Epidemiology of Parkinson

Disease
a a,b,
Andrea Lee, MD , Rebecca M. Gilbert, MD, PhD *

KEYWORDS
 Parkinson disease  Epidemiology  Neuroepidemiology
 Neurodegenerative disorder

KEY POINTS
 Parkinson disease (PD) is the second most common neurodegenerative disorder, present-
ing with bradykinesia, rigidity, tremor, and postural instability.
 Incidence rates of PD are 8 to 18 per 100,000 person-years based on prospective
population-based studies with either record-based or in-person case finding.
 Nonmotor symptoms include autonomic dysfunction, sleep disorders, mood disorders,
cognitive abnormalities, and pain and sensory disorders. Hallucinations and dementia
predict later nursing home placement.
 There are 18 PD-related gene loci that have been identified to date, with at least 7 disease-
causing genes.
 PD is a very complicated condition for physicians to optimally manage, with specific reha-
bilitation needs and complicated psychosocial dynamics, all that evolve with time.

INTRODUCTION
Epidemiology
Parkinson disease (PD) is the second most common neurodegenerative disorder after
Alzheimer disease and refers to the clinical presentation of bradykinesia, rigidity,
tremor, and postural instability. The main known risk factor is increased age. The esti-
mated prevalence of PD in industrialized countries is 0.3% in the general population,
1.0% in people older than 60 years, and 3.0% in those aged 80 years and older, with
incidence rates of PD of 8 to 18 per 100,000 person-years based on prospective
population-based studies with either record-based or in-person case finding.1–3 The
median age of onset is 60 years; the mean duration of the disease from diagnosis

The authors have nothing to declare.

a
Department of Neurology, New York University School of Medicine, 240 East 38th Street,
20th Floor, New York, NY 10016, USA; b The Marlene and Paolo Fresco Institute for Parkinson’s
and Movement Disorders, New York University Langone Medical Center, 240 East 38th Street,
20th Floor, New York, NY 10016, USA
* Corresponding author. The Marlene and Paolo Fresco Institute for Parkinson’s and Movement
Disorders, New York University Langone Medical Center, 240 East 38th Street, 20th Floor,
New York, NY 10016.
E-mail address: [email protected]

Neurol Clin 34 (2016) 955–965

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0733-8619/16/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved.
956 Lee & Gilbert

to death is 15 years, although patients can live for decades with PD.4,5 Sex differences
exist in PD.6 In addition to older age, male sex is recognized as a prominent risk factor
in developing PD. Both incidence and prevalence of PD are 1.5 to 2.0 times higher in
men than in women.7 Age at onset is 2.1 years later in women (53.4 years) than in men
(51.3 years). Women present with a milder PD phenotype, as evidenced by higher pre-
sentation of tremor (67%) than men (48%) and a slower rate of motor impairment. An-
imal studies suggest that estrogen may play a neuroprotective role against cell death
of striatal dopaminergic neurons. Nonmotor symptoms that are more prevalent in
women are anxiety, depression, and constipation, whereas men suffered more from
daytime sleepiness, drooling, and sexual symptoms.8

Natural History
The natural history of disability and progression of motor symptoms in PD has been
well studied since the seminal article by Hoehn and Yahr in 1967.9 The Hoehn and
Yahr (H&Y) scale is the most commonly used system for describing the progression
of PD. The transition from H&Y scale stage II to stage III is considered a pivotal
milestone in PD when gait and balance impairment result in disability in many gait-
dependent activities, such as walking, dressing, bathing, and housework. In one
longitudinal study, the time to reach H&Y scale III was 7.73 years.10 Male sex, gait dis-
order, lack of tremor, and lack of asymmetry as presenting clinical features are asso-
ciated with poorer long-term survival.11

