Imaging Techniques to Evaluate Morphological Correlates of Cognitive Dysfunction in Multiple Sclerosis Patients

Czech version

Authors: I. Obhlídalová ¹; M. Keřkovský2ihash2ihash4 ^{,3 ,3 ,3}
Authors‘ workplace: Neurologická klinika LF MU a FN Brno ¹; Radiologická klinika LF MU a FN Brno ²; CEITEC – Středoevropský technologický institut, MU, Brno ³
Published in: Cesk Slov Neurol N 2012; 75/108(2): 170-178
Category: Review Article

Overview

Cognitive dysfunction in patients with multiple sclerosis is quite common and has a great impact on the quality of patient’s social and professional life. High frequency and severity of these symptoms encourage objectivization of their morphological correlates. Besides the conventional magnetic resonance imaging techniques, commonly used for the disease diagnostics and activity monitoring, alternative procedures, such as magnetization transfer imaging, functional magnetic resonance, MR spectroscopy or diffusion tensor imaging, are also available. The use of the majority of these techniques is currently rather experimental and their practical application is under intensive investigation.

Key words:
multiple sclerosis – cognitive dysfunction – magnetic resonance – magnetization transfer – functional magnetic resonance – diffusion tensor imaging – spectroscopy – positron emission tomography

Sources

1. Havrdová E. Roztroušená skleróza mozkomíšní. In: Havrdová E (ed). Neuroimunologie. 3rd ed. Praha: Maxdorf 2001: 231.

2. Benedict RH. Integrating cognitive function screening and assessment into the routine care of multiple sclerosis patients. CNS Spectr 2005; 10(5): 384–391.

3. Rao SM, Leo GJ, Bernardin L, Unverzang F. Cognitive dysfunction in multiple sclerosis. Frequency, patterns and prediction. Neurology 1991; 41(5): 685–691.

4. Jennekens-Schinkel A, Sanders EA. Decline of cognition in multiple sclerosis: dissociable deficits. J Neurol Neurosurg Psychiatry 1986; 49(12): 1354–1360.

5. Peyser JM, Edwards KR, Poser CM, Filskov SB. Cognitive function in patients with multiple sclerosis. Arch Neurol 1980; 37(9): 577–579.

6. Rao SM. Multiple sclerosis. In: Cummings JL (ed). Subcortical demention. New York: Oxford University Press 1990: 164–180.

7. Feldman RG, Albert ML, Willis AL. The “subcortical dementia” of progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 1974; 37(2): 121–130.

8. Beatty WW. A strategy for studying memory disorders in multiple sclerosis. In: Square RL, Butters N (eds). Neuropsychology of memory. New York: NY Guilford Press 1992: 285–298.

9. Beatty WW, Goodkin DE, Menson N, Beatty PA. Cognitive disturbances in patients with relapsing-remitting multiple sclerosis. Arch Neurol 1989; 46(10): 1113–1119.

10. Rao SM, Leo GJ, Haughton VM, St. Aubin-Faubert P, Bernardin L. Correlation of magnetic resonance imaging with neuropsychological testing in multiple sclerosis. Neurology 1989; 39(2): 161–166.

11. Ron MA, Callanan MM, Warrington EK. Cognitive abnormalitites oïn multiple sclerosis: a psychometric and MTI study. Psychol Med 1991; 21(1): 59–68.

12. Gainotti G. Measures of cognitive and emotional changes in multiple sclerosis and underlying models of brain dysfunction. J Neurol Sci 2006; 245(1–2): 15–20.

13. Vaněčková M, Seidl Z, Krásenský J, Horáková D, Havrdová E, Němcová J et al. Naše zkušenosti s MR monitorováním pacientů s roztroušenou sklerózou v klinické praxi. Cesk Slov Neurol N 2010; 73/106(6): 716–720.

