Brain N-acetylaspartate is elevated in Pelizaeus–Merzbacher disease with PLP1 duplication
Abstract
Objective: To assess alterations in brain metabolites of patients with Pelizaeus–Merzbacher disease (PMD) with the proteolipid protein gene 1 (PLP1) duplications using quantitative proton MRS.
Methods: Five unrelated male Japanese patients with PMD with PLP1 duplications were analyzed using automated proton brain examination with the point resolved spectroscopy technique (repetition and echo time of 5,000 and 30 msec). Localized spectra in the posterior portion of the centrum semiovale were acquired, and absolute metabolite concentrations were calculated using the LCModel.
Results: Absolute concentrations of N-acetylaspartate (NAA), creatine (Cr), and myoinositol (MI) were increased by 16% (p < 0.01), 43% (p < 0.001), and 31% (p < 0.01) in patients with PMD as compared with age-matched controls. There was no statistical difference in choline concentration.
Conclusion: The increased concentration of NAA, which could not be detected by previous relative quantitation methods, suggests two possibilities: axonal involvement secondary to dysmyelination, or increased cell population of oligodendrocyte progenitors. Elevated Cr and MI concentrations may reflect the reactive astrocytic gliosis. Our study thus emphasizes the importance of absolute quantitation of metabolites to investigate the disease mechanism of the dysmyelinating disorders of the CNS.
Get full access to this article
View all available purchase options and get full access to this article.
Supplementary Material
File (takanashi.doc)
- Download
- 308.50 KB
References
1.
Seitelberger F. Pelizaeus–Merzbacher disease. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology. Vol 10 : Leukodystrophies and poliodystrophies. Amsterdam: North Holland, 1970: 150–202.
2.
Hudson LD. Pelizaeus–Merzbacher disease and the allelic disorder X-linked spastic paraplegia type 2. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease, 8th ed. New York: McGraw-Hill, 2001: 5789–5798.
3.
Sistermans EA, de Coo RFM, De Wijs IJ Van Oost BA. Duplication of the proteolipid protein gene is the major cause of Pelizaeus–Merzbacher disease. Neurology . 1998; 50: 1749–1754.
4.
Inoue K, Osaka H, Imaizumi K, et al. Proteolipid protein gene duplication causing Pelizaeus–Merzbacher disease: molecular mechanism and phenotypic manifestations. Ann Neurol . 1999; 45: 624–632.
5.
Seitelberger F. Neuropathology and genetics of Pelizaeus–Merzbacher disease. Brain Pathol . 1995; 5: 267–273.
6.
Takanashi J, Sugita K, Tanabe Y, et al. MR-revealed myelination in the cerebral corticospinal tract as a marker for Pelizaeus–Merzbacher’s disease with proteolipid protein gene duplication. AJNR Am J Neuroradiol . 1999; 20: 1822–1828.
7.
Inoue K, Osaka H, Kawanishi C, et al. Mutations in the proteolipid protein gene in Japanese families with Pelizaeus–Merzbacher disease. Neurology . 1997; 48: 283–285.
8.
Pouwels PJW, Brockmann K, Kruse B, et al. Regional age dependence of human brain metabolites from infancy to adulthood as detected by quantitative localized proton MRS. Pediatr Res . 1999; 46: 474–485.
9.
Grodd W, Krageloh–Mann I, Klose U, Sauter R. Metabolic and destructive brain disorders in children: findings with localized proton MR spectroscopy. Radiology . 1991; 181: 173–181.
10.
van der Knaap MS, van der Grond J, Luyten RR, et al. 1H and 31P magnetic resonance spectroscopy of the brain in degenerative cerebral disorders. Ann Neurol . 1992; 31: 202–211.
11.
Howe FA, Maxwell RJ, Saunders DE, et al. Proton spectroscopy in vivo. Magn Reson Q . 1993; 9: 31–59.
12.
Takanashi J, Sugita K, Ishii I, et al. Evaluation of Pelizaeus–Merzbacher disease with proton magnetic resonance spectroscopy. AJNR Am J Neuroradiol . 1997; 18: 533–535.
