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

erage lesion MTR fitted a multiparametric model significantly separating MS from SID patients, with a significantly higher risk of having MS with increasing lesion volume and decreasing lesion MTR values. No conventional or MT MRI-derived variables significantly separated MS patients as a group from NSLE patients. Similar results were obtained by Bosma et al. (2000a,b), who found that NSLE patients had significantly lower brain MTR histogram peak height than age-matched healthy controls and SLE patients without overt CNS involvement, independent of the presence of T2-visible white matter lesions. In patients during the acute stage of NSLE (Bosma et al. 2000b), the average MTR histogram peak height was found to be lower than that of patients with chronic inactive NSLE, SLE and MS. More recently, Bosma et al. (2002) also investigated the relationship between brain MTR histogram-derived quantities and clinical status in 24 patients with NSLE. Significant correlations were found between MTR histogram peak height and measures of neurologic, cognitive and

psychiatric functioning, whereas no significant relationship was observed between MT MRI findings and NSLE patients’ disease duration.

Available data show that the presence of CNS dysfunction in SLE is associated with a diffuse, MT MRI-detectable damage of the brain parenchyma, whereas this does not seem to be the case for other SID (Rovaris et al. 2000b). Such damage is probably primarily present in the NABT and does not greatly depend upon the burden of T2-visible white matter abnormalities. Indeed, the latter abnormalities can also be found in 30%–40% (Rovaris et al. 2000b; Bosma et al. 2000a,b) of SLE patients without overt CNS disturbances,but MTR histogram-derived quantities of these patients do not significantly differ from those of healthy controls. Moreover, when brain MTR histograms are obtained after the exclusion of pixels belonging to T2-visible lesions, the observed differences between NSLE patients and normal controls or patients with other SID do not change (Rovaris et al. 2000b). It remains to be established which is the

causal relationship between the extent and nature of NSLE-related diffuse brain tissue damage and MT MRI-detectable abnormalities. The contribution of NAWM pathology appears to be relevant for a number of reasons. First, despite the concomitant finding of brain atrophy in NSLE (Bosma et al. 2000a,b), the magnitude of the decrease of brain MTR histogram peak height in comparison with SLE and healthy controls did not change when this metric was normalized for brain volume, thus suggesting that atrophy per se cannot explain the observed MT MRI abnormalities. Second, a preliminary, ROI-based study (Campi et al. 1996) did not find any difference in NAWM MTR values between SLE patients and age-matched healthy subjects. Third, on the one hand, macromolecules that contribute to the MT effect in the brain tissue are mainly cerebrosides and phospholipids,which are the major components of myelinated white matter tracts (Brochet and Dousset 1999), and, on the other, NAWM constitutes a great portion of the NABT. Thus, it is conceivable that changes in the MTR histogram characteristics of the latter compartment mainly depend upon diffuse, MRI-undetectable white matter abnormalities leading to demyelination and loss of axons. Admittedly, these speculations need to be confirmed by further studies with a separate analysis of white and gray matter MTR histograms in NSLE and other SID. Preliminary MT MRI data (personal observations, unpublished results) seem to suggest that normal-appearing gray matter damage, if any, is minimal in SID, independently of the presence of overt CNS involvement or T2-visible white matter abnormalities. This is in contrast with what has been found in MS patients, for whom gray matter damage seems to play a central role in the pathobiology of CNS dysfunction (Miller et al. 2003).

The potential usefulness of MT MRI as a paraclinical tool to monitor SID evolution is suggested by the ability of the technique to differentiate the active from the chronic stage of NSLE (Bosma et al.2000b),as well as by the observed, significant association between volumetric MT MRI data and NSLE patients’ clinical status (Bosma et al. 2002). As regards the application of MT MRI to the diagnostic work-up of SID patients with CNS disturbances, Bosma et al. (2000a) found nearly no overlap between the individual MTR histogram peak height values of NSLE patients and those of either SLE patients or healthy controls, yielding a 95% specificity in the diagnostic classification of subjects with a cut-off value of 96.8. When the multiparametric model proposed by Rovaris et al. (2000b) was used to classify patients with MRI-visible white matter abnormalities as MS or SID other than NSLE,

