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31. Grandinetti A, Morens DM, Reed D, et al. Prospective study of
cigarette smoking and the risk of developing idiopathic Par-
kinson’s disease. Am J Epidemiol 1994;139:1129–1138.
32. Haack DG, Baumann RJ, McKean HE, et al. Nicotine expo-
sure and Parkinson disease. Am J Epidemiol 1981;114:191–200.
33. Hardman JG, Gilman AG, Limbird LE. Goodman & Gilman’s
the pharmacological basis of therapeutics. 9th ed. New York:
McGraw-Hill, 1996.
34. Montgomery EB, Baker KB, Lyons K, et al. Abnormal perfor-
mance on the PD test battery by asymptomatic first-degree
relatives. Neurology 1999;52:757–762.
35. Richardson PJ, Kase H, Jenner PG. Adenosine A
2A
receptor
antagonists as new agents for the treatment of Parkinson’s
disease. Trends Pharmacol Sci 1997;18:338–344.
36. Ferre S, von Euler G, Johansson B, et al. Stimulation of high-
affinity adenosine A
2
receptors decreases the affinity of dopa-
mine D
2
receptors in rat striatal membranes. Proc Natl Acad
Sci USA 1991;88:7238–7241.
37. Ledent C, Vaugeois J-M, Schiffmann SN, et al. Aggressive-
ness, hypoalgesia and high blood pressure in mice lacking the
adenosine A sub 2a receptor. Nature 1997;388:674–678.
38. Hellenbrand W, Boeing H, Robra B-P, et al. Diet and Parkin-
son’s disease II: a possible role for the past intake of specific
nutrients: results from a self-administered food-frequency ques-
tionnaire in a case-control study. Neurology 1996;47:644–650.
39. Sackett DL. Bias in analytic research. J Chronic Dis 1979;32:
51–63.
40. Morens DM, Grandinetti A, Davis JW, et al. Evidence against
the operation of selective mortality in explaining the associa-
tion between cigarette smoking and reduced occurrence of
idiopathic Parkinson disease. Am J Epidemiol 1996;144:400–
404.
41. Ellenberg JH. Differential postmorbidity mortality in observa-
tional studies of risk factors for neurologic disorders. Neuro-
epidemiology 1994;13:187–194.
Parkinson’s disease and parkinsonism in
a longitudinal study
Two-fold higher incidence in men
M. Baldereschi, MD; A. Di Carlo, MD; W.A. Rocca, MD, MPH; P. Vanni, MD; S. Maggi, MD; E. Perissinotto, ScD;
F. Grigoletto, ScD; L. Amaducci, MD†; and D. Inzitari, MD, for the ILSA Working Group*
Article abstract—Objective: To determine the incidence of parkinsonism and PD in the Italian elderly, and to explore the
relation with age and gender. Methods: In eight Italian municipalities, a population-based, parkinsonism-free cohort was
followed for an average of 3 years. At the end of the follow-up, the cohort survivors were directly contacted (screening and
clinical examination). Cohort members who had died were studied using death certificates, clinical records, and informa-
tion gathered from relatives and general practitioners. Parkinsonism diagnosis and subtyping were made according to
specified diagnostic criteria. Results: The cohort consisted of 4,341 individuals (65 to 84 years of age): 596 died before the
examination, 2,863 (76.4% of the survivors) completed the screening procedure, and 882 refused to participate. The
authors found 68 incident cases of parkinsonism: 42 PD (62%), 7 drug-induced parkinsonism (10%), 8 parkinsonism in
dementia (12%), 8 vascular parkinsonism (12%), and 3 parkinsonism, unspecified (5.8%). Average annual incidence rate
(per 100,000 person-years) in the population aged 65 to 84 years, adjusted to the 1992 Italian population, was 529.7 (95%
CI, 400.5 to 658.9) for parkinsonism, and 326.3 (95% CI, 224.1 to 427.5) for PD. Incidence rates for both parkinsonism and
PD increased with age in both men and women; men had higher rates in every age group. Age-adjusted relative risk in
men compared with women was 1.66 (95% CI, 1.02 to 2.70) for parkinsonism and 2.13 (95% CI, 1.11 to 4.11) for PD.