14. Solomon MA. MRI in MS diagnosis. Neurology 1987; 37(9): 1566–1567.

15. Miller HD, Ormerod IE, Gibson A, de Boulay EP, Rudge P, McDonald WI. MR brain scanning in patiens with vasculitis: differentiation from multiple sclerosis. Neuroradiology 1987; 29(3): 226–231.

16. Ormerod IE, Miller DH, McDonald WI, Boulay EP, Rudge P, Kendall BE et al. The role of NMR imaging in the assessment of multiple sclerosis and isolated neurological lesions: a quantitative study. Brain 1987; 110(6): 1579–1616.

17. Software SepINRIA. Available from: http://www.sop.inria.fr/asclepios/software/SepINRIA/.

18. Ashton EA, Takahashi C, Berg MJ, Goodman A, Totterman S, Ekholm S. Accuracy and reproducibility of manual and semiautomated quantification of MS lesions by MRI. J Magn Reson Imaging 2003; 17(3): 300–308.

19. Zijdenbos AP, Dawant BM, Margolin RA, Palmer AC. Morphometric analysis of white matter lesions in MR images: method and validation. IEEE Trans Med Imaging 1994; 13(4): 716–724.

20. Van Leemput K, Maes F, Vandermeulen D, Colchester A, Suetens P. Automated segmentation of multiple sclerosis lesions by model outlier detection, IEEE transactions on medical imaging 2001; 20(8): 677–688.

21. Arnett PA, Rao SM, Bernardin L, Grafman J, Yetkin FZ, Lobeck L. Relationship between frontal lobe lesions and Wisconsin Card Sorting Test performance in patients with multiple sclerosis. Neurology 1994; 44(3): 420–425.

22. Foong J, Rozewicz L, Quaghebeur G, Davie CA, Kartsounis LD, Thompson AJ et al. Executive functions in multiple sclerosis. The role of frontal lobe pathology. Brain 1997; 120(1): 15–26.

23. Lazeron RH, Boringa JB, Schouten M, Uitdehaag BM, Bergers E, Lindeboom J et al. Brain atrophy and lesion load as explaining parameters for cognitive impairment in multiple sclerosis. Mult Scler 2005; 11(5): 524–531.

24. Truyen L, van Waesberghe JH, van Walderveen MA, van Oosten BW, Polman CH, Hommes OR et al. Accumulation of hypointense lesions (“black holes”) on T1 spin-echo MRI correlates with disease progression in multiple sclerosis. Neurology 1996; 47(6): 1469–1476.

25. Barkhof F, McGowan JC, van Waesberghe JH, Grossman RI. Hypointense multiple sclerosis lesions on T1-weighted spin echo magnetic resonance images: their contribution in understanding multiple sclerosis evolution. J Neurol Neurosurg Psychiatry 1998; 64 (Suppl 1): 77–79.

26. Rovaris M, Filippi M, Falautano M, Minicucci L, Rocca MA, Martinelli V et al. Relation between MR abnormalities and patterns of cognitive impairment in multiple sclerosis. Neurology 1998; 50(6): 1601–1608.

27. Patti F, Amato MP, Trojano M, Bastianello S, Tola MR, Goretti B et al. Cognitive impairment and its relation with disease measures in mildly disabled patients with relapsing-remitting multiple sclerosis: baseline results from the Cognitive Impairment in Multiple Sclerosis (COGIMUS) study. Mult Scler 2009; 15(7): 779–788.

28. Rao SM, Bernardin L, Ellington L, Ryan SB, Burg LS. Cerebral disconnection in multiple sclerosis. Relationship to atrophy of the corpus callosum. Arch Neurol 1989; 46(8): 918–920.

29. Pozzilli C, Bastianello S, Padovani A, Passafiume D, Millefiorini E, Bozzao L et al. Anterior corpus callosum atrophy and verbal fluency in multiple sclerosis. Cortex 1991; 27(3): 441–445.

30. Swirsky-Sacchetti T, Mitchell DR, Seward J, Gonzales C, Lublin F, Knobler R et al. Neuropsychological and structural brain lesions in multiple sclerosis: a regional analysis. Neurology 1992; 42(7): 1291–1295.

