April 10, 2003
Current Neurology and Neuroscience Reports
Volume 3, Number 3: May 2003 • Demyelinating Disorders • pp. 238-245
by Francesca Bagnato, MD and Joseph A. Frank, MD
The use of nonconventional magnetic resonance imaging techniques (eg, magnetization transfer, magnetic resonance spectroscopy, and diffusion weighted imaging) allows for an accurate characterization of lesions as compared with conventional or standard approaches in demyelinating diseases. Magnetization transfer, magnetic resonance spectroscopy, and diffusion weighted imaging have revolutionized our understanding of demyelinating diseases because these techniques have been used to identify pathologic changes of normal-appearing brain tissue and characterize the differences in lesions. Metrics derived from these methods correlate with clinical disability and provide more accurate tools for monitoring disease activity and treatment effect over time. Quantitative T1 and T2 relaxation time maps provide additional information on demyelinating diseases, allowing for the evaluation of myelin water and distribution of water within tissues. Finally, the measurement of central nervous system atrophy has become a valuable element in determining the course of multiple sclerosis.
Demyelinating diseases (DDs) are characterized by the destruction of the myelin sheaths of the nerve fibers, the relative sparing of the other elements of the nervous tissue, the infiltration of inflammatory cells in a perivascular distribution, a particular distribution of lesions (often perivenous and primarily in white matter [WM], either in multiple small disseminated foci or in larger foci spreading from one or more center), and the relative lack of Wallerian or secondary degeneration of fiber tracts . The diseases fulfilling these criteria and with an unknown etiology are termed DDs (Table 1) [1, 2]. Multiple sclerosis (MS) is one of the most common DDs, affecting between 250,000 and 350,000 people in United States.
Magnetic resonance imaging (MRI) is the most sensitive tool for diagnosis and monitoring of DDs. A variety of MRI techniques are currently available, and advances in MRI measures can be used to elucidate the pathology of DDs. Contrast-enhancing lesions (CELs) on T1 weighted images (T1W) following intravenous injection of gadopentate dimeglumine (Gd-DTPA) are a hallmark of inflammatory activity and blood-brain barrier disruption [3**]; in addition, the use of the triple dose of Gd-DTPA or the single dose of Gd-DTPA in combination with magnetization transfer (MT) pulse increases the conspicuity and number of CELs . T1 hypointense lesions, so called black holes (BHs), represent a wide range of pathologies, from acute inflammation usually observed at the time of contrast enhancement to more chronic lesions associated with axonal loss with astrogliosis [3**, 4, 5]. Hyperintense lesions on conventional and fast spin echo proton density, T2W, and fluid-attenuated inversion recovery (FLAIR) are sensitive markers for the detection of the disease, but they lack pathologic specificity . Hyperintense T2 lesions can be observed during any stage of any type of DD, though the shape and the size can provide a distinctive marker of the extent of the disease [7*].
Nonconventional MRI techniques (Table 2) have been used to assess DDs
and have increased our knowledge of the pathology of such diseases because
they provide an increased level of specificity with regard to underlying
Table 1: Classification of the demyelinating diseases
|Magnetization transfer images
|MRI--magnetic resonance imaging.|
Table 2: Features of nonconventional MRI measures
Magnetization Transfer Imaging
Magnetization transfer imaging (MTI) measures the exchange of magnetization between bound (macromolecular) protons and free (mobile) protons in tissues. If an off-resonance radio frequency pulse is used to selectively saturate the bound proton fraction, the signal intensity of the images is reduced because of the transfer reaction between the two proton pools. The percent reduction in signal intensity on images obtained with the saturation pulse compared with images obtained without the pulse is expressed as the MT ratio (MTR). Lower MTRs indicate the reduced capacity of the macromolecule bound to water to exchange MT with the water-free molecules and may reflect several pathologic processes in the central nervous system (CNS). In addition to the MTR, the rate constant for protons between ratios can be determined [8*]. MTR in the normal-appearing white matter (NAWM) measured from brains of MS patients decreases 1 to 12 months prior to the detection of a CEL. Serial studies show that MTR decreases dramatically at the time of lesion enhancement, and following contrast enhancement there is a gradual increase or recovery of the MTR within the lesion, suggestive of recovery following the acute inflammatory process . MTRs were lower in active inflammatory lesions with ring enhancement, and when these findings were observed the MTR of these lesions did not recover back to MTR levels found for NAWM . The duration of contrast enhancement as well as the dose of contrast used (ie, triple vs single dose) was also related to the decrease in the MTR within lesions. CELs appearing only after the triple dose of contrast exhibit higher levels of MTRs compared with CELs following a single dose of contrast . These results suggest that MTR has the ability to depict CELs with various degrees of damage (ie, demyelination and axonal damage/loss). MS lesions on T2W scans have a wide range of MTR values, consistent with the known pathologic heterogeneity . Post-mortem studies on T1-BHs confirm a relationship between the MTR and the degree of damage associated with demyelination and axonal density (ie, loss) . Lesions with extensive tissue destruction (eg, T1-holes) have MTR values that are similar to cerebral spinal fluid (CSF) , whereas lesions with a 10% to 30% reduction in MTR probably represent various stages of demyelination or remyelination. Abnormal values of MTR compared with control subjects were also seen in the normal-appearing gray matter (NAGM) of MS patients. An inverse correlation between lesion MTR and clinical disability in cross-sectional studies has been demonstrated . An example of the relationship between MT histograms (ie, distribution of the number of pixels with similar MTR values derived from MTR map of whole brain) with clinical disability is presented in Figure 1. MTR analysis may be a useful method in monitoring disease progression of the spinal cord (SC) and the optic nerve (ON) .
