Eric D. Schwartz

MRI diffusion coefficients in spinal cord correlate with axon morphometry.

Following spinal cord injury, diffusion MRI (DWI) has been shown to detect injury and functionally significant neuroprotection following treatment that otherwise would go undetected with conventional MRI. The underlying histologic correlates to directional apparent diffusion coefficients (ADC) obtained with DWI have not been determined, however, and we address this issue by directly correlating ADC values with corresponding axon morphometry in the normal rat cervical spinal cord. ADC values transverse (perpendicular) and longitudinal (parallel) to axons both correlate with axon counts, however each directional ADC reflects distinct histologic parameters. DWI may therefore be capable of providing specific histologic data regarding the integrity of white matter.

Indirect Measurement of Regional Axon Diameter in Excised Mouse Spinal Cord with Q-space Imaging: Simulation and Experimental Studies

Q-space imaging (QSI), a diffusion MRI technique, can provide quantitative tissue architecture information at cellular dimensions not amenable by conventional diffusion MRI. By exploiting regularities in molecular diffusion barriers, QSI can estimate the average barrier spacing such as the mean axon diameter in white matter (WM). In this work, we performed ex vivo QSI on cervical spinal cord sections from healthy C57BL/6 mice at 400 MHz using a custom-designed uniaxial 50T/m gradient probe delivering a 0.6 microm displacement resolution capable of measuring axon diameters on the scale of 1 microm. After generating QSI-derived axon diameter maps, diameters were calculated using histology from seven WM tracts (dorsal corticospinal, gracilis, cuneatus, rubrospinal, spinothalamic, reticulospinal, and vestibulospinal tracts) each with different axon diameters. We found QSI-derived diameters from regions drawn in the seven WM tracts (1.1 to 2.1 microm) to be highly correlated (r(2)=0.95) with those calculated from histology (0.8 to 1.8 microm). The QSI-derived values overestimated those obtained by histology by approximately 20%, which is likely due to the presence of extra-cellular signal. Finally, simulations on images of synthetic circular axons and axons from histology suggest that QSI-derived diameters are informative despite diameter and axon shape variation and the presence of intra-cellular and extra-cellular signal. QSI may be able to quantify nondestructively changes in WM axon architecture due to pathology or injury at the cellular level.

Diffusion-weighted MRI and the evaluation of spinal cord axonal integrity following injury and treatment

Diffusion-based magnetic resonance imaging (MRI) (DWI) has been shown experimentally to detect both injury and functionally significant neuroprotection of injured spinal cord white matter that would otherwise go undetected with conventional MRI techniques. The diffusion of water in the central nervous system (CNS) is thought to be affected by both its location (intracellular or extracellular), and by diffusion barriers formed by cell membranes and myelin sheaths. There is, however, controversy concerning how to obtain, interpret, and present DWI data. Computer simulations and MR microscopy have been helpful in resolving some of these issues, as well as determining exact histologic correlates to DWI findings.

Relation of vision to global and regional brain MRI in multiple sclerosis

Objective: To examine the relation between low-contrast letter acuity, an emerging visual outcome for multiple sclerosis (MS) clinical trials, and brain MRI abnormalities in an MS cohort. Methods: T2 lesion volume and brain parenchymal fraction were determined for whole brain and within visual pathway regions of interest. Magnetization transfer ratio histograms were examined. Vision testing was performed binocularly using low-contrast letter acuity (2.5%, 1.25% contrast) and high-contrast visual acuity (VA). Linear regression, accounting for age and disease duration, was used to assess the relation between vision and MRI measures. Results: Patients (n = 45) were aged 44 ± 11 years, with disease duration of 5 years (range <1 to 21), Expanded Disability Status Scale score of 2.0 (0 to 6.0), and binocular Snellen acuity of 20/16 (20/12.5 to 20/25). The average T2 lesion volume was 18.5 mm3. Patients with lower (worse) low-contrast letter acuity and high-contrast VA scores had greater T2 lesion volumes in whole brain (2.5% contrast: p = 0.004; 1.25%: p = 0.002; VA: p = 0.04), Area 17 white matter (2.5%: p < 0.001; 1.25%: p = 0.02; VA: p = 0.01), and optic radiations (2.5%: p = 0.001; 1.25%: p = 0.02; VA: p = 0.007). Within whole brain, a 3-mm3 increase in lesion volume corresponded, on average, to a 1-line worsening of low-contrast acuity, whereas 1-line worsening of high-contrast acuity corresponded to a 5.5-mm3 increase. Conclusions: Low-contrast letter acuity scores correlate well with brain MRI lesion burden in multiple sclerosis (MS), supporting validity for this vision test as a candidate for clinical trials. Disease in the postgeniculate white matter is a likely contributor to visual dysfunction in MS that may be independent of acute optic neuritis history.

Ex vivo MR determined apparent diffusion coefficients correlate with motor recovery mediated by intraspinal transplants of fibroblasts genetically modified to express BDNF.

