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ARTICLE

Premotor Parkinsons Disease: Concepts and Denitions


Andrew Siderowf, MD, MSCE1* and Anthony E. Lang, MD2

1
Parkinsons Disease and Mov Disord. Center, Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
2
Moverment Disorders Center and the Edmond J. Safra Program in Parkinsons Disease, Toronto Western Hospital and the Department of
Medicine, University of Toronto, Toronto, Ontario, Canada

A B S T R A C T : Parkinsons disease (PD) has a pro- high-risk populations (eg, patients with rapid eye move-
dromal phase during which nonmotor clinical features ment behavior disorder or LRRK2 mutations) would
as well as physiological abnormalities may be present. enrich the sample for cases with underlying PD. Ulti-
These premotor markers could be used to screen for mately, the role of preclinical detection of PD will be
PD before motor abnormalities are present. The tech- determined by the ability of emerging therapies to inu-
nology to identify PD before it reaches symptomatic ence clinical outcomes. As such, implementation of
Braak Stage 3 (substantia nigra compacta [SNc] large-scale screening strategies awaits the arrival of
involvement) already exists. The current challenge is to clearly safe and effective therapies that address the
dene the appropriate scope of use of predictive testing underlying pathogenesis of PD. Future research will es-
for PD. Imaging technologies such as dopamine trans- tablish more denitive biomarkers capable of revealing
porter imaging currently offer the highest degree of ac- the presence of disease in advance of SNc involvement
curacy for identifying premotor PD, but they are with the promise of the potential for introducing dis-
expensive as screening tools, and abnormalities on ease-modifying therapy even before the development of
these studies would only be evident at Braak Stage 3 evidence of dopamine deciency. V C 2012 Movement

or higher. Efciency is greatly enhanced by combining Disorder Society


imaging with a prescreening test such as olfactory test-
ing. This 2-step process has the potential to greatly
reduce costs while retaining diagnostic accuracy. Alter- Key Words: Parkinsons disease; early detection; sen-
natively, or in concert with this approach, evaluating sitivity; specicity

Screening for disease before it begins or becomes screening for colon or breast cancer is not whether
symptomatic is emerging as the standard approach there should be screening, but how often. If screening
throughout medicine. It is widely accepted that risk and prevention are expected in these conditions, why
factors for coronary heart disease and stroke can be should neurodegenerative disorders such as Parkin-
identied and modied. Likewise, the question in sons disease (PD) be different? PD has a prolonged

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*Correspondence to: Dr Andrew Siderowf, Parkinsons Disease and Movement Disorders Center, Department of Neurology, University of Pennsylvania,
330 South 9th Street, Philadelphia, PA 19107, USA; Andrew.siderowf@uphs.upenn.edu
This article is partially adapted from the following publications: Siderowf A, Stern MB. Premotor Parkinsons disease: clinical features, detection, and
prospects for treatment. Ann Neurol. 2008; 64:S139S147; Lang AE. A critical appraisal of the premotor symptoms of Parkinsons disease: potential
usefulness in early diagnosis and design of neuroprotective trials. Mov Disord. 2011;26:775783.
Relevant conicts of interest/nancial disclosures: Andrew Siderowf is supported by a Morris K. Udall Parkinsons Disease Research Center of
Excellence grant from NINDS (NS-053488) and has been supported by SAP4100027296, a health research grant awarded by the Department of Health
of the Commonwealth of Pennsylvania from the Tobacco Master Settlement Agreement under Act 2001-77; has received consulting fees from Teva
Neuroscience, Ipsen Pharmaceuticals, Schering-Plough, Merck Serono, and General Electric; has received speaking honoraria from Teva Neuroscience;
and has received research support from Avid Radiopharmaceuticals. Anthony Lang has served as an adviser for Abbott, Allon Therapeutics, Astra Zenica,
Avanir Pharmaceuticals, Biovail, Boerhinger-Ingelheim, Cephalon, Ceregene, Eisai, GSK, Lundbeck A/S, Medtronic, Merck Serono, Novartis, Santhera,
Solvay, and Teva; has received grants from Canadian Institutes of Health Research, Dystonia Medical Research Foundation, Michael J. Fox Foundation,
National Parkinson Foundation, and Ontario Problem Gambling Research Centre; has received publishing royalties from Saunders, Wiley-Blackwell, Johns
Hopkins Press, and Cambridge University Press; and has served as an expert witness in cases related to the welding industry.
Full nancial disclosures and author roles may be found in the online version of this article.
Received: 12 December 2011; Revised: 6 January 2012; Accepted: 30 January 2012
Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.24954

