Skip to main content
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2000 Feb;68(2):157–161. doi: 10.1136/jnnp.68.2.157

Changes in the normal appearing brain tissue and cognitive impairment in multiple sclerosis

M Filippi 1, C Tortorella 1, M Rovaris 1, M Bozzali 1, F Possa 1, M Sormani 1, G Iannucci 1, G Comi 1
PMCID: PMC1736794  PMID: 10644780

Abstract

OBJECTIVES—To assess (a) whether the changes in the normal appearing brain tissue (NABT), as revealed by magnetisation transfer (MT) histogram analysis, correlates with cognitive dysfunction in patients with multiple sclerosis and (b) the relative contribution of these changes by comparison with that of multiple sclerosis lesions visible on conventional MRI.
METHODS—Dual echo, T1 weighted and MT scans of the brain were obtained in 12 patients with multiple sclerosis with cognitive impairment and in seven without cognitive impairment. Lesion loads were assessed from T2 and T1 weighted scans. To create MT histograms of the NABT, multiple sclerosis lesion outlines from dual echo scans were superimposed automatically and nulled out from the coregistered and scalp stripped MTR maps. Average lesion MT ratio (MTR) and brain size were also measured.
RESULTS—T2 and T1 lesion loads were significantly higher and the average lesion MTR and brain size were significantly lower in the group of cognitively impaired patients. Patients with cognitive deficits also had significantly lower average MTR and peak location of the NABT histogram. Logistic regression analysis showed that 68% of the total variance was explained by average NABT-MTR alone. A multivariable regression model showed that NABT-MTR was the only factor that significantly correlated with cognitive impairment in these patients (p=0.001).
CONCLUSIONS—The extent of abnormalities which go undetected when using conventional MRI is relevant in determining cognitive impairment in multiple sclerosis.



