Histopathology, electrodiagnostic testing, and magnetic resonance imaging show significant peripheral and central nervous system myelin abnormalities in the cat model of alpha-mannosidosis.

Alpha-mannosidosis is a disease caused by the deficient activity of alpha-mannosidase, a lysosomal hydrolase involved in the degradation of glycoproteins. The disease is characterized by the accumulation of mannose-rich oligosaccharides within lysosomes. The purpose of this study was to characterize the peripheral nervous system (PNS) and central nervous system (CNS) myelin abnormalities in cats from a breeding colony with a uniform mutation in the gene encoding alpha-mannosidase. Three affected cats and 3 normal cats from 2 litters were examined weekly from 4 to 18 wk of age. Progressively worsening neurological signs developed in affected cats that included tremors, loss of balance, and nystagmus. In the PNS, affected cats showed slow motor nerve conduction velocity and increased F-wave latency. Single nerve fiber teasing revealed significant demyelination/remyelination in affected cats. Mean G-ratios of nerves showed a significant increase in affected cats compared to normal cats. Magnetic resonance imaging of the CNS revealed diffuse white matter signal abnormalities throughout the brain of affected cats. Quantitative magnetization transfer imaging showed a 8%-16% decrease in the magnetization transfer ratio in brain white matter of affected cats compared to normal cats, consistent with myelin abnormalities. Histology confirmed myelin loss throughout the cerebrum and cerebellum. Thus, histology, electrodiagnostic testing, and magnetic resonance imaging identified significant myelination abnormalities in both the PNS and CNS that have not been described previously in alpha-mannosidosis.

Global estimation of myelination in the developing brain on the basis of magnetization transfer imaging: a preliminary study.

BACKGROUND AND PURPOSE: In the developing brain, myelination occurs in an orderly and predetermined sequence. The aim of this study was to determine whether such changes can be tracked using volumetric magnetization transfer imaging. METHODS: Three-dimensional magnetization transfer imaging was performed in 50 children (age range, 0.6-190 months) with no evidence of developmental delay or structural abnormalities. Volumetric magnetization transfer ratio (MTR) parameters generated of the whole brain were mean MTR and height and location of the MTR histogram peak. Relationships between volumetric MTR parameters and age were assessed using nonlinear regression analysis. RESULTS: With age, all volumetric MTR parameters changed exponentially in a way that was best expressed by the function y = a + b.exp(-x/c) (P < .0001). The peak height of the MTR histogram was the parameter that changed most predictably and that continued to change for the longest period of time. CONCLUSION: With this preliminary study, we show that by using volumetric MTR analysis, it is possible to monitor changes in the developing brain, presumably the myelination progress. This method has a potential role for detecting myelination disorders in the pediatric population, for studying the natural history of these diseases, and for monitoring the effects of treatment.

Magnetization transfer imaging of the canine brain: a review.

Magnetization transfer imaging is a modality capable of examining the non-water components of brain tissue by examining the effects they have on water protons. It may be used qualitatively to increase the visibility of lesions seen during magnetic resonance angiography and following the administration of an intravenous paramagnetic contrast medium. Quantitatively, it can be used to examine the effect of pathology on magnetization transfer contrast, to provide a measurement of myelination, as well as to quantify disease progression in trauma, neoplasia, neurodegeneration and other disorders of the brain. This paper reviews the theory of magnetization transfer imaging, its applications, and provides an example of its use in examining the canine brain.

Magnetization transfer ratio histogram analysis of gray matter in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: Gray matter may be affected by multiple sclerosis (MS), a white matter disease. Magnetization transfer ratio (MTR) is a sensitive and quantitative marker for structural abnormalities, and has been used frequently in the imaging of MS. In this study, we evaluated the amount of MTR of gray matter among patients with relapsing-remitting MS and healthy control subjects as well as the correlation between gray matter MTR abnormality and neurologic disability associated with relapsing-remitting MS. METHODS: We obtained fast spin-echo dual-echo and magnetization transfer (with and without MT saturation pulses) images from eighteen patients with relapsing-remitting MS and 18 age-matched healthy control subjects. Gray matter was segmented using a semiautomated system. Gray matter MTR histogram parameters, Kurtzke Expanded Disability Status Scale (EDSS), total T2 lesion volume, and gray matter volumes were obtained for statistical analysis. RESULTS: A significant difference was found in gray matter MTR between patients with relapsing-remitting MS and healthy subjects (mean and median). Gray matter MTR histogram normalized peak heights in patients inversely correlated with EDSS (r = -0.65, P =.01). There was also an inverse correlation between mean MTR of gray matter and total T2 lesion volume. CONCLUSION: The MTR of gray matter significantly differed between patients with relapsing-remitting MS and healthy control subjects, suggesting that MS is a more diffuse disease affecting the whole brain, and neuronal damage accumulates in step with T2 lesion volume. Our finding of the relationship between gray matter MTR and EDSS indicates that measurement of gray matter abnormality may be a potentially useful tool for assessing clinical disability in MS.

