Книги по МРТ КТ на английском языке / MR Imaging in White Matter Diseases of the Brain and Spinal Cord - K Sartor Massimo Filippi Nicola De Stefano Vincent Dou

Conventional MRI Techniques in Multiple Sclerosis

and the accumulation of T2 burden, chronic black holes, and progressive brain and spinal cord atrophy likely reflect worsening disease irrespective of the clinical status. What is required before they can be used and applied in the management of the individual is the validation of what these changes mean for the long-term outcome of the individual patient and how they are modified and affected by treatment.

14.7 Summary

Conventional MRI techniques include measures of new inflammation (new and enlarging T2W lesions, gadolinium-enhancing T1W lesions), measures of acute and chronic disease (total T2 volume or BOD), and measures of degeneration (global brain and spinal cord atrophy, and chronic black holes on T1W images). Combined, they provide a unique insight into the dynamics of MS lesion development and the long-term pathological consequences on CNS tissues. The limited clinical correlation reflects, in part, the unique sensitivity of MRI to detect clinically silent disease. Although not required for the clinical diagnosis of MS, conventional MRI methods can be invaluable in establishing an earlier diagnosis. These techniques can also be standardized on routine clinical MRI scanners and used in multicenter therapeutic trials. Conventional MRI measures have become important outcome measures in clinical trials of new therapies for MS. It is likely that conventional MRI measures will be augmented, rather than replaced, by newer methods as the conventional methods reflect the basic pathological processes of MS. However, additional validation will be needed before they can be used to effectively monitor treatment response in the individual patient.

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CONTENTS

15.1Introduction 225

15.2MT MRI 226

15.2.3Correlations with Clinical Manifestations and Disability 228

15.2.4 MT MRI to Monitor Treatment Efficacy 228

15.3DW MRI 229

15.3.3 Correlations with Clinical Manifestations and Disability 231

15.41H-MRS 231

15.5Functional MRI 234

15.5.1 Correlations with Structural Tissue Damage 235

15.5.2Correlations with Clinical Manifestations and Disability 235

15.6Conclusions 236 References 236

15.1 Introduction

Multiple sclerosis (MS) is the commonest chronic inflammatory demyelinating disease affecting the central nervous system (CNS) of young adults in western countries, leading, in the majority of cases, to severe and irreversible clinical disability. Pathologically, the essential brain lesion in MS has always been considered the demyelinated plaques, which are widely distributed throughout the brain and spinal cord.The evolution of these lesions may be extremely variable in a given patient and between different patients.

M. Filippi, MD; M.A. Rocca, MD

Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy.

The application of conventional magnetic resonance imaging (cMRI) to the study of MS has greatly improved our ability to diagnose MS and to monitor its evolution. The sensitivity of T2-weighted MRI in the detection of MS lesions and that of post-contrast T1-weighted images to detect lesions with an increased blood–brain barrier permeability associated with inflammatory activity make it possible to demonstrate the dissemination of MS lesions in space and time earlier than with clinical assessment and to detect disease activity with an increased sensitivity with respect to clinical evaluation of relapses (McDonald et al. 2001). However, the magnitude of the relationship between cMRI measures of disease activity or burden and the clinical manifestations of the disease is weak (Rovaris and Filippi 1999; Molyneux et al. 2001). This clinical/MRI discrepancy is likely to be the result, at least partially, of the inability of cMRI to quantify the extent and to define the nature of MSrelated tissue damage.

Pathological studies (Lumsden 1970; Kidd et al. 1999; Peterson et al. 2001) have shown that MS is not exclusively a demyelinating disease and that demyelination alone is not sufficient to explain the neurological deficits of the disease. There are compelling pieces of evidence that axonal damage is one of the main contributors to the clinical manifestations of the disease and to its clinical worsening over time. Pathologically, marked axonal transection in inflamed MS lesions has been demonstrated by several authors (Ferguson et al.1997; Trapp et al.1998).The pathological heterogeneity of MS lesions, which can range from lesions which undergo a significant remyelination after their acute formation to lesions with permanent axonal loss, has to be considered among the factors responsible for the limited ability of cMRI to provide an accurate picture of MS-related tissue damage. In addition, lesions located in the gray matter (GM) have also been described in MS (Lumsden 1970; Kidd et al.1999; Peterson et al.2001).Although MS cortical lesions are characterized by the paucity of inflammatory changes, they are associated with neuronal injury, including neuritic swelling, and den-

