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Objective: To use diffusion basis spectrum imaging (DBSI) to assess how damage to normal-appearing white matter (NAWM) in the corpus callosum (CC) influences neurologic impairment in people with MS (pwMS)., Methods: Using standard MRI, the primary pathologies in MS of axonal injury/loss, demyelination, and inflammation are not differentiated well. DBSI has been shown in animal models, phantoms, and in biopsied and autopsied human CNS tissues to distinguish these pathologies. Fifty-five pwMS (22 relapsing-remitting, 17 primary progressive, and 16 secondary progressive) and 13 healthy subjects underwent DBSI analyses of NAWM of the CC, the main WM tract connecting the cerebral hemispheres. Tract-based spatial statistics were used to minimize misalignment. Results were correlated with scores from a battery of clinical tests focused on deficits typical of MS., Results: Normal-appearing CC in pwMS showed reduced fiber fraction and increased nonrestricted isotropic fraction, with the most extensive abnormalities in secondary progressive MS (SPMS). Reduced DBSI-derived fiber fraction and increased DBSI-derived nonrestricted isotropic fraction of the CC correlated with worse cognitive scores in pwMS. Increased nonrestricted isotropic fraction in the body of the CC correlated with impaired hand function in the SPMS cohort., Conclusions: DBSI fiber fraction and nonrestricted isotropic fraction were the most useful markers of injury in the NAWM CC. These 2 DBSI measures reflect axon loss in animal models. Because of its ability to reveal axonal loss, as well as demyelination, DBSI may be a useful outcome measure for trials of CNS reparative treatments., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Diffusion basis spectrum imaging (DBSI) combines discrete anisotropic diffusion tensors and the spectrum of isotropic diffusion tensors to model the underlying multiple sclerosis (MS) pathologies. We used clinical MS subtypes as a surrogate of underlying pathologies to assess DBSI as a biomarker of pathology in 55 individuals with MS. Restricted isotropic fraction (reflecting cellularity) and fiber fraction (representing apparent axonal density) were the most important DBSI metrics to classify MS using brain white matter lesions. These DBSI metrics outperformed lesion volume. When analyzing the normal-appearing corpus callosum, the most significant DBSI metrics were fiber fraction, radial diffusivity (reflecting myelination), and nonrestricted isotropic fraction (representing edema). This study provides preliminary evidence supporting the ability of DBSI as a potential noninvasive biomarker of MS neuropathology., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

In vivo human optic nerve diffusion magnetic resonance imaging (dMRI) is technically challenging with two outstanding issues not yet well addressed: (i) non-linear optic nerve movement, independent of head motion, and (ii) effect from partial-volumed cerebrospinal fluid or interstitial fluid such as in edema. In this work, we developed a non-linear optic nerve registration algorithm for improved volume alignment in axial high resolution optic nerve dMRI. During eyes-closed dMRI data acquisition, optic nerve dMRI measurements by diffusion tensor imaging (DTI) with and without free water elimination (FWE), and by diffusion basis spectrum imaging (DBSI), as well as optic nerve motion, were characterized in healthy adults at various locations along the posterior-to-anterior dimension. Optic nerve DTI results showed consistent trends in microstructural parametric measurements along the posterior-to-anterior direction of the entire intraorbital optic nerve, while the anterior portion of the intraorbital optic nerve exhibited the largest spatial displacement. Multi-compartmental dMRI modeling, such as DTI with FWE or DBSI, was less subject to spatially dependent biases in diffusivity and anisotropy measurements in the optic nerve which corresponded to similar spatial distributions of the estimated fraction of isotropic diffusion components. DBSI results derived from our clinically feasible (∼10 min) optic nerve dMRI protocol in this study are consistent with those from small animal studies, which provides the basis for evaluating the utility of multi-compartmental dMRI modeling in characterizing coexisting pathophysiology in human optic neuropathies., (Copyright © 2019. Published by Elsevier Inc.)

Inflammation occurs after HIV infection and persists, despite highly active antiretroviral therapy (HAART). Diffusion tensor imaging (DTI) measures HIV-associated white matter changes, but can be confounded by inflammation. Currently, the influence of inflammation on white matter integrity in well-controlled HIV+ patients remains unknown. We used diffusion basis spectral imaging (DBSI)-derived cellularity to isolate restricted water diffusion associated with inflammation separated from the anisotropic diffusion associated with axonal integrity. Ninety-two virologically suppressed HIV+ patients on HAART and 66 HIV uninfected (HIV-) controls underwent neuropsychological performance (NP) testing and neuroimaging. NP tests assessed multiple domains (memory, psychomotor speed, and executive functioning). DTI- and DBSI-derived fractional anisotropy (FA) maps were processed with tract-based spatial statistics for comparison between both groups. Cellularity was assessed regarding age, HIV status, and NP. Within the HIV+ cohort, cellularity was compared with clinical (HAART duration) and laboratory measures of disease (eg, CD4 cell current and nadir). NP was similar for both groups. DTI-derived FA was lower in HIV+ compared with HIV- individuals. By contrast, DBSI-derived FA was similar for both groups. Instead, diffuse increases in cellularity were present in HIV+ individuals. Observed changes in cellularity were significantly associated with age, but not NP, in HIV+ individuals. A trend level association was seen between cellularity and HAART duration. Elevated inflammation, measured by cellularity, persists in virologically well-controlled HIV+ individuals. Widespread cellularity changes occur in younger HIV+ individuals and diminish with aging and duration of HAART.