Magnetization transfer imaging and proton MR spectroscopy in the evaluation of axonal injury: correlation with clinical outcome after traumatic brain injury.

BACKGROUND AND PURPOSE: Current imaging does not permit quantification of neural injury after traumatic brain injury (TBI) and therefore limits both the development of new treatments and the appropriate counseling of patients concerning prognosis. We evaluated the utility of magnetization transfer ratio (MTR) and proton MR spectroscopy in identifying patients with neuronal injury after TBI. METHODS: Thirty patients with TBI (21-77 years old; mean age, 42 years; admission Glasgow Coma Scale (GOS) scores 3-15; mean score, 11) were studied on a 1.5-T system with magnetization transfer imaging and MR spectroscopy of the splenium. Magnetization transfer imaging was also performed in the brain stem in all patients, and other areas of the brain were sampled in one patient. The splenium of the corpus callosum and brain stem were studied because these are often affected by diffuse axonal injury. Scans were obtained 2 to 1129 days after injury (median, 41 days). MTR was considered abnormal if it was more than 2 SD below normal. Proton MR spectroscopy was used to calculate the N-acetylaspartate (NAA)/creatine (Cr) ratio. GOS was determined at least 3 months after injury. RESULTS: In 10 patients with a GOS of 1 to 4, the mean NAA/Cr was 1.24 +/- 0.28; two of these patients had abnormal MTR in normal-appearing white matter (NAWM). In 20 patients with a GOS of 5, the mean NAA/Cr was 1.53 +/- 0.37 (P < .05); four of these patients had abnormal MTR in NAWM. MTR abnormalities in NAWM were identified in six patients, but these changes did not correlate with GOS or MR spectroscopy changes. CONCLUSION: MTR and MR spectroscopy can quantify damage after TBI, and NAA levels may be a sensitive indicator of the neuronal damage that results in a worse clinical outcome.

Characterization of experimental spinal cord injury with magnetization transfer ratio histograms.

This study was designed to characterize the severity of tissue damage in experimental spinal cord injury using magnetization transfer (MT) histogram analysis. Seven Sprague-Dawley rats were subjected to laminectomy and standard weight-drop injury to the spinal cord (four rats at 15 cm drop-height and three rats at 2.5 cm). Three control animals underwent laminectomy without weight-drop. After sacrifice, the animals were scanned at 1.9 T with a pulsed off-resonance MT technique. Following magnetic resonance (MR) imaging, the cords were embedded in paraffin and sectioned into 5-microm sections for semiquantitative histopathological analysis. Composite histograms were generated using data spanning an axial distance of 3 cm centered on the injury site. MT histogram parameters, such as the amount of tissue with statistical correspondence to normal white matter, were highly predictive of histopathological results, including myelination state and neurofilament damage. Less correlation with edema was observed, suggesting that the technique was most sensitive to true tissue alteration.

Multiple sclerosis: magnetization transfer histogram analysis of segmented normal-appearing white matter.

PURPOSE: To investigate and characterize the global distribution of magnetization transfer (MT) ratio values of normal-appearing white matter (NAWM) in patients with relapsing-remitting multiple sclerosis (MS) and test the hypothesis that the MT histogram for NAWM reflects disease progression. MATERIALS AND METHODS: Conventional and MT magnetic resonance (MR) images were obtained in 23 patients and 25 healthy volunteers. Clinical tests for comparison with the MT histogram parameters included the Extended Disability Status Scale and the ambulation index. Lesion load calculated with T2-weighted MR images and whole-brain and white matter volumes were measured. RESULTS: The location of the MT histogram peak and the mean MT ratio for NAWM were significantly lower in patients with MS than in control subjects. In longitudinal studies, the histogram peak location and mean MT ratio shifted in the direction of normal values as the duration of disease increased. A mean of 26.5% of the volume of new lesions identified on the later studies were demonstrated to have originated in NAWM corresponding to "lost" pixels on the histogram. CONCLUSION: MT histogram analysis of NAWM, including longitudinal analysis, may provide new prognostic information regarding lesion formation and increase understanding of the course of the disease.

