NEUROL-1580; No.

of Pages 13

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Available online at

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www.sciencedirect.com

Neuroepidemiology

Epidemiology of Parkinson’s disease

A. Elbaz a,b,c,*, L. Carcaillon d, S. Kab a,b,c, F. Moisan c

a
Inserm, centre for research in epidemiology and population health, U1018,
epidemiology of ageing and age related diseases, 94807 Villejuif, France
b
University Paris-Sud, UMRS 1018, 94807 Villejuif, France
c
Département santé travail, institut de veille sanitaire (InVS), 94415 Saint-Maurice, France
d
Département des maladies chroniques et des traumatismes, institut de veille sanitaire (InVS),
94415 Saint-Maurice, France

info article abstract

Article history: Parkinson’s disease (PD) is the second most common neurodegenerative disease after
Received 13 May 2015 Alzheimer’s. PD is considered a multifactorial disorder that results, in most cases, from
Received in revised form the combined effects of multiple risk and protective factors, including genetic and envi-
25 August 2015 ronmental ones. This review discusses some of the methodological challenges involved in
Accepted 1st September 2015 assessing the descriptive, prognostic and etiological epidemiological studies of PD, and
Available online xxx summarizes their main findings.
# 2015 Elsevier Masson SAS. All rights reserved.
Keywords:
Parkinson’s disease
Epidemiology

symptoms are most often unilateral or markedly asymme-

1. Parkinson’s disease
Described by James Parkinson in 1817, Parkinson’s disease (PD)
is a chronic neurodegenerative disease characterized by the
loss of dopaminergic neurons in the substantia nigra which
leads to decreased levels of dopamine in the striatum and
disrupted motor control. Neuronal eosinophilic inclusions
known as Lewy bodies and aggregation of alpha-synuclein
protein are hallmarks of the disease. Many other neuronal cell
populations are also affected and account for the presence of
non-motor symptoms. The main pathophysiological mecha-
nisms include mitochondrial dysfunction, abnormal aggrega-
tion of alpha-synuclein and oxidative stress [1].
The cardinal signs of PD include rest tremor, slowness of
movement, rigidity and postural instability. At disease onset,
trical; they become more pronounced as the disease pro-
gresses and eventually become a source of disability. A variety
of non-motor symptoms can precede motor symptoms or
develop over the course of the disease, and include consti-
pation, anosmia, depression, psychosis, cognitive dysfunc-
tion and dementia.
Apart from a pathological examination of the brain, there is
currently no other laboratory test or imaging technique that
can diagnose PD with certainty. Its diagnosis is purely clinical,
and relies on medical history and neurological evaluation;
additional tests may be useful for ruling out other causes of
parkinsonism. Compared with the final diagnoses obtained at
autopsy, diagnoses made by neurologists are relatively good,
albeit imperfect (positive predictive value = 76%) [2]; never-
theless, they have improved over the past few decades [3]