We describe a novel imaging method to assess central nervous system pathology called "Diffusion Basis Spectrum Imaging" (DBSI). Diffusion tensor imaging (DTI) has been widely used to estimate axonpathology and demyelination. However, in the settings of acute inflammation and chronic tissue loss asare common in multiple sclerosis, DTI signals can lead to false interpretations. DBSI is a computationallynovel method that separates isotropic from anisotropic components in imaging voxels. Isotropicdiffusion is believed to reflect inflammatory components (cells, edema), as well as intrinsic cells andextracellular space. DBSI enables the measurement of axial and radial diffusivities within the anisotropiccomponents of imaging voxels, which reflect the integrity of axon fibers and myelin, respectively., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: To assess the capability of signal-to-noise ratio enhancing reconstruction (SER) to reduce the acquisition time for quantitative white matter injury assessment., Methods: Four single-average diffusion tensor imaging (DTI) datasets were acquired for each animal from four mouse cohorts: two models of spinal cord injury and two control groups. Quantitative parameters (apparent diffusion coefficient, relative anisotropy, axial and radial diffusivities) were computed from (I) single-average data with traditional reconstruction; (II) single-average data with SER; (III) four-average data with traditional reconstruction; and (IV) single-average data with optimized multicomponent nonlocal means (OMNLM) denoising. These approaches were compared based on coefficients of variation (COVs) and whether estimated diffusion parameters were sensitive to injury., Results: SER yielded better COVs for diffusivity and anisotropy than traditional reconstruction of single-average data, and yielded comparable COVs to that achieved with four-average data. In addition, diffusion parameters obtained using SER with single-average data had comparable injury sensitivity to those obtained from four-average data, while diffusion parameters obtained from OMNLM and traditional reconstruction of single-average data had limited sensitivity., Conclusion: A four-fold reduction in the number of averages for quantitative diffusion imaging of small animal white matter injury is feasible using SER. Our results also underscore the need to validate nonlinear methods using task-based measures on an application-by-application basis., (© 2015 Wiley Periodicals, Inc.)

Purpose: To improve signal-noise-ratio of in vivo mouse spinal cord diffusion tensor imaging using-phase aligned multiple spin-echo technique., Material and Methods: In vivo mouse spinal cord diffusion tensor imaging maps generated by multiple spin-echo and conventional spin-echo diffusion weighting were examined to demonstrate the efficacy of multiple spin-echo diffusion sequence to improve image quality and throughput. Effects of signal averaging using complex, magnitude and phased images from multiple spin-echo diffusion weighting were also assessed. Bayesian probability theory was used to generate phased images by moving the coherent signals to the real channel to eliminate the effect of phase variation between echoes while preserving the Gaussian noise distribution. Signal averaging of phased multiple spin-echo images potentially solves both the phase incoherence problem and the bias of the elevated Rician noise distribution in magnitude image. The proposed signal averaging with Bayesian phase-aligned multiple spin-echo images approach was compared to the conventional spin-echo data acquired with doubling the scan time. The diffusion tensor imaging parameters were compared in the mouse contusion spinal cord injury. Significance level (p-value) and effect size (Cohen's d) were reported between the control and contused spinal cord to inspect the sensitivity of each approach in detecting white matter pathology., Results: Compared to the spin-echo image, the signal-noise-ratio increased to 1.84-fold using the phased image averaging and to 1.30-fold using magnitude image averaging in the spinal cord white matter. Multiple spin-echo phased image averaging showed improved image quality of the mouse spinal cord among the tested methods. Diffusion tensor imaging metrics obtained from multiple spin-echo phased images using three echoes and two averages closely agreed with those derived by spin-echo magnitude data with four averages (two times more in acquisition time). The phased image averaging correctly reflected pathological features in contusion spinal cord injury., Conclusion: Our in vivo imaging results indicate that averaging the phased multiple spin-echo images yields an 84% signal-noise-ratio increase over the spin-echo images and a 41% gain over the magnitude averaged multiple spin-echo images with equal acquisition time. Current results from the animal model of spinal cord injury suggest that the phased multiple spin-echo images could be used to improve signal-noise-ratio., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The effect of extra-fiber structural and pathological components confounding diffusion tensor imaging (DTI) computation was quantitatively investigated using data generated by both Monte-Carlo simulations and tissue phantoms. Increased extent of vasogenic edema, by addition of various amount of gel to fixed normal mouse trigeminal nerves or by increasing non-restricted isotropic diffusion tensor components in Monte-Carlo simulations, significantly decreased fractional anisotropy (FA) and increased radial diffusivity, while less significantly increased axial diffusivity derived by DTI. Increased cellularity, mimicked by graded increase of the restricted isotropic diffusion tensor component in Monte-Carlo simulations, significantly decreased FA and axial diffusivity with limited impact on radial diffusivity derived by DTI. The MC simulation and tissue phantom data were also analyzed by the recently developed diffusion basis spectrum imaging (DBSI) to simultaneously distinguish and quantify the axon/myelin integrity and extra-fiber diffusion components. Results showed that increased cellularity or vasogenic edema did not affect the DBSI-derived fiber FA, axial or radial diffusivity. Importantly, the extent of extra-fiber cellularity and edema estimated by DBSI correlated with experimentally added gel and Monte-Carlo simulations. We also examined the feasibility of applying 25-direction diffusion encoding scheme for DBSI analysis on coherent white matter tracts. Results from both phantom experiments and simulations suggested that the 25-direction diffusion scheme provided comparable DBSI estimation of both fiber diffusion parameters and extra-fiber cellularity/edema extent as those by 99-direction scheme. An in vivo 25-direction DBSI analysis was performed on experimental autoimmune encephalomyelitis (EAE, an animal model of human multiple sclerosis) optic nerve as an example to examine the validity of derived DBSI parameters with post-imaging immunohistochemistry verification. Results support that in vivo DBSI using 25-direction diffusion scheme correctly reflect the underlying axonal injury, demyelination, and inflammation of optic nerves in EAE mice., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Clinicopathological paradox has hampered significantly the effective assessment of the efficacy of therapeutic intervention for multiple sclerosis. Neuroimaging biomarkers of tissue injury could guide more effective treatment by accurately reflecting the underlying subclinical pathologies. Diffusion tensor imaging-derived directional diffusivity and anisotropy indices have been applied to characterize white matter disorders. However, these biomarkers are sometimes confounded by the complex pathologies seen in multiple sclerosis and its animal models. Recently, a novel technique of diffusion basis spectrum imaging has been developed to quantitatively assess axonal injury, demyelination and inflammation in a mouse model of inflammatory demyelination. Lenaldekar, which inhibits T-cell expansion in a non-cytolytic manner, has been shown to suppress relapses and preserve white matter integrity in mice with experimental autoimmune encephalomyelitis. In this study, relapsing-remitting experimental autoimmune encephalomyelitis was induced through active immunization of SJL/J mice with a myelin proteolipid protein peptide. The therapeutic efficacy of Lenaldekar treatment was evaluated via daily clinical score, cross-sectional ex vivo diffusion basis spectrum imaging examination and histological analysis. Lenaldekar greatly reduced relapse severity and protected white matter integrity in these experimental autoimmune encephalomyelitis mice. Diffusion basis spectrum imaging-derived axial diffusivity, radial diffusivity and restricted diffusion tensor fraction accurately reflected axonal injury, myelin integrity and inflammation-associated cellularity change, respectively. These results support the potential use of diffusion basis spectrum imaging as an effective outcome measure for preclinical drug evaluation., (Copyright © 2014 John Wiley & Sons, Ltd.)

