Journal of Neurology

, Volume 253, Issue 4, pp 434–440 | Cite as

Diffuse structural and metabolic brain changes in Fabry disease

  • S. Marino
  • W. Borsini
  • S. Buchner
  • M. Mortilla
  • M. L. Stromillo
  • M. Battaglini
  • A. Giorgio
  • P. Bramanti
  • A. Federico
  • N. De Stefano
ORIGINAL COMMUNICATION

Abstract

Objectives

To assess structural and metabolic brain changes in subjects affected by Fabry disease (FD) or carrying the disease mutation.

Background

FD is an X–linked metabolic disorder due to α-galactosidase A deficiency, which leads to storage of glycosphingolipids in many tissues and organs. Previous MR studies have shown structural and metabolic brain abnormalities in FD patients. It is not clear, however, whether tissue damage can be seen in both the brains of hemizygous and heterozygous and whether quantitative MR metrics are useful to monitor disease evolution.

Design/Methods

We studied 4 males and 4 females with FD. Each subject underwent brain proton MRI/MR spectroscopic imaging (MRSI) examinations to obtain measures of total brain volumes, total brain lesion volumes, magnetization transfer ratios (MTr) in WM and central brain levels of N–acetylaspartate (NAA) to creatine (Cr). A second MR examination was performed in five subjects after 2 years.

Results

Focal WM lesions were found in 2 males and 1 female. The MTr values were always low in the WM lesions of FD subjects (p < 0.001) and also were low in the normal–appearing WM of 2 affected males. Total brain volumes were never decreased in FD subjects. Brain NAA/Cr values were significantly (p = 0.005) lower in FD subjects than in normal controls and correlated closely with Rankin scale measures (r = –0.79). On follow–up examinations, no significant MR changes were found. However, the small changes in NAA/Cr correlated closely with changes in Rankin scores (r = –0.86).

Conclusions

Subtle structural and metabolic tissue damage can extend beyond WM lesions in FD subjects. Diffuse brain NAA/Cr decrease can be found in FD subjects in relation to the degree of their CNS involvement and its evolution over time.

Key words

magnetic resonance spectroscopy magnetization transfer brain atrophy Fabry disease 