60% of patients with MS and 91% of those with SID were correctly classified. More recently (Rovaris et al. 2002), the value of brain MTR histogram-derived findings for the differential diagnosis between MS and SID other than NSLE in individual cases has been investigated. Only one SLE of 44 SID patients had an average brain MTR one standard deviation below the control group mean value, whereas this was the case for 33 of 64 MS patients (52%); the combined evaluation of cervical cord MRI and brain MT MRI findings made it possible to correctly classify as MS or SID all but one patient, supporting a more extensive use of these two techniques to differentiate between MS and SID when non-specific MRI abnormalities of brain white matter are detected. That MT MRI might serve as a diagnostic tool in the work-up of SLE patients has also been indicated by the preliminary results obtained by Dehmeshki et al. (2002), using a multivariate discriminant analysis approach.

23.4 Di usion-Weighted 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 one third of its trace, and some other dimensionless

indexes of anisotropy, such as fractional anisotropy (FA) (Basser and Pierpaoli 1996). Inflammation and demyelination have the potential to alter the permeability or geometry of structural barriers to water molecular diffusion in the brain white matter, thus leading to DW MRI-detectable changes. Recently, a preliminary, post mortem high field MRI study of the spinal cord of patients with MS (Mottershead et al. 2003) reported that myelin content and axonal density of the specimens correlated strongly with diffusion anisotropy, but only weakly with ADC values.

Available DW MRI studies of SLE patients (Moritani et al. 2001; Bosma et al. 2003; Jennings et al. 2003) reveal that areas with decreased ADC values, corresponding to T2-visible white matter lesions, can be seen in 10%–20% of patients (Moritani et al. 2001; Jennings et al. 2003), suggesting the presence of acute or subacute ischemic damage. Less frequently, ADC values can be increased within T2-isointense or slightly T2-hyperintense lesions (Moritani et al. 2001), indicating the presence of vasogenic edema or demyelination. Bosma et al. (2003), using a histogram analysis technique, found that the average ADC values in the brain of 11 NSLE patients were significantly higher than those of age-matched healthy controls, even though the visual inspection of DW images did not reveal other abnormalities than those visible on the corresponding T2-weighted MRI scans, i.e. subtle white matter hyperintensities, in about 50% of these patients. These data are consistent with those obtained using MT MRI (Rovaris et al. 2000b; Bosma et al. 2000a, b), indicating the presence of diffuse, structural brain damage. On the contrary, DW MRI studies of NBD (Hiwatashi et al. 2003; Kunimatsu et al. 2003) show that both acute and chronic white matter lesions have higher ADC values than the NABT areas, confirming the primarily inflammatory pathogenesis of white matter damage in this condition.

23.5

Magnetic Resonance Spectroscopy

MRS can complement conventional MRI in the assessment of patients with CNS disorders, by defining several chemical correlates of the pathological changes occurring within and outside T2-visible lesions (De Stefano and Federico 2001). Proton MRS of the brain at long echo times reveals major resonances from tetramethylamines [mainly from choline-containing phospholipids (Cho)], from cre-

atine and phosphocreatine (Cr) and from N-acetyl groups [mainly N-acetyl-aspartate (NAA)]. Reduced N-acetyl aspartate (NAA) levels are associated with axonal dysfunction, while increased Cho, inositol and lactate concentrations are correlated with membrane turnover, possibly secondary to inflammation and demyelination (De Stefano and Federico 2001).

