Identifying Prodromal Parkinson’s Disease:
Pre-Motor Disorders in Parkinson’s Disease
Ronald B. Postuma, MD, MSc,1,2* Dag Aarsland, MD, PhD,3Paolo Barone, MD, PhD,4David J. Burn, MD, FRCP,5
Christopher H. Hawkes, MD, FRCP,6Wolfgang Oertel, MD, PhD,7and Tjalf Ziemssen, MD8
1Department of Neurology, McGill University, Montreal General Hospital, Montreal, Quebec, Canada
2Centre d’E´tudes Avanc? ees en M? edecine du Sommeil, Hopital du Sacre-Coeur, Montreal, Canada
3Department of Old Age Psychiatry, Psychiatric Clinic, Stavanger University Hospital, Stavanger, Norway
4Centro per le Malattie Neurodegenerative, University of Salerno, Salerno, Italy
5Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom
6Neuroscience Centre, Institute of Cell and Molecular Science, Barts and
The London School of Medicine and Dentistry, London, United Kingdom
7Department of Neurology, Philipps-Universit€ at, Marburg, Germany
8Autonomes und neuroendokrinologisches Funktionslabor, Neurologische Klinik und Poliklinik,
Universit€ atsklinikum Carl Gustav Carus, Technische Universit€ at Dresden, Germany
ABSTRACT: Increasing recognition that Parkinson’s
disease (PD) may start outside of the substantia nigra has
led to a rapidly expanding effort to define prodromal
stages of PD, before motor signs permit classical diagno-
sis. Many of these efforts center around the identification
of clinical non-motor symptoms and signs of disease.
There is now direct evidence that olfaction, rapid eye
movement (REM) sleep behavior disorder (RBD), consti-
pation, and depression can be present in prodromal PD.
In addition, there is suggestive evidence that visual
changes, other autonomic symptoms, and subtle cogni-
tive changes may also be present at prodromal stages. A
critical issue in utility of these prodromal markers will be
assessment of sensitivity, specificity, and positive and
negative predictive values. Although these have yet to be
fully defined, olfactory deficits, some visual changes, and
autonomic symptoms occur in the majority of PD patients
at diagnosis, suggesting good potential sensitivity. How-
ever, with the exception of RBD and perhaps some spe-
predictive value of these markers may be insufficient to
be used alone as identifiers of prodromal disease. The
evidence for the utility of olfaction, RBD, autonomic
markers, visual changes, mood disorders, and cognitive
loss as markers of prodromal PD and the potential sensi-
tivity and specificity of these markers are summarized.
C2012 Movement Disorder Society
Key Words: Parkinson’s disease; prediction; non-
motor; sensitivity; specificity
Pathophysiologic Basis for Clinical
Markers of Prodromal PD
It has become clear that Parkinson’s disease (PD)
can have a prodromal stage, a period during which
neurodegeneration has begun, but motor signs permit-
ting classical diagnosis are not defined. Often, this
prodromal stage is characterized by important non-
motor features. The basis for this non-motor pro-
drome is that the pathologic process may not start in
the substantia nigra pars compacta (SNpc). This was
most prominently suggested in the 2003 staging sys-
tem of Braak. Based upon examination of a-synuclein
deposition patterns, Braak concluded that the first
*Correspondence to: Dr. Ronald B. Postuma, Department of Neurology,
L7-312 Montreal General Hospital, 1650 Cedar Ave., Montreal, Quebec,
Canada H3G 1A4; email@example.com
Relevant conflicts of interest/financial disclosures: Ronald B.
Postuma received research funds from the Weston Foundation, the
Webster Foundation, the Fonds de la Recherche en Sante Quebec, the
Canadian Institute of Health Research, and the Parkinson Society of
Canada. Dag Aarsland received research support from Novartis, Merck
Serono, and Lundbeck.
Full financial disclosures and author roles may be found in the online
version of this article.
Received: 21 October 2011; Revised: 21 December 2011; 24 February
2012; Accepted: 13 March 2012
Published online in Wiley Online Library (wileyonlinelibrary.com).
A R T I C L E
Movement Disorders, Vol. 27, No. 5, 2012
stage of PD involves deposition in anterior olfactory
nucleus and dorsal motor nucleus of the vagus.1Sub-
sequent revisions suggest peripheral autonomic ganglia
and unmyelinated lamina-1 spinal cord neurons may
also be stage 1 features.2Stage 2 consists of pontome-
dullary involvement (lower raphe, reticular formation,
coeruleus/subcoeruleus complex), Stage 3 affects mid-
brain (including SNpc), and at Stages 4 to 6 cortical
structures are affected. With some important modifica-
tions and exceptions, other groups generally confirm
However, limitations should be
noted. PD is heterogeneous, and many patients may
not followthis classic
model assessed a-synuclein deposition, which may not
correlate with neurodegeneration; 1 study suggested
that even advanced stages of a-synuclein deposition
can be present without parkinsonism or dementia.9If
SNpc structures degenerate more readily than other
brainstem structures when exposed to aberrant synu-
clein processing, motor findings could conceivably
present before non-motor features. Also, speed of pro-
gression through early stages is unknown—if progres-
sion is rapid, the prodromal non-motor interval will
be short, limiting the effectiveness of predictive
Despite these important limitations, the recognition
that the initial pathology of PD may occur outside the
SNpc suggests that screening for non-motor manifesta-
tions may detect prodromal PD. These markers
include olfaction, rapid eye movement (REM) sleep
depression, visual changes, and cognition (Table 1).
Nature of Defect
In parkinsonism there is impaired olfactory identifi-
cation, discrimination, and threshold in >80% of
patients.10,11Many of the remaining ?20% may in
fact not have PD. Although there were initial claims
for a specific class of odor defect (eg, pizza or oil of
wintergreen on the University of Pennsylvania Smell
Identification Test [UPSIT]12), this is probably incor-
rect, and variable results have been noted according to
country of origin and the type of smell test used.13It
is also apparent that only ?40% with PD are aware
of impaired smell sense. Those who are unaware prob-
ably have mild impairment.11Whatever the explana-
tion, simply asking a patient about their sense of smell
is unproductive; the modality has to be properly meas-
ured. The defect appears to be uninfluenced by medi-
cation, is bilateral14and most find that the severity of
microsmia correlates with measures of disease dura-
tion and severity.11,15–17In 1 cross-sectional modeling
study,18it was thought unlikely that the PD olfactory
defect was due to simple aging: a healthy person
would need to live until the age of 106 to 160 years
to exhibit the degree of microsmia shown by a typical
PD patient aged 60 years (Fig. 1).