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References

  1. 1.
    Bagley LJ, McGowan JC, Grossman RI, Sinson G, Kotapka M, Lexa FJ, et al. (2000) Magnetization transfer imaging of traumatic brain injury. J Magn Reson Imaging 11:1–8CrossRefPubMedGoogle Scholar
  2. 2.
    Bjartmar C, Battistuta J, Terada N, Dupree E, Trapp BD (2002) N-acetylaspartate is an axon-specific marker of mature white matter in vivo: a biochemical and immunohistochemical study on the rat optic nerve. Ann Neurol 51:51–58CrossRefPubMedGoogle Scholar
  3. 3.
    Borsini W, Giuliacci G, Torricelli F, Pelo E, Martinelli F, Scordo MR (2002) Anderson- Fabry disease with cerebrovascular complications in two Italian families. Neurol Sci 23:49–53CrossRefPubMedGoogle Scholar
  4. 4.
    Brady RO, Schiffmann R (2000) Clinical features of and recent advances in therapy for Fabry disease. JAMA 284:2771–2775CrossRefPubMedGoogle Scholar
  5. 5.
    Brenner RE, Munro PM, Williams SC, Bell JD, Barker GJ, Hawkins CP, et al. (1993) The proton NMR spectrum in acute EAE: the significance of the change in the Cho:Cr ratio. Magn Reson Med 29:737–745PubMedGoogle Scholar
  6. 6.
    Crutchfield KE, Patronas NJ, Dambrosia JM, Frei KP, Banerjee TK, Barton NW, et al. (1998) Quantitative analysis of cerebral vasculopathy in patients with Fabry disease. Neurology 50:1746–1749PubMedGoogle Scholar
  7. 7.
    de Haan R, Limburg M, Bossuyt P, van der Meulen J, Aaronson N (1995) The clinical meaning of Rankin ‘handicap’ grades after stroke. Stroke 26:2027–2030PubMedGoogle Scholar
  8. 8.
    De Stefano N, Matthews PM, Arnold DL (1995) Reversible decreases in N-acetylaspartate after acute brain injury. Magn Reson Med 34:721–727PubMedGoogle Scholar
  9. 9.
    De Stefano N, Narayanan S, Francis GS, Arnaoutelis R, Tartaglia MC, Antel JP, et al. (2001) Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol 58:65–70CrossRefPubMedGoogle Scholar
  10. 10.
    De Stefano N, Narayanan S, Matthews PM, Mortilla M, Dotti MT, Federico A, et al. (2000) Proton MR spectroscopy to assess axonal damage in multiple sclerosis and other white matter disorders. J Neurovirol 6 (Suppl 2):121–129Google Scholar
  11. 11.
    Eng CM, Desnick RJ (1994) Molecular basis of Fabry disease: mutations and polymorphisms in the human alphagalactosidase A gene. Hum Mutat 3:103–111CrossRefPubMedGoogle Scholar
  12. 12.
    Filippi M, Campi A, Dousset V, Baratti C, Martinelli V, Canal N, et al. (1995) A magnetization transfer imaging study of normal-appearing white matter in multiple sclerosis. Neurology 45:478–482PubMedGoogle Scholar
  13. 13.
    Fox NC, Schott JM (2004) Imaging cerebral atrophy: normal ageing to Alzheimer’s disease. Lancet 363:392–394CrossRefPubMedGoogle Scholar
  14. 14.
    Grewal RP, McLatchey SK (1992) Cerebrovascular manifestations in a female carrier of Fabry’s disease. Acta Neurol Belg 92:36–40PubMedGoogle Scholar
  15. 15.
    Grossman RI, Gomori JM, Ramer KN, Lexa FJ, Schnall MD (1994) Magnetization transfer: theory and clinical applications in neuroradiology. Radio Graphics 14:279–290Google Scholar
  16. 16.
    Hanyu H, Asano T, Sakurai H, Iwamoto T, Takasaki M, Shindo H, et al. (1999) Magnetization transfer ratio in cerebral white matter lesions of Binswanger’s disease. J Neurol Sci 166:85–90CrossRefPubMedGoogle Scholar
  17. 17.
    Iannucci G, Dichgans M, Rovaris M, Bruning R, Gasser T, Giacomotti L, et al. (2001) Correlations between clinical findings and magnetization transfer imaging metrics of tissue damage in individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke 32:643–648PubMedGoogle Scholar
  18. 18.
    Jardim L, Vedolin L, Schwartz IV, Burin MG, Cecchin C, Kalakun L, et al. (2004) CNS involvement in Fabry disease: clinical and imaging studies before and after 12 months of enzyme replacement therapy. J Inherit Metab Dis 27:229–240CrossRefPubMedGoogle Scholar
  19. 19.
    Kado H, Kimura H, Tsuchida T, Yonekura Y, Tokime T, Tokuriki Y, et al. (2001) Abnormal magnetization transfer ratios in normal-appearing white matter on conventional MR images of patients with occlusive cerebrovascular disease. AJNR Am J Neuroradiol 22:922–927PubMedGoogle Scholar
  20. 20.
    Kaye EM, Kolodny EH, Logigian EL, Ullman MD (1988) Nervous system involvement in Fabry’s disease: clinicopathological and biochemical correlation. Ann Neurol 23:505–509CrossRefPubMedGoogle Scholar
  21. 21.
    Miller DH, Barkhof F, Frank JA, Parker GJ, Thompson AJ (2002) Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 125:1676–1695CrossRefPubMedGoogle Scholar
  22. 22.
    Mitsias P, Levine SR (1996) Cerebrovascular complications of Fabry’s disease. Ann Neurol 40:8–17CrossRefPubMedGoogle Scholar
  23. 23.
    Moore DF, Altarescu G, Barker WC, Patronas NJ, Herscovitch P, Schiffmann R (2003) White matter lesions in Fabry disease occur in ‘prior’ selectively hypometabolic and hyperperfused brain regions. Brain Res Bull 62:231–240CrossRefPubMedGoogle Scholar
  24. 24.
