The Neuroradiology Journal 21: 228-235, 2008
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Metabolite Changes in Normal Appearing Cervical Spinal Cord in Two Patients with Multiple Sclerosis. A Proton MR Spectroscopic Analysis M. MAFFEI, A.F. MARLIANI, F. SALVI**, V. CLEMENTI*, R. AGATI, M. LEONARDI Neuroradiology and ** Neurology Department, Bellaria Hospital; Bologna, Italy *GE Healthcare Technologies, Italy
Key words: spinal cord, proton magnetic resonance spectroscopy, metabolite quantification, 3 Tesla, multiple sclerosis
SUMMARY – We describe two cases of multiple sclerosis (MS) analyzed with Proton MR Spectroscopy (1H-MRS) with the voxel placed along the main axis of the normal appearing cervical spinal cord over three main space planes, orthogonally set. Relative concentrations expressed by the absolute concentration ratios of total NAA (tNAA), choline (Cho), myo-inositol (mI) and creatine plus phosphocreatine (Cr) were compared with the metabolites of ten healthy volunteers. We found a significant increase in mI/Cr and a small increase in Cho/Cr in the first patient, whereas the second patient had a decrease in NAA/Cr and NAA/Cho ratios. 1H-MRS will disclose biochemical changes in MS, even in normal appearing spinal cord, as already described in normal appearing cerebral tissue: these biochemical changes may provide significant information on disease prognosis.
Introduction Non-conventional MRI techniques, including magnetization transfer MRI, diffusion tensor MRI, and proton MR spectroscopy have been applied to improve our understanding of the pathophysiology of MS. These techniques may provide information on the structural and biochemical changes occurring within and outside macroscopic MS lesions (inflammation, demyelinazation, axonal loss), namely in the normal-appearing white and grey matter 19. Proton MR spectroscopy (1H-MRS) is currently considered a useful technique for evaluating axonal damage and demyelization in multiple sclerosis (MS) on the brain 1-12. However, only one spectroscopic cervical MS study has been published because of the technical difficulties 13. Recently our group published a protocol for quantitative single voxel cervical spinal cord spectroscopy with the first mean relative concentrations ratios for NAA, Cr, Cho and mI in a group of ten healthy volunteers using a clini228
cal 3T system 14. The present study applied the same acquisition and post-processing protocol to study metabolite changes on the normal appearing cervical spinal cord in two patients with MS. Patient History Case 1: A 72-year-old woman with secondary progressive MS (SPMS) with delayed onset (six years ago). The spinal cord MR study, conducted at that time, showed a first demyelinating lesion in C4 and a second one in C7-D1, not modified by gadolinium administration, whereas brain MR failed to disclose any lesions. Follow-up MR, conducted six years later at the onset of dorsal cervical pain, confirmed the C7-D1 lesion, but did not clearly display the C4 lesion (figures 1 and 2). Case 2: A 25-year-old woman with relapsing remitting MS (RRMS), with sudden onset diplopia which resolved without therapy after
M. Maffei
Metabolite Changes in Normal Appearing Cervical Spinal Cord in Two Patients with Multiple Sclerosis
Figure 1 A,B) Case 1: sagittal FSE T2-w fat sat: note the demyelinating lesion in C7-D1.
