MR imaging methods unite to monitor MS progress

Multiple sclerosis is an inflammatory autoimmune disease of the central nervous system. It is characterized by pathological changes that include inflammation, demyelination, and axonal injury.

MRI has become integral to the clinical management of MS over the past 20 years. Conventional MRI of the brain and spinal cord has proved to be the most important tool for the diagnosis of MS and observation of the disease's progress. Conventional MRI techniques have also been used to probe the efficacy of disease-modifying treatments in therapeutic trials. This is due mainly to the sensitivity and reproducibility of conventional MRI in the detection of MS-related damage.

The correlation between conventional MRI data and clinical findings remains weak, however. This paradox could be due, in part, to the poor specificity of MRI in relation to the heterogeneous pathological substrates of MS. Conventional MRI is also unable to quantify the extent of damage in normal-appearing tissue outside macroscopic lesions.

Emerging techniques, including magnetization transfer MRI, diffusion tensor MRI, and proton MR spectroscopy (MRS), are now aiding our understanding of the pathophysiology of MS. These techniques may yield information about structural and biochemical changes occurring within and outside macroscopic MS lesions, particularly in the normal-appearing white and gray matter. They could also significantly improve our ability to monitor inflammatory demyelination and axonal injury. The use of functional MRI offers the possibility to assess the mechanisms of adaptive cortical reorganization, which may limit the irreversible consequences of MS tissue injury.

Conventional MRI plays a dominant role in the diagnosis of MS. This is perhaps not surprising, given that it is the most sensitive way to detect macroscopic MS lesions and their changes. T2-weighted, T1-weighted, and gadolinium-enhanced imaging are all used to identify MS lesions and quantify tissue atrophy.

MS plaques can be found throughout the brain. They have a predilection for the periventricular region, corpus callosum, brain stem, U-fibers, optic nerves, and cervical spinal cord. The abnormalities of the corpus callosum, U-fibers, and optic nerves allow MS to be differentiated from other neurological diseases such as cerebrovascular disease. Although MS predominantly affects white matter, lesions can also be detected in gray matter and the corticosubcortical area, but with less sensitivity. Only 10% to 30% of cortical lesions can be detected by MRI.¹

MS lesions often appear as isointense to normal white matter on T1-weighted images. They can be hypointense if chronic tissue injury has occurred. An accumulation of hypointense lesions (black holes) correlates with disease progression and disability. In the acute inflammatory phase, enhancing lesions are often detected following administration of gadolinium. This reflects the disruption of the blood-brain barrier.

Contrast-enhanced T1-weighted MRI provides an in vivo marker of inflammatory activity. This method detects disease activity five to 10 times more often than does the clinical evaluation of relapsed patients. This suggests that most enhancing lesions are clinically silent. If an enhancing lesion is observed on T1-weighted MRI, a hyperintense lesion will be seen in the same location on T2-weighted MRI. The gadolinium enhancement will disappear over a four to six-week period. The extent of the new hyperintense lesion usually decreases and reduces in intensity as edema resolves and some tissue repair occurs.

Supratentorial, subcortical, and cortical lesions are better detected by fast fluid-attenuated inversion recovery (FLAIR) imaging than T2-weighted MRI. Volumetric MRI provides objective information on brain atrophy. This is regarded as the ultimate consequence of all brain pathological processes found in MS.

The spinal cord is frequently involved in MS, especially at the cervical level. Lesions from the spinal cord tend to be multifocal on T2-weighted MRI. Most plaques are located in the dorsolateral area and span fewer than two vertebral body segments. Spinal cord lesions that enhance with gadolinium occur frequently during the acute phase of the disease. Spinal cord atrophy, which mostly reflects axonal loss, is also observed too.

Optic neuritis often appears as the first clinical sign of MS. This can be related to lesions on the optic nerve.

Detection is possible with a fat-suppression technique combined with contrast-enhanced MRI, or the use of short-tau inversion recovery (STIR) imaging.