Both interferon b (IFNb) and steroid therapies promote lesion recovery as measured by MTR [15*]. However, MTR of the NAWM over time does not seem to be affected by IFNb . Whole brain MT histograms obtained in other DDs demonstrate different patterns compared with MS patients. MTR values of NAWM and cervical SC of patients with acute disseminated encephalomyelitis (ADEM) or Devic's neuromyelitis optica (DNO) are similar to age-matched control subjects, suggesting a more focal pathologic process in these diseases compared with MS [17, 18].
Figure 1: Magnetization transfer (MT) ratio histograms of three multiple sclerosis (MS) patients with different Expanded Disability Status Score (EDSS) and normal control subjects. MT ratio histograms are shifted to the left (lower MT ratio values) and have been found to have lower peak heights in patients with increased disability. These results suggest that there is more microscopic damage and atrophy in this individual compared with the early relapsing remitting MS patient. (Courtesy of N. Richert.)
Magnetic Resonance Spectroscopy
In vivo proton magnetic resonance spectroscopy (1H-MRS) measures tissue metabolites and, therefore, biochemical changes in lesions, NAWM, and NAGM of MS patients. Brain metabolites measured by 1H-MRS are N-acetyl-aspartate (NAA), creatinine (Cr), choline (Cho), lactate (Lac), mobile lipids, myo-inositol (Ins), glutamate, and glutamine. MRS studies can be acquired from either specific regions of interest (ROI) (ie, single voxel) or from the entire brain (ie, slab volume to multisclice multivoxel spectroscopic imaging). Acute MS plaques may exhibit a range of MRS patterns depending upon lesion pathology. Decreases in NAA concentration may be detected and have been shown to parallel reduction of the axonal density on histopathology . Chronic MS plaques (ie, T1-BHs) have a lower NAA concentration correlating to the degree of the T1 hypointensity . The NAA levels from lesions of patients with benign MS were higher compared with lesions in relapsing remitting (RR) and secondary progressive (SP) MS patients, suggesting less damage, axonal loss, or axonal dysfunction . Finally, the whole brain NAA concentration is lower in MS patients than normal control subjects, although this technique is not widely available and has only been used to evaluate relatively few MS patients .
Absolute increases in the concentrations of both Cho and Ins can be observed in demyelinating lesions associated with gliosis. CELs associated with a large infiltration of mononuclear cells may show detectable levels of Lac. Lac has been associated with the lymphocyte and macrophage anaerobic glycolytic metabolism during inflammation, and elevated levels can be found up to 6 to 10 weeks following the appearance of CELs . Figure 2 contains examples of multislice, multivoxel proton spectroscopic imaging in a RRMS patient with a large, enhancing lesion separated by 3 months (Fig. 2B). The metabolic maps demonstrate changes in NAA, Cho, and Lac as the lesion resolves over time. Averaged spectra obtained from the lesion show a decrease in NAA and an increase in Cho signals and the presence of lactate/lipids in Figure 2A that resolves over 3 months. The heterogeneous patterns of active plaques on MRS are also detected in lesions of patients with Balo's concentric sclerosis. These tumorfactive lesions may exhibit a reduction in the NAA/Cr ratio, an increase in the Cho/Cr ratio, and lactate .
