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Background: Chronic cerebrospinal venous insufficiency (CCSVI) was implicated in the pathophysiology of multiple sclerosis (MS)., Objective: We evaluated neurosonography (NS), magnetic resonance venography (MRV), and transluminal venography (TLV) in subsets of MS patients drawn from a single-center, prospective, case-control study of 206 MS and 70 non-MS volunteers., Methods: As previously reported, findings on high-resolution B-mode NS imaging with color and spectral Doppler of the extracranial and intracranial venous drainage consistent with CCSVI were similar among MS and non-MS volunteers (3.88% vs 7.14%; p = 0.266). Ninety-nine MS participants consented to intravascular contrast-enhanced 3D MRV to assess their major systemic and intracranial venous circulation, and 40 advanced to TLV that included pressure measurements of the superior vena cava, internal jugular, brachiocephalic, and azygous veins., Results: NS findings and MRV patterns were discrepant for 26/98 evaluable subjects, including four with abnormal findings on NS that had normal venous anatomy by MRV. In no instance were TLV pressure gradients indicative of clinically significant functional stenosis encountered. The three imaging approaches provided generally consistent data with discrepancies referable to inherent technique properties., Conclusions: Our findings lend no support for altered venous outflow dynamics as common among MS patients, nor do they likely contribute to the disease process.

Objective: Chronic cerebrospinal venous insufficiency (CCSVI) has been implicated in the pathophysiology of multiple sclerosis (MS). We sought to determine whether neurosonography (NS) provides reliable information on cerebral venous outflow patterns specific to MS., Methods: This was a single-center, prospective case-control study of volunteer MS and non-MS participants. A neurosonologist, blind to the subjects' diagnosis, used high-resolution B-mode imaging with color and spectral Doppler to systematically investigate, capture, and record extracranial and intracranial venous drainage. These neuroimaging results were evaluated and scored by an expert blinded to subjects' information and with no interactions with the participants., Results: Altogether, 276 subjects were studied: 206 with MS and 70 non-MS. MS patients were older than non-MS subjects (48.3±9.9 vs 44.3±11.8 years, p<0.007), with durations from first symptoms and diagnosis of 13.7±10 and 9.9±7.8 years, and Expanded Disability Status Scale of 2.6±2.0. Overall, 82 subjects (29.7%) fulfilled 1 of 5 NS criteria proposed for CCSVI; 13 (4.7%) fulfilled 2 criteria required for diagnosis, and none fulfilled >2 criteria. The distribution of subjects with 0, 1, or 2 criteria did not differ significantly across all diagnostic groupings, between MS and non-MS subjects, or within MS subgroups. CCSVI was present in 7.14% of non-MS and 3.88% of MS patients (p=0.266). No significant differences emerged between MS and non-MS subjects for extracranial or intracranial venous flow rates., Interpretation: NS findings described as CCSVI are much less prevalent than initially reported, and do not distinguish MS from other subjects. Our findings do not support the hypothesis that CCSVI is causally associated with MS., (© 2013 American Neurological Association.)

Spinal cord injury (SCI) results in immediate disruption of the spinal vascular network, triggering an ischemic environment and initiating secondary degeneration. Promoting angiogenesis and vascular stability through the induction of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1), respectively, provides a possible therapeutic approach in treating SCI. We examined whether supplementing the injured environment with these two factors, which are significantly reduced following injury, has an effect on lesion size and functional outcome. Sustained delivery of both VEGF(165) and Ang-1 was realized using viral vectors based on the adeno-associated virus (AAV), which were injected directly into the lesion epicenter immediately after injury. Our results indicate that the combined treatment with VEGF and Ang-1 resulted in both reduced hyperintense lesion volume and vascular stabilization, as determined by magnetic resonance imaging (MRI). Western blot analysis indicated that the viral vector expression was maintained into the chronic phase of injury, and that the use of the AAV vectors did not exacerbate infiltration of microglia into the lesion epicenter. The combined treatment with AAV-VEGF and AAV-Ang-1 improved locomotor recovery in the chronic phase of injury. These results indicate that combining angiogenesis with vascular stabilization may have potential therapeutic applications following SCI.