* Corresponding author. Hôpital Paul-Brousse, bâtiment 15/16, 16, avenue Paul-Vaillant-Couturier, 94807 Villejuif cedex, France.
E-mail address: alexis.elbaz@inserm.fr (A. Elbaz).
http://dx.doi.org/10.1016/j.neurol.2015.09.012
0035-3787/# 2015 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Elbaz A, et al. Epidemiology of Parkinson’s disease. Revue neurologique (2015), http://dx.doi.org/10.1016/
j.neurol.2015.09.012
NEUROL-1580; No. of Pages 13
2 revue neurologique xxx (2015) xxx–xxx
and can be further improved if movement-disorder specialists
are involved (positive predictive value = 98%) [4].
PD is the most common cause of parkinsonism. Other
neurodegenerative diseases characterized by the presence of
parkinsonism, such as multiple system atrophy and pro-
gressive supranuclear palsy, are rare and their risk factors
have rarely been studied. The present review is restricted
solely to PD.
2. Epidemiological tools
2.1. Descriptive studies
Door-to-door studies, where everyone in a given population is
screened and then examined to confirm the diagnosis, are
considered the reference approach. They have the advantage
of detecting undiagnosed patients. However, non-participa-
tion may be a problem if it can influence the outcome, and the
screening instrument needs to be highly sensitive. Also, these
studies are expensive and difficult to implement, and yet can
usually detect only a limited number of affected persons. In
addition, different diagnostic criteria can have a major impact
on frequency estimates [5]. PD registries represent an
alternative [6], but their feasibility is not straightforward, as
there may be multiple sources of patients, the diagnosis is
mainly clinical and there may be important variations in
access to specialized healthcare.
Death certificates fail to identify a large number of PD
patients because the disease is not always mentioned [7,8],
and they can also lead to diagnostic misclassification. In a
recent Spanish study, PD was rarely reported as the primary
cause of death (14.6%) [9]. Another study that searched for PD
mentioned anywhere on the death certificate reported a 57%
frequency [10].
Databases of large drug claims are increasingly available
and offer an interesting opportunity to identify patients with
specific conditions. However, as antiparkinsonian drugs are
not exclusively specific to PD, validation is an important step.
A few studies, including one in France, have shown that the
identification of PD patients using antiparkinsonian drug
claims is a valid approach, particularly when several drugs
and dosages are taken into account [11–14].
2.2. Etiological studies
Because the incidence of PD is not high, many epidemiological
studies of the etiology of PD have relied on a case-control,
rather than cohort, design. Only in a few large cohort studies
with long follow-up has PD diagnosis been ascertained and a
sufficient number of cases identified [15–21].
While this review will not discuss in detail the advantages
and disadvantages of case-control vs cohort studies, it is
worth mentioning a few important points. In case-control
studies based on prevalent cases, the collection of exposure
data is retrospective and involves subjects who already have
the disease. As PD mainly affects elderly people, this
approach has obvious consequences for the assessment of
exposures over long periods of time, and the collected data
are at risk of being inaccurate or include missing values. This
Please cite this article in press as: Elbaz A, et al. Epidemiology of Parkinson’s disease. Revue neurologique (2015), http://dx.doi.org/10.1016/
j.neurol.2015.09.012
is likely to be more severe with older participants when
exposure periods are distant in time and for detailed data. In
addition, PD may be responsible for cognitive impairment,
especially in those with more advanced disease, which can
lead to recall biases.
Increasingly, however, as a large number of studies are
performed for specific questions, meta-analyses are becoming
available, thereby allowing for pooled analyses, examination
of sources of heterogeneity and testing for publication bias.
2.3. Prognostic studies
These are based on cohorts of PD patients followed over time.
The majority have been hospital-based or performed as part of
clinical trials, and rely on highly selected patients attending
referral centers (younger patients, familial forms of disease,
atypical presentations), leading to issues regarding data
generalizability. Many studies have included prevalent rather
than incident patients, and there are as yet few studies
involving incident patients from the general population
followed over time [22]. More efforts are needed in this area,
and such studies should tend towards harmonization of
assessment tools.
3. Descriptive epidemiology
3.1. Incidence and prevalence
PD incidence is usually comprised between 10 and 50/
100,000 person-years, and its prevalence between 100 and
300/100,000 population [23,24]. Although it is the second most
common neurodegenerative disease after Alzheimer’s, PD
remains relatively uncommon. However, due to the general
aging of the population, the number of PD patients is expected
to double by 2030 [25].
PD frequency increases sharply with age. It is rare before
age 50 years, and its incidence and prevalence both increase
progressively after age 60; based on a meta-analysis of
prevalence studies, its prevalence rose from 107/100,000 per-
sons between ages 50 and 59 years to 1087/100,000 persons
between 70 to 79 years [24]. PD is usually more common in
men than women, with a male-to-female ratio of about
1.5 [26–28]. Possible explanations for this difference include
more frequent occupational exposures in men, neuropro-
tection from estrogens in women and X-linked genetic
factors.
In France, based on reimbursement data of antiparkinso-
nian drugs from the French National Health Insurance System
(Système national d’information inter-régimes de l’assurance mala-
die), it is estimated that there were around 150,000 prevalent
cases (prevalence = 2.30/1000 population) and 25,000 incident
cases (incidence = 0.39 per 1000 person-years) in 2010 (Fig. 1)
[29].
Geographical differences in PD frequency have been
reported, but are difficult to interpret because of differences
in finding cases and population characteristics. A collaborative
study conducted in four European countries using similar
case-finding methods and diagnostic criteria did not reveal
any differences [30]. On the other hand, a meta-analysis of six
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revue neurologique xxx (2015) xxx–xxx 3

Fig. 1 – Prevalence and incidence of Parkinson’s disease (PD) in France in 2010. The numbers of patients with prevalent and
incident PD were estimated from nationwide drug-claims databases based on social security systems [13,29]. The slight
decrease after age 85 years is partly explained by the lack of identification of patients in institutions with internal
pharmacies. The average age at PD onset was 74.8 years overall, and 74.0 years in men and 75.6 years in women.

studies found a lower prevalence in Africa than in either
Europe or North America [31], whereas there was no
significant difference between African-Americans and Cau-
casians in the United States [32]. The prevalence and incidence
of PD also appear to be slightly lower in Asian than in Western
countries [24,33], although some studies have found similar
estimates [34]. It is unclear whether such differences are due
to environmental factors or whether they reflect methodolo-
gical differences across studies.
Very few studies have examined temporal trends in PD
frequency. Diagnosis of the disease and rules for coding death
certificates have evolved over time, which makes interpreting
trends over time difficult [35]. A study in Minnesota, however,
has shown that the incidence of PD remained stable over a
short period of time (1976–1990) [36], whereas a Finnish study
comparing the incidence and prevalence of PD in 1971 and
1992 found increases only in men [37].
3.2. Prognosis
Understanding PD prognosis is necessary for improving the
management and care of PD patients. Although there are
effective symptomatic treatments, there is no cure, and the
disease is progressive with worsening of the motor and non-
motor symptoms responsible for the patient’s increasing
disability. The neuropathological staging system proposed by
Braak et al. [38] has allowed better characterization of the
neuropathological basis underlying the progression of PD.
Here, the focus is on three outcomes: death, dementia and
cancer. Additional markers of clinical progression are dis-
cussed elsewhere [39].
3.2.1. Mortality
Life expectancy and mortality risk in PD patients have been
extensively studied [22]. The vast majority of studies found a
significantly higher risk of mortality in PD cases compared
with people free of the disease of similar age and gender,
although the magnitude of the risk varied across studies,
ranging from 1.26 to 3.79 [22]. Some studies found no
significant differences in survival related to PD [40–43], but
they lacked statistical power, had short follow-up durations or
were based on selected populations. As shown in a meta-
analysis, differences in study design and, in particular,
inclusion of prevalent or incident cases and duration of
follow-up can explain some of the heterogeneity [22]. Based on
inception cohorts that followed incident PD cases, there was