Fingolimod (FTY720) is an orally available sphingosine-1-phosphate (S1P) receptor modulator reducing relapse frequency in patients with relapsing-remitting multiple sclerosis (RRMS). In addition to immunosuppression, neuronal protection by FTY720 has also been suggested, but remains controversial. Axial and radial diffusivities derived from in vivo diffusion tensor imaging (DTI) were employed as noninvasive biomarkers of axonal injury and demyelination to assess axonal protection by FTY720 in experimental autoimmune encephalomyelitis (EAE) mice. EAE was induced through active immunization of C57BL/6 mice using myelin oligodendrocyte glycoprotein peptide 35-55 (MOG(35-55)). We evaluated both the prophylactic and therapeutic treatment effect of FTY720 at doses of 3 and 10 mg/kg on 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 when compared with EAE mice without treatment. Therapeutic treatment by FTY720 did not prevent EAE onset, but reduced disease severity, improving axial and radial diffusivity towards the control values without statistical significance. Consistent with previous findings, in vivo DTI-derived axial and radial diffusivity correlated with clinical scores in EAE mice. The results support the use of in vivo DTI as an effective outcome measure for preclinical drug development., (Copyright © 2013 John Wiley & Sons, Ltd.)

The dysmyelinated axons of shiverer mice exhibit impaired conduction characteristics, similar to early postnatal axons before myelination, whereas the patterns of neuronal activity and connectivity are relatively comparable with those of wild-type myelinated axons. This unique dysmyelination pattern is exploited in the present study to determine the role of compact myelin in 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 the 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., (Copyright © 2013 John Wiley & Sons, Ltd.)

Objective: This study assessed the tissue integrity of major cervical cord tracts by using diffusion tensor imaging (DTI) to determine the relationship with specific clinical functions carried by those tracts., Methods: This was a cross-sectional study of 37 patients with multiple sclerosis or neuromyelitis optica with remote cervical cord disease. Finger vibratory thresholds, 25-foot timed walk (25FTW), 9-hole peg test (9HPT), and Expanded Disability Status Scale were determined. DTI covered cervical regions C1 through C6 with 17 5-mm slices (0.9 × 0.9 mm in-plane resolution). Regions of interest included posterior columns (PCs) and lateral corticospinal tracts (CSTs). Hierarchical linear mixed-effect modeling included covariates of disease subtype (multiple sclerosis vs neuromyelitis optica), disease duration, and sex., Results: Vibration thresholds were associated with radial diffusivity (RD) and fractional anisotropy (FA) in the PCs (both p < 0.01), but not CSTs (RD, p = 0.29; FA, p = 0.14). RD and FA in PCs, and RD in CSTs were related to 9HPT (each p < 0.0001). 25FTW was associated with RD and FA in PCs (p < 0.0001) and RD in CSTs (p = 0.008). Expanded Disability Status Scale was related to RD and FA in PCs and CSTs (p < 0.0001). Moderate/severe impairments in 9HPT (p = 0.006) and 25FTW (p = 0.017) were more likely to show combined moderate/severe tissue injury within both PCs and CSTs by DTI., Conclusions: DTI can serve as an imaging biomarker of spinal cord tissue injury at the tract level. RD and FA demonstrate strong and consistent relationships with clinical outcomes, specific to the clinical modality.

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] μm(2)/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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Concurrent and/or progressive degeneration of upper and lower motor neurons (LMNs) causes neurological symptoms and dysfunctions in motor neuron diseases (MNDs) such as amyotrophic lateral sclerosis (ALS). Although brain lesions are readily detected, magnetic resonance imaging of the brainstem and cervical spinal cord lesions resulting from damage to LMNs has proven to be difficult. With the development of mouse models of MNDs, a noninvasive neuroimaging modality capable of detecting lesions resulting from axonal and neuronal injury in mouse brainstem and cervical spinal cord could improve our understanding of the underlying mechanism of MNDs and aid in the development of effective treatments. Here we present a protocol that allows the concomitant acquisition of high-quality in vivo full-diffusion tensor magnetic resonance images from the mouse brainstem and cervical spinal cord using the actively decoupled, anatomically shaped pair of coils--the surface-receive coil and the minimized volume-transmit coil. To improve the data quality, we used a custom-made nose cone to monitor respiratory motion for synchronizing data acquisition and assuring physiological stability of mice under examination. The protocol allows the acquisition of in vivo diffusion tensor imaging of the mouse brainstem and cervical spinal cord at 117 μm × 117 μm in-plane resolution with a 500-μm slice thickness in 1 h on a 4.7-T horizontal small animal imaging scanner equipped with an actively shielded gradient coil capable of pulsed gradient strengths up to 18 G cm(−1) with a gradient rise time of ≤295 μs.

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 greater than or equal to 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 with 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 with controls (p<0.001, p=0.001), but did not differ between the two diseases. Radial diffusivity and fractional anisotropy 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 with 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.

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.