Clinical Subtypes
Subtypes of PD have emerged, with patients classified according to distinct clinical fea-
tures, such as motor phenotype, or age of onset.12 Patients presenting with tremor at
onset have a slower progression of disease than those with a postural-instability-gait dif-
ficulty (PIGD) phenotype.13 The PIGD form of PD is associated with a faster rate of cogni-
tive decline and a higher incidence of dementia, whereas those with tremor-predominant
PD start to show signs of dementia only after PIGD symptoms develop.14 Patients with
late-onset PD (aged >60 years) are often characterized by the PIGD subtype,15 whereas
young-onset PD (aged 20–40 years) presents more often with tremor, rigidity, dystonia
and a higher rate of levodopa-related motor complications, such as dyskinesias.12

Nonmotor Symptoms
In addition to motor dysfunction, nonmotor symptoms (NMSs) of PD are recognized to
play an extremely important role in adversely affecting the quality of life of patients with
PD and may precede the formal diagnosis by decades.17 The Braak hypothesis16 sug-
gests that Lewy bodies, the cellular abnormalities seen in neurons of Parkinson
diseased brains, are found in multiple brain stem nuclei, causing non motor symptoms
prior to their appearance in the areas of the brain that cause motor symptoms. In
recent studies, at least one NMS was reported by almost 100% of patients with
PD.18–20 Some suggest that the NMSs of dementia and hallucinations are the stron-
gest predictors of nursing home placement for patients with PD.18 NMSs are broadly
classified as autonomic dysfunction, sleep disorders, mood disorders, cognitive ab-
normalities, and pain and sensory disorders. Of these, dysautonomia, rapid eye move-
ment (REM) sleep behavior disorder (RBD), depression, and olfactory disturbance
have been shown to often predate the onset of motor symptoms of PD.

Dysautonomia
Dysautonomia associated with PD mainly consists of gastrointestinal dysfunction,
genitourinary abnormalities, and cardiovascular dysfunction with orthostatic
 Epidemiology of Parkinson Disease 957

hypotension. Constipation is one of the most common NMSs with a prevalence

ranging from 50% to 70%.21,22 It was even described in James Parkinson’s23 original
essay on PD and often precedes the development of motor symptoms.22 Genitouri-
nary dysfunction due to detrusor overactivity is the most frequent urodynamic abnor-
mality,24 which leads to urinary urgency, frequency, incontinence, and nocturia; it is
estimated to have a prevalence of 25% to 50%.25 Sexual dysfunction in men with
PD presents mainly as erectile dysfunction, although decreased sexual drive and dif-
ficulty with arousal and orgasm have been reported in both sexes. Cardiovascular
dysfunction is present in almost 60% of patients with PD.18 Orthostatic hypotension
can be one of the most debilitating cardiovascular NMSs and may manifest in an array
of symptoms, including lightheadedness, fatigue, dyspnea on exertion, foggy thinking,
or blurred vision.

Sleep disturbances
Sleep disturbances are exceedingly common in PD, and its prevalence may approach
90%.26 These disturbances include RBD, restless legs syndrome, periodic limb move-
ments of sleep, insomnia, and excessive daytime somnolence.27 The most common
form of sleep disturbance is sleep fragmentation with frequent awakenings, leading
to excessive daytime somnolence. The problem is multifactorial and compounded
by impaired ability to turn in bed due to rigidity and bradykinesia, nocturia, medication
effects, and periodic limb movements.18 Similar to constipation, RBD often precedes
the motor onset of PD and has gained attention as a possible predictor for the devel-
opment of the disease. RBD is characterized by acting out a dream during character-
istic REM sleep, when there should be atonia on polysomnography.28 The prevalence
of RBD in PD may be in the range of 25% to 50%, and some studies suggest that pa-
tients with RBD have an 80% to 90% risk of eventually developing PD.18 It is important
to identify RBD in patients with PD because it can potentially be dangerous to the bed
partner and can be effectively treated with medication.

Mood disorders
Mood disorders, such as depression, anxiety, and apathy, are common in PD. Like
constipation and RBD, depression may precede motor manifestations and be an early
prodromal sign of PD. One meta-analysis reported a prevalence of major depressive
disorder in 17%, minor depression in 22%, and dysthymia in 13% of patients with
PD.29 Anxiety disorders, including generalized anxiety disorder, agoraphobia, panic
disorder, and social phobia, are present in individuals with PD at a prevalence of
20% to 40%.21 One meta-analysis suggests that apathy may be present in 40% of in-
dividuals with PD.30 The lack of motivation marked by reduced goal-oriented behavior
and decreased emotional expressivity has been shown to contribute significantly to
caregiver burden and has negative implications for treatment and long-term care.