A diagnosis of MS is based on demonstrable clinical findings in defined anatomical locations and over a certain time period. The international scientific community has now established MRI criteria that correlate to dissemination in space and in time. The criteria complement clinical observations in patients with suspected MS and other laboratory data. They have been shown to have a high sensitivity and specificity for the subsequent development of clinically defined MS in patients who present with an initial clinical episode suggestive of the disease.^2-5

As well as its crucial role in diagnosing MS, MRI is often used to assess the disease burden. This quantitative evaluation is based on lesion loads seen on T1- and T2-weighted MRI and any newly active gadolinium-enhancing lesions. Such observations may eventually be performed automatically. Computer-assisted evaluation would provide a fast, objective, and precise way of monitoring the natural history of the disease. These surrogate markers are used extensively in clinical trials to assess the value of disease-modifying drugs. They could also be used to guide therapeutic decisions in individual patients.

Despite the fundamental role of conventional MRI in the diagnosis and management of MS, several issues are worth remembering:

• The ability to detect lesions on MRI depends on the scanner's field strength.
• The number of enhancing lesions can be influenced by the contrast dose.
• Cortical lesions are not commonly seen on conventional MRI.

ALTERNATIVE TECHNIQUES

The relationship between conventional MR-based measures of disease activity and clinical manifestations remains weak.

A number of alternative MRI techniques have consequently been investigated that could improve our understanding of the evolution and pathophysiology of MS. These techniques are providing new quantitative information on processes such as inflammation, demyelination, and axonal loss. In the near future, they will also be used in longitudinal studies to monitor the effects of new MS drugs.

• Proton MRS (1H-MRS). This technique offers a way to study in vivo brain metabolites. Quantitative analysis of metabolites such as choline (Cho), creatine, lactate, lipids, myo-inositol, and N-acetylaspartate (NAA) makes it possible to monitor the progressive and relative contributions of inflammation, myelin damage and repair, and axonal injury in the different subtypes and stages of MS.

Proton MRS can complement conventional MRI studies by correlating the pathological changes occurring within and outside lesions visible on T2-weighted images with chemical markers. For example, a decrease in concentration of the metabolite NAA is regarded as secondary to axonal dysfunction or loss. An increase in choline and lactate reflects acute inflammatory and demyelinating changes (Figure 1). The presence or increase of additional metabolites, such as lipids and myo-inositol, indicates ongoing myelin damage and glial activation, respectively.

Localized and whole-brain 1H-MRS studies have revealed metabolic abnormalities inside apparently normal white and gray matter that is adjacent to-or distant from-MS lesions.⁶ These diffuse changes are present at early stages of disease. The extent to which NAA decreases and choline increases in these areas of gray and white matter progresses over time. This suggests that the chemical markers could be sufficiently sensitive to detect diffuse demyelination and axonal dysfunction in normal-appearing tissue and could monitor the potential therapeutic effects of MS drugs in clinical trials.⁷ Proton MRS has also been used to detect axonal damage in the spinal cords of MS patients.⁸

Despite the high specificity of 1H-MRS compared with MRI, and the relatively large number of clinical 1H-MRS studies on MS patients, MRS is not used for the routine monitoring of such patients. Vendors are now marketing MR scanners, however, that have integrated, user-friendly spectroscopy packages. This will help MRS to become a more common modality in clinical practice.

• Diffusion tensor imaging (DTI). Diffusion tensor MRI exploits the molecular diffusion of water within biological tissues. Pathological processes associated with MS alter tissue integrity. The resulting increase in the random molecular motion of water within tissue is reflected by an increase in the apparent diffusion coefficient. It is also possible to derive the mean diffusivity, which represents the ADC independent from the orientation of tissue, and the fractional anisotropy, which indicates the degree of anisotropy of water diffusion inside tissue. FA is also an indirect indication of the organization of the tissue matrix (especially oriented within large white-matter bundles).

DTI abnormalities (reduced FA and increased mean diffusivity) have shown that damage to the brain and spinal cord in MS is not limited to focal and macroscopic lesions. This damage is also present in the normal-appearing white and gray matter, even at early stages of disease. DTI abnormalities progress over time in relation to the clinical evolution of the disease.⁹ Diffusion tensor MRI has also revealed abnormalities in the spinal cords of MS patients, reflecting diffuse injury to normal-appearing white and gray matter.¹⁰

The structural integrity of white-matter bundles belonging to a specific network can be assessed using DTI tractography. This makes it possible to track white-matter bundles that connect distant cortical areas (Figure 2). In MS patients, this technique can be used to determine the extent of damage affecting white-matter bundles involved in specific systems, such as the motor or cognitive networks. It has also been demonstrated that diffuse structural damage mechanisms of adaptive structural white matter are present at the very early stages of MS, confirming that compensatory functional processes can be supported by structural substrates.¹¹

DTI could become a powerful surrogate predictor of long-term disease progression in terms of disability. It could also be used to monitor the evolution of MS in clinical trials and, possibly, in individual patients.