Objective: To evaluate directional diffusivities within the optic nerve in a first event of acute optic neuritis to determine whether decreased axial diffusivity (AD) would predict 6-month visual outcome and optic nerve integrity measures., Design: Cohort study., Setting: Academic multiple sclerosis center. Patients  Referred sample of 25 individuals who presented within 31 days after acute visual symptoms consistent with optic neuritis. Visits were scheduled at baseline, 2 weeks, and 1, 3, 6, and 12 months., Main Outcome Measures: Visual acuity, contrast sensitivity, visual evoked potentials (VEPs), and thickness of the retinal nerve fiber layer (RNFL)., Results: An incomplete 6-month visual recovery was associated with a lower baseline AD (1.50 μm(2)/ms [95% confidence interval {CI}, 1.36-1.64 μm(2)/ms for incomplete recovery vs 1.75 μm(2)/ms [95% CI, 1.67-1.83 μm(2)/ms] for complete recovery). Odds of complete recovery decreased by 53% (95% CI, 27%-70%) for every 0.1-unit decrease in baseline AD. A lower baseline AD correlated with worse 6-month visual outcomes in visual acuity (r = 0.40, P = .03), contrast sensitivity (r = 0.41, P = .02), VEP amplitude (r = 0.55, P < .01), VEP latency (r = -0.38, P = .04), and RNFL thickness (r = 0.53, P = .02). Radial diffusivity increased between months 1 and 3 to become higher in those with incomplete recovery at 12 months than in those with complete recovery (1.45 μm(2)/ms [95% CI, 1.31-1.59 μm(2)/ms] vs 1.19 μm(2)/ms [95% CI, 1.10-1.28 μm(2)/ms])., Conclusions: Decreased AD in acute optic neuritis was associated with a worse 6-month visual outcome and correlated with VEP and RNFL measures of axon and myelin injury. Axial diffusivity may serve as a marker of axon injury in acute white matter injury.

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.

Diffusion tensor MRI (DTI) is a method for the noninvasive assessment of cellular organization and integrity in vivo. In this study, in vivo DTI was performed to demonstrate its ability to reflect photoreceptor cell alignment in adult C57BL/6 wild-type mice. Age-matched retinal degeneration 1 (rd1) mice were employed as a negative control, i.e. loss of the photoreceptor cell layer. In wild-type mice, DTI-estimated cell alignment suggests that the MR-detected outer retinal layer comprises cells aligning perpendicular to the retinal surface, consistent with the known organization of photoreceptor cells. The MR-detected outer retinal layer exhibits a lower apparent diffusion coefficient and higher fractional anisotropy than the other two MR-detected retinal layers (p < 0.05 for all comparisons). In rd1 mice, the remaining MR-detected retinal layer exhibits different cell alignment, apparent diffusion coefficient and fractional anisotropy from that of the MR-detected outer retinal layer in wild-type mice (p < 0.05 for all comparisons), reflecting the degeneration of photoreceptor cells in rd1 mouse retina. Overall, our findings suggest that in vivo DTI assessment of mouse retina with normal physiology or degenerative pathology is feasible., (Copyright © 2010 John Wiley & Sons, Ltd.)

Acute necrotizing encephalopathy and acute disseminated encephalomyelitis are 2 rare types of acute postinfectious encephalopathy in children. Acute necrotizing encephalopathy is characterized by multiple symmetric lesions in the thalami, putamena, cerebral and cerebellar white matter, and brainstem. Acute disseminated encephalomyelitis is an immune-mediated demyelinating central nervous system disorder that predominantly affects the white matter. Diffusion magnetic resonance imaging is sensitive to measuring water diffusion in the central nervous system in human and animal models. Recent studies have demonstrated that by using an analytical approach to directional diffusivity-derived parameters, the axial diffusivity and the radial diffusivity, one can assess the extent of axonal or myelin injury in the central nervous system white matter. We applied directional diffusivity to acute necrotizing encephalopathy, acute disseminated encephalomyelitis, and control subjects correlating with neuropathology findings. In acute necrotizing encephalopathy, axonal injury without demyelination, noted on biopsy samples of brain tissue, was suggested by a decreased apparent diffusion coefficient, unchanged fractional anisotropy, and decreased axial and radial diffusivity. In acute disseminated encephalomyelitis, an increased apparent diffusion coefficient, decreased fractional anisotropy, unchanged axial diffusivity, and markedly increased radial diffusivity compatible with active inflammatory demyelination were noted, consistent with tissue biopsy sample neuropathology. In conclusion, diffusion tensor parameters can potentially depict more microstructural changes than conventional magnetic resonance imaging in postinfectious encephalopathy in children., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Degeneration of motor neurons and their associated axons is a hallmark of amyotrophic lateral sclerosis, but reliable noninvasive lesion detection is lacking. In vivo diffusion tensor imaging was performed to evaluate neurodegeneration in the brainstem and cervical spinal cord of wild-type and G93A-SOD1 transgenic mice, an animal model of amyotrophic lateral sclerosis. A statistically significant reduction in the apparent diffusion coefficient was observed in the motor nuclei VII and XII of G93A-SOD1 transgenic mice relative to wild-type mice. No significant difference in diffusion anisotropy was observed in dorsal white or gray matter in cervical and lumbar segments of the spinal cord. In contrast, statistically significant decreases in axial diffusivity (diffusivity parallel to the axis of the spinal cord) and apparent diffusion coefficient were found in the ventrolateral white matter of G93A-SOD1 mice in both the cervical and lumbar spinal cord. The reduction in axial diffusivity, suggestive of axonal injury, in the white matter of the spinal cord of G93A-SOD1 mice was verified by immunostaining with nonphosphorylated neurofilament. The present study demonstrates that in vivo diffusion tensor imaging-derived axial diffusivity may be used to accurately evaluate axonal degeneration in an animal model of amyotrophic lateral sclerosis., (Copyright © 2010 John Wiley & Sons, Ltd.)

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.

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 (lambda perpendicular) and decreases in axial diffusivity (lambda parallel) 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 lambda perpendicular and decrease in lambda parallel, consistent with previously characterized demyelination and axonal damage in these regions. In the Twitcher spinal cord, a statistically significant decrease in lambda parallel was identified in both the dorsal and ventrolateral white matter, relative to normal controls. These results were consistent with immunofluorescence evidence of axonal damage in these areas as detected by staining for nonphosphorylated neurofilaments (SMI32). Increase in lambda perpendicular 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. Correlative 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 the 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.

