Cerebrospinal fluid choline levels in Parkinson's disease.

Reply
E. Heber-Katz
The observations of Jung and colleagues concerning our recent report [l] in the Amah of N e u d o u relate to the frequency of specific VP8-bearing TcRs in experimental allergic
encephalomyelitis (EAE)- and experimental allergic neuritis
(EAN)-specificT-cell lines. The results presented are in fact
not at odds with our published results.
The key point that these investigators make is that in the
exploration of 10 neuritogenic T-cell lines, only 1 was very
strongly positive for Vp8.2, a second was moderately positive, and 2 others were weakly positive as measured cytofluorometrically with the new anti-Vp8.2 reagent, monoclonal
antibody (mAb) R78 [2]. Their point is that although Vp8.2
is highly representative of the rat EAE system, which was in
fact first observed by our laboratory 13, 41 and has been
confirmed by others and these investigators as well, VQ8.2
is at best only weakly represented in EAN T-cell lines.
Our paper [ 11clearly and straightforwardly states that the
methodology (our Vp8 probe) used allows us to say that Vp8
family members are represented within the population of two
EAN lines, but that it cannot distinguish between the five
family members we have identified (141, unpublished data).
We specifically made it clear that Vf38.2 may not be the
dominant neuritogenic V region. Furthermore, the main
thrust of our paper was that the combination of Vu2Vp8 was
seen in the cell lines and, as previously found for EAE 131
and EAU [ 5 , 61, that we found doned hybridomas that used
these V regions in combination. Our results published in this
paper confirm and extend our V-region disease hypothesis
171 to a third autoimmune disease, EAN.
We have new data soon to be submitted for publication
that, in fact, addresses the Vp8 subfamily usage in EAN. Five
out of five SP26 peptide-specific lymph node T-cell lines
were found to be Vp8+ in terms of hybridization, and sequencing revealed that four Vp8 family members are being
used in response to SP26 peptide. Clearly, the EAN response is not as restricted as the EAE response in terms of
specific use of the Vp8.2 family member as Jung and colleagues have carefully shown using R78. The key observation
of Vol2VpS in combination stands, however, and has been
extended.
Finally, it should be noted that although there is no real
difference in the conclusion between our original report and
the report by Jung and colleagses, there are in fact differences between the experimental methodologies. In particular, our lines are primed to SP26 peptide and are poorly
responsive to P2 protein, but, however, are highly neuritogenic, whereas the neuritogenic lines of Jung and colleagues
are P2 specific and most are cross-reactive to SP26. Thus,
these cells are likely drawn from different populations and
have possibly different fine specificities.
The Wistar Institute
Philadelphia, PA
References
1.
Clark L, Heber-Karz E, Rosrami A. Shared T cell receptor gene
usage in experimental allergic neuritis and encephalomyelitis.
Ann Neurol 1992;31:587-592
114 Annals of Neurology
Vol 34 No 1 July 1993
2. Torres-Nagel NE, Gold DP, Hunig T. Identification of rat
TdV8.2, 8.5, and 20 gene products by monoclonal antibodies.
Immunogenetics 1993;37 :304- 308
3. Burns F, Li X, Shen N, et al. Both rat and mouse TcRs specific
for the encephalitogenic determinant of MBP use similar V a
and Vp chain genes even though the MHC and encephalitogenic
determinants being recognized are different. J Exp Med 1989;
169127-39
4. Zhang X-M, Heber-Kacz E. Encephalitogenic T cells in adult
Lewis rats appear to be products of early ontogeny. J lmmunol
1332;148:746
5. Gregorson DS, Fling SP, Merryman CF, et al. Conserved TcR V
gene usage by uveirogenic T cells. Clin Immunol Immunopathol
1991;58:154
6. Merryman CF. Donoso LA, Zhang XM, et al. Characterization
of a new potent immunopathogenic epitope in S-antigen which
elicits T cells expressing VpS and Va2 genes. J Immunol 1991;
14675
7. Heber-Katz E, Acha-Orbea H. The V-region hypothesis: evidence from autoimmune encephalomyelitis. Immunol Today
1989;10:164
Cerebrospinal Fluid
Choline Levels in
Parkinson's Disease
Aycel Nasr, MD," Nathalie Bertrand, PhD,I
Maurice Giroud, MD," Lucia Septien, MD,*
Pierre Gras, MD,* Raymond Dumas, MD,"
Alain Beley, PhD,? and Jean Bralet, PhDt
Manyam and colleagues [l] have reported a 60% decrease
in cerebrospinal fluid (CSF) choline levels in patients with
Parkinson's disease (PD) compared with age-matched controls. This finding suggests that measurement of CSF choline
may be used as a diagnostic tool in patients with P D but
disagrees with previous studies 12-4J, which failed to observe significant changes in CSF choline levels in patients
with PD. According to Manyam and colleagues [ 11, the discrepancy might originate from differences in the age of corresponding control subjects. Using high-performance liquid
chromatography and electrochemical detection, we have
measured CSF choline levels in 21 patients with idiopathic
PD (mean age, 68.9 2 12.6 yr; mean % SD) and in 20
age-matched control subjects (mean age, 68.2 ? 12.8 yr).
PD patients with no cognitive impairments (Mini-Mental
State Examination) were evaluated for motor function by the
New York University P D Scale (average of 65 % 15 points
on the 100-point scale) and for depression by the Hamilton
Score. They were classified into two subgroups according to
the presence (n = 7) or the absence (n = 14) of depression.