Partially conflicting results have been achieved by MRS studies of patients with SLE and CNS involvement (Davie et al. 1995; Chinn et al. 1997; Sibbitt et al. 1997; Sabet et al. 1998; Friedman et al. 1998; Lim et al. 2000; Handa et al. 2003). Sibbitt et al. (1997) found that lower NAA/Cr and higher lipid levels in the NAWM of patients with major symptoms of NSLE than in patients without or with minor CNS disturbances. Increased lipid levels were not associated with the presence of T2-visible white matter lesions. These findings have been confirmed by more recent studies (Lim et al. 2000; Handa et al. 2003). Other authors (Davie et al. 1995), however, failed to demonstrate significant correlations between MRS-derived measures and presence or severity of neuropsychiatric symptoms. In the latter study (Davie et al. 1995), the pattern of MSR abnormalities did not allow differentiation of SLE lesions from MS plaques. Sabet et al. (1998) investigated the MRS patterns of SLE patients with or without secondary APS. They found that the burden of T2-weighted MRI abnormalities and the severity of brain atrophy were significantly higher in SLE patients with APS than in those without. In addition, in SLE patients with APS, NAA/Cr levels were significantly decreased and Cho/Cr levels increased when compared to normal controls and patients without APS. These changes were present both within MRI-visible white matter lesions and in the NAWM. Interestingly, the results of a linear regression analysis showed that reduced NAA/Cr was more closely related to increased levels of IgG antiphospholipid antibodies (aPL) than the presence of APS. These data suggest that the presence of aPL indicates an increased risk for brain injury in SLE patients, independently of the development of concomitant APS. The presence of brain abnormalities at a microscopic level might be a consequence of direct, immune-me- diated tissue damage secondary to SLE more than the result of diffuse ischemic injury due to APS. However, these findings may also be consistent with a direct interaction between IgG aPL and brain cells, leading to progressive tissue damage in SLE patients with aPL positivity, even when the clinical features of APS are absent. On the other hand, Friedman et al. (1998), in an MRI/MRS study of 42 patients with SLE, reported a significant association between small, focal white

matter lesions and decreased NAA/Cr ratios, as well as between increased Cho/Cr ratios and cerebral infarctions, concluding that cerebrovascular abnormalities may be the basis of diffuse cerebral damage in NSLE, with small vessel injury as the major factor responsible for white matter axonal loss. Recently, an MRS study (Cellerini et al. 2003) of 17 BD patients has found that NAA/Cr and Cho/Cr levels in the NAWM do not differ between patients and agematched healthy controls, nor between patients with and those without CNS disturbances. MR spectra from contrast-enhancing white matter lesions were also obtained in two cases, both in the acute phase and at follow-up, showing a normalization of NAA/ Cr and Cho/Cr values after steroid therapy.

23.6 Conclusions

Conventional MRI can demonstrate the presence of white matter focal damage in the brain of patients with SID, but the observed patterns of T2-visible lesions have a limited diagnostic specificity, as well as a modest correlation with the clinical manifestations of CNS dysfunction related to these disorders. Available data underpin the need for developing standardized criteria for diagnostic image interpretation in the work-up of patients with SID, similar to what has been done for MS, with particular emphasis on cases at the onset of the neurological disturbances. The integration of brain scanning with imaging of the spinal cord might reasonably improve the diagnostic value of conventional MRI findings when a differential diagnosis between MS and SID has to be made.

Quantitative MR-based techniques seem to be able to contribute both to the in vivo investigation of white matter pathology in SID and to the diagnostic workup of individual patients. The results of MT MRI, DW MRI and MRS studies of NSLE were all consistent with the presence of clinically relevant NAWM damage in this condition, whereas this does not seem to be the case for other SID. The pathogenesis of NAWM damage in NSLE might be secondary to both smallvessel ischemic injury and immune-mediated brain tissue disruption. The few available data obtained in patients with BD seem to indicate that the pathobiology of white matter damage in this condition is primarily inflammatory-based and limited to T2-visible abnormalities. Further multiparametric and longitudinal studies will probably allow us to better define the role of quantitative MR-based techniques for

helping in the diagnostic work-up of SID, investigating the natural course of these diseases and, ideally, providing surrogate markers of disease evolution to monitor treatment efficacy in experimental trials.