Please cite this article in press as: Elbaz A, et al. Epidemiology of Parkinson’s disease. Revue neurologique (2015), http://dx.doi.org/10.1016/
j.neurol.2015.09.012
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an estimated pooled mortality ratio of 1.52 (95% CI: 1.23–1.88)
with little heterogeneity, a 5% annual decrease in survival of
PD patients and a mean median survival of 12.6 years from
disease onset compared with 16.0 years in non-PD subjects.
Mortality ratios increased with longer follow-ups. No robust
evidence was found that mortality decreased after the
introduction of levodopa.
There is remarkable individual variability in time to
death after PD diagnosis, although individual prognostic
factors are still poorly understood. When compared with
age-matched PD-free subjects, younger PD patients have a
higher mortality risk than older patients [10,44,45]. The risk
of mortality increases with motor-function deterioration
[46], severity of axial impairment [47] and the presence
of dementia [44,45,47]. As regards causes of death, the
leading ones in PD are heart disease, pneumonia and stroke
[40,48–51].
One study surveyed the records of 129 subjects with
pathologically proven PD who were separated into five groups
according to age at time of death to compare those who had
reached the advanced stage of disease in terms of age. Four
milestones of advanced disease (frequent falls, visual hallu-
cinations, dementia and need for residential care) happened at
a similar time prior to death in each group, irrespective of the
age at which they occurred. These observations suggest that
the disease can be subdivided into a variable early-middle
phase followed by the more stereotypical late period of
milestone accumulation, which appears to be less influenced
by age at onset than the previous phase. The accumulation of
multiple milestones was associated with high scores for
cortical Lewy bodies [52].
3.2.2. Dementia
Another major aspect of PD prognosis pertains to the
development of cognitive impairment and dementia. A
systematic review reported that PD-related dementia repre-
sents 3–4% of all dementia patients [53]. Given the specificity
and importance of PD-related dementia, specific diagnostic
criteria have been developed for this outcome in PD [54,55].
The annual incidence of dementia in PD varied from 30 to 95/
1000 person-years [39], and the relative risk of developing
dementia in PD was estimated to be between 1.7 and 5.9
compared with subjects free of PD [56–59]. The heterogeneity
across studies can be explained by differences in study design
(including the source of cases), inclusion of prevalent or
incident cases, duration of follow-up, criteria used for
dementia and type of comparator group. The main factors
influencing the risk of dementia in PD are PD duration [43,60],
older age at PD diagnosis [39,43,61,62] and greater PD severity
[63,64]. A growing body of evidence suggests that dementia is
responsible for a considerable amount of the reduced life
expectancy in PD patients [47,57,60].
3.2.3. Cancer
A large body of epidemiological evidence shows a decreased
cancer risk in PD. A meta-analysis of 29 studies found an
inverse relationship between cancer and PD (OR: 0.73, 95% CI:
0.63–0.83) [65]. PD patients have lower lifelong tobacco use
than non-PD subjects (see below), and smoking is a major risk
factor for many cancers; studies looking at different types of
Please cite this article in press as: Elbaz A, et al. Epidemiology of Parkinson’s disease. Revue neurologique (2015), http://dx.doi.org/10.1016/
j.neurol.2015.09.012
cancer showed a strong inverse association between smoking-
related cancers and PD [65]. However, a decreased risk of
cancers unrelated to smoking (colon, rectum, prostate) has
also been shown, albeit weaker than for smoking-related
cancers, thereby suggesting that other mechanisms may be
involved [65,66]. An alternative hypothesis involves genetic
factors influencing cell-cycle regulation that may protect
against cancer while predisposing to PD development; for
instance, the parkin gene, one of the genes responsible for
recessive familial PD, plays a role in cancer etiology and
progression [67].
In contrast to the overall reduced risk of developing cancer,
melanoma has been shown to occur with a greater frequency
in PD [68]. This association is found both before and after
diagnosis, so levodopa treatment is unlikely to be an
explanation. Common genetic factors are also unlikely to
account for this association [66,69]. It has been suggested that
a shared embryonic origin of melanocytes and neurons in the
neural crest may be involved.
In view of the complex relationship between cancer and PD,
more research is needed to clarify the mechanisms underlying
these associations and the potential implications.
4. Risk and protective factors
PD is considered a multifactorial disorder that is caused, in
most cases, by the combined effects of multiple factors,
including genetic and environmental ones. Approximately 10–
15% of PD patients report a family history of PD among their
first-degree relatives [70]. In a minority of patients, a single
gene mutation associated with Mendelian transmission of the
disease is found; 15 causal genes are currently identified, and
their mutations are most often associated with a younger age
of onset [71]. Genetic susceptibility has also been implicated in
sporadic forms [72]. Although a genetic risk score, composed
of multiple variants independently associated with disease
risk, has poor predictive power overall (area under the receiver
operator curve = 0.616), it decreases with increasing age across
the continuum of age at onset, thereby suggesting that the
accumulation of common polygenic alleles with relatively low
effect sizes makes a greater contribution to early, rather than
late, onset PD [73,74]. Similarly, twin studies have found low
