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Early cognitive decline is associated with prion protein codon 129 polymorphism.

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Early Cognitive Decline Is Associated with Prion
Protein Codon 129 Polymorphism
Esther A. Croes, MD, PhD,1 Bart Dermaut, MD, PhD,2
Jeanine J. Houwing-Duistermaat, PhD,1
Marleen Van den Broeck,2 Marc Cruts, PhD,2
Monique M. B. Breteler, MD, PhD,1
Albert Hofman, MD, PhD,1
Christine van Broeckhoven, PhD, DSc,2
and Cornelia M. van Duijn, PhD1,2
A common polymorphism in the gene encoding the prion
protein (PRNP) is known to determine susceptibility to
Creutzfeldt–Jakob disease.1 This polymorphism at codon
129 encodes for either methionine (M) or valine (V). There
is an increasing interest in the role of this protein in other
neurodegenerative processes including Alzheimer’s disease.2
Here, we address the question whether genetic variability of
the PRNP codon 129 polymorphism plays an (agedependent) role in cognitive decline.
PRNP codon 129 genotypes were determined in 965 randomly selected participants from a population-based study,
the Rotterdam Study.3 The subjects were sampled in four
10-year age categories (age range, 55–95 years). Cognitive
performance was assessed by the Mini-Mental State Examination (MMSE) and the Geriatric Mental State Schedule.
Based on Diagnostic and Statistical Manual–III-R criteria,
screen-positive persons were further evaluated for the presence of dementia by two neurologists. After a mean
follow-up of 6.5 ⫾ 0.6 years 418 (43%) participants were
reexamined. Reasons for loss to follow-up were death
(63%), refusal (33%), and inability to undergo the MMSE
Genotype and allele frequencies were in Hardy–Weinberg
equilibrium (MV, n ⫽ 440; MM, n ⫽ 435; VV, n ⫽ 90;
p ⫽ 0.16). We found no evidence for a shift in allele frequencies with age. The baseline MMSE scores did not differ
between the genotypes.
For the assessment of cognitive decline, all prevalent demented subjects were excluded. In the analyses adjusting
for age, sex, education, baseline MMSE, and having the
apolipoprotein E4 allele, we found a significantly higher
decline in cognitive performance in V homozygous subjects
aged 55 to 64 years ( p ⬍ 0.01) compared with the reference group MV (Fig). We further found more patients with
dementia in V homozygotes ( p ⬍ 0.01). Age at onset was
lower in demented PRNP129 VV carriers (MV, 85.4 years;
MM, 86.3 years; VV, 84.4 years), but numbers were too
low to reach statistical significance.
Previously, significantly lower MMSE scores were observed in V homozygous subjects aged 66 to 71 years.4
We recently described an increased prevalence of this genotype in patients with early-onset Alzheimer’s disease.5 In
line with these findings, here we report a shift in cognitive
decline toward early age in carriers of PRNP129 VV.
Interestingly, in sporadic Creutzfeldt–Jakob disease patients
with genotype VV, the risk for developing the disease is
also only significantly increased at early age (⬍49
Our data and those of others support the view of an in
Fig. Annual decline in Mini-Mental State Examination
(mmse) score in relation to the PRNP codon 129 polymorphism, in three age categories. Age categories 75 to 84 and 85
to 95 years were combined to increase the number.
creased susceptibility for neurodegeneration in carriers of the
PRNP129 VV genotype early in life.
This work was supported by European Union grants (CT98-7022
and CT98-0208, C.M.v.D., C.v.B.).
Department of Epidemiology and Biostatistics, Erasmus MC,
Rotterdam, The Netherlands; and 2Department of Molecular
Genetics, Flanders Interuniversity Institute for Biotechnology,
University of Antwerp, Antwerp, Belgium
© 2003 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
1. Alperovitch A, Zerr I, Pocchiari M, et al. Codon 129 prion protein genotype and sporadic Creutzfeldt-Jakob disease. Lancet
2. Casadei VM, Ferri C, Calabrese E, et al. Prion protein gene
polymorphism and Alzheimer’s disease: one modulatory trait of
cognitive decline? J Neurol Neurosurg Psychiatry 2001;71:
279 –280.
3. Hofman A, Grobbee DE, de Jong PT, van den Ouweland
FA. Determinants of disease and disability in the elderly:
the Rotterdam Elderly Study. Eur J Epidemiol 1991;7:
403– 422.
4. Berr C, Richard F, Dufouil C, et al. Polymorphism of the prion
protein is associated with cognitive impairment in the elderly:
the EVA study. Neurology 1998;51:734 –737.
5. Dermaut B, Croes EA, Rademakers R, et al. PRNP Val129 homozygosity increases risk for early-onset Alzheimer’s disease. Ann
Neurol 2003;53:409 – 412.
