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Further evidence that interactions between CYP2D6 and pesticide exposure increase risk for Parkinson's disease.

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LETTERS
Preoperative Response to Levodopa is the Best
Predictor of Transplant Outcome
Curt R. Freed, MD,1 Robert E. Breeze, MD,1
Stanley Fahn, MD,2 and David Eidelberg, MD3
Patient selection may be the explanation for the negative results seen in the neurotransplantation study for Parkinson’s
disease (PD) reported by Olanow and colleagues.1 Their primary outcome variable, the United Parkinson’s Disease Rating Scale (UPDRS) motor “off ” score, failed to improve in
transplant patients despite positron emission tomography
(PET) scan and autopsy evidence of graft survival. Their results are in contrast with our earlier double-blind study in
which grafted subjects showed significant improvement in
motor “off ” scores for the group as a whole ( p ⫽ 0.04) as
well as for the younger subjects ( p ⬍ 0.01).2
Our subsequent analysis has shown that the preoperative
response to L-dopa is the best predictor of transplant outcome.3 Before transplant, our younger group (ⱕ60) improved 79% with L-dopa, whereas older subjects (61–75
years) improved only 54%.2 Regression analysis using all
subjects showed that motor “off ” scores improved by 33%
of the L-dopa response at 1 year and 50% at 2 years after
transplant. There was no independent contribution of age or
disease severity. Transplant subjects in the study by Olanow
and colleagues1 had an average improvement in “off ” scores
of only 58% with L-dopa preoperatively. We would suggest
that they check the relation between preoperative L-dopa response and subsequent transplant outcome.
There were other differences in the two studies. We used
no immunosuppression and yet observed survival of transplants in 85% of patients by PET scan or autopsy. Our findings indicate that immunosuppression is probably unnecessary for human fetal neurotransplantation.
Both double-blind studies included subjects who had
failed drug therapy, with most having drug-induced dyskinesias. Since 1990, we have noted dyskinesias after transplant
that usually improve with reductions in L-dopa doses.2 In 3
of our 34 transplant patients4 and in 3 of their 21 patients,
deep brain stimulating electrodes into pallidum or subthalamic nucleus (STN) have been needed to control dyskinesias. Olanow and colleagues reported mild “off ” dyskinesias
in 53% of transplant patients, demonstrating the partial dopamine effect of transplants in this dyskinesia-prone group.
We agree that neither transplants nor deep brain stimulation into STN can improve the “best on ” state produced by
L-dopa and both are associated with some risk of persistent
dyskinesias.5 Clinical signs that do not respond to L-dopa
probably represent more extensive brain pathology than the
loss of dopamine neurons. Who is the “ideal ” transplant
subject? From our data, it is a patient disabled by the “off ”
state who has an excellent response to L-dopa (⬎70% improvement in UPDRS motor “off ” scores) and who does not
have drug-induced dyskinesias. An open question is whether
transplants can prevent the progression of PD and the development of dyskinesias in patients who do not already have
that drug complication.
896
1
University of Colorado School of Medicine, Denver, CO;
Columbia-Presbyterian Medical Center, New York; and
3
North Shore University Hospital, Manhasset, NY
2
References
1. Olanow CW, Goetz CG, Kordower JH, et al. A double-blind
controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol 2003;54:403– 414.
2. Freed CR, Greene PE, Breeze RE, et al. Embryonic dopamine
cell transplantation for severe Parkinson’s disease. N Engl J Med
2001;344:710 –719.
3. Freed CR, Bjugstad KB, Breeze RE, et al. Stable outcome five
years after embryonic dopamine cell transplantation for Parkinson’s disease is compatible with ongoing transplant development
or lack of disease progression. Mov Disord 2002;17:S216.
4. Ma Y, Feigin A, Dhawan V, et al. Dyskinesia after fetal cell
transplantation for parkinsonism: a PET study. Ann Neurol
2002;52:628 – 634
5. Krack P, Batir A, Blercom NV, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 2003;349:1925–1934.
DOI: 10.1002/ana.20085
Reply
C. Warren Olanow, MD, Thomas B. Freeman, MD,
and Jeffrey H. Kordower, PhD
We share with Freed and colleagues the hope that transplantation strategies might improve the quality of life for patients
with Parkinson’s disease. Unfortunately, both of our doubleblind studies of fetal nigral transplantation failed to meet
their primary end points.1,2 It is, nonetheless, appropriate to
consider that better results might be obtained with modified
transplant protocols. In secondary analyses, Freed and colleagues found that patients younger than 60 years had improved motor scores after transplantation,1 whereas in our
study greater improvement was observed in the subpopulation with milder disease, but no age effect was detected.2
The preoperative response to L-dopa did not predict outcome in our study. They do not think that immunosuppression is required because they observed survival of transplants
in 85% of patients based on positron emission tomography
and autopsy studies. However, we had higher numbers of
surviving cells at postmortem using 6 months of immunosuppression,2,3 and still we detected immune changes consistent with a partial immune response.2,4 Furthermore, we observed a loss of clinical benefit when cyclosporine was
withdrawn.2 We therefore feel that more prolonged and not
less immunosuppression may be required to optimize results.