concordance for the disease except when the disease begins at
an early age [75,76]. Thus, in a large proportion of cases, PD is
not explained by genetic factors, especially when the disease
does not appear in young patients, whereas epidemiological
and toxicological studies provide important results for the role
of environmental factors.
It has become increasingly clear that PD starts many years
before the motor symptoms become evident and PD is
diagnosed. Brain imaging techniques show that motor signs
appear when dopaminergic neuronal loss is already signifi-
cant. Cohort studies show that non-motor symptoms, such as
anosmia, constipation or rapid eye movement (REM) sleep
disorders, may be present for years before the onset of motor
signs – up to 20 years in some studies [77]. These findings may
help to define more precisely the periods of vulnerability to
better assess relevant exposures; it is also possible that the
effects of repeated insults may accumulate before motor
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symptoms appear, in which case, assessing cumulative
exposures before the onset of motor symptoms is warran-
ted. Nevertheless, the fact that motor and non-motor
symptoms are present before diagnosis needs to be
carefully considered in the interpretation of epidemiologi-
cal findings, as they may influence exposures and induce
associations (reverse causation).
Many exposures have been examined in relation to PD, and
this review addresses some of the most commonly examined
ones. Where meta-analyses are available, these sources have
been favored, with descriptions of specific studies that bring
additional information. The interested reader can access a
more detailed review that thoroughly examines risk and
protective factors elsewhere [78].
4.1. Smoking
For over 30 years, numerous studies have reported an inverse
association between smoking and PD. A meta-analysis of
44 case-control and four cohort studies found a 60% lower PD
risk among ever-smokers compared with never-smokers [79].
Despite different methodologies and populations, between-
study heterogeneity was low to moderate. The same rela-
tionship was present in an analysis of individual data from
eight case-control studies and thee cohort studies from the US
[80]. This robust inverse association is characterized by a dose–
response relationship, with decreasing associations as the
number of pack-years or years of smoking increase [79]. More
recently, a cohort study sought to distinguish the respective
roles of duration and intensity of smoking, and found that
duration seemed to be more important than intensity [81].
This observation is important as it suggests that many years of
smoking are required before observing a decreased risk of PD,
which represents a significant limitation for testing any
potential therapeutics.
The inverse relationship between smoking and PD is seen
in both men and women [80,81], whereas no interaction
between smoking and education or exposure to pesticides has
been demonstrated [80,82]. A similar relationship was obser-
ved with other forms of tobacco use: PD patients less often
smoke pipes or cigars and chew tobacco less often than do
controls [80]. In addition, a stronger inverse association
between smoking and PD was observed among cases with
younger onset of disease (< 75 years) compared with cases
with older onset of disease ( 75 years) [80]. On the other hand,
cohort studies of PD patients suggest that smoking has no
effect on disease progression [83].
The causality of the association remains controversial, and
several alternative hypotheses have been proposed [84,85].
First, survival bias does not appear to be responsible because
several cohort studies have confirmed it; in addition, smoking
does not appear to be associated with higher mortality among
cases vs non-cases [10]. Second, reverse causation may play a
role: PD patients may stop smoking more often or begin
smoking less often before disease onset than those who do not
develop PD [86] due to a reduced appetite for cigarettes or less
responsiveness to nicotine during the prodromal phase of PD.
It has also been hypothesized that prodromal personality
traits associated with a decreased appetite for smoking could
play a role. Low novelty-seeking has been associated with PD
Please cite this article in press as: Elbaz A, et al. Epidemiology of Parkinson’s disease. Revue neurologique (2015), http://dx.doi.org/10.1016/
j.neurol.2015.09.012
5
in two case-control studies [87,88]. A cohort study of more
than 6800 people followed for 40 years could find no
association between sensation-seeking and PD [89]. Other
traits, such as being introverted, conservative, socially
vigilant, tense [90] or anxious, have been found to be
associated with PD [91]. However, an inverse association
between smoking and PD has been reported as early as
20 years before disease onset [80,81]; this hypothesis would
therefore be plausible if there was a very long prodromal
phase. Third, a shared smoking and PD risk factor could be
hypothesized, but it is unlikely to be genetic, as the inverse
association between smoking and PD is also present when
comparing affected twins with their healthy, non-PD, co-twins
[92,93].
In recent years, investigators have devised novel study
designs to address these issues. Two case-control studies
focused on passive smoking, which is less likely to be affected
by genetic factors, personality traits or other behaviors, and
found an inverse association between PD and living or working
with smokers [94,95]. Another case-control study evaluated
the dietary intake of nicotine derived from plants in the
Nicotiana species of the Solanaceae family (tomatoes, peppers,
eggplant, potatoes) and found an inverse association [96].
On the other hand, the association may reflect biological