ten days. Two years later, three months ago, the patient showed an episode of retrobulbar neuritis, followed by facial nerve palsy. Brain MR showed multiple demyelinating lesions some of which were contrast enhancing
at supratentorial level and in the left middle cerebellar peduncle, an evident sign of disease activity (figure 3). Cervical spine MR failed to display any spinal signal changes (figure 4). 229
Metabolite Changes in Normal Appearing Cervical Spinal Cord in Two Patients with Multiple Sclerosis
M. Maffei
Methods Both patients underwent cervical spine MR examination including sagittal and coronal fast spin-echo T2-weighted, axial gradient T2*weighted, orthogonally set images. 1H-MRS VOI (approximately 8×9×29 mm in case 1 and 6×11×36 mm in case 2 ) was prescribed along the main axis of the cord between the C2-C3 levels where the spinal cord showed no signal changes, using a 3T whole-body system (SIGNA EXCITE 3T GE Medical Systems, Milwaukee,WI, USA) equipped with a standard eight channel phased array spinal coil. PRESS (TR 2000 ms and TE 35 ms) and CHESS (to provide water suppression) sequences were used with six saturation bands next to the VOI to minimize fat contamination. 400 repetitions and 16 additional acquisi-
Figure 2 A) Case 1: axial GRE T2-w: the demyelinating lesion is clearly displayed in the left part of the spinal cord.
Table 1
tNAA/Cr
tNNA/Cho
Cho/Cr
mI/Cr
Case 1
1.50
2.4
0.63
3.47
Case 2
0.96
2.2
0.43
1.57
Healthy Cervical Spinal Cord Mean +/- SD
1.4+/–0.3
3.2 +/–0.9
0.45 +/–0.04
1.6 +/–0.2
CV (%)
23
27
9
13
tions with unsuppressed water were collected, obtaining a total spectrum acquisition time of approximately 14 minutes (figure 5 A,B). MRS data were analyzed by the user-independent fitting routine LC Model 15. Relative concentrations expressed by the absolute concentration ratios of total NAA (tNAA), choline (Cho), myoinositol (mI) and creatine plus phosphocreatine (Cr) were calculated. The main metabolite ratios were compared with the healthy metabolites content previously published (same protocol, ten healthy volunteers, mean age 35±12 years) 14. The patients provided informed written consent. Results Case 1 (SPMS): Calculation of the relative concentrations of the main metabolites showed a significant increase in myo-inositol and a slight increase in choline (figure 6A). Case 2 (RRMS): A decrease of tNAA was 230
noted in the normal appearing cervical spine during brain activity (figure 6B). All the findings are summarized in table 1. Discussion Proton MR spectroscopy ((1)H-MR spectroscopy) is a well-established method for the in vivo investigation of normal-appearing white matter (NAWM) in patients with multiple sclerosis. In recent years, many studies have reported metabolite changes in normal appearing cerebral tissue in patients with different types of MS. Vrenken reported results in a group of 76 patients with different types of MS (primary progressive, relapsing-remitting, and secondary progressive). The concentration ratio of total N-acetyl-aspartate (tNAA)/total creatine (tCr) was decreased in the normal appearing white matter (NAWM) of all patients compared to controls. Remarkably, this was entirely due
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The Neuroradiology Journal 21: 228-235, 2008
A
B
C
D
Figure 3 A-C) Case 2: axial FSE T2-w: several small hyperintense demyelinating lesions can be seen in the left middle cerebellar peduncle and the semiovale centres. D) FSE T1-w after gadolinium injection showing pathological enhancement of one of the demyelinating lesions.
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Metabolite Changes in Normal Appearing Cervical Spinal Cord in Two Patients with Multiple Sclerosis
Figure 4 A) Case 2: sagittal FSE T2-w: the cervical spinal cord shows no signal changes.
