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Background: Most prognostic studies on Parkinson Main Outcome Measures: Incident dementia and
disease have been hospital based or have applied death. Adjusted hazard ratios were calculated through
register-based case-finding methods. Potential under- Cox proportional hazards regression analysis.
representation of mild cases may have given biased
results. Results: Patients with Parkinson disease had an increased
risk of dementia (hazard ratio, 2.8; 95% confidence inter-
Objective: To evaluate whether Parkinson disease is val, 1.8-4.4), which was especially pronounced in partici-
associated with an increased risk of dementia and pants carrying at least 1 apolipoprotein E gene (APOE) 2
death. allele (13.5; 4.5-40.6). Parkinson disease was associated with
an increased mortality risk (1.8; 1.5-2.3). The association
Design: Population-based cohort study. Parkinson dis- consistently diminished when analyses were sequentially
ease and dementia were assessed through in-person ex- restricted to patients with shorter disease duration and af-
amination at baseline (1990-1993) and 2 follow-up vis- ter adjustment for the occurrence of dementia.
its (1993-1994 and 1997-1999). Computerized linkage
to medical and municipality records provided addi- Conclusions: Especially patients with Parkinson dis-
tional information on disease outcomes and mortality. ease who carry an APOE 2 allele have an increased risk
of developing dementia. Increased mortality risk in Par-
Setting: General population. kinson disease is dependent on disease duration and is
only modest in the absence of dementia.
Participants: A total of 6969 participants, including 99
prevalent and 67 incident cases of Parkinson disease. Arch Neurol. 2005;62:1265-1269
T
HE PREVALENCE OF PARKIN- nosis of patients with PD varies with
son disease (PD), the sec- apolipoprotein E (APOE) genotype, be-
ond most common neuro- cause previous studies have shown con-
degenerative disorder, is flicting results.2-6
expected to increase as In a prospective population-based co-
populations worldwide age. Insight into hort study involving in-person examina-
the prognosis is therefore desirable. Par- tion of all participants, we evaluated the
kinson disease has been associated with an prognosis of PD with respect to dementia
increased risk of developing dementia and and mortality, studying both prevalent
a reduced life expectancy. However, most cases identified at baseline and incident
prognostic studies have been hospital cases diagnosed during follow-up. We
based, yielding results that are not repre- furthermore investigated to what extent re-
sentative of the general population. Our duced survival in patients with PD is due
group previously showed that, even in to their higher risk of dementia, and whether
population-based studies, a considerable APOE genotype influences prognosis.
proportion of cases of PD remain undiag-
Author Affiliations: nosed when case finding relies on
Departments of Epidemiology METHODS
and Biostatistics (Drs de Lau,
medical records only and no population
Schipper, Hofman, and Breteler) screening is done.1 The potential under- THE ROTTERDAM STUDY
and Neurology (Drs de Lau and representation of relatively mild cases in
Koudstaal), Erasmus Medical register-based studies might result in over- The Rotterdam Study is a prospective popula-
Center, Rotterdam, estimating the risk of dementia or mor- tion-based cohort study among 7983 subjects
the Netherlands. tality. Another issue is whether the prog- 55 years and older. At baseline (1990-1993) and
HR (95% CI)
Abbreviations: APOE, apolipoprotein E gene; CI, confidence interval; NA, not applicable; HR, hazard ratio; PD, Parkinson disease; plus sign, plus any other allele.
*Model 1 was adjusted for age and sex; model 2 was adjusted for age, sex, and educational level.
Disease Duration*
Abbreviations: CI, confidence interval; HR, hazard ratio; PD, Parkinson disease.
*Categories #5 y and "5 y are mutually exclusive; categories "2 y and incident cases are subgroups of the "5 y category.
At time of study entry (prevalent cases) or diagnosis (incident cases).
Model 1 was adjusted for age and sex; model 2 was adjusted for age, sex, and occurrence of dementia (time dependent).
RISK OF DEMENTIA change the results, but adjusting for occurrence of de-
mentia yielded lower mortality HRs. The effect of PD on
At baseline, 22% of the participants with PD and 4% of survival was not different for men and women, or by strata
those without PD were diagnosed as having dementia. of APOE genotype (data not shown). Within PD cases,
Demented patients with PD were significantly older than mortality risk was influenced by disease duration (HR
those without dementia. Of the cohort free of dementia increase per year, 1.03; 95% CI, 0.99-1.07) and by oc-
at baseline, 21 (15.1%) of the 139 patients with PD and currence of dementia (HR, 2.85; 95% CI, 1.77-4.62).
318 (4.9%) of the 6512 participants without PD devel-
oped dementia during follow-up. The presence of PD was
COMMENT
associated with a significantly increased risk of demen-
tia (HR, 2.80; 95% CI, 1.79-4.38; Table 2). Results were
similar after additional adjustments and for subgroups The strengths of this study are its population-based na-
of disease duration at baseline. However, restricting analy- ture, size, and almost complete follow-up. In addition,
ses to only incident PD cases resulted in a higher esti- thorough case ascertainment for PD and dementia was
mate (HR, 4.74; 95% CI, 2.49-9.02). Disease duration did ensured through in-person instead of record-based screen-
not seem to affect dementia risk within PD cases (HR in- ing methods. The use of strict diagnostic criteria en-
crease per year, 0.96; 95% CI, 0.84-1.09). hanced diagnostic accuracy, and continuous monitor-
The association of PD with incident dementia was more ing of participants after diagnosis enabled us to revise
pronounced in participants with at least 1 APOE 4 al- diagnoses on the basis of additional information. Fur-
lele (HR, 6.27; 95% CI, 3.07-12.82), and especially in those thermore, because we followed up prevalent as well as
carrying at least 1 APOE 2 allele (HR, 13.46; 95% CI, incident PD cases, we could evaluate the effect of dis-
4.46-40.64), compared with 3/3 carriers. ease duration on prognosis and potential bias in preva-
lent cohorts.
MORTALITY RISK An increased risk of dementia associated with PD has
repeatedly been reported, with relative risks varying from
During follow-up, 90 (54.2%) of the 166 patients with 1.7 to 5.9.11-14 Our estimate of a 2.8-times increased risk
PD and 1623 (23.9%) of the 6803 participants without is relatively low. A possible explanation is the low aver-
PD died. Median survival after diagnosis of PD was 9.1 age disease severity in our study, which resulted from our
years (95% CI, 7.4-10.9 years). Overall, PD was associ- screening methods, through which we identified a large
ated with a significantly increased mortality risk (HR, 1.83; number of previously unrecognized patients with mild
95% CI, 1.47-2.26) (Table 3). However, HRs consis- PD.1,7 Moreover, we consider it likely that patients with
tently decreased when the analyses were sequentially re- PD who agreed to participate at baseline had fewer cog-
stricted to patients in whom PD was diagnosed more re- nitive complaints and thus a lower risk of future demen-
cently. Additional adjustments did not substantially tia than nonresponders, which may have led us to un-
Correction