Comprehensive in vivo longitudinal studies that include multi-modal magnetic resonance imaging (MRI) and a battery of behavioral assays to assess functional outcome were performed at multiple time points up to 56 days post-traumatic spinal cord injury (SCI) in rodents. The MRI studies included high-resolution structural imaging for lesion volumetry, and diffusion tensor imaging (DTI) for probing the white matter integrity. The behavioral assays included open-field locomotion, grid walking, inclined plane, computerized activity box performance, and von Frey filament tests. Additionally, end-point histology was assessed for correlation with both the MRI and behavioral data. The temporal patterns of the lesions were documented on structural MRI. DTI studies showed significant changes in white matter that is proximal to the injury epicenter and persisted to day 56. White matter in regions up to 1 cm away from the injury epicenter that appeared normal on conventional MRI also exhibited changes that were indicative of tissue damage, suggesting that DTI is a more sensitive measure of the evolving injury. Correlations between DTI and histology after SCI could not be firmly established, suggesting that injury causes complex pathological changes in multiple tissue components that affect the DTI measures. Histological evidence confirmed a significant decrease in myelin and oligodendrocyte presence 56 days post-SCI. Multiple assays to evaluate aspects of functional recovery correlated with histology and DTI measures, suggesting that damage to specific white matter tracts can be assessed and tracked longitudinally after SCI.

Longitudinal in vivo proton magnetic resonance spectroscopy (1H-MRS) and immunohistochemistry were performed to investigate the tissue degeneration in traumatically injured rat spinal cord rostral and caudal to the lesion epicenter. On 1H-MRS significant decreases in N-acetyl aspartate (NAA) and total creatine (Cr) levels in the rostral, epicenter, and caudal segments were observed by 14 days, and levels remained depressed up to 56 days post-injury (PI). In contrast, the total choline (Cho) levels increased significantly in all three segments by 14 days PI, but recovered in the epicenter and caudal, but not the rostral region, at 56 days PI. Immunohistochemistry demonstrated neuronal cell death in the gray matter, and reactive astrocytes and axonal degeneration in the dorsal, lateral, and ventral white-matter columns. These results suggest delayed tissue degeneration in regions both rostrally and caudally from the epicenter in the injured spinal cord tissue. A rostral-caudal asymmetry in tissue recovery was seen both on MRI-observed hyperintense lesion volume and the Cho, but not NAA and Cr, levels at 56 days PI. These studies suggest that dynamic metabolic changes take place in regions away from the epicenter in injured spinal cord.

Vascular endothelial growth factor (VEGF) is being investigated as a potential interventional therapy for spinal cord injury (SCI). In the current study, we examined SCI-induced changes in VEGF protein levels using Western blot analysis around the epicenter of injury. Our results indicate a significant decrease in the levels of VEGF(165) and other VEGF isoforms at the lesion epicenter 1 day after injury, which was maintained up to 1 month after injury. We also examined if robust VEGF(165) decrease in injured spinal cords affects neuronal survival, given that a number of reported studies show neuroprotective effect of this VEGF isoform. However, exogenously administered VEGF(165) at the time of injury did not affect the number of sparred neurons. In contrast, exogenous administration of VEGF antibody that inhibits actions of not only VEGF(165) but also of several other VEGF isoforms, significantly decreased number of sparred neurons after SCI. Together these results indicate a general reduction of VEGF isoforms following SCI and that isoforms other than VEGF(165) (e.g., VEGF(121) and/or VEGF(189)) provide neuroprotection, suggesting that VEGF(165) isoform is likely involved in other pathophysiological process after SCI.

Compromised blood-spinal cord barrier (BSCB) is a factor in the outcome following traumatic spinal cord injury (SCI). Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis and vascular permeability. The role of VEGF in SCI is controversial. Relatively little is known about the spatial and temporal changes in the BSCB permeability following administration of VEGF in experimental SCI. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies were performed to noninvasively follow spatial and temporal changes in the BSCB permeability following acute administration of VEGF in experimental SCI over a post-injury period of 56 days. The DCE-MRI data was analyzed using a two-compartment pharmacokinetic model. Animals were assessed for open field locomotion using the Basso-Beattie-Bresnahan score. These studies demonstrate that the BSCB permeability was greater at all time points in the VEGF-treated animals compared to saline controls, most significantly in the epicenter region of injury. Although a significant temporal reduction in the BSCB permeability was observed in the VEGF-treated animals, BSCB permeability remained elevated even during the chronic phase. VEGF treatment resulted in earlier improvement in locomotor ability during the chronic phase of SCI. This study suggests a beneficial role of acutely administered VEGF in hastening neurobehavioral recovery after SCI.

