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

affinity for pathologic cells, MI appears to be poised to add a powerful tool to our diagnostic capabilities. The 8-T MR images have shown histologic quality. These images possess ultra-high resolution capable of visualizing microanatomic details. MI is capable of monitoring the cell trafficking. With regard to MS etiology, this aspect of MI offers the ability of directing cells to a specific target in the body. A wide range of cellular processes such as macrophage infiltration into CNS, leukocyte role in inflammatory diseases, and hematopoietic stem cell targeting have and will become available for imaging. These novel imaging strategies may provide methods for detecting early inflammatory events, at the cellular level, before the consequences of inflammation become macroscopically detectable by traditional imaging techniques. This would amount to a strategic transition in diagnostic imaging modalities. Such a transition could usher in the era of a functional and physiological approach versus the present conventional anatomic approach.

On another front, the need for possible extrapolation of animal results to human subjects necessitates that all possible enhancements that could be achieved be exploited in human scanners as well. Currently, whole body research scanners operate at 9.4 T. There are plans for construction of a few neuroimaging centers equipped with 3-T, 7-T, 9.4-T and 11.7-T MR systems for human clinical trials. Other scanners include 11.7-T and 14-T units for primate studies, and an up to 17-T MR scanner for rodent studies. Imaging centers are growing in number and size. Centers typically have 30–50 members, with some larger MR research units employing up to 200 researchers. The prospect of fruitful research in MR, and particularly in active areas such as MI, has brought biologists, physicists, engineers, and chemists into collaborative projects. These multidisciplinary efforts have given rise to innovative techniques such as MI. With higher field strength and more complex imaging techniques it is inevitable that targeted MR MI will accelerate its expansion to other areas of in vivo physiology imaging. MI is not restricted by the same limitations as other functional imaging techniques. The ability to probe cellular events and monitor their spatiotemporal evolution unrestricted by the time frame of fMRI is looming in many laboratories.

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11.2.1Problems in Imaging Infants

(Premature or Term-Born) 154

11.2.2Limits of MR Imaging of the Developing Brain 156

11.3MR Imaging of the Brain in Fetuses and Prematures 157

11.1

The Factors of Early Brain Development

The brain development corresponds to morphological and maturational changes, which result from the histogenesis, synaptogenesis and myelination.

11.1.1

The Morphological Changes

Brain 157

11.3.2The Intrinsic Anatomy of the Fetal

and Premature Brain 159

11.4MR Imaging of the Brain in Term-Born Infants 163

11.4.1 The Brain at Term 163

11.4.1.1T1 Imaging 163

11.4.1.2T2 Imaging 165

11.4.2 The Brain at 4 Months 165

11.4.2.1T1 Imaging 165

11.4.2.2T2 Imaging 168

11.4.3 The Brain from 8 to 12 Months 168

11.4.3.1T1 Imaging 168

11.4.3.2T2 Imaging 168

11.4.4 The Brain at 18–24 Months 168

11.5MR Morphometry, Diffusion, and Spectroscopy 168

11.5.1Morphometry 168

11.5.2Diffusion Imaging 169

11.5.3Spectroscopy 171

11.6.3Destructive Lesions and the Developing Brain 172

11.7Conclusions 173 References 173

C. Raybaud, MD FRCPC

Division Head of Neuroradiology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8

nomena: the first one is the global process leading the neuroepithelium from the embryonal epiblast to an essentially recognizable brain; the second consists of the cellular development and organization, with the changes in brain weight and surface configuration (that is the developing sulcation).

The steps leading from the midline epiblast to the central nervous system (embryonic period) are outside the scope of this chapter. Briefly, they include the neurulation (differentiation of the neuroectoderm, and formation of the neural tube), the formation of the cerebral vesicles with the specific development of the anterior neural plate (forebrain) and of the rhombencephalon (hindbrain), the opening of the 4th ventricle together with the formation of the leptomeninges and of the dura. From the end (week 7) of the embryonic period, the neuroepithelial cells proliferate and, till midgestation (week 20), build up the cerebral cortex together with the telencephalic commissures. This cellular proliferation, along with migration and differentiation, accounts for the increase in brain weight during the embryonic and early fetal stages.

