close

Вход

Забыли?

вход по аккаунту

?

Apolipoprotein E genotypes and age at onset of Parkinson's disease.

код для вставкиСкачать
Apolipoprotein E and Parkinson’s Disease
Rivka Inzelberg, MD,*t Diana Paleacu, MD,*$
Joab Chapman, M D , PhD,*$
and Amos D. Korczyn, M D , MSc**
We read with interest the article by Zareparsi and colleagues.’ The authors analyzed the influence of the apolipoprotein E (ApoE) ~4 allele on the age at onset of Parkinson’s disease (PD) and found its presence to be associated
with earlier onset age. They suggested that family history of
PD and the presence of the ~4 allele have a cumulative effect
for younger age at onset.
We have examined 121 consecutive unrelated PD patients. DNA was obtained from blood leukocytes and the
number of ~4 alleles carried by a subject was identified as
described elsewhere.’ We compared the ages at onset of E4
carriers and those who were not ~4 carriers by Student’s t
test.
Thirty-four patients carried the ~4 allele (21 males) and
88 did not (65 males). The mean age of the whole cohort
was 74.9 ? 9.2 years and the mean age at onset was 68.2 t
11.3 years. The age at onset among ~4 carriers (67.1 t 10.4
years) was similar to the age at onset of non-E4 carriers
(68.7 2 11.6 years) ( p > 0.1).
Fourteen patients reported the presence of P D patients in
their families of whom 5 carried the ~4 allele and 9 did not.
The age at onset for patients with familial history was significantly younger than for those who did not report the
presence of PD patients in their families (60.1 t 10.3 vs
69.4 ? 11.1 years, mean 2 SD; p < 0.001). This finding
was consistent in patients who carried the &4 allele (61.4 t
7.2 years [familial history present] vs 68.1 ? 10.6 years [familial history absent]; p < 0.01) and among patients who
were non-E4 carriers (59.4 2 12.1 years [familial history
present] vs 69.7 t 11.2 years [familial history absent], p <
0.01). Thus, the presence of a positive family history of I’D
advances the onset by 6.7 years in ~4 carriers versus 10.3
years in noncarriers; the ages at onset in familial patients are
not significantly different in ~4 carriers (61.4
7.2 years)
than noncarriers (59.4
12.1 years) ( p > 0.1). This suggests that the effect of family history is not influenced by the
presence of the ~4 allele.
Our results do no show any influence of the ApoE genotype on the age at onset of PD and thus do not confirm the
findings of Zareparsi and co-workers.’ The discrepancy between these results can be due to the characteristics of the
study cohorts. The patients of Zareparsi and co-workers’ included an unusually high percentage of patients with a positive family history of P D (50%). The authors reported a
significantly younger age at onset in familial cases, as confirmed in our patient population. W e did not observe, however, any influence of the ApoE genotypes in subpopulations,
when family history was considered. Another study has also
reported that the ~4 allele carriers do not present with
younger age at onset.3
We have previously shown that ApoE haplotypes do not
influence the occurrence of dementia in PD4 or its rate of
progre~sion.~
It remains to be seen whether the E4 allele has
an impact on the onset and progression of PD.
+
+
294
Annals of Neurology
Vol 44
No 2
August 1998
*Tel-Aviv University, Sackler Faculty of Medicine, Ramat
Aviv, ?Department o f Neurology, Hillel Yaffe Medical Center,
Hadera, and $Department o f Neurology, Tel-Aviv Sourasky
Medical Center, Tel-Aviv, Israel
References
1. Zareparsi S, Kaye J , Camicioli R, et al. Modulation of age at
onset of Parkinson’s disease by apolipoprotein E genotypes. Ann
Neurol 1997;42:655-658
2. Chapman J, Estupinan J, Asherov A, Goldfarb LG. A simple and
efficient method for Apolipoprotein E genotype determination.
Neurology 1996;46:1484-1485
3. Whitehead AS, Bertrandy S, Finnan F, et al. Frequency of the
apolipoprotein E ~4 allele in a case-control study of early onset
Parkinson’s disease. J Neurol Neurosurg Psychiatry 1996;61:
347-351
4. Inzelberg R, Chapman J, Treves TA, et al. Apolipoprotein E4 in
Parkinson’s disease dementia: new data and meta-analysis of published data. Alzheimer Dis Assoc Disord 1998;12:45-48
5. Paleacu D, Inzelberg R, Chapman J, et al. Apolipoprotein E ~4
allele does not influence the development of dementia in parkinsonian patients. In: Fisher A, Hanin I, Yoshida M, eds. Progress
in Alzheimer’s and Parkinson’s disease, advances in behavioral
biology. New York: Plenum Press, 1998 (In press)
Apolipoprotein E Genotypes and Age at Onset of
Parkinson’s Disease
Ralil de la Fuente-Fernindez, MD, Angeles Sellers, MD,
Katrin Beyer, MSc, and Jose I. Lao, MD
Zareparsi and colleagues’ recently reported that the presence
of the ~4allele of apolipoprotein E (ApoE) gene is associated
with an earlier age at onset of Parkinson’s disease (PD). We
have conducted a similar study, whose results, reported here,
clearly conflict with those of Zareparsi and colleagues.’
We studied 105 consecutive, nondemented PD patients
(age, 67.3 ? 7.7 years), and 105 age-matched controls (age,
67.2 t 9.1 years). The severity of parkinsonism in the “off
state was assessed by using both Hoehn and Yahr staging and
the Modified Columbia Scale. All clinical assessments were
performed without knowledge of the ApoE genotypes. In a
similar manner, ApoE genotyping2 was determined without
knowledge of the results of the clinical assessments.
