NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE

Implications of nocturnal symptoms towards the early diagnosisof Parkinson’s disease

Elizabeth J. Slow • Ronald B. Postuma •

Anthony E. Lang

Received: 27 November 2013 / Accepted: 22 January 2014

� Springer-Verlag Wien 2014

Abstract Nocturnal symptoms are frequent in Parkinson

disease (PD) and consist of nocturnal sleep disorders such

as REM sleep behavior disorder (RBD) and restless legs

syndrome. There is an increasing need for reliable, early,

pre-motor diagnosis of PD, since motor symptoms occur

when there is already significant neuronal loss. Recent

prospective studies have shown that over 80 % of idio-

pathic RBD patients over time converted to PD and related

synucleinopathies. RBD patients have autonomic, visual,

and olfactory dysfunction as well as neuroimaging abnor-

malities similar to those seen in PD. Studies have shown

that neuroimaging abnormalities and visual and olfactory

dysfunction can help predict which RBD patients will

likely convert to a neurodegenerative diagnosis within a

short follow-up period. These factors make RBD an ideal

population for prediction to PD conversion, allowing future

testing and eventual use of neuroprotective strategies.

Keywords Parkinson disease � REM sleep behavior

disorder � Pre-motor diagnosis � Restless legs syndrome �Excessive daytime sleepiness

Introduction

The diagnosis of Parkinson disease (PD) relies on well-

established clinical diagnostic criteria based on the onset of

typical motor symptoms including rest tremor, bradykine-

sia, postural instability and rigidity. It has become clear

that the pathological process, sometimes termed Lewy

body disease or synucleinopathy based on the hallmark

neuropathological findings, begins years or even decades

before the onset of motor symptoms. The terms ‘‘pre-

motor’’ or ‘‘prodromal’’ have both been used to describe

those symptoms that typically precede the diagnosis of PD

(Table 1). These symptoms likely represent neuronal dys-

function or degeneration in parts of the nervous system

other than the classic substantia nigra pars compacta cell

degeneration typically thought of as the histopathologic

hallmark of PD. The presence of olfactory dysfunction

(Haehner et al. 2009), autonomic disturbances (Abbott

et al. 2001) in the form of constipation or urinary com-

plaints, depression (Leentjens et al. 2003) and visual dys-

function (Biousse et al. 2004) including disturbed color

vision are typical prodromal features of PD. The presence

of any of these features increases the risk of future ‘‘con-

version’’ to PD.

As the field of PD moves towards potential neuropro-

tective strategies, there is an increasing need for reliable

pre-motor diagnosis. By some estimates, 40–50 % of

substantia nigra neuronal loss and 60–70 % striatal dopa-

mine depletion is already present at the onset of motor

symptoms in PD. The ability to diagnose PD prior to motor

symptom onset would facilitate not only the development

and testing of neuroprotective drugs, but also in the future

allows ‘‘pre-treatment’’ of patients to either halt the disease

(even before the development of typical motor features) or

at the very least delay progression. While olfactory,

E. J. Slow � A. E. Lang (&)

Division of Neurology, Movement Disorders Center, Toronto

Western Hospital, University of Toronto, 399 Bathurst St,

7 McL, Toronto, ON M5T 2S8, Canada

e-mail: lang@uhnresearch.ca

R. B. Postuma

Department of Neurology, Montreal General Hospital,

McGill University, Montreal, QC, Canada

R. B. Postuma

Centre d’Etudes Avancees en Medicine du Sommeil, Hopital du

Sacre-coeur de Montreal, Montreal, QC, Canada

123

J Neural Transm

DOI 10.1007/s00702-014-1168-4

autonomic and visual dysfunction are clearly pre-motor

manifestations of PD, they are relatively common in the

general population and have heterogeneous causes. The

specificity and, therefore, positive-predictive value for

identification of pre-motor PD using these symptoms is

low.

One avenue with great potential for identification of pre-

motor PD is within the realm of sleep disorders. Sleep

disorders have long been recognized as an important non-

motor feature of PD. In his original ‘‘Essay on the shaking

palsy’’, James Parkinson mentioned ‘‘the sleep becomes

much disturbed’’ (Parkinson 2002). Nocturnal sleep disor-

ders described in patients with PD include REM sleep

behavior disorder (RBD), insomnia and restless legs syn-

drome (RLS). Of these, RBD, in particular may predate the

onset of motor manifestations of PD by several years, may

allow early diagnosis of PD and may serve as an important

prodromal/preclinical marker for the disease.