dritic and axonal transections (Peterson et al. 2001). These lesions are usually missed on conventional T2weighted images because of their small size, their relaxation characteristics which result in poor contrast between them and the surrounding normal GM and because of partial volume effects with cerebrospinal fluid. Another reason for the clinical/MRI discrepancy in MS is the inability of cMRI to measure and quantify the presence and extent of normal-appear- ing tissue damage. Post-mortem studies have shown subtle changes in the normal-appearing brain tissue (NABT) from MS patients, which include diffuse astrocytic hyperplasia, patchy edema, and perivascular cellular infiltration, as well as axonal damage (Allen and McKeown 1979; Evangelou et al. 2000;

Bjartmar et al. 2001).

Modern quantitative MR techniques have the potential to overcome some of the limitations of cMRI. Metrics derived from magnetization transfer (MT) (Filippi et al. 1999a) and diffusion-weighted (DW) (Filippi and Inglese 2001) MRI enable us to quantify the extent and severity of structural changes occurring within and outside cMRI-visible lesions of patients with MS. Proton MR spectroscopy (1H- MRS) (Filippi et al. 2001a) can add information on the biochemical nature of such changes. Functional MRI (fMRI) (Filippi and Rocca 2003) can provide new insights into the role of cortical adaptive changes in limiting the clinical consequences of MS structural damage.

This chapter provides an update of the current “state-of-the-art” of the application of structural, metabolic and functional MR-based techniques to the study of MS pathophysiology.

15.2 MT MRI

The basic principles of MT MRI are described elsewhere in this book. An example of a magnetization transfer ratio (MTR) map is shown in Fig. 15.1. On MTR maps, the degree of signal loss depends on the density of macromolecules in a given tissue, and low MTR values indicate a reduced capacity of the macromolecules in the CNS to exchange magnetization with the surrounding water molecules, reflecting damage to myelin or to the axonal membrane. MT MRI has several advantages over cMRI in the assessment of MS. First of all, it provides quantitative information with a high specificity to demyelination and axonal loss, the more disabling substrates of MS pathology. Secondly, it enables us to assess the “invisible” disease burden in the brain tissue which does not show macroscopic abnormalities on cMRI. Thirdly, with the application of MTR histogram analysis, it provides, from a single procedure, multiple parameters influenced by both the macroand microscopic lesion burden, that might also be used as paraclinical measures of MS evolution, either natural or modified by treatment.

A post-mortem study in MS (van Waesberghe et al. 1999) has provided the most compelling evidence that a marked reduction of MTR values in MS diseased tissues indicates severe structural damage, by showing strong correlations of MTR values from MS lesions and normal-appearing white matter (NAWM) with the percentage of residual axons and the degree of demyelination. More recently, a study performed on human specimens has confirmed the sensitivity

of this technique towards the different pathological substrates of the disease, by showing that MTR values of remyelinated lesions are higher than those of demyelinated lesions and lower than those of the NAWM (Barkhof et al. 2003).

15.2.1

MT MRI Findings in Individual MS Lesions

The following are the main findings obtained by the application of MT MRI for the study of individual MS lesions:

1.New enhancing lesions are pathologically heterogeneous, as suggested by the demonstration that MTR values are higher: (a) in homogeneously enhancing lesions, which probably represent new lesions, than in ring-enhancing lesions, which may represent pre-existent, reactivated lesions (Silver et al. 1998); (b) in lesions enhancing on a single scan than in those enhancing on two or more serial scans (Filippi et al. 1998a); (c) in lesions enhancing after the injection of a triple dose of gadolinium than in those enhancing after the injection of a standard dose (Filippi et al. 1998b).

2.MTR changes can be detected in NAWM before lesion formation (Filippi et al. 1998c; Goodkin et al. 1998; Pike et al. 2000; Fazekas et al. 2002).

3.Longitudinal studies have shown that, in new enhancing lesions, MTR drops dramatically when the lesions start to enhance and can show a partial or complete recovery in the subsequent 1–6 months (Dousset et al. 1998; Filippi et al. 1998a,b; Goodkin et al. 1998; Silver et al. 1998; van Waesberghe et al. 1998).

4.Established MS lesions are also heterogeneous, as shown by the demonstration of lower MTR values in hypointense lesions than in lesions that are isointense to NAWM on T1-weighted scans (van Waesberghe et al. 1998).

5.Average lesion MTR has been found to be lower in patients with relapsing-remitting (RR) MS than in those with clinically isolated syndromes (CIS) suggestive of MS (Filippi et al. 1999), whereas no differences have been found in cross-sectional studies between patients with RRMS and those with secondary progressive (SP) MS (Filippi et al. 1999b) or between patients with SPMS and those with primary progressive (PP) MS (Rovaris et al. 2001). However, longitudinal studies have shown a more severe and faster decline of average lesion MTR values in SPMS patients than in patients with other disease phenotypes (Rocca et al. 1999;

Filippi et al. 2000a), consistent with the unfavorable clinical evolution of these patients.

15.2.2

MT MRI Findings in NABT

The pathological abnormalities observed in the NAWM of MS patients (Allen and McKeown 1979; Evangelou et al. 2000; Bjartmar et al. 2001) have the potential to modify the relative proportions of mobile and bound protons in the affected tissue and, as a consequence, the corresponding MTR values. Therefore, MT MRI can show NABT microstructural abnormalities not detected when using conventional imaging. MT MRI analysis of the NABT can be performed using either a region of interest (ROI) approach, or, alternatively, a histogram analysis. More recently, with the development of new techniques capable of automatically segmenting the NAWM and the NAGM, it has become possible to study these two tissue compartments separately.

The following are the main results obtained by the application of MT MRI to the study of the NABT of MS patients:

1.Using ROI-analysis, a reduction of MTR values has been shown in the NAWM of MS patients with all the major MS phenotypes (Filippi et al. 1995; Loevner et al. 1995). More recently, MTR changes, of a lower magnitude than those observed in T2visible lesions, have also been detected in the dirty-appearing white matter of MS patients (Ge et al. 2003).

2.The application of histogram analysis (Filippi et al. 1999b; Iannucci et al. 2000; Kalkers et al. 2001; Rovaris et al. 2001; Tortorella et al. 2000; Traboulsee et al. 2002) to the study of the NABT and of the NAWM confirmed and extended the previous findings obtained with ROI analysis, by showing that these abnormalities can be detected even in patients with CIS suggestive of MS (Iannucci et al. 2000; Traboulsee et al. 2002), are more pronounced in SPMS and PPMS patients than in patients with the other disease phenotypes (Tortorella et al. 2000), and are similar between patients with SPMS and those with PPMS (Rovaris et al. 2001) (Fig. 15.2).

3.NABT MTR values tend to decline over time in all MS phenotypes, even if these changes seem to be more pronounced in SPMS patients (Filippi et al. 2000a).

4.NABT MTR values are only partially correlated with the extent of macroscopic lesions and the

severity of intrinsic lesion damage (Tortorella et al. 2000), thus suggesting that NABT pathology does not only reflect Wallerian degeneration of axons traversing large focal abnormalities, but they may also represent small focal abnormalities beyond the resolution of conventional scanning and independent of larger lesions.

5.Using ROI (Cercignani et al.2001) and histogram analysis (Cercignani et al. 2001; Ge et al. 2001, 2002; Dehmeshki et al. 2003), MT MRI abnormalities have also been shown in the NAGM of MS patients, including those with PPMS (Dehmeshki et al. 2003). As shown for the NABT, also NAGM changes are more pronounced in patients with SPMS than in those with RRMS (Ge et al. 2002).

Fig. 15.2. Average MTR graphs of normal-appearing brain tissue from healthy controls (dotted line), primary progressive (PP) multiple sclerosis (MS) (gray line) and secondary progressive (SP) MS (black line) patient groups. PPMS and SPMS patients had lower average brain MTR and MTR histogram peak height than healthy controls, suggesting a diffuse NABT damage

15.2.3

Correlations with Clinical Manifestations and Disability

Due to its capability of quantifying the extent and the severity of tissue damage within T2-visible lesion and NABT, MT MRI is increasing the degree of correlation between MRI and clinical findings, as summarized below:

1.Moderate to strong correlations between various brain MTR histogram-derived metrics and the severity of physical disability have been shown by several studies (Iannucci et al. 1999;

Dehmeshki et al. 2001; Kalkers et al. 2001; Traboulsee et al. 2003). These correlations have been found to be stronger in patients with RRMS and SPMS than in other disease phenotypes (Dehmeshki et al. 2001; Kalkers et al. 2001).

2.Subtle MTR changes in the NABT (Rovaris et al. 1998; van Buchem et al. 1998) and in the cortical/subcortical (Rovaris et al. 2000) brain tissue are well correlated with the presence of neuropsychological impairment in MS patients. In addition, a multivariate analysis of several MRI and MT MRI variables, has demonstrated that average NABT MTR is more strongly associated to cognitive impairment in MS patients than the extent of T2-visible lesions and their intrinsic tissue damage (Filippi et al. 2000b).

3.MTR histogram parameters from the cerebellum and brainstem of MS patients are significantly associated with impairment of these functional systems (Iannucci et al. 1999).

4.NAGM MTR metrics are correlated with the severity of clinical disability in patients with RR (Ge et al. 2001) and PP (Dehmeshki et al. 2003) MS.

5.Longitudinal studies (Iannucci et al. 2000; Santos et al. 2002; Rovaris et al. 2003) demonstrated that MT MRI metrics are useful markers to monitor disease evolution. In patients at presentation with CIS, the extent of NABT changes has been found to be an independent predictor of subsequent evolution to clinically definite MS (Iannucci et al. 2000); whereas in patients with established MS, NAWM MTR reduction has been shown to predict the accumulation of clinical disability over the subsequent 5 years (Santos et al. 2002; Rovaris et al. 2003).

15.2.4

MT MRI to Monitor Treatment E cacy

MT MRI holds substantial promise to provide good surrogate markers for MS evolution (Filippi et al. 2002a). As a consequence, several recent MS clinical trials have already incorporated MT MRI, with a view to assessing the impact of treatment on demyelination and axonal loss. MT MRI has been used in phase II and phase III trials for RRMS (injectable and oral interferon beta-1a, interferon beta-1b, and oral glatiramer acetate) and SPMS (interferon beta1b and immunoglobulins). In these phase III trials, MT MRI acquisition has been limited to highly-spe- cialized MR centers and only subgroups of patients

(about 50–100 per trial) have been studied using this technique. Two phase II studies have shown that treatment with interferon beta-1b (Richert et al. 2001) or interferon beta-1a (Kita et al. 2000) favorably modifies the recovery of MTR values which follows the cessation of gadolinium enhancement in newly-formed lesions from RRMS patients. On the contrary, Richert et al. (2001) did not find any significant difference in the MTR values of NAWM ROI before and during interferon beta-1b therapy, as well as in the parameters derived from whole brain MTR histograms (Richert et al. 1998) in RRMS patients. More recently, it has also been shown that treatment with interferon beta-1b does not affect the MTR loss seen in whole brain tissue and NAWM of patients with SPMS recruited in the European phase III trial (Inglese et al. 2003a).

15.3 DW MRI

Diffusion is the microscopic random translational motion of molecules in a fluid system. In the CNS, diffusion is influenced by the microstructural components of tissue, including cell membranes and organelles. The diffusion coefficient of biological tissues (which can be measured in vivo by MRI) is, therefore, lower than the diffusion coefficient in free water and for this reason is named apparent diffusion coefficient (ADC) (Le Bihan et al. 1986). Pathological processes which modify tissue

integrity, thus resulting in a loss or increased permeability of “restricting” barriers, can determine an increase of the ADC. Since some cellular structures are aligned on the scale of an image pixel, the measurement of diffusion is also dependent on the direction in which diffusion is measured. As a consequence, diffusion measurements can give information about the size, shape, integrity, and orientation of tissues (Le Bihan et al. 1991). A measure of diffusion which is independent of the orientation of structures is provided by the mean diffusivity (MD), the average of the ADCs measured in three orthogonal directions.A full characterization of diffusion can be obtained in terms of a tensor (Basser et al. 1994), a 3×3 matrix which accounts for the correlation existing between molecular displacement along orthogonal directions. From the tensor, it is possible to derive MD, equal to the one third of its trace, and some other dimensionless indexes of anisotropy. One of the most used of these indices is named fractional anisotropy (FA) (Pierpaoli et al. 1996). A more detailed description of technical aspects of DW MRI is provided in another chapter of this book.

The pathological elements of MS have the potential to alter the permeability or geometry of structural barriers to water molecular diffusion in the brain (Fig. 15.3). The application of DW MRI technology to MS is, therefore, appealing to provide quantitative estimates of the degree of tissue damage and, as a consequence, to improve the understanding of the mechanisms leading to irreversible disability.

15.3.1

DW MRI Findings in Individual MS Lesions

The following are the main findings obtained by the application of DW MRI for the study of individual MS lesions:

1.Consistently with their pathological heterogeneity, T2-visible lesions are characterized by highly variable ADC, MD, and FA values (Horsfield et al. 1996; Droogan et al. 1999; Werring et al. 1999, 2000a; Filippi et al. 2000c, 2001b; Cercignani et al. 2000, 2001; Rocca et al. 2000). In particular, ADC and MD values have been shown to be higher in T1-hypointense than in T1-isointense lesions (Droogan et al. 1999; Werring et al. 1999; Filippi et al. 2000c, 2001b).

2.While FA values are consistently lower in enhancing than in non-enhancing lesions (Werring et al. 1999; Filippi et al. 2001b), conflicting results have been achieved when comparing ADC or MD between these two lesion populations. While some studies reported higher ADC or MD values in non-enhancing than in enhancing lesions (Droogan et al. 1999; Werring et al. 1999), others, based on larger samples of patients and lesions, did not report any significant difference between the two lesion populations (Filippi et al. 2000c, 2001b). The heterogeneity of enhancing lesions has also been underlined by the demonstration that water diffusivity is markedly increased in ring-enhancing lesions when compared to homogeneously-enhanc- ing lesions (Roychowdhury et al. 2000), or in the non-enhancing portions of enhancing lesions when compared with enhancing portions (Roychowdhury et al. 2000).

3.As for MT MRI,DW MRI changes have been shown in regions that will develop new lesions (Rocca et al. 2000; Werring et al. 2000a).

15.3.2

DW MRI Findings in NABT

As for MT MRI, DW MRI analysis of regions that appear as “normal” on conventional imaging can be performed using either an ROI or histogram analysis. The major findings derived by the application of DW MRI to the assessment of NABT pathology of MS patients are the following:

1.ROIs of the NAWM of MS patients have increased ADC or MD and decreased FA values when compared to the corresponding white matter

from controls. However, these abnormalities are milder than those measured in T2-visible lesions (Horsfield et al. 1996; Droogan et al. 1999; Werring et al. 1999, 2000a; Filippi et al. 2000c, 2001b; Cercignani et al. 2000, 2001; Rocca et al. 2000; Ciccarelli et al. 2001).

2.MD and FA changes in the whole brain and in the NABT have been shown also using histogram analysis in all the major MS clinical phenotypes (Cercignani et al. 2000, 2001; Nusbaum et al. 2000), including PPMS (Rocca et al. 2003a).

3.Using ROI (Cercignani et al. 2001) and histogram analysis (Cercignani et al. 2001; Bozzali et al. 2002; Rovaris et al. 2002a), MD changes have been shown to involve also the NAGM of MS patients (Fig. 15.4). Consistently with their worse clinical evolution, these changes tend to be more pronounced in patients with the progressive forms of the disease (Bozzali et al. 2002; Rovaris et al. 2002a), whereas no MD abnormalities have been detected in the NAGM and NAWM of patients with early RRMS (Griffin et al. 2001).

4.In a 1-year follow up study, Caramia et al. (2002)

Fig. 15.4. Mean diffusivity (MD) histogram of the normalappearing gray matter (NAGM) from a group of healthy controls (gray line) and a large sample of MS patients (black line). All MD histogram-derived metrics of the NAGM were significantly different between healthy controls and MS population, indicating the presence of structural damage of this tissue compartment

showed the development of MD abnormalities in the NAWM of CIS patients that evolved to definite MS. In an 18-month follow up study, OrejaGuevara et al. (2003) showed that NAGM changes in patients with RRMS worsen over time.

15.3.3

Correlations with Clinical Manifestations and Disability

The following are the major results obtained by the application of DW MRI to investigate the correlations between structural brain changes and the clinical manifestations of the disease:

1.While correlations between DW MRI findings and MS clinical manifestations or disability were not found in some of the earliest studies (Horsfield et al. 1996; Droogan et al. 1999; Cercignani et al. 2000; Filippi et al. 2000c), with improved DW MRI technology and increased numbers of patients studied, correlations between DW MRI findings and MS clinical manifestations or disability are now emerging (Castriota Scanderbeg et al. 2000; Nusbaum et al. 2000; Cercignani et al. 2001; Filippi et al. 2001b; Rovaris et al. 2002a).

2.In a large sample of MS patients, average lesion MD, but not average lesion FA, was found to be significantly correlated, albeit moderately, with clinical disability (Filippi et al. 2001b). Interestingly, in patients with SPMS a moderate and significant correlation was found between average lesion MD or FA and disability (Castriota Scanderbeg et al. 2000; Filippi et al. 2001b), whereas no significant correlation was found between disability and T2 lesion volume. On the contrary, a significant correlation between disability and T2 lesion volume was found in patients with RRMS, where, in turn, there was no correlation between average lesion MD or FA and disability (Filippi et al. 2001b). These findings suggest that mechanisms leading to disability are likely to be different in patients with RRMS and SPMS.

3.DW MRI metrics of specific brain structures, such as the pyramidal tracts (Wilson et al. 2003) or the cerebellar peduncles (Ciccarelli et al. 2001) are strongly correlated with the impairment of these functional systems.

4.In patients with RRMS, a moderate correlation between cognitive impairment and NAGM MD histogram metrics has been shown (Rovaris et al. 2002b).

15.4

1H-MRS

Water suppressed, proton MR spectra of normal human brain at long echo times reveal four major

resonances: one at 3.2 ppm from tetramethylamines (mainly from choline-containing phospholipids [Cho]), one at 3.0 ppm from creatine and phosphocreatine (Cr), one at 2.0 ppm from N-acetyl groups (mainly NAA), and one 1.3 ppm from the methyl resonance of lactate (Lac). NAA is a marker of axonal integrity, while Cho and Lac are considered as chemical correlates of acute inflammatory/demyelinating changes (Filippi et al. 2001a). 1H-MRS studies with shorter echo times can detect additional metabolites, such as lipids and myoinositol (mI), which are also regarded as markers of ongoing myelin damage.Additional technical information on 1H-MRS are given elsewhere in this book.

1H-MRS can complement cMRI in the assessment of MS patients, by defining simultaneously several chemical correlates of the pathological changes occurring within and outside T2-visible lesions. An immunopathologic study (Bitsch et al. 1999) has shown that a decrease in NAA levels is correlated with axonal loss, while an increase in Cho correlates with the presence of active demyelination and gliosis.

15.4.1

1H-MRS Findings in Individual MS Lesions

As shown by other non-conventional MRI techniques, 1H-MRS can depict the heterogeneous pathological substrates of T2-visible MS lesions. The following are the major insights provided by the application of 1H- MRS to the study of MS lesions:

1. 1H-MRS of acute MS lesions at both short and long echo times reveals increases in Cho and Lac resonance intensities (Davie et al. 1994; De Stefano et al. 1995a), which reflect the releasing of membrane phospholipids and the metabolism of inflammatory cells, respectively. In large, acute demyelinating lesions, decreases of Cr can also be seen (De Stefano et al. 1995a). Short echo time spectra can detect transient increases in visible lipids, released during myelin breakdown, and mI (Narayana et al. 1998). All these changes are usually associated with a decrease in NAA. After the acute phase and over a period of days to weeks, there is a progressive reduction of raised Lac resonance intensities to normal levels. Resonance intensities of Cr also return to normal within a few days. Cho, lipid and mI resonance intensities return to normal over months. The signal intensity of NAA may remain decreased or show partial recovery, starting soon after the acute phase and lasting for several months (Arnold et al. 1992;