We agree with the suggestion that off-medication dyskinesia
observed in more than half of our cases likely reflects a
transplant-related dopaminergic effect. Interestingly, we
noted that in at least some individuals these dyskinesias strikingly resemble diphasic dyskinesias, which are associated with
suboptimal dopamine levels.2 This suggests that protocols
that provide greater numbers of surviving dopamine cells
and/or more physiological delivery of dopamine may both
enhance clinical benefit and reduce the risk of off-medication
dyskinesia. Further laboratory studies to test this hypothesis
in animal models are required before performing further
clinical studies. Thus, whereas transplantation currently re-
© 2004 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
mains an experimental therapy that cannot be recommended
for PD patients, it is possible that better results with less
adversity could be obtained with a different transplant protocol. Finally, we agree that the nondopaminergic pathology
found in Parkinson’s disease may represent the most important limitation of current cell-based strategies that rely exclusively on dopamine cell replacement.
References
1. Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl
J Med 2001;344:710 –719.
2. Olanow CW, Goetz CG, Kordower JH, et al. A double blind
controlled trial of fetal nigral transplantation in Parkinson’s disease. Ann Neurol 2003;54:403– 414.
3. Kordower JH, Freeman TB, Snow BJ, et al. Post mortem evidence of dopamine graft survival and striatal reinnervation in a
Parkinson’s disease patient displaying improved motor function
following fetal nigral transplantation. N Engl J Med 1995;332:
1118 –1124.
4. Kordower JH, Styren S, DeKosky ST, et al. Fetal grafting for
Parkinson’s disease: expression of immune markers in two patients with functional fetal nigral implants. Cell Transplant
1997;6:213–219.
DOI: 10.1002/ana.20086
Further Evidence That Interactions between
CYP2D6 and Pesticide Exposure Increase Risk for
Parkinson’s Disease
Yifu Deng, MD,1 Beth Newman, PhD,1
Michael P. Dunne, PhD,1
Peter A. Silburn, FRACP, PhD,2
and George D. Mellick, PhD2
The recent article by Elbaz and colleagues1 suggested that
CYP2D6 poor metabolizers (PMs), who were exposed to
pesticides, exhibit an increased risk for PD compared with
unexposed subjects and pesticide-exposed CYP2D6 extensive
metabolizers (EMs). We were particularly interested by this
finding, given that our analysis of Australian Parkinson’s disease (PD) cases and controls shows an almost identical result.
We used polymerase chain reaction and restriction fragment length polymorphism methods to genotype CYP2D6
PM alleles (*3, *4, and *5) in 393 PD cases (226 men and
167 women; mean age, 67 years [SD, 10]; mean age at onset, 60 years [SD11] and 389 healthy, aged controls [110
men and 279 women; mean age, 64 years [SD11]). All subjects were examined by a movement disorders neurologist.
Cases were diagnosed as probable or definite idiopathic PD
using standard clinical diagnostic criteria. History of lifelong
exposure to herbicides and pesticides was evaluated using a
structured questionnaire. Exposure was classified into three
categories: (1) regular exposure (weekly exposure for a period
of 6 months or more), (2) occasional exposure (less than regular), and (3) rare exposure (unaware of any exposure).
Odds ratios were calculated by unconditional logistic regression and adjusted for the following potential confounding factors: age, sex, family history of PD, and smoking status.
Similar to Elbaz and colleagues,1 our analysis showed that
pesticide exposure combined with PM genotype significantly
Table. Odds Ratios for PD (relative to “rarely exposed” EM
controls) for the Various Pesticide Exposure and CYP2D6
Genotype Groups
Exposure to pesticides
Group
Rare, OR
(95% CI)
Occasional, OR
(95% CI)
Regular, OR
(95% CI)
EMs
Carriers
PMsa
1.00
0.95 (0.59–1.54)
0.29 (0.11–0.80)b
1.24 (0.82–1.86)
0.89 (0.54–1.47)
2.09 (0.80–5.43)
1.33 (0.63–2.83)
3.27 (1.21–8.80)b
8.41 (1.01–69.76)c
a
The respective frequencies of the *3 and *4 alleles were 1.15% and
22.3% in cases and 1.29% and 22.3% in controls (all genotypes
were in Hardy–Weinberg equilibrium). Three cases and one control
were homozygous for the *5 allele.
b
p ⬍ 0.02;
c
p ⬍ 0.05.