REM sleep behavior disorder

REM Sleep Behavior Disorder is a parasomnia character-

ized by the loss of REM sleep muscle atonia and dream-

enacting behaviors. Gold standard diagnosis is based on

polysomnography, but RBD questionnaires including the

Mayo Sleep Questionnaire (Boeve et al. 2011) and the

RBD Screening Questionnaire (Stiasny-Kolster et al. 2007)

have also been validated for population studies. Prevalence

of RBD in PD populations is estimated to range between 30

and 50 % (Mollenhauer et al. 2013), but varies during the

course of the illness. In a population-based study cogni-

tively normal individuals aged 70–89, who screened posi-

tive for probable RBD by a validated questionnaire, were at

a 2.2-fold increased risk of developing PD or cognitive

impairment over a 4-year period compared to individuals

who did not have features of RBD (Boot et al. 2012). Note

that this is a likely underestimate, since both false-positive

and false-negative diagnoses would likely decrease the

differences between groups.

The best evidence for RBD as a pre-motor manifes-

tation of PD comes from several prospective, longitu-

dinal studies of idiopathic RBD (iRBD) patients initially

referred for evaluation to a sleep disorder center. The

data are from three studies from Montreal (Postuma

et al. 2009a), Barcelona (Iranzo et al. 2013, 2006) and

Minnesota (Schenck et al. 1996, 2013) summarized in

Table 2. In each study, patients presenting with idio-

pathic RBD were followed longitudinally and assessed

over time for the onset of movement disorders and/or

dementia. During the course of follow-up, patients

gradually converted from a diagnosis of idiopathic RBD

to a neurodegenerative diagnosis. The two studies with

the longest follow-up to date (12 and 22 years) found a

very similar conversion rate of idiopathic RBD to neu-

rodegenerative disease of 81–82 % (21/26 in the Min-

nesota study and 36/44 in the Barcelona study). The

third and largest study by Postuma et al. showed a

conversion rate of 28 % (26/93), but this study had a

mean follow-up rate of only 5.2 years, and likely will

show a much higher conversion rate with follow-up over

time. Earlier publications of the Minnesota and Barce-

lona group similarly showed a lower conversion rate

[45 % after 5 years in the Barcelona study (Iranzo et al.

2006) and 38 % after 6 years in the Minnesota study

(Schenck et al. 1996)]. The three studies found a very

similar time from iRBD onset to development of neu-

rodegenerative disease (11.5, 12 and 14.2 years) (Pos-

tuma et al. 2009a; Iranzo et al. 2013; Schenck et al.

2013). Most interestingly, in the Barcelona prospective

longitudinal study of iRBD patients, only four patients

remained free of neurodegenerative disease diagnosis.

All four of these patients were found to have decreased

striatal dopamine transporter (DAT) uptake on single-

photon emission computed tomography (SPECT), one

had SN hyperechogenicity by transcranial sonography

(TCS) and two had olfactory dysfunction, suggesting

that these four patients would also convert to a neuro-

degenerative disorder with time (Iranzo et al. 2013). This

suggests that overtime, given a long enough follow-up,

all patients with idiopathic RBD will eventually convert

to PD or related synucleinopathy.

Neurodegenerative conditions that iRBD patients were

eventually diagnosed with included PD, dementia with

Lewy bodies (DLB), multiple system atrophy (MSA) and

other dementia (ranging from mild cognitive impairment to

fulfilling Alzheimer disease clinical criteria). Interestingly,

the approximate ratio of each condition within the three

studies was relatively consistent. At last reported follow-

Table 1 Pre-motor manifestations of Parkinson disease

Strong evidence

REM sleep behavior disorder

Excessive daytime sleepiness

Olfactory dysfunction

Constipation

Depression

Possible link

Restless legs syndrome

Visual disturbances

Anxiety

Apathy

Other autonomic dysfunction (e.g., cardiac)

Cognitive changes

Fatigue

E. J. Slow et al.

123

up, of the patients who did convert to a neurodegenerative

condition, most patients converted to PD (44, 54 and

62 %), or DLB (39, 27 and 14 %), followed by dementia/

cognitive impairment (14, 15, and 14 %) and least often

MSA (3, 4 and 9 %) (Iranzo et al. 2013; Postuma et al.