Olfactory impairment, usually less severe than idio-
pathic PD, may be found in multiple system atro-
uncommonly in progressive supranuclear palsy, corti-
essential tremor, and dystonia.19,21–24If a patient is
TABLE 1. Summary of Clinical Markers of Premotor PD
Marker Level of evidencea
Olfaction High (population-based studies,38
High (3 cohort studies48–50)
High (>80% of early PD) Low (up to one-third of elderly
population has olfactory loss)
High (up to 65% risk of disease
at 10 years)
REM sleep behavior disorder
Low (50% of PD patients have
RBD, one-half of these precede
Moderate-high (most early PD
patients have symptoms)
Unknown for RR variability; high
for MIBG (most PD patients are
Low (30%–40% of PD patients
Unknown—most PD patients
have abnormalities—unclear if
present early in PD
Autonomic symptoms High for constipation,77,78low/
moderate for other symptoms
Low (no prospective studies, one
negative RBD study)
Low (one-third of general
population has symptoms)
Unknown Cardiac autonomic markers
(RR variability, MIBG
Depression Moderate (case-control studies,
conflicting cohort studies)
Moderate for color vision
(prospective RBD study29),
low for others
Low (one-third of general
Visual abnormalities: saccadic
tomography; color vision
Cognitive impairmentLowUnknown—subtle cognitive
changes difficult to detect
changes may be nonspecific
aLevel of evidence is considered high if there is direct evidence that it predicts PD, based upon prospective studies documenting abnormalities in persons
initially free of disease; moderate if there is either evidence from case-control studies or evidence in high-risk subpopulations (eg, RBD); and low if evidence is
only indirect (eg, abnormalities present early in disease).
PD, Parkinson’s disease; REM, rapid eye movement; RBD, REM sleep behavior disorder; RR, ventricular cardiac cycle (an indicator of ventricular rate); MIBG,
P O S T U M AE TA L .
Movement Disorders, Vol. 27, No. 5, 2012
suspected to have PD and on testing has normal smell
function then the diagnosis should be reappraised.
Microsmia is sensitive (>80%) but not specific for
PD; this sensitivity is not clearly different from trans-
Olfactory abnormalities are found in familial syn-
dromes such as: PARK1/4, PARK2, PARK6, PARK8,
and PARK9, and those with glucocerebrosidase gene
(GBA) mutations.25,26Data are awaited for PARK10-17
and POLG1 mutations. Non-manifesting carriers of
PARK2 and PARK8 mutations had normal smell in 1
study27whereas non-manifesting carriers of the PARK6
mutation had abnormal olfaction.28These observations
are preliminary and based on small subject numbers but
it cannot be assumed at present that microsmia is a reli-
able predictive marker in carriers of monogenetic PD.
Defective smell sense correlates with other modal-
ities in the established phase of PD; eg, RBD, reduced
color vision, constipation, episodic verbal memory,
between hyposmia and transcranial ultrasound of the
substantia nigra,123I-metaiodobenzylguanidin (MIBG)
heart scan, olfactory bulb size, limbic acetylcholinester-
ase activity, and dopamine transporter imaging.33–38In
the prodromal period, RBD, dopamine transporter
imaging, and incidental brain stem Lewy bodies39all
show a correlation with olfaction.40,41
Is Microsmia a Prodromal Feature?
Several strands of evidence suggest that smell
impairment is a prodromal phenomenon42although
estimates of prodromal phase duration vary from 2 to
Back-projection of the cross-sectional
model implies that the olfactory defect begins around
the time of birth.18This would indicate commence-
ment in utero or a genetic predisposition from birth.
Another explanation is that there is a subsequent acute
premotor event that results in a steeper decline away
from the effect of simple age-related deterioration (see
downsloping arrow; Fig. 1).
Observations of Braak et al.1suggest that the earliest
alpha-synuclein changes occur in the dorsal motor nucleus
of the vagus and olfactory bulb. The prospective study by
Ponsen et al.43revealed that 40 of 78 relatives of PD
patients were hyposmic at baseline and 4 of these devel-
oped PD after 2 years. Sommer et al.44examined 30 peo-
ple with idiopathic anosmia of whom 11 had abnormal
substantia nigra transcranial ultrasound and 5 showed de-
fective dopamine transporter imaging. Two later devel-
oped clinical signs of PD and a further 2 were borderline.
The prospective Honolulu Asia Aging Study39used the
Brief Smell Identification test (BSIT-12-odours) in 2267
males with 7-year follow-up. After 4 years, 19 developed
PD and this diagnosis correlated with low baseline BSIT.
Autopsy on 163 without clinical PD revealed 7 who dis-
played incidental brainstem Lewy bodies, the number of
which correlated with baseline BSIT.40
Despite these persuasive findings, no test has shown
unequivocally that anosmia precedes imaging changes.
The evidence for prior microsmia (also constipation,
RBD, depression, obesity) is strong and based on pro-
spective studies some with pathological confirmation.45
However, these are all parameters that are relatively
easy to document and there may be subtle changes (in
the cerebral cortex, for example) that are difficult to
detect by current techniques. Therefore we may be
measuring the differential sensitivities of our detection
techniques.41For example, the England footballer, Ray
Kennedy showed minimal motor changes on video
recordings of his matches at least 10 years before his
first recognized symptoms of parkinsonism.46Further-
more, in a study of 62 PD-discordant twin pairs47all
cases (but not co-twins) had an abnormal UPSIT. 19
co-twins were retested with BSIT 7 years later and
although 2 developed PD, neither had impaired UPSIT
scores at baseline. Similarly, in the Honolulu Asia
Aging Study, olfaction had no predictive value when
assessed >4 years before PD onset.39This suggests that
olfactory impairment may only be apparent with in a
few years before onset of motor symptoms.
Microsmia has a prevalence of >80% in idiopathic
PD. It is probably an early feature that progresses slowly
and it is not simple aging. Modeling implies that it may
develop as an acute event or that is present from birth.
The balance of evidence suggests it is a prodromal fea-
ture that may predict PD. The diagnosis of PD should
be reconsidered if olfaction is normal on testing by
reliable methods such UPSIT, BSIT, or Sniffin’ Sticks.48
FIG. 1. Decline of UPSIT scores in controls (A) and patients (C),
assuming linear regression. Black dots represent PD patients and open
circles are controls. The large downsloping arrow indicates a proposed
acute event causing a decline in olfaction from the healthy control level.
The hypothetical regression line (B) represents the effect of aging alone.
The accelerated deterioration of smell function with age in PD is repre-
sented by the gray-shaded area between lines B and C.
I D E N T I F Y I N GP R O D R O M A LP D
Movement Disorders, Vol. 27, No. 5, 2012
RBD is characterized by loss of the normal atonia of
REM sleep,49such that patients move in apparent
response to dream content. Diagnosis depends on pol-
ysomnogram, mainly because conditions such as non-
REM parasomnias and obstructive sleep apnea can
mimic RBD. Treatment is primarily with clonazepam
0.5 to 2.0 mg or melatonin 3 to 12 mg at bedtime.
The ability of RBD to identify prodromal neurode-
generative diseases has been established in 3 cohort
studies.50–52These were all based in sleep disorders
clinics and found relatively consistent results, with
between 28% and 45% of patients converting to a
neurodegenerative syndrome at a mean 5-year follow-
up; 10-year disease estimates range from 40% to
65%.52–54In the 2 series that included neuropsycho-
logical assessment, approximately one-half developed
parkinsonism and half developed dementia. The me-
dian latency between RBD symptom onset and defined
disease ranged from 12 to 14 years.
In these studies, 2 key findings emerge that suggest
potential for RBD as a prodromal PD marker:
1. The risk of neurodegeneration is high. One of the
biggest limitations of clinical markers of prodro-
mal PD is their lack of specificity. For example,
anosmia, constipation and depression are experi-
enced by 20% to 40% of the population, but
only a small minority will develop PD.39In con-
trast, with risk estimates as high as 65%, RBD is
by far the strongest clinical predictor of neurode-
generative disease available. In other words, the
specificity of RBD in diagnosing prodromal PD is
high (although sensitivity is low, since only half
of PD patients have RBD).55This implies that if
a neuroprotective agent were developed, idio-
pathic RBD patients might be potential candi-
dates for therapy.