Clinical studies investigating the relationship between MRS metrics and disability have shown a decreased NAA/Cr ratio over time, correlating to an increase in T2 lesion load. Furthermore, small changes in NAA/Cr ratio have been correlated with clinical course as measured by the means of the Expanded Disability Status Score (EDSS) . IFNb-1b has been reported to increase the level of NAA/Cr compared with pretreatment values in RRMS patients. The increase in NAA/Cr from a section of white matter at the level of the corpus callosum was evident by the sixth month on therapy compared with baseline period .
Diffusion Weighted and Diffusion Tensor Images
Diffusion weighted imaging (DWI) utilizes the random (Brownian) movements of water molecules in tissues. The unrestricted diffusion observed in the CSF of the lateral ventricles has the highest diffusion coefficient, whereas the motion of water movements within axons between myelin has the lowest diffusion coefficient. DWI measures the diffusion and anisotropy of water within tissues.
Figure 2: Proton magnetic resonance spectroscopic imaging
(MRSI) in a relapsing remitting multiple sclerosis (RRMS) patient.
A, MRSI and spectra of a large enhancing lesion at the time of an acute exacerbation. Metabolic maps of N-acetyl-aspartate (NAA, 2.02 ppm), choline (Cho, 3.2 ppm), creatine (Cre, 3.0 ppm), and lactate/lipids (Lac, 1.3 ppm) are shown. There is a clear decrease in NAA and increase in Cho and the presence of Lac and lipids in area of lesion that is also seen in graph of spectrum. Spectrum is a graphic representation of concentration of metabolites, with a specific chemical shift expressed in parts per million.
B, MRSI and spectra approximately 3 months later after exacerbation resolves and RRMS patient returns to baseline. Recovery of NAA and a decrease in Cho is noted along with a disappearance of lactate lipid signal. (PPM--parts per million; ROI--region of interest.) (Courtesy of BK Lewis, J. Frank, B. Bielekova, R. Martin, H. McFarland.)
Diffusivity is influenced by the degree of anisotropy of the tissue, and the measurement of diffusivity is usually referred to as the apparent diffusion coefficient (ADC). Also, pathologic changes of tissue influence the motion behavior of the water, and the ADC has been found to be increased in lesions and NAWM of MS patients compared with healthy subjects . ADC is significantly higher in lesions from SPMS rather than in those from RRMS patients, and is correlated to the degree of hypointensity of BHs . However, because of limitations of diffusion imaging due to changes that occur in tissue as a result of fixation, ADC measurements have not been correlated to pathology.
In the CNS, water diffusion is higher along the axons rather than across them , thus water molecules experience differing rates of diffusion or movement following encounter axons along different directions. This phenomenon is called anisotropy, and the complexity of these movements is expressed by a mathematical measure, the diffusion tensor (DT). Anisotropy in the brain is highly influenced by the directions of the fiber tracts and pathologic changes (ie, demyelination, axonal loss and remyelination) in the CNS. The DT imaging provides a measure of the amount of the diffusion of water in tissue (ie, mean diffusivity [MD]) or its directional bias (ie, fractional anisotropy [FA]) . FA is lower in NAWM and higher in NAGM of patients with MS at any stage of the disease, and the high FA detected in the cortical NAGM has also been observed in the deep gray matter of basal ganglia . These observations are in accordance with the fact that in normal subjects the white matter is composed by aligned fibers, thus showing a high FA, whereas the gray matter is less structured, thus having a lower value for the FA. Pathologic processes such as demyelination and axonal loss that alter these structures result in a decrease in the FA in white matter. FA has been shown to be lower in the regions of the NAWM surrounding MS lesions as compared with values obtained from contralateral NAWM at the same level as the MS lesion . In MS lesions, the highest MD and the lowest FA were usually detected in CELs, followed (in descending order) by T1 hypointense BHs and T1 isointense lesions without enhancement. Nevertheless, the differences in MD and FA measured in hypointense and T1 isointense nonenhancing lesions were not considered to be significant . Finally, similar measures were determined from the MTR histograms. ADC histogram metrics of the NAWM of patients with ADEM are similar to age-matched normal subjects , thus strengthening the concept that ADEM is more of a focal disease compared with MS. ADC histogram measures have been shown to correlate with MRS NAA/Cr and brain volume in MS. There have been reports demonstrating strong correlations between diffusion metrics and either clinical or demographic findings in MS patients. ADC and/or FA correlate with disease duration  and EDSS score . Further studies are required to provide a clearer understanding of the relationship between the findings on diffusion imaging and the pathologic processes associated with DD.