2009a; Schenck et al. 2013). Furthermore, if one includes

all PD, DLB and MSA under the umbrella category

‘‘synucleinopathy’’, the three studies show a striking sim-

ilarity in the percentage of patients converting to a syn-

ucleinopathy (86, 85, and 86 %). This data suggest that

when followed over time, iRBD patients who convert to a

neurodegenerative condition will overwhelmingly manifest

signs and symptoms of a synucleinopathy.

This still leaves approximately 15 % of patients devel-

oping a neurodegenerative disease without signs of par-

kinsonism, fulfilling clinical criteria for cognitive

dysfunction/dementia. Are these patients manifesting

symptoms of a different pathological process? It is

important to note that diagnosis of DLB requires emer-

gence of core clinical symptoms, which may not be

apparent early in the course of the dementia. Therefore,

many patients classified as non-specific dementia in fact

have DLB. Two RBD cases from the Minnesota group who

manifested clinical signs consistent with Alzheimer disease

(AD) without evidence of parkinsonism underwent post-

mortem neuropathological assessment. Neuropathology in

both cases showed findings consistent with AD (neuropil

threads, neurofibrillary tangles and degenerative plaques)

and alpha-synucleinopathy or Lewy body (LB) disease (LB

inclusions present, most predominantly in the limbic

system) (Schenck et al. 2013). Neuropathological findings

from both cases were, therefore, characterized as ‘‘high

likelihood Alzheimer disease plus limbic-predominant

Lewy body disease’’ (Schenck et al. 2013). Three patients

from the Barcelona group also underwent neuropathologi-

cal assessment (Iranzo et al. 2013). The ante-mortem

diagnosis of PD in two patients and DLB in one patient

were confirmed on neuropathology, again consistent with

underlying Lewy body disease/synucleinopathy (Iranzo

et al. 2013). Boeve et al. reported the neuropathologic

findings of 172 RBD cases collected from eight centers in

Europe and North America. RBD preceded the onset of

neurodegenerative symptoms (including parkinsonism,

cognitive impairment or autonomic dysfunction) in 51 %

of patients in this series, again at an average of 10 years

prior to manifestation of a neurodegenerative syndrome. In

the remaining 49 % of patients, RBD occurred either

concurrently or evolved after the onset of neurodegenera-

tive symptoms. The primary clinical diagnoses in this

cohort included DLB, PD, MSA and AD. 94 % (160/170)

of neurodegenerative syndromes had a synucleinopathy

evident on autopsy including a patient who had a pre-

mortem diagnosis of idiopathic RBD, without development

of any other neurologic symptoms or signs prior to death

(Boeve et al. 2013). When considering those patients who

manifested RBD before the onset of neurodegenerative

features, this percentage increased from 96 % when RBD

occurred 5 years prior to onset up to 100 % when RBD

preceded onset of other neurodegenerative signs by greater

than 20 years (Boeve et al. 2013). Finally, selecting only

Table 2 Summary of three prospective studies of RBD followed longitudinally with subsequent conversion to a neurodegenerative diagnosis

Study Initial

iRBD

(N)

Follow-

up

(years)

Conversion to

neurodegenerative

diagnosis (N)

Time to

conversion

(years)

Neurodegenerative diagnosis (N) Other

PD DLB MSA Cognitive

(MCI/

dementia)

Barcelona

Iranzo et al. (2006) 44 5 20 11.5 9 6 1 4

Iranzo et al. (2013) 44 12 36 12 16 14 1 5 DAT, TCS, olfactory changes

in N = 4 remaining

Montreal

Postuma et al.

(2009a)

93 5 26 11.5 14 7 1 4 N = 4 dementia were AD

Minnesota

Schenck et al.

(1996)

29 6 11 12.7 11

Schenck et al.