Inflammation occurs after HIV infection and persists, despite highly active antiretroviral therapy (HAART). Diffusion tensor imaging (DTI) measures HIV-associated white matter changes, but can be confounded by inflammation. Currently, the influence of inflammation on white matter integrity in well-controlled HIV+ patients remains unknown. We used diffusion basis spectral imaging (DBSI)-derived cellularity to isolate restricted water diffusion associated with inflammation separated from the anisotropic diffusion associated with axonal integrity. Ninety-two virologically suppressed HIV+ patients on HAART and 66 HIV uninfected (HIV-) controls underwent neuropsychological performance (NP) testing and neuroimaging. NP tests assessed multiple domains (memory, psychomotor speed, and executive functioning). DTI- and DBSI-derived fractional anisotropy (FA) maps were processed with tract-based spatial statistics for comparison between both groups. Cellularity was assessed regarding age, HIV status, and NP. Within the HIV+ cohort, cellularity was compared with clinical (HAART duration) and laboratory measures of disease (eg, CD4 cell current and nadir). NP was similar for both groups. DTI-derived FA was lower in HIV+ compared with HIV- individuals. By contrast, DBSI-derived FA was similar for both groups. Instead, diffuse increases in cellularity were present in HIV+ individuals. Observed changes in cellularity were significantly associated with age, but not NP, in HIV+ individuals. A trend level association was seen between cellularity and HAART duration. Elevated inflammation, measured by cellularity, persists in virologically well-controlled HIV+ individuals. Widespread cellularity changes occur in younger HIV+ individuals and diminish with aging and duration of HAART.

PurposeTo evaluate optic nerve diffusion tensor imaging (DTI) parameters in glaucoma patients and controls, and to correlate DTI parameters with the rim area obtained with Heidelberg retina tomography (HRT) and with the severity of glaucomatous damage using the Glaucoma Staging System.DesignPilot study.MethodsTwenty-seven patients with glaucoma and 12 control subjects underwent DTI and HRT imaging. Main outcome measures included: fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity, HRT rim area, and Glaucoma Staging System stage.ResultsIn group comparison, mean diffusivity (1.33 vs. 0.91 μm/ms, P=0.0002), axial diffusivity (1.70 vs. 1.43 μm/ms, P=0.036), and radial diffusivity (1.24 vs. 0.71 μm/ms, P0.05).ConclusionsDTI may be a useful technique for detection and evaluation of glaucomatous damage in the optic nerve, particularly for patients in whom conventional imaging and perimetry are not possible. Future studies are needed to evaluate how DTI parameters change longitudinally with glaucomatous damage within the visual pathways and address cerebrospinal fluid partial volume effects in diffusion tensor quantification, especially for patients with advanced glaucoma stage.

BackgroundMultiple Sclerosis (MS) is characterized by the pathological trafficking of leukocytes into the central nervous system (CNS). Using the murine MS model, experimental autoimmune encephalomyelitis (EAE), we previously demonstrated that antagonism of the chemokine receptor CXCR7 blocks endothelial cell sequestration of CXCL12, thereby enhancing the abluminal localization of CXCR4-expressing leukocytes. CXCR7 antagonism led to decreased parenchymal entry of leukocytes and amelioration of ongoing disease during EAE. Of note, animals that received high doses of CXCR7 antagonist recovered to baseline function, as assessed by standard clinical scoring. Because functional recovery reflects axonal integrity, we utilized diffusion tensor imaging (DTI) to evaluate axonal injury in CXCR7 antagonist- versus vehicle-treated mice after recovery from EAE.MethodsC57BL6/J mice underwent adoptive transfer of MOG-reactive Th1 cells and were treated daily with either CXCR7 antagonist or vehicle for 28 days; and then evaluated by DTI to assess for axonal injury. After imaging, spinal cords underwent histological analysis of myelin and oligodendrocytes via staining with luxol fast blue (LFB), and immunofluorescence for myelin basic protein (MBP) and glutathione S-transferase-π (GST-π). Detection of non-phosphorylated neurofilament H (NH-F) was also performed to detect injured axons. Statistical analysis for EAE scores, DTI parameters and non-phosphorylated NH-F immunofluorescence were done by ANOVA followed by Bonferroni post-hoc test. For all statistical analysis a p < 0.05 was considered significant.ResultsIn vivo DTI maps of spinal cord ventrolateral white matter (VLWM) axial diffusivities of naïve and CXCR7 antagonist-treated mice were indistinguishable, while vehicle-treated animals exhibited decreased axial diffusivities. Quantitative differences in injured axons, as assessed via detection of non-phosphorylated NH-F, were consistent with axial diffusivity measurements. Overall, qualitative myelin content and presence of oligodendrocytes were similar in all treatment groups, as expected by their radial diffusivity values. Quantitative assessment of persistent inflammatory infiltrates revealed significant decreases within the parenchyma of CXCR7 antagonist-treated mice versus controls.ConclusionsThese data suggest that CXCR7 antagonism not only prevents persistent inflammation but also preserves axonal integrity. Thus, targeting CXCR7 modifies both disease severity and recovery during EAE, suggesting a role for this molecule in both phases of disease.