Full Text

The Full Text of this article is available as a PDF (122.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams C. W. Pathology of multiple sclerosis: progression of the lesion. Br Med Bull. 1977 Jan;33(1):15–20. doi: 10.1093/oxfordjournals.bmb.a071388. [DOI] [PubMed] [Google Scholar]
  2. Allen I. V., McKeown S. R. A histological, histochemical and biochemical study of the macroscopically normal white matter in multiple sclerosis. J Neurol Sci. 1979 Mar;41(1):81–91. doi: 10.1016/0022-510x(79)90142-4. [DOI] [PubMed] [Google Scholar]
  3. Arnett P. A., Rao S. M., Bernardin L., Grafman J., Yetkin F. Z., Lobeck L. Relationship between frontal lobe lesions and Wisconsin Card Sorting Test performance in patients with multiple sclerosis. Neurology. 1994 Mar;44(3 Pt 1):420–425. doi: 10.1212/wnl.44.3_part_1.420. [DOI] [PubMed] [Google Scholar]
  4. Arstila A. U., Riekkinen P., Rinne U. K., Laitinen L. Studies on the pathogenesis of multiple sclerosis. Participation of lysosomes on demyelination in the central nervous system white matter outside plaques. Eur Neurol. 1973;9(1):1–20. doi: 10.1159/000114197. [DOI] [PubMed] [Google Scholar]
  5. Baddeley A., Della Sala S., Papagno C., Spinnler H. Dual-task performance in dysexecutive and nondysexecutive patients with a frontal lesion. Neuropsychology. 1997 Apr;11(2):187–194. doi: 10.1037//0894-4105.11.2.187. [DOI] [PubMed] [Google Scholar]
  6. Barbosa S., Blumhardt L. D., Roberts N., Lock T., Edwards R. H. Magnetic resonance relaxation time mapping in multiple sclerosis: normal appearing white matter and the "invisible" lesion load. Magn Reson Imaging. 1994;12(1):33–42. doi: 10.1016/0730-725x(94)92350-7. [DOI] [PubMed] [Google Scholar]
  7. Brooks D. J., Leenders K. L., Head G., Marshall J., Legg N. J., Jones T. Studies on regional cerebral oxygen utilisation and cognitive function in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1984 Nov;47(11):1182–1191. doi: 10.1136/jnnp.47.11.1182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Comi G., Filippi M., Martinelli V., Campi A., Rodegher M., Alberoni M., Sirabian G., Canal N. Brain MRI correlates of cognitive impairment in primary and secondary progressive multiple sclerosis. J Neurol Sci. 1995 Oct;132(2):222–227. doi: 10.1016/0022-510x(95)00168-2. [DOI] [PubMed] [Google Scholar]
  9. De Stefano N., Matthews P. M., Narayanan S., Francis G. S., Antel J. P., Arnold D. L. Axonal dysfunction and disability in a relapse of multiple sclerosis: longitudinal study of a patient. Neurology. 1997 Oct;49(4):1138–1141. doi: 10.1212/wnl.49.4.1138. [DOI] [PubMed] [Google Scholar]
  10. De Stefano N., Narayanan S., Matthews P. M., Francis G. S., Antel J. P., Arnold D. L. In vivo evidence for axonal dysfunction remote from focal cerebral demyelination of the type seen in multiple sclerosis. Brain. 1999 Oct;122(Pt 10):1933–1939. doi: 10.1093/brain/122.10.1933. [DOI] [PubMed] [Google Scholar]
  11. Dousset V., Grossman R. I., Ramer K. N., Schnall M. D., Young L. H., Gonzalez-Scarano F., Lavi E., Cohen J. A. Experimental allergic encephalomyelitis and multiple sclerosis: lesion characterization with magnetization transfer imaging. Radiology. 1992 Feb;182(2):483–491. doi: 10.1148/radiology.182.2.1732968. [DOI] [PubMed] [Google Scholar]
  12. Filippi M., Campi A., Dousset V., Baratti C., Martinelli V., Canal N., Scotti G., Comi G. A magnetization transfer imaging study of normal-appearing white matter in multiple sclerosis. Neurology. 1995 Mar;45(3 Pt 1):478–482. doi: 10.1212/wnl.45.3.478. [DOI] [PubMed] [Google Scholar]
  13. Filippi M., Horsfield M. A., Adèr H. J., Barkhof F., Bruzzi P., Evans A., Frank J. A., Grossman R. I., McFarland H. F., Molyneux P. Guidelines for using quantitative measures of brain magnetic resonance imaging abnormalities in monitoring the treatment of multiple sclerosis. Ann Neurol. 1998 Apr;43(4):499–506. doi: 10.1002/ana.410430414. [DOI] [PubMed] [Google Scholar]
  14. Filippi M., Horsfield M. A., Campi A., Mammi S., Pereira C., Comi G. Resolution-dependent estimates of lesion volumes in magnetic resonance imaging studies of the brain in multiple sclerosis. Ann Neurol. 1995 Nov;38(5):749–754. doi: 10.1002/ana.410380509. [DOI] [PubMed] [Google Scholar]