Conclusions: Incidence of parkinsonism and PD increased with age, PD was the most common type of parkinsonism, and
men had a risk of developing PD twice that of women.
NEUROLOGY 2000;55:1358–1363
Few studies provide age-specific
1-3
or age- and sex-
specific
4-7
incidence rates for PD, and in all studies
except two,
3,8
case finding was based on medical
records. Studies based on the enumeration of known
cases of PD in the community likely underestimate the
frequency of PD because they exclude patients who
have not reached medical attention or patients whose
records were lost or not retrieved.
9
In a previous Italian
*See the Appendix on page 1363 for a list of the ILSA Working Group members.
†Deceased.
From the Italian National Research Council (CNR CSFET-ILSA Study) (Drs. Baldereschi and Di Carlo), Florence, Italy; Departments of Health Sciences
Research and Neurology (Dr. Rocca), Mayo Clinic and Mayo Foundation, Rochester, MN; Department of Neurological and Psychiatric Sciences (Drs. Vanni,
Amaducci, and Inzitari), University of Florence, Italy; Italian National Research Council (CNR-Centre on Aging) (Dr. Maggi), Padova, Italy; and Institute of
Hygiene (Drs. Perissinotto and Grigoletto), University of Padova, Italy.
The ILSA was supported by the Italian National Research Council, as part of the Progetto Finalizzato Invecchiamento, through annual grants to each
research unit from 1991 through 1995. Dr. Rocca was supported in part by the National Institutes of Health, grant NS 33978.
Received November 12, 1999. Accepted in final form July 20, 2000.
Address correspondence and reprint requests to Dr. Marzia Baldereschi, CNR CSFET, ILSA Study, Via Pancaldo 21, 50127, Firenze, Italy; e-mail:
baldereschi@mail.area.fi.cnr.it
1358 Copyright © 2000 by AAN Enterprises, Inc.
prevalence survey involving the direct contact of each
subject in the community, 39% of women with PD and
30% of men with PD had never been diagnosed before
the survey.
10
Here we investigate the incidence of parkinsonism and
PD in the Italian Longitudinal Study on Aging (ILSA), a
population-based epidemiologic study involving the direct
contact (screening and clinical examination) of a large,
nationwide sample of the Italian elderly. We also study
the distribution of parkinsonism and PD by age and sex.
Methods. This investigation was part of the ILSA, a
multicenter community-based study of prevalence, inci-
dence, and determinants of major age-associated condi-
tions of the elderly. More detailed information about the
overall study methods and objectives has been provided
elsewhere.
11
Study population. The eight centers involved in the
ILSA were the entire municipalities of Casamassima (Bari
Province), Fermo (Macerata Province) Impruneta (Firenze
Province), and Rubano-Selvazzano (Padova Province) and
well-defined city districts of Catania, Genova, Milano, and
Napoli. On March 1, 1992, using the population registers,
all of the inhabitants of the eight study centers aged 65 to
84 years, free-living or institutionalized, were stratified by
5-year age group (65 to 69, 70 to 74, 75 to 79, and 80 to 84
years) and gender. Using the equal allocation strategy, in
each study center, 88 individuals of each gender were ran-
domly selected and allocated to each age stratum, yielding
a sample of 704. The total sample size across the eight
centers totalled 5,632 individuals.
The parkinsonism-free cohort was identified within the
overall ILSA sample using a cross-sectional study carried
out in 1992 to 1993, which led to the detection of the
prevalent cases of parkinsonism (baseline survey).
9,12
The
parkinsonism-free cohort was followed for an average of 3
years. All of the cohort individuals were contacted again
during the second cross-sectional study carried out in 1995
to 1996.