2. Latency to clinical disease is long. A latency esti-
mate of 13 years indicates a long window in
which to intervene with neuroprotective therapy.
This may make RBD the ideal condition for pre-
However, no marker is the ideal candidate, and cav-
eats must be noted. First, most RBD patients do not
present to physicians. As of 2011, the largest reported
cohort of idiopathic RBD is 93 patients.52This is a
major challenge to those who would wish to identify
RBD patients for neuroprotective therapy. Second,
RBD diagnosis is not simple—definitive diagnosis cur-
rently requires polysomnography.56Although com-
plexity of diagnosis is not a major practical barrier for
neuroprotective trials, it would be a barrier for even-
tual screening of RBD in an age of neuroprotective
therapy. RBD screening questionnaires may ease this
problem, although positive predictive value (especially
for an uncommon condition) must be defined.57–59
Third, as recognition of RBD improves, it is likely
that milder cases will come to medical attention—
disease risk may not be the same in these cases. There
are preliminary suggestions that ‘‘milder’’ RBD, char-
acterized by less REM atonia loss, may have a lower
risk of developing PD.60Similarly, the risk of develop-
ing neurodegeneration in antidepressant-triggered RBD
may be very different than in the pure idiopathic form.
Fourth, many patients will develop dementia with Lewy
bodies (DLB), so RBD is not a specific PD marker. Fifth,
generalizability is uncertain. In a recent prospective com-
prehensive follow-up, 16 of 21 patients who developed
neurodegeneration had evidence of both parkinsonism
and cognitive impairment at disease onset.30,61This is a
pattern unlike typical PD, in which dementia occurs
late. Moreover, RBD occurs in only 30% to 50% of
PD patients, and there is evidence that RBD may mark
a subtype of PD, characterized especially by more pro-
nounced autonomic dysfunction, akinetic-rigid subtype,
and increased risk of cognitive impairment and demen-
tia.62–66If the non-motor prodrome differs in PD
patients who start with idiopathic RBD, results may
not completely generalize to the entire PD population.
Finally, if conversion from idiopathic RBD to disease is
the primary outcome in a neuroprotective trial, this
could mean a study duration of several years, beyond
funding timelines of most pharmaceutical companies.
RBD and Other Prodromal Markers
Other than potential for neuroprotective trials,
studying patients with RBD may help evaluate other
potential prodromal markers; by providing a high-risk
group that can be tested before developing disease,
utility of potential markers can be assessed directly.
appear—they suggest that severity of REM atonia,60
impaired olfaction,30and reduced color vision30(but
cardiac cycle, an indicator of ventricular rate, [RR]
variability67) may be able to identify prodromal neu-
rodegeneration. To illustrate the power of these
markers, the 5-year risk of neurodegenerative disease
in RBD rises dramatically from 14% to 65% if anos-
mia is present at baseline (similar results were found
for color vision—see Color Discrimination below). In
addition, RBD patients (albeit only a minority) have
abnormalities on SNpc markers such as transcranial
ultrasound of the substantia nigra and dopaminergic
functional neuroimaging, which can predict who will
develop parkinsonism.68Other potential markers such
as quantitative tests of movement speed,69anxiety/
depression, personality changes,66subtle cognitive dys-
waking electroencephalograph (EEG)
volumetric magnetic resonance imaging
P O S T U M A E T A L .
Movement Disorders, Vol. 27, No. 5, 2012
(MRI) changes,73cerebral blood flow changes,74and
diffusion tensor imaging73,75are currently being eval-
uated in RBD patients for their potential to identify
Autonomic dysfunction is an important clinical non-
motor symptom that appears to represent an early
manifestation of PD.76As noted above, Braak et al.1
observed early occurrence of lesions in important
autonomic centers in brainstem before characteristic
changes in the SNpc. The other hallmark, peripheral
postganglionic sympathetic denervation, may occur
even earlier.77Clinically, autonomic (eg, gastrointesti-
nal) symptoms are common in patients with early and
untreated PD, but symptoms are generally mild.78
One potential prodromal sign of PD, constipation,
was associated with subsequent development of PD in
the Honolulu Heart Study79and the Rochester Epide-
miology Project.80Constipation, as early as 20 or more
years before the onset of motor symptoms, is associated
with an increased risk of PD. In the Honolulu study, a
single question regarding bowel movement frequency
was asked at baseline. Those reporting a bowel move-
ment frequency of <1 per day had an odds ratio (OR)
for PD of 2.3 compared to those with 1 per day.
Modern imaging technology allows comprehensive
assessment of the autonomic nervous system using
MIBG, which is taken up by postganglionic adrenergic
neurons like norepinephrine. Mitsui et al.81observed a
significant reduction of MIBG uptake in cardiac
sympathetic efferents irrespective of disease severity,
disease duration, treatment, and preexisting dysauto-
nomic signs. Further studies indicate that the large
majority of patients with PD have abnormal MIBG-
scintigraphy, even early in disease.82,83Unfortunately
no studies have directly assessed if MIBG scintigraphy
can identify prodromal PD.
Regarding clinical testing of the autonomic nervous
system, there are hints that cardiovascular dysautono-
mia may be a potential marker of prodromal PD. In a
small pilot study, Valappil et al.84demonstrated a
significantdecreased heart rate
in electrocardiograms of patients with RBD. These
differences appear to be more readily identified in low-
frequency fluctuations (which are related both to
sympathetic and parasympathetic function) than high-
frequency components (which primarily reflect respira-
tion-driven vagal input).62However, cardiac autonomic
abnormalities did not predict risk of neurodegenerative
disease in the prospective cohort of RBD patients, sug-
gesting that further research is needed to identify which
autonomic abnormalities are truly predictive.67Other
promising markers have been developed especially in
cardiovascular autonomic testing: baroreflex sensitivity
and HRV have been described to be decreased in PD
patients, depending on their clinical stage.85–87New
innovative algorithms as the trigonometric spectral
analysis (TRS) are available to quantify even subtle
alterations.88,89Their potential role in prodromal PD is
still under investigation.
In summary, methodology of autonomic assessment
is currently insufficiently developed to be applied in
approaches. As a further limitation, specificity of auto-
nomic dysfunction is probably low, as other frequent
conditions (eg. diabetes, drug treatment) can also lead
to autonomic dysfunction. On the other hand, auto-
nomic dysfunction could be a prognostic marker of
mortality even in prodromal PD, as increased cardio-
vascular mortality has been suggested in PD90,91and
increased cardiovascular mortality.92
Depression is common in PD and is considered to
be a major contributor to poor quality of life, disability,
and survival. Depression in PD has been related to mul-
tiple neurotransmitter dysfunctions, including dopamine
(SNpc), serotonin (raphe nuclei), and noradrenaline
(locus coeruleus). The involvement of both raphe nuclei
and locus coeruleus at Braak stage 2, might indicate
depression as a prodromal symptom of PD.