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as a risk state for Alzheimers disease (AD).5 Prediag-


nostic PD is conceptually distinct from the other levels
of the PARS framework because clinical features of
PD are apparent in the prediagnostic phase. As tests
such as dopamine transporter (DAT) imaging become
more widely used, patients with mild parkinsonian
signs and biomarker evidence of dopamine deciency
may come to be diagnosed with PD, and this category
would be reclassied as early, minimally symptomatic
disease.

Premotor Phase
FIG. 1. The PARS pyramid. In this conceptual model there are 4
stages that precede clinically manifest PD: prephysiological, preclini-
Patients with premotor PD have nonmotor symp-
cal, premotor, and prediagnostic. There are a relatively large number toms such as decreased sense of smell, depression, and
of individuals that have a predisposition to develop PD, but only a various gastrointestinal and other systemic features
fraction progress to each succeeding level. Ultimately, the number of
individuals who develop clinically manifest PD is a small fraction of
that have been shown to predate the classical motor
the at-risk pool. features of Parkinsons disease. Recognizable clinical
features, including neuropsychiatric and sleep symp-
prodromal phase during which early signs of neuronal toms, autonomic dysfunction, and olfactory loss, often
injury can be detected by technology that already precede motor symptoms of PD (Table 1). Although
exists. The missing elements in progress toward identi- these features are not universal, they are present to
fying PD during its premotor phase (the time before variable degrees in most PD patients before the diag-
the classic motor features of tremor, rigidity, and bra- nosis of PD is made. Premotor features that have been
dykinesia become apparent) are a better understanding strongly linked to PD include olfactory disturbance,69
of how to deploy existing diagnostic technology and, excessive daytime sleepiness,10 rapid eye movement
crucially, development of disease-modifying treatments behavior disorder,1113 constipation,14,15 and depres-
that are shown to be most effective when treatment is sion.1618 The premotor phase may also have other
begun as early as possible. At present, there is an features that have been linked less strongly to PD
emerging consensus on the features that make up including subtle changes in cognition and personality
premotor PD and a growing body of evidence on the or increases in fatigue or anxiety.1925
performance of several diagnostics as screening tools
for PD. Preclinical Phase
Preclinical PD refers to physiological changes that
Classication of Premotor PD can be detected using biomarker techniques in the ab-
sence of any clinical features. Table 2 summarizes sev-
Premotor PD can be divided into stages leading to eral of the tests available to identify preclinical PD.
manifest PD based on the presence of clinical, physio- Changes on neuroimaging tests such as DAT SPECT
logical, or risk markers of disease. Working backward and [18F]-uorodopa PET are examples of preclinical
from recognizable PD that could be diagnosed based PD2628 Evidence of cardiac sympathetic denervation
on accepted criteria such as those of the UK Brain demonstrated by metaiodobenzylguanidine (MIBG)
Bank,1 these stages include: (1) the prediagnostic SPECT imaging of postganglionic sympathetic neurons
phase, (2) the premotor phase, (3) the preclinical is another example of a preclinical marker.2932 Trans-
phase, and (4) the prephysiological phase. The term cranial ultrasound of the midbrain is another modality
Parkinsons disease at risk syndrome (PARS)2,3
describes a hierarchical classication pyramid for TABLE 1. Possible premotor features of Parkinsons
patients who do not yet have clinical PD (Fig. 1). disease