31. Huber SJ, Paulson GW, Shuttleworth EC, Chakeres D, Clapp LE, Pakalnis A et al. Magnetic resonance imaging correlates of dementia in multiple sclerosis. Arch Neurol 1987; 44(7): 732–736.

32. Brownell B, Hughes JT. The distribution of plaques in the cerebrum in multiple sclerosis. J Neurol Neurosurg Psychiatry 1962; 25: 315–320.

33. Lumsden CE. The neuropathology of multiple sclerosis. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology. Amsterdam: North-Holland 1970: 217–309.

34. Kidd D, Barkhof F, McConnell R, Algra PR. Allen IV, Revesz T. Cortical lesions in multiple sclerosis. Brain 1999; 122(1): 17–26.

35. Rovaris M, Youstry T, Calori G, FeslG, Voltz R, Filippi M. Sensitivity and reproducibility of fast FLAIR, FSE and TGSE sequences for the MRI assessment of brain lesions load in multiple sclerosis: a preliminary study. J Neuroimaging 1997; 7(2): 98–102.

36. De Coene B, Hajnal JV, Gatehouse P, Longmore DB, White SJ, Oatridge A, Pennock JM et al. MR of the brain using fluid-attenuated inversion recovery (FLAIR) pulse sequences. AJNR Am J Neuroradiol 1992; 13(6): 1555–1564.

37. Bakshi R, Ariyaratana S, Benedict RHB, Jacobs L. Fluid-attenuated inversion-recovery MRI detects cortical and juxtacortical MS lesions. Arch Neurol 2001; 58(5): 742–748.

38. Geurts JJ, Pouwels PJ, Uitdehaag BM, Polman CH, Barkhof F, Castelijns JA. Intracortical lesions in multiple sclerosis: improved detection with 3D double inversion-recovery MR imaging. Radiology 2005; 236(1): 254–260.

39. Pouwels PJ, Kuijer JP, Mugler JP 3rd, Guttmann CR, Barkhof F. Human gray matter: feasibility of single-slab 3D double inversion-recovery high-spatial-resolution MR imaging. Radiology 2006; 241(3): 873–879.

40. Nelson F, Poonawalla AH, Hou P, Huang F, Wolinsky JS, Narayana PA. Improved identification of intracortical lesions in multiple sclerosis with phase-sensitive inversion recovery in combination with fast double inversion recovery MR imaging. AJNR Am J Neuroradiol 2007; 28(9): 1645–1649.

41. Moriarty DM, Blackshaw AJ, Talbot PR, Griffiths HL, Snowden JS, Hillier VF et al. Memory dysfunction inmultiple sclerosis corresponds to juxtacortical lesion load on fast fluid attenuated inversion recovery MR images. AJNR Am J Neuroradiol 1999; 20(10): 1956–1962.

42. Rovaris M, Filippi M, Minicucci L, Iannucci G, Santuccio G, Possa F et al. Cortical/subcortical disease burden and cognitive impariment in patients with multiple sclerosis. AJNR Am J Neuroradiol 2000; 21(2): 402–408.

43. Calabrese M, Agosta F, Rinaldi F, Mattisi I, Grossi P, Favaretto A et al. Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis. Arch Neurol 2009; 66(9): 1144–1150.

44. Poonawalla AH, Hasan KM, Gupta RK, Ahn CW, Nelson F, Wolinsky JS, Narayana PA. Diffusion-tensor MR imaging of cortical lesions in multiple sclerosis: initial findings. Radiology 2008; 246(3): 880–886.

45. McAlpine D. Symptoms and signs. In: McAlpine D, Lumsden CE, Acheson ED. Multiple sclerosis: a reappraisal. 2nd ed. Edinburgh: Churchill Livingstone 1972: 174–177.