Case finding strategies. Cases of parkinsonism were
identified using the same two-phase procedure both at
baseline and at follow-up. In each study center, the staff
consisted of one or two interviewers, one clinical investiga-
tor, one neurologist (the neurologist from Impruneta was
one of the authors, A. Di C.), and one geriatrician. All of
the staff were centrally trained. In phase 1, trained inter-
viewers administered a questionnaire about symptoms of
parkinsonism (tremor of head, arms, or legs), about previ-
ous diagnoses of parkinsonism (either by a neurologist or
by a primary care physician), and about antiparkinsonian
drug treatments to each sampled individual. Moreover, a
brief neurologic examination (check for elbow tone or rest-
ing tremor) was administered by the trained clinical inves-
tigator. All individuals who reported at least one symptom
of parkinsonism, a diagnosis of parkinsonism, antiparkin-
sonian drug treatments, or who had at least one positive
test result at the brief neurologic examination were consid-
ered to have screened positive and were extensively evalu-
ated by the trained neurologists in phase 2. The structured
clinical workup in phase 2 included the motor examination
of the Unified Parkinson’s Disease Rating Scale,
13
a stan-
dardized medical history, a brief summary of the natural
history of the disease, and a review of previous clinical
records (when available). Through phase 2, we confirmed
the diagnosis of parkinsonism and defined specific types of
parkinsonism. Two years after the baseline survey, the
overall study population was followed up by telephone in-
terview to determine the vital status. Information regard-
ing individuals who either had died or were unable to
answer the interview was obtained from the general prac-
titioners working in the study communities and from the
surviving relatives. Information about presence of parkin-
sonism, drug prescriptions, other diseases, hospitalization,
and institutionalization was gathered from the general
practitioner or the relatives. Hospital discharge diagnoses
and death certificate diagnoses also were available for
each subject who had died. When the time of parkinsonism
onset for deceased individuals was unclear, we used the
midpoint between the date of screening for the baseline
survey and the date of death. Information was gathered
with the same procedure for individuals who had died be-
tween the telephone interview and the second cross-
sectional survey. The medical information available for
deceased individuals was reviewed entirely by the adjudi-
cation panel (see later).
Incident cases of parkinsonism included all of the indi-
viduals who were free of parkinsonism at baseline but
developed parkinsonism during the follow-up.
Diagnostic criteria. Parkinsonism was diagnosed when
at least two of four cardinal signs (rest tremor, rigidity,
bradykinesia, and impaired postural reflexes) were present
in an individual not receiving antiparkinsonian medica-
tion, or if one or more cardinal signs, documented by medical
history, were improved by antiparkinsonian treatment. PD
was defined among those affected by parkinsonism by exclu-
sion of all other possible causes. Parkinsonism associated
with other causes included the following: 1) parkinsonism in
dementia: the onset of dementia clearly preceded the occur-
rence of parkinsonism (dementia is another disease inves-
tigated in the ILSA sample through a screening and a
clinical confirmation, the latter by the same neurologist
that ruled the parkinsonism diagnosis; therefore, we could
provide reliable dementia onset); 2) parkinsonism with as-
sociate features (e.g., multiple system atrophy or progres-
sive supranuclear palsy); 3) drug-induced parkinsonism:
use of neuroleptics or other antidopaminergic drugs in the
6 months preceding the onset of symptoms and with no
history of parkinsonism; 4) vascular parkinsonism: clear
time relationship between a cerebrovascular event and the
onset of atypical parkinsonism, preferably supported by
neuroimaging, usually without tremor; and 5) parkinson-
ism unspecified: no clear time relationship with possible
causes (e.g., dementia or antidopaminergic drugs, or more
than one possible cause). Patients otherwise fulfilling the
criteria for PD but who showed no disease progression over
15 years or who were not responsive to antiparkinsonian
drugs were classified as unspecified. To increase the diag-
nostic reliability across the eight study centers and be-
tween patients who were living and those who had died, all
putative cases were independently reviewed by an adjudi-
cation panel of senior neurologists who were kept unaware
of the initial diagnosis made in each center. In case of
disagreement, the diagnosis by the panel replaced the orig-
inal diagnosis.
Data analysis. Excluded from the incident cohort were
prevalent patients with parkinsonism at baseline and non-
November (1 of 2) 2000 NEUROLOGY 55 1359
responders to the follow-up examination. Rates per
100,000 person-years were estimated per 5-year age
groups (65 to 84 years) and gender. Age- and gender-
specific incidence rates were calculated as the number of
new cases divided by the person-years at risk. The 95% CI
were based on the Poisson distribution. Person-years for
individuals who did not develop parkinsonism were calcu-
lated as the time between the screening test for the base-
line survey and the screening test for the follow-up survey
or death. For subjects who developed parkinsonism,
person-years were calculated as the time between the
screening test of the baseline survey and the reported par-
kinsonism onset, or the midpoint between the baseline
screening test and the follow-up screening test (when the
onset could not be defined clearly) or death.