Strongest evidence Suggested links


Prediagnostic Phase
Olfactory decit Other autonomic dysfunction (eg, cardiac)
At the second level is the prediagnostic category, in Constipation Visual disturbances
which patients have classic PD symptoms and clinical Sleep disorders (EDS, RBD) Cognitive changes
features but do not fulll PD diagnostic criteria at the Depression and anxiety Apathy
Fatigue
next level; many patients have parkinsonian signs but
Personality characteristics
do not technically fulll criteria required for the diag-
nosis of PD.4 These patients with mild parkinsonian EDS, excessive daytime sleepiness; RBD, rapid eye movement behavior
signs have the equivalent of mild cognitive impairment disorder.

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TABLE 2. Ancillary tests that can be used to diagnose rent technology. To an observer, an individual in the
pre-clinical PD prephysiological phase would appear normal by all
measures but might be known to possess an environ-
Test Sensitivity Specicity Availability Cost
mental or genetic risk factor. Genetic information
Olfactory testing Broad Low about PD, in particular, is accumulating at an impres-
Neuropsychological  Broad Moderate sive pace, and testing for mutations in the parkin and
testing LRRK2 genes is now commercially available. These
Transcranial ultrasound Restricted Moderate
gene tests have the potential to make the diagnosis of
Cardiac MIBG imaging Broad High
Dopamine transporter Restricted High preclinical PD at the time of birth, because they iden-
SPECT tify a lifelong trait rather than an evolving pathologi-
[18F]uorodopa PET Restricted High cal state. The risk imparted by genetic factors varies
Genetic testing  Restricted High depending on the particular gene involved. Individuals

with certain environmental exposure could be consid-
Not clinically useful; somewhat useful; sufciently accurate to be useful;
because PD is so rare, only highly specic tests provide useful information.
ered in a prephysiological state for the purpose of risk
stratication. Such epidemiological factors associated
with PD include pesticide and other environmental
that can reveal preclinical signs of PD. PD patients
exposures,49 demographic characteristics such as mid-
have an area of increased echogenicity in the substan-
life adiposity,50 and lifestyle preferences like caffeine
tia nigra.3335 One study showed that more than 60%
and tobacco use.51,52
of normal subjects with increased echogenicity were
also found to have reduction of 18F-dopa uptake in
the striatum.36 Another study found that almost 50% Detection of Premotor PD: Methodological
of rst-degree relatives of PD patients show increased Issues
echogenicity of the substantia nigra.37 These modal- The detection of premotor PD requires the integra-
ities will be discussed in details in other sections of tion of information on underlying disease frequency
this supplement. (incidence and prevalence) and results from diagnostic
Biopsy of peripheral tissue such as autonomic plex- tests. To understand how to interpret information
uses in the colon as representatives of the enteric from such tests, it is useful to review a few basic con-
nervous system could be markers of preclinical PD. cepts and terminology.
Lewy pathology including Lewy bodies and Lewy neu- Many tests rely on the use of biomarkers to identify
rites occurs in intrinsic postganglionic neurons in the individuals with a given state or trait. The NIH Bio-
myenteric and submucosal plexuses from the esophagus markers Denitions Working Group53 dened a bio-
to the colon.3840 Correspondingly, Lewy pathology marker as a characteristic that is objectively measured
has been detected in tissue from the enteric nervous and evaluated as an indicator of normal biological
system of patients with incidental Lewy bodies.41,42 processes, pathogenic processes, or pharmacologic
Two recent studies demonstrated Lewy pathology in response to a therapeutic intervention. Frequently,
colonic biopsy specimens in PD patients but not con- biological tests are described as being state or trait
trols.43,44 From the perspective of the progressive stages biomarkers. A state biomarker measures the current
of PD proposed by Braak and his colleagues,45 involve- status of disease. Trait biomarkers measure a character-
ment of the substantia nigra compacta as evaluated by istic that does not change over time, such as a genetic
presynaptic radioligands on PET or SPECT and pre- mutation. Examples of biomarkers used in screening
sumably by nigral hyperechogenicity on transcranial for PD include imaging biomarkers such as dopamine
sonography would establish the disease at stage 3 or imaging or biochemical biomarkers such as measuring
greater. Evidence of involvement of other regions such alpha-synuclein levels in blood or spinal uid.54,55
as the peripheral autonomic nervous system could Regardless of the technology or analyte, these bio-
occur in even earlier stages. marker tests can be evaluated using metrics common
to all diagnostic tests: sensitivity, specicity, positive
predictive value (PPV), and negative predictive value
Prephysiological Phase (NPV). Values for sensitivity and specicity can be cal-
Finally, prephysiologic patients have no evidence culated for all diagnostic tests. These metrics are
suggestive of PD but possess traits,such as a genetic intrinsic characteristics of a test and generally do not
mutation that confer a high risk of developing PD in vary, depending on population being studied. Sensitiv-
the future.4648 The term prephysiological is intended ity is dened as the proportion of people with a given
to convey the idea that no signs of disease can be condition who have a positive test. Specicity is
detected either clinically or by physiological probes dened as the proportion of the people who do not
such as dopamine imaging. Subtle molecular abnor- have a given condition who have a negative test.
malities could be present but beyond detection by cur- Highly sensitive tests are clinically useful when the