PD ⫽ Parkinson’s disease; EM ⫽ extensive metabolizer; OR ⫽
odds ratio; CI ⫽ confidence interval; PM ⫽ poor metabolizer.
increases the risk for PD. In addition, we found that subjects
who are carriers of one CYP2D6 PM allele (ie, heterozygotes) were also at increased risk (see Table). Interestingly, in
rarely exposed subjects we found that PMs were actually less
common in the PD group; the Elbaz study showed a similar
but nonsignificant trend.
One advantage of our data is the inclusion of all three
common PM alleles (*3 and *5 as well as the *4 allele examined by Elbaz and colleagues1). A disadvantage of our
analysis is the mismatching for sex of our control group.
Moreover, our controls are largely a convenience group made
up of patient spouses and volunteers rather than populationbased subjects. We currently are repeating our study in a
more appropriate randomly ascertained case–control cohort.
Our results support the findings of Elbaz and colleagues1
and suggest that interactions between pesticide exposure and
CYP2D6 genetic polymorphisms may play an important role
in PD. Moreover, these findings also confirm the necessity of
considering the interaction between environmental exposure
and genetic traits when investigating the risk factors for PD.
This work was supported by Parkinson’s Queensland Incorporated,
the Brain Foundation of Australia (G.D.M.), and the Geriatric
Medical Foundation of Queensland (G.D.M.).
1
Centre for Health Research, School of Public Health,
Queensland University of Technology; and 2University of
Queensland School of Medicine and the Department of
Neurology, Princess Alexandra Hospital, Queensland, Australia
Reference
1. Elbaz A, Levecque C, Clavel J, et al. CYP2D6 polymorphism,
pesticide exposure, and Parkinson’s disease. Ann Neurol 2004;
55:430 – 434.
DOI: 10.1002/ana.20143
Annals of Neurology
Vol 55
No 6
June 2004
897
Increased ␤-Secretase Activity in Cerebrospinal
Fluid of Alzheimer’s Disease Subjects
five control cases showed the presence of a BACEimmunoreactive species indistinguishable from that observed
in human brain1 (Fig, A). BACE activity was measured using
R. M. Damian Holsinger, PhD,
Catriona A. McLean, MD, Steven J. Collins, MD,
Colin L. Masters, MD, and Geneviève Evin, PhD
An invariant feature of Alzheimer’s disease (AD) is the accumulation of A␤ amyloid deposits in the brain of affected individuals. A␤ is generated by the proteolytic processing of an
integral membrane protein, the amyloid precursor protein
(APP), by ␤- and ␥-secretases. ␤-Secretase (BACE) is a novel
transmembrane protease localized to intracellular compartments and the plasma membrane. Because BACE initiates A␤
amyloid biogenesis, much emphasis has been placed on this
enzyme as a probable target for therapeutic intervention. We
have demonstrated that the levels of BACE protein and activity are significantly increased in the brain of AD patients compared with control subjects.1 This finding has been confirmed
by subsequent independent studies.2,3 As part of our investigations on BACE, we have been able to detect its presence and
enzymatic activity in cerebrospinal fluid (CSF). Western blotting of CSF (from the NH&MRC Tissue Resource Centre,
Melbourne, Australia) obtained postmortem from five AD and
Fig. (A) Detection of ␤-secretase (BACE) immunoreactivity in
human cerebrospinal fluid. BACE immunoreactivity was detected in 20␮g of cerebrospinal fluid (CSF) protein using
Western blotting conditions with BACE C-terminal antibody
00/6 as described previously.1 A 70kDa signal (arrow) was
observed, similar to that detected in BACE-transfected SHSY5Y cells and in human brain.1 (B) Detection of BACE
enzymatic activity in CSF. BACE activity was measured using
a quenched-fluorescence decapeptide substrate. Thirty micrograms of CSF was incubated at pH 4.0 in the presence of
5␮M substrate, and fluorescence production was monitored for
2.5 hours at 37°C (excitation ⫽ 340nm; emission ⫽
405nm). A protease inhibitor cocktail, including pepstatin A,
was included in the reaction to block nonspecific protease activity. Specificity of substrate cleavage was further established
by demonstrating complete abolition of fluorescence in the presence of BACE inhibitor STA-200 (1␮M; MP Biomedicals,
Seven Hills, NSW, Australia). (C) Comparison of BACE enzymatic activity in Alzheimer’s disease (AD) and control postmortem CSF. BACE activity was measured in five AD and
five control samples, and the fluorescence values obtained at
2.5 hours were compared. Horizontal bars indicate the mean
values and demonstrate a statistically significant threefold (p
⫽ 0.002) increase of BACE activity in the AD samples. (D)
Detection of BACE activity in antemortem CSF. Because of
the scarcity of antemortem CSF samples, a similar but more
sensitive BACE activity assay was used that involves timeresolved fluorescence detection (excitation ⫽ 340nm; emission
⫽615nm; TruPoint ␤-secretase assay kit; Perkin-Elmer,
Rowville, VIC, Australia). The enzymatic reaction was performed for 2.5 hours at 23° C using 1␮g of CSF protein.