    Moore DF, Ye F, Schiffmann R, Butman JA (2003) Increased signal intensity in the pulvinar on T1-weighted images: a pathognomonic MR imaging sign of Fabry disease. AJNR Am J Neuroradiol 24:1096–1101PubMedGoogle Scholar
  25. 25.
    Narayanan S, De Stefano N, Francis GS, Arnaoutelis R, Caramanos Z, Collins DL, et al. (2001) Axonal metabolic recovery in multiple sclerosis patients treated with interferon beta-1b. J Neurol 248:979–986CrossRefPubMedGoogle Scholar
  26. 26.
    Pike GB, De Stefano N, Narayanan S, Francis GS, Antel JP, Arnold DL (1999) Combined magnetization transfer and proton spectroscopic imaging in the assessment of pathologic brain lesions in multiple sclerosis. AJNR Am J Neuroradiol 20:829–837PubMedGoogle Scholar
  27. 27.
    Pike GB, Glover GH, Hu BS, Enzmann DR (1993) Pulsed magnetization transfer spin-echo MR imaging. J Magn Reson Imaging 3:531–539PubMedGoogle Scholar
  28. 28.
    Rudick RA, Fisher E, Lee JC, Simon J, Jacobs L (1999) Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS.Multiple Sclerosis Collaborative Research Group. Neurology 53:1698–1704PubMedGoogle Scholar
  29. 29.
    Sachdev P (2004) Homocysteine, cerebrovascular disease and brain atrophy. J Neurol Sci 226:25–29CrossRefPubMedGoogle Scholar
  30. 30.
    Simmons ML, Frondoza CG, Coyle JT (1991) Immunocytochemical localization of N-acetyl-aspartate with monoclonal antibodies. Neuroscience 45:37–45CrossRefPubMedGoogle Scholar
  31. 31.
    Smith SM, De Stefano N, Jenkinson M, Matthews PM (2001) Normalized accurate measurement of longitudinal brain change. J Comput Assist Tomograph 25:466–475CrossRefGoogle Scholar
  32. 32.
    Smith SM, Zhang Y, Jenkinson M, Chen J, Matthews PM, Federico A, et al. (2002) Accurate, robust and automated longitudinal and cross-sectional brain change analysis. NeuroImage 17:479–489CrossRefPubMedGoogle Scholar
  33. 33.
    Takanashi J, Barkovich AJ, Dillon WP, Sherr EH, Hart KA, Packman S (2003) T1 hyperintensity in the pulvinar: key imaging feature for diagnosis of Fabry disease. AJNR Am J Neuroradiol 24:916–921PubMedGoogle Scholar
  34. 34.
    Tanabe JL, Ezekiel F, Jagust WJ, Reed BR, Norman D, Schuff N, et al. (1999) Magnetization transfer ratio of white matter hyperintensities in subcortical ischemic vascular dementia. AJNR Am J Neuroradiol 20:839–844PubMedGoogle Scholar
  35. 35.
    Tedeschi G, Bonavita S, Banerjee TK, Virta A, Schiffmann R (1999) Diffuse central neuronal involvement in Fabry disease: a proton MRS imaging study. Neurology 52:1663–1667PubMedGoogle Scholar
  36. 36.
    Tedeschi G, Lundbom N, Raman R, Bonavita S, Duyn JH, Alger JR, et al. (1997) Increased choline signal coinciding with malignant degeneration of cerebral gliomas: a serial proton magnetic resonance spectroscopy imaging study. J Neurosurg 87:516–524PubMedCrossRefGoogle Scholar
  37. 37.
    van der Flier WM, van Buchem MA, van Buchem HA (2003) Volumetric MRI predicts rate of cognitive decline related to AD and cerebrovascular disease. Neurology 60:1558–1559PubMedGoogle Scholar
  38. 38.
    van der Flier WM, van den Heuvel DM, Weverling-Rijnsburger AW, Spilt A, Bollen EL, Westendorp RG, et al. (2002) Cognitive decline in AD and mild cognitive impairment is associated with global brain damage. Neurology 59:874–879PubMedGoogle Scholar
  39. 39.
    van Waesberghe JH, Kamphorst W, De Groot CJ, van Walderveen MA, Castelijns JA, Ravid R, et al. (1999) Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability. Ann Neurol 46:747–754CrossRefPubMedGoogle Scholar
  40. 40.
    Vion-Dury J, Nicoli F, Salvan AM, Confort-Gouny S, Dhiver C, Cozzone, et al. (1995) Reversal of brain metabolic alterations with zidovudine detected by proton localised magnetic resonance spectroscopy (letter). Lancet 345:60–61CrossRefPubMedGoogle Scholar
  41. 41.
    Walters RJ, Fox NC, Schott JM, Crum WR, Stevens JM, Rossor MN, et al. (2003) Transient ischaemic attacks are associated with increased rates of global cerebral atrophy. J Neurol Neurosurg Psychiatry 74:213–216CrossRefPubMedGoogle Scholar
  42. 42.
    Whybra C, Kampmann C, Willers I, Davies J, Winchester B, Kriegsmann J, et al. (2001) Anderson-Fabry disease: clinical manifestations of disease in female heterozygotes. J Inherit Metab Dis 24:715–724CrossRefPubMedGoogle Scholar

Copyright information

© Steinkopff-Verlag 2006

Authors and Affiliations

  • S. Marino
    • 1
    • 4
  • W. Borsini
    • 2
  • S. Buchner
    • 2
  • M. Mortilla
    • 3
    • 4
  • M. L. Stromillo
    • 4
  • M. Battaglini
    • 4
  • A. Giorgio
    • 4
  • P. Bramanti
    • 1
  • A. Federico
    • 4
  • N. De Stefano
    • 4
  1. 1.Centro Studi NeurolesiMedical School University of MessinaItaly
  2. 2.Department of Neurology and PsychiatryUniversity of FlorenceItaly
  3. 3.Department of RadiologyChildren Hospital Anna MeyerFlorenceItaly
  4. 4.Neurology & Neurometabolic UnitDept. Neurological and Behavioral Sciences University of SienaSienaItaly

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