mechanisms that remain poorly elucidated. One study
showed inhibition of the monoamine oxidase B (MAO-B)
enzyme in the brains of smokers, and suggested that smoking
may have a protective effect for dopaminergic neurons [97].
Others have suggested that nicotine may have antioxidant
properties [98]. A recent study showed that, of five compounds
found in cigarette smoke (anabasine, cotinine, hydroquinone,
nicotine and nornicotine), nicotine and hydroquinone led to
the greatest inhibition of alpha-synuclein fibrillization [99].
One of the main difficulties in toxicological studies is the large
number of smoke components (over 4000 different molecules);
nevertheless, more work needs to be done in this area to better
understand this intriguing association and to elucidate
whether it is causal or not.
4.2. Coffee- and tea-drinking
Caffeine and some of its metabolites (theophylline, paraxan-
thine) are antagonists of adenosine A2A receptors, and in-vivo
studies in mice have demonstrated their ability to attenuate
the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahy-
dropyridine (MPTP) [100].
A meta-analysis (eight case-control and four cohort
studies) of the relationship between coffee-drinking and PD
found a 30% decreased risk for coffee drinkers compared with
non-drinkers [79]. This relationship was independent of
smoking, and risk reduction increased as the number of cups
per day increased. Also, a recent cohort study reported that the
risk of PD decreased by 40% among those who drank more
than three cups of coffee per day [101].
Other studies have assessed the total intake of caffeine
based on coffee, tea, cola and chocolate consumption. A meta-
analysis of 26 studies reported a 25% reduction in PD risk
among caffeine consumers with a dose–response relationship
[102]. These results are not explained by smoking. Further-
more, the association between caffeine intake and PD is
NEUROL-1580; No. of Pages 13
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observed in people who do not drink coffee, and whose
sources of caffeine are mainly tea and colas [103].
Some studies have separately assessed coffee with and
without caffeine, and no decreased risk of PD was found with
decaffeinated coffee [15]. Similarly, one study found an
association between black tea (which contains caffeine) and
PD, but not with green tea (which does not contain caffeine)
[20]. Thus, caffeine seems to be the best candidate to explain
this association.
The relationship between caffeine or coffee and PD appears
to be less strong in women than in men [102]. An interaction
between coffee and postmenopausal hormone replacement
therapy (HRT) has been suggested to explain this difference
[104], as the inverse association was observed only in women
not taking HRT.
The same types of biases as cited for smoking could play a
role here, but have been less often studied with coffee and
caffeine. However, adenosine A2A receptors are abundantly
expressed on striatal neurons and, in animal models, their
blockade extends the efficacy of levodopa. This suggests that
adenosine A2A receptor antagonists may be useful in PD
patients with motor fluctuations. However, while the results
were inconclusive for the first drugs tested in humans
(istradefylline, preladenant), additional clinical trials are
underway to test the safety and efficacy of other
A2A antagonists (tozadenant) – with encouraging results so
far [105,106].
4.3. Pesticides
The hypothesis of a link between PD and pesticide exposure
appeared in the early 1980s, after several cases of parkinso-
nism followed intravenous injection of MPTP. MPTP is
metabolized into 1-methyl-4-phenylpyridinium (MPP+), an
inhibitor of the mitochondrial respiratory chain with neuro-
toxic properties in dopaminergic cells. The molecule has a
chemical structure similar to that of paraquat, a non-selective
herbicide marketed since the 1960s and widely used ever
since. Following this observation, numerous studies have
examined the relationship of farming and exposure to
pesticides with PD.
A meta-analysis of 46 studies reported that the risk of PD is
about 1.6 times higher in people exposed to pesticides, with a
stronger association for herbicides (OR: 1.40) and insecticides
(OR: 1.50), albeit with significant heterogeneity across studies.
The association was weaker for fungicides (OR: 1.0), but these
compounds were examined in a limited number of studies
[107]. Two other meta-analyses found similar results [108,109].
Exposure assessment represents the main limitation of
several studies: few studies collected information on the types
of products, many combined professional and domestic
exposures, few performed gender-stratified analyses, and
very few assessed dose–effect relationships or involved work-
exposure matrices or industrial hygienists [107]. A recent
French study performed among farmers reported a stronger
dose–effect relationship for intensity of exposure than for
duration [110]. The study also showed that the association
with pesticides was present for tremor-dominant PD, the most
typical form of PD. In addition, there was a stronger
association for farmers working in vineyards than for those
Please cite this article in press as: Elbaz A, et al. Epidemiology of Parkinson’s disease. Revue neurologique (2015), http://dx.doi.org/10.1016/
j.neurol.2015.09.012
working in other types of agriculture [110]. Among specific
pesticides, there is some evidence of an association for
pesticides that induce oxidative stress or inhibit mitochon-
drial complex I [111] and, in particular, organochlorine
insecticides [18,112].
In addition to professional exposures, studies performed in
California using a pesticide registry and geographical infor-
mation systems found an increased risk of PD for people
exposed in their residential environment [113–115].
Toxicological evidence of neurotoxic effects of some