(2013)

26* 22 21 14.2 13 3 2 3 N = 3 dementia were N = 2 AD,

N = 1 NYD

iRBD idiopathic REM sleep behavior disorder, PD Parkinson disease, DLB dementia with Lewy bodies, MSA multiple system atrophy, MCI mild

cognitive impairment, DAT dopamine transporter, TCS transcranial ultrasound, AD Alzheimer disease, N number, NYD not yet diagnosed

* 3 of the original 29 patients were lost to follow-up

Early diagnosis of Parkinson’s disease

123

polysomnographic-proven RBD patients (eliminating

potential false-positive diagnoses), increased proportion of

neurodegenerative synucleinopathy to 98 %.

It should not be surprising that RBD and PD share

similar pathology given the current proposed pathophysi-

ology of both RBD and PD. Work from animal models has

implicated brainstem structures in the development of RBD

including the sublateral dorsal nucleus and proceruleus

complex, the medullary ventral gigantocellular reticular

nucleus and the magnocellular reticular formation (Siegel

2006). These nuclei send projections to the anterior horn

cells throughout the spinal cord, either directly or indi-

rectly. During REM sleep, these projections effectively

inhibit the anterior horn cells, with resulting paralysis of

limb, trunk and bulbar skeletal musculature, corresponding

to electromyographic atonia on polysomnography (Boeve

2013). The Braak staging system of PD, based on autopsy

series, proposes an ascending spread of alpha-synuclein

pathology, starting in the medulla (Braak et al. 2003; Bo-

eve 2013). In this system, Stage I shows pathology in

dorsal motor nucleus of the vagal nerve and the olfactory

bulb/anterior olfactory nucleus complex, with possible

resulting autonomic dysfunction and hyposmia. In Stage 2,

pathology ascends to involve the sublateral dorsal nucleus/

proceruleus complex and the magnocellular reticular for-

mation as well as the raphe nucleus and locus coeruleus.

This can lead to changes in sleep as well as mood and

behavior. Dysfunction and eventual degeneration of the

sublateral dorsal nucleus/proceruleus complex and the

magnocellular reticular formation lead to loss of inhibition

of the anterior horn cells and the potential onset of REM

sleep without atonia, which can further manifest as RBD in

late Stage 2 or 3. It is not until Braak stage 3 that pathology

ascends to the level of the pars compacta of the substantia

nigra, resulting in overt PD motor symptoms and signs by

Braak stage 4.

The hypothesis of spread of synucleinopathy throughout

the brainstem can also explain the finding of olfactory and

autonomic dysfunction in iRBD patients, as these struc-

tures are likely affected early in the disease course.

Olfactory dysfunction has been reported in a number of

studies of iRBD patients (Miyamoto et al. 2010; Shin et al.

2013). Autonomic dysfunction in the form of reduced

cardiac 123I-MIBG uptake (Miyamoto et al. 2006) and

reduced heart rate variability (Postuma et al. 2010b) was

present in iRBD patients when compared to age-matched

controls. Autonomic signs and symptoms including

increased systolic blood pressure drop and the presence of

erectile dysfunction and constipation were found in iRBD

patients in comparison to controls (Postuma et al. 2006,

2009b). Both autonomic dysfunction and olfactory dys-

function are proposed to be early pre-motor symptoms of

PD based on the Braak staging system (Braak stage 1) and

indeed are commonly found in early clinical PD. Color

vision has been shown to be impaired in PD patients and is

similarly affected in patients with iRBD (Postuma et al.

2006, 2009b). There have been reports of mild impairments

in motor function in iRBD patients compared to controls as

measured by the Purdue Pegboard Test, alternate tap test

and Timed ‘Up and Go’ test (Postuma et al. 2009b).

Cognitive dysfunction has also been noted in iRBD

patients (Gagnon et al. 2009, 2012). The presence of mild

motor impairment and cognitive dysfunction may simply

herald the onset of a neurodegenerative disease, and if

followed, these patients would soon meet the diagnostic

criteria for a neurodegenerative disorder. Indeed, on motor

tests, the mean values for iRBD were intermediate between

controls and patients with PD (Postuma et al. 2009b). Mild

motor abnormalities were also shown to predict a diagnosis

of defined neurodegeneration in RBD (Postuma et al.