Cognitive disturbances
One of the most feared complications of PD for patients and their caregivers is the
development of dementia. Cognitive dysfunction in PD may present in varying de-
grees.31 The prevalence of dementia is greater than 75% in individuals who survive
10 years with the PD diagnosis.32 Mild cognitive impairment affects 18.9% to
38.2% of patients in the early stages of the disorder.33

Pain and sensory disturbances

Several sensory abnormalities have been described in individuals in PD. Olfactory
impairment is among the earliest NMSs of PD and is present in approximately 90%
of early stage PD cases.34 Vision problems occur in the PD population in the form
958 Lee & Gilbert

of reduced contrast sensitivity, color discrimination, and dry eye syndrome. Issues
affecting structures around the eye occur in those with PD, such as seborrheic ble-
pharitis and meibomian gland disease.35 Pain is a frequent problem in PD that
worsens over the course of the disease, and patients who have pain are more
depressed and have a poorer quality of life than those who do not. Pain was present
in 76% of patients with PD in one cross-sectional study36 and can be categorized as
musculoskeletal, dystonic, central neuropathic, radicular, and other (nonradicular low
back pain, arthritic, visceral).

Neurogenetics
Over the past 2 decades there has been an explosion of research on the genetics of PD;
18 PD-related gene loci have been identified to date, with at least 7 disease-causing
genes, including alpha-synuclein-synuclein, leucine-rich repeat kinase 2 (LRRK2), Par-
kin, PTEN-induced putative kinase-1 (PINK1), DJ-1, ATPase type 13A2 (ATP3A2), and
glucocerebrosidase. Mutations of these genes have been identified as the cause of rare
familial forms of PD. It is estimated that monogenic PD accounts for about 5% of all PD
cases in either an autosomal dominant or autosomal recessive inheritance pattern.
LRRK2 mutations are the most common and have been associated with 1% of spo-
radic PD cases and account for 4% of hereditary parkinsonism cases. LRRK2 muta-
tions generally give rise to a benign tremor-predominant disease phenotype that
resembles sporadic PD,37 particularly asymmetric parkinsonism with tremor but with
a decreased risk of cognitive and olfactory impairment.12 Mutations in 4 genes (Parkin,
DJ-1, PINK1, and ATP13A2) cause recessive early onset parkinsonism (age of onset
<40 years). Parkin mutations are the second most common genetic cause of L-dopa
responsive parkinsonism and account for one-third to one-half of all young-onset
PD, whereas mutations in the other 3 genes are more rare.4 The Parkin mutation pheno-
type has a slow and benign course compared with sporadic PD, with good response to
dopaminergic drugs and sleep benefit (patients do better in the morning).

Management in Different Settings to Modify Outcome

PD is a very complicated condition for physicians to optimally manage, with multiple
motor and nonmotor manifestations, specific rehabilitation needs, and complicated
psychosocial dynamics that evolve with time. Despite this, recent data demonstrated
that only 58% of patients with PD saw a neurologist (as opposed to an internist, family
medicine physician, or geriatrician) in the 3 years under study. Those who were cared
for by a neurologist, however, had lower rates of admission to nursing home, lower
rates of hip fracture, and improved survival.38 Women and minorities were less likely
to be seen by a neurologist than white men.
Although evidence strongly suggests that outcomes improve with treatment by a
neurologist, it is less clear whether specialty within neurology offers benefits over
general neurology. For example, there are movement disorder fellowships that train
board certified neurologists in PD care, PD centers that offer comprehensive multi-
disciplinary care for patients, and PD-specific hospital units. These programs are
being closely studied to determine whether these types of specific care lead to
better outcomes for patients, lower health care costs, or both. If they do, methods
to deliver this specialized care to larger numbers of people will be necessary. To
that end, PD-specific telemedicine is currently being studied.