46. Poser S. Multiple sclerosis: an analysis of 812 cases by means of electronic data processing. Berlin: Springer 1978.

47. Day TJ, Fisher AG, Mastaglia FL. Alexia with agraphia in multiple sclerosis. J Neurol Sci 1987; 78: 343–348.

48. Miller DH, Barkhof F, Frank JA, Parker GJM, Thompson AJ. Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 2002; 125(8): 1676–1695.

49. Chard DT, Griffin CM, Parker GJM, Kapoor JR. Thompson AJ, Miller HD. Brain atrophy in cliniccaly early relapsing-remitting multiple sclerosis. Brain 2002; 125(2): 327–337.

50. De Stefano N, Matthews PM, Filippi M, Agosta F, De Luca M, Bartolozzi ML et al. Evidence of early cortical atrophy in. MS: Revalence to white matter changes and disability. Neurology 2003; 60(7): 1157–1162.

51. Zivadinov R, Sepcic J, Nasuelli D, de Masi R, Bragadin LM, Tommasi MA et al. A longitudinal study of brain atrophy and cognitive disturbances in the early phase of relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 2001; 70(6): 773–780.

52. Software SIENA. Available from: http://www.fmrib.ox.ac.uk/fsl/siena/index.html.

53. Rao SM, Glatt S, HammekeTA, McQuillen MP, Khatri BO, Rhodes AM et al. Chronic-progressive multiple sclerosis: relationship between cerebral ventricular size and neuropsychological impairment. Arch Neurol 1985; 42(7): 678–682.

54. Berg D, Mäurer M, Warmuth-Metz M, Rieckmann P, Becker G. The correlation between ventricular diameter measured by transcranial sonography and clinical disability andcognitive dysfunction in patients with multiple sclerosis. Arch Neurol 2000; 57(9): 1289–1292.

55. Comi G, Filippi M, Martinelli V, Sirabian G, Visciani A, Campi A et al. Brain magnetic resonance imaging correlates of cognitive impairment in multiple sclerosis. J Neurol Sci 1993; 115 (Suppl 1): 66–73.

56. Edwards SG, Liu C, Blumhardt LC. Cognittive correlates of supratentorial atrophy on MRI in multiple sclerosis. Acta Neurol Scand 2001; 104(4): 214–223.

57. Amato MP, Bartolozzi ML, Zipoli V, Portaccio E, Mortilla M, Guidi L et al. Neocortical volume decrease in relapsing remmiting MS patients with mild cognitive impariment. Neurology 2004; 63(1): 80–93.

58. Bermel RA, Bakshi R, Tjoa C, Puli SR, Jacobs L. Bicaudate ratio as a magnetic resonance imaging marker of brain atrophy in multiple sclerosis. Arch Neurol 2002; 59(2): 275–280.

59. Benedict RH, Weinstock-Guttman B, FishmanI, Sharma J, Tjoa C, Bakshi R. Prediction of neuropsychological impairment in multiple sclerosis. Arch Neurol 2004; 61(2): 226–230.

60. Sailer M, Fischl B, Salat D, Tempelmann C, Schönfeld MA et al. Focal thinning of the cerebral cortex in multiple sclerosis. Brain 2003; 126(8): 1734–1744.

61. Calabrese M, Rinaldi F, Mattisi I, Grossi P, Favaretto A, Atzori M et al. Widespread cortical thinning characterizes patients with MS with mild cognitive impairment. Neurology 2010; 74(4): 321–328.

62. Filippi M, Miller DH. Magnetic resonance imaging in the differential diagnosis and monitoring the treatment of multiple sclerosis. Curr Opin Neurol 1996; 9(3): 178–186.

63. Filippi M, Campi A, Dousset V, Baratti C, Martinelli V, Canal N, Scotti G et al. A magnetization transfer imaging study of normal-appearing white matter in multiple sclerosis. Neurology 1995; 45(3): 478–482.