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number of people who could contribute false-positive


tests is much larger than the number who can be true-
positives. As a result, the specicity of the test, which
can be represented as 1  the false-positive rate, needs
to be very high. Even if a test is 99% specic, in a dis-
ease like PD with a frequency of fewer than 1% of the
population,56 the number of false-positive tests will
outnumber true-positives. All diagnostic tests produce
at least some false-positive and false-negative results.
Even genetic tests can produce false-positive results
because of reduced penetrance. One solution to this
problem is to screen only populations at highest risk.
Figure 3 illustrates the advantages to this approach.
Specic high-risk groups are described, below.
FIG. 2. A 2 3 2 table illustrating the 4 scenarios that could apply to
diagnostic tests (A: true-positive results; B: false-positive results; D: Another key issue is the cost of testing. Using cur-
true-negative results; C: false- negative results). Sensitivity is calcu- rent technology, it is possible to identify people who
lated as A/A 1 C; specificity as D/B 1 D. Positive predictive value
are at high risk for developing PD in the near future.
(PPV) is calculated as A/A 1 B and NPV as calculated as D/C 1 D.
Because the denominator for PPV and NPV includes values from both For example, the DAT ligand ioupane (123I)
the affected (disease is present) and unaffected (disease is absent) (I-123)N-x-uoropropyl-2b- carbomethoxy-3b-(4-iodo-
groups, its value depends on the relative proportion of people from
phenyl) nortropaneDaTSCAN for SPECT imaging is
each group in a given population or study cohort. As the proportion of
unaffected people increases, PPV also decreases and NPV increases. now available in the United States. It has been com-
mercially available in other parts of the world for a
number of years. However, it is expensive, and it is
results are negative, implying that a person is very not yet clear whether payers and hospital formularies
unlikely to have a disease. Conversely specic tests are will adopt DaTSCAN widely. In the case of screening
useful when they are positive, indicating that the dis- for PD, large numbers of at-risk individuals would
ease is very likely to be present. need to be scanned, and the vast majority would have
In contrast to sensitivity and specicity, the metrics, or normal testing. The challenge is to screen out low-risk
PPV and NPV, are characteristics of a test applied in a cases using cheaper methods and to reserve DaTSCAN
specic population. PPV and NPV depend on the charac- for only the highest-risk individuals. Table 2 shows the
teristics of the test (sensitivity and specicity) and on the
underlying prevalence of the condition. PPV is dened as
the proportion of people with a positive test that have
the disease. As the prevalence of PD increases in the pop-
ulation sampled, the PPV also increases. Therefore, when
considering the utility of the features to be described as
predictors of disease, it is important to consider both the
frequency of the feature in the general population (false-
positives) as well as the expected frequency of Parkin-
sons disease in that same population (prevalence). Nega-
tive predictive value is dened as the proportion of
people who have a negative test who do not have disease.
PPV and NPV are generally more relevant to making
decisions for individual patients than sensitivity and spec-
icity. PPV is the probability that a patient has a given
condition after a test for that condition has come back
positive. Figure 2 shows how sensitivity, specicity, PPV,
and NPF can be calculated from a 2  2 table.
One correlate of the foregoing discussion is that
screening tests for PD need to be extremely sensitive if
they are to be used in unselected populations. PD is FIG. 3. Effect of increasing prevalence on the ratio of false-positive to
relatively rare in the general population (approxi- true-positive tests for less common disorders. Even very specific tests
have high false-positive rates when a disease is not common. A test
mately 1 in 1000). As a result, the PPV of a test to with 99% specificity still gives the same number of false-positive tests
detect PD will be low unless specicity is very high. as true-positive tests in a disorder with a population prevalence of 1/
This is because the PPV is dened as the number of 1000 (similar to PD). Assuming 95% sensitivity and 99% specificity, as
prevalence increases, the proportion of positive tests that are true-
positive tests/(the number of positive tests the num- positives increases from about 50% to more than 90%. (adapted from
ber of false-positive tests). When a disease is rare, the Tanner, Ann Epidemiol. 1996;6:438441).