References

Akman-Demir G, Serdaroglu P, Tasçi B and the Neuro-Behçet Study Group (1999) Clinical patterns of neurological involvement in Behçet’s disease: evaluation of 200 patients. Brain 122:2171–2181

Barkhof F, Filippi M, Miller DH et al (1997) Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 120:2059–2069

Basser PJ, Pierpaoli C (1996) Microstructural features measured using diffusion tensor imaging. J Magn Reson B 111:209–219

Basser PJ, Mattiello J, Le Bihan D (1994) Estimation of the effective self-diffusion tensor from the NMR spin-echo. J Magn Reson B 103:247–254

Bell CL, Partington C, Robbins M et al (1991) Magnetic resonance imaging of central nervous system lesions in patients with lupus erythematosus. Correlation with clinical remission and antineurofilament and anticardiolipin antibody titers. Arthritis Rheum 34:432–441

Bosma GPT, Rood MJ, Zwinderman AH et al (2000a) Evidence of central nervous system damage in patients with neuropsychiatric systemic lupus erythematosus, demonstrated by magnetization transfer imaging. Arthr Reum 43:48–54 Bosma GPT, Rood MJ, Huizinga TWJ et al (2000b) Detection of cerebral involvement in patients with active neuropsychiatric systemic lupus erythematosus by the use of volumetric magnetization transfer imaging. Arthr Reum 43:428–2436 Bosma GPT, Middelkoop HAM, Rood MJ et al (2002) Association of global brain damage and clinical functioning in neuropsychiatric systemic lupus erythematosus. Arthr

Reum 46:2665–2672

Bosma GPT, Huizinga TWJ, Mooijaart SP et al (2003) Abnormal brain diffusivity in patients with neuropsychiatric systemic lupus erythematosus. AJNR Am J Neuroradiol 24:850–854

Bot JCJ, Barkhof F, Lycklama à Nijeholt G et al (2002) Differentiation of multiple sclerosis from other inflammatory disorders and cerebrovascular disease: value of spinal MR imaging. Radiology 223:46–56

Boumpas DT, Patronas NJ, Dalakas MC et al (1990) Acute transverse myelitis in systemic lupus erythematosus: magnetic resonance imaging and review of the literature. J Rheumatol 17:89–92

Brochet B, Dousset V (1999) Pathological correlates of magnetization transfer imaging abnormalities in animal models and humans with multiple sclerosis. Neurology 53 [Suppl 3]:S12–S17

Calabrese LH, Duna GF, Lie T (1997) Vasculitis in the central nervous system. Arthritis Rheum 40:1189–1201

Campi A, Filippi M, Gerevini S et al (1996) Multiple white matter lesions of the brain. Magnetization transfer ratios in systemic lupus erythematosus and multiple sclerosis. Int J Neuroradiol 2:134–140

White Matter Pathology in Systemic Immune-Mediated Diseases

Cellerini M, Bartolucci M, Mortilla M et al (2003) MR imaging and proton MR spectroscopy of the brain in Behçet’s disease. Rivista di Neuroradiologia 16:267–274

Chinn RJS, Wilkinson ID, Hall-Craggs MA et al (1997) Magnetic resonance imaging of the brain and cerebral proton spectroscopy in patients with systemic lupus erythematosus. Arthritis Rheum 40:36–46

Coban O, Bahar S, Akman-Demir G et al (1996) A controlled study of reliability and validity of MRI findings in neuroBehçet disease. Neuroradiology 38:312–316

Csépàny T, Bereczki D, Kollar J et al (2003) MRI findings in central nervous system systemic lupus erythematosus are associated with immunoserological parameters and hypertension. J Neurol 250:1348–1354

Davie CA, Fenstein A, Kartsounis LD et al (1995) Proton magnetic resonance spectroscopy of systemic lupus erythematosus involving the central nervous system. J Neurol 242:522–528

Dehmeshki J, van Buchem MA, Bosma GPT et al (2002) Systemic lupus erythematosus: diagnostic application of magnetization transfer ratio histograms in patients with neuropsychiatric symptoms – initial results. Radiology 222:722–728

Deodhar AA, Hochenedel T, Bennett RM (1999) Longitudinal involvement of the spinal cord in a patient with lupus related transverse myelitis. J Rheumatol 26:446–449

De Stefano N Federico A (2001) Overview of magnetic resonance spectroscopy studies in white matter diseases other than multiple sclerosis. In: Filippi M, Arnold DL, Comi G (eds) Magnetic resonance spectroscopy in multiple sclerosis. Springer, Milan, pp 121-133

