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

Many normal patients have periventricular smooth rims located around the frontal or occipital horns.

Most often, spin-echo (SE) sequences with a long TR and long TE (T2-weighted SE) are used to show white matter abnormalities. If intermediately long TEs (i.e. 40–60 ms) are employed, the lesions have a higher signal than CSF and the surrounding white matter, which improves their identification (protondensity images). Another MR sequence that is particularly suited for the identification of LA is FLAIR (Fig. 25.2). It uses a very long inversion time to suppress CSF, providing an even better contrast between white matter hyperintensities and CSF spaces. In

the elderly, the homogenous low background signal allows for a dramatic demonstration of white matter abnormalities. As previously mentioned, it is the best sequence for separating lacunes,Virchow-Robin spaces and LA (Barkhof and Scheltens 2002).

A variety of scales have been proposed to rate the impact of white matter abnormalities. They have the advantage of providing a semiquantitative and standardized method for reporting LA, but are usually plagued with subjective interpretations and modifications which can lead to a high interand even intraobserver variability (Fazekas et al. 2002). Although no scale has been universally accepted,under the auspices of the European task force on age-related white matter changes a new rating scale was developed and validated for both CT and MRI. Five brain regions are rated following a four-point scale (frontal, pari- eto-occipital, infratentorial, cerebellar and temporal areas). Overall, it showed a good inter-rater reliability for MRI and moderate when CT was used (Wahlund et al. 2001) (Table 25.2, and Fig. 25.3).

The white matter abnormalities commonly found on MRI in the elderly are non-specific and tell the clinician little about their pathogenesis, other than to possibly suggest ischemia. Table 25.3 presents a clinicopathological classification of vascular dementia.

Table 25.2. The age-related white matter changes (ARWMC) scale for CT and MRI.

White matter lesions

0 No lesions

1 Focal lesions

2 Beginning confluence of lesions

3Diffuse involvement of the entire region with or without U fiber involvement

Basal ganglia lesions

0 No lesions

1 1 focal lesion (≥ 5 mm)

2 > 1 focal lesion

3 Confluent lesions

Taken from Wahlund et al. (2001). The following areas are used for rating: frontal, parieto-occipital, temporal, infratentorial/cerebellum, and basal ganglia. Each hemisphere is rated separately.

Fig. 25.2. T2-weighted (top) and FLAIR (bottom) images. The very long inversion time used in FLAIR images results in improved contrast between CSF spaces and white matter hyperintensities

25.5.1 Di usion-Weighted and Di usion Tensor Imaging

Diffusion-weighted imaging (DWI) has the ability to detect (even small) acute and subacute infarcts with great accuracy. It also permits the identification of ischemic lesions in otherwise asymptomatic

Table 25.3. Vascular dementia. [Modified with permission from Roman (2002)]

Large-vessel

•Multi-infarct dementia

•Strategic infarct dementia

Small vessel

Subcortical ischemic vascular dementia

•Binswanger’s

•Lacunar dementia (état lacunaire)

•CADASIL

Cortical-subcortical

•Hypertensive and arteriolosclerotic angiopathy

•Cerebral amyloid angiopathies

•Venous occlusions

•Collagen-vascular diseases with dementia

•Other hereditary forms

Ischemic-hypoperfusive

•Diffuse anoxic-ischemic encephalopathy

•Selective vulnerability with restricted injury

•Border-zone infarction

•Incomplete white matter infarction

Hemorrhagic vascular dementia

•Traumatic subdural hematoma

•Subarachnoid hemorrhage

•Cerebral hemorrhage

individuals. Because of these, it may be useful in the longitudinal assessment of patients with LA to monitor the development of new ischemic lesions in the white matter.