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TABLE 3. Identifying 100 at risk individualsimpact of targeting high-risk groups for a 2-stage screening approach
using olfactory testing followed by dopamine transporter imaging

PD incidence Subjects to screen to Number of PET/SPECT Percentage of


Population (cases/100,000 person-years) identify 100 at risk scans required positive scans

General population 40 104,156 10,503 1%


First-degree relatives of PD patients 120 34,719 3559 3%
First-degree relatives of LRRK2 carriers 1000 4166 504 20%
Diagnosed with RBD 4000 1042 192 52%

The table shows the number of individuals that would need to be screened based on 4 possible target populations to identify 100 subjects with abnormal
imaging. Incidence rates are drawn from the literature for the general population,92 rst-degree relatives of PD patients,93 rst-degree relatives of known
LRRK2 carriers,47 and patients diagnosed with RBD.11 The primary screen (olfactory testing) is assumed to be 80% sensitive and 90% specic when applied
within 3 years of disease onset.

accuracy, availability, and cost of representative tests. calcium consumption,65 fewer bowel movements in
Targeting high-risk groups for screening and using a midlife,66 and environmental exposure to pesticides67
2-stage screening process that images only subjects may also increase the risk of PD.
who are at highest risk based on prescreening with a
less expensive tests are 2 ways to address the problems Combining Tests into a 2-Stage Strategy
described above; these approaches are obviously not
Two-stage screening, where the rst test is relatively
mutually exclusive.
inexpensive but sensitive and moderately specic, is an
approach that reduces the number of expensive con-
Targeting of High-Risk Groups rmatory tests. Using imaging as the second test in a
Efciency of screening for PD can be greatly 2-step process reduces costs by lowering the number
enhanced by targeting individuals at highest risk for of scans (or other more denitive but expensive assess-
testing. The efciency gained by targeting high-risk ments) that need to be performed. To have a high
individuals is highlighted in Table 3. The key concept is overall accuracy rate, the rst-stage test must be at
that raising the underlying prevalence of disease (ie, least as sensitive as imaging. As a secondary screen,
enriching the sample for possible underlying PD) imaging can weed out false-positive tests, but it can-
greatly increases the positive predictive value of a test. not recapture false-negative cases that were not
Several potential means could be used to increase the referred for imaging. The primary screen must also be
underlying prevalence of premotor PD in the target reasonably specic because the number of scans that
population. The 2 strongest risk factors for PD are hav- needs to be performed depends on the false-positive
ing a family member who has a known genetic muta- rate (1  specicity) of the primary screening test.
tion and having a diagnosis of idiopathic rapid eye Olfactory testing is moderately sensitive for PD
movement behavior disorder (RBD). Although pene- approximately 80% of newly diagnosed PD patients have
trance of LRRK2 in incomplete, the risk of PD in a abnormal olfaction68and moderately specic in that
LRRK2 carrier is still approximately 20 times higher about 90% of low-risk individuals will have normal
than in a noncarrier.47 The risk of PD is greatest in olfaction for their age.69 These ndings suggest that olfac-
patients with RBD. In fact, the 10-year risk of PD in a tory testing is not sufcient by itself to screen for PD, but
person with RBD is roughly equivalent to the lifetime it may be a reasonable tool combined with a more sensi-
risk in a LRRK2 carrier. However, certain barriers tive test to detect premotor PD, especially in enriched
exist to using RBD as a marker of PD risk in large-scale populations already dened to have a higher proportion
studies including the nding that RBD appears to be a of PD cases than in the general population. The strategy
relatively rare disorder and a polysomnogram is of a 2-step screen of olfactory testing followed by imaging
required for diagnostic certainty.57 It may be possible has been tested in a study of rst-degree relatives of PD
to use surveys of patients or bed partners to identify patients70 and is being tested in a large cohort of 5000
signicant numbers of people with RBD symptoms. individuals in the Parkinson Disease At-Risk Syndrome
Surveys for RBD have been developed58,59 and should study (http://www.parsinfosource.com).
be validated for use in large-scale screening studies.
Stratication based on common demographic factors
may also raise the prior probability of PD to a modest
Timing and Frequency of PD
degree. Lifestyle risk factors for PD including not Screening: Does Premotor PD Have
smoking and drinking fewer caffeinated beverages a Predictable Course?
have been extensively documented6063 and may pro-
duce up to a 5-fold modication of the risk of PD.64 The neuropathological staging system proposed by
Other factors such as less midlife adiposity,65 greater Braak and colleagues45 suggests a characteristic spread