  15. Filippi M., Iannucci G., Tortorella C., Minicucci L., Horsfield M. A., Colombo B., Sormani M. P., Comi G. Comparison of MS clinical phenotypes using conventional and magnetization transfer MRI. Neurology. 1999 Feb;52(3):588–594. doi: 10.1212/wnl.52.3.588. [DOI] [PubMed] [Google Scholar]
  16. Filippi M., Rocca M. A., Horsfield M. A., Rovaris M., Pereira C., Yousry T. A., Colombo B., Comi G. Increased spatial resolution using a three-dimensional T1-weighted gradient-echo MR sequence results in greater hypointense lesion volumes in multiple sclerosis. AJNR Am J Neuroradiol. 1998 Feb;19(2):235–238. [PMC free article] [PubMed] [Google Scholar]
  17. Filippi M., Yousry T., Baratti C., Horsfield M. A., Mammi S., Becker C., Voltz R., Spuler S., Campi A., Reiser M. F. Quantitative assessment of MRI lesion load in multiple sclerosis. A comparison of conventional spin-echo with fast fluid-attenuated inversion recovery. Brain. 1996 Aug;119(Pt 4):1349–1355. doi: 10.1093/brain/119.4.1349. [DOI] [PubMed] [Google Scholar]
  18. Foong J., Rozewicz L., Quaghebeur G., Davie C. A., Kartsounis L. D., Thompson A. J., Miller D. H., Ron M. A. Executive function in multiple sclerosis. The role of frontal lobe pathology. Brain. 1997 Jan;120(Pt 1):15–26. doi: 10.1093/brain/120.1.15. [DOI] [PubMed] [Google Scholar]
  19. Fu L., Matthews P. M., De Stefano N., Worsley K. J., Narayanan S., Francis G. S., Antel J. P., Wolfson C., Arnold D. L. Imaging axonal damage of normal-appearing white matter in multiple sclerosis. Brain. 1998 Jan;121(Pt 1):103–113. doi: 10.1093/brain/121.1.103. [DOI] [PubMed] [Google Scholar]
  20. Gawne-Cain M. L., O'Riordan J. I., Thompson A. J., Moseley I. F., Miller D. H. Multiple sclerosis lesion detection in the brain: a comparison of fast fluid-attenuated inversion recovery and conventional T2-weighted dual spin echo. Neurology. 1997 Aug;49(2):364–370. doi: 10.1212/wnl.49.2.364. [DOI] [PubMed] [Google Scholar]
  21. Grimaud J., Millar J., Thorpe J. W., Moseley I. F., McDonald W. I., Miller D. H. Signal intensity on MRI of basal ganglia in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1995 Sep;59(3):306–308. doi: 10.1136/jnnp.59.3.306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Keiper M. D., Grossman R. I., Hirsch J. A., Bolinger L., Ott I. L., Mannon L. J., Langlotz C. P., Kolson D. L. MR identification of white matter abnormalities in multiple sclerosis: a comparison between 1.5 T and 4 T. AJNR Am J Neuroradiol. 1998 Sep;19(8):1489–1493. [PMC free article] [PubMed] [Google Scholar]
  23. Kurtzke J. F. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983 Nov;33(11):1444–1452. doi: 10.1212/wnl.33.11.1444. [DOI] [PubMed] [Google Scholar]
  24. Loevner L. A., Grossman R. I., Cohen J. A., Lexa F. J., Kessler D., Kolson D. L. Microscopic disease in normal-appearing white matter on conventional MR images in patients with multiple sclerosis: assessment with magnetization-transfer measurements. Radiology. 1995 Aug;196(2):511–515. doi: 10.1148/radiology.196.2.7617869. [DOI] [PubMed] [Google Scholar]
  25. Lublin F. D., Reingold S. C. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996 Apr;46(4):907–911. doi: 10.1212/wnl.46.4.907. [DOI] [PubMed] [Google Scholar]
  26. Miki Y., Grossman R. I., Udupa J. K., Wei L., Kolson D. L., Mannon L. J., Grossman M. Isolated U-fiber involvement in MS: preliminary observations. Neurology. 1998 May;50(5):1301–1306. doi: 10.1212/wnl.50.5.1301. [DOI] [PubMed] [Google Scholar]
  27. Miller D. H., Albert P. S., Barkhof F., Francis G., Frank J. A., Hodgkinson S., Lublin F. D., Paty D. W., Reingold S. C., Simon J. Guidelines for the use of magnetic resonance techniques in monitoring the treatment of multiple sclerosis. US National MS Society Task Force. Ann Neurol. 1996 Jan;39(1):6–16. doi: 10.1002/ana.410390104. [DOI] [PubMed] [Google Scholar]
