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CD95 (APO-1Fas) and Parkinson's disease.

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axonal
This is likely to be a good thing. In this study,
the decrease in enhancing lesions accompanies the decrease
in clinical relapses, and many small and larger studies suggest
that this is a robust finding. Can we state that this decrease
in acute inflammatory activity will necessarily result in less
disability in individuals as measured by the EDSS? The answer is: Not at this time, but results from our study show an
effect of treatment on decreased disability progression, and
relapse,” and this decrease is paralleI to and proportionate to
a decrease in enhancing lesions and parallel to and proportionate to a decrease in the number and volume of T2hyperintense lesions.’.‘ This is reassuring.
Neither clinical nor M R measures are ideal in definitive
(phase 111) multiple sclerosis clinical trials. Clinical outcome
measures require very large sample sizes and a long followup. Clinically expressed relapses are only a small fraction of
the discrete inflammatory central nervous system events. Our
conclusion remains that gadolinium-enhancing lesion analyses can provide objective and quantitative results that support a treatment effect. T2-lesion analyses should show proportionate changes in the expected direction, to exclude the
(unlikely) possibility that a therapy could unIink the chain of
events from acute inflammatory to chronic T2 residua (footprints). M R is not a formal clinical surrogate, but it is an
important categorizing, prognostic, and pathophysiologic
measure that is likely to increase in acceptance in the neurologic community. M R is becoming accepted as a primary
outcome measure in phase 1-11 treatment trial^,^ yet does not
tell the whole story in phase 111 trials. In the future, more
specific MR-based measures of tissue damage related to axonal injury may become important.
Patients will always want to know that the therapy they
receive will result in improvement in function. They will also
be encouraged to know that treatment is likely to be influencing lesions at an early stage. These lesions might otherwise contribute to disability at a later stage. The ability to
predict the future accumulation of lesions is so far a unique
contribution of MR-based data in clinical trials.
“Department of Radiology, University of Colorado Health
Sciences Center, Denver, CO; TDepartment of Neurology,
Buffalo General Hospital, Buffalo, N E and $Biogen, Inc,
Cambridge, MA
References
1 . Simon JH, Jacobs LD, Campion M, et al. Magnetic resonance
studies of intramuscular interferon p-la for relapsing multiple
sclerosis. Ann Neurol 1998;43:79-87
2. The IFNB Multiple Sclerosis Study Group and the University of
British Columbia MS/MRI llalysis Group. Interferon beta-lb in
the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology 1995;45:1277-1285
3. Miller DH, Albert PS, Barkhof F, et al. Guidelines for the use of
magnetic resonance techniques in monitoring the treatment of
multiple sclerosis. Ann Neurol 1996;39:6-16
4. Koudriaveeva T, Thompson AJ, Fiorelli M, et al. Gadolinium enhanced MRI predicts clinical and MRI disease activity in
relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatty 1997;62:285-287
5. Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in
the lesions of multiple sclerosis. N Engl J Med 1998;338:278-285
6. Jacobs LD, Cookfair DL, Rudick RA, et a!. Intramuscular inter-
feron p- 1a for disease progression in relapsing multiple sclerosis.
Ann Neurol 1936;39:285-234
CD95 (APO-l/Fas) and Parkinson’s Disease
Andreas Hartrnann, MD,*t Stephane Hunot, PhD,*
and Etienne C. Hirsch. PhD*
Zipp and colleagues‘ have recently reported that serum levels
of soluble CD95 (APO-l/Fas) are increased in patients with
relapsing-remitting multiple sclerosis (MS). As part of the
control group with their 71 patients with MS, 25 of 66 individuals were suffering from neurodegenerative diseases. However, the kinds of neurodegenerative diseases included in the
study, and how the values in various disease groups differed
compared with the 19 healthy individuals that were part of the
control group, are not specified. This information might be
interesting to consider, as patients suffering from Alzheimer‘s
disease and Parkinson’s disease (PD) have been shown to express the CD95 receptor, which is undetectable in healthy
brain parenchyma: indicating that the CD95 receptorlligand
system may play a role in che pathogenesis of chese neurodegenerative diseases. Moreover, Mogi and associates3 have measured significantly increased levels of soluble CD95, by
enzyme-linked immunosorbent assay, in basal ganglia extracts
(caudate/putamen) from PD patients compared with cont r o l ~ They
. ~ also demonstrated a positive correlation between
soluble CD95 and tumor necrosis factor-a (TNFa) levels,
thus indicating that inflammatory phenomena may indeed
play a role in the pathogenesis of I’D. Unfortunately, the authors failed to provide data involving the substantia nigra as
the primary disease locus in PD. However, increased density
of TNFa-positive glial cells has been observed in the parkinsonian substantia nigra! In addition, nuclear translocation of
NF-KB is highly increased in dopaminergic neurons of PD
patients compared with controls, a final proinflammatory
pathway that could be triggered by either the TNF or the
CD95 receptor systems5 We therefore wonder if this likely
activation of cytokine receptors in I’D, even if certainly less
pronounced than in MS, might be reflected by alterations in
serum levels of soluble CD95 compared with healthy controls.
*INSEM U 289, CHU Piti.i-Salp&t&re, Paris, France; and
fDepartment of Neurology, Pbillipps University of Marburg,
Marburg, Germany
References
1. Zipp F, Weller M, Calabresi PA, et al. Increased serum levels of
soluble CD95 (APO-l/Fas) in relapsing-remirting multiple sclerosis. Ann Neurol 1998;43:116-120
2. Dowling P, Shang G, Raval S,et al. Involvement of the CD95
(APO-1IFas) receptor/ligand system in multiple sclerosis brain. J
Exp Med 1996;184:1513-15 18
3. Mogi M, Harada M, Kondo T, et al. The soluble form of Fas
molecule is elevated in parkinsonian brain tissues. Neurosci Lett
1996;220:195-198
4. Boka G, Anglade P, Wallach D, et al. Immunocytochemical
analysis of tumor necrosis factor and its receptors in Parkinson’s
disease. Neurosci Lett 1994;172:151-154
5. Hunot S, Brugg B, &card D, et al. Nuclear translocation of
NF-KB is increased in dopaminergic neurons of patients with Parkinson’s disease. Proc Natl Acad Sci USA 1997;34:7531-7536
Annals of Neurology
Vol 44
No 3
September 1998 425
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