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of Lewy body pathology as the features of PD evolve. need to be performed. Clearly, screening as infre-
Although there are clearly deviations from this pat- quently as possible without sacricing accuracy pro-
tern,7173 predictable evolution of pathology does vides the best return on investment. It is possible that
occur in many patients. It would be reasonable to pro- the progression of PD pathology varies depending on
pose that clinical features associated with different a number of pathogenetic factors that have yet to be
brain regions would also develop in an orderly fash- determined. In the future, advances in our understand-
ion. If this were the case, understanding the order of ing may permit variable screening approaches depend-
onset of clinical and observable physiological features ing on the presence of additional markers of
could guide screening strategies for premotor PD. predisposition to disease.
Several studies support the concept that dopaminer-
gic decits are present prior to the onset of the clinical
motor features of PD. One simple proof of this idea is Potential Uses of Screening in
that bilateral striatal dopaminergic decits can be Practice and Research
demonstrated in patients with unilateral clinical signs
of PD.26 Studies that have attempted to back-project The means to detect PD before motor symptoms
to the onset of a dopamine decit in the striatum become apparent already exists. In some cases, PD can
based on degree of dopamine loss in PD patients with be detected before any physiological abnormalities are
varying disease duration have generally suggested a present. Several key issues must be addressed before
range of between 2 and 8 years,7477 although some preclinical testing can be recommended as part of clin-
estimates suggest a much longer latency period.78 ical practice, and there are no recommendations from
Although several studies have suggested dependable any ofcial organization regarding screening for PD.
evolution of clinical PD in patients with pathologically To begin to formulate such recommendations, it is
reduced striatal dopamine levels based on PET or helpful to consider other disorders where predictive
SPECT,79,80 it is not certain that all individuals with testing is available, such as Huntingtons disease
pathologically reduced striatal dopamine will evolve (HD). The International Huntington Disease Associa-
into clinical PD. tion and World Federation of Neurology produced
As described above, olfactory decits probably de- guidelines for use of at-risk testing.85 These rules
velop shortly before the onset of motor impairment in emphasize the right of the individual to decide
PD. Studies of the latency between olfactory and whether to be tested, the need to provide information
motor impairment have been limited by most studies and counseling both before and after testing, and the
sampling olfactory function once, and it is uncertain need for condentiality and access of all at-risk sub-
how long decits have been present. Nonetheless, the jects to testing if they wish to be tested. Similar guide-
available studies are relatively consistent and suggest a lines for implementation of predictive testing for PD
latency of 24 years.9,8183 The duration of RBD prior could reduce the potential for breeches of condential-
to onset of a parkinsonian disorder is likely to be ity and ineffective communication of risk information.