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M. Maffei
to an increase in tCr in MS patients, whereas there was no difference in tNAA. Separate quantification of the two tNAA components yielded no significant difference in NAA (Nacetyl-aspartate), whereas the concentration of normal appearing grey matter (NAAG) Nacetyl-aspartyl-glutamate was slightly but significantly elevated in MS patients. Myo-inositol (Ins) was strongly increased in MS patients, and choline-containing compounds (Cho) were mildly increased. There were no metabolite differences between disease types, and no correlations with disability scores 10. Gustafsson found a lower total concentration of N-acetyl compounds (tNAA), including N-acetylaspartate and N-acetyl aspartylglutamate, in 14 patients with clinically definite MS and normal MR imaging of the brain compared with the healthy control subjects. Unexpectedly, patients with MS presented significantly lower cholinecontaining compounds (Cho) compared with healthy control subjects, and this finding has not been reported previously 20. Tiberio, analysing 20 RRMS subjects for two years, observed that at baseline the concentration of tNAA was significantly reduced in the NAWM of the MS patients compared to the control group. NAWM tNAA concentrations tended to recover from baseline, but otherwise tissue metabolite profiles did not change significantly in the MS subjects. While neuronal and axonal damage is apparent from the early clinical stages of MS, this study suggests that initially it may be partly reversible 21. On the basis of these results, we also measured the metabolite concentration in normal appearing cervical spine cord of patients with MS. In both cases, we observed metabolic changes in a normal appearing area of cervical spinal cord. Case 1 (SPMS) showed a significant increase in myo-inositol and a slight increase in choline, suggesting gliosis and/or elevated membrane turnover (figure 6A). Case 2 (RRMS) showed a significant decrease of NAA, a marker of neuronal viability and axonal integrity. We are not able to extrapolate a theory from these few results, nor can we compare our results with literature reports. However, the method utilized in this study proved suitable to explore metabolic changes in normal appearing spinal cord. Many more patients and follow up examinations are required to confirm whether the biochemical changes in normal appearing spine are indicative of disease prognosis and to monitor the effects of therapy.
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The Neuroradiology Journal 21: 228-235, 2008
A
Figure 5 Localization of rectangular 1H-MRS VOI along the main axis of the cord between the C2-C3 levels of case 1 (A) and case 2 (B) see page 234.
References 1 Narayana PA: Magnetic resonance spectroscopy in the monitoring of multiple sclerosis. J Neuroimaging 15: 46S-56S, 2005. 2 Bhakoo KK, Pearce D: In vitro expression of N-acetyl aspartate by oligodendrocytes: Implications for proton magnetic resonance spectroscopy signal in vivo. J Neurochem 74: 254-262, 2000. 3 Jung RE, Yeo RA, Chiulli SJ et Al: Biochemical markers of cognition: a proton MR spectroscopy study of normal human brain. Neuroreport 10: 3327-3331, 1999. 4 Ross BD, Ernst T, Kreis R et Al: 1H MRS in acute traumatic brain injury. J Magn Reson Imaging 8: 829840, 1998. 5 Leary SM, Davie CA, Parker GJ et Al: 1H magnetic
resonance spectroscopy of normal appearing white matter in primary progressive multiple sclerosis. J Neurol 246: 1023-1026, 1999. 6 De Stefano N, Matthews PM, Antel JP et Al: Chemical pathology of acute demyelinating lesions and its correlation with disability. Ann Neurol 38: 901-909, 1995. 7 Arnold DL, Matthews PM, Francis GS et Al: Proton magnetic resonance spectroscopic imaging for metabolic characterization of demyelinating plaques. Ann Neurol 31: 235-241, 1992. 8 Castillo M, Smith JK, Kwock L: Correlation of myo-inositol levels and grading of cerebral astrocytomas. Am J Neuroradiol 21: 1645-1649, 2000.
233
Metabolite Changes in Normal Appearing Cervical Spinal Cord in Two Patients with Multiple Sclerosis
B
A
Figure 6 Spectrum from case 1 (A) and case 2 (B).
