Published ahead of print on March 11, 2010
doi: 10.3174/ajnr.A2053

American Journal of Neuroradiology 31:E45, May 2010
© 2010 American Society of Neuroradiology

K. Bendfeldt^a, L. Kappos^a, E.W. Radue^a and S. Borgwardt^a
aMedical Image Analysis Centre University Hospital Basel Basel, Switzerland

We read with great interest the article by Filippi and Rocca entitled “MR Imaging of Gray Matter Involvement in Multiple Sclerosis: Implications for Understanding Disease Pathophysiology and Monitoring Treatment Efficacy.”¹The authors reported on how advances in MR imaging technology and methods of analysis are contributing to the detection of focal lesions and occult pathology and atrophy in multiple sclerosis (MS). They concluded that the application of quantitative MR imaging–based techniques has shown consistently that gray matter (GM) is not spared by MS and that GM damage is present in all MS phenotypes since the earliest clinical stages of the disease, affects various GM compartments, and is associated with the main clinical manifestations of MS. They discussed several aspects of GM pathology, including focal macroscopic lesions, intrinsic diffuse changes, and irreversibletissue loss.

To date, relatively little is known about the spatiotemporal relationship of regional white matter (WM) and GM changes. A recent cross-sectional study using MR imaging–based lesion probability maps (LPMs) showed that retrograde damage of the perikarya from axonal injury within MS plaques might be crucial to the genesis of GM atrophy.² In this study, an association of focal WM damage in the optic radiations with upstream GM atrophy of the lateral geniculate nucleus and visual cortex in the calcarine sulcus of the occipital lobe was found. To develop a better understanding of the longitudinal spatiotemporal relations between regional GM and WM changes in patients with MS, our group studied the associations of regional WM lesion changes and regional GM volume reductions in patient groups with either “progressive” or “nonprogressive” WM lesion load. Voxel-wise regional brain volume changes were assessed by using voxel-based morphometry (VBM), a structural image analysis method that avoids an a priori knowledge about the relationship among these anatomic structures and queries the entire brain.³ We also used LPMs, obtained from T2-weighted or T1-weighted structural MR imaging of a large sample of patients with MS and applied “optimized” VBM to compare WM and GM changes.⁴

By using LPMs, we demonstrated a more widespread regional distribution pattern of WM lesions in the progressive group compared with the nonprogressive group of patients with relapsing-remitting MS.⁴ This might be a central issue predicting further lesion development as well as development of GM atrophy in patients with MS. Furthermore, the longitudinal VBM analysis revealed spatial T2 lesion changes in parts of the cerebral projection, commissural, and association fiber systems only in the progressive group. These changes were accompanied by GM volume reductions in specific cortical regions predilected for atrophy. Multiple disconnections between different areas of cortical networks could relate to widespread cortical atrophy and cognitive impairment, commonly observed in MS. A small number of nonprogressive lesions located in WM tracts (ie, of the associative cortex) might have interrupted relatively few connections with little or no effect on regional GM volumes in the nonprogressive group. A larger number of progressive lesions, however, accompanied by a widespreadspatial distribution, could have interrupted a higher number of associative connections, thereby contributing to the progression of GM atrophy in the progressive group. Further large-scale studies using VBM or other measures for estimation of regional brain volumes may help to disentangle the spatiotemporal relations between regional GM and WM pathology and could impact current views on MS pathogenesis.

References

1. Filippi M, Rocca MA. MR imaging of gray matter involvement in multiple sclerosis: implications for understanding disease pathophysiology and monitoring treatment efficacy. AJNR Am J Neuroradiol 2009 Dec 31. [Epub ahead of print]
2. Sepulcre J, Goni J, Masdeu JC, et al.Contribution of white matter lesions to gray matter atrophy in multiple sclerosis: evidence from voxel-based analysis of T1 lesions in the visual pathway. Arch Neurol 2009;66:173–79[Abstract/Free Full Text]
3. Bendfeldt K, Kuster P, Traud S, et al. Association of regional gray matter volume loss and progression of white matter lesions in multiple sclerosis: a longitudinal voxel-based morphometry study. Neuroimage 2009;45:60–67[CrossRef][Medline]
4. Bendfeldt K, Blumhagen JO, Egger H, et al. Spatiotemporal distribution pattern of white matter lesion volumes and their association with regional gray matter volume reductions in relapsing-remitting multiple sclerosis.Human Brain Mapping. 2010 Jan 27 [Epub ahead of print]