CSF choline levels were not significantly altered in patients
with PD (2.17 2 0.08 nmol/ml in patients with associated
depression and 2.79 ? 0.80 nmol/ml in patients without
depression) when compared with controls (2.37 ? 0.58
nmol/ml). These results d o not confirm the data reported by
Manyam and colleagues [11 and the reasons for this discrepancy are unclear. Therapy is probably not a factor because
our patients received carbidopdlevodopa, as did one group
of patients from the study by Manyam and colleagues [I).
-
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Transfer of Multiple
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0 PARKINSON
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Howard L. Lipton, MD
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Relation between cerebrospinalfluid choline concentrutton and
age in control subjects (sold line; n = 20; r = 0.22, NS, and
in patients with Parkinson’s disease without depression (dotted
line; n = 14; r = 0.65, p < 0.01).
The severity of the disease and the presence of associated
disorders such as dementia may represent important factors
that were not addressed in the study by Manyam and colleagues 111.
We also examined the relation between age and CSF choline levels. A significant positive correlation was found in
patients with PD but not in control subjects (Fig). PD is
characterized by cholinergic hyperactivity in striatum and by
degenerative processes affecting mainly nigral dopaminegic
neurons, but also cholinergic neurons in the basal forebrain
[S). It is unlikely that CSF choline could be affected by
changes in acetylcholine metabolism because the choline in
that pool represents only a tiny fraction of central nervous
system choline. More likely, the age-related increase in CSF
choline observed in patients with PD may reflect an increased
rate of phospholipid breakdown, suggesting an acceleration
of neuronal degeneration with aging in patients with PD.
*Service de Neurologie
H@itai G&t%alde Dijon
t Laboratoire de Phamcodynamie
Fact& de Phamacie
Universite‘de Bourgogne, France
References
E, Colliver JA. Cerebrospinal fluid
choline levels are decreased in Parkinson’s disease. Ann Neurol
1. Manyam BV, Giacobini
1990;27:683-685
2. Aquilonius SM, Nystrom B, Schubereh J, Sundwall A. Cerebrospinal fluid choline in extrapyramidal disorders.J Neurol Neurosurg Psychiatry 1972;35:720-725
3. Welch MJ, Markham CH, Jenden DJ. Acetylcholine and choline
in cerebrospinal fluid of patients with Parkinson’s disease and
Huntington’s chorea. J Neurol Neurosurg Psychiatry 1976;
39~367-374
4. Flentge F, van der Meumen WMH, Lakke JPWF, Teelken AW.
CSF choline levels in groups of patients with cranial trauma or
extrapyramidal disorders. J Neurol Neurosurg Psychiatry 1984;
47:207-209
5. Nakano I, Hirano A. Parkinson’s disease: neuron loss in the nucleus basalis without concomitant Alzheimer’s disease. Ann Neurol 1984;15:415-4 18
In the July 1992 issue of the Proceedmgs of the Nutzonal Academy of Scienca (USA) 111, Y . Saeki and colleagues reported
the tranfer of a multiple sclerosis (MS)-like disease and pathology to severe combined immunodeficiency (SCID)
mice with MS cerebrospinal fluid (CSF) mononuclear cells
(MNC). Only CSF M N C from patients with MS in an exacerbated state transferred disease and pathological changes. The
authors conclude that CSF M N C from MS patients in exacerbation are encephalitogenic, therefore supporting the notion
that MS is autoimmune. O n the other hand, clear evidence
of cellular immunity to neuroantigens in MS versus control
subjects is still lacking. Because this study is of importance
and interest to the neurological community, and the Proceedings of the National Acu&my of Sciences (USA) does not publish letters, I am writing to the Annals with commentary.
Saeki and colleagues [l] note that the possibility of transfer
of an infectious agent, such as a virus, is not excluded. Another explanation of these results needs to be considered,
namely reactivation of a latent virus or induced spread of an
indlgenous virus in recipient mice. Because the time of onset
of clinical signs (4-6 weeks after inoculation) and distribution
and character of the pathologcal changes are typical of
Theiler’s murine encephalomyelitis virus (TMEV) infection,
the possibility of TMEV complicating these experiments
needs to be excluded. TMEV is ubiquitous in non-barrier
mouse colonies and it has been a contaminant in other experiments where human tissues and fluids were passaged in mice
[2, 31. Trauma from the intracisternal injection in a mouse
with TMEV viremia could disseminate this virus to the CNS.
As is sometimes the case in such studies, control mice may
not have been inoculated contemporaneously, thus mice used
at different times may not have been infected or not had
viremia, thereby explaining the lack of disease in the control
animals. The SCID mucation in these studies was o n a congenic background (BALB/c - C57BW6) normally resistant
to TMEV-induced demyelinating disease. However, the fact
that the host is immunodeficient probably itself confers some
degree of susceptibility to TMEV. In addition, it has recently
been found that some BALBlc substrains are susceptible to
TMEV.
Saeki and colleagues [l}could readily determine whether
TMEV is present by immunostaining spinal cord sections
from their affected mice for TMEV antigens. In the meantime, the authors and others interested in reproducing these
experiments should be aware of the potential complication
of TMEV in non-barrier mouse colonies.
D@mtment of Neurology
Mount Sinai School 4Medicine
Nem York. N Y
Annals of Neurology
Vol 34
No 1 July 1993 115