  28. Miller D. H., Barkhof F., Berry I., Kappos L., Scotti G., Thompson A. J. Magnetic resonance imaging in monitoring the treatment of multiple sclerosis: concerted action guidelines. J Neurol Neurosurg Psychiatry. 1991 Aug;54(8):683–688. doi: 10.1136/jnnp.54.8.683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Orsini A., Grossi D., Capitani E., Laiacona M., Papagno C., Vallar G. Verbal and spatial immediate memory span: normative data from 1355 adults and 1112 children. Ital J Neurol Sci. 1987 Dec;8(6):539–548. doi: 10.1007/BF02333660. [DOI] [PubMed] [Google Scholar]
  30. Paulesu E., Perani D., Fazio F., Comi G., Pozzilli C., Martinelli V., Filippi M., Bettinardi V., Sirabian G., Passafiume D. Functional basis of memory impairment in multiple sclerosis: a[18F]FDG PET study. Neuroimage. 1996 Oct;4(2):87–96. doi: 10.1006/nimg.1996.0032. [DOI] [PubMed] [Google Scholar]
  31. Peyser J. M., Edwards K. R., Poser C. M., Filskov S. B. Cognitive function in patients with multiple sclerosis. Arch Neurol. 1980 Sep;37(9):577–579. doi: 10.1001/archneur.1980.00500580073013. [DOI] [PubMed] [Google Scholar]
  32. Pozzilli C., Bastianello S., Padovani A., Passafiume D., Millefiorini E., Bozzao L., Fieschi C. Anterior corpus callosum atrophy and verbal fluency in multiple sclerosis. Cortex. 1991 Sep;27(3):441–445. doi: 10.1016/s0010-9452(13)80039-1. [DOI] [PubMed] [Google Scholar]
  33. Rao S. M., Leo G. J., Haughton V. M., St Aubin-Faubert P., Bernardin L. Correlation of magnetic resonance imaging with neuropsychological testing in multiple sclerosis. Neurology. 1989 Feb;39(2 Pt 1):161–166. doi: 10.1212/wnl.39.2.161. [DOI] [PubMed] [Google Scholar]
  34. Robb R. A., Hanson D. P., Karwoski R. A., Larson A. G., Workman E. L., Stacy M. C. Analyze: a comprehensive, operator-interactive software package for multidimensional medical image display and analysis. Comput Med Imaging Graph. 1989 Nov-Dec;13(6):433–454. doi: 10.1016/0895-6111(89)90285-1. [DOI] [PubMed] [Google Scholar]
  35. Rovaris M., Filippi M., Calori G., Rodegher M., Campi A., Colombo B., Comi G. Intra-observer reproducibility in measuring new putative MR markers of demyelination and axonal loss in multiple sclerosis: a comparison with conventional T2-weighted images. J Neurol. 1997 Apr;244(4):266–270. doi: 10.1007/s004150050083. [DOI] [PubMed] [Google Scholar]
  36. Rovaris M., Filippi M., Falautano M., Minicucci L., Rocca M. A., Martinelli V., Comi G. Relation between MR abnormalities and patterns of cognitive impairment in multiple sclerosis. Neurology. 1998 Jun;50(6):1601–1608. doi: 10.1212/wnl.50.6.1601. [DOI] [PubMed] [Google Scholar]
  37. Shallice T. Specific impairments of planning. Philos Trans R Soc Lond B Biol Sci. 1982 Jun 25;298(1089):199–209. doi: 10.1098/rstb.1982.0082. [DOI] [PubMed] [Google Scholar]
  38. Swirsky-Sacchetti T., Mitchell D. R., Seward J., Gonzales C., Lublin F., Knobler R., Field H. L. Neuropsychological and structural brain lesions in multiple sclerosis: a regional analysis. Neurology. 1992 Jul;42(7):1291–1295. doi: 10.1212/wnl.42.7.1291. [DOI] [PubMed] [Google Scholar]
  39. Trapp B. D., Peterson J., Ransohoff R. M., Rudick R., Mörk S., Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998 Jan 29;338(5):278–285. doi: 10.1056/NEJM199801293380502. [DOI] [PubMed] [Google Scholar]
  40. West J., Fitzpatrick J. M., Wang M. Y., Dawant B. M., Maurer C. R., Jr, Kessler R. M., Maciunas R. J., Barillot C., Lemoine D., Collignon A. Comparison and evaluation of retrospective intermodality brain image registration techniques. J Comput Assist Tomogr. 1997 Jul-Aug;21(4):554–566. doi: 10.1097/00004728-199707000-00007. [DOI] [PubMed] [Google Scholar]
  41. van Buchem M. A., Grossman R. I., Armstrong C., Polansky M., Miki Y., Heyning F. H., Boncoeur-Martel M. P., Wei L., Udupa J. K., Grossman M. Correlation of volumetric magnetization transfer imaging with clinical data in MS. Neurology. 1998 Jun;50(6):1609–1617. doi: 10.1212/wnl.50.6.1609. [DOI] [PubMed] [Google Scholar]
  42. van Buchem M. A., McGowan J. C., Kolson D. L., Polansky M., Grossman R. I. Quantitative volumetric magnetization transfer analysis in multiple sclerosis: estimation of macroscopic and microscopic disease burden. Magn Reson Med. 1996 Oct;36(4):632–636. doi: 10.1002/mrm.1910360420. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Publishing Group

RESOURCES