Definition of Depression in PD
The lack of adequate diagnostic criteria93and the
presence of substantial overlap between symptoms
of PD and symptoms of depression contribute to
the difficulty in defining depression in PD. Interest-
ingly, regardless of the clinical categorization of spe-
cific depressive disorders based on the Diagnostic
(DSM-IV), approximately 35% of PD patients had
clinically significant symptoms of depression.94The
difficulty in characterizing depression in PD may
account for the variety of prevalence figures in the
Depression in Early and in Prodromal PD
Depressive symptoms precede motor symptoms in
30% of PD patients95and are reported as a presenting
complaint in 12% to 22% of patients.96,97In the ab-
sence of prospective studies, both case-control and
cohort studies suggest a risk ratio for the association
between 1.20 and 3.13.98In a study on 105,416 peo-
ple from 1985 to 2000, of 338 incident cases of PD,
31 patients (9.2%) had a history of depression, as
compared with 4.0% of controls (OR: 2.4).99Interval
between the first depressive episode and PD diagnosis
I D E N T I F Y I N GP R O D R O M A L P D
Movement Disorders, Vol. 27, No. 5, 2012
varied from 1 month to 36 years, averaging 10.1
years. The incidence seems to increase during the last
few years before the diagnosis of PD is made. Simi-
larly, a recent study from the General Practitioner
Database revealed a higher risk of developing PD in
individuals treated with antidepressants and a recent
history of depression.100On the other hand, the Mayo
Clinic Cohort Study of Personality and Aging showed
that a depressive trait of the Minnesota Multiphasic
increased PD risk.101
Considering that depression is common in the gen-
eral population and based upon the above findings,
depression alone is unlikely to be useful as a marker
of prodromal PD (in other words, its specificity is
low). However, recent evidence suggests that depres-
sion may be associated with potential markers of PD
such as family history and substantia nigra hyperecho-
genicity.102The relevance of this association for a
later diagnosis of PD needs to be determined in pro-
Visual system involvement in PD may occur at mul-
tiple points in the visual pathway, from retina to
higher visual cortical processing areas. Control of eye
movements may also be affected, although often in a
subtle way. Dopamine is found in the retina, primarily
in the amacrine-A18 cell subtype. The density of these
cells is low, but each cell has widespread dendritic
arborization and long fine axons, thereby establishing
a network with other amacrine and bipolar cells.
There is a tonic diurnal variation in retinal dopamine
concentration, with lower levels at night and higher
levels during the day, in counter-phase with retinal
melatonin. Dopamine is thought to act in both the
outer and inner retinal layers as a chemical messenger
for light adaptation, regulating ‘‘center-surround’’ field
size, and promoting flow of information through cone
Since PD generally affects older persons, a host of
degenerations, glaucoma) need to be ruled out before
symptoms are attributed to underlying PD. Even
allowing for this, visual symptoms are common in
established PD, ranging from complaints of blurred or
double vision, to symptoms of impaired motion per-
ception and contrast discrimination. Such symptoms
are often over-looked and are not always easy for
patients to describe. If dementia develops, the range of
visual problems frequently expands to include percep-
tual disturbances and complex visual hallucinations.
Visual disturbances are far less studied as a prodro-
mal feature so much of the following is speculative,
with inferences drawn from studies in ‘‘early’’ PD.
Hypometria and an increased error percentage in
volitional saccades have been described in PD. Sacca-
dic hypometria may be quantified as saccadic gain or
as percentage of trials with a multiple step pattern
(MSP). A high MSP frequency in relatively early PD
has been reported using a demanding memory-guided
saccadic task and a high-resolution video-based eye
tracking system, when compared with age-matched
controls.105The MSP measure demonstrated good sen-
sitivity (87%) and excellent specificity (96%) in dis-
criminating PD patients from controls. Of interest, an
abnormal MSP was also detected in 4 of 5 clinically
unaffected LRRK2 mutation-positive siblings of PD
Visual Evoked Potentials and Pattern
A delay in visual evoked potential (VEP) latency to
sinusoidal gratings at a mid-spatial frequency has been
a consistent finding in PD, with this change being
reversed by administration of levodopa. Pattern elec-
troretinography (PERG) measures the electrical contri-
bution from predominantly retinal ganglion cells of
the inner retina. A specific medium-frequency deficit
has been described in PD, which is sensitive to dopa-
minergic therapy. Receptor-blocking studies suggest
that dopamine-D2 receptors are primarily involved in
‘‘tuning’’ the PERG response to stimuli of different
spatial frequencies,103,106although D1 receptors may
also play a role.104However, it is unclear how these
findings may translate into a sensitive pre-motor
Optical Coherence Tomography
Direct morphological evidence of retinal involve-
ment in PD may be obtained noninvasively using opti-
cal coherence tomography (OCT). Time-domain OCT
can assess the thickness of the retinal nerve-fiber layers
(RNFL) and macula with a 10-lm axial resolution,
whilenewer Fourier domain
improved at 3 to 5 lm. Age, ethnicity, and intraocular
pressures need to be considered when interpreting
nerve-fiber layer thinning, and technical issues as well
as ophthalmological comorbidities which may prevent
the assessment in up to 20% of subjects.107The de-
nominator of all subjects assessed (as opposed to only
those in whom OCT measurements could be made)
and disease duration have not been consistently stated
in the literature. RNFL thinning has been reported in
some108–111but not all107,112studies in PD, and where
differences occur, they have been expressed as group
effects. Macular thinning has been reported when
RNFL thickness was normal.112We are not aware of
OCT resolution is
P O S T U M AE T A L .
Movement Disorders, Vol. 27, No. 5, 2012
studies directly assessing OCT as a prodromal PD
Color vision is abnormal in PD and may be related
to disease duration.113,114More recently, color vision
has been studied as a potential prodromal marker in
subjects with RBD. Using the Farnsworth-Munsell 100
(FM-100) test, and a score of 100 as the cutoff for
low-average color vision, 17 of 23 patients with RBD
tested below the average range compared with 8 of 22
controls (P ¼ .0049).69Moreover, abnormal color
vision correlatedwith olfactory
impaired motor speed in this study. Most recently, in
a prospective study over 5 years, patients with RBD
destined to develop either dementia or parkinsonism
on follow-up were more likely to have abnormal base-
line FM-100 scores compared to those who remained
with normal color vision was 70.3% versus 26.0%
with impaired vision (P ¼ .009). Although the authors
pointed out that with limited follow-up labeling some-
one as ‘‘disease-free’’ may be erroneous (they may still
develop disease at a later stage), their data indicated
impaired color vision had 73% sensitivity and 50%
specificity for identifying disease. These figures could
be improved by combining olfactory testing with color
vision. Color vision testing may therefore offer a cost-
effective means of enhancing screening programs for
Dementia commonly develops as PD advances.115,116
In addition, cognitive impairment (CI) occurs in 30%
to 40% of nondemented subjects, which is usually
labeled as mild cognitive impairment (PD-MCI).117
PD-MCI has clinical significance due to its functional
consequences and the association between early CI and
shorter time to dementia.118
The mechanisms underlying cognitive impairment in
PD are only partially known. Most studies found that
cortical and limbic Lewy bodies119or amyloid plaque
pathology120are the main cause of dementia in PD. In
addition, there is abundant evidence supporting the
role of cholinergic deficits for cognitive impairment in
PD, and atrophy of cholinergic neurons in the basal
forebrain may occur at Braak Stage 3,1similar to the
occurrence of nigral pathology. Noradrenergic (locus
ceruleus) and serotonergic (raphe nuclei) nuclei are
involved already at Braak Stage 2, and may contribute
to early and even prodromal cognitive deficits such as
attention and vigilance deficits.121
CI in Early PD
of population-based Three
cohorts have demonstrated impairment across a range
of cognitive domains122–125already at the time of PD
diagnosis, with 19% to 36% being impaired on at
least 1 cognitive domain. These studies support previ-
ous reports that executive and attentional deficits
occur early in PD, and also convincingly demonstrate
early memory and visuospatial impairment.