During the second half of gestation, the neuronal migration is achieved, and a significant number (30%–50%) of neurons are actually bound to disappear by apoptosis, as part of the organization of the brain. From then on, and during infancy, the cortical synaptogenesis develops tremendously, peaking at 2 years (Huttenlocher 1990),with the concomitant development of the fiber network, the increase of the

metabolic activity that becomes mostly aerobic (and is therefore accompanied with an increase of the vascularity), the enormous development of the supporting cells, mostly the astrocytes, and of course, mostly after birth but beginning already in the fetus,the mass production of myelin by the oligodendrocytes. While the brain weighs approximately 80 g at 20 weeks of gestation, it weighs 350 g at birth at 40 weeks (a fourfold increase in 4.5 months), 1000 g at 1 year (threefold increase in 12 months), and 1400 g at 18 years (40% increase in nearly two decades). This early increase in volume concerns the cortex more than the subcortical white matter (Hüppi et al. 1998a), with an important tangential growth of the cortical plate, at least in the higher mammals, and therefore a cortical folding resulting in the species-specific sulcal/gyral pattern.

11.1.2

The Internal Appearance

The internal appearance of the parenchyma (that is the tissular organization of the cellular layers within the cortical mantle) also evolves according to the stages of histogenesis (Fees-Higgins and Larroche 1987), mostly during the fetal period and the first 2 post-natal years. The histogenetic processes include the proliferation, the differentiation and the migration of the cells toward their anatomical destination, and their organization.Because myelin is made of lipids, the maturation also leads to a significant change of the physical-chemical composition of the brain: the fatty myelin replaces the water, and some of its components modify the relaxivity of the water protons. The medical consequence of this is that, as MRI reflects the physical-chemical status of the brain, the orderly changes of the maturation will be reflected in the MR images, allowing a direct evaluation of normal development, as well as of the diseases that affect these processes.

All neural cells originate from common neural stem cells. These proliferate in the germinal matrices (McConnell 1995). Two different germinal matrices exist in the cerebral hemispheres (Lavdas et al. 1999; Letinic and Rakic 2001; Nadarajah and

Parnavelas 2002). The germinal matrix of the mantle lines the ventricular wall under the white matter of the hemispheres, lateral to the basal ganglia; it produces the cells for the cortical plate, namely the pyramidal neurons and the astrocytes. The germinal matrix of the ganglionic eminence covers the surface of the basal ganglia; it produces the interneu-

rons for both the cortical plate and the basal ganglia. Seemingly parts of both matrices may produce the oligodendrocytes for the white matter tracts to be myelinated. The germinal matrices are the sites of the cellular proliferation. There are two stages in this proliferation, depending on the type of division (McConnell 1995; Rakic 1995). The initial one is the stage of symmetrical division, in which a stem cell produces two identical stem cells. The second stage is of asymmetrical division, in which a stem cell produces another stem cell and a differentiated cell. The number of division cycles probably accounts for the differences of neural development between lower and higher mammals (Rakic 1995; Caviness et al. 1995). It is estimated that there are approximately 30– 35 cycles of divisions in the primates, against 7–11 in the rodents. If one cycle fails, the pool of brain cells is theoretically cut by 50%. In the very early stage of development, the germinal matrix of the mantle produces early, transient neurons to form a primary cortical preplate (or plexiform layer), which serves as an organizer for the coming cortical plate (Meyer et al. 2000; Xie et al. 2002).

There are basically four types of brain cells: the pyramidal neurons, the astrocytes, the interneurons and the oligodendrocytes.

The pyramidal neurons represent 80% of the neuronal population of the cortex. They are glutamatergic excitatory cells. They originate from the germinal matrix of the cerebral mantle lateral to the ganglionic eminence, deep to the future white matter. They migrate radially toward the brain surface (Sidman and Rakic 1973), settling within the pre-existing preplate to form the cortical plate (Meyer et al. 2000). In the process, the preplate is split in two layers. The superficial layer forms the (future) molecular layer (or layer 1) with its transient Cajal-Retzius cells (CRCs). The deep layer forms the transient subplate (Kostovic and Rakic 1990) which eventually attenuates during the second half of gestation to disappear about birth. The migration of the pyramidal neurons is conducted by specialized guiding cells, the radial glia (Sidman and Rakic 1973) from which they actually differentiate even during the migration (Tamamaki et al. 2001). This migration process is also under the control of the CRCs (MarinPadilla 1998),which stop the neurons before they reach the brain surface. Therefore, in the successive waves of migration, young neurons pass the older ones to be stopped only before the molecular layer and as a consequence, the oldest neurons

form the deep layers (5 and 6) of the cortex, the youngest ones, the superficial layers (2 and 3): this is called the “inside-out process”. The migration of the forebrain pyramidal neurons continues until mid-gestation (20–23 weeks). After that no neurons are produced in the brain, except in the hippocampal dentate gyrus (granule cells) and in the olfactory bulbs (Barres 1999).