We considered the different types of parkinsonism as
competing causes of parkinsonism.
A forward stepwise Cox proportional hazards model
14
was used to estimate the relative risks of parkinsonism
associated with age and gender. Age and gender were en-
tered as covariates. Age was entered into the models as a
continuous variable (1-year increment). Using the same
covariates, another forward stepwise Cox proportional haz-
ards model was used to estimate the relative risk of PD.
Individuals who died were treated as censored from their
date of death. Individuals who either did not die or did not
develop parkinsonism were treated as censored observa-
tions from the time of their follow-up screening test.
Our analyses were run on a personal computer using
the 1995 release of Statistical Package for the Social Sci-
ences (SPSS) statistical software (SPSS, Inc., Chicago, IL).
15
Results. The sample attrition at each step of the ILSA
surveys is sketched in the figure. Among the 4,502 individ-
uals screened in the baseline survey, we identified 161
prevalent cases of parkinsonism. Thus, the cohort at risk
consisted of 4,341 individuals. Among them, 596 (13.7%)
died before they were contacted the second time. The
screening procedure was completed by 2,863 (76.4%) of the
survivors. The final cohort (3,084 individuals) included in
the analyses consisted of the 2,863 screened individuals in
addition to the 221 deceased individuals with reliable med-
ical information (see later). The median duration of
follow-up was 3.9 years (range 0.04 to 6.2). A total of
12,152 person-years were available for the analyses.
Refusals. The 882 subjects who refused to participate
in the follow-up examination had a median age of 75.2
years (range 65 to 85) and were older than the participants
(median age 72.4 years; range 65 to 85). Women refused
the follow-up visit more often than men (55% versus 45%).
Results of a logistic regression model, where being a re-
fusal was the dependent variable, indicated that the indi-
viduals who refused to participate in the follow-up
examination were significantly older, more frequently
women, and more educated than participants. The odds
ratios were 1.04 (95% CI, 1.02 to 1.06) for 1-year age incre-
ments, 0.75 (95% CI, 0.65 to 0.89) for male gender, and 1.03
(95% CI, 1.01 to 1.05) for 1-year increments of schooling.
Deceased subjects. Subjects who had died were older
(mean age 77.8 ⫾ 5.2; median age 79.2 years; range 65.3 to
85 years) than survivors (mean age 73.9 ⫾ 5.6; median age
73.3 years; range 65 to 85). Men died more frequently than
women (59.2% versus 40.8%). Again, these results were
confirmed by a logistic regression model, where being dead
was the dependent variable. The odds ratios were 1.13
(95% CI, 1.11 to 1.15) for 1-year age increments, 1.64 (95%
CI, 1.36 to 1.98) for male gender, and 0.97 (95% CI, 0.95 to
0.99) for 1-year increments of schooling. All of the 596
death certificates were retrieved. We obtained adequate
information from relatives and general practitioners for
221 deceased individuals (37.1%). Among these 221 indi-
viduals, we identified eight incident cases of parkinsonism,
of whom four had PD. The 221 dead individuals did not
differ significantly regarding age and gender distribution
from the remaining 375 dead individuals without reliable
medical information.
Among both the 2,863 screened individuals and the 221
deceased individuals with reliable information, a total of
68 individuals were identified as incident cases of parkin-
sonism. Forty-two (62%) individuals met the criteria for
PD, 7 (10%) had drug-induced parkinsonism, 8 (12%) had
parkinsonism in dementia, and 8 (12%) had vascular par-
kinsonism. The remaining three cases (5.8%) were classi-
fied as parkinsonism, unspecified. PD was the most
common type of parkinsonism in both men (67.4%) and
women (52%). Drug-induced (16%) parkinsonism and par-
kinsonism in dementia (16%) were the second most com-
mon types in women; by contrast, vascular parkinsonism
was more common (16.7%) than drug-induced parkinson-
ism (6.8%) and parkinsonism in dementia (9.1%) in men.
