diffusion imaging. We also recommend using a mixed-effects model to account for systematic measurement bias depending on cord segment.
doi:10.1016/j.neuroimage.2012.11.014
PMCID: PMC3604900  PMID: 23178538
Directional diffusivity; Outlier rejection; Non-negative eigenvalue priors; Reduced FOV; Cardiac gating; Cervical spinal cord; Lateral corticospinal tract; Posterior column; Diffusion tensor imaging; Reproducibility
21.  White-Matter Diffusion fMRI of Mouse Optic Nerve 
NeuroImage  2012;65:209-215.
Non-invasive assessment of white-matter functionality in the nervous system would be a valuable basic neuroscience and clinical diagnostic tool. Using standard MRI techniques, a visual-stimulus-induced 27% decrease in the apparent diffusion coefficient of water perpendicular to the axonal fibers (ADC⊥) is demonstrated for C57BL/6 mouse optic nerve in vivo. No change in ADC|| (diffusion parallel to the optic nerve fibers) was observed during visual stimulation. The stimulus-induced changes are completely reversible. A possible vascular contribution was sought by carrying out the ADC⊥ measurements in hypercapnic mice with and without visual stimulus. Similar effects were seen in room-air-breathing and hypercapnic animals. The in vivo stimulus-induced ADC⊥ decreases are roughly similar to literature reports for ex vivo rat optic nerve preparations under conditions of osmotic swelling. The experimental results strongly suggest that osmotic after-effects of nerve impulses through the axonal fibers are responsible for the observed ADC decrease.
doi:10.1016/j.neuroimage.2012.10.021
PMCID: PMC3513522  PMID: 23085108
Diffusion; White Matter; Optic Nerve; fMRI; Mouse
22.  Simultaneous and Noninvasive Imaging of Cerebral Oxygen Metabolic Rate, Blood Flow and Oxygen Extraction Fraction in Stroke Mice 
NeuroImage  2012;64:437-447.
Many brain diseases have been linked to abnormal oxygen metabolism and blood perfusion; nevertheless, there is still a lack of robust diagnostic tools for directly imaging cerebral metabolic rate of oxygen (CMRO2) and cerebral blood flow (CBF), as well as the oxygen extraction fraction (OEF) that reflects the balance between CMRO2 and CBF. This study employed the recently developed in vivo 17O MR spectroscopic imaging to simultaneously assess CMRO2, CBF and OEF in the brain using a preclinical middle cerebral arterial occlusion mouse model with a brief inhalation of 17O-labeled oxygen gas. The results demonstrated high sensitivity and reliability of the noninvasive 17O-MR approach for rapidly imaging CMRO2, CBF and OEF abnormalities in the ischemic cortex of the MCAO mouse brain. It was found that in the ischemic brain regions both CMRO2 and CBF were substantially lower than that of intact brain regions, even for the mildly damaged brain regions that were unable to be clearly identified by the conventional MRI. In contrast, OEF was higher in the MCAO affected brain regions. This study demonstrates a promising 17O MRI technique for imaging abnormal oxygen metabolism and perfusion in the diseased brain regions. This 17O MRI technique is advantageous because of its robustness, simplicity, noninvasiveness and reliability: features that are essential to potentially translate it to human patients for early diagnosis and monitoring of treatment efficacy.
doi:10.1016/j.neuroimage.2012.09.028
PMCID: PMC3508145  PMID: 23000789
In vivo17O MRS imaging; CMRO2; CBF; OEF; Stroke
23.  Increased Radial Diffusivity in Spinal Cord Lesions in Neuromyelitis Optica Compared to Multiple Sclerosis 
Background
Multiple sclerosis (MS) and neuromyelitis optica (NMO) both affect spinal cord with notable differences in pathology.
Objective
Determine the utility of diffusion tensor imaging (DTI) to differentiate the spinal cord lesions of NMO from MS within and outside T2 lesions.
Methods
Subjects ≥12 months from a clinical episode of transverse myelitis underwent a novel transaxial cervical spinal cord DTI sequence. Ten subjects with NMO, 10 with MS, and 10 healthy controls were included.
Results
Within T2 affected white matter regions, radial diffusivity was increased in both NMO and MS compared to healthy controls (p<0.001, respectively), and to a greater extent in NMO than MS (p<0.001). Axial diffusivity was decreased in T2 lesions in both NMO and MS compared to controls (p<0.001, p=0.001), but did not differ between the two diseases. Radial diffusivity and FA within white matter regions upstream and downstream of T2 lesions were different from controls in each disease.
Conclusions
Higher radial diffusivity, within spinal cord white matter tracts derived from diffusion tensor imaging were appreciated in NMO compared to MS, consistent with the known greater tissue destruction seen in NMO. DTI also detected tissue alterations outside T2 lesions, and may be a surrogate of anterograde and retrograde degeneration.
doi:10.1177/1352458512436593
PMCID: PMC3360125  PMID: 22354742
diffusion tensor imaging; neuromyelitis optica (NMO); multiple sclerosis (MS); spinal cord; MRI
24.  In vivo diffusion tensor imaging of the mouse retina: A noninvasive visualization of tissue organizations 
NMR in biomedicine  2010;24(5):447-451.
Diffusion tensor MRI (DTI) is a method to noninvasively assess cellular organization and integrity in vivo. In the present study, in vivo DTI was performed to demonstrate its capability of reflecting the photoreceptor cell alignment in adult C57BL/6 wildtype (WT) mice. Age-matched retinal degeneration 1 (rd1) mice were employed as the negative control, i.e., loss of photoreceptor cell layer. In WT mice, DTI estimated cell alignment suggests that the MR-detected outer retina layer comprises cells aligning perpendicular to the retinal surface, consistent with the known organization of photoreceptor cells. The MR-detected outer retina layer exhibited lower apparent diffusion coefficient (ADC) and higher fractional anisotropy (FA) than the other two MR-detected retina layers (p < 0.05 for all comparisons). In rd1 mice, the remaining MR-detected retina layer exhibits different cell alignment, ADC, or FA from that of MR-detected outer retina layer in WT mice (p < 0.05 for all comparisons), reflecting the degeneration of photoreceptor cells in rd1 mouse retina. Overall, our finding suggests that in vivo DTI assessment of mouse retina with normal physiology or degenerative pathology is feasible.
doi:10.1002/nbm.1609
PMCID: PMC3738013  PMID: 20931570
retina; diffusion tensor MRI; apparent diffusion coefficient; cell alignment; fractional anisotropy
25.  The MT pool size ratio and the DTI radial diffusivity may reflect the myelination in shiverer and control mice 
NMR in biomedicine  2009;22(5):480-487.
A quantitative magnetization transfer (qMT) technique was employed to quantify the ratio of the sizes of the bound and free water proton pools in ex vivo mouse brains. The goal was to determine the pool size ratio sensitivity to myelin. Fixed brains from both shiverer mice and control littermates were imaged. The pool size ratio in the corpus callosum of shiverer mice was substantially lower than that in the control mice, while there was no distinguishable difference in the pool size ratio in the gray matter. These results correlate with diffusion tensor imaging (DTI) derived radial diffusivity which previously was shown to reflect myelin integrity in this animal model. Histological study reveals the presence of myelin in control mice white matter and the absence of myelin in shiverer mice white matter, supporting the qMT and DTI results. Our findings support the view that qMT may be used for estimating myelin integrity.
doi:10.1002/nbm.1358
PMCID: PMC3711249  PMID: 19123230
quantitative magnetization transfer; pool size ratio; diffusion tensor imaging; radial diffusivity; corpus callosum; myelin

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