Magnetization transfer imaging in the detection of injury associated with mild head trauma.

BACKGROUND AND PURPOSE: Most traumatic brain injuries are classified as mild, yet in many instances cognitive deficits result. The purpose of this study was to investigate possible relationships between quantitative magnetization transfer imaging (MTI) and neurocognitive findings in a cohort of patients with mild head trauma but negative findings on conventional MR images. METHODS: We examined 13 patients and 10 healthy volunteers with a standard MR protocol including fast spin-echo and gradient-echo imaging, to which was added quantitative MTI. MTI was performed with a modified gradient-echo sequence incorporating pulsed, off-resonance saturation. Both region-of-interest analysis and contour plots were obtained from the MTI data. A subgroup of nine patients was examined with a battery of neuropsychological tests, comprising 25 measures of neurocognitive ability. RESULTS: The magnetization transfer ratio (MTR) in the splenium of the corpus callosum was lower in the patient group as compared with the control group, but no significant reduction in MTR was found in the pons. Individual regional MTR values were significantly reduced in two cases, and contour plot analysis revealed focal areas of abnormality in the splenium of four patients. All the patients showed impairment on at least three measures of the neuropsychological test battery, and in two cases a significant correlation was found between regional MTR values and neuropsychological performance. CONCLUSION: Our results suggest that MTI and contour plot analysis may add sensitivity to the MR imaging examination of patients with traumatic brain injury.

Magnetization transfer imaging of traumatic brain injury.

Magnetization transfer imaging (MTI) has been shown to be sensitive for the detection of white matter abnormalities in entities such as multiple sclerosis, progressive multifocal leukoencephalopathy, and wallerian degeneration. Our hypothesis was that MTI would detect traumatic white matter abnormalities (TWMA) and provide information additional to that obtainable with routine spin- and gradient-echo imaging. We hypothesized that the presence of TWMA defined by MTI would correlate with outcome following TBI. Twenty-eight victims of head trauma and 15 normal controls underwent magnetic resonance imaging including MTI. Magnetization transfer ratios (MTR) were calculated for areas of shearing injury and for normal-appearing white matter (NAWM) in locations frequently subject to diffuse axonal injury. Abnormal MTRs were detected in NAWM in eight patients. All eight had persistent neurologic deficits, including cognitive deficits, aphasia, and extremity weakness. Seven of the 28 patients had no abnormal findings on neurologic exam at discharge, transfer, or follow-up. None of these patients had an abnormal MTR in NAWM. In the remaining 13 patients, who had persistent neurologic deficits, no regions of abnormal MTR were detected in NAWM. MTI is a sensitive method for the detection of TWMA. Detection of abnormal MTR in NAWM that is prone to axonal injury may predict a poor patient outcome. The presence of normal MTR in NAWM in these areas does not necessarily confer a good outcome, however.

Investigating demyelination in the brain in a canine model of globoid cell leukodystrophy (Krabbe disease) using magnetization transfer contrast: preliminary results.

PURPOSE: This study was designed to examine the use of quantitative magnetization transfer imaging (MTI) in naturally occurring globoid cell leukodystrophy (GLD) in the Cairn terrier. METHOD: A model of GLD was established via a breeding colony, and a total of seven animals were studied with MTI, including two dogs with GLD, one of which underwent whole-body irradiation (725 cGy) and bone marrow transplantation from a genotypically normal littermate. The remaining dogs served as untreated, irradiated, and unirradiated controls. RESULTS: Region-of-interest (ROI) analysis of the MTI showed a decrease in MT ratio (MTR) in the internal capsule of the untreated/affected dog compared with age-matched controls but revealed similar results in the two other study animals. On MT contour plotting, inside-to-out gradients of MTR mimicked the demyelination pathology of the disease in the untreated/affected dog. CONCLUSION: MT contour plotting demonstrated patterns of MT abnormality in the untreated/affected dog that were consistent with histopathology, establishing a clear relationship between pathology-proven demyelination and MTR as well as a striking contrast to the patterns of radiation damage.

