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Identifying Prodromal Parkinson’s Disease:
Pre-Motor Disorders in Parkinson’s Disease
Ronald B. Postuma, MD, MSc,
1,2
* Dag Aarsland, MD, PhD,
3
Paolo Barone, MD, PhD,
4
David J. Burn, MD, FRCP,
5
Christopher H. Hawkes, MD, FRCP,
6
Wolfgang Oertel, MD, PhD,
7
and Tjalf Ziemssen, MD
8
1
Department of Neurology, McGill University, Montreal General Hospital, Montreal, Quebec, Canada
2
Centre d’E
´tudes Avanc
ees en M
edecine du Sommeil, Hopital du Sacre-Coeur, Montreal, Canada
3
Department of Old Age Psychiatry, Psychiatric Clinic, Stavanger University Hospital, Stavanger, Norway
4
Centro per le Malattie Neurodegenerative, University of Salerno, Salerno, Italy
5
Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom
6
Neuroscience Centre, Institute of Cell and Molecular Science, Barts and
The London School of Medicine and Dentistry, London, United Kingdom
7
Department of Neurology, Philipps-Universit€
at, Marburg, Germany
8
Autonomes 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-
cific autonomic measures, specificity, and positive
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.
V
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; ronald.postuma@mcgill.ca
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).
DOI: 10.1002/mds.24996
ARTICLE
Movement Disorders, Vol. 27, No. 5, 2012 617
stage of PD involves deposition in anterior olfactory
nucleus and dorsal motor nucleus of the vagus.
1
Sub-
sequent revisions suggest peripheral autonomic ganglia
and unmyelinated lamina-1 spinal cord neurons may
also be stage 1 features.
2
Stage 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
these findings.
3–5
However, limitations should be
noted. PD is heterogeneous, and many patients may
not follow this classic progression.
3,4,6–8
Braak’s
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.
9
If
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
markers.
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
behavior disorder (RBD), autonomic dysfunction,
depression, visual changes, and cognition (Table 1).
Olfaction
Nature of Defect
In parkinsonism there is impaired olfactory identifi-
cation, discrimination, and threshold in >80% of
patients.
10,11
Many 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.
13
It
is also apparent that only 40% with PD are aware
of impaired smell sense. Those who are unaware prob-
ably have mild impairment.
11
Whatever 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 bilateral
14
and most find that the severity of
microsmia correlates with measures of disease dura-
tion and severity.
11,15–17
In 1 cross-sectional modeling
study,
18
it 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-
phy
19
and dementia with Lewy bodies
20
but
uncommonly in progressive supranuclear palsy, corti-
cobasal degeneration, drug-induced parkinsonism,
essential tremor, and dystonia.
19,21–24
If a patient is
TABLE 1. Summary of Clinical Markers of Premotor PD
Marker Level of evidence
a
Sensitivity Specificity
Olfaction High (population-based studies,
38
prospective studies
29
)
High (>80% of early PD) Low (up to one-third of elderly
population has olfactory loss)
REM sleep behavior disorder High (3 cohort studies
48–50
) Low (50% of PD patients have
RBD, one-half of these precede
disease)
High (up to 65% risk of disease
at 10 years)
Autonomic symptoms High for constipation,
77,78
low/
moderate for other symptoms
Moderate-high (most early PD
patients have symptoms)
Low (one-third of general
population has symptoms)
Cardiac autonomic markers
(RR variability, MIBG
scintigraphy
Low (no prospective studies, one
negative RBD study)
Unknown for RR variability; high
for MIBG (most PD patients are
abnormal)
Unknown
Depression Moderate (case-control studies,
conflicting cohort studies)
Low (30%–40% of PD patients
have depression)
Low (one-third of general
population has)
Visual abnormalities: saccadic
abnormalities; retinography;
optical coherence
tomography; color vision
Moderate for color vision
(prospective RBD study
29
),
low for others
Unknown—most PD patients
have abnormalities—unclear if
present early in PD
Unknown
Cognitive impairment Low Unknown—subtle cognitive
changes difficult to detect
Unknown—subtle cognitive
changes may be nonspecific
a
Level of evidence is considered high if there is direct evidence that it predicts PD, based upon prospective studies documenting abnorm alities 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,
123
I-metaiodobenzylguanidin.
POSTUMA ET AL.
618 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-
porter imaging.
6
Olfactory abnormalities are found in familial syn-
dromes such as: PARK1/4, PARK2, PARK6, PARK8,
and PARK9, and those with glucocerebrosidase gene
(GBA) mutations.
25,26
Data are awaited for PARK10-17
and POLG1 mutations. Non-manifesting carriers of
PARK2 and PARK8 mutations had normal smell in 1
study
27
whereas non-manifesting carriers of the PARK6
mutation had abnormal olfaction.
28
These 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.
Non-Motor Correlations
Defective smell sense correlates with other modal-
ities in the established phase of PD; eg, RBD, reduced
color vision, constipation, episodic verbal memory,
and motor score.
29–33
There is also correlation
between hyposmia and transcranial ultrasound of the
substantia nigra,
123
I-metaiodobenzylguanidin (MIBG)
heart scan, olfactory bulb size, limbic acetylcholinester-
ase activity, and dopamine transporter imaging.
33–38
In
the prodromal period, RBD, dopamine transporter
imaging, and incidental brain stem Lewy bodies
39
all
show a correlation with olfaction.
40,41
Is Microsmia a Prodromal Feature?
Several strands of evidence suggest that smell
impairment is a prodromal phenomenon
42
although
estimates of prodromal phase duration vary from 2 to
50 years.