234
B
M. Maffei
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9 Saraf-Lavi E, Bowen BC, Pattany PM et Al: Proton MR spectroscopy of gliomatosis cerebri: case report of elevated myoinositol with normal choline levels. Am J Neuroradiol 24: 782-784, 2003. 10 Vrenken H, Barkhof F, Uitdehaag BM et Al: Spectroscopic evidence for glial increase but not for neuro-axonal damage in MS normal-appearing white matter. Magn Reson Med 53: 256-266, 2005. 11 Fernando KT, McLean MA, Chard DT et Al: Elevated white matter myo-inositol in clinically isolated syndromes suggestive of multiple sclerosis. Brain 127: 1361-9, 2004. 12 Bitsch A, Bruhn H, Vougioukas V et Al: Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy. Am J Neuroradiol 20: 1619-27,1999. 13 Kendi ATK, Tan FU, Kendi M et Al: MR spectroscopy of cervical spinal cord in patients with multiple sclerosis. Neuroradiology 46: 764-769, 2004. 14 Marliani AF, Clementi V, Albini Riccioli L et Al: Quantitative proton magnetic resonance spectroscopy of the human cervical spinal cord at 3 Tesla. Magn Reson Med 57: 160-3, 2007. 15 Provencher SW: Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30: 672-679, 1993. 16 Davie CA, Barker GJ, Webb S et Al: Persistent functional deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss. Brain 117: 49-58, 1994. 17 Davie CA, Hawkins CP, Barker GJ et Al: Serial proton magnetic resonance spectroscopy in acute multiple sclerosis lesions. Brain 117: 49-58, 1994. 18 Narayana PA, Doyle TJ, Lai D et Al: Serial proton magnetic resonance spectroscopic imaging, contrastenhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis. Ann Neurol 43: 56-71,1998.
The Neuroradiology Journal 21: 228-235, 2008
19 Pelletier J, Audoin B, Ranjeva JP: Future of non conventional MR techniques in MS. Rev Neurol 163: 6636, 2007. 20 Gustafsson MC, Dahlqvist O, Jaworski J et Al: Low choline concentrations in normal-appearing white matter of patients with multiple sclerosis and normal MR imaging brain scans. Am J Neuroradiol 28: 1306-12, 2007. 21 Tiberio M, Chard DT, Altmann DR et Al: Metabolite changes in early relapsing-remitting multiple sclerosis. A two year follow-up study. J Neurol 253: 224-30, 2006.
M. Maffei, MD Neuroradiology Department Bellaria Hospital Via Altura, 3 40129 Bologna, Italy. E-mail: [email protected]
235
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Metabolite Changes in Normal Appearing Cervical Spinal Cord in Two Patients with Multiple Sclerosis. A Proton MR Spectroscopic Analysis M. MAFFEI, A.F. MARLIANI, F. SALVI**, V. CLEMENTI*, R. AGATI, M. LEONARDI Neuroradiology and ** Neurology Department, Bellaria Hospital; Bologna, Italy *GE Healthcare Technologies, Italy
Key words: spinal cord, proton magnetic resonance spectroscopy, metabolite quantification, 3 Tesla, multiple sclerosis
SUMMARY – We describe two cases of multiple sclerosis (MS) analyzed with Proton MR Spectroscopy (1H-MRS) with the voxel placed along the main axis of the normal appearing cervical spinal cord over three main space planes, orthogonally set. Relative concentrations expressed by the absolute concentration ratios of total NAA (tNAA), choline (Cho), myo-inositol (mI) and creatine plus phosphocreatine (Cr) were compared with the metabolites of ten healthy volunteers. We found a significant increase in mI/Cr and a small increase in Cho/Cr in the first patient, whereas the second patient had a decrease in NAA/Cr and NAA/Cho ratios. 1H-MRS will disclose biochemical changes in MS, even in normal appearing spinal cord, as already described in normal appearing cerebral tissue: these biochemical changes may provide significant information on disease prognosis.