Table 1 shows the age- and sex-specific average annual
incidence rates of parkinsonism (new cases per 100,000
person-years). Rates increase with advancing age both in
men and women; however, the incidence in women also
was high in the age class 65 to 69 years. Rates for men
Figure. Attrition of the sampled population from the Ital-
ian Longitudinal Study on Aging at each step of the two
study surveys.
1360 NEUROLOGY 55 November (1 of 2) 2000
were higher than for women in every age group except the
younger one (65 to 69 years). However, in each age stra-
tum, the 95% CI overlapped, possibly because of small
number of cases.
The average annual incidence rate for parkinsonism
(per 100,000 person-years) in the population aged 65 to 84
years, adjusted to the 1992 Italian population, was 529.7
(95% CI, 400.5 to 658.9).
The age- and sex-specific incidence rates for PD are
reported in table 2. PD rates parallel those of parkinson-
ism in age and sex patterns: the incidence rates increase
with age in both men and women, and men had higher
rates than women in every age group. However, men and
women had similar rates in the age group 65 to 69 years.
In each age stratum, the 95% CI for the incidence rates
overlapped, possibly because of the small number of cases.
The average annual incidence rate of PD (per 100,000
person-years) in the population aged 65 to 84 years, ad-
Table 1 Number of cases of parkinsonism (n), person-years at risk, and incidence rates per 100,000 person-years (95% CI) in the ILSA
cohort subjects by sex and age group
Subjects 65–69 y 70–74 y 75–79 y 80–84 y
Total
Crude Adjusted*
Men
n 5 6 16 16 43 37.8
Person-years 1848 1781 1489 1167 6285 —
Incidence 271 337 1074 1371 684 601
(95% CI) (33–508) (67–606) (548–1601) (699–2043) (480–889) (410–793)
Women
n 8 4 5 8 25 24.7
Person-years 1766 1564 1345 1193 5867 —
Incidence 453 256 372 670 426 422
(95% CI) (139–767) (50–506) (46–698) (206–1135) (259–593) (256–588)
Total
n 13 10 21 24 68 64.3
Person-years 3613 3345 2834 2360 12.152 —
Incidence 360 299 741 1017 560 529
(95% CI) (164–555) (114–484) (424–1058) (610–1424) (427–693) (400–658)
* Adjusted to the Italian population, 1992.
ILSA ⫽ Italian Longitudinal Study on Aging.
Table 2 Number of cases (n) and average annual incidence rates per 100,000 person-years (95% CI) of PD in the ILSA cohort by sex and
age group
Subjects 65–69 y 70–74 y 75–79 y 80–84 y
Total
Crude Adjusted*
Men
n 4 6 8 11 29
Incidence rate 216 337 537 942 461 411
(95% CI) (40–429) (67–606) (165–909) (386–1499) (293–629) (253–570)
Women
n422513
Incidence rate 227 128 149 419 222 217
(95% CI) (05–449) (01–305) (01–355) (52–786) (101–342) (98–337)
Total
n88101642
Incidence rate 221 239 353 678 346 326
(95% CI) (68–375) (73–405) (134–572) (346–1010) (241–450) (224–427)
* Adjusted to the Italian population, 1992.
ILSA ⫽ Italian Longitudinal Study on Aging.
November (1 of 2) 2000 NEUROLOGY 55 1361
justed to the 1992 Italian population, was 326.3 (95% CI,
224.1 to 427.5).
We used the Cox regression analysis to summarize the
pattern of incidence rates seen in the stratified analyses;
results are shown in table 3. The risk of becoming affected
by parkinsonism was 1.09 (95% CI, 1.05 to 1.15) for every
increasing year of age; the risk for developing PD was 1.10
(95% CI, 1.04 to 1.16) for every increasing year of age. Men
had a relative risk for parkinsonism of 1.66 (95% CI, 1.02 to
2.7) and a relative risk for PD of 2.13 (95% CI, 1.11 to 4.11).