DOI: 10.1002/ana.10658
Association between a Polymorphism of BrainDerived Neurotrophic Factor Gene and Sporadic
Parkinson’s Disease
Toshihiro Masaki, MD, PhD,1,2 Sachio Matsushita, MD,2
Hiroyuki Arai, MD, PhD,3 Atsushi Takeda, MD, PhD,4
Yasuto Itoyama, MD, PhD,4 Hitoshi Mochizuki, MD,1,5
Keiko Kamakura, MD, PhD,5 Shinji Ohara, MD, PhD,6
and Susumu Higuchi, MD, PhD2
Recently, it was reported that homozygosity of AA for the
V66M (196A/G) polymorphism of the BDNF (brain-derived
neurotrophic factor) gene is significantly more frequent in
idiopathic Parkinson’s disease (PD) than in normal controls,
although there was no difference in the allele frequencies of
the polymorphism between the two groups.1 Because several
lines of evidence show that BDNF might promote survival of
dopaminergic neurons in substantia nigra2– 4 and that the expression of BDNF mRNA might be reduced in the PD substantia nigra,5 it seems plausible that genetic variation in
BDNF affects the risk for PD.
To attempt to confirm this potentially important observation, we have performed a replication study, which was
approved by the ethics committee of the National Institute
on Alcoholism, Kurihama National Hospital. The subjects
were 291 Japanese patients with idiopathic PD (mean
age ⫾ SD, 65.7 ⫾ 8.99 years), and 291 age- and sex-
matched normal controls (65.6 ⫾ 9.21 years). All patients
included were evaluated by clinical neurology experts, and
idiopathic PD was diagnosed when at least two of the three
cardinal symptoms of Parkinson’s disease (rest tremor, rigidity, bradykinesia) were present, and there were no atypical clinical features or secondary causes of parkinsonism.
Cases with familial PD were excluded from the sample of
PD patients. Genotyping of the V66M polymorphism was
performed by a polymerase chain reaction restriction fragment length polymorphism method, using an endonuclease
All genotypes were found to be in Hardy–Weinberg
equilibrium. As shown in the Table, the allele frequency of
196(A) was significantly less frequent in PD patients compared with that in normal controls ( p ⫽ 0.021), although
there was no significant difference between the two groups
in the genotype frequencies ( p ⫽ 0.064).
Although our results apparently contradict those previously reported,1 neither study produced data convincing
enough to conclusively exclude the validity of the other’s
finding. Further study will be needed to draw conclusions
concerning the effect of BDNF genetic variation on the risk
of PD.
Department of Neurology, and 2Division of Clinical Research
National Institute on Alcoholism, Kurihama National
Hospital, Yokosuka, Kanagawa; Departments of 3Geriatrics,
and 4Neurology Tohoku University School of Medicine,
Sendai; 5Third Department of Internal Medicine, National
Defense Medical College, Tokorozawa; and 6Department of
Neurology, National Chushin-Matsumoto Hospital,
Matsumoto, Japan
1. Momose Y, Murata M, Kobayashi K, et al. Association studies
of multiple candidate genes for Parkinson’s disease using single
nucleotide polymorphisms. Ann Neurol 2002;51:133–136.
2. Hyman C, Hofer M, Barde YA, et al. BDNF is a neurotrophic
factor for dopaminergic neurons of the substantia nigra. Nature
1991;350:230 –232.
3. Murer MG, Yan Q, Raisman-Vozari R. Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol 2001;63:71–124.
4. Siegel GJ, Chauhan NB. Neurotrophic factors in Alzheimer’s
disease and Parkinson’s disease brain. Brain Res Brain Res Rev
2000;33:199 –227.
Table. Comparative Frequencies of Polymorphism (V66M) of the BDNF Gene in Patients with Parkinson’s Disease
1 (%)
2 (%)
230 (39.5)
352 (60.5)
269 (46.2)
313 (53.8)
(␹2 ⫽ 5.34, df ⫽ 1, p ⫽ 0.021)
1 (%)
51 (17.5)
64 (22.0)
2 (%)
3 (%)
128 (44.0)
112 (38.5)
141 (48.5)
86 (29.6)
(␹2 ⫽ 5.51, df ⫽ 2, p ⫽ 0.064)
Allele 1 ⫽ A; allele 2 ⫽ G; genotype 1 ⫽ allele 1*allele 1; genotype 2 ⫽ allele 1*allele 2; genotype 3 ⫽ allele 2*allele 2; Odds ratio concerning
allele 1: 0.76.
PD ⫽ Parkinson’s disease.
Annals of Neurology
Vol 54
No 2
August 2003
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