Early CI and Diagnostic Criteria
There has been much debate regarding the nosologi-
cal classification of combined dementia and parkinson-
ism. Dementia preceding motor symptoms or in the
first year is considered a feature suggesting diagnoses
other than PD.126DLB criteria127state that DLB
‘‘should be diagnosed when dementia occurs before or
concurrently with parkinsonism, and PDD should be
used to describe dementia that occurs in the context
of PD.’’ The same approach was adopted in the recent
criteria for PDD.128Similarly, the recently proposed
criteria for PD-MCI from a Movement Disorders Soci-
ety Task Force, state that cognitive decline should
occur ‘‘in the context of established PD....’’129There
is still a debate as to whether this distinction between
DLB and CI in PD is valid, or whether they should
rather be considered as overlapping syndromes of one
Lewy body disease.130
MCI and Subsequent Lewy Body Disease
It is frequently stated that people with non-amnestic
MCI may indeed suffer from disorders other than Alz-
heimer’s disease (AD). Could CI represent a prodrome
for PD? In one of the very few empirical studies,
Molano131described in detail the clinical course of
people diagnosed as MCI and who at autopsy had
Lewy body disease. Of the 8 patients identified, all
developed parkinsonism: 5 developed parkinsonism 2
to 5 years after CI, 2 simultaneous, and 1 within 1
year before CI. All cases were diagnosed clinically as
DLB. Thus, there is no doubt that some patients with
parkinsonism have prodromal CI, but according to
current consensus criteria, these patients are diagnosed
as DLB and not PD.
Therefore, although CI can occur prior to parkin-
sonism, current diagnostic criteria would identify all
patients with substantial CI as having DLB or alter-
nate diagnoses; this precludes assessment of the sensi-
tivity and specificityof
identification of prodromal PD.
There is clear evidence that non-motor features can
identify prodromal PD. Direct evidence for predictive
value varies between manifestations, but there is direct
I D E N T I F Y I N GP R O D R O M A LP D
Movement Disorders, Vol. 27, No. 5, 2012
evidence that impaired olfaction, RBD, constipation,
and depression are potential prodromal markers.
Based upon the prevalence of the manifestations in
early disease, the maximal sensitivity is probably pres-
ent for olfaction (80%–90% affected), followed by au-
marker), and RBD (40%). With the probable excep-
tion of RBD (up to 65% risk), specificity of all clinical
symptom markers is probably low. Research into pro-
dromal PD is rapidly expanding, and other markers,
or combinations of markers, may eventually demon-
strate sufficient utility in PD prediction to select
patients for future disease modifying therapy.
1.Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN,
Braak E. Staging of brain pathology related to sporadic Parkin-
son’s disease. Neurobiol Aging 2003;24:197–211.
2.Braak H, Sastre M, Bohl JR, de Vos RA, Del Tredici K. Parkin-
son’s disease: lesions in dorsal horn layer I, involvement of para-
sympathetic and sympathetic pre- and postganglionic neurons.
Acta Neuropathol 2007;113:421–429.
3. Zaccai J, Brayne C, McKeith I, Matthews F, Ince PG. Patterns
and stages of alpha-synucleinopathy: relevance in a population-
based cohort. Neurology 2008;70:1042–1048.
4.Halliday G, Hely M, Reid W, Morris J. The progression of
pathology in longitudinally followed patients with Parkinson’s
disease. Acta Neuropathol 2008;115:409–415.
5.Dickson DW, Uchikado H, Fujishiro H, Tsuboi Y. Evidence in
favor of Braak staging of Parkinson’s disease. Mov Disord 2010;
6.Dickson DW, Fujishiro H, Delledonne A, et al. Evidence that
incidental Lewy body disease is pre-symptomatic Parkinson’s
disease. Acta Neuropathol 2008;115:437–444.
7. Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK. The
dorsal motor nucleus of the vagus is not an obligatory trigger site
of Parkinson’s disease: a critical analysis of alpha-synuclein stag-
ing. Neuropathol Appl Neurobiol 2008;34:284–295.
8.Halliday GM, McCann H. The progression of pathology in Par-
kinson’s disease. Ann N Y Acad Sci 2010;1184:188–195.
9. Parkkinen L, Pirttila T, Alafuzoff I. Applicability of current stag-
ing/categorization of alpha-synuclein pathology and their clinical
relevance. Acta Neuropathol 2008;115:399–407.
10.Doty RL, Stern MB, Pfeiffer C, Gollomp SM, Hurtig HI. Bilateral
olfactory dysfunction in early stage treated and untreated idio-
pathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 1992;
11.Hawkes CH, Shephard BC, Daniel SE. Olfactory dysfunction in
Parkinson’s disease. J Neurol Neurosurg Psychiatry 1997;62:
12. Hawkes CH, Shephard BC. Selective anosmia in Parkinson’s dis-
ease? Lancet 1993;341:435–436.
13. Hawkes CH, Doty RL. Neurology of olfaction. Cambridge: Cam-
bridge University Press; 2009.
14. Doty RL, Deems DA, Stellar S. Olfactory dysfunction in parkin-
sonism: a general deficit unrelated to neurologic signs, disease
stage, or disease duration. Neurology 1988;38:1237–1244.
15.Deeb J, Shah M, Muhammed N, et al. A basic smell test is as sen-
sitive as a dopamine transporter scan: comparison of olfaction,
taste and DaTSCAN in the diagnosis of Parkinson’s disease. QJM
16. Siderowf A, Newberg A, Chou KL, et al. [99mTc]TRODAT-1
SPECT imaging correlates with odor identification in early Par-
kinson disease. Neurology 2005;64:1716–1720.
17. Pearce RK, Hawkes CH, Daniel SE. The anterior olfactory nu-
cleus in Parkinson’s disease. Mov Disord 1995;10:283–287.
18. Hawkes CH. Parkinson’s disease and aging: same or different
process? Mov Disord 2008;23:47–53.
19.Shah M, Muhammed N, Findley LJ, Hawkes CH. Olfactory tests
in the diagnosis of essential tremor. Parkinsonism Relat Disord
20. Olichney JM, Murphy C, Hofstetter CR, et al. Anosmia is very
common in the Lewy body variant of Alzheimer’s disease. J Neu-
rol Neurosurg Psychiatry 2005;76:1342–1347.
21.Silveira-Moriyama L, Hughes G, Church A, et al. Hyposmia in
progressive supranuclear palsy. Mov Disord 2010;25:570–577.
22.Hawkes C. Olfaction in neurodegenerative disorder. Mov Disord
23. Silveira-Moriyama L, Schwingenschuh P, O’Donnell A, et al.
Olfaction in patients with suspected parkinsonism and scans with-
out evidence of dopaminergic deficit (SWEDDs). J Neurol Neuro-
surg Psychiatry 2009;80:744–748.