Discussion. There are three major findings from
this large population-based study of the frequency
and distribution of parkinsonism in the Italian el-
derly. First, the incidence of parkinsonism increases
with age. Second, men have a higher risk of develop-
ing parkinsonism than women. Third, PD is the most
common type of parkinsonism and shows age and sex
patterns similar to parkinsonism.
Studies of the incidence of parkinsonism and PD
are few, and only two of them were based on a direct
contact with each individual in the study sample.
3,8
The ILSA rates for PD are comparable with those
from the Rotterdam Study,
8
but the figures are
higher than those from the Honolulu Heart Study,
which also showed a different age pattern after 80
years of age.
3
In that study, the cohort was directly
surveyed for the first time in 1965 and then followed
through record-based case identification procedures.
The most recent survey, involving a direct contact
with surviving members of the cohort, took place in
1991 to 1994. Incident cases may have been under-
counted because patients who did not come to medi-
cal attention during the 26 to 29 years of passive
follow-up were not included in the incidence esti-
mates. Previous studies on the incidence of PD in
Italy used a record-based case finding strategy and
yielded considerably lower rates,
6,16
probably because
of undercounting of cases, as discussed earlier.
In the Rotterdam Study, as well as in the older
birth cohort of men from the Honolulu Hearth Study,
PD incidence decreased after 79 years of age. The
study design just described may account for the inci-
dence decline after age 75: because of less intensive
cohort surveillance at the ages of peak risk, many
cases of PD could have been missed in older cohort
members. Such individuals may have died, declined
follow-up evaluation, or developed obscuring medical
conditions before the time of the subsequent re-
screening. The same age pattern also was reported
from the study on Olmsted County, Minnesota. The
drop in incidence for the oldest men in the Minne-
sota Study may be an artifact because parkinsonism
subtyping may be unreliable in the presence of co-
morbidity at extreme ages.
17
On the other hand, in
our study, in the younger birth cohort of the Hono-
lulu Heart Study, and among women in the study on
Olmsted County, Minnesota, incidence rates contin-
ued to increase with advancing age. The incidence
rates of PD increased consistently through age 85,
also in the Northern Manhattan Study.
7
PD has been
suggested to be the result of the interaction between
normal aging and environmental or genetic risk fac-
tors.
18,19
If this theory is correct, we expect the risk of
PD to increase with increasing age, regardless of the
intensity and timing of the genetic and environmen-
tal factors. In support of this theory are two patho-
logic observations. Autopsy study of individuals
clinically unaffected by PD shows a linear decrease
in the number of dopaminergic neurons in the sub-
stantia nigra with advancing age.
20
Another autopsy
study shows that the number of Lewy bodies in the
substantia nigra increases with age in clinically un-
affected subjects.
21
Both of these observations sug-
gest that there is an underlying aging process of the
dopaminergic neurons in all individuals. This theory
also predicts that the incidence (risk) of PD will in-
crease continuously with age and reach its maximum
at extreme ages. The continuing increase in inci-
dence after age 75 years found in our study suggests
that PD is an aging-related condition. Record-based
epidemiologic studies find contrasting sex patterns
for PD; discrepancies in referral to medical services
may have accounted for those differences, as sug-
gested by De Rijk et al.
9
On the other hand, the
recent Minnesota study based on a records-linkage
system shows higher incidence rates for men in an
area where medical care was equal for elderly men
and women.
22
Furthermore, the cumulative PD inci-
dence to age 90 was significantly lower for women
than for men across three different ethnic groups
residing in northern Manhattan.
7
The Honolulu
Heart Study
3
examined men only, and the direct-
contact survey of the Rotterdam Study
8
did not show
any sex difference. The ILSA is the first study to
directly contact individuals in the general population
to support the hypothesis that men have a higher
risk of developing parkinsonism and PD compared
with women. Although the reason for the male pre-
dominance remains unknown, the female steroid
hormone may be involved in the etiology of PD.
23-25
In
the CNS, estrogen provides neuroprotection medi-
ated through multiple mechanisms, including anti-
apoptotic protection, protection against oxidative
stress, and neurotrophic effects.
23
Nevertheless, the
ILSA group of nonrespondents includes significantly
more women compared with the group of study par-
ticipants. This might be a potential source of selec-
tion bias with possible underestimation of the
incidence of parkinsonism and PD for women.