BackgroundMultiple Sclerosis (MS) is characterized by the pathological trafficking of leukocytes into the central nervous system (CNS). Using the murine MS model, experimental autoimmune encephalomyelitis (EAE), we previously demonstrated that antagonism of the chemokine receptor CXCR7 blocks endothelial cell sequestration of CXCL12, thereby enhancing the abluminal localization of CXCR4-expressing leukocytes. CXCR7 antagonism led to decreased parenchymal entry of leukocytes and amelioration of ongoing disease during EAE. Of note, animals that received high doses of CXCR7 antagonist recovered to baseline function, as assessed by standard clinical scoring. Because functional recovery reflects axonal integrity, we utilized diffusion tensor imaging (DTI) to evaluate axonal injury in CXCR7 antagonist- versus vehicle-treated mice after recovery from EAE.MethodsC57BL6/J mice underwent adoptive transfer of MOG-reactive Th1 cells and were treated daily with either CXCR7 antagonist or vehicle for 28 days; and then evaluated by DTI to assess for axonal injury. After imaging, spinal cords underwent histological analysis of myelin and oligodendrocytes via staining with luxol fast blue (LFB), and immunofluorescence for myelin basic protein (MBP) and glutathione S-transferase-π (GST-π). Detection of non-phosphorylated neurofilament H (NH-F) was also performed to detect injured axons. Statistical analysis for EAE scores, DTI parameters and non-phosphorylated NH-F immunofluorescence were done by ANOVA followed by Bonferroni post-hoc test. For all statistical analysis a p < 0.05 was considered significant.ResultsIn vivo DTI maps of spinal cord ventrolateral white matter (VLWM) axial diffusivities of naïve and CXCR7 antagonist-treated mice were indistinguishable, while vehicle-treated animals exhibited decreased axial diffusivities. Quantitative differences in injured axons, as assessed via detection of non-phosphorylated NH-F, were consistent with axial diffusivity measurements. Overall, qualitative myelin content and presence of oligodendrocytes were similar in all treatment groups, as expected by their radial diffusivity values. Quantitative assessment of persistent inflammatory infiltrates revealed significant decreases within the parenchyma of CXCR7 antagonist-treated mice versus controls.ConclusionsThese data suggest that CXCR7 antagonism not only prevents persistent inflammation but also preserves axonal integrity. Thus, targeting CXCR7 modifies both disease severity and recovery during EAE, suggesting a role for this molecule in both phases of disease.

• Diffusion MRI measures the effect of tissue microstructures on Brownian motion of water to assess histopathology. • DTI radial diffusivity (reflecting demyelination and edema) predicts future tissue damage in MS. • Diffusion basis spectrum imaging (DBSI) models multiple diffusion tensors, improving pathologic specificity. • DBSI isotropic tensors (representing cellularity and edema) predict future tissue damage in MS. • DBSI may provide additional histopathologic insights in acute MS lesions. Diffusion basis spectrum imaging (DBSI) extracts multiple anisotropic and isotropic diffusion tensors, providing greater histopathologic specificity than diffusion tensor imaging (DTI). Persistent black holes (PBH) represent areas of severe tissue damage in multiple sclerosis (MS), and a high PBH burden is associated with worse MS disability. This study evaluated the ability of DBSI and DTI to predict which acute contrast-enhancing lesions (CELs) would persist as T 1 hypointensities (i.e. PBHs) 12 months later. We expected that a higher radial diffusivity (RD), representing demyelination, and higher DBSI-derived isotropic non-restricted fraction, representing edema and increased extracellular space, of the acute CEL would increase the likelihood of future PBH development. In this prospective cohort study, relapsing MS patients with ≥1 CEL(s) underwent monthly MRI scans for 4 to 6 months until gadolinium resolution. DBSI and DTI metrics were quantified when the CEL was most conspicuous during the monthly scans. To determine whether the CEL became a PBH, a follow-up MRI was performed at least 12 months after the final monthly scan. The cohort included 20 MS participants (median age 33 years; 13 women) with 164 CELs. Of these, 59 (36 %) CELs evolved into PBHs. At Gd-max, DTI RD and AD of all CELs increased, and both metrics were significantly elevated for CELs which became PBHs, as compared to non-black holes (NBHs). DTI RD above 0.74 conferred an odds ratio (OR) of 7.76 (CI 3.77–15.98) for a CEL becoming a PBH (AUC 0.80, CI 0.73–0.87); DTI axial diffusivity (AD) above 1.22 conferred an OR of 7.32 (CI 3.38–15.86) for becoming a PBH (AUC 0.75, CI 0.66–0.83). DBSI RD and AD did not predict PBH development in a multivariable model. At Gd-max, DBSI restricted fraction decreased and DBSI non-restricted fraction increased in all CELs, and both metrics were significantly different for CELs which became PBHs, as compared to NBHs. A CEL with a DBSI non-restricted fraction above 0.45 had an OR of 4.77 (CI 2.35–9.66) for becoming a PBH (AUC 0.74, CI 0.66–0.81); a CEL with a DBSI restricted fraction below 0.07 had an OR of 9.58 (CI 4.59–20.02) for becoming a PBH (AUC 0.80, 0.72–0.87). Our findings suggest that greater degree of edema/extracellular space in a CEL is a predictor of tissue destruction, as evidenced by PBH evolution. [ABSTRACT FROM AUTHOR]

Diffusion tensor imaging (DTI) has been employed for over 2 decades to noninvasively quantify central nervous system diseases/injuries. However, DTI is an inadequate simplification of diffusion modeling in the presence of coexisting inflammation, edema and crossing nerve fibers. We employed a tissue phantom using fixed mouse trigeminal nerves coated with various amounts of agarose gel to mimic crossing fibers in the presence of vasogenic edema. Diffusivity measures derived by DTI and diffusion basis spectrum imaging (DBSI) were compared at increasing levels of simulated edema and degrees of fiber crossing. Furthermore, we assessed the ability of DBSI, diffusion kurtosis imaging (DKI), generalized q‐sampling imaging (GQI), q‐ball imaging (QBI) and neurite orientation dispersion and density imaging to resolve fiber crossing, in reference to the gold standard angles measured from structural images. DTI‐computed diffusivities and fractional anisotropy were significantly confounded by gel‐mimicked edema and crossing fibers. Conversely, DBSI calculated accurate diffusivities of individual fibers regardless of the extent of simulated edema and degrees of fiber crossing angles. Additionally, DBSI accurately and consistently estimated crossing angles in various conditions of gel‐mimicked edema when compared with the gold standard (r2 = 0.92, P = 1.9 × 10−9, bias = 3.9°). Small crossing angles and edema significantly impact the diffusion orientation distribution function, making DKI, GQI and QBI less accurate in detecting and estimating fiber crossing angles. Lastly, we used diffusion tensor ellipsoids to demonstrate that DBSI resolves the confounds of edema and crossing fibers in the peritumoral edema region from a patient with lung cancer metastasis, while DTI failed. In summary, DBSI is able to separate two crossing fibers and accurately recover their diffusivities in a complex environment characterized by increasing crossing angles and amounts of gel‐mimicked edema. DBSI also indicated better angular resolution compared with DKI, QBI and GQI. [ABSTRACT FROM AUTHOR]

