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.

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.

Magnetization transfer imaging in progressive multifocal leukoencephalopathy.

We report a patient with biopsy-proven progressive multifocal leukoencephalopathy (PML) who was serially imaged with MRI and magnetization transfer imaging. The magnetization transfer ratio (MTR) was profoundly and significantly diminished when compared with normal control subjects. The pattern of MTR was distinct from that of MS and periventricular ischemic white matter disease. Magnetization transfer imaging techniques may aid in the differential diagnosis of PML.

Correlation of volumetric magnetization transfer imaging with clinical data in MS.

We examined the relations between quantitative volumetric estimates of cerebral lesion load based on magnetization transfer imaging (MTI), clinical data, and measures of neuropsychological function in 44 patients with clinically diagnosed MS. In this population we assessed the correlation between several volumetric MTI measures, measures of neurologic function (Kurtzke Expanded Disability Status Scale and Ambulation Index), and disease duration using Spearman's correlation coefficient. Patients were classified on the basis of neuropsychological test performance as severely impaired, moderately impaired, and normal. We assessed differences between these groups with respect to MTI results using the Kruskal-Wallis test. MTI measures corrected for brain volume were found to correlate with disease duration (p < 0.01) and showed suggestive correlations with measures of neurologic impairment (p < 0.05). Individual neuropsychological tests correlated with MTI measures corrected and not corrected for brain volume (p < 0.001). An MTI measure not corrected for brain volume differed (p < 0.05) between severely impaired, moderately impaired, and normal patients. These preliminary results suggest that volumetric MTI analysis provides new measures that reflect more accurately the global lesion load in the brain of MS patients, and they may serve as a method to study the natural course of the disease and as an outcome measure to evaluate the effect of drugs.

Molar volume relationships and the specific inhibition of a synaptosomal enzyme by psychoactive cannabinoids.

The ability of a number of lipophilic compounds to inhibit the mouse-brain synaptosomal enzyme acyl coenzyme A:lysophosphatidylcholine acyltransferase has been measured in vitro. Psychoactive cannabinoids inhibit the enzyme at concentrations much lower than is predicted from their capacity to act as lipid-soluble anesthetics. Nonpsychoactive cannabinoids do not show specific inhibition. Molar volume relationships are used to show that, while all lipid-soluble molecules exert some inhibitory effect in proportion to their ability to dissolve in biological membranes, psychoactive cannabinoids have an inhibitory effect greatly in excess of their anesthetic potency. The isoprenoid convulsant thujone has been suggested to have psychoactivity similar to cannabinoids but does not mimic the cannabinoids in inhibiting the synaptosomal enzyme. Molar volumes and specific interactions are used in structure-activity correlations which yield information on the relative concentrations of biophase in drug-responsive systems and the specificity of membrane-active drugs.

Magnetization transfer imaging of periventricular hyperintense white matter in the elderly.

PURPOSE: To characterize with magnetization transfer imaging the pathologic substrate of the nonspecific periventricular hyperintense white matter changes seen on T2-weighted images of elderly patients. METHODS: Twenty-one elderly patients with periventricular hyperintense white matter on T2-weighted MR images and eleven control subjects were studied using MT technique. Magnetization transfer ratios (MTRs) were calculated for the periventricular hyperintense white matter and normal-appearing white matter. These MTRs were correlated with histopathologic changes that have previously been reported as well as with established MTRs for other lesions. RESULTS: The MTRs (mean, 35.2; SD, 1.2) in the periventricular hyperintense white matter are lower than those in the normal white matter of the patient (mean, 40.8; SD, 1.4) and control (mean, 41.3; SD, 1.8) groups. These MTRs are much higher than those of demyelinating lesions but are similar to those of experimental lesions with just edema. CONCLUSION: Because MTR may reflect to some extent histopathologic changes and thus provide more specificity than conventional pulse sequences, the main pathologic substrate accounting for the lower MTR in periventricular hyperintense white matter is probably the increased water content in reactive astrocytes.

Multiple sclerosis lesions: relationship between MR enhancement pattern and magnetization transfer effect.

PURPOSE: To investigate the relationship between the enhancement pattern of a multiple sclerosis lesion and its magnetization transfer effect. METHODS: Fifty-four lesions were chosen from 29 patients with multiple sclerosis on the basis of enhancement pattern on contrast-enhanced T1-weighted MR images. They included 14 homogeneously enhancing lesions, 26 nonenhancing lesions, and 14 ring-enhancing lesions. Magnetization transfer ratios of the homogeneously enhancing lesions, nonenhancing lesions, and central portion of the ring-enhancing lesions were measured. Means were calculated and compared. RESULTS: The magnetization transfer ratios for homogeneously enhancing lesions were higher (mean, 32.2%; SD, 3.4%) than those for nonenhancing lesions (mean 29.4%; SD, 4.3%) and for the central portion of ring-enhancing lesions (mean, 24.5%; SD, 4.0%). Significant differences were found between the ring-enhancing lesions and the homogeneously enhancing lesions and between the ring-enhancing lesions and the nonenhancing lesions. CONCLUSION: We found a relationship between decreased magnetization transfer ratios and those enhancement patterns in which myelin is known to be decreased histopathologically. Thus, use of the magnetization transfer technique may increase the specificity of MR imaging in assessing the extent of residual myelination in multiple sclerosis lesions.