pesticides is reviewed elsewhere [116–118]. Given the evi-
dence, since 2012 in France, PD has been recognized as an
occupational disease for agricultural workers who fulfil
specific conditions: diagnosis confirmed by a neurologist;
and professional exposure to pesticides for 10 or more years.
4.4. Brain injury
In a recent meta-analysis of 22 studies (only one cohort study),
a history of head injury with loss of consciousness was
associated with an increased risk of developing PD (OR: 1.57,
95% CI: 1.35–1.83) [119]. This association also persisted in an
analysis restricted to 13 studies of higher quality (OR: 1.46, 95%
CI: 1.33–1.82). There was, however, some evidence in favor of
publication bias that may have led to overestimation of the
association.
In a case-control study based on twin pairs discordant for
PD, a dose–effect relationship was observed based on the
number of head injuries, with more severe head injuries
associated with a greater risk of PD [120]. This is in agreement
with other studies showing stronger associations for injuries
resulting in unconsciousness or hospitalization than for
milder traumas [121,122].
Several possible mechanisms might explain this associa-
tion. Head trauma and its repair process trigger inflammatory
mechanisms that may be deleterious to the brain. Head
trauma can disrupt the blood–brain barrier, allowing neuro-
toxins to penetrate the brain [122,123]. Head trauma may also
trigger aggregation of alpha-synuclein protein; one study
showed that the association between head trauma and PD was
stronger among people who carry a genetic polymorphism
associated with higher levels of alpha-synuclein, thus raising
the hypothesis that head injury may initiate and/or accelerate
neurodegeneration when levels of synuclein are high [124].
There are, however, possible sources of bias that have been
addressed in more recent studies. Recall bias may be an issue,
as PD patients may be prone to overreporting previous head
traumas as a possible cause of disease. However, a few studies
have relied on medical records and found similar associations
[122,123]; thus, recall bias is unlikely to fully explain the
association. Reverse causation may be another issue, as
patients may be at higher risk of falls during the prodromal
phase, when subtle motor signs are already present. In a large
Swedish registry that assessed head injuries based on medical
records, head injuries with hospitalization were associated
with PD [123]. The authors excluded head traumas that
occurred at 1, 5, 10 and > 10 years before the diagnosis;
although the odds ratio (OR) was markedly attenuated, there
was still a significant 20% increased risk for head injuries
occurring > 10 years before diagnosis [123]. Furthermore, in a
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revue neurologique xxx (2015) xxx–xxx
study from Canada, associations between PD and head trauma
were not substantially attenuated by excluding head traumas
that occurred at 5, 10 and 20 years before PD diagnosis [121].
4.5. Solvents
Solvents represent a broad class of compounds with many
commercial applications, including metal degreasing, dry
cleaning, paint thinners and detergents. Therefore, exposure
is relatively widespread at workplaces and at home. Many
solvents are lipophilic and able to enter the central and
peripheral nervous systems [125].
Despite differences in chemical structure, especially
between chlorinated and non-chlorinated agents, solvents
are treated as a single entity in the majority of studies. In a
meta-analysis of 16 case-control studies, PD was associated
with solvents (OR: 1.35, 95% CI: 1.09–1.67) [109]. The associa-
tion was slightly stronger when only six studies of the highest
quality were considered (OR: 1.58, 95% CI: 1.23–2.04). However,
no association was reported in two cohort studies that
collected data on solvents [16,126].
Specific solvents have been investigated in greater detail in
a twin study [127]. Lifetime exposures to six solvents was
inferred by industrial hygienists and/or occupational medi-
cine physicians who were all unaware of PD status, but used
work-related task-specific structured questionnaires, exten-
sive probability databases and multiple reference sources.
Based on 99 discordant twin pairs (49 monozygotic, 50 mono-
zygotic), the smoking-adjusted PD risk was increased for those
who had ever been exposed to trichloroethylene (OR: 6.1, 95%
CI: 1.2–33) and perchloroethylene (OR: 10.5, 95% CI: 0.97–113.0).
This finding is consistent with a rodent model of trichloroe-
thylene-induced parkinsonism, which revealed key patholo-
gical and neurochemical PD features [128]. Further studies of
the association between PD and solvents are needed to better
understand which products are more likely to be involved, to
characterize any dose–effect relationships and to identify the
relevant windows of exposure.
4.6. Uric acid
Serum uric acid (UA) plays a major role as an antioxidant, a
property that may explain why UA confers protection in
cellular PD models and attenuates toxin-induced loss of
primary neurons in lab cultures [129].
Several epidemiological studies have examined the asso-
ciation between UA or gout and PD, and most reported an
inverse association with a dose–effect relationship in some. In
a meta-analysis of cohort and nested case-control studies in
which UA was measured before diagnosis, high levels
(> 6.8 mg/dL) were associated with a 33% risk reduction (OR:
0.67, 95% CI: 0.50–0.91) [130]. This association was present in
men, but not in women [130], a difference that could be due to
lower UA levels or increased mitochondrial respiration
efficiency related to estrogens in women.
Although this inverse association may be causal, it could
also be due to reverse causation, as PD patients may change
their diet or other behaviors years before the diagnosis
because of constipation or other non-motor symptoms. Some