Clinic based
A recent randomized controlled study compared patients who received care from a
general neurologist with those who received care from a movement disorders
 Epidemiology of Parkinson Disease 959

physician who was part of a multidisciplinary outpatient setting with dedicated PD

nurses and social workers. Patients followed by the multidisciplinary team had
improved scores on measures of quality of life as well as motor performance.39 The
study investigators discussed that the study design did not allow separation of the
benefits conferred by seeing a movement disorders physician from the benefits
conferred by the multidisciplinary nature of the program. Nevertheless, if this finding
holds in future studies, it will become necessary to scale up this type of care to reach
larger numbers of patients.
Hospital based
Hospitalization offers unique challenges to patients with PD. It is very difficult for a
traditional hospital floor to dispense medications as frequently and as on time as pa-
tients with PD often need. If doses are late or missed, motor function, including ability
to swallow, can be severely affected, which, in turn, can increase deconditioning, in-
crease fall risk, impede inpatient physical therapy efforts, and potentially keep patients
from swallowing their next doses of medication, which can all lead to a downward spi-
ral. Patients with PD are at an increased risk for dysautonomia and hallucinations
when medically ill, which can be difficult to manage. Finally, patients with PD may
be given medications while hospitalized, for nausea or psychosis, that can worsen
their parkinsonism. For these reasons, a pilot PD-specific hospital unit, in which phy-
sicians and staff had PD-specific training and on which PD medications were readily
available, was created and its outcomes were studied.40 The PD unit had more accu-
rate and on-time medication delivery to patients, shorter lengths of stay, and better
patient satisfaction scores.
Telemedical
The way to increase the number of patients able to be seen by PD specialists is
through telemedicine. This method of providing care is developing rapidly and is
improving in its scope and possibilities alongside the technologies available to support
it. The studies that have been performed so far to evaluate telemedicine have been
small and most were not performed in randomized, controlled trials (RCTs). Neverthe-
less, the studies have been promising, demonstrating patient satisfaction with the
method, vast savings in travel and time, and improvements in motor performance
and quality of life, likely to the same degree as face-to-face encounters.41 So far, tele-
medicine for PD has been used exclusively in wealthy countries, although the potential
for meeting needs in the developing world is exciting.

PUBLIC HEALTH ASPECTS

Risk Factors
Factors that may increase risk of Parkinson disease
The cause or causes of PD have not been firmly established and, like most chronic dis-
eases, are expected to be a combination of modifiable (eg, environmental exposures
that increase or mitigate risk) and nonmodifiable factors (eg, genetic factors). Under-
standing the modifiable causes is vital to a public health policy of PD management.
However, conflicting data exist for most of these factors making it difficult to formulate
a public health response without further study.

Pesticides The observation that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

(MPTP), an accidental byproduct of the manufacturing of the synthetic opioid
1-methyl-4-phenyl-4-propionoxypiperidine (MPPP), could cause a PD phenotype
sparked interest in the possibility that other environmental toxins could be damaging
to dopaminergic cells as well.42 Toxins that resemble MPTP were suspected,
960 Lee & Gilbert

including 2 pesticides, paraquat and rotenone. Most human data concerning the rela-
tionship between these and other pesticides comes from case-control studies in
which patients and controls were asked via a questionnaire about their exposures.
Recall bias is a particular concern in this type of study, as patients who have PD
are invested in finding a cause of their condition and may over-report exposure. The
data collection varies widely among studies in the level of detail concerning amount
and type of exposure as well as analysis of confounding factors, such as smoking,
which has shown to have a protective effect.43

Occupation related Additional studies have shown that farming as an occupation may
also confer an increased risk of PD, although this is difficult to separate from exposure
to pesticides. Welding, with its exposure to manganese, has also been studied as a
risk factor for PD. An interesting recent study that collected occupational history of
cases and controls found that artistic occupations tend to be protective from PD.
The hypothesis given for this finding is that patients with premotor PD and lower dopa-
mine levels may have subtle cognitive and behavioral changes that limit novelty
seeking and, therefore, may gravitate to more structured occupations.44