Technical issues for MRI examination of the spinal cord.

Examination of the spinal cord by magnetic resonance imaging is discussed with respect to modern techniques and equipment. Care must be taken in protocol design to maximize resolution and signal strength while providing diagnostic contrast. Artifacts, including truncation, magnetic susceptibility, and those due to motion, may be present and strategies for their mitigation are discussed in this review.

Technical issues for MRI examination of the posterior fossa.

Examination of the posterior fossa by magnetic resonance imaging is discussed with respect to modern techniques and equipment, and including recent results of non-conventional studies in multiple sclerosis. Optimal protocol design will maximize resolution and signal strength while providing diagnostic contrast. Motion artifact from the sigmoid and transverse sinuses may appear as ghosting and can be mitigated with proper imaging parameter choices.

Serial analysis of magnetization-transfer histograms and Expanded Disability Status Scale scores in patients with relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: Magnetization transfer ratio histogram peak height (MTR-HPH) has been shown to correlate with macroscopic and microscopic brain disease in patients with multiple sclerosis (MS). We studied the changes in MTR-HPH and in Kurtzke's Expanded Disability Status Scale (EDSS) scores over time in a group of patients with relapsing-remitting MS. METHODS: Twenty adult patients with relapsing-remitting MS (four men and 16 women) were followed up for a period of 334 to 1313 days. In all, 86 MR imaging studies of the brain were obtained, and MTR-HPH was calculated for each MR examination by using a semiautomated technique. Changes in MTR-HPH were compared between patients over the study's duration. A neurologist specialized in the care of MS patients assessed the EDSS score for each patient as a measure of clinical disability. RESULTS: Serial MR data showed a subtle but significant decline in MTR-HPH with time. No significant changes in EDSS scores were noted over the same period. CONCLUSION: Patients with relapsing-remitting MS have a significant progressive decline in normalized MTR-HPH, which is independent of EDSS score. MTR-HPH measurements can be used to monitor subclinical disease in patients with relapsing-remitting MS over a short time frame of 1 to 4 years. This parameter might be applied in future therapeutic trials to assess its usefulness.

MR imaging quantitation of gray matter involvement in multiple sclerosis and its correlation with disability measures and neurocognitive testing.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system and manifests both physical and neurocognitive disabilities. Although predominantly a disease of the white matter, MS is also characterized by lesions in the gray matter. Previous pathologic studies have found that cortical and deep gray matter lesions comprised 5% and 4%, respectively, of total lesions. Using software for lesion detection and quantitation, our study was designed to determine MS involvement in the cortical and deep gray matter and to correlate gray matter lesion load with neurocognitive function and the Kurtzke Expanded Disability Status Scale. METHODS: Using a semiautomated segmentation algorithm that detected and delineated all possible brain MS lesions on MR images, we investigated gray matter lesion volume in 18 patients with untreated relapsing-remitting MS. Cortical and deep gray matter lesions then were correlated with the neurocognitive and physical disability measurements. RESULTS: We found that cortical gray matter lesions comprised approximately 5.7% of the total lesion volume, whereas deep gray matter lesions comprised another 4.6% in this patient cohort. No strong correlations were found between gray matter lesions and disability status or neurocognitive function. CONCLUSION: These results are similar to those found in previous pathologic studies. The cortical lesion load in cases of relapsing-remitting MS, as measured by MR imaging, represents less than 6% of the total lesion volume and does not correlate with disability measures or neurocognitive tests.

The physical basis of magnetization transfer imaging.

Magnetization transfer imaging (MTI) refers to an application of magnetic resonance imaging (MRI) designed as a means of exploring characteristics of non-water components in tissue. Compared with conventional MR imaging, where differences in brightness on images reflect differences in observed relaxation times, MTI theory incorporates the influence of additional parameters, specifically those reflecting the exchange of protons between molecules of water and molecules of more-solid, structural components. Thus, MTI offers the potential of a window on tissue structure, and structural components that are normally not resolvable with MRI. The theory arises from the idea that the spin magnetization of macromolecular components of tissue can be indirectly observed via observation of the conventionally visible spins of tissue water. The extent of influence of the magnetization transfer process can be reflected in a normalized index derived from two magnetic resonance images, which is known as the magnetization transfer ratio. Exploitation of this effect is of current interest in multiple sclerosis because it offers the potential for gains in specificity as well as sensitivity of the magnetic resonance examination.