13.
Spalice A, Popolizio T, Parisi P, Scarabino T, Iannetti P. Proton MR spectroscopy in connatal Pelizaeus–Merzbacher disease. Pediatr Radiol . 2000; 30: 171–175.
14.
Bonavita S, Schiffmann R, Moore DF, et al. Evidence for neuroaxonal injury in patients with proteolipid protein gene mutations. Neurology . 2001; 56: 785–788.
15.
Mader I, Roser W, Kappos L, et al. Serial proton MR spectroscopy of contrast-enhancing multiple sclerosis plaques: absolute metabolic values over 2 years during a clinical pharmacological study. AJNR Am J Neuroradiol . 2000; 21: 1220–1227.
16.
Suhy J, Rooney WD, Goodkin DE, et al. 1H MRSI comparison of white matter and lesions in primary progressive and relapsing-remitting MS. Mult Scler . 2000; 6: 148–155.
17.
Provencher SW. Estimation of metabolite concentrations from localized in vivo NMR spectra. Magn Reson Med . 1993; 30: 685–695.
18.
Frahm J, Hanefeld F. Localized proton magnetic resonance spectroscopy of brain disorders in childhood. In: Bachelard HS, ed. Magnetic resonance spectroscopy and imaging in neurochemistry, vol 8: advances in neurochemistry. New York: Plenum Press, 1997:329–402.
19.
Wittsack HJ, Kugel H, Roth B, Heindel W. Quantitative measurements with localized 1H MR spectroscopy in children with Canavan disease. J Magn Reson Imaging . 1996; 6: 889–893.
20.
Varho T, Komu M, Sonninen P, et al. A new metabolite contributing to N-acetylaspartate signal in 1H MRS of the brain in Salla disease. Neurology . 1999; 52: 1668–1672.
21.
Colello RJ, Pott U. Signals that initiate myelination in the developing mammalian nervous system. Mol Neurobiol . 1997; 15: 83–100.
22.
McKerracher L, David S, Jackson DL, et al. Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron . 1994; 13: 805–811.
23.
Mukhopadhyay G, Doherty P, Walsh FS, et al. A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration. Neuron . 1994; 13: 757–767.
24.
Canoll PD, Musacchio JM, Hardy R, et al. GGF/neuregulin is a neuronal signal that promotes the proliferation and survival and inhibits the differentiation of oligodendrocyte progenitors. Neuron . 1996; 17: 229–243.
25.
Vartanian T, Goodearl A, Viehöver A, Fischbach G. Axonal neuregulin signals cells of the oligodendrocyte lineage through activation of HER4 and Schwann cells through HER2 and HER3. J Cell Biol . 1997; 137: 211–220.
26.
Buttery PC, ffrech-Constant C. Laminin-2/integrin interactions enhance myelin membrane formation by oligodendrocytes. Mol Cell Neurosci . 1999; 14: 199–212.
27.
Anderson TJ, Schneider A, Barrie JA, et al. Late-onset neurodegeneration in mice with increased dosage of the proteolipid protein gene. J Comp Neurol . 1998; 394: 506–519.
28.
Vance JM. Charcot–Marie–Tooth disease type 2. Ann NY Acad Sci . 1999; 883: 42–46.
29.
Nishiyama A. Glial progenitor cells in normal and pathological states. Keio J Med . 1999; 47: 205–208.
30.
Nishiyama A, Chang A, Trapp BD. NG2+ glial cells: a novel glial cell population in the adult brain. J Neuropathol Exp Neurol . 1999; 58: 1113–1124.
31.
Knapp PE, Skoff RP, Redsone DW. Oligodendroglial cell death in jimpy mice: an explanation for the myelin deficit. J Neurosci . 1986; 6: 2813–2822.
32.
Urenjak J, Williams SR, Gadian DG, Noble M. Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci . 1993; 13: 981–989.
33.
Bhakoo KK, Pearce D. In vitro expression of N-acetyl aspartate by oligodendrocytes implications for proton magnetic resonance spectroscopy signal in vivo. J Neurochem . 2000; 74: 254–262.