41
Back-projection of the cross-sectional
model implies that the olfactory defect begins around
the time of birth.
18
This 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.
1
suggest 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.
43
revealed 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.
44
examined 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 Study
39
used 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.
41
For 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.
46
Further-
more, in a study of 62 PD-discordant twin pairs
47
all
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.
39
This suggests that
olfactory impairment may only be apparent with in a
few years before onset of motor symptoms.
Conclusion
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.
IDENTIFYING PRODROMAL PD
Movement Disorders, Vol. 27, No. 5, 2012 619
RBD
RBD is characterized by loss of the normal atonia of
REM sleep,
49
such 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.
50–52
These 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%.
52–54
In 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.
39
In 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).
55
This 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-
ventative therapy.
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.
52
This 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.
56
Although 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.
60
Similarly, 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.
30,61
This 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.
62–66
If 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.
Results of prospective studies are beginning to
appear—they suggest that severity of REM atonia,
60
impaired olfaction,
30
and reduced color vision
30
(but
perhaps not electrocardiograph [EKG]–ventricular
cardiac cycle, an indicator of ventricular rate, [RR]
variability
67
) 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.
68
Other potential markers such
as quantitative tests of movement speed,
69
anxiety/
depression, personality changes,
66
subtle cognitive dys-
function,
70,71
waking electroencephalograph (EEG)
slowing,
72
volumetric magnetic resonance imaging
POSTUMA ET AL.
620 Movement Disorders, Vol. 27, No. 5, 2012
(MRI) changes,
73
cerebral blood flow changes,
74
and
diffusion tensor imaging
73,75
are currently being eval-
uated in RBD patients for their potential to identify
prodromal PD.
Autonomic Dysfunction
Autonomic dysfunction is an important clinical non-
motor symptom that appears to represent an early
manifestation of PD.
76
As 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.
77
Clinically, 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 Study
79
and the Rochester Epide-
miology Project.
80
Constipation, 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.
81
observed 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.
82,83
Unfortunately
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.
84
demonstrated a
significant decreased heart rate variability (HRV)
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).
62
However, 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.
67
Other
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.
85–87
New
innovative algorithms as the trigonometric spectral
analysis (TRS) are available to quantify even subtle
alterations.
88,89
Their potential role in prodromal PD is
still under investigation.
In summary, methodology of autonomic assessment
is currently insufficiently developed to be applied in
prodromal PD, although there are promising
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 PD
90,91
and
subtle autonomic dysfunction is associated with
increased cardiovascular mortality.
92
Depression
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 criteria
93
and 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
and Statistical Manual of Mental Disorders-IV
(DSM-IV), approximately 35% of PD patients had
clinically significant symptoms of depression.
94
The
difficulty in characterizing depression in PD may
account for the variety of prevalence figures in the
literature.
Depression in Early and in Prodromal PD
Depressive symptoms precede motor symptoms in
30% of PD patients
95
and are reported as a presenting
complaint in 12% to 22% of patients.
96,97
In the ab-
sence of prospective studies, both case-control and
cohort studies suggest a risk ratio for the association
between PD and premorbid depression ranging
between 1.20 and 3.13.
98
In 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).
99
Interval
between the first depressive episode and PD diagnosis
IDENTIFYING PRODROMAL PD
Movement Disorders, Vol. 27, No. 5, 2012 621
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.
100
On the other hand, the Mayo
Clinic Cohort Study of Personality and Aging showed
that a depressive trait of the Minnesota Multiphasic
Personality Inventory was not associated with
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.
102
The relevance of this association for a
later diagnosis of PD needs to be determined in pro-
spective studies.
Visual Dysfunction
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
circuits.
103,104
Since PD generally affects older persons, a host of
age-related visual pathologies (cataracts, macular
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.
Saccadic Deficits
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.
105
The 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
subjects.
Visual Evoked Potentials and Pattern
Electroretinography
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,
103,106
although D1 receptors may
also play a role.
104
However, it is unclear how these
findings may translate into a sensitive pre-motor
biomarker.
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,
while newer Fourier domain OCT resolution is
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.
107
The 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
some
108–111
but not all
107,112
studies in PD, and where
differences occur, they have been expressed as group
effects. Macular thinning has been reported when
RNFL thickness was normal.
112
We are not aware of
POSTUMA ET AL.
622 Movement Disorders, Vol. 27, No. 5, 2012
studies directly assessing OCT as a prodromal PD
marker.
Color Discrimination
Color vision is abnormal in PD and may be related
to disease duration.
113,114
More 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 (P¼.0049).
69
Moreover, abnormal color
vision correlated with olfactory dysfunction and
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
disease-free.
30
Disease-free survival (Kaplan-Meier)
with normal color vision was 70.3% versus 26.0%
with impaired vision (P¼.009). 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
prodromal PD.
Cognitive Impairment
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
Mechanisms
The mechanisms underlying cognitive impairment in
PD are only partially known. Most studies found that
cortical and limbic Lewy bodies
119
or amyloid plaque
pathology
120
are 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,
1
similar 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
Three studies of population-based incident PD
cohorts have demonstrated impairment across a range
of cognitive domains
122–125
already 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.
126
DLB criteria
127
state 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.
128
Similarly, 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....’’
129
There
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,
Molano
131
described 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 specificity of cognitive changes in
identification of prodromal PD.
Conclusions
There is clear evidence that non-motor features can
identify prodromal PD. Direct evidence for predictive
value varies between manifestations, but there is direct
IDENTIFYING PRODROMAL PD
Movement Disorders, Vol. 27, No. 5, 2012 623
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-
tonomic dysfunction (50%–80%, depending on
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.
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