In one study, more than one third of patients with vascular dementia associated with small vessel disease were found to have high-signal abnormalities on DWI suggestive of recent ischemia (Choi et al. 2000). In this study the mean apparent diffusion coefficient (ADC) was 0.71±0.15×10–3 mm2/S, the lesions were small (ranging from 0.07 to 2.40 ml), and

Fig. 25.3. ARWMC rating scale. Left, T2-weighted image showing a grade 2 rating score. Right, example of a grade 3 score. [Taken with permission from Wahlund et al. (2001)]

located most commonly in the deep white matter. Remarkably, 20% of asymptomatic individuals had evidence of (silent) ischemia in the cerebral white matter, while some others had multiple small lesions suggesting either a proximal source of embolism or global hypoperfusion (Choi et al. 2000). The severity of LA also seems to correlate with a higher ADC value, and it has been suggested that DWI can be used to differentiate acute and chronic stroke lesions from LA (Helenius et al. 2002). Another potential advantage of this technique is the use of whole brain ADC histograms as a more reliable, quantitative tool to monitor disease progression at various time points (Mascalchi et al. 2002). Although promising, this needs to be further validated.

High b value diffusion MRI (high-b DWI), using b values >3000 s/mm2, may be a more sensitive technique to identify disorders of myelin. In a small, preliminary study of two patients, high-b DWI was analyzed using the q-space approach (Fig. 25.4); a significant reduction in restricted diffusion (attributed to axonal loss and demyelination) much larger than the corresponding hyperintense lesions on T2weighted or FLAIR images was observed. If corroborated, this finding would suggest that high-b DWI is a more sensitive technique for identifying early white matter changes, and that the extent of white matter abnormalities in these patients may be greater than currently assumed (Assaf et al. 2002).

The rate of diffusion of water molecules in normal white matter is not the same in all directions. In white matter tracts, the diffusion is less restricted along the long axis of the axons than across them. Diffusion tensor imaging (DT-MRI) measures the extent to which diffusion is directional (anisotropic), and the fractional anisotropy (FA) is an index of directionality of diffusion. Using this technique,

Jones et al. (1999) found a characteristic pattern of moderate elevation in diffusion trace with a marked loss of FA in patients with LA. The authors postulated that these findings are consistent with the pathological correlate of axonal loss and gliosis commonly observed in LA, both of which would tend to result in decreased anisotropy. DT-MRI was also used to study the normal appearing white matter of patients with LA. Similar findings (increased mean diffusivity and decreased FA) were also found in white matter that appeared normal as assessed by T2-weighted images. Moreover, these subtle changes in DT-MRI correlated with cognitive dysfunction. The pathological substrate of this abnormality is unknown, but these findings also suggest that DTMRI may be a more sensitive technique for the identification of early white matter changes in LA (O’Sullivan et al. 2001).

25.5.2

Magnetization Transfer MRI

Magnetization transfer (MT) is a technique used for tissue characterization. It measures the interaction

between water protons bound to proteins and other macromolecules (such as those in myelin) and unbound tissue water protons. It has been extensively used in the characterization of multiple sclerosis lesions, and is believed to be more specific for white matter damage. This imaging modality has been applied to subjects with LA, and the MT ratios have been reported to be lower than that of normal white matter (38.6±4.5 and 47.3±2.1, respectively), but not nearly as low as in patients with frank demyelination (26.4±5.0). This finding has been attributed to a lesser extent to demyelination or ischemic damage, and more to increased water content (Reidel et al. 2003).

In patients with dementia and LA, the mean MT ratio is also significantly lower than in non-demented patients with similar degrees of LA (37.4+1.5 versus 41.3±1.4), suggesting differences in the pathological substrate (Fig. 25.5). Moreover, the MT ratio of areas of periventricular hyperintensities correlates well with the mini-mental state examination score (Hanyu et al. 1999). Taken together, these findings suggest that in patients with dementia and LA the white matter changes likely are more severe than in non-demented patients.

25.5.3

Magnetic Resonance Spectroscopy

Proton magnetic resonance spectroscopic imaging (1H-MRSI) reveals the distribution of the amino acid N-acetylaspartate (NAA) in the brain. NAA is exclusively found in neurons and is considered to be an indicator of neuronal density and metabolism. In patients with LA several interesting findings have been reported. First, decreased levels of NAA were found in the cortex independent of the amount of atrophy, and the frontal cortex NAA seemed to correlate inversely with the volume of white matter hyperintensities. These findings were quite unexpected and suggest that a subcortical injury could induce secondary changes in the cortex (Capizzano et al. 2000).