64. Werring DJ, Clark CA, Barker GJ, Thompson AJ, Miller DH. Diffusion tensor imaging of lesions and normal-appearing white matter in multiple sclerosis. Neurology 1999; 52(8): 1626–1632.

65. Stevenson VL, Parker GJ, Barker GJ, Birnie K, Tofts PS, Miller HD et al. Variations in T1 and T2 relaxation times of normal appearing white matter and lesions in multiple sclerosis. J Neurol Sci 2000: 178(2): 81–87.

66. Neema M, Stankiewicz J, Arora A, Dandamudi VS, Batt CE, Guss ZD et al. T1- and T2-based MRI measures of diffuse gray matter and white matter damage in patients with multiple sclerosis. J Neuroimaging 2007; 17 (Suppl 1): 16–21.

67. Ormerod IEC, Johnson G, MacManus D, du Boulay EPHG, Macdonald WI. Relaxation times of apparently normal cerebral white matter in multiple sclerosis. Act Radiol 1986; 369 (Suppl): 382–384.

68. Feinstein A, Youl B, Thompson A. Acute optic neuritis. A cognitive and magnetic resonance imaging study. Brain 1992; 115(5): 1403–1415.

69. Gass A, Barker GJ, Kidd D, Thorpe JW, MacManus DG, Brennan A et al. Correlation of magnetization transfer ratio with disability in multiple sclerosis. Ann Neurol 1994; 36(1): 62–67.

70. van Buchem MA, Grossman RI, Armstrong C, Polansky M, Miki Y, Heyning FH et al. Correlation of volumetric magnetization transfer imaging with clinical data in MS. Neurology 1998; 50(6): 1609–1617.

71. Filippi M, Rocca MA, Minicucci L, Martinelli V, Ghezzi A, Bergamaschi R et al. Magnetization transfer imaging of patients with definite MS and negative conventional MRI. Neurology 1999; 52(4): 845–848.

72. Loevner LA, Grossman RI, Cohen JA, Lexa FJ, Kessler D, Kolson DL. Microscopic disease in normalappearing white matter on conventional MR imaging in patients with multiple sclerosis: assessment with magnetization-transfer measurements. Radiology 1995; 196(2): 511–515.

73. Filippi M, Tortorella C, Rovaris M, Bozzali M, Possa F, Iannucci G et al. Changes in the normal appearing brain tissue and cognitive impairment in multiple sclerosis. J Neurol Neurosurg Psychiatry 2000; 68(2): 157–176.

74. Zivadinov R, de Masi R, Nasuelli D, Bragadin LM, Ukmar M, Pozzi-Mucelli RS et al. MRI techniques and cognitive impairment in the early phase of relapsing remitting multiple sclerosis. Neuroradiology 2001; 43(4): 272–278.

75. Deloire MSA, Ruer A, Hamel D, Bonner M, Douset V, Brochet B. MRI predictors of cognitive outcome in early multiple sclerosis. Neurology 2011; 76(13): 1161–1167.

76. Audoin B, Duong MVA, Ranjeva JP, Ibarrola D, Malikova I, Confort-Gouny S et al. Magnetic resonance study of influence of tissue damage and cortical reorganization on PASAT performance at earliest stage of multiple sclerosis. Hum Brain Mapp 2005; 24(3): 216–228.

77. Keřkovský M, Šprláková-Puková A, Kašpárek T, Fadrus P, Mechl M, Válek V. Duffision tensor imaging – současné MR zobrazení bílé hmoty mozku. Cesk Slov Neurol N 2010; 73/106(2): 136–142.

78. Griffin CM, Declan TC, Ciccarelli O, Kapoor R, Barker GJ, Thompson AJ et al. Diffusion tensor imaging in early relapsing-remitting multiple sclerosis. Mult Scler 2001; 7: 290–297.

79. Cercignani M, Inglese M, Pagani E, Comi G, Filippi M. Mean diffusivity and fractional anisotropy histograms of patients with multiple sclerosis. AJNR Am J Neuroradiol 2001; 22(5): 952–958.