24.Kruger S, Haehner A, Thiem C, Hummel T. Neuroleptic-induced
parkinsonism is associated with olfactory dysfunction. J Neurol
25.Silveira-Moriyama L, Munhoz RP, de J Carvalho M, et al. Olfac-
tory heterogeneity in LRRK2 related Parkinsonism. Mov Disord
26.Saunders-Pullman R, Hagenah J, Dhawan V, et al. Gaucher dis-
ease ascertained through a Parkinson’s center: imaging and clini-
cal characterization. Mov Disord 2010;25:1364–1372.
27.Alcalay RN, Siderowf A, Ottman R, et al. Olfaction in Parkin
heterozygotes and compound heterozygotes: the CORE-PD study.
28.Ferraris A, Ialongo T, Passali GC, et al. Olfactory dysfunction in
Parkinsonism caused by PINK1 mutations. Mov Disord 2009;24:
29.Postuma RB, Montplaisir J. Transcranial ultrasound and olfaction
in REM sleep behavior disorder: testing predictors of Parkinson’s
disease. Sleep Med 2010;11:339–340.
30. Postuma RB, Gagnon JF, Vendette M, Desjardins C, Montplaisir
J. Olfaction and Color vision identify impending neurodegenera-
tion in REM behavior disorder. Ann Neurol 2011;69:811–818.
31. Stiasny-Kolster K, Doerr Y, Moller JC, et al. Combination of ‘idio-
pathic’ REM sleep behaviour disorder and olfactory dysfunction as
possible indicator for alpha-synucleinopathy demonstrated by do-
pamine transporter FP-CIT-SPECT. Brain 2005;128(Pt 1):126–137.
32.Ramjit AL, Sedig L, Leibner J, et al. The relationship between
anosmia, constipation, and orthostasis and Parkinson’s disease
duration: results of a pilot study. Int J Neurosci 2010;120:67–70.
33. Postuma RB, Gagnon JF, Montplaisir J. Clinical prediction of
Parkinson’s disease—planning for the age of neuroprotection. J
Neurol Neurosurg Psychiatry 2010;81:1008–1013.
34.Lee PH, Yeo SH, Kim HJ, Youm HY. Correlation between car-
diac 123I-MIBG and odor identification in patients with Parkin-
son’s disease and multiple system atrophy. Mov Disord 2006;21:
35. Lee PH, Yeo SH, Yong SW, Kim YJ. Odour identification test
and its relation to cardiac 123I-metaiodobenzylguanidine in
patients with drug induced parkinsonism. J Neurol Neurosurg
36.Iijima M, Osawa M, Momose M, et al. Cardiac sympathetic
degeneration correlates with olfactory function in Parkinson’s dis-
ease. Mov Disord 2010;25:1143–1149.
37. Bohnen NI, Muller ML, Kotagal V, et al. Olfactory dysfunction,
central cholinergic integrity and cognitive impairment in Parkin-
son’s disease. Brain 2010;133(Pt 6):1747–1754.
38.Spiegel J, Hellwig D, Mollers MO, et al. Transcranial sonography
and [123I]FP-CIT SPECT disclose complementary aspects of Par-
kinson’s disease. Brain 2006;129(Pt 5):1188–1193.
39.Ross GW, Petrovitch H, Abbott RD, et al. Association of olfac-
tory dysfunction with risk for future Parkinson’s disease. Ann
40.Ross GW, Abbott RD, Petrovitch H, et al. Association of olfac-
tory dysfunction with incidental Lewy bodies. Mov Disord 2006;
41. Hawkes CH. The prodromal phase of sporadic Parkinson’s dis-
ease: does it exist and if so how long is it? Mov Disord 2008;23:
42.Hawkes CH, Del Tredici K, Braak H. A timeline for Parkinson’s
disease. Parkinsonism Relat Disord 2010;16:79–84.
P O S T U M A E TA L .
Movement Disorders, Vol. 27, No. 5, 2012
43. Ponsen MM, Stoffers D, Booij J, van Eck-Smit BL, Wolters EC,
Berendse HW. Idiopathic hyposmia as a preclinical sign of Par-
kinson’s disease. Ann Neurol 2004;56:173–181.
44. Sommer U, Hummel T, Cormann K, et al. Detection of presymp-
tomatic Parkinson’s disease: combining smell tests, transcranial
sonography, and SPECT. Mov Disord 2004;19:1196–1202.
45.Ross W, Petrovitch H, Abbott RD, et al. Association of olfactory
dysfunction with risk of future Parkinson’s disease. Mov Disord
46.Lees AJ. When did Ray Kennedy’s Parkinson’s disease begin?
Mov Disord 1992;7:110–116.
47.Marras C, Goldman S, Smith A, et al. Smell identification ability
in twin pairs discordant for Parkinson’s disease. Mov Disord
48.Hummel T, Sekinger B, Wolf SR, Pauli E, Kobal G. ‘Sniffin’
Sticks’: olfactory performance assessed by the combined testing of
odour identification, odor discrimination and olfactory threshold.
Chem Senses 1997;22:39–52.
49. Schenck CH, Mahowald MW. REM sleep behavior disorder: clin-
ical, developmental, and neuroscience perspectives 16 years after
its formal identification in SLEEP. Sleep 2002;25:120–138.
50.Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of
a parkinsonian disorder in 38% of 29 older men initially diag-
nosed with idiopathic rapid eye movement sleep behaviour disor-
der. Neurology 1996;46:388–393.
51.Iranzo A, Molinuevo JL, Santamaria J, et al. Rapid-eye-movement
sleep behaviour disorder as an early marker for a neurodegenera-
tive disorder: a descriptive study. Lancet Neurol 2006;5:572–577.
52.Postuma RB, Gagnon JF, Vendette M, Fantini ML, Massicotte-
Marquez J, Montplaisir J. Quantifying the risk of neurodegenera-
tive disease in idiopathic REM sleep behavior disorder. Neurol-
53. Iranzo A, Molinuevo JL, Santamaria J, et al. Sixty-four percent of
patients with idiopathic REM sleep behavior disorder developed a
neurological disorder after a mean clinical follow-up of seven
years. Sleep 2008;31:A280.
54. Schenck CH, Mahowald MW. REM behavior disorder (RBD):
delayed emergence of parkinsonism and/or dementia in 65% of
older men initially diagnosed with idiopathic RBD, and an analy-
sis of the minimum and maximum tonic and/or phasic electro-
myographic abnormalities found during REM sleep. Sleep 2003;
55. Gagnon JF, Postuma RB, Mazza S, Doyon J, Montplaisir J.
Rapid-eye-movement sleep behaviour disorder and neurodegener-
ative diseases. Lancet Neurol 2006;5:424–432.
56.American Academy of Sleep Medicine. The International Classifi-
cation of Sleep Disorders: Diagnostic and Coding Manual (ICSD-
2). 2nd ed. Westchester, IL: American Academy of Sleep Medi-
57.Boeve BF, Molano JR, Ferman TJ, et al. Validation of the Mayo
Sleep Questionnaire to screen for REM sleep behavior disorder in
an aging and dementia cohort. Sleep Med 2011;12:445–453.
58. Li SX, Wing YK, Lam SP, et al. Validation of a new REM sleep
behavior disorder questionnaire (RBDQ-HK). Sleep Med 2010;
59.Stiasny-Kolster K, Mayer G, Schafer S, Moller JC, Heinzel-Guten-
brunner M, Oertel WH. The REM sleep behavior disorder screen-
ing questionnaire—a new diagnostic instrument. Mov Disord
60. Postuma RB, Gagnon JF, Rompre S, Montplaisir J. Severity of
REM atonia loss in idiopathic REM sleep behavior disorder pre-
dicts Parkinson disease. Neurology 2010;74:239–244.