Table 3 Estimated adjusted relative risks (95% CI) of becoming
affected by parkinsonism or PD in the ILSA cohort (Cox
proportional hazards models)
Risk factor Parkinsonism PD
Age (1-y increment) 1.09 1.10
(1.05–1.15) (1.04–1.16)
Male gender 1.66 2.13
(1.02–2.70) (1.11–4.11)
ILSA ⫽ Italian Longitudinal Study on Aging.
1362 NEUROLOGY 55 November (1 of 2) 2000
Our study has several strengths: first, the study
sample. In each Italian municipality, the entire pop-
ulation is registered in the population register. Our
sampling frames were the population registers of
eight Italian municipalities. Although much care
was given to selecting centers in northern (Rubano-
Selvazzano, Genova, and Milano), central (Fermo,
Impruneta), and southern Italy (Catania, Napoli,
Casamassima), in rural, suburban, and urban areas,
the sample might not be thoroughly representative
of the entire national elderly population, given that
it was not drawn as a random national sample. Our
sample, which included both free-dwelling and insti-
tutionalized individuals, provides a more population-
based estimate of parkinsonism and PD compared
with either “door-to-door” or record-based surveys.
Furthermore, we were able to perform the clinical
ascertainment on all who screened positive. One lim-
itation of the ILSA is the lack of clinical ascertain-
ment of a sample of individuals who screened
negative. However, our screening procedure, vali-
dated against the clinical diagnosis of parkinsonism
in each study site, proved to have high accuracy (sen-
sitivity 100%, specificity 65%).
Our methods of follow-up and case detection are
intensive, with only 29% attrition over 3 years (only
1,257 of the 4,341 individuals of the parkinsonism-
free cohort could not be followed-up). Nevertheless,
because of the rarity of the disease, there were few
incident cases per each age and sex stratum, leading
to unstable estimates. Because of the small numbers,
we could not investigate the age and sex pattern of
other less common types of parkinsonism. Additional
years of follow-up will improve the precision of our
incidence estimates.
Acknowledgment
The authors thank Ms. M. E. Della Santa for preparing the manuscript.
Appendix
The ILSA Working Group: M. Baldereschi, MD, A. Di Carlo, MD,
S. Maggi, MD, CNR (Italian National Research Council, Italy); G.
Scarlato, MD, L. Candelise, MD, E. Scarpini, MD (University of
Milano, Italy); F. Grigoletto, ScD, E. Perissinotto, ScD, L. Battis-
tin, MD, M. Bressan, MD, G. Enzi, MD, G. Bortolan, ScD (Univer-
sity of Padova, Italy); C. Loeb, MD, CNR (Italian National
Research Council, Genova, Italy); C. Gandolfo, MD (University of
Genova, Italy); N. Canal, MD, M. Franceschi, MD (San Raffaele
Institute, Milano, Italy); A. Ghetti, MD, R. Vergassola, MD (USL
10, Firenze, Italy); D. Inzitari, MD (University of Firenze, Italy);
S. Bonaiuto, MD, F. Fini, MD, A. Vesprini, MD, G. Cruciani, MD
(INRCA Fermo, Italy); A. Capurso, MD, P. Livrea, MD, V. Lepore,
MD (University of Bari, Italy); L. Motta, MD, G. Carnazzo, MD
(University of Catania, Italy); F. Rengo, MD (University of Napoli,
Italy).
References
1. Gudmundsson KR. A clinical survey of parkinsonism in Ice-
land. Acta Neurol Scand 1967;43:1–61.
2. Fall PA, Axelson O, Fredriksson M, et al. Age-standardized
incidence and prevalence of Parkinson’s disease in a Swedish
community. J Clin Epidemiol 1996;49:637–641.
3. Morens DM, Davis JW, Grandinetti A, et al. Epidemiologic
observations on Parkinson’s disease: incidence and mortality
in a prospective study of middle-aged men. Neurology 1996;46:
1044–1050.
4. Marttila RJ, Rinne UK. Epidemiology of Parkinson’s disease
in Finland. Acta Neurol Scand 1976;53:81–102.