Introduction Non-conventional MRI techniques, including magnetization transfer MRI, diffusion tensor MRI, and proton MR spectroscopy have been applied to improve our understanding of the pathophysiology of MS. These techniques may provide information on the structural and biochemical changes occurring within and outside macroscopic MS lesions (inflammation, demyelinazation, axonal loss), namely in the normal-appearing white and grey matter 19. Proton MR spectroscopy (1H-MRS) is currently considered a useful technique for evaluating axonal damage and demyelization in multiple sclerosis (MS) on the brain 1-12. However, only one spectroscopic cervical MS study has been published because of the technical difficulties 13. Recently our group published a protocol for quantitative single voxel cervical spinal cord spectroscopy with the first mean relative concentrations ratios for NAA, Cr, Cho and mI in a group of ten healthy volunteers using a clini228
cal 3T system 14. The present study applied the same acquisition and post-processing protocol to study metabolite changes on the normal appearing cervical spinal cord in two patients with MS. Patient History Case 1: A 72-year-old woman with secondary progressive MS (SPMS) with delayed onset (six years ago). The spinal cord MR study, conducted at that time, showed a first demyelinating lesion in C4 and a second one in C7-D1, not modified by gadolinium administration, whereas brain MR failed to disclose any lesions. Follow-up MR, conducted six years later at the onset of dorsal cervical pain, confirmed the C7-D1 lesion, but did not clearly display the C4 lesion (figures 1 and 2). Case 2: A 25-year-old woman with relapsing remitting MS (RRMS), with sudden onset diplopia which resolved without therapy after
M. Maffei
Metabolite Changes in Normal Appearing Cervical Spinal Cord in Two Patients with Multiple Sclerosis
Figure 1 A,B) Case 1: sagittal FSE T2-w fat sat: note the demyelinating lesion in C7-D1.
ten days. Two years later, three months ago, the patient showed an episode of retrobulbar neuritis, followed by facial nerve palsy. Brain MR showed multiple demyelinating lesions some of which were contrast enhancing
at supratentorial level and in the left middle cerebellar peduncle, an evident sign of disease activity (figure 3). Cervical spine MR failed to display any spinal signal changes (figure 4). 229
Metabolite Changes in Normal Appearing Cervical Spinal Cord in Two Patients with Multiple Sclerosis
M. Maffei
Methods Both patients underwent cervical spine MR examination including sagittal and coronal fast spin-echo T2-weighted, axial gradient T2*weighted, orthogonally set images. 1H-MRS VOI (approximately 8×9×29 mm in case 1 and 6×11×36 mm in case 2 ) was prescribed along the main axis of the cord between the C2-C3 levels where the spinal cord showed no signal changes, using a 3T whole-body system (SIGNA EXCITE 3T GE Medical Systems, Milwaukee,WI, USA) equipped with a standard eight channel phased array spinal coil. PRESS (TR 2000 ms and TE 35 ms) and CHESS (to provide water suppression) sequences were used with six saturation bands next to the VOI to minimize fat contamination. 400 repetitions and 16 additional acquisi-
Figure 2 A) Case 1: axial GRE T2-w: the demyelinating lesion is clearly displayed in the left part of the spinal cord.
Table 1
tNAA/Cr
tNNA/Cho
Cho/Cr
mI/Cr
Case 1
1.50
2.4
0.63
3.47
Case 2
0.96
2.2
0.43
1.57
Healthy Cervical Spinal Cord Mean +/- SD
1.4+/–0.3
3.2 +/–0.9
0.45 +/–0.04
1.6 +/–0.2
CV (%)
23
27
9
13
tions with unsuppressed water were collected, obtaining a total spectrum acquisition time of approximately 14 minutes (figure 5 A,B). MRS data were analyzed by the user-independent fitting routine LC Model 15. Relative concentrations expressed by the absolute concentration ratios of total NAA (tNAA), choline (Cho), myoinositol (mI) and creatine plus phosphocreatine (Cr) were calculated. The main metabolite ratios were compared with the healthy metabolites content previously published (same protocol, ten healthy volunteers, mean age 35±12 years) 14. The patients provided informed written consent. Results Case 1 (SPMS): Calculation of the relative concentrations of the main metabolites showed a significant increase in myo-inositol and a slight increase in choline (figure 6A). Case 2 (RRMS): A decrease of tNAA was 230
noted in the normal appearing cervical spine during brain activity (figure 6B). All the findings are summarized in table 1. Discussion Proton MR spectroscopy ((1)H-MR spectroscopy) is a well-established method for the in vivo investigation of normal-appearing white matter (NAWM) in patients with multiple sclerosis. In recent years, many studies have reported metabolite changes in normal appearing cerebral tissue in patients with different types of MS. Vrenken reported results in a group of 76 patients with different types of MS (primary progressive, relapsing-remitting, and secondary progressive). The concentration ratio of total N-acetyl-aspartate (tNAA)/total creatine (tCr) was decreased in the normal appearing white matter (NAWM) of all patients compared to controls. Remarkably, this was entirely due
www. centauro. it
The Neuroradiology Journal 21: 228-235, 2008
A
B
C
D
Figure 3 A-C) Case 2: axial FSE T2-w: several small hyperintense demyelinating lesions can be seen in the left middle cerebellar peduncle and the semiovale centres. D) FSE T1-w after gadolinium injection showing pathological enhancement of one of the demyelinating lesions.