studies, which excluded cases during the first years of follow-
Please cite this article in press as: Elbaz A, et al. Epidemiology of Parkinson’s disease. Revue neurologique (2015), http://dx.doi.org/10.1016/
j.neurol.2015.09.012
7
up in their sensitivity analyses, found consistent results, but
the follow-up may not have been long enough and was thus
insufficient to fully exclude reverse causation as a potential
explanation.
Additional studies have examined the role of UA in relation
to disease progression and linked higher UA concentrations to
less severe progression [130], but not with risk of dementia
[131]. One study found that the risk of progression to disability
requiring dopaminergic treatment increased with an increas-
ing number of SLC2A9 alleles associated with lower UA
concentrations [132]. The Safety of Urate Elevation in PD
(SURE-PD) study, a randomized, double-blind, placebo-
controlled, dose-ranging trial of inosine, is currently under-
way and has reported that inosine is generally safe, tolerable
and effective in raising serum and cerebrospinal fluid levels of
UA in early PD [133].
4.7. Consumption of dairy products
Higher consumption of dairy products has been associated
with increased PD risk in several cohort studies; in a meta-
analysis of four such studies, the combined relative risk for the
highest intake was 1.6 (95% CI: 1.3–2.0) [134]. An association
was also reported in a recent prospective cohort from Greece
(OR: 1.33, 95% CI: 1.07–1.65) after adjusting for several
confounders, including gender, smoking, farming, caffeine
and energy intakes [135]; this association was independent of
calcium intake, as no association was observed with either
cheese or yoghurt.
Potential explanations for this association include conta-
mination of dairy products with neurotoxins or decreased
circulating levels of UA associated with greater dairy food
consumption [134]. Again, reverse causation cannot be
excluded.
4.8. Anti-inflammatory drugs
Because neuroinflammatory factors are believed to play a role
in the pathogenesis of PD [136,137] and non-steroidal anti-
inflammatory drugs (NSAIDs) exhibit neuroprotective effects
in animal PD models, some studies have investigated whether
anti-inflammatory medications, especially NSAIDs, confer
protection against PD [138].
In a meta-analysis of seven studies (five case-control and
two cohort studies), a modest reduction in PD risk was
associated with NSAIDs (OR: 0.87, 95% CI: 0.75–1.00) [139]. An
inverse association was found for non-aspirin NSAIDs (OR:
0.85, 95% CI: 0.77–0.94), including ibuprofen (OR: 0.75, 95% CI:
0.64–0.89), but not for aspirin (OR: 1.08, 95% CI: 0.92–1.27). For
non-aspirin NSAIDs, analyses stratified by duration of use and
intensity of use yielded results consistent with a dose–
response relationship. Ibuprofen activates peroxisome pro-
liferator-activated receptor (PPAR)-g, and PPAR agonists have
been shown to exert neuroprotective actions against oxidative
damage, inflammation and apoptosis in several neurodege-
nerative disorders, including PD, both in vivo and in vitro [140].
These findings support the hypothesis that non-aspirin
NSAIDs may confer protection against PD and warrant further
investigation as they may have important clinical implica-
tions. Nevertheless, potential biases may account for these
NEUROL-1580; No. of Pages 13
8 revue neurologique xxx (2015) xxx–xxx
findings [139]. First, NSAID use for non-motor manifestations
several years before PD diagnosis, such as pain-related
stiffness, can happen. Second, the lower mortality risk in
PD patients who use NSAIDs compared with other PD patients
may also play a role.
4.9. Vascular risk factors, statins and calcium-channel
blockers
The role of vascular risk factors has been investigated
primarily because of their role in other neurodegenerative
diseases, such as Alzheimer’s. In addition, some of the drugs
used to treat vascular risk factors have been shown to exert
neuroprotective effects.
The evidence regarding diabetes is inconclusive, as studies
have reported conflicting results [78]. One prospective study
found a modest increased risk of PD associated with diabetes;
however, the diagnosis of diabetes was clustered around the PD
diagnosis, and was more apparent among men with short
diabetes duration and those without diabetes complications
[48]. Therefore, this association may be explained by surveil-
lance bias, and additional well-designed studies are necessary.
Studies of hypertension show no association or lower risk
of PD in hypertensive subjects [78], a finding that may be
explained by reverse causation when blood pressure is
measured at around the time of PD diagnosis. Thus, additional
studies with midlife assessment of hypertension are needed.
Regarding cholesterol, a few prospective studies have
reported an inverse association between increasing levels of
cholesterol and PD [141–143]. Secondary analysis of the
DATATOP trial has also provided preliminary evidence that
higher total serum cholesterol concentrations may be asso-
ciated with modest slowing of the clinical progression of PD
[144]. As for other biomarkers, this inverse association may be
causal, but it may also be due to reverse causation as PD
patients may change their diet or other behaviors years before
the diagnosis.
Statins are widely used worldwide and are effective for
reducing cholesterol levels. One meta-analysis of eight (five
case-control and three cohort) studies showed a 20% risk
reduction of PD in statin users; there was, however, marked
heterogeneity across studies and evidence of publication bias
[145]; further studies, and particularly of the role of long-term
statin use, are needed. One recent study evaluated the
association between discontinuation of statin use and the
incidence of PD in a Chinese population free of PD that had
