Neurology -- Correspondence for Ge et al., 62 (4) 624-627

Correspondence published:

Reply to Kamholz et al: Oded Gonen, MD (15 July 2004)

Neuronal cell injury precedes brain atrophy in multiple sclerosis: John A. Kamholz, James Y. Garbern (15 July 2004)

Reply to Kamholz et al 15 July 2004

Oded Gonen, MD,
Department of Radiology, New York University School of Medicine
650 First Avenue, 6th Floor New York, NY 10016
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Re: Reply to Kamholz et al

oded.gonen{at}med.nyu.edu Oded Gonen, MD

We thank Kamholz et al for their comments and agree that the “pathophysiology of MS may be more complex than previously appreciated.” In relapsing-remitting MS, the more rapid decline of whole brain N- acetylaspartate (WBNAA) concentration versus the fractional brain parenchyma volume (fBPV) suggests that neuronal/axonal dysfunction or loss (NAA decline) may precede parenchyma loss.
Axonal injury was recently reassessed and found to be a significant feature in MS in both lesions and normal appearing white matter (NAWM) [1,2] confirming our findings of widespread NAA loss. Moreover, it has been shown, [2] using advanced immunohistopathology, that axonal loss can occur without apparent damage to the surrounding myelin sheath in both spinal NAWM and lesions.
Although axonal injury can result from chronic demyelination due to the loss of trophic support from the myelin, it has been reported that it is also attributed to direct inflammatory neurotoxic attack in acute lesions or neurodegeneration distant from lesions. [1] In either case, a significant amount of normal appearing myelin remains intact.
Histopathology has also shown that there is a significant decrease in the average axonal density (axons per unit area) in both lesions, ~61%, and NAWM, ~34%, in the corpus callosum and ~57% in the cervical spine. [3,4] Furthermore, it has also been demonstrated that there is a correlation between axonal injury and inflammatory mediators but not demyelination [1,5], which could also lead to NAA loss without atrophy. NAA loss has also been observed in EAE mouse model axons that are normally myelinated. [6]
Combined with reactive gliosis, (i.e., axon replacement by astrocytes [which results in NAA loss but (partially) conserves volume] the above findings support our observations and assertions that axonal pathology is not necessarily directly linked to atrophy and myelin loss. As we discuss in our paper, it is also possible that NAA decrease is due to diffuse abundant axonal dysfunction (as opposed to loss) which may be partially recoverable, as reported by De Stefano in the paper cited by Dr. Kamholz et al.
We concur with Kamholz et al assertion that the number of possible complex mechanisms does suggest caution when evaluating relationships between NAA alterations, axonal loss, demyelination, gliosis and atrophy and that the connections within these pathological processes may not be straightforward.
References
1. Trapp, B.D, Peterson, J, Ransohoff, R. M, Rudick, R, Mork, S, and Bo, L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338:278-285.
2. Bjartmar C, Kidd G, Mork S, Rudick R, Trapp BD. Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Annals Neurology 2000;48:893-901
3. Lovas G, Szilagyi N, Majtenyi K, Palkovits M, Komoly S. Axonal changes in chronic demyelinated cervical spinal cord plaques. Brain 2000;123:308-317.
4. Evangelou N, Konz D, Esiri MM, Smith S, Palace J, Matthews PM. Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis. Brain 2000;123:1845-9
5. Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Bruck W. Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 2000; 123:1174-83
6. Fruttiger, M, Montag, D, Schachner, M, and Martini R. Crucial role for the myelin-associated glycoprotein in the maintenance of axon-myelin integrity. Eur J Neurosci 1995;7:511-515.

Neuronal cell injury precedes brain atrophy in multiple sclerosis 15 July 2004

John A. Kamholz,
Wayne State University School of Medicine
Elliman Building, 421 E. Canfield, Detroit, MI 48201,
James Y. Garbern
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Re: Neuronal cell injury precedes brain atrophy in multiple sclerosis

jkamholz{at}med.wayne.edu John A. Kamholz, et al.

Ge et al report that whole brain NAA concentration decreases over time in MS patients more rapidly than brain volume. [1] These findings imply that axonal dysfunction precedes brain atrophy in patients with MS, suggesting that axonal dysfunction is the cause of atrophy.
In their discussion, the authors state, “…axons might die from direct damage from early inflammation, followed by Wallerian degeneration, leaving behind largely intact but empty myelin sheaths." We disagree with this statement and its interpretation.
Wallerian degeneration has been investigated in animals and humans, and is associated with a stereotyped set of events culminating in both axonal degeneration and demyelination. [2,3] Although the time course of demyelination associated with Wallerian degeneration may take several weeks, empty intact myelin sheaths are not found after this process.
An alternative explanation for the data of Ge et al is that there is widespread, decreased axonal NAA expression in MS brain prior to the onset of Wallerian degeneration and demyelination, suggesting that the primary insult in MS affects neuronal NAA metabolism without causing demyelination. This interpretation is consistent with studies reporting decreased NAA levels in the brain of patients with MS early in the disease in apparently normal white matter [4], as well as the demonstration that decreased levels of NAA can be reversible. [5]
These data suggest that the pathophysiology of MS may be more complex than previously thought.
References
1). Ge Y, Gonen O, Inglese M, Babb JS, Markowitz CE, Grossman RI. Neuronal cell injury precedes brain atrophy in multiple sclerosis. Neurology 2004; 62: 624-627.
2). Ramón y Cajal S (1928) Degeneration and Regeneration of the Nervous System. In: (May RM, ed), p 769p. Oxford: Oxford University Press.
3). Scherer SS, Easter SS, Jr. Degenerative and regenerative changes in the trochlear nerve of goldfish. J Neurocytol 1984;13:519-565.
4). Fu L, Matthews PM, et al. Imaging axonal damage of normal- appearing white matter in multiple sclerosis. Brain 1998; 121: 103-113.
5). De Stefano N, Narayanan S, et al. In vivo evidence for axonal dysfunction remote from focal cerebral demyelination of the type seen in multiple sclerosis. Brain 1999; 122: 1933-1939.