• Magnetization transfer. Magnetization transfer imaging is a quantitative technique. It draws on the exchange between the bounded pool of protons (macromolecules) and the free pool of protons (MRI visible) to provide crucial information on the extent of tissue damage associated with MS. The magnetization transfer ratio (MTR) is a unique marker of tissue matrix disorder occurring within and outside MRI-visible MS lesions. The technique has dramatically changed our understanding of MS disease mechanisms, in particular the pathophysiological processes related to inflammation and demyelination.

Reduced MTR values have been reported in the normal-appearing white and gray matter of MS patients. The severity of this damage has been shown to be associated with disability.¹² MTR abnormalities within normal-appearing white and gray matter at the early stages of disease are predictive of clinical disability (physical and cognitive impairment) over time.¹³ A transient MTR increase, however, has been linked to the renormalization of acute inflammatory episodes or remyelination.¹⁴

Reliable MTR measurements can also be obtained from the cervical cord and the optic nerve. MTR of the cervical cord is significantly lower in MS patients than in control subjects. The lower the MTR, the greater a patient's disability.¹⁵ Decreases to MTR in the optic nerve have similarly been correlated with the degree of visual dysfunction and with electrophysiological parameters. MTR is more specific and more sensitive than conventional MRI for the characterization of myelin disorder, remyelination processes, and occult pathology in MS.

• Functional MRI. Some MS patients with numerous CNS lesions have normal motor and/or cognitive functionality. This suggests that the severity of clinical symptoms is not solely dependent on the lesion load visible on T2-weighted imaging. A complex balance of tissue damage, tissue repair, and cortical reorganization could instead limit the clinical consequences of MS.

Functional MRI can provide crucial information about the extent and nature of brain plasticity (Figure 3). Adaptive cerebral plasticity of the cortical motor system has been documented extensively.¹⁶ This cortical motor reorganization is present at the earliest stages of MS and may help maintain normal motor performance despite tissue damage.

Functional MRI can also show how compensatory cortical activation increases according to the extent of diffuse white-matter damage. This, then, helps mask the clinical expression (cognitive/suppressed) of brain pathology at the earliest stages of disease.¹⁷ Some fMRI studies of brain connectivity (functional and effective connectivity) have demonstrated changes in brain network organization secondary to diffuse white-matter damage.^18,19

Any future use of fMRI to study the mechanisms of brain adaptation will increase our understanding of the functional significance of pathological changes observed in MS.

• High-field MRI. MRI systems operating at 3T, 4.7T, and even 7T have been installed at sites worldwide. This technology may be relevant to routine MS diagnosis and disease monitoring, and also to basic scientific research. One of the most obvious advantages of high-field MRI is the high signal-to-noise ratio, which makes it easier to detect lesions. It also has the potential to detect cortical lesions, which are often obscure at conventional field strengths.²⁰ These improvements may allow MS to be diagnosed earlier. They may also improve our understanding of disease pathophysiology related to MRS, DTI, and fMRI.²¹

Conventional MRI has had a dramatic impact on the diagnosis of MS, therapeutic monitoring of the disease, and our understanding of its natural history. Nonstandard MRI techniques are also helping to build a more complete picture of the pathological mechanisms of MS. None of the available MRI techniques can describe the complexity of MS and its evolution in isolation. Our ability to monitor this disease depends on the development and validation of multiparametric approaches. This is particularly true if MRI is to be used in clinical trials.

PROF. PELLETIER and PROF. AUDOIN are neurologists specializing in MS who are based at Timone Hospital in Marseille. They conduct research into MS at the Center for Magnetic Resonance in Biology and Medicine (CRMBM), Université de la Méditerranée, Marseille. PROF. RANJEVA is a neuroscientist at the CRMBM. PROF. COZZONE is a biophysicist and director of the CRMBM.

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