Functional Magnetic Resonance Imaging
In response to a given task, brain electrical activity increases and is accompanied by an increase in blood flow and relative oxygen consumption. Because the rise of blood flow is greater than the oxygen consumption, an increase in the ratio of oxyemoglobin to deoxyhemoglobin is generated. The increase in this ratio results in an increase in signal intensity on T2* weighted images. Functional MRI (fMRI) is dependent on the difference in regional percent change in signal intensities on T2* weighted images observed when comparing an activation task to resting states.
Clinical studies using fMRI have recently been performed in patients with MS. These fMRI studies have focused evaluating potential differences in the way the MS patients' brains respond to activation paradigms compared with healthy subjects. Results from various studies indicate that MS patients will tend to recruit additional areas of ipsilateral and contralateral cortex in response to simple and complex activation tasks, which may allow for investigation into the brain's ability to reorganize following focal lesions and provide a basis for developing theories about the plasticity and recovery after an exacerbation in MS patients. MS patients tend to demonstrate a larger area of activation associated with an increase in clinical disability that tends to decrease with recovery of neurologic function . Although fMRI studies can provide potentially important insights into the ability of the MS patients to compensate for neurologic disabilities, there are several technical limitations that should be considered when applying this technique. Due to the heterogeneity of MS lesion in space, fMRI studies have tended to be performed in more homogeneous populations of clinically isolated syndrome or primary progressive MS patients [32, 33]. However, the correlations between the activation patterns and the localization of the T2 abnormalities in MS patients have been relatively weak. Future studies will require more sophisticated approaches in analyzing fMRI results and correlating these findings with other imaging measures of microscopic and macroscopic disease activity in order to understand the role that brain plasticity plays in function recovery in DDs.
Figure 3: Registered T1 weighted images from a relapsing remitting multiple sclerosis patient demonstrating the progression of cerebral atrophy over 7 years.
Central Nervous System Atrophy Measurement
Atrophy is the loss of mass per unit of volume. Progression of cerebral atrophy (CA) over time is a physiologic phenomenon of aging, alcohol consumption, and steroid use [34**]. Atrophy occurs more rapidly in DDs as a result of an irreversible damage of the brain or the SC (Fig. 3). The pathologic substrates that contribute to atrophy in DDs are not well documented, and studies evaluating the progression in CA are being performed in MS patients. Inflammation, demyelination, axonal and neuronal loss, and glyosis are common pathologic features of MS lesions, and the progression of CA occurs when repair mechanisms fail to occur. Wallerian degeneration also contributes to atrophy in the CNS, with smaller axons being more susceptible to inflammatory damage. Identification of GM lesions in MS has been difficult. However, GM lesions and neuronal loss contribute to the progression of atrophy observed in MS patients. An increase in the water content as a result of inflammation or edema can result in an overestimation of the brain volume. Pseudo-increases in brain volume can be observed with inflammatory disease activity in RRMS patients compared with patients with SPMS . CA represents both microscopic and macroscopic disease process, and it has been correlated to the NAA/Cr ratio, the MT histogram, and the T1 hypointense lesion volume.
Several image analysis techniques are currently being used to measure CA, spinal cord atrophy (SCA), and optic nerve atrophy (ONA) [36, 37], including linear and regional measures, whole brain segmentation approaches, and brain registration-based methods. Miller et al. [34**] have recently reviewed the varied approaches for semiautomatic to automatic segmentation of the brain and determining CA. Recommendations for determining CA in MS patients included the use of pulse sequences with high GM, WM ,and CSF contrast, preferably with T1W and three-dimensional (3D) techniques. For evaluating SCA, pulse sequences with high contrast between SC and CSF are required. In addition, the positioning of the patient and of the ROI has to be reproducible for serial longitudinal studies. The measurement of ONA is difficult because of the size of the optic nerve. Methods based on manual outlining, on semi-automated outline of 3D images, or on automated whole nerve volume measurements require complex analysis and, therefore, limit their validity in clinical studies .