Objective: Multiple sclerosis (MS) lesions are heterogeneous with regard to inflammation, demyelination, axonal injury, and neuronal loss. We previously developed a diffusion basis spectrum imaging (DBSI) technique to better address MS lesion heterogeneity. We hypothesized that the profiles of multiple DBSI metrics can identify lesion‐defining patterns. Here we test this hypothesis by combining a deep learning algorithm using deep neural network (DNN) with DBSI and other imaging methods. Methods: Thirty‐eight MS patients were scanned with diffusion‐weighted imaging, magnetization transfer imaging, and standard conventional MRI sequences (cMRI). A total of 499 regions of interest were identified on standard MRI and labeled as persistent black holes (PBH), persistent gray holes (PGH), acute black holes (ABH), acute gray holes (AGH), nonblack or gray holes (NBH), and normal appearing white matter (NAWM). DBSI, diffusion tensor imaging (DTI), and magnetization transfer ratio (MTR) were applied to the 43,261 imaging voxels extracted from these ROIs. The optimized DNN with 10 fully connected hidden layers was trained using the imaging metrics of the lesion subtypes and NAWM. Results: Concordance, sensitivity, specificity, and accuracy were determined for the different imaging methods. DBSI‐DNN derived lesion classification achieved 93.4% overall concordance with predetermined lesion types, compared with 80.2% for DTI‐DNN model, 78.3% for MTR‐DNN model, and 74.2% for cMRI‐DNN model. DBSI‐DNN also produced the highest specificity, sensitivity, and accuracy. Conclusions: DBSI‐DNN improves the classification of different MS lesion subtypes, which could aid clinical decision making. The efficacy and efficiency of DBSI‐DNN shows great promise for clinical applications in automatic MS lesion detection and classification. [ABSTRACT FROM AUTHOR]

Human obesity is associated with low-grade chronic systemic inflammation, alterations in brain structure and function, and cognitive impairment. Rodent models of obesity show that high-calorie diets cause brain inflammation (neuroinflammation) in multiple regions, including the hippocampus, and impairments in hippocampal-dependent memory tasks. To determine if similar effects exist in humans with obesity, we applied Diffusion Basis Spectrum Imaging (DBSI) to evaluate neuroinflammation and axonal integrity. We examined diffusion-weighted magnetic resonance imaging (MRI) data in two independent cohorts of obese and non-obese individuals (Cohort 1: 25 obese/21 non-obese; Cohort 2: 18 obese/41 non-obese). We applied Tract-based Spatial Statistics (TBSS) to allow whole-brain white matter (WM) analyses and compare DBSI-derived isotropic and anisotropic diffusion measures between the obese and non-obese groups. In both cohorts, the obese group had significantly greater DBSI-derived restricted fraction (DBSI-RF; an indicator of neuroinflammation-related cellularity), and significantly lower DBSI-derived fiber fraction (DBSI-FF; an indicator of apparent axonal density) in several WM tracts (all corrected p < 0.05). Moreover, using region of interest analyses, average DBSI-RF and DBSI-FF values in the hippocampus were significantly greater and lower, respectively, in obese relative to non-obese individuals (Cohort 1: p = 0.045; Cohort 2: p = 0.008). Hippocampal DBSI-FF and DBSI-RF and amygdalar DBSI-FF metrics related to cognitive performance in Cohort 2. In conclusion, these findings suggest that greater neuroinflammation-related cellularity and lower apparent axonal density are associated with human obesity and cognitive performance. Future studies are warranted to determine a potential role for neuroinflammation in obesity-related cognitive impairment. [ABSTRACT FROM AUTHOR]

Hippocampal CA1 inflammation and dendritic loss are common in epilepsy. Quantitative detection of coexisting brain inflammation and injury could be beneficial in monitoring disease progression and assessing therapeutic efficacy. In this work, we used conventional diffusion tensor imaging (DTI, known to detect axonal injury and demyelination) and a novel diffusion basis spectrum imaging (DBSI, known to detect axonal injury, demyelination, and inflammation) to detect hippocampal CA1 lesions resulting from neuronal dendritic injury/loss and concomitant inflammation in Theiler's murine encephalomyelitis virus (TMEV)-induced seizure mice. Following the cross-sectional ex vivo diffusion magnetic resonance imaging measurements, immunohistochemistry was performed to validate DTI and DBSI findings. Both DTI and DBSI detected immunohistochemistry-confirmed dendritic injury in the hippocampal CA1 region. Additionally, DBSI-derived restricted isotropic diffusion tensor fraction correlated with 4',6-diamidine-2'-phenylindole dihydrochloride (DAPI)-positive nucleus counts, and DBSI-derived fiber fraction correlated with dendrite density assessed by microtubule-associated protein 2 staining. DTI-derived fractional anisotropy (FA) correlated with dendrite density and negatively correlated with DAPI-positive nucleus counts. Although both DTI and DBSI detected hippocampal injury/inflammation, DTI-FA was less specific than DBSI-derived pathological metrics for hippocampal CA1 dendritic injury and inflammation in TMEV-induced seizure mice. [ABSTRACT FROM AUTHOR]

The article discusses the use of diffusion tensor imaging (DTI) to differentiate the spinal cord lesions caused by neuromyelitis optica (NMO) with multiple sclerosis (MS). It states that DTI shows that radial diffusivity is much greater with NMO than with MS. It says that the results shows much greater tissue destruction caused by NMO than caused by MS.