Secondly and not surprisingly, decreased levels of NAA were found in these same patients, which is consistent with a greater susceptibility of the white matter to chronic ischemic changes. Thirdly, when patients with Alzheimer disease (AD) were compared with patients diagnosed with vascular dementia, they had a significantly lower NAA/creatine ratio in the hippocampus, suggesting that low hippocampal NAA may be relatively specific for AD and that it may help differentiate it from vascular dementia (Capizzano et al. 2000; Schuff et al. 2003).

When otherwise healthy individuals with white matter lesions, controls, and patients with LA and dementia are compared, the NAA/creatine and NAA/ choline ratios of the hyperintense white matter in asymptomatic individuals are virtually the same as those found in healthy controls. In demented patients

with LA however, these ratios are reduced, suggesting chronic demyelination or ischemia. This technique may help identify clinically relevant white matter lesions and may also have a role in the diagnosis of vascular dementia.

25.5.4 Perfusion MRI

With recent advances in technique, it is now possible to calculate absolute regional cerebral blood flow (CBF) from MRI using an exogenous paramagnetic contrast agent with an accuracy and spatial resolution that is equal to or better than that of PET studies. Perfusion MRI has been applied to patients with LA in two settings. One has been to measure CBF and cerebral blood volume (CBV) in the actual area of white matter abnormalities. In one such study, the mean white matter CBF of regions of LA was reduced by almost 40% when compared to healthy controls, and this reduction was apparent in all regions of white matter (i.e. anterior, posterior, and superior). Interestingly, grey matter CBV in this same study was significantly increased in the LA group (Markus et al. 2000). The relevance of this finding is unknown at present, but further supports the notion of cortical dysfunction or injury triggered by subcortical insults.

The other setting in which perfusion MRI has been applied is in quantifying CBF in normal appearing white matter in patients with known LA. It has been found that CBF is significantly reduced in the periventricular white matter of these patients (17.9 vs 21.6 ml/100 g/min in controls). Such a reduction, however, was not found in the centrum semiovale (O’Sullivan et al. 2002). These findings support chronic hypoperfusion and ischemic damage with “incomplete infarction” as the underlying pathophysiologic mechanism in this condition. Perfusion MRI could also be used to identify areas of normal appearing white matter that are at risk by virtue of their decreased CBF value and potentially allow interventions that could prevent further injury.

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CONTENTS

26.1Introduction 377

26.2Degenerative Dementias 378

26.2.1Alzheimer Disease 378

26.2.1.1Conventional MR 378

26.2.1.2Non-conventional MR 379

26.2.2 Fronto-temporal Dementia (FTD) 380

26.2.2.1Conventional MR 380

26.2.2.2Non-conventional MR 380

26.3Degenerative Ataxias 380

26.3.1Conventional MR 381

26.3.2Non-conventional MR 381

26.3.2.11H-MRS 381

26.3.2.2MTI 383

26.3.2.3Diffusion MR 383

26.4.1Conventional MR 384

26.4.2Non-conventional MR 384

26.4.2.11H-MRS 384

26.4.2.2MTI 386

26.4.2.3Diffusion MR 386

26.5Conclusions 386 References 386

26.1 Introduction

Degenerative diseases of the central nervous system (CNS) comprise a variety of sporadic or inherited conditions characterized by progressive neuronal dysfunction and loss of unknown or incompletely known etiopathogenesis which typically are selective of some neuronal systems (Adams and Victor 1985). While the neuropathological hallmark of degenerative diseases of the CNS is a generally symmetric gray matter cortical or subcortical damage, white matter

M. Mascalchi, MD

Professor, Sezione di Radiodiagnostica, Dipartimento di Fisiopatologia Clinica, Università di Firenze, Viale Morgagni, 85, 50134 Firenze, Italy

changes in the brain or spinal cord are increasingly recognized as a frequent magnetic resonance (MR) finding in most of them. In some instances they are apparent in the conventional MR examination and are useful diagnostic features, in other cases they are not visible in the conventional MR examination but can be demonstrated using non-conventional MR techniques.

Conventional MR imaging includes T1, proton density and T2 (with and without inversion recovery RF pulse to attenuate the CSF signal) weighted sequences. The non-conventional MR include proton MR spectroscopy (1H-MRS), magnetization transfer imaging (MTI), and diffusion MR imaging.