Fazekas F, Barkhof F, Filippi M et al (1999) The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis. Neurology 53:448–456

Fieschi C, Rasura M, Anzini A et al (1998) Central nervous system vasculitis. J Neurol Sci 153:159–171

Friedman SD, Stidley CA, Brooks WM et al (1998) Brain injury and neurometabolic abnormalities in systemic lupus erythematosus. Radiology 209:79–84

Gerber S, Biondi A, Dormont D et al (1996) Long-term MR follow-up of cerebral lesions in neuro-Behçet disease. Neuroradiology 38:761–768

Gumà A, Aguileira C, Acebes J et al (1998) Meningeal involvement in Behçet disease: MRI. Neuroradiology 40:512–515 Hachulla E, Michon Pasturel U, Leys D et al (1998) Cerebral magnetic resonance imaging in patients with or without

antiphospholipid antibodies. Lupus 7:124–131

Handa R, Sahota P, Kumar M et al (2003) In vivo proton magnetic resonance spectroscopy (MRS) and single photon emission computerized tomography (SPECT) in systemic lupus erythematosus (SLE). Magn Reson Imaging 21:1033– 1037

Hiwatashi A, Garber T, Moritani T et al (2003) Diffusionweighted MR imaging of neuro-Behçet’s disease: case report. Neuroradiology 45:468–471

Ijdo JW, Conti-Kelly AM, Greco P et al (1999) Anti-phospho- lipid antibodies in patients with multiple sclerosis and MSlike illnesses: MS or APS? Lupus 8:109–115

Jennings JE, Sundgren PC, Attwood J et al (2004) Value of MRI of the brain in patients with systemic lupus erythematosus and neurologic disturbance. Neuroradiology 461:15–21

Karussis D, Leker RR, Ashkenazi A et al (1998) A subgroup of multiple sclerosis patients with anticardiolipin antibodies

351

and unusual clinical manifestations: do they represent a new nosological entity? Ann Neurol 44:629–634

Kozora E, West SG, Kotzin BL et al (1998) Magnetic resonance imaging abnormalities and cognitive deficits in systemic lupus erythematosus patients without overt central nervous system disease. Arthritis Rheum 41:41–47

Kunimatsu A, Abe O, Aoki S et al (2003) Neuro-Behçet’s disease: analysis of apparent diffusion coefficients. Neuroradiology 45:524–527

Le Bihan D, Breton E, Lallemand D et al (1986) MR imaging of intravoxel incoherent motions: application to diffusion and perfusion in neurologic disorders. Radiology 161:401–407 Le Bihan D, Turner R, Pekar J et al (1991) Diffusion and perfusion imaging by gradient sensitization: design, strategy and

significance. J Magn Reson Imaging 1:7–8

Lee SH, Yoon PH, Park SJ et al (2001) MRI findings in neuroBehçet’s disease. Clin Radiol 56:485–494

Liem MD, Gzesh DJ, Flanders AE (1996) MRI and angiographic diagnosis of lupus cerebral vasculitis. Neuroradiology 38:134–136

Lim K, Suh CH, Kim HJ et al (2000) Systemic lupus erythematosus: brain MR imaging and single-voxel hydrogen 1 MR spectroscopy. Radiology 217:43–49

Lycklama à Nijeholt GJ, van Walderveen MAA, Castelijns JA et al (1998) Brain and spinal cord abnormalities in multiple sclerosis. Correlation between MRI parameters, clinical subtypes and symptoms. Brain 121:687–697

Mascalchi M, Cosottini M, Cellerini M et al (1998) MRI of spinal cord involvement in Behçet disease: case report. Neuroradiology 40:255–257

Mattioli F, Capra R, Rovaris M et al (2002) Frequency and patterns of subclinical cognitive impairment in patients with ANCA-associated small vessel vasculitides. J Neurol Sci 195:161–166

Maubon AJ, Pothin A, Ferru JM et al (1998) Unselected brain 0.5 T MR imaging: comparison of lesion detection and characterization with three T2-weighted sequences. Radiology 208:671–678

Miller DH, Ormerod IEC, Gibson A et al (1987) MR brain scanning in patients with vasculitis: differentiation from multiple sclerosis. Neuroradiology 29:226–231