Magnetic resonance imaging studies have demonstrated that CA occurs in all subtypes of MS. In addition, changes of regional CA may also correlate with disability at varying levels. Drugs may alter the progression of CA in MS patients. Steroids slow the progression of CA over time in MS patients ; however, the effect of short-term steroids for exacerbation is unclear . Also IFNb appears to slow progression of CA over time by decreasing the amount of the inflammatory activity . Overall, however, most clinical trials in MS have not demonstrated a clear impact of the progression of CA over the entire length of time of the study [40, 41].
T1 and T2 Relaxation Time Maps
The measurement of the T1 and T2 relaxation times (RT) of the brain allows an assessment of either the nonvisible pathology or the severity of pathologic changes in a given MS lesion. T1 and T2 RT have been calculated within each voxel from T1 and T2, and maps can be generated using multislice techniques. Results obtained so far have demonstrated a prolonged T1/T2 RT in the NAWM and NAGM of either RRMS or SPMS patients [42, 43, 44], with T1 RT maps more sensitive than MTR in detecting pathologic changes in both NAWM and NAGM . The age and the activity of a lesion, as well as its location, influence the RT of the lesion . In particular, a shorter T1 and T2 RT component may overlap with T1 and T2 RT of the NAWM and are characteristic of lesions found in the posterior fossa. Acute MS plaques exhibit abnormally high T1 and T2 RT profiles, and these profiles usually change during the evolution of the lesion . In addition, T1RT of T1 BHs has been shown to correlate with NAA and Ins, thus reflecting the severity of axonal damage , but this correlation is no longer evident with the CA . Overall, the relationship between WM T1 maps and clinical disability assessed by the EDSS score  has been demonstrated. It has been suggested that short components on T2 maps reflect water associated with myelin and, therefore, this technique provides information into the demyelination process in MS patients . In vivo myelin measurement has important applications in the clinical management of MS and other WM diseases. Unfortunately, relatively few sites are able to perform this technique of obtaining T2RT maps.
Magnetic Resonance Imaging at High Magnetic Fields
The majority of clinical and research studies performed in MS patients use clinical 1.5-Tesla MR units; however, with the increasing number of 3 Tesla and above scanners being purchased for fMRI and proton MRS, an increasing number of studies will be performed at these field strengths. To date, there have been relatively few studies performed at high magnetic fields. Keiper et al.  compared conventional fast spin echo imaging in MS patients at 1.5 versus 4.0 Tesla and were able to identify more T2 hyperintensities that were smaller in size and located in perivascular spaces at the higher field strength. The authors concluded that MRI at 4 Tesla depicts WM abnormalities in MS patients not detectable at 1.5 Tesla through higher resolution with comparable signal to noise ratio and imaging times .
Magnetic resonance spectroscopy performed at 4.1 Tesla demonstrated similar results in changes of NAA/Cr and NAA/Cho in MS lesions and NAWM in MS patients compared with healthy subjects . The potential benefit of high-strength MRS is that the voxel sizes can potentially be decreased and, therefore, the spectral intensities obtained have less contamination due to partial volume effects from adjacent tissues. In addition, because of the possible increase in signal to noise ratio, it is possible that DTI and the quantitative measures of diffusivity and FA will become more reliable, especially as voxel sizes decrease.
It is important to note that there are several limitations to high-strength MR studies. Imaging at the base of the brain may be difficult due to susceptibility artifacts, especially when using gradient echo pulse sequences. The ability to perform MTI and FLAIR pulse sequences may be limited because of radio frequency power deposition. Despite these limitations, high-field neuroimaging is becoming more common and, therefore, future research studies and clinical trials may soon be performed at 3 Tesla or above.
Magnetic resonance imaging has been used as an outcome measure in clinical trials for monitoring the effects of new therapies. It also has a key role in defining the diagnosis of all the DDs. Nonconventional MRI techniques have provided information about the various pathologies of DDs. Atrophy measure, MTR, MRS, and DWI are in vivo noninvasive methods that provide useful information. Outcome measures derived from these nonconventional imaging techniques have been shown to strongly correlate with clinical disability, and these correlations tend to be more robust as compared with conventional MRI measures. However, some of these MRI techniques, although widely available, may be more difficult to implement in clinical practice or in clinical trials because of differences in MRI scans and pulse sequences used to obtain the images. Further studies may utilize these nonconventional techniques and be able to incorporate their measures and compare these MRI scores for the understanding of the diseases. Multiparametric models may provide more detailed information about the different pathologic processes in MS.
References and Recommended Reading
Recently published papers of particular interest have been highlighted as:
* Of importance
** Of major importance
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