1H-MRS enables an in vivo biochemical characterization of operator selectable volume of interest through the evaluation of the absolute or relative concentrations of some proton containing metabolites such as N-acetyl-aspartate (NAA), which is a marker of neuronal integrity and function, creatine plus phosphocreatine (Cr), which are markers of cell density and energy state, choline-containing compounds (Cho), which are markers of membrane metabolism, myo-inositol (mI), which is a marker of glial cell density, and glutamine (Gln) and glutamate (Glu). Although in many 1H-MRS studies of degenerative diseases of the CNS it was claimed that the volume of interest was placed in the cortical gray matter, with the current resolution of the single and multi-voxel techniques used for 1H-MRS there is always partial volume with the white matter and the spectral findings variably reflect also white matter changes.

Magnetization transfer imaging (MTI) is based on the interaction between protons in a relatively free state and those in a restricted motion state and indirectly reflects the capacity of the molecules of the tissue matrix to exchange energy with the surrounding water molecules (McGowan et al. 1998). A decrease of the MT ratio usually indicates a damage of the tissue matrix.

Diffusion MR imaging exploits the sensitivity of MR to motion of water molecules and provides a sensitive tool to explore the integrity of tissue and

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cellular barriers to water motion (Schaefer et al. 2000; Dong et al. 2004). The evaluation of maps of apparent diffusion coefficients (ADC) or mean diffusivity (D) evaluation is emerging as a quantitative, reproducible, and sensitive method to assess white and gray matter brain diseases (Cercignani et al. 2000; Bozzali et al. 2001; Cercignani et al. 2003). In particular, analysis of the brain D can provide regional and global quantification not only of the macroscopic damage shown as areas of prolonged T2 but also of microscopic tissue damage which is not demonstrated by T2 weighted images. To this end, region of interest and histogram approaches are complementary. In fact, histogram analysis is intrinsically more powerful from a statistical point of view than region of interest analysis (Chun et al. 2000) and is more suited to evaluate diffuse pathological processes as those underlying degenerative diseases of the CNS (van Buchem 1999). On the other hand, the loss of spatial information associated to histogram analysis can be compensated using regions of interest analysis based on an a priori knowledge of the distribution of the pathological damage.

In this chapter we shall review the most frequent degenerative diseases of the CNS in which conventional and non-conventional MR studies have documented significant “macroscopic” or “microscopic” white matter changes.

26.2

Degenerative Dementias

26.2.1

Alzheimer Disease

Although the neuropathological hallmarks of Alzheimer disease (AD), namely intracellular neurofibrillary tangles and extracellular amyloid plaques, are observed in the cerebral gray matter, diffuse white matter damage which is related to microvascular pathology is demonstrated in the brains of AD patients (Brun and Englund 1986; Sjobeck et al. 2003). Moreover, Kril et al. (2002) observed that the degree of hippocampal neuronal loss and atrophy was similar in demented patients fulfilling the neuropathological criteria for small vessel disease dementia and AD, respectively. These data indicate that even on a pathological basis, a complete separation of AD from white matter damage due to vascular disease is not always possible.

M. Mascalchi

26.2.1.1 Conventional MR

Proton density and T2 weighted images can show focal or diffuse white matter signal hyperintensity in patients with clinically probable AD (Fazekas et al. 1987). The most characteristic hyperintensities are symmetric and located along the cerebral periventricular regions or in the subcortical hippocampal and sylvian regions (Fazekas et al. 1987; Scheltens et al. 1990) (Fig. 26.1). Interestingly, de Leeuw et al. (2004) recently reported that white matter lesions were present on MR imaging in 29% of patients with a clinical diagnosis of probable AD and that there was a correlation between white matter signal changes, especially in the frontal and parieto-occipital regions, and hippocampal atrophy suggesting a relationship between vascular and typical AD pathology.

Although a loss of bulk of the white matter contributes to the pattern and progression of global and regional atrophy demonstrated by 3D T1 weighted images in cross-sectional and longitudinal studies in AD (Chan et al. 2001; Rusinek et al. 2003), most volumetric studies in AD measured the hippocampal formations alone (Jack et al. 2002; Dixon et al. 2002).