Magnetization transfer histogram methodology: its clinical and neuropsychological correlates.

OBJECTIVE: To review studies on the assessment of correlations between magnetization transfer ratio (MTR) histogram analysis and measures of clinical and neuropsychological function. BACKGROUND: Since its recent introduction, MTR histogram analysis has attracted attention in the field of multiple sclerosis (MS). METHODS: In this paper, studies are discussed that deal with MTR histogram analysis. The principles of MTR, application of MTR methodology as regional and volumetric MTR analysis, clinical and neuropsychological correlates, and potential use of MTR histogram analysis as an estimate of cerebral lesion load in MS are discussed respectively. RESULTS: In several preliminary studies, it has been shown that in MS patients, measures derived from MTR histograms correlate with measures of clinical and particularly neuropsychological function. CONCLUSION: MTR histogram analysis is a promising method to estimate cerebral lesion load in MS patients. Before it can be routinely used as an outcome measure in clinical trials, a number of questions about this technique have to be addressed.

Magnetization transfer contrast: its utility as a technique and its application to central nervous system pathology.

Magnetic resonance (MR) imaging is the pre-eminent modality for the detection and characterization of central nervous system pathology. However, in a variety of disease processes, histopathologic studies have often shown more extensive abnormalities in the brain and spinal cord than could be detected on conventional MR images. Magnetization transfer contrast (MTC) can be used qualitatively to augment differences between tissues and to accentuate gadolinium enhancement. Additionally, MTC may be used quantitatively to characterize tissues and potentially to detect otherwise microscopic disease.

Characterization of white matter lesions in multiple sclerosis and traumatic brain injury as revealed by magnetization transfer contour plots.

BACKGROUND AND PURPOSE: Magnetization transfer imaging provides information about the structural integrity of macromolecular substances, such as myelin. Our objective was to use this imaging technique and contour plotting to characterize and to define the extent of white matter lesions in multiple sclerosis and traumatic brain injury. METHODS: Magnetization transfer imaging was performed of 30 multiple sclerosis plaques and 10 traumatic white matter lesions. Magnetization transfer ratios (MTRs) were calculated for the lesions, for the normal- or abnormal-appearing surrounding white matter, and for remote normal-appearing white matter. MTR contour plots were constructed about these lesions. RESULTS: The contour plot appearance of MS plaques differed from that of traumatic white matter lesions. There was a gradual increase in MTR values at points at increasing distances from the center of the MS plaques; this was true for those lesions with and without surrounding T2 signal abnormality (halos). In contrast, there was an abrupt transition in MTR values between traumatic lesions and normal-appearing surrounding white matter. Additionally, the size of the MTR abnormality exceeded the size of the T2 signal abnormality for the MS plaques. CONCLUSION: MTR contour plots permit characterization and border definition of white matter lesions. Analysis of the contour plots suggests that MS is a centrifugal process with the lowest MTR within the center of the lesion. In contrast, traumatic white matter injuries are discrete lesions with abrupt transitions between the abnormal lesion and normal brain.

Diffuse axonal pathology detected with magnetization transfer imaging following brain injury in the pig.

This study was designed to evaluate with magnetization transfer imaging (MTI) and conventional magnetic resonance (MR) imaging the manifestation of diffuse axonal injury (DAI) in an animal model of injury via nonimpact coronal plane rotational acceleration. A second objective was to investigate the diagnostic use of quantitative MTR imaging based on statistical parameters in a single subject, as opposed to grouped analysis. Seven mini-swine were subjected to brain trauma known to produce isolated DAI and to MR imaging at two time points. Following sacrifice, the brains were harvested for histopathologic examination. Magnetization transfer ratio (MTR) maps were generated for double-blinded comparison of regions with abnormal MTR values and regions with documented DAI. Positive and negative predictive values for MTR detection of DAI were 67 and 56%, respectively, and in acute studies alone, 89 and 61%. Gains in sensitivity over conventional imaging for detection of DAI were demonstrated.