61. Postuma RB, Gagnon JF, Vendette M, Montplaisir JY. Idiopathic
REM sleep behavior disorder in the transition to degenerative dis-
ease. Mov Disord 2009;24:2225–2232.
62. Postuma RB, Montplaisir J, Lanfranchi P, et al. Cardiac auto-
nomic denervation in Parkinson’s disease is linked to REM sleep
behavior disorder. Mov Disord 2011;26:1529–1533.
63.Gagnon JF, Vendette M, Postuma RB, et al. Mild cognitive
impairment in rapid eye movement sleep behavior disorder and
Parkinson’s disease. Ann Neurol 2009;66:39–47.
64.Postuma RB, Gagnon JF, Vendette M, Charland K, Montplaisir J.
Manifestations of Parkinson disease differ in association with
REM sleep behavior disorder. Mov Disord 2008;23:1665–1672.
65.Postuma RB, Gagnon JF, Vendette M, Massicotte-Marquez J,
Charland K, Montplaisir J. REM sleep behavior disorder in Par-
kinson’s disease is associated with specific motor features. J Neu-
rol Neurosurg Psychiatry 2008;79:1117–1121.
66. Postuma RB, Gagnon JF, Vendette M, Montplaisir J. Markers of
neurodegeneration in idiopathic REM sleep behavior disorder and
Parkinson disease. Brain 2009;132:2298–2307.
67. Postuma RB, Lanfranchi PA, Blais H, Gagnon JF, Montplaisir JY.
Cardiac autonomic dysfunction in idiopathic REM sleep behavior
disorder. Mov Disord 2010;25:2304–2310.
68. Iranzo A, Lome~ na F, Stockner H, et al.; Sleep Innsbruck Barce-
lona (SINBAR) group. Decreased striatal dopamine transporters
uptake and substantia nigra hyperechogenicity as risk markers of
synucleinopathy in patients with idiopathic rapid-eye-movement
sleep behaviour disorder: a prospective study. Lancet Neurol
69.Postuma RB, Lang AE, Massicotte-Marquez J, Montplaisir J.
Potential early markers of Parkinson disease in idiopathic REM
sleep behavior disorder. Neurology 2006;66:845–851.
70. Massicotte-Marquez J, Decary A, Gagnon JF, et al. Executive
dysfunction and memory impairment in idiopathic REM sleep
behavior disorder. Neurology 2008;70:1250–1257.
71. Ferini-Strambi L, Di Gioia MR, Castronovo V, Oldani A, Zuc-
coni M, Cappa SF. Neuropsychological assessment in idiopathic
REM sleep behavior disorder (RBD): does the idiopathic form of
RBD really exist? Neurology 2004;62:41–45.
72. Fantini ML, Gagnon JF, Petit D, et al. Slowing of electroencepha-
logram in rapid eye movement sleep behavior disorder. Ann Neu-
73.Scherfler C, Frauscher B, Schocke M, et al. White and gray matter
abnormalities in idiopathic rapid eye movement sleep behavior
disorder: a diffusion-tensor imaging and voxel-based morphome-
try study. Ann Neurol 2011;69:400–407.
74.Mazza S, Soucy JP, Gravel P, et al. Assessing whole brain perfu-
sion changes in patients with REM sleep behavior disorder. Neu-
75.Unger MM, Belke M, Menzler K, et al. Diffusion tensor imaging
in idiopathic REM sleep behavior disorder reveals microstructural
changes in the brainstem, substantia nigra, olfactory region, and
other brain regions. Sleep 2010;33:767–773.
76. Ziemssen T, Fuchs G, Greulich W, Reichmann H, Schwarz M,
Herting B. Treatment of dysautonomia in extrapyramidal disor-
ders. J Neurol 2011;258(Suppl 2):S339–S345.
77.Orimo S, Takahashi A, Uchihara T, et al. Degeneration of cardiac
sympathetic nerve begins in the early disease process of Parkin-
son’s disease. Brain Pathol 2007;17:24–30.
78.Ziemssen T, Reichmann H. Cardiovascular autonomic dysfunc-
tion in Parkinson’s disease. J Neurol Sci 2010;289:74–80.
79.Abbott RD, Petrovitch H, White LR, et al. Frequency of bowel
movements and the future risk of Parkinson’s disease. Neurology
80. Savica R, Carlin JM, Grossardt BR, et al. Medical records docu-
mentation of constipation preceding Parkinson disease: a case-
control study. Neurology 2009;73:1752–1758.
81.Mitsui J, Saito Y, Momose T, et al. Pathology of the sympathetic
nervous system corresponding to the decreased cardiac uptake in
123I-metaiodobenzylguanidine (MIBG) scintigraphy in a patient
with Parkinson disease. J Neurol Sci 2006;243:101–104.
82.Spiegel J, Hellwig D, Farmakis G, et al. Myocardial sympathetic
degeneration correlates with clinical phenotype of Parkinson’s dis-
ease. Mov Disord 2007;22:1004–1008.
83. Oka H, Toyoda C, Yogo M, Mochio S. Cardiovascular dysauto-
nomia in de novo Parkinson’s disease without orthostatic hypo-
tension. Eur J Neurol 2011;18:286–292.
84.Valappil RA, Black JE, Broderick MJ, et al. Exploring the electro-
cardiogram as a potential tool to screen for premotor Parkinson’s
disease. Mov Disord 2010;25:2296–2303.
85.Schmidt C, Herting B, Prieur S, et al. Valsalva manoeuvre in
patients with different Parkinsonian disorders. J Neural Transm
86.Friedrich C, Rudiger H, Schmidt C, et al. Baroreflex sensitiv-
ity and power spectral analysis during autonomic testing in
Mov Disord 2010;25:
I D E N T I F Y I N G P R O D R O M A LP D
Movement Disorders, Vol. 27, No. 5, 2012
87.Friedrich C, Rudiger H, Schmidt C, et al. Baroreflex sensitivity Download full-text
and power spectral analysis in different extrapyramidal syn-
dromes. J Neural Transm 2008;115:1527–1536.
88. Gasch J, Reimann M, Reichmann H, Rudiger H, Ziemssen T.
Determination of baroreflex sensitivity during the modified
Oxford maneuver by trigonometric regressive spectral analysis.
PLoS One 2011;6:e18061.
89.Reimann M, Friedrich C, Gasch J, Reichmann H, Rudiger H,
Ziemssen T. Trigonometric regressive spectral analysis reliably
maps dynamic changes in baroreflex sensitivity and autonomic
tone: the effect of gender and age. PLoS One 2010;5:e12187.
90. Bennett DA, Beckett LA, Murray AM, et al. Prevalence of parkin-
sonian signs and associated mortality in a community population
of older people. N Engl J Med 1996;334:71–76.
91. Mattock C, Marmot M, Stern G. Could Parkinson’s disease fol-
low intra-uterine influenza?: a speculative hypothesis. J Neurol
Neurosurg Psychiatry 1988;51:753–756.
92.La Rovere MT, Pinna GD, Hohnloser SH, et al. Baroreflex sensi-
tivity and heart rate variability in the identification of patients at
risk for life-threatening arrhythmias: implications for clinical tri-
als. Circulation 2001;103:2072–2077.