Voxel based morphometry (VBM) was introduced in 2000 as a new approach for global and regional estimation of brain volumes which is based on the statistical parametric mapping (SPM) soft-

Fig. 26.1. Alzheimer disease. Axial T2 weighted FLAIR image shows symmetric hyperintensity in the hippocampus and subhippocampal white matter of a patient with probable AD

ware developed for nuclear medicine and functional MR techniques. SPM analysis combines a strong statistical power with an observer unbiased high resolution analysis (Ashburner and Friston 2000). Curiously, many studies employing VBM emphasized regional cortical gray matter loss (Baron et al. 2001; Frisoni et al. 2002; Karas et al. 2003), but none explored possible white matter volume changes in AD.

26.2.1.2 Non-conventional MR

26.2.1.2.1 1H-MRS

In degenerative diseases of the CNS, 1H-MRS shows a decrease of the concentration of NAA or of the NAA/Cr ratio in the areas where there is the maximal neuronal damage and loss on neuropathological examination.

Spectroscopy was employed since the early 1990s in the evaluation of patients with clinical diagnosis of AD. Single voxels and MR spectroscopic imaging acquisitions were performed with volumes of interest placed in a number of sites, which included the occipital region (Shonk et al. 1995), the frontal region (Ernst et al. 1997), the parietal region (Schuff et al. 2002) the hippocampus (Dixon et al. 2002) the posterior cingulate (Kantarci et al. 2003) and the subcortical white matter (Catani et al. 2000).

The two main findings of 1H-MRS in AD, essentially independent of the voxel locations, are a decrease of NAA concentration or NAA/Cr ratio and an increase of mI concentration or of the mI/Cr ratio, which can be expressed as NAA/mI ratio (Shonk et al. 1995). The sensitivity and the specificity of the two 1H-MRS findings considered alone or combined for differentiation of mildly demented cases from age matched controls and for differentiation of AD from others dementias are high but not perfect (Shonk et al. 1995; Rapaport 2002; Catani et al. 2000). The decrease of NAA, NAA/Cr or NAA/mI correlate with the severity of the disease as judged based on the clinical and neuropsychological evaluation (Chantal et al. 2002; Waldman and Rai 2003), but its capacity to mark disease progression or cognitive decline in longitudinal studies is controversial (Jessen et al. 2001; Dixon et al. 2002).

This notwithstanding, 1H-MRS was employed as a surrogate marker to evaluate the efficacy of a drug in a randomized clinical trial in patients with AD (Kishnan et al. 2003).

26.2.1.2.2 MTI

Bozzali et al. (2001) reported that the peak of the MT ratio histogram of the cerebral hemispheres and of the temporal lobes was reduced in patients with AD as compared to age matched healthy controls. Similar results in the whole brain, temporal and frontal lobes of patients with AD and mild cognitive impairment were reported in a study showing that the cognitive decline in these two categories of patients correlated with the relative peak height of the whole brain MT ratio histogram (van der Flier et al. 2002).

26.2.1.2.3 Di usion MR

Two early studies of diffusion MR imaging in patients with clinical suspicion of AD employed the region of interest analysis in order to detect possible D changes in the cortical gray matter and subcortical white matter (Hanyu et al. 1998; Bozzao et al. 2001). Although both studies failed to demonstrate significant D changes in the hippocampi, one study (Hanyu et al. 1998) reported an increase of D and a decrease of anisotropy in the white matter of the temporal lobe which correlated with the clinical severity. Moreover, ADC perpendicular to the commissural fibers of the corpus callosum was increased and anisotropy decreased in patients with AD, the latter correlating with the mini-mental state examination score (Hanyu et al. 1999). Subsequent studies with diffusion tensor imaging confirmed the increase of D and the reduction of the fractional anisotropy in the association white matter tracts but not in the internal capsule of patients with clinical diagnosis of AD (Rose et al. 2000; Bozzali et al. 2002). Moreover, a strong correlation was reported between the score at the mini-mental state examination and an average overall white matter D and fractional anisotropy (Bozzali et al. 2002). Using histogram analysis after segmentation of the gray and white matter based on different FA, Bozzali et al. (2001) confirmed the increase of D in the cerebral white matter and cortical gray matter in patients with AD.

Interestingly,loss of anisotropy of the frontal white matter was found to increase with age and to correlate with neuropsychological evidence of cognitive decline in normal aging (O’Sullivan et al. 2001).