Reply

Published ahead of print on March 11, 2010
doi: 10.3174/ajnr.A2047

American Journal of Neuroradiology 31:E46, May 2010
© 2010 American Society of Neuroradiology

M. Filippi^a and M.A. Rocca^a
aNeuroimaging Research Unit Institute of Experimental Neurology Division of Neuroscience Scientific Institute and University Hospital San Raffaele Milan, Italy

We read with interest the comments from Drs Bendfeldt, Radue, Borgwardt, and Kappos to our recently published review.(1) Our scope was to summarize the most promising results obtained from the use of MR imaging for the assessment of gray matter (GM) pathology and dysfunction in patients with multiple sclerosis (MS) and to envisage the possible implications of such findings in the monitoring of new experimental treatments. As we discussed,the topic is extremely broad and includes not only our improved ability to detect macroscopic lesions in the GM(2) but also an urgent need to apply, in a systematic way, MR imaging techniques with the potential of quantifying occult damage in the GM, GM tissue volume loss, and topographic distribution of GM abnormalities and of establishing the role of brain plasticity in limiting the clinical consequences of tissue injury.

As pointed out by Bendfeldt and coworkers in their letter, the core part of which is strikingly similar to another letter they published previously,(3) and by ourselves in the review article, one of the results of this research was the demonstration of an association between T2 lesions in the white matter (WM) and GM abnormalities. Such an association has been demonstrated by many studies(1) in patients with MS by using different techniques and is supported by pathologic findings,(4) which showed that WM changes are accompanied by a significant burden of demyelination in the GM. Among these many studies, we also quoted the one that Bendfeldt et al published last year inNeuroimage,(5) and we are grateful to these authors for pointing out that an additional article dealing with the same issue is “in press,” which, for obvious reasons, we could not quote. Unfortunately, however, the biologic meaning of such a relationship and its timing are poorly known issues, which require further research. Voxel-wise methods for defining the regional distribution of lesions in the WM, combined with a regional assessment of GM atrophy distribution and progression, are certainly promising, especially in the context of longitudinal studies.

Nevertheless, as we discussed in our article,(1) there are many aspects of GM pathology in MS that have emerged during the past few years that also need to be considered. One of the most important is the presence of GM macroscopic lesions, which, as is the case of WM plaques, accumulate with time and are related to the progression of brain atrophy and disability.(6,7) How these GM lesions evolve with respect to WM ones is yet unclear. Another important aspect is the damage to “critical” WM fiber bundles, which might also be responsible for selective GM atrophy and disconnection syndromes in MS. As a consequence, we believe that the idea of responding in a clear-cut manner to such an important research question by applying voxel-based morphometry and lesion probability maps in isolation reflects a rather simplisticview of MS pathobiology and is likely to be insufficient.

References

1. Filippi M, Rocca MA. MR imaging of gray matter involvement in multiple sclerosis: implications for understanding disease pathophysiology and monitoring treatment efficacy. AJNR Am J Neuroradiol 2009 Dec 31 [Epub ahead of print]
2. Geurts JJ, Bo L, Pouwels PJ, et al.Cortical lesions in multiple sclerosis: combined postmortem MR imaging and histopathology. AJNR Am J Neuroradiol 2005;26:572–77[Abstract/Free Full Text]
3. Bendfeldt K, Radue EW, Borgwardt SJ, et al. Progression of gray matter atrophy and its association with white matter lesions in relapsing-remitting multiple sclerosis. J Neurol Sci 2009;285:268–69, author reply 69[CrossRef][Medline]
4. Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005;128:2705–12[Abstract/Free Full Text]
5. Bendfeldt K, Kuster P, Traud S, et al. Association of regional gray matter volume loss and progression of white matter lesions in multiple sclerosis: a longitudinal voxel-based morphometry study. Neuroimage 2009;45:60–67[CrossRef][Medline]
6. Calabrese M, Rocca M, Atzori M, et al. A 3-year magnetic resonance imaging study of cortical lesions in relapse-onset multiple sclerosis. Ann Neurol 2010;67:376–83[Medline]
7. Calabrese M, Rocca MA, Atzori M, et al. Cortical lesions in primary progressive multiple sclerosis: a 2-year longitudinal MR study. Neurology 2009;72:1330–36[Abstract/Free Full Text]