80. Cercignani M, Bammer R, Sormani MP, Fazekas F, Filippi M. Inter-sequence and inter-imaging unit variability of diffusion tensor MR imaging histogram-derived metrics of the brain in healthy volunteers. AJNR Am J Neuroradiol 2003; 24(4): 638–643.

81. Bookstein FL. “Voxel-based morphometry” should not be used with imperfectly registered images. Neuroimage 2001; 14(6): 1454–1462.

82. Ashburner J, Friston KJ. Voxel-based morphometry – the methods. Neuroimage 2000; 11(6): 805–821.

83. Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE et al. Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data. Neuroimage 2006; 31(4): 1487–1505.

84. Software TBSS. Available from: http://fsl.fmrib.ox.ac.uk/fsl/tbss/.

85. Rovaris M, Iannucci G, Falautano M, Possa F, Martinelli V, Comi G et al. Cognitive dysfunction in patients with mildly disabling relapsing-remitting multiple sclerosis: an exploratory study with diffusion tensor MR imaging. J Neurol Sci 2002; 195(2): 103–109.

86. Benedict RH, Bruce J, Dwyer MG, Weinstock-Guttman B, Tjoa C, Tavazzi E et al. Diffusion-weighted imaging predicts cognitive impariment in multiple sclerosis. Mult Scler 2007; 13(6): 722–730.

87. Roosendaal SD, Geurts JJG, Vrenken H, Hulst HE, Cover KS, Castelijns JA et al. Regional DTI differences in multiple sclerosis patients. Neuroimage 2009; 44(4): 1397–1403.

88. Dineen RA, Vilisaar J, Hlinka J, Bradshaw CM, Morgan PS, Constatinescu CS et al. Disconnection as mechanism for cognitive dysfunction in multiple sclerosis. Brain 2009; 132(1): 239–249.

89. Chollet F, Dipiero V, Wise RJS, Brooks DJ, Dolan RJ, Frackowiak RS. The functional anatomy of motor recovery after stroke in humans: A study with positron emission tomography. Ann Neurol 1999; 29(1): 63–71.

90. Yoshiura T, Hasuo K, Mihara F, Masuda K, Morioka T, Fukui M. Increased activity of the ipsilateral motor cortex during a hand motor task in patients with brain tumor and paresis. AJNR Am J Neuroradiol 1997; 18(5): 865–869.

91. Filippi M, Rocca MA, Falini A, Caputo D, Ghezzi A, Colombo B et al. Correlations between structural CNS damage and functional MRI changes in primary progressive MS. Neuroimage 2002; 15(3): 537–546.

92. Pantano P, Iannetti GD, Caramia F, Mainero C, Di Legge S, Bozzao L et al. Cortical motor reorganization after a single clinical attack of multiple sclerosis. Brain 2002; 125(7): 1607–1615.

93. Werring DJ, Bullmore ET, Toosy AT, Miller DH, Barker GJ, MacManus DG et al. Recovery from optic neuritis is associated with a change in the distribution of cerebral response to visual stimulation: a functional magnetic resonance imaging study. J Neurol Neurosurg Psychiatry 2000; 68(4): 441–449.

94. Cabeza R, Nyberg J. Imaging Cognition II: An Empirical Review of 275 PET and fMRI Studies. J Cogn Neurosci 2000; 12(1): 1–47.

95. Cabeza R. Cognitive neuroscience of aging: contributions of functional neuroimaging. Scand J Psychol 2001; 42(3): 277–286.

96. Staffen W, Mair A, Zauner H, Unterrainer J, Niederhofer H, Kutzelnigg A et al. Cognitive function and fMRI on patients with multiple sclerosis: evidence for compensatory cortical activation during an attention task. Brain 2002; 125(6): 1275–1282.

97. Audoin B, Ibarrola D, Ranjeva JP, Confort-Gouny S, Malikova I, Ali-Chérif A et al. Compensatory cortical activation observed by fMRI during a cognitive task at the earliest stage of MS. Hum Brain Mapp 2003; 20(2): 51–58.