Miller DH, Grossman RI, Reingold SC et al (1998) The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain 121:3–24

Miller DH, Thompson AJ, Filippi M (2003) Magnetic resonance studies of abnormalities in the normal appearing white matter and grey matter in multiple sclerosis. J Neurol 250:1407–1419

Mok CC,Lau CS,Chan EY et al (1998) Acute transverse myelopathy in systemic lupus erythematosus: clinical presentation, treatment and outcome. J Rheumatol 25:467–473

Moritani T, Shrier DA, Nugamuchi Y et al (2001) Diffusionweighted echo-planar MR imaging of CNS involvement in systemic lupus erythematosus. Acad Radiol 8:741–753

Morrissey SP, Miller DH, Hermaszawski R et al (1993) Magnetic resonance imaging in the central nervous system in Behçet’s disease. Eur Neurol 33:287–293

Mottershead JP, Schmierer K, Clemence M et al (2003) High field MRI correlates of myelin content and axonal density in multiple sclerosis. A post-mortem study of the spinal cord. J Neurol 250:1293–1301

Nadeau SE (1997) Diagnostic approach to central and peripheral nervous system vasculitis. Neurol Clin 15:759–777

352

Provenzale JM, Allen NB (1996) Wegener granulomatosis: CT and MR findings. AJNR Am J Neuroradiol 17:785–792 Provenzale JM, Barboriak DP, Gaensler EH et al (1994) Lupus-

related myelitis: serial MR findings. AJNR Am J Neuroradiol 15:1911–1917

Rovaris M, Filippi M (2003) Magnetization transfer imaging. In: Filippi M., Comi G (eds) New frontiers of MR-based techniques in multiple sclerosis. Springer, Milan, p 19

Rocca MA, Mastronardo G, Horsfield MA et al (1999) Comparison of three MR sequences for the detection of cervical cord lesions in multiple sclerosis. AJNR Am J Neuroradiol 20:1710–1716

Rovaris M, Inglese M, Viti B et al (2000a) The contribution of fast-FLAIR MRI for lesion detection in the brain of patients with systemic autoimmune diseases. J Neurol 247:29–33

Rovaris M, Viti B, Ciboddo G et al (2000b) Brain involvement in systemic immune-mediated diseases: magnetic resonance and magnetisation transfer imaging study. J Neurol Neurosurg Psychiatry 68:170–177

Rovaris M, Viti B, Ciboddo G et al (2000c) Cervical cord magnetic resonance imaging in systemic immune-mediated diseases. J Neurol Sci 176:128–130

Rovaris M, Holtmannspotter M, Rocca MA et al (2002) Contribution of cervical cord MRI and brain magnetization transfer imaging to the assessment of individual patients with multiple sclerosis: a preliminary study. Mult Scler 8:52–58

Sabet A, Sibbitt WL Jr, Stidley CA, Danska J, Brooks WM (1998) Neurometabolite markers of cerebral injury in the antiphospholipid antibody syndrome of systemic lupus erythematosus. Stroke 29:2254–2260

Sailer M, Burchert W, Ehrenheim C et al (1997) Positron emission tomography and magnetic resonance imaging

M. Rovaris and M. Filippi

for cerebral involvement in patients with systemic lupus erythematosus. J Neurol 244:186–193

Salmaggi A, Lamperti E, Eoli M et al (1994) Spinal cord involvement and systemic lupus erythematosus: clinical and magnetic resonance findings in 5 patients. Clin Exp Rheumatol 12:389–394

Sibbit WL, Haseler LJ, Griffey RR et al (1997) Neurometabolism of active neuropsychiatric lupus determined with proton MR Spectroscopy. AJNR Am J Neuroradiol 18:1271–1277

Triulzi F, Scotti G (1998) Differential diagnosis of multiple sclerosis: contribution of magnetic resonance techniques. J Neurol Neurosurg Psychiatry 64 [Suppl 1]:S6–S14