93.Marsh L, McDonald WM, Cummings J, Ravina B. Provisional
diagnostic criteria for depression in Parkinson’s disease: report of
an NINDS/NIMH Work Group. Mov Disord 2006;21:148–158.
94. Reijnders JS, Ehrt U, Weber WE, Aarsland D, Leentjens AF. A
systematic review of prevalence studies of depression in Parkin-
son’s disease. Mov Disord 2008;23:183–189.
95. Santamaria J, Tolosa E, Valles A. Parkinson’s disease with depres-
sion: a possible subgroup of idiopathic parkinsonism. Neurology
96. Barone P, Antonini A, Colosimo C, et al. The PRIAMO study: a
multicenter assessment of nonmotor symptoms and their impact
on quality of life in Parkinson’s disease. Mov Disord 2009;24:
97. O’sullivan SS, Williams DR, Gallagher DA, Massey LA, Silveira-
Moriyama L, Lees AJ. Nonmotor symptoms as presenting com-
plaints in Parkinson’s disease: a clinicopathological study. Mov
98.Ishihara L, Brayne C. A systematic review of depression and men-
tal illness preceding Parkinson’s disease. Acta Neurol Scand 2006;
99. Leentjens AF, Van den Akker M, Metsemakers JF, Lousberg R,
Verhey FR. Higher incidence of depression preceding the onset of
Parkinson’s disease: a register study. Mov Disord 2003;18:
100.Alonso A, Rodriguez LA, Logroscino G, Hernan MA. Use of anti-
depressants and the risk of Parkinson’s disease: a prospective
study. J Neurol Neurosurg Psychiatry 2009;80:671–674.
101. Bower JH, Grossardt BR, Maraganore DM, et al. Anxious per-
sonality predicts an increased risk of Parkinson’s disease. Mov
102. Liepelt-Scarfone I, Behnke S, Godau J, et al. Relation of risk fac-
tors and putative premotor markers for Parkinson’s disease. J
Neural Transm 2011;118:579–585.
103. Archibald NK, Clarke MP, Mosimann UP, Burn DJ. The retina in
Parkinson’s disease. Brain 2009;132(Pt 5):1128–1145.
104. Bodis-Wollner I, Tzelepi A. The push-pull action of dopamine on
spatial tuning of the monkey retina: the effects of dopaminergic
deficiency and selective D1 and D2 receptor ligands on the pat-
tern electroretinogram. Vision Res 1998;38:1479–1487.
105. Blekher T, Weaver M, Rupp J, et al. Multiple step pattern as a
biomarker in Parkinson disease. Parkinsonism Relat Disord 2009;
106. Bodis-Wollner I. Retinopathy in Parkinson disease. J Neural
107. Archibald NK, Clarke MP, Mosimann UP, Burn DJ. Retinal
thickness in Parkinson’s disease. Parkinsonism Relat Disord 2011;
108. Inzelberg R, Ramirez JA, Nisipeanu P, Ophir A. Retinal nerve
fiber layer thinning in Parkinson disease. Vision Res 2004;44:
109. Altintas O, Iseri P, Ozkan B, Caglar Y. Correlation between reti-
nal morphological and functional findings and clinical severity in
Parkinson’s disease. Doc Ophthalmol 2008;116:137–146.
110.Hajee ME, March WF, Lazzaro DR, et al. Inner retinal layer
thinning in Parkinson disease. Arch Ophthalmol 2009;127:
111. Moschos MM, Tagaris G, Markopoulos I, et al. Morphologic
changes and functional retinal impairment in patients with Par-
kinson disease without visual loss. Eur J Ophthalmol 2011;21:
112. Aaker GD, Myung JS, Ehrlich JR, Mohammed M, Henchcliffe C,
Kiss S. Detection of retinal changes in Parkinson’s disease with
spectral-domain optical coherence tomography. Clin Ophthalmol
113. Price MJ, Feldman RG, Adelberg D, Kayne H. Abnormalities in
color vision and contrast sensitivity in Parkinson’s disease. Neu-
114.Muller T, Kuhn W, Buttner T, et al. Colour vision abnormalities
do not correlate with dopaminergic nigrostriatal degeneration in
Parkinson’s disease. J Neurol 1998;245:659–664.
115. Buter TC, van den Hout A, Matthews FE, Larsen JP, Brayne C,
Aarsland D. Dementia and survival in Parkinson disease: a 12-
year population study. Neurology 2008;70:1017–1022.
116. Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. The
Sydney multicenter study of Parkinson’s disease: the inevitability
of dementia at 20 years. Mov Disord 2008;23:837–844.
117.Aarsland D, Bronnick K, Williams-Gray C, et al. Mild cognitive
impairment in Parkinson disease: a multicenter pooled analysis.
118. Williams-Gray CH, Evans JR, Goris A, et al. The distinct cogni-
tive syndromes of Parkinson’s disease: 5 year follow-up of the
CamPaIGN cohort. Brain 2009;132(Pt 11):2958–2969.
119. Aarsland D, Perry R, Brown A, Larsen JP, Ballard C. Neuropa-
thology of dementia in Parkinson’s disease: a prospective, com-
munity-based study. Ann Neurol 2005;58:773–776.
120. Sabbagh MN, Adler CH, Lahti TJ, et al. Parkinson disease with
dementia: comparing patients with and without Alzheimer pathol-
ogy. Alzheimer Dis Assoc Disord 2009;23:295–297.
121. Kehagia AA, Barker RA, Robbins TW. Neuropsychological and
clinical heterogeneity of cognitive impairment and dementia in
Lancet Neurol 2010;9:
122.Rosenthal E, Brennan L, Xie S, et al. Association between cogni-
tion and function in patients with Parkinson disease with and
without dementia. Mov Disord 2010;25:1170–1176.
123. Foltynie T, Brayne CE, Robbins TW, Barker RA. The cognitive
ability of an incident cohort of Parkinson’s patients in the UK.
The CamPaIGN study. Brain 2004;127(Pt 3):550–560.
124. Elgh E, Domellof M, Linder J, Edstrom M, Stenlund H, Forsgren
L. Cognitive function in early Parkinson’s disease: a population-
based study. Eur J Neurol 2009;16:1278–1284.
125. Aarsland D, Bronnick K, Larsen JP, Tysnes OB, Alves G. Cogni-
tive impairment in incident, untreated Parkinson disease: the Nor-
wegian ParkWest study. Neurology 2009;72:1121–1126.
126.Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson
disease. Arch Neurol 1999;56:33–39.
127. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and manage-
ment of dementia with Lewy bodies: third report of the DLB
Consortium. Neurology 2005;65:1863–1872.
128.Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria
for dementia associated with Parkinson’s disease. Mov Disord
129. Litvan I, Aarsland D, Adler CH, et al. MDS task force on mild
cognitive impairment in Parkinson’s disease: critical review of
PD-MCI. Mov Disord 2011;26:1814–1824.
130.McKeith I. Commentary: DLB and PDD: the same or different?
Is there a debate? Int Psychogeriatr 2009;21:220–224.
131.Molano J, Boeve B, Ferman T, et al. Mild cognitive impairment
associated with limbic and neocortical Lewy body disease: a clini-
copathological study. Brain 2010;133(Pt 2):540–556.
P O S T U M AE T A L .
Movement Disorders, Vol. 27, No. 5, 2012