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Cerebrospinal fluid amino acids in amyotrophic lateral sclerosis.

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LETTERS
Cerebrospinal Fluid Amino
Acids in Amyotrophic
Lateral Sclerosis
Malte E. Kornhuber, MD,"
and Johannes Kornhuber, MDI
Rothstein and colleagues [ 11 reported elevated cerebrospinal
fluid (CSF) values for glutamate and aspartate in patients with
amyotrophic lateral sclerosis (ALS), supporting the hypothesis of disturbed glutamatergic neurotransmission in ALS. In
the same issue of the Annals, Perry and associates [2] failed
to demonstrate increased CSF-glutamate or aspartate values
in ALS. Except for these discrepancies, both studies agree
that a number of CSF amino acids (AA) are elevated in ALS.
Since blood-CSF barrier dysfunction is frequent in ALS 131,
and since a high serum to CSF gradient exists for most AA,
the finding of elevated CSF-AA may be an epiphenomenon
secondary to disturbed blood-CSF barrier. This would also
explain the elevated values for glutamate and aspartate reported by Rothstein and colleagues El], since the plasma to
CSF ratio of these AA is especially high- 100:1 for glutamate
and 20:l for aspartate compared to 7:1 for valine, 2.5:l for
serine, and 1:l for glutamine, respectively 141. With respect
to the discrepancies in the aspartate and glutamate values
between the two studies, we would like to stress the influence
of p H on stored specimens after acid deproteinization. The
formation of glutamate and aspartate from glutamine and
asparagine, respectively, is more likely in acid than in neutral
solution { 5 ] . Thus differences in the p H of stored specimens
could have resulted in different values for these AA.
In conclusion, we think both studies C1, 21 support a
blood-CSF barrier disturbance instead of glutamatergic dysfunction in ALS. In fact, if the neurodegeneration in ALS
were due to an overabundance of glutamate and/or glycine
at the NMDA-type glutamate receptor, then ALS patients
should benefit from therapy with NMDA-antagonists. This
is not the case because therapy with the NMDA-antagonist
amantadine 161 failed to improve the course of the disease
(for review see [7]).
"Max Planck Institate f i r Psychiatrie
Martinsried, Gemzany
t Universitatsnervenklinik
Wurzbarg, Germany
Rderences
1. Rothstein JD, Tsai G, Kuncl RW, e t al. Abnormal excitatory
amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol 1990;28:18-25
2. Perry TL, Krieger C, Hansen S, e t al. Amyotrophic lateral sclerosis: amino acid levels in plasma and cerebrospinal fluid. Ann Neu-
rol 1990;28:12-17
3. Aposrolski S, Nikolic J, Bugarski-Prokopljevic C, et al. Serum
and CSF immunological findings in ALS. Acta Neurol Scand
1991$3~96-98
4. Hamberger A, Nystrom B, Wickelso C, e t al. Amino acid gradients in the choroid plexus-cerebrospinal fluid-extracellular fluid
system. In: Fuxe K, Agnati LF (eds). Volume transmission in
the brain: novel mechanisms for neural transmission. New York:
Raven Press, 1991;299-305
5. Kornhuber ME, Balabanova S, Heiligensetzer G, et al. Stability
of human blood serum amino acids after storage at different p H
and temperature conditions. Clin Chim Acta 1991;197:189-200
6. Kornhuber J, Bormann J, Hubers M, et a]. Effects of the 1amino-adamancanes at the MK-801-binding site of the NMDAreceptor-gated ion channel: a human postmortem brain study.
Eur J Pharmacol Mol Pharmacol Sect 1991;206:297-300
7. Tandan R, Bradley WG. Amyotrophic lateral sclerosis: Part 1.
Clinical features, pathology, and ethical issues In management.
Ann Neurol 1985;18:271-280
Reply
Jeffrey D. Rothstein, MD, PhD, and
Ralph W. Kuncl, MD, PhD
The hypothesis of a disturbed blood-CSF barrier attempts
to explain the high values we observed for CSF glutamate
and aspartate as resulting from the generally high serum to
CSF gradient for amino acids. If that were true, the steepness
of the normal gradient should correlate linearly with the percent change in CSF we observed for ezlery other amino acid
in ALS. However, glycine, isoleucine, proline, cystine, and
citrulline also have high plasma/CSF ratios (>200: 1 to
15: 11, and those concentrations were normal in our ALS
specimens. Furthermore, when we examined the relationship
of the normal amino acid gradient to the percent increase in
spinal fluid amino acids in ALS (Fig), there was no overall
correlation ( r = - 0.065, n = 19). Glutamate and aspartate
were clearly outliers among the amino acids. Thus, the abnormalities we observed are not merely an epiphenomenon of
a defective blood-CSF barrier. The finding is not an artifact
of acidification, because a different analytical method, eliminating acidification of the CSF, continues to show abnormally
increased levels of CSF glutamate and aspartate in ALS [l].
The claim that "blood-CSF barrier dysfunction is frequent
in ALS" appears to be an overstatement. The cited report
(reference [31 above) and one other 121 did measure an increased ratio of CSFiserum albumin in patients with various
motor neuron disorders compared with normal controls, but
when neurological disease controls have been used, no increased ratio was found [3]. Direct measurement of transcapillary albumin leakage 141 and pathological examination of
vessels or meninges [ 5 ] have proved to be normal in ALS.
Regarding amantadine, the drug can act only as a weak
NMDA receptor antagonist. Given how little we know about
the localization of glutamate receptor subtypes o n motor neurons and that non-NMDA receptors may in fact play the
more prominent role [GI, a negative clinical result proves
little about the pathophysiological role of glutamate in ALS.
The quoted clinical trials of amantadine were uncontrolled,
the dosages and duration of therapy were not reported, and
they were of insufficient duration (12 weeks). It is difficult
to test pathophysiological hypotheses using clinical trials, but
a poorly designed trial is no test at all.
It is most important to note that extracellular concentrations of glutamate and aspartate in the CNS are not merely
the result of blood-CSF barrier partitioning but are highly
regulated by a high-affinity, high-capacity transporter. Teleologically speaking, specific transporters must be important
for endogenous transmitters that are themselves potentially
neurotoxic. In this regard, we now have convincing evidence
that a defect exists in neurotransmitter glutamate transport
in ALS, both in brain and spinal cord [7}.
Copyright 0 1992 by the American Neurological Association
449
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acid, lateral, amin, sclerosis, amyotrophic, fluid, cerebrospinal
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