Trysberg E, Nylen K, Rosengren LE et al (2003) Neuronal and astrocytic damage in systemic lupus erythematosus patients with central nervous system involvement. Arthr Reum 48:2710–2712

van Buchem MA, McGowan JC, Kolson DL et al (1996) Quantitative volumetric magnetization transfer analysis in multiple sclerosis: estimation of macroscopic and microscopic disease burden. Magn Reson Med 36:632–636

Waterloo K, Omdal R, Sjoholm H et al (2001) Neuropsychological dysfunction in systemic lupus erythematosus is not associated with changes in cerebral blood flow. J Neurol 248:595–602

Weingarten K, Filippi C, Barbut D et al (1997) The neuroimaging features of the cardiolipin antibody syndrome. Clin Imaging 21:6–12

West SG, Emlen W, Wener MH et al (1995) Neuropsychiatric lupus erythematosus: a 10-year prospective study on the value of diagnostic tests. Am J Med 99:153–163

Yoshioka H, Matsubara T, Miyanomae Y et al (1996) Spinal cord MRI in neuro-Behçet disease. Neuroradiology 38:661–662

CONTENTS

24.1Introduction 355

24.2Macrostructural Changes 355

24.2.1Volume Changes 355

24.2.2 White Matter Hyperintensities 356

24.3Microstructural Changes 359 References 360

24.1 Introduction

Defining what is normal and abnormal in the aging brain is a problematic task, and defining normality and abnormality of the changes that the white matter is subject to is even more. Age-associated brain changes develop over a continuum and become symptomatic (for example with the development of memory disturbances) only after a given threshold is overcome, such that sub-threshold changes may be regarded as normal and above-threshold changes as abnormal while they actually are only different severity stages of the same pathophysiological process. To complicate things further, the symptomatic threshold of one type of age-associated lesions (say subcortical microvascular disease) is modulated by the presence and severity of lesions with a different pathophysiology (senile plaques and neurofibrillary tangles) that may also become symptomatic with a threshold effect. These are the main reasons why the clinical effect of age-associated white matter changes has been hotly debated in the last 20 years and the issue is still only partly resolved.

G. B. Frisoni, MD and Neurologist

Head, LENITEM - Laboratory of Epidemiology Neuroimaging & Telemedicine, IRCCS San Giovanni di Dio FBF - The National Center for Research and Care of Alzheimer Disease, Via Pilastroni 4, 25125 Brescia, Italy

24.2

Macrostructural Changes

24.2.1

Volume Changes

The volume of the white matter – relative to the intracranial volume – increases until middle age and decreases afterwards (Hildebrand et al., 1993). Guttmann et al. (1998) have measured white matter volume in 72 healthy volunteers aged between 18 and 81 years and found that the volume remained stable until around age 50, to decrease significantly afterwards: beginning at age 60, the proportion of persons with white matter volumes below 2 SD below the mean for 20-year-old subjects increased progressively and at age 80 none had volumes above such value (Guttmann et al., 1998). These findings have been confirmed by another MR-based structural study on the frontal lobe of 70 healthy men aged 19 to 76 years showing that white matter volume increased until age 44 years for the frontal lobes and age 47 years for the temporal lobes and then declined (Bartzokis et al., 2001). Based on personal data on 229 healthy subjects (71 men and 158 women) of 40 years of age and older, we have found a quadratic relationship of age with white matter volume with decrease starting around age 50 with no right-left difference. The relationship was quadratic in men and women, but white matter loss was more accentuated in men (Riello et al., 2005) (Fig. 24.1).

Other studies have suggested differential aging of the white matter in men and women. Murphy et al. (1996) have found that the effect of aging on the brain in men affects more the frontal and temporal lobes, and in women the parietal lobes and the hippocampus. This makes sense in view of the higher frequency of Alzheimer disease (affecting primarily the hippocampus) in women and of white matter disease such as subcortical vascular dementia (affecting mainly the frontal lobes) in men. Dubb et al. (2003) have carried out a sophisticated voxel based analysis of the callosum and found that the anterior part

of the callosum (the splenium) contracts with age in men more than in women. The greater white matter loss in men might be related to vascular diseases and vascular risk factors, that are known to be more prevalent in men. The hypothesis is supported by observations indicating that hypertension is associated with smaller brain volumes (Heijer et al., 2003; Goldstein et al., 2002).

