Neurology -- Correspondence for Hanefeld et al., 65 (5) 701-706

Correspondence published:

Quantitative proton MRS of Pelizaeus–Merzbacher disease: Evidence of dys- and hypomyelination: Omar A. Khan (27 October 2005)

Reply to Khan: Peter Dechent, F. A. Hanefeld, K. Brockmann, P.J.W. Pouwels, B. Wilken, and J. Frahm (27 October 2005)

Quantitative proton MRS of Pelizaeus–Merzbacher disease: Evidence of dys- and hypomyelination 27 October 2005

Omar A. Khan,
Wayne State University School of Medicine
4201 St Antoine; 8D-UHC, Detroit, MI 48201
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Re: Quantitative proton MRS of Pelizaeus–Merzbacher disease: Evidence of dys- and hypomyelination

okhan{at}med.wayne.edu Omar A. Khan

Hanefeld et al [1] report interesting findings from a quantitative proton MRS study of Pelizaeus-Merzbacher disease (PMD). The proton MRS observations made by the authors have implications for childhood dysmyelinating disorders and also adult demyelinating disorders including multiple sclerosis (MS). However, we request response and clarification on some aspects of their data.
We would like to inquire why the authors did not use point-resolved spectroscopy (PRESS) instead of stimulated echo acquisition mode (STEAM) if they planned to do single-voxel imaging instead of chemical shift imaging employing multiple voxels. In our and others' experience, even with short echo times of 30 or 20 ms, the signal to noise from PRESS is much better and reproducible than STEAM, particularly in single voxel imaging studies.
We appreciate the argument Hanefeld et al present regarding the elevated tNAA levels in PMD patients. However, the relative increased density of axons by itself should not account for the elevation in tNAA using abosolute levels. It would be important to examine "relatively" less affected parts of the white matter to demonstrate this "gradient" effect dependent on the relative density of axons. It would be interesting to see if the authors have this data gathered during their studies with PMD patients. Other mechanisms including an exaggerated neuronal response in the presence of widespread myelin absence accounting for some of the elevation in tNAA should be explored.
Can the authors comment on the source of "free" myo-inositol (Ins) signal in PMD? Is it entirely as a result of rapid membrane turnover and astroctyic proliferation or are other mechanisms also involved? Although thought to be an astrocytic marker [2], Ins, which we are studying in MS, it is not clear if one can differentiate the "free" Ins signal from astrocytes and oligodendrocytes, which may be important in inflammatory injury (which is not the case in PMD but in MS).
References
1. Hanefeld FA, Brockmann K, Pouwels PJW, Wilken B, Frahm J, Dechent P. Quantitative proton MRS of Pelizaeus-Merzbacher disease. Evidence of dys- and hypomyelination. Neurology 2005;65:701-706.
2. Brand A, Richter-Landsberg C, Leibfritz D. Multinuclear NMR studies on and energy metabolism of glial and neuronal cells. Dev Neurosci 1993;15:289-298.
Disclosure: The author reports no conflicts of interest.

Reply to Khan 27 October 2005

Peter Dechent,
MR-Forschung in der Neurologie und Psychiatrie
Humanmedizin, Georg-August-Universitaet, 37099 Goettingen, Germany,
F. A. Hanefeld, K. Brockmann, P.J.W. Pouwels, B. Wilken, and J. Frahm
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Re: Reply to Khan

pdechen{at}gwdg.de Peter Dechent, et al.

We thank Dr. Khan for his comments and inquiries. Assuming otherwise identical conditions the use of three 90° rf pulses in STEAM as opposed to one 90° rf pulse followed by two 180° refocusing pulses in PRESS results in a better spatial definition of the VOI (individual slice profiles). This particularly holds true if the duration of the rf pulses is kept short to minimize echo times. As a consequence, STEAM results in less contamination from outer volume signals and allows for a safe positioning of the VOI close to tissue boundaries without the need of additional suppression techniques. Moreover, STEAM will always have a shorter echo time than PRESS which involves two echo times. Thus, PRESS looses part of its SNR advantage by slightly stronger T2 attenuation. Finally, even for the same echo time as in STEAM, PRESS doubles the unwanted J modulation of strongly spin-coupled metabolite resonances (glutamate, glutamine, myo-inositol, glucose, taurine).
Cheng et al [3] found an excellent correlation between neuronal loss shown by traditional neurohistopathology and a decrease of the tNAA level measured by proton MRS. Therefore, a close correlation between increased density of axons and elevated tNAA levels can be concluded. We are not aware of any evidence for an "exaggerated neuronal response" in PMD.
The concentration of myo-inositol (Ins) as a secondary messenger involved in cellular signal processing is much too small for a reliable detection by localized proton MRS. [4] The Ins signal detected by MRS reflects free Ins, an important non-nitrogenous organic osmolyte in mammalian brain tissue. [5] There is no evidence for a "special" source of free Ins in PMD. Ins has been detected in high concentrations in astrocytic cell cultures and identified as an astrocytic marker for in vivo MRS studies. [2] On the other hand, oligodendrocytes show very high concentrations of choline-containing compounds (Cho). An increase of Cho rather than Ins indicates rapid membrane turnover as seen in demyelinating conditions. Nevertheless, classical demyelinating disorders in childhood are often accompanied by elevated Ins as well.
References
3. Cheng LL, Ma MJ, Becerra L, et al. Quantitative neuropathology by high resolution magic angle spinning proton magnetic resonance spectroscopy. Proc Natl Acad Sci U S A. 1997;94:6408-6413.
4. Berridge MJ. Inositol triphosphate and calcium signalling. Nature 1993;361:315-325.
5. Thurston JH, Sherman WR, Hauhart RE, Kloepper RF. Myo-inositol: A newly identified nonnitrogenous osmoregulatory molecule in mammalian brain. Ped Research 1989;26:482-485.
The authors report no conflicts of interest.