The purpose of this study was to determine whether apparent diffusion coefficients (ADCs) in ex vivo spinal cord white matter, calculated from diffusion weighted MR (DWI) images, correlate with axonal growth and behavioral recovery following subtotal hemisection and transplantation of fibroblasts genetically modified to express brain derived neurotrophic factor (BDNF). These genetically modified fibroblasts have been shown to promote axonal growth, diminish retrograde degenerative changes in axotomized Red nucleus neurons, and are associated with behavioral recovery. Since changes in ADC appear to reflect damage to axons and myelin sheaths, which conventional MR techniques do not identify, partial repair mediated by BDNF-secreting fibroblasts should be detected with ADC measures. Accordingly, we transplanted unmodified fibroblasts (Fb-UM) or fibroblasts modified to secrete BDNF (Fb-BDNF) into cervical subtotal hemisection cavities in adult rats. Rats with Fb-BDNF transplants showed significantly greater behavioral recovery over 12 weeks, as measured by tests of forelimb exploration and open field locomotor activity. Lesion sizes and transplant survival did not differ between the two groups, but immunocytochemical examination showed substantial growth of axons into the Fb-BDNF grafts and little growth into the Fb-UM grafts. Fixed spinal cords were imaged in a 9.4-T magnet. ADCs perpendicular (tADC) and parallel (lADC) to the long axis of the cord were measured in the dorsal lateral white matter, rostral and caudal to the transplant. tADC values and anisotropy index (AI = tADC/lADC) were elevated in both transplant types, indicating white matter damage, but were closer to normal in rats with Fb-BDNF, consistent with known neuroprotection and axonal growth elicited by BDNF. Closer to normal tADC and AI values correlated with improved behavioral recovery. These findings suggest that high-resolution imaging with measurement of tADC and lADC can provide a measure of functionally significant repair that may otherwise go undetected with conventional MR techniques.

Distinguishing ischemic stroke from the stroke-like lesions of MELAS using apparent diffusion coefficient mapping

We report two patients with migraine, acute visual field defects and other neurological symptoms who were found to have high T(2) signal and FLAIR abnormalities on brain MRI in temporal and parieto-occipital regions. In these patients, the apparent diffusion coefficient (ADC) of their lesions was increased, distinguishing these lesions from those of ischemic stroke. Both were ultimately diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). We conclude that conventional MRI when used with diffusion-weighted MR imaging may be invaluable in detecting mitochondrial-related CNS dysfunction.

Assessment of axonal fiber tract architecture in excised rat spinal cord by localized NMR q-space imaging: Simulations and experimental studies†

NMR q‐space imaging is a method designed to obtain information from porous materials where diffusion‐diffraction phenomena were observed from which pore size was derived. Recently, the technique has been applied to the study of biological structures as well. Although diffusive diffraction has so far not been observed in multicellular systems, displacement profiles have been used with some success as a means to estimate structure size. However, there have been no quantitative correlations of the retrieved structure sizes with histology. Clearly, the complexity of tissue architecture poses significant challenges to the interpretation of q‐space data. In this work, simulations were first performed on a two‐compartment model to demonstrate the effects of interference of the diffraction patterns arising from intra and extra‐axonal compartments and finite boundary permeability on q‐space data. Second, q‐space echo attenuation was simulated on the basis of histologic images of various rat spinal cord fiber tracts and the information obtained from the displacement profiles were compared with structural parameters computed from the histologic images. The results show that calculated mean displacements and kurtosis parallel mean axon size and axonal density. Finally, spatially localized q‐space measurements were carried out at the locations where simulations had previously been performed, resulting in displacement data that support those obtained by simulation. The data suggest the NMR q‐space approach has potential for nondestructive analysis of the axonal architecture in the mammalian spinal cord. Magn Reson Med 52:733–740, 2004.

In vivo DTI evaluation of white matter tracts in rat spinal cord.

To determine whether differences in specific spinal cord white matter (WM) tracts can be detected with in vivo DTI.

Diffusion-weighted imaging of the spinal cord

Spinal cord DWI may be useful in providing information not available with conventional MR imaging. More work, however, is required to explain what the qualitative and quantitative results actually represent. Computer simulations and detailed radiologic-histologic correlations will therefore be necessary.

Complete regression of intracranial arteriovenous malformations.

BACKGROUND Spontaneous and complete regression of intracranial arteriovenous malformations (AVMs) is a rare occurrence, with only 59 angiographically proven cases reported in the English literature. We present three new cases and perform a literature review to determine possible mechanisms underlying this unusual phenomenon. METHODS Three patients with angiographically proven AVMs demonstrated complete obliteration of the AVM on follow-up angiography. Two patients had MRIs performed at the time of follow-up angiography. RESULTS A literature review of all reported cases shows that the vast majority (88%) of spontaneously closing AVMs had a single draining vein as did our three cases. In addition, hemodynamic alterations of intracranial (IC) blood flow, including intracranial hemorrhage, were seen in a majority (79%) of patients, including two of our three cases. MRI was performed in two of our three cases and showed a thrombosed-draining vein in both. CONCLUSIONS Complete spontaneous regression of intracranial AVMs is a rare occurrence. The phenomenon seems to require the interaction of hemodynamic changes in compromising or closing the limited, usually single, venous drainage pathway from the AVM. Hemorrhage may contribute to the effect by further compromising flow though the lesion, or it may merely be a phenomenon associated with the effects of venous hypertension on the AVM nidus.