98. Mainero C, Caramia F, Pozzilli C, Pisani A, Pestalozza I, Borriello G et al. fMRI evidence of brain reorganization during attention and memory tasks in multiple sclerosis. Neuroimage 2004; 21(3): 858–867.

99. Sweet LH, Rao SM, Primeau M, Mayer AR, Cohen RA. Functional magnetic resonance imaging of working memory among multiple sclerosis patients. J Neuroimaging 2004; 14(2): 150–157.

100. Hillary FG, Chiaravalloti ND, Ricker JH, Steffener J, Bly BM, Lange G et al. An investigation of working memory rehearsal in multiple sclerosis using fMRI. J Clin Exp Neuropsychol 2003; 25(7): 965–978.

101. Penner IK, Opwis K, Kappos L. Relation between functional brain imaging, cognitive impairment and cognitive rehabilitation in patients with multiple sclerosis. J Neurol 2007; 254 (Suppl 2): 1153–1157.

102. Lazeron RH, Rombouts SA, Scheltens P, Polman CH, Barkhof F. An fMRI study of planning-related brain activity in patients with moderately advanced multiple sclerosis. Mult Scler 2004; 10(5): 549–555.

103. Davie CA, Barker GJ, Thompson AJ, Tofts PS, McDonald WI, Miller DH. 1H magnetic resonance spectroscopy of chronic cerebral white matter lesions and normal appearing white matter in multiple sclerosis. J Neurol Neurosurg Psychiatry 1997; 63(6): 736–742.

104. Leary SM, Davie CA, Parker GJ, Stevenson VL, Wang L, Barker GJ et al. 1H magnetic resonance spectroscopy of normal appearing white matter in primary progressive multiple sclerosis. J Neurol 1999; 246(11): 1023–1026.

105. Pan JW, Krupp LB, Elkins LE, Coyle PK. Cognitive dysfunction lateralizes with NAA in multiple sclerosis. Appl Neuropsychol 2001; 8(3): 155–160.

106. Foong J, Rozewicz L, Davie CA, Thompson AJ, Miller DH, Ron MA. Correlates of executive function in multiple sclerosis: the use of magnetic resonance spectroscopy as an index of focal pathology. J Neuropsychiatry Clin Neurosci 1999; 11(1): 45–50.

107. Brooks DJ, Leenders KL, Head G, Pantano P, Incoccia C, Bastianello S et al. Studies on regional cerebral oxygen utilization and cognitive function in multiple sclerosis. J Neurol Neurosurg Psychiatry 1984; 47(11): 1182–1191.

108. Blinkenberg M, Rune K, Jensen CV, Ravnborg M, Kyllingsbæk S, Holm S et al. Cortical cerebral metabolism correlates with MRI lesion load and cognitive dysfunction in MS. Neurology 2000; 54(3): 558–564.

109. Paulesu E, Perani D, Fazio F, Comi G, Pozzilli C, Martinelli V et al. Functional basis of memory impairment in multiple sclerosis: a[18F]FDG PET study. Neuroimage 1996; 4(2): 87–96.

110. Sun X, Tanaka M, Kondo S, Okamoto K, Hirai S. Clinical significance of reduced cerebral metabolism in multiple sclerosis: a combined PET and MRI study. Ann Nucl Med 1998; 12(2): 89–94.

111. Lycke J, Wikkelsö C, Bergh AC, Jacobsson L, Andersen O. Regional cerebral blood flow in multiple sclerosis measured by single photon emission tomography with technetium-99m hexamethylpropyleneamine oxime. Eur Neurol 1993; 33(2): 163–167.

112. Pozzilli C, Passafiume D, Bernardi S, Pantano P, Incoccia C, Bastianello S et al. SPECT, MRI and cognitive functions in multiple sclerosis. J Neurol Neurosurg Psychiatry 1991; 54(2): 110–115.