Traumatic brain injury Traumatic brain injury (TBI) may predispose a person to
develop PD later in life. The data exploring this correlation have been contradictory,
and recall bias (those with PD are more likely to remember a past head trauma) as
well as reverse causation (those with imbalance from PD are more likely to suffer
from a head trauma) have been cited as reasons that studies have been faulty. Two
recent studies explored this issue. One followed the medical records of patients
who presented to an emergency department with head trauma versus trauma that
did not involve the head. Patients with TBI had a higher likelihood of developing PD
later in life.45 The second study administered questionnaires to patients with PD
and controls and determined, unlike other case-control studies of similar design,
that there was no increased history of TBI in the PD population.46

Factors that may mitigate risk of Parkinson disease

Caffeine The first suggestion that caffeine could be protective in PD came in 1996 with
a questionnaire-based study examining ingestion of specific foods in a case-
controlled manner. Patients with PD reported drinking less coffee than controls.47
This study was followed up by prospective data collection. In 2 large cohorts followed
over time, an inverse association was found between PD and caffeine consumption in
the forms of coffee, tea, and other caffeine sources.48 Recommending caffeine for pa-
tients who already have PD can be difficult because caffeine can worsen tremor.
Molecularly, caffeine inhibits the adenosine receptor, and adenosine inhibitors have
since been developed for the treatment of PD. Istradefylline is one such compound,
already approved for use in Japan and being studied in a clinical trial in the United
States. Other adenosine inhibitors are also in clinic trials in the United States.
Cigarette smoking Numerous studies have identified an inverse association between
smoking and PD. Because smoking itself cannot be recommended to patients with
PD, as it presents numerous health risks, researchers have tried to harness the
seeming protective effect of smoking in other ways. A clinical trial of the nicotine patch
as a neuroprotective agent in PD is set to start. However, the assertion that smoking is
protective in PD came under question in a recent study that suggested that patients
with PD had lower smoking rates because low dopamine levels make it easier to
quit and harder to become addicted.49 This theory suggests that prodromal PD is pro-
tective of smoking addiction and not the other way around.
 Epidemiology of Parkinson Disease 961

Alcohol consumption Because epidemiologic data suggested that smoking and cof-
fee intake may reduce the risk of developing PD, alcohol consumption was studied as
well. A recent review of all the studies performed from 2000 to 2014 looked at this rela-
tionship and found conflicting results. In general, prospective studies showed an
increased risk of PD in the setting of moderate alcohol use, whereas case control
studies showed a decreased risk. The question of alcohol’s relationship to PD is,
therefore, still not fully understood.50
Nonsteroidal antiinflammatory drugs Laboratory data suggest that neuroinflamma-
tion can play a role in the eventual death of neurons in PD, and that decreasing this
inflammation could be neuroprotective. Several studies have tried to determine
whether ingestion of nonsteroidal antiinflammatory drugs (NSAIDs) could reduce the
risk of developing PD. A recent Cochrane review of these data concluded that nonas-
pirin NSAIDs, with the most data on ibuprofen, may reduce the risk of developing
PD.51

Statins Statins have been shown to have antiinflammatory properties and the hypoth-
esis was developed that they may be potential neuroprotective agents. Statins are
already one of the most commonly prescribed drugs, which increase the interest in
these medications. A recent analysis of statin use and its correlation to PD rates
was prospectively studied in 2 ongoing large cohorts. Regular use of statins was asso-
ciated with a modest reduction of PD risk.52

Calcium channel blockers Calcium channel blockade can protect neurons from exci-
totoxicity in cell culture and animal models of PD. These data led to a phase II trial
testing the neuroprotective effects of the calcium channel blocker isradipine in pa-
tients with early PD.53 Despite the propensity of patients with PD to have low blood
pressures, the drug was tolerated and the results led to the development of a larger
phase III clinical trial, which is ongoing.54
Hyperuricemics Preclinical data suggested that elevated plasma levels of uric acid
was protective against PD. In large cohorts of patients with PD followed over
time, higher urate levels predicted a more benign disease course. In addition,
prospectively collected data of healthy individuals correlated higher urate levels
to lower rates of PD. Because of these findings, a phase II trial of inosine, a pre-
cursor of urate, was conducted in patients with early PD.55 Results showed that
elevating uric acid was possible and safe in patients with early PD. Although not
powered to determine whether there was a clinical improvement in patients with
elevated urate levels, preliminary data was promising and will likely lead to a phase
III trial.