A few studies have failed to find age-related white matter loss but all included few subjects above age 40 (Good et al., 2001; Gur et al.,1999).

The above findings on volumetric changes of the white matter are at odds with shrinkage of the gray matter, that starts much earlier, around age 20, suggesting that the neurobiological bases of the changes might be different.

Recently, a few studies have been carried out with prospective MR imaging showing brain tissue loss in cognitively normal persons with aging (Resnick et al., 2003; Scahill et al., 2003; Tang et al., 2001). Few studies have disaggregated the effect of aging on the gray and white matter. Resnick and colleagues have quantified the scans of 92 non demented older adults between 59 and 85 years of age using scans taken at baseline and after 2 and 4 years (Resnick et al., 2003). They found widespread white matter loss in the frontal, parietal, temporal, and occipital lobes between –0.43 and –0.58% per year in the subgroup of 24 healthy persons,while loss in those 68 with some medical problems was about 40% greater. Notably, gray matter loss had a more regional effect (greater loss in the parietal lobes) and was more affected by medical problems (about 100% greater in those with medical problems).

24.2.2

White Matter Hyperintensities

24.2.2.1

Morphologic Features

WMHs can be grouped according to morphologic features into smooth caps or halo, punctate, and confluent. The smooth caps and halo are located in the periventricular white matter adjacent to the ependimal layer. Caps are usually less than 10 mm thick, and the halo tends to be progressively thinner from anterior to posterior (Fig. 24.2).

Punctate and confluent lesions can be located in the periventricular or deep white matter (Fig. 24.2). Punctate hyperintensities are small (diameter less than 5 mm), round, with a regular boundary, and tend to be multiple in the same patient. Confluent lesions are larger than punctate (usually >5 mm), have irregular shape and boundaries, and seem to be originated by the confluence of smaller lesions.When periventricular,confluent lesions tend to be separated by the ventricles or the smooth periventricular halo by a more or less thin region of apparently normal white matter.

24.2.2.2 Pathophysiology

The periventricular caps or halo – which strictly speaking should not be called “lesions” – are symmetrical and can outline the ventricles more or less completely. A number of studies have shown that these hyperintensities develop as a consequence of

local non vascular conditions including the loose network of myelinated fibers,the convergence of the flow of interstitial water to this area with large veins, and the frequently observed disruption of the ependymal layer (ependymitis granularis) (Fazekas et al., 1998a; Sze et al., 1986) (Table 24.1). Histopathological findings are disruption of the ependymal lining

– which might lead to accumulation of CSF in the periventricular white matter – with a thin rim of subependymal gliosis and a wider, smooth band of white matter tissue with reduced staining for myelin around the lateral ventricles (Fazekas et al., 1998a; Sze et al., 1986) (Table 24.1). Notably, vascular arteriolar changes are absent (Fazekas et al., 1993). These hyperintensities have the same pathological substrate in cognitively normal persons and in patients with Alzheimer disease (Scheltens et al., 1995). In Alzheimer disease an additional pathogenetic mechanism might be the looser arrangement of fibers following cerebral atrophy (Fazekas et al., 1998a), as

supported by the observation of a significant correlation between ventricular enlargement and the thickness of periventricular hyperintensity (Fazekas et al., 1996) (Table 24.1). The reported demyelination of the smooth caps and halo (Sze et al., 1986) might be due to chronic oedema, which has been shown to cause demyelination (Feigin & Popoff, 1963).

Punctate hyperintensities can be associated with variable histopathologic correlates (Fazekas et al., 1998b), but most studies argue for perivascular tissue changes as the prevailing morphologic substrate (Fazekas et al., 1998a) (Table 24.1). Pathophysiological mechanisms include impaired diffusion of nutritional compounds through thickened vessel walls (Kirkpatrick & Hayman, 1987; van Swieten et al., 1991), mechanic damage to the surrounding tissue by a water hammer effect of pulsating arterioles (Awad et al., 1986) or both. Interestingly – and in agreement with epidemiological studies showing