5. Rajput AH, Offord KP, Beard CM, Kurland LT. Epidemiology
of parkinsonism: incidence, classification, and mortality. Ann
Neurol 1984;16:278–282.
6. Granieri E, Carreras M, Casetta I, et al. Parkinson’s disease
in Ferrara, Italy, 1967 through 1987. Arch Neurol 1991;48:
854–857.
7. Mayeux R, Marder K, Cote LJ, et al. The frequency of idio-
pathic Parkinson’s disease by age, ethnic group, and sex in
Northern Manhattan, 1988–1993. Am J Epidemiol 1995;142:
820–827.
8. Breteler MMB, De Rijk MC, Ott A, Graveland GA, van der
Meche´ FGA, Hofman A. Incidence of Parkinson’s disease in a
population-based study: The Rotterdam Study. Neurology
1996;46(suppl 2):A332. Abstract.
9. De Rijk MC, Tzourio C, Breteler MMB, et al., for the
EUROPARKINSON Study Group. Prevalence of parkinsonism
and Parkinson’s disease in Europe: the EUROPARKINSON
collaborative study. J Neurol Neurosurg Psychiatry 1997;62:
10–15.
10. Morgante L, Rocca WA, Di Rosa AE, et al., for the Sicilian
Neuro-Epidemiologic Study (SNES) Group. Prevalence of Par-
kinson’s disease and other types of parkinsonism: a door-to-
door survey in three Sicilian municipalities. Neurology 1992;
42:1901–1907.
11. Maggi S, Zucchetto M, Grigoletto F, et al., for the ILSA Group.
The Italian Longitudinal Study on Aging (ILSA): design and
methods. Aging Clin Exp Res 1994;6:464–473.
12. The Italian Longitudinal Study on Aging Working Group.
Prevalence of chronic diseases in older Italians: comparing
self-reported and clinical diagnoses. Int J Epidemiol 1997;26:
995–1002.
13. Fahn S, Elton RL, Members of the UPDRS Development Com-
mittee. Unified Parkinson’s disease rating scale. In: Fahn S,
Marsden CD, Calne DB, eds. Recent Developments in Parkin-
son’s Disease, vol 2. Florham Park, NJ: MacMillan Healthcare
Information, 1987:153–163.
14. Cox DR. Regression models and life tables. J R Stat Soc (B)
1972;34:187–220.
15. Norusis MJ. SPSS for Windows: Base System User’s Guide
and Advanced Statistics. Release 6.0. Chicago: SPSS Inc.,
1993.
16. Rosati G, Granieri E, Pinna L, et al. The risk of Parkinson
disease in Mediterranean people. Neurology 1980;30:250–255.
17. Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Inci-
dence and distribution of parkinsonism in Olmsted County,
Minnesota, 1976–1990. Neurology 1999;52:1214–1220.
18. Ben-Shlomo Y. How far are we in understanding the cause of
Parkinson’s disease? J Neurol Neurosurg Psychiatry 1996;61:
4–16.
19. Langston JW. Predicting Parkinson’s disease. Neurology
1990;40(suppl 3):70–74.
20. Fearnley JM, Lees AJ. Ageing and Parkinson’s disease: sub-
stantia nigra regional selectivity. Brain 1991;114:2283–2301.
21. Gibb WR, Lees AJ. The relevance of the Lewy body to the
pathogenesis of idiopathic Parkinson’s disease. J Neurol Neu-
rosurg Psychiatry 1988;51:745–752.
22. Melton LJ III. History of the Rochester Epidemiology Project.
Mayo Clin Proc 1996;71:266–274.
23. Sawada H, Shimohama S. Neuroprotective effects of estradiol
in mesencephalic dopaminergic neurons. Neurosci Biobehav
Rev 2000;24:143–147.
24. Miller DB, Ali SF, O’Callaghan JP, Laws SC. The impact of
gender and estrogen on striatal dopaminergic neurotoxicity.
Ann NY Acad Sci 1998;844:153–165.
25. Green PS, Simpinks JW. Neuroprotective effects of estrogens:
potential mechanisms of action. Int J Dev Neurosci 2000;18:
347–358.
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