Although the sample numbers were too low to allow statistical
analysis, the results indicate an increase in BACE activity in
AD, further supporting data obtained with postmortem samples.
898
Annals of Neurology
Vol 55
No 6
June 2004
‹
a fluorogenic assay based on the sequence-specific cleavage of a
peptide spanning the ␤-secretase site of APP Swedish mutant
(MCA-SEVNLDAEFR[Ednp]KRR-NH2; MP Biomedicals,
Seven Hills, NSW, Australia). A t test assuming unequal variances indicated a statistically significant threefold increase
( p ⫽ 0.002) of ␤-secretase activity in AD samples as compared with normal controls (see Fig, C). BACE activity was
also detected in antemortem CSF, and its levels were higher in
AD than in controls (see Fig, D).
Our results suggest a novel mechanism by which neurotoxic A␤ species could be generated in human brain. It has
been established that APP cycles between membrane compartments and the cell surface and cleavage of APP within
cellular compartments has been considered to be the principal source of A␤ generation. However, studies have demonstrated that A␤ can be produced from APP at the cell surface.4 Recent data also have demonstrated endocytosis of
exogenously added recombinant BACE that was recovered in
endosomes and Golgi and capable of sustaining the production of APP fragments, including A␤.5 The data we present
indicate that there exists an extracellular pool of active secreted BACE, and we propose that this may cleave cell surface APP or be endocytosed by neurons and contribute to
intracellular protein of A␤. Overall, data from both brain
and CSF demonstrate an increase in BACE activity in AD
compared with controls and identifies BACE as a potential
diagnostic marker for AD.
Department of Pathology, The University of Melbourne and
the Mental Health Research Institute, Parkville, Victoria
3010, Australia
References
1. Holsinger RMD, McLean CA, Beyreuther K, Masters CL et al.
Increased expression of amyloid precursor ␤-secretase in Alzheimer’s disease. Ann Neurol 2002; 51:783-786.
2. Fukumoto H, Cheung BS, Hyman BT and Irizarry, MC.
␤-secretase protein and activity are increased in the neocortex in
Alzheimer’s disease. Arch Neurol 2002; 59:1381-1389.
3. Yang L-B, Lindholm K, Yan R, Citron M, et al., Elevated
␤-secretase expression and enzymatic activity detected in sporadic
Alzheimer disease. Nat Med 2003; 9(1):3-4.
4. Chyung JH and Selkoe DJ. Inhibition of receptor mediated endocytosis demonstrates generation of amyloid ␤-protein at the
cell surface. J Biol Chem 2003; 278(51):51035-51043.
5. Huang X, Chang W, Koelsch G and Tang J. Endocytosis of
exogenously added memapsin 2 (␤-secretase) catalytic domain by
cultured cells. International Conference on Aspartic Proteases
and Inhibitors, Kyoto, Japan. Abstract P-19. November 14-16,
2003.
DOI: 10.1002/ana.20144
Correction
Maraganore DM, Lesnick TG, Elbaz A, ChartierHarlin, M-C, Gasser T, Krüger R, Hattori N, Mellick GD, Quattrone A, Satoh J-i, Toda T, Wang J,
Ioannidis JPA, de Andrade M, Rocca WA, and the
UCHL1 Global Genetics Consortium. UCHL1 Is a
Parkinson’s Disease Susceptibility Gene. Ann Neurol 2004;55:512–521 (April 2004).
Due to an author oversight, Dr. Toda’s name was
incorrectly reproduced in the original article. The correct spelling is Tatsushi Toda.
The authors regret this oversight.
DOI: 10.1002/ana.20165
Annals of Neurology
Vol 55
No 6
June 2004
899
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