2012b). When traced backwards in time, abnormalities

deviated from normal control values approximately

4–8 years before diagnosis of full parkinsonism.

Neuroimaging of iRBD has shown similar changes as

those found in PD. Patients with PD have hyperechoge-

nicity of the substantia nigra (SN) by TCS (Berg et al.

2008), thought to reflect increased iron content. Similarly,

patients with iRBD have increased SN hyperechogenicity

when compared to controls (Stockner et al. 2009; Iwanami

et al. 2010; Shin et al. 2013), either similar to that seen in

PD patients (Iwanami et al. 2010) or intermediate between

controls and PD patients (Shin et al. 2013). PET studies

with [11C]dihydrotetrabenazine showed reductions in

striatal binding, particularly in the posterior putamen in

iRBD patients compared to controls (Albin et al. 2000),

suggesting reduced numbers of dopaminergic SN neurons.

Finally, functional neuroimaging with ligands that bind to

dopamine transporters (DAT) of the presynaptic dopamine

nerve terminals give a quantitative measurement of striatal

dopaminergic innervation, which is decreased in PD

patients compared to controls (Booij et al. 1997), indicating

damage to the SN dopaminergic system. Decreased striatal

dopamine transporter uptake was noted in 17/43 (40 %) of

iRBD patients compared to controls in a study from 2010

(Iranzo et al. 2010). A subset of these iRBD patients

(N = 20) underwent serial DAT imaging at baseline, 1.5

and 3 years. A greater number of iRBD patients had

reduced transporter uptake at 3 years compared to baseline

(13 vs. 10, respectively) when compared to controls. At the

3-year time point, the iRBD group showed greater reduc-

tion in DAT ligand uptake compared to baseline values and

compared to controls, suggesting progressive nigrostriatal

cell degeneration (Iranzo et al. 2011).

While autonomic and olfactory dysfunction, color vision

and neuroimaging abnormalities are present in patients

with idiopathic RBD, are any of these changes predictive

E. J. Slow et al.

123

of conversion to a neurodegenerative disorder? In the

iRBD patients who were followed with serial DAT scans

over 3 years, at the end of the study three iRBD patients

had converted to a diagnosis of PD. These three patients

had the lowest dopamine transporter uptake values at

baseline and had increased reductions at the 3-year follow-

up (Iranzo et al. 2011). Another study looking at a larger

cohort of iRBD patients (N = 43) examined both dopa-

mine transporter uptake and SN hyperechogenicity at

baseline and then examined them at follow-up in 2.5 years

for signs/symptoms consistent with conversion to a neu-

rodegenerative disorder. Twenty-seven of these iRBD

patients (60 %) had reduced dopamine transporter uptake

and/or SN hyperechogenicity at baseline and eight of these

patients had developed a neurodegenerative disorder by the

2.5-year follow-up (5 PD, 2 DLB and 1 MSA). Those

iRBD patients with normal neuroimaging at baseline

remained clinically disease-free. The authors calculated the

sensitivity of these combined tests (transcranial ultrasound

and DAT imaging) at 100 % for prediction of conversion

of iRBD to synucleinopathy at 2.5 years, with a specificity

of 55 % (Iranzo et al. 2010) (note that specificity is artifi-

cially low, since many of the test-positive, neurodegener-

ative disease-negative cases will eventually convert to a

neurodegenerative diagnosis given adequate follow-up

time). Each test individually, however, had lower sensi-

tivity; 75 % for DAT imaging, and 63 % for transcranial

ultrasound. Olfaction and color vision were measured

annually over 5 years in a prospective cohort study of 62

iRBD patients. Twenty-one patients developed a neurode-

generative disorder during follow-up (4 parkinsonism, 16

parkinsonism/dementia, 1 isolated dementia). When com-

pared to the remaining iRBD patients in the study who

remained disease-free over 5 years, iRBD patients destined

to develop a neurodegenerative disorder had significantly

worse baseline olfaction and color vision (Postuma et al.

2011). The severity of REM atonia (i.e., increased severity)

at baseline in iRBD patients was predictive for the devel-

opment of a neurodegenerative disorder, most clearly for

PD (