A positive family history of PD in first-degree relatives was
present in 16 PD patients (15%). Patients with and without
family history of PD differed significantly in their age at onset of symptoms (54.5 ? 9.6 vs 60 ? 9.6 years, respectively;
p = 0.036). ApoE genotypes of patients were as follows: E2/
83, 7 (6.7%); ~ 2 1 ~ 14 (1%);
,
&3/&3,81 (77.1%); and ~ 3 / ~ 4 ,
16 (15.2%). There were no differences in ApoE allele frequencies between patients and controls (in particular, the frequency of the ~4 allele was 0.08 in patients and 0.10 in
controls, p = 0.50). The age at onset of PD was 63.4 -+- 8.8
years in E4 carriers and 58.2 t 9.8 years in the group of
patients without the ~4 allele ( p = 0.047). The KaplanMeier plot (Fig) shows the age-at-onset distribution curves of
the groups of patients with and without the E4 allele (log
rank statistic, 2.64; p = 0.10). After adjustment for duration
of symptoms, there were no differences in the severity of parkinsonism between ~4 carriers and patients without the ~4
allele, using either Hoehn and Yahr staging ( p = 0.11) or
the Modified Columbia Scale ( p = 0.73).
.d
Y
Ll
0
.4
a
2
& .2
0.0
1
.
Fig. Age at onset of Parkinson j disease in €4 carriers and
patients without the ~4 allele.
We failed to replicate the findings of Zareparsi and colleagues.’ In fact, we found some evidence that PD symptoms
could appear even later in the group of patients with the ~4
allele than in the group without. However, several studies
(including ours) have shown that ApoE allele frequencies are
not altered in PD, which suggests that the ~4 allele must not
contribute to the cause of PD. In addition, we found that
the ~4 allele does not alter the progression of parkinsonism.
Hence, it is hard to believe that the presence of the ~4 allele
can modulate in any way the age at onset of PD.
Departments of Neurology and Molecular Genetics, EuroEpes
Biomedical Research Center, Santa Marta de Babio, 15166
Bergondo, La Coruiia, Spain
References
1. Zareparsi S , Kaye J, Camicioli R, et al. Modulation of the age at
onset of Parkinson’s disease by apolipoprotein E genotypes. Ann
Neurol 1997;42:655-658
2. Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hha I. J
Lipid Res 1990;31:545-548
Reply
Sepideh Zareparsi, MS,* and Haydeh Payami, PhD*?
Several studies have examined the association of apolipoprotein E (ApoE) with Parkinson’s disease (PD) by comparing
gene frequencies in patients versus controls.’ The results have
been mostly negative; hence, the general assumption that
ApoE is not associated with PD. Our study was the first to
ask if ApoE is associated with onset age of PD.’ The results
were preliminary but provocative: onset of PD was earliest in
~4 carriers, intermediate in ~3 homozygotes, and latest in ~2
carriers. This pattern resembles the association of ApoE with
onset of Alzheimer’s disease and suggests that ApoE may be
a modifier of PD onset.
In the study by Inzelberg and associates, onset age of PD
was earlier in ~4 carriers (consistent with our observation),
but the difference was not statistically significant. O n one
hand, it is possible that the trend toward earlier onset in ~4
carriers was due to chance in both studies. An alternate possibility is that their study may not have had the power to
reach significance, as their sample size was less than one-third
of the minimum required. As pointed out by Inzelberg and
associates, the two patient populations differed significantly.
They differed in age at onset, ethnic origin, and, most important, in phenotype. None of our patients was demented
at the time of diagnosis. The study by Inzelberg and colleagues did not address the dementia status of the patients,
but extrapolating from their earlier publication^,^^^ up to
60% of their patients may have been demented.
The study by de la Fuente-Fernandez and collaborators
may be more comparable with ours because their patients
were not demented and had relatively early onset. They may
have differed in ethnicity, however, as ours were originally
from northern Europe and theirs from southern Europe. The
results of the study be de la Fuente-Fernandez and colleagues
clearly contradict ours. Whether the opposing results are due
to chance, disease heterogeneity, or differences in patient
populations remains to be seen. Carefully designed studies
with sample sizes of at least 400 patients are needed to properly assess the effect of ApoE on age at onset of PD.
Departments of *Molecular and Medical Genetics,
and fNeurology, Oregon Health Sciences University,
Portland, OR
References
1. Zareparsi S, Kaye J, Camicioli R, et al. Modulation of the age at
onset of Parkinson’s disease by apolipoprotein genotypes. Ann
Neurol 1997;42:655- 658
2. Inzelberg R, Chapman J, Treves TA, et al. Apolipoprotein E4 in
Parkinson’s disease and dementia: new data and meta-analysis of
published studies. Alzheimer Dis Assoc 1998;12:45-48
3. Paleacu D, Inzelberg R, Chapman J, et al. Apolipoprotein E &4
allele does not influence the development of dementia in parkinsonian patients. In: Fisher A, Hanin I, Yoshida M, eds. Progress
in Alzheimer‘s and Parkinson’s disease, advances in behavioral
biology. New York: Plenum Press (In press)
Annals of Neurology
Vol 44
No 2
August 1998 295
Документ
Категория
Без категории
Просмотров
5
Размер файла
219 Кб
Теги
apolipoprotein, disease, parkinson, age, genotypes, onset
1/--страниц
Пожаловаться на содержимое документа