34.
Siesjo BK, Folbergrova J, MacMillan V. The effect of hypercapnia upon intracellular pH in the brain, evaluated by the bicarbonate-carbonic acid method and from the creatine phosphokinase equilibrium. J Neurochem . 1972; 19: 2483–2495.
35.
Danielsen ER, Ross B. The clinical significance of metabolites. In: Danielsen ER, Ross B. ed. Magnetic resonance spectroscopy diagnosis of neurological diseases. New York: Marcel Dekker, 1999: 23–43.
36.
Bitsch A, Bruhn H, Vougioukas V, et al. Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy. AJNR Am J Neuroradiol . 1999; 20: 1619–1627.
37.
De Stefano N, Matthews PM, Antel JP, Preul M, Francis G, Arnold DL. Chemical pathology of acute demyelinating lesions and its correlation with disability. Ann Neurol . 1995; 38: 901–909.
38.
Farina L, Bizzi A, Finocchiaro G, et al. MR imaging and proton MR spectroscopy in adults Krabbe disease. AJNR Am J Neuroradiol . 2000; 21: 1478–1482.
39.
Witter B, Debuch H, Klein H. Lipid investigation of central and peripheral nervous system in connatal Pelizaeus–Merzbacher’s disease. J Neurochem . 1980; 34: 957–962.
40.
Danielsen ER, Ross B. Basic physics of MRS. In: Danielsen ER, Ross B. ed. Magnetic resonance spectroscopy diagnosis of neurological diseases. New York: Marcel Dekker, 1999: 5–22.
Information & Authors
Information
Published In
Copyright
© 2002.
Publication History
Received: June 5, 2001
Accepted: September 28, 2001
Published online: January 22, 2002
Published in print: January 22, 2002
Authors
Metrics & Citations
Metrics
Citations
Download Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.
Cited By
- Neurochemistry evaluated by magnetic resonance spectroscopy in a patient with FBXO28-related developmental and epileptic encephalopathy, Brain and Development, 45, 10, (583-587), (2023).https://doi.org/10.1016/j.braindev.2023.07.003
- Altered high-energy phosphate and membrane metabolism in Pelizaeus–Merzbacher disease using phosphorus magnetic resonance spectroscopy, Brain Communications, 4, 4, (2022).https://doi.org/10.1093/braincomms/fcac202
- Clinical 1H MRS in childhood neurometabolic diseases — part 2: MRS signatures, Neuroradiology, 64, 6, (1111-1126), (2022).https://doi.org/10.1007/s00234-022-02918-9
- Astrocyte and Oligodendrocyte Cross-Talk in the Central Nervous System, Cells, 9, 3, (600), (2020).https://doi.org/10.3390/cells9030600
- Neurogenetics of Pelizaeus–Merzbacher disease, Neurogenetics, Part II, (701-722), (2018).https://doi.org/10.1016/B978-0-444-64076-5.00045-4
- Degenerative Disorders of the Newborn, Volpe's Neurology of the Newborn, (823-858.e11), (2018).https://doi.org/10.1016/B978-0-323-42876-7.00029-6
- Pelizaeus–Merzbacher Disease, Developmental Neuropathology, (417-425), (2018).https://doi.org/10.1002/9781119013112.ch34
- Childhood leukodystrophies: A literature review of updates on new definitions, classification, diagnostic approach and management, Brain and Development, 39, 5, (369-385), (2017).https://doi.org/10.1016/j.braindev.2017.01.001
- Interstitial de novo 18q22.3q23 deletion: clinical, neuroradiological and molecular characterization of a new case and review of the literature, Molecular Cytogenetics, 9, 1, (2016).https://doi.org/10.1186/s13039-016-0285-1
- Reprint of “Hypomyelinating disorders: An MRI approach, Neurobiology of Disease, 92, (46-54), (2016).https://doi.org/10.1016/j.nbd.2015.10.022
- See more
Loading...
View Options
Get Access
Login options
Check if you have access through your login credentials or your institution to get full access on this article.
Personal login Institutional LoginPurchase Options
Purchase this article to get full access to it.