231
Metabolite Changes in Normal Appearing Cervical Spinal Cord in Two Patients with Multiple Sclerosis
Figure 4 A) Case 2: sagittal FSE T2-w: the cervical spinal cord shows no signal changes.
232
M. Maffei
to an increase in tCr in MS patients, whereas there was no difference in tNAA. Separate quantification of the two tNAA components yielded no significant difference in NAA (Nacetyl-aspartate), whereas the concentration of normal appearing grey matter (NAAG) Nacetyl-aspartyl-glutamate was slightly but significantly elevated in MS patients. Myo-inositol (Ins) was strongly increased in MS patients, and choline-containing compounds (Cho) were mildly increased. There were no metabolite differences between disease types, and no correlations with disability scores 10. Gustafsson found a lower total concentration of N-acetyl compounds (tNAA), including N-acetylaspartate and N-acetyl aspartylglutamate, in 14 patients with clinically definite MS and normal MR imaging of the brain compared with the healthy control subjects. Unexpectedly, patients with MS presented significantly lower cholinecontaining compounds (Cho) compared with healthy control subjects, and this finding has not been reported previously 20. Tiberio, analysing 20 RRMS subjects for two years, observed that at baseline the concentration of tNAA was significantly reduced in the NAWM of the MS patients compared to the control group. NAWM tNAA concentrations tended to recover from baseline, but otherwise tissue metabolite profiles did not change significantly in the MS subjects. While neuronal and axonal damage is apparent from the early clinical stages of MS, this study suggests that initially it may be partly reversible 21. On the basis of these results, we also measured the metabolite concentration in normal appearing cervical spine cord of patients with MS. In both cases, we observed metabolic changes in a normal appearing area of cervical spinal cord. Case 1 (SPMS) showed a significant increase in myo-inositol and a slight increase in choline, suggesting gliosis and/or elevated membrane turnover (figure 6A). Case 2 (RRMS) showed a significant decrease of NAA, a marker of neuronal viability and axonal integrity. We are not able to extrapolate a theory from these few results, nor can we compare our results with literature reports. However, the method utilized in this study proved suitable to explore metabolic changes in normal appearing spinal cord. Many more patients and follow up examinations are required to confirm whether the biochemical changes in normal appearing spine are indicative of disease prognosis and to monitor the effects of therapy.
www. centauro. it
The Neuroradiology Journal 21: 228-235, 2008
A
Figure 5 Localization of rectangular 1H-MRS VOI along the main axis of the cord between the C2-C3 levels of case 1 (A) and case 2 (B) see page 234.