The astrocytes are glial cells. They support the neurons, being interposed between the vessels and the neurons. They also assist the neuronal function, especially in the management of the neurotransmitters. They are initially produced together with the neurons in the germinal matrix of the mantle, and constitute the radial glia which guides the neurons toward the surface. Recent studies have shown that in fact, the neuron is produced by the radial glia and still differentiating while separating from it (Tamamaki et al. 2001). After the end of the neuronal migration, the cells of the radial glial become the cortical astrocytes. Other astrocytes keep being produced by the germinal matrix until it disappears, especially for the superficial cortical layers (Gressens et al. 1992). In contrast with neurons, astrocytes do die and form during the whole life by division of pre-existing astrocytes.

The interneurons are GABAergic inhibitory neurons, making up 20% of the cortical neuronal population. They originate from the germinal matrix of the ganglionic eminence over the future basal ganglia. From there, some migrate toward the cortex, while others move toward the basal ganglia and the thalamus (Lavdas et al. 1999; Zhu et al. 1999; Letinic and Rakic 2001; Nadarajah and

Parnavalas 2002). Their migration to the cortex is not well understood yet.They seem first to follow the fibers toward the cortex, then migrate inward to the germinal matrix of the mantle, where they get “messages” to be assigned a final position into the cortex, which they reach by outward migration.

The oligodendrocytes remain the most mysterious cells of the central nervous system, although they have been extensively studied (Baumann and Pham-Dinh 2001). It is not even clear whether they represent a single or multiple different lineages (Baumann and Pham Dinh 2001). Their best known role is the mass production of myelin, which has been extensively documented (Yakovlev and Lecours 1966; Holms 1986;

Brody et al. 1987; Kinney et al. 1988). Myelin facilitates the conduction of the potentials along

the axons, and the extensive myelination of the white matter is a characteristics of the development of the young brain during the end of gestation and the first years after birth. While the normal turn-over of the myelin components has been evaluated (in the range of several months to a year), the turn-over of the oligodendrocytes themselves is unknown. They seem to originate in restricted ventral or laterobasal areas of the prosencephalon (Bauman and Pham-Dinh 2001). They proliferate (myelination gliosis) and migrate toward the axonal fascicles when they are still in the progenitor stage. As dysmyelinating diseases often present with quite specific fascicular patterns (van der Knaap et al. 1991), it seems likely that the position of the oligodendrocytes is genetically defined.

After completion of the cortical plate, synaptogenesis develops intensively, especially after birth and during the first 2 years of life (Huttenlocher 1990). This means a tremendous expansion of the fibers network, and particularly of the axons. It has been demonstrated that the subplate, the transient subcortical remnant of the primary preplate (Kostovic and Rakic 1990) acts as a waiting zone for the axons approaching the cortex before the cortical organization is ready. This concerns the thalamo-cortical fibers, the association fibers as well as the commissural fi- bers (Kostovic and Rakic 1990; Super et al. 1998). In the hippocampus, this role of waiting zone may be played by the superficial molecular layer (Super et al. 1998). Synaptogenesis induces a significant increase of the needs of oxygen, with the subsequent development of an adapted vascularity (Raybaud 1990) and blood flow. The enormous development of the axons and dendrites, with their species-specific organization and attachments are likely to be responsible for the shaping of a species-specific cortical sulcal/gyral pattern (van Essen 1997). It makes up the white matter, which in mature humans represents 50% of the volume of the hemispheres (this does not take the intracortical fibers into account).