After a primary traumatic injury, spinal cord tissue undergoes a series of pathobiological changes, including compromised blood-spinal cord barrier (BSCB) integrity. These vascular changes occur over both time and space. In an experimental model of spinal cord injury (SCI), longitudinal dynamic contrast-enhanced MRI (DCE-MRI) studies were performed up to 56 days after SCI to quantify spatial and temporal changes in the BSCB permeability in tissue that did not show any visible enhancement on the post-contrast MRI (non-enhancing tissue). DCE-MRI data were analyzed using a two-compartment pharmacokinetic model. These studies demonstrate gradual restoration of BSCB with post-SCI time. However, on the basis of DCE-MRI, and confirmed by immunohistochemistry, the BSCB remained compromised even at 56 days after SCI. In addition, open-field locomotion was evaluated using the 21-point Basso-Beattie-Bresnahan scale. A significant correlation between decreased BSCB permeability and improved locomotor recovery was observed.

To overcome some of the limitations of an implantable coil, including its invasive nature and limited spatial coverage, a three-element phased-array coil is described for high-resolution magnetic resonance imaging (MRI) of rat spinal cord. This coil allows imaging both thoracic and cervical segments of rat spinal cord. In the current design, coupling between the nearest neighbors was minimized by overlapping the coil elements. A simple capacitive network was used for decoupling the next neighbor elements. The dimensions of individual coils in the array were determined based on the signal-to-noise ratio (SNR) measurements performed on a phantom with three different surface coils. SNR measurements on a phantom demonstrated higher SNR for the phased array coil relative to two different volume coils. In vivo images acquired on rat spinal cord with our coil demonstrated excellent gray and white matter contrast. To evaluate the performance of the phased array coil under parallel imaging, g-factor maps were obtained for acceleration factors of 2 and 3. These simulations indicate that parallel imaging with an acceleration factor of 2 would be possible without significant image reconstruction-related noise amplifications., ((c) 2008 Wiley-Liss, Inc.)

Regional values of fractional anisotropy (FA) and mean diffusivity (D(av)) of in vivo and excised rat spinal cords were measured using an iscosahedral encoding scheme that is based on 21 uniformly distributed and alternating gradient directions with an echo planar imaging (EPI) readout. Based on the water phantom studies, this scheme was shown to provide unbiased estimation of FA. The stability of the scanner during the acquisition of diffusion tensor imaging (DTI) data was evaluated. Repeated measurements of the FA values demonstrated excellent reproducibility, as assessed by the Bland-Altman analysis. These studies demonstrated a reduced anisotropy in excised samples relative to in vivo cords. Diffusion in the spinal cord gray matter was shown to be anisotropic. The FA value in the dorsal white matter (WM) was found to be higher relative to the ventral WM. Results from these studies should provide the necessary baseline data for serial in vivo DTI of injured spinal cord., (Copyright 2004 Wiley-Liss, Inc.)

Descriptions of diffusion anisotropy in MR Diffusion Tensor Imaging are often based on scalar indices such as surface-to-volume ratio, volume ratio, fractional anisotropy and rotational anisotropy. Recently, Mohr diagram was introduced to visualize the anisotropic diffusion information, but in a graphical form. Even though both scalar indices and the Mohr diagram are derived from the elements of the diffusion tensor, so far, the relationships between these measures and the key aspects of the Mohr diagram have not been established. This paper demonstrates these relationships both qualitatively and quantitatively for two microscopically heterogeneous biologic tissues, kidney and spinal cord.

In vivo diffusion tensor imaging of normal rat spinal cord was performed using a multi-segmented, blipped EPI sequence at 7 T field strength. At high diffusion weighting, the signal exhibited a non-monoexponential decay that was fitted to a biexponential function, associated with the fast and slow components of diffusion in the cord tissue, using a nonlinear regression analysis along with a constrained optimization procedure. From the measured tensors, the eigenvalues and the maps of invariant scalar measures (fractional anisotropy, relative anisotropy, volume ratio, and trace) were calculated and analyzed statistically. The results were combined to quantitatively characterize the anisotropic properties of the fast and slow diffusions in white- and gray matter of live spinal cords.

Abstract: In vivo diffusion tensor imaging (DTI) of rat cervical and thoracic spinal cord was performed using a three-element phased array coil at 7 T. The magnetic field was shimmed over the spinal cord in real time using an in-house developed automatic algorithm. Echo planar imaging (EPI)-based diffusion-weighted images (DWIs) were acquired with 21 gradient encoding directions. The DWIs were tensor encoded, and diffusion tensor metrics, fractional anisotropy (FA), mean diffusivity (MD), longitudinal diffusivity (λ 0) and transverse diffusivity (λ ⊥) were determined for both white matter (WM) and gray matter (GM). The results on six normal rats indicated no significant differences in the diffusion tensor metrics between thoracic and cervical regions. However, the DTI-derived metrics in cervical spinal cord from our study are somewhat different from the published results in rats. The possible reasons for these differences are suggested. [Copyright &y& Elsevier]