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ARTICLES: C. Malmeström, S. Haghighi, L. Rosengren, O. Andersen, and J. Lycke Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS Neurology 2003; 61: 1720-1725 [Abstract] [Full text] [PDF]

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Jan N. Lycke, Clas Malmeström, Sara Haghighi, Lars Rosengren, Oluf Andersen   (3 February 2004)

Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS

Jagannadha R Avasarala   (3 February 2004)

Reply to Avasarala 3 February 2004
Jan N. Lycke Institute of Clinical Neuroscience, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden, Clas Malmeström, Sara Haghighi, Lars Rosengren, Oluf Andersen Send Correspondence to journal: Re: Reply to Avasarala jan.lycke{at}neuro.gu.se Jan N. Lycke, et al.	We thank Dr Avasarala for the comments regarding our study. There are no methodological problems to measure S-100B or NSE in serum. However, the mechanism by which CNS proteins enter CSF and serum differ. Passage to CSF is relatively unrestricted, and consequently levels of markers in CSF reflect the glial and nerve cell injury. Passage to serum is influenced by the function of the blood brain barrier (the integrity of the endothelial lining of the vascular bed), which means that serum-S-100B not only reflects the glial cell injury. In MS patients, the parenchymal damage is probably too small even during acute relapses and the function of the blood-brain barrier is relatively undisturbed to allow increased levels of CNS-derived proteins in serum. Furthermore, both S-100B and NSE are found in extra neuronal tissue; S-100B in adipose tissue and NSE in neuroendocrine cells. Thus, in serum neither of these markers truly reflects specific damage of nerve and glial cells. CSF samples were randomly taken in the patient and control groups. The concern of Dr. Avasarala that the estrus cycle of the individual should influence the results and conclusions is superfluous. Moreover, the CSF GFAP and NFL levels were not associated to gender. It is well known from various experimental studies that glucocorticoids influences the tissue concentrations of GFAP [1, 2], but if this change is large enough to affect CSF levels is not known. Approximately half of the prospectively followed patients with acute relapses had been subjected to methylprednisolone treatment. The levels between these and non treated did not differ. However, we agree with Dr. Avasarala that the effect of immunomodulatory treatment on astroglial cell reactivity is a subject for future studies. Neither NSE or S-100B are specific markers for MS. These markers are not tissue specific, which argues against serum determinations if CSF can be obtained. In CSF, levels are increased following any substantial injury to nerve or glial cells. Cell injury is a consequence of many neurological diseases, and the result of assays of brain cell damage markers have to be interpreted within the clinical context of the patients. References 1. O'Callaghan JP, Brinton RE, McEwen BS. Glucocorticoids regulate the synthesis of glial fibrillary acidic protein in intact and adrenalectomized rats but do not affect its expression following brain injury. J Neurochem 1991;57:860-869. 2. O'Callaghan JP, Brinton RE, McEwen BS. Glucocorticoids regulate the concentration of glial fibrillary acidic protein throughout the brain. Brain Res 1989;494:159-161.
Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS 3 February 2004
Jagannadha R Avasarala, Wake Forest University Health Sciences Medical Ctr Blvd., Winston-Salem, NC 27157 Send Correspondence to journal: Re: Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS jagan{at}wfubmc.edu Jagannadha R Avasarala	A recent article by Malmestrom et al [1] evaluated the usefulness of CNS-derived proteins in the CSF of patients with multiple sclerosis (MS) as markers of disease activity. While the study presents interesting data, it is intriguing why CSF and not serum was chosen for assay of S100B and neuron-specific enolase (NSE). Are there methodological concerns for serum-based assays for these proteins? The authors report that levels of glial fibrillary acidic protein (GFAP) in MS patients were higher compared to controls but it is important to note that GFAP expression fluctuates with the normal estrus cycle[2] and the authors present no evidence that GFAP levels were controlled for this variable in this study. Moreover, in rat hippocampus, transcriptional regulation of GFAP is inhibited by corticosteroids [3] a fact that would perhaps adversely influence GFAP levels in CSF of patients with relapses on steroids. The effect(s) of immunomodulatory agents on the proteins studied in patients with secondary progressive also MS also remains unclear. The authors point out that S100B, a 21-kDa calcium- binding protein produced and released primarily by astrocytes in the CNS as a biological marker for MS disease activity is questionable when one considers that levels of S100B rise following traumatic brain injury [4] and stroke. [5] Lastly, NSE levels are elevated in patients following cerebral ischemia, lung carcinoma and other diseases. S100B and NSE are perhaps not specific enough to be markers of MS disease activity. References 1.Malmestrom C, Haghighi S, Rosengren L, Andersen O, Lycke J. Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS. Neurology 2003;61:1720-1725. 2.Kohama SG, Goss JR, McNeill TH, Finch CE. Glial fibrillary acidic protein mRNA increases at proestrus in the arcuate nucleus of mice. Neurosci Lett. 1995; 183:164-166. 3.Rozovsky I, Laping NJ, Krohn K, Teter B, O'Callaghan JP, Finch CE. Transcriptional regulation of glial fibrillary acidic protein by corticosterone in rat astrocytes in vitro is influenced by the duration of time in culture and by astrocyte-neuron interactions. Endocrinology 1995:136:2066-2073. 4.Ingebrigtsen T, Waterloo K, Jacobsen EA, Langbakk B, Romner B. Traumatic brain damage in minor head injury: relation of serum S-100 protein measurements to magnetic resonance imaging and neurobehavioural outcome. Neurosurgery 1999;45:468-475. 5.Wunderlich MT, Ebert AD, Kratz T, Goertler M, Jost S, Herrmann M. Early neurobehavioural outcome after stroke is related to release of neurobiochemical markers of brain damage. Stroke 1999;30:1190-1195.