initiated statin therapy [146]. Continued use of lipophilic
statins was associated with a 60% decreased risk of PD
compared with statin discontinuation; there was no associa-
tion between hydrophilic statins and PD incidence. It has been
hypothesized that the beneficial role of statins in PD may be
the result of attenuation of neuroinflammatory processes due
to inhibition of the expression of inflammatory mediators,
such as interleukin-6 and tumor necrosis factor-a, and
protection against reactive oxygen species.
The basal activity of dopaminergic neurons is driven by
voltage-dependent L-type Ca2+ channels, and blocking Cav1.3
Ca2+ channels in adult neurons protects them in models of PD
both in vitro and in vivo [147]. A meta-analysis of five
observational studies showed that calcium-channel blocker
Please cite this article in press as: Elbaz A, et al. Epidemiology of Parkinson’s disease. Revue neurologique (2015), http://dx.doi.org/10.1016/
j.neurol.2015.09.012
(CCB) use was associated with a 25% reduction in PD risk; this
pattern was evident both for dihydropyridine and non-
dihydropyridine CCBs, albeit based on only two studies
[148]. Another study followed hypertensive Chinese patients
who were free of PD, dementia and stroke, and examined the
association between different antihypertensive drugs and
incidence of PD [149]. The use of dihydropyridine, but not non-
dihydropyridine, CCBs, and of centrally acting CCBs rather
than peripheral ones, were associated with a reduced risk of
PD. In addition to observational studies, a phase-II randomi-
zed, double-blind, parallel-group trial – Safety, tolerability and
efficacy assessment of dynacirc CR in Parkinson disease
(STEADY-PD) – included 99 subjects with early PD not
requiring dopaminergic therapy randomized to either 5, 10
or 20 mg of isradipine CR (a dihydropyridine CCB shown to be
neuroprotective in animal models of PD) or a matching
placebo daily [150]. Tolerability of isradipine was dose-
dependent, and the trial established 10 mg as the maximum
tolerable dosage of those tested. However, while there were no
statistically significant differences in efficacy between the
active treatments or placebo, there was a suggestion of a trend
towards increasing benefit with the 10-mg and 20-mg dosages.
A large placebo-controlled trial is now required to assess the
efficacy of isradipine 10 mg/day in PD.
4.10. Gene–environment interactions
In recent years, there has been a growing interest in
investigating gene–environment interactions in PD. One study
performed in France among male farmers heavily exposed to
pesticides found that exposures to organochlorine insecticides
interact with the ABCB1 gene (which codes for P-glycoprotein, a
transmembrane transporter acting as an active efflux pump for
a wide range of endogenous molecules and xenobiotics at the
blood–brain barrier) to increase PD risk. Thus, in men
professionally exposed to organochlorines, polymorphisms
associated with a reduced ability of ABCB1 to clear xenobiotics
from the brain increased the risk of PD [151]. These findings
support the hypothesis of gene-by-pesticides interactions in
the development of PD, and need to be replicated in larger
studies and other populations. There are other examples of
potential interactions between pesticides and other genes
[152–155], or head trauma and the alpha-synuclein gene [124].
These studies pose a number of methodological challenges,
including the need for appropriate exposure-assessment
methods and very large sample sizes, as the number of
subjects needed to detect interactions is usually large.
Replication is another major issue, as few of the above-
mentioned examples have been reproduced to date. One
report using a genome-wide approach to investigate genes
interacting with coffee-drinking showed evidence of an
interaction with the GRIN2A gene [156]. Yet, upon closer
inspection of the data, the interaction was explained by an
association between coffee-drinking and the gene, but in the
controls and not among the cases. A further large-scale
replication effort failed to reproduce the finding and found no
association among controls either [157].
Epigenetics is another emerging field that may represent a
potential mechanism to account for the effects of environ-
mental factors in PD [158,159]. Epidemiological studies where
NEUROL-1580; No. of Pages 13
revue neurologique xxx (2015) xxx–xxx
biological samples have been obtained have the potential to
assess epigenetic changes in PD-related and other genes, and
the influence of environmental factors on these changes. One
issue, however, is to what extent epigenetic changes seen in
peripheral tissues can be correlated with epigenetic changes
in the brain.
5. Conclusion
The identification of several PD genes has provided important
clues towards understanding the pathophysiology of the
disease. However, the proportion of cases explained by these
mutations is small and, in most cases, PD is likely to result
from the combined effects of several factors with weak-to-
moderate effects.
Through different approaches, epidemiological studies
have provided important clues towards a better understand-
ing of PD progression and prognosis, as well as evidence in
favor of the role of environmental exposures in disease
etiology. The degree of evidence is variable, although some
may have important clinical implications and are currently
being explored through clinical trials. Epidemiological studies
have generated results that can be studied experimentally to
understand the mechanisms leading from such exposures to
neuronal loss. Thus, multidisciplinary teamwork involving
epidemiologists, toxicologists and geneticists is essential to
better understand the etiology of PD.
Disclosure of interest
The authors declare that they have no competing interest.
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