References 1 Narayana PA: Magnetic resonance spectroscopy in the monitoring of multiple sclerosis. J Neuroimaging 15: 46S-56S, 2005. 2 Bhakoo KK, Pearce D: In vitro expression of N-acetyl aspartate by oligodendrocytes: Implications for proton magnetic resonance spectroscopy signal in vivo. J Neurochem 74: 254-262, 2000. 3 Jung RE, Yeo RA, Chiulli SJ et Al: Biochemical markers of cognition: a proton MR spectroscopy study of normal human brain. Neuroreport 10: 3327-3331, 1999. 4 Ross BD, Ernst T, Kreis R et Al: 1H MRS in acute traumatic brain injury. J Magn Reson Imaging 8: 829840, 1998. 5 Leary SM, Davie CA, Parker GJ et Al: 1H magnetic
resonance spectroscopy of normal appearing white matter in primary progressive multiple sclerosis. J Neurol 246: 1023-1026, 1999. 6 De Stefano N, Matthews PM, Antel JP et Al: Chemical pathology of acute demyelinating lesions and its correlation with disability. Ann Neurol 38: 901-909, 1995. 7 Arnold DL, Matthews PM, Francis GS et Al: Proton magnetic resonance spectroscopic imaging for metabolic characterization of demyelinating plaques. Ann Neurol 31: 235-241, 1992. 8 Castillo M, Smith JK, Kwock L: Correlation of myo-inositol levels and grading of cerebral astrocytomas. Am J Neuroradiol 21: 1645-1649, 2000.
233
Metabolite Changes in Normal Appearing Cervical Spinal Cord in Two Patients with Multiple Sclerosis
B
A
Figure 6 Spectrum from case 1 (A) and case 2 (B).
234
B
M. Maffei
www. centauro. it
9 Saraf-Lavi E, Bowen BC, Pattany PM et Al: Proton MR spectroscopy of gliomatosis cerebri: case report of elevated myoinositol with normal choline levels. Am J Neuroradiol 24: 782-784, 2003. 10 Vrenken H, Barkhof F, Uitdehaag BM et Al: Spectroscopic evidence for glial increase but not for neuro-axonal damage in MS normal-appearing white matter. Magn Reson Med 53: 256-266, 2005. 11 Fernando KT, McLean MA, Chard DT et Al: Elevated white matter myo-inositol in clinically isolated syndromes suggestive of multiple sclerosis. Brain 127: 1361-9, 2004. 12 Bitsch A, Bruhn H, Vougioukas V et Al: Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy. Am J Neuroradiol 20: 1619-27,1999. 13 Kendi ATK, Tan FU, Kendi M et Al: MR spectroscopy of cervical spinal cord in patients with multiple sclerosis. Neuroradiology 46: 764-769, 2004. 14 Marliani AF, Clementi V, Albini Riccioli L et Al: Quantitative proton magnetic resonance spectroscopy of the human cervical spinal cord at 3 Tesla. Magn Reson Med 57: 160-3, 2007. 15 Provencher SW: Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30: 672-679, 1993. 16 Davie CA, Barker GJ, Webb S et Al: Persistent functional deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss. Brain 117: 49-58, 1994. 17 Davie CA, Hawkins CP, Barker GJ et Al: Serial proton magnetic resonance spectroscopy in acute multiple sclerosis lesions. Brain 117: 49-58, 1994. 18 Narayana PA, Doyle TJ, Lai D et Al: Serial proton magnetic resonance spectroscopic imaging, contrastenhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis. Ann Neurol 43: 56-71,1998.
The Neuroradiology Journal 21: 228-235, 2008
19 Pelletier J, Audoin B, Ranjeva JP: Future of non conventional MR techniques in MS. Rev Neurol 163: 6636, 2007. 20 Gustafsson MC, Dahlqvist O, Jaworski J et Al: Low choline concentrations in normal-appearing white matter of patients with multiple sclerosis and normal MR imaging brain scans. Am J Neuroradiol 28: 1306-12, 2007. 21 Tiberio M, Chard DT, Altmann DR et Al: Metabolite changes in early relapsing-remitting multiple sclerosis. A two year follow-up study. J Neurol 253: 224-30, 2006.
M. Maffei, MD Neuroradiology Department Bellaria Hospital Via Altura, 3 40129 Bologna, Italy. E-mail: [email protected]
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