Characterization of multiple sclerosis plaques with T1-weighted MR and quantitative magnetization transfer.

PURPOSE: To investigate the relationship between the appearance of multiple sclerosis lesions identified on unenhanced T1-weighted images and their corresponding magnetization transfer ratios. METHODS: A total of 119 white matter lesions seen on T2-weighted images in 17 patients with multiple sclerosis were evaluated. Axial T1-weighted images were used to classify the lesions as isointense to white matter (10 lesions), hypointense to white matter but hyperintense to gray matter (44 lesions), hypointense to gray matter (59 lesions), and relatively isointense to cerebrospinal fluid (6 lesions). The magnetization transfer ratio of each lesion was calculated, and an average magnetization transfer ratio for each subcategory was determined. RESULTS: The magnetization transfer ratio values became progressively lower with increasing hypointensity of lesions on T1-weighted images. The average magnetization transfer ratio for lesions isointense to white matter, hypointense to white matter but hyperintense to gray matter, hypointense to gray matter, and relatively isointense to cerebrospinal fluid was 34.90 +/- 2.67 mean +/- SD), 30.93 +/- 3.57, 27.27 +/- 3.56, and 23.62 +/- 2.83, respectively. All groups were significantly different from each other. CONCLUSION: Lesions isointense to white matter exhibited higher magnetization transfer ratio values than lesions that were hypointense. These findings are consistent with relative preservation of the myelin structure in the former, perhaps indicating that these lesions are predominantly inflammatory (edematous) in nature. The proportionately lower magnetization transfer ratio values of lesions that appear progressively more hypointense on T1-weighted images may reflect varying degrees of demyelination, with increasing lesion hypointensity corresponding to more breakdown in the macromolecular structure. These results suggest that T1-weighted images may be useful in characterizing the underlying pathologic substrate in multiple sclerosis plaques.

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.

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.

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.

Comparison of T2 lesion volume and magnetization transfer ratio histogram analysis and of atrophy and measures of lesion burden in patients with multiple sclerosis.

PURPOSE: The purpose of this study was twofold: first, to compare two different measures of lesion burden in patients with multiple sclerosis (MS), the magnetization transfer ratio (MTR) histogram and T2 lesion volume; and, second, to investigate the relationship between lesion burden and atrophy in patients with MS. METHODS: Thirty patients with MS were examined with MR imaging, including fast spin-echo T2- and proton density-weighted sequences as well as magnetization transfer sequences. The lesion burden in each subject was quantitated by MTR histographic analysis and by a computer-based method for calculating the total volume of lesions on T2-weighted images. Additionally, the CSF volume, the brain parenchymal volume, and the percentage of brain parenchymal volume were determined in all patients by using this method and were compared with measurements in eight control subjects. RESULTS: Significant loss of parenchymal volume was seen in patients with MS as determined by increased CSF volume and decreased percentage of brain parenchymal volume relative to that in age-matched control subjects. An inverse correlation was observed between the peak height of the MTR histogram and T2 lesion volume. T2 lesion volume corresponded positively with CSF volume and inversely with percentage of brain parenchymal volume. The peak height of the MTR histogram corresponded positively with percentage of brain parenchymal volume and inversely with CSF volume. CONCLUSION: MS patients sustain a significant loss of parenchymal volume (atrophy), which corresponds strongly with increasing lesion burden. T2 lesion volume and peak height of the MTR histogram show good correlation, and the peak height of the MTR histogram shows a superior correlation with measures of brain atrophy as compared with measurements of T2 lesion volume, suggesting that the MTR histogram may be a better indicator of global disease burden than is T2 lesion volume.

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.

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 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.

Global volumetric estimation of disease burden in multiple sclerosis based on magnetization transfer imaging.

We report a semiautomated postprocessing method based on magnetization transfer MR imaging that can quantify the extent of global disease in patients with multiple sclerosis. The technique combines segmentation and quantitative analysis of imaging data reflecting the structural integrity of white matter. Applications of this technique may include assessment of disease progress and of the efficacy of experimental therapeutic intervention. The height of the histogram peak corresponding to white matter was found to be lowered in patients with multiple sclerosis and the overall distribution of magnetization transfer ratios was shifted to lower values.

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.

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.