Exercise Recent studies have demonstrated that exercise can improve motor function
in PD as well as some of the nonmotor symptoms of PD, such as fatigue, cognition,
and depression. A recent meta-analysis reviewed the evidence of RCTs controlled
studies of exercise of all types conducted between the years of 2013 and 2015.56
Thirty-three studies of exercise and physical therapy techniques of various modalities,
including aerobic exercise, strength training, and balance training, were conducted.
Benefits were found in different exercise paradigms. One particular study highlighted
the phenomenon that exercises of diverse types had benefits on functioning in PD.
Shulman and colleagues57 conducted a trial with 3 arms: high-intensity treadmill
training, low-intensity treadmill training, and stretching and resistance exercises. All
groups increased gait speed; but interestingly, the stretching and resistance group
increased by the biggest margin.
962 Lee & Gilbert

Infectious Disease Causation: Implications for Public Health

In recent years, a series of new theories have been proposed to explain the root cause of
PD. They introduce the possibility of additional modifiable risk factors for PD and present
new challenges from a public health perspective. Public health implications of this the-
ory would be profound as it suggests that PD could be transmitted person to person.
Enteric-pathogen
In addition to the understanding that Lewy bodies affects multiple brain areas, it has
also been long established that Lewy bodies can be found in neurons far from the
brain, most notably the enteric nervous system and autonomic ganglion.48 One recent
theory posits that PD is caused by an enteric pathogen, which then traverses up the
vagus nerve to gain entry into the brain. A recent epidemiologic study analyzed PD
rates in patients who had previously received a complete vagotomy or a selected va-
gotomy to treat peptic ulcer disease from 1977 to 1995 in Demark. Results showed a
lower incidence of PD in those who had received a complete vagotomy as compared
both with controls and with those who received a selected vagotomy.58 The data were
interpreted to mean that lacking the vagus nerve was protective of PD as it prevented
transmission of microorganisms from the gut to the brain. A related theory argues that
intestinal flora plays an important role in PD and that the microbiome of patients with
PD differs from that of controls.59 These theories substantiate the need to search for a
potential infectious agent, introduced through the gut, which could contribute to the
development of PD.
Prions
The Braak hypothesis suggests that the pathologic hallmark of PD, the abnormal
accumulation of alpha-synuclein into Lewy bodies, occurs in a stepwise fashion
from the lower brainstem to the midbrain to the cortex. The lower brain stem contains
centers of parasympathetic function, sleep regulation, and mood, which are affected
by the disease before the midbrain, where the substantia nigra and the dopaminergic
neurons responsible for the motor symptoms of PD are located.16 Therefore, although
it seems that Parkinson pathology travels from one neuronal region to another, it is not
yet clear how that movement occurs. A new theory that is gaining traction is that the
responsible agent is abnormally aggregated alpha-synuclein itself, which would make
PD transmission akin to that of a prion disease. It was recently shown that alpha-
synuclein can take on different conformations with different potentials to propagate
their conformations,60 the hallmark of a prion. In addition, autopsies of patients who
received fetal cell transplants under experimental protocols in the early 1990s
revealed that Lewy bodies were present in the fetal transplant as well.61 One way to
explain how the relatively young cells had the identical Lewy body pathology as their
elderly neighbors was to hypothesize that the Lewy body migrated from 1 cell to the
other.

CONCLUSION

Although much is understood about PD, much is yet a mystery. As more research un-
covers the basic biology of how PD develops, this will translate into public health op-
portunities to prevent or improve this difficult and multi-faceted disease.

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