much longer. Again, as noted above, latency may Even if testing were available, there may be limited
average approximately 10 years but can be up to 20 interest in being tested among at-risk individuals. A
years, and cases with a latency period as long as 50 test for parkin gene mutations is commercially avail-
years have been reported.84 Finally, there may be gaps able in the United States, but there is little use of this
of 1020 years between enteric symptoms such as con- test to identify at-risk individuals outside research set-
stipation and midlife obesity and the onset of motor tings. Likewise, dopamine transporter imaging has
features of PD.14,50 been available in Europe, and it has not been adopted
To implement screening for PD, it will be important in at-risk individuals. The experience with preclinical
to develop a more precise understanding of the time- testing for HD illustrates some of the issues related to
line of emergence of nonmotor clinical features of PD uptake of preclinical diagnostic tests. Surveys of indi-
and the timing of the onset of dopaminergic abnor- viduals at risk for HD conducted prior to the wide-
malities in the striatum. In almost any case, at-risk spread availability of predictive testing suggested that
individuals would need to be screened on an ongoing 56%81% of family members were interested in test-
basis to detect the earliest signs of disease. The fre- ing.8688 However, when testing became available,
quency of screening depends on the time course of the only 10%20% of at-risk individuals decided to be
evolution of synuclein pathology. If pathology evolves tested.89,90 In a survey of family members of PD
rapidly, then more frequent screening would be patients, 76% of respondents expressed at least some
required to identify at-risk individuals at a point when interest in presymptomatic testing for PD. Not surpris-
the pathological process could be interrupted. Con- ingly, the interest increased substantially in a scenario
versely, indolent pathology would require less frequent where effective preventive treatment was available.91
screening intervals. A better knowledge of this timeline These results show that individuals at risk for PD may
will inform the frequency with which screening would not want to be tested for the sake of the knowledge

Movement Disorders, Vol. 27, No. 5, 2012 613


S I D E R O W F A N D L A N G

alone but would consider testing if preventive treat- 14. Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM,
Curb JD et al. Frequency of bowel movements and the future risk
ment were available. of Parkinsons disease. Neurology. 2001;57:456462.
Although the role of predictive testing in the clinic 15. Savica R, Rocca WA, Ahlskog JE. When does Parkinson disease
remains uncertain, it is reasonable to pursue research start?Arch Neurol. 2010;67:798801.
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R, Verhey FRJ. Higher incidence of depression preceding the onset
ical features of premotor PD and to dene the useful- of Parkinsons disease: a register study. Mov Disord. 2003;18:
ness of various diagnostic tests in populations with 414418.
different risk proles. A long-term goal of this 17. Shiba M, Bower JH, Maraganore DM, et al. Anxiety disorders and
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18. Gonera EG, vantHof M, Berger HJC, vanWeel C, Horstink WIM.
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