Abstract: In adult rats, locomotor deficits following a contusive thoracic spinal cord injury (SCI) are caused primarily by white matter loss/dysfunction at the epicenter. This loss/dysfunction decreases descending input from the brain and cervical spinal cord, and decreases ascending signals in long propriospinal, spinocerebellar and somatosensory pathways, among many others. Predicting the long-term functional consequences of a contusive injury acutely, without knowledge of the injury severity is difficult due to the temporary flaccid paralysis and loss of reflexes that accompany spinal shock. It is now well known that recovery of high quality hindlimb stepping requires only 12–15% spared white matter at the epicenter, but that forelimb–hindlimb coordination and precision stepping (grid or horizontal ladder) require substantially more trans-contusion communication. In order to translate our understanding of the neural substrates for functional recovery in the rat to the clinical arena, common outcome measures and imaging modalities are required. In the current study we furthered the exploration of one of these approaches, diffusion tensor magnetic resonance imaging (DTI), a technique now used commonly to image the brain in clinical research but rarely used diagnostically or prognostically for spinal cord injury. In the adult rat model of SCI, we found that hyperacute (<3h post-injury) DTI of the lateral and ventral white matter at the injury epicenter was predictive of both electrophysiological and behavioral (locomotor) recovery at 4weeks post-injury, despite the presence of flaccid paralysis/spinal shock. Regions of white matter with a minimum axial diffusivity of 1.5μm2/ms at 3h were able to conduct action potentials at 4weeks, and axial diffusivity within the lateral funiculus was highly predictive of locomotor function at 4weeks. These observations suggest that acute DTI should be useful to provide functional predictions for spared white matter following contusive spinal cord injuries clinically. [Copyright &y& Elsevier]

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. [ABSTRACT FROM PUBLISHER]

Abstract: 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 βAPP 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. [Copyright &y& Elsevier]

Study Design: Prospective cohort study.Objective: The aim was to assess the association between diffusion tensor imaging (DTI) and diffusion basis spectrum imaging (DBSI) measures and cervical spondylotic myelopathy (CSM) clinical assessments at baseline and two-year follow-up.Summary Of Background Data: Despite advancements in diffusion-weighted imaging, few studies have examined associations between diffusion magnetic resonance imaging (MRI) markers and CSM-specific clinical domains at baseline and long-term follow-up.Materials and Methods: A single-center prospective cohort study enrolled 50 CSM patients who underwent surgical decompression and 20 controls from 2018 to 2020. At initial evaluation, all patients underwent diffusion-weighted MRI acquisition, followed by DTI and DBSI analyses. Diffusion-weighted MRI metrics assessed white matter integrity by fractional anisotropy, axial diffusivity, radial diffusivity, and fiber fraction. To improve estimations of intra-axonal anisotropic diffusion, DBSI measures intra-/extra-axonal fraction and intra-axonal axial diffusivity. DBSI also evaluates extra-axonal isotropic diffusion by restricted and nonrestricted fraction. Clinical assessments were performed at baseline and two-year follow-up and included the modified Japanese Orthopedic Association (mJOA); 36-Item Short Form Survey physical component summary (SF-36 PCS); SF-36 mental component summary; neck disability index; myelopathy disability index; and disability of the arm, shoulder, and hand. Pearson correlation coefficients were computed to compare associations between DTI/DBSI and clinical measures. A False Discovery Rate correction was applied for multiple comparisons testing.Results: At baseline presentation, of 36 correlations analyzed between DTI metrics and CSM clinical measures, only DTI fractional anisotropy showed a positive correlation with SF-36 PCS ( r =0.36, P =0.02). In comparison, there were 30/81 (37%) significant correlations among DBSI and clinical measures. Increased DBSI axial diffusivity, intra-axonal axial diffusivity, intra-axonal fraction, restricted fraction, and extra-axonal anisotropic fraction were associated with worse clinical presentation (decreased mJOA; SF-36 PCS/mental component summary; and increased neck disability index; myelopathy disability index; disability of the arm, shoulder, and hand). At latest follow-up, increased preoperative DBSI intra-axonal axial diffusivity and extra-axonal anisotropic fraction were significantly correlated with improved mJOA.Conclusions: This findings demonstrate that DBSI measures may reflect baseline disease burden and long-term prognosis of CSM as compared with DTI. With further validation, DBSI may serve as a noninvasive biomarker following decompressive surgery.Level Of Evidence: 3. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Correlation of diffusion tensor imaging (DTI) with histochemical staining for demyelination and axonal damage in multiple sclerosis (MS) ex vivo human cervical spinal cords. Background: In MS, demyelination, axonal degeneration, and inflammation contribute to disease pathogenesis to variable degrees. Based upon in vivo animal studies with acute injury and histopathologic correlation, we hypothesized that DTI can differentiate between axonal and myelin pathologies within humans. Methods: DTI was performed at 4.7 T on 9 MS and 5 normal control fixed cervical spinal cord blocks following autopsy. Sections were then stained for Luxol fast blue (LFB), Bielschowsky silver, and hematoxylin and eosin (H&E). Regions of interest (ROIs) were graded semi-quantitatively as normal myelination, mild (<50%) demyelination, or moderate–severe (>50%) demyelination. Corresponding axonal counts were manually determined on Bielschowsky silver. ROIs were mapped to co-registered DTI parameter slices. DTI parameters evaluated included standard quantitative assessments of apparent diffusion coefficient (ADC), relative anisotropy (RA), axial diffusivity and radial diffusivity. Statistical correlations were made between histochemical gradings and DTI parameters using linear mixed models. Results: Within ROIs in MS subjects, increased radial diffusivity distinguished worsening severities of demyelination. Relative anisotropy was decreased in the setting of moderate–severe demyelination compared to normal areas and areas of mild demyelination. Radial diffusivity, ADC, and RA became increasingly altered within quartiles of worsening axonal counts. Axial diffusivity did not correlate with axonal density (p =0.091). Conclusions: Increased radial diffusivity can serve as a surrogate for demyelination. However, radial diffusivity was also altered with axon injury, suggesting that this measure is not pathologically specific within chronic human MS tissue. We propose that radial diffusivity can serve as a marker of overall tissue integrity within chronic MS lesions. This study provides pathologic foundation for on-going in vivo DTI studies in MS. [Copyright &y& Elsevier]

Abstract: 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 (117μm×59μm×500μm) were acquired at 4.7T 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. [Copyright &y& Elsevier]

Abstract: 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 β-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. [Copyright &y& Elsevier]