The synaptogenesis is also accompanied by the development of myelination.As stated above, the myelination has been extensively studied over the past decades, histologically and chemically. It develops according to a well defined program, roughly said from the cord to the hemispheres, the sensory structures before the motor before the associative ones (Yakovlev and Lecours 1966), and in the hemisphere, from the back to the front. In fact things are more complex. The primary systems (sensory-motor,

auditory, visual, and the hippocampi) are myelinated first. In each system, the myelination of the fibers proceeds toward the cortex. The associative areas myelinate last, especially the anterior frontal and the anterior temporal cortices. Central myelination occurs in the portions of the basal ganglia adjacent to the posterior limbs of the internal capsules (PLICs). Together with the brainstem, this area appears already well developed even before birth.

On MR imaging, the demonstration of the myelination processes depends on two phenomena. The first is the depiction of the precursors of myelin. These precursors, cholesterol and specially galactocerebrosides, have a strong magnetization transfer effect (Fralix et al. 1991; Koenig 1991; Kucharczyk et al. 1994), and as such appear early on T1 imaging as a bright signal. The second is the replacement of water by the fatty myelin. The brain of fetus and neonates contains approximately 90% water; in the adult it drops to 70% in the white matter, and to 85% in the cortex after completion of the myelination.As the water is dark on T1 and bright on T2, the myelination reverses the white matter appearance to bright on T1 and dark on T2.

11.2

MR Imaging: Technical Considerations

11.2.1

Problems in Imaging Infants (Premature or Term-Born)

Conventional T1 and T2 sequences are used in neonates as in mature children or adults. T1 imaging includes spin-echo (SE) or gradient-echo (GE) imaging, and T2 imaging, spin-echo (SE) or turbo-spin-echo (TSE) sequences.These are more heavily T2-weighted sequences, and show “more” myelination than standard SE. Inversion-recovery (IR) sequences are heavily T1 weighted and yield superb images of the maturation of the brain (Christophe et al. 1990).

It was observed from the outset that the relaxation times in infants were different from those in adults (Holland et al. 1986); as they are strongly dependent on the stage of the maturation, MR imaging can be used to evaluate the progresses of myelination in normal and diseased brains (Barkovich et al. 1988;

Bird et al. 1989; Christophe et al. 1990; van der Knaap and Valk 1990; Girard et al.1991; Martin et al. 1991; Sie et al. 1997; Barkovich 1998), to a degree

that no other imaging modality had permitted before. This evolving normality should be taken into account to appreciate disease.But another consequence of this maturation process is that in the first months of life, the design of the sequences should be adapted to the physical-chemical status,that is the degree of maturation, of the cerebral tissue. Typically, when designing a T2w SE sequence, the TR is chosen to be three times longer than the calculated T1 in order to eliminate all T1 contamination effect (Kastler et al. 2001). In adults, at 1.5 T, the calculated T1 is approximately 750 ms: the TR of the T2w sequence should therefore be around 2250 ms, with a TE of about 90 ms. In neonates, depending on the part of the brain examined, the calculated T1 is around 3000 ms (personal data); this correlates with the high content of free water. Consequently, the TR of the T2w SE sequence should be set around 10,000 ms. In normal SE sequences, this would lead to too long an acquisition time, but it can be achieved in a couple of minutes with TSE techniques (although TSE yield images slightly different from standard SE, the myelination appearing “more advanced”). Also, as the T2 value is longer in infants than in adults, the TE should be prolonged at 120 ms to obtain as much T2 effect as possible, while keeping enough signal. In a similar way, in a T1w sequence, the TR having only to be maintained below the calculated T1 (Kastler et al.2001),it can be chosen longer for neonates than for mature children, resulting in a better signal-to-noise ratio.

Another sequence routinely used in mature patients is the FLAIR sequence. It is a T2w sequence in which the signal of the free water has been suppressed by a 2200 ms pulse. The FLAIR images seem somewhat confusing in the first months and years (Fig. 11.1), but they can also be understood from the changing composition of the parenchyma (Ashikaga et al. 1999; Murakami et al. 1999). In the heavily hydrated neonatal brain, the signal of the white matter is canceled as well, so that it appears dark, and therefore looks the same as on T1 imaging. But as the myelination proceeds, the signal increases quickly and the white matter becomes fully bright by 4 or 5 months. Later, as on regular T2w images, the signal decreases progressively, but over a much longer span of time (up until 4 years of age).

To summarize, as the different types of sequences represent different factors of the physical-chemical composition of the brain, they evolve at their own pace which does not necessarily reflect the histology. As a consequence, the infantile brain appears mature at about 12 months on T1 images (when the magnetization transfer effect is predominant); at about

2 years on T2 images (where the loss of signal due to the accumulation of myelin predominates); and at about 4 years on FLAIR images. These three patterns remain consistent in normal patients; they may diverge in disease, and should therefore be read accordingly.

11.2.2

Limits of MR Imaging of the Developing Brain

Even adapted to the developing brain, these approaches present two types of insufficiencies. The first is that the clinical images obtained from MR are not quantitative images similar to those of the X-ray scanner,but images of which the contrast results from the relative signals of the various structures under examination. As each structure matures according to its own timetable and pace, a given one may seem myelinating in the late fetus because nothing else is myelinated, but less myelinated months later because the rest of the brain then becomes more mature more quickly.To compensate for this,semi-quantitative imaging using relaxometry (images made with absolute relaxation time measurements) can be used, but they are time consuming and therefore not ethically acceptable in clinical conditions. Thus the milestones of maturation used by most correspond to patterns produced at a given time by the relative myelination of the most significant structures of the brain (Barkovich et al. 1988; Bird et al. 1989).

The second insufficiency of MR imaging regarding myelination is that it shows a so-called mature pattern while the brain is still developing: one year (T1), two years (T2), four years (FLAIR), whereas we know from histology that the myelination process is not completed until the end of adolescence. This means that a normal mature appearance may correspond to a maturation which is not complete. Sequences sensitive to the late maturational changes have still to be developed and clinically evaluated (Steen et al.1997). Also, the term “myelination delay”, commonly used in clinical practice, should be avoided unless successive studies have shown an improvement. And even if this is the case, the “normal” stage attained may be only the myelination stage of the age of 2 or 4 years.

A last point is important to keep in mind when reading the brain development through the MR signals. This point is that the signal intensity of the brain tissue reflects the myelination in normal subjects only. In a diseased brain, a low T1, high T2 signal may reflect absence of, or poor, myelination, but it may also mean a de-myelination. Beyond the myelination

status, it may express edema, or gliosis, or even a focal dysplasia of the brain tissue.

11.2.3

Special Problems of MR Imaging in Fetuses

Imaging fetuses is possible only at and after midpregnancy. The main reason for this is the size of the fetal brain (approximately 50 mm diameter at that stage), which yields little signal in the abdominal cavity (abdominal volume and especially fat volume) and allows only a poor imaging definition, the size of the voxels being disproportionate to the size of the brain. Another problem, at any time, is motion: the fetus moves with the mother’s organs, following respiration; this effect is diminished when the head is incarcerated in the pelvis. The fetus himself has his/her own motion, as a whole or when sucking, moving limbs, etc. Other motion artifacts result from the moving fluids and gas of the bowels, and from the flowing blood in moving aorta and vena cava. The magnetic field homogeneity is altered, and the signal received from the fetal brain uneven. Sedating the mother (and therefore the fetus) does not seem to improve things significantly, and may be unacceptable for the parents.

Therefore the imaging technique should compensate for these difficulties. Imaging equipment is important, especially the abdominal coil, as much as possible multiple and in phase array, to get a more homogeneous signal. The most dramatic improvement has been brought about by the introduction of ultrafast,“snapshot” single-slice T2 imaging, making it possible to minimize motion effects. Yet this ultrafast imaging,when used post-natally,is of suboptimal quality as compared with the conventional, adapted T2 sequences. But it allows a fairly good depiction of the fetal brain anatomy at as early as 18 weeks. For T1 imaging, only conventional GE sequences are available; they last a couple of minutes, and are therefore more often altered by the motion artifacts. They are still needed for proper identification of the tissues, as a complement to T2 imaging. Fat saturation reduces the loss of signal in the fat. Slices should be as thin as possible, and the fastest acquisition time compatible with the diagnostic needs should be obtained when defining the sequences.

Other sequences are not used routinely. Angio MR can be used, but without contrast agent (time of flight, TOF), to avoid any risk regarding toxicity. DWI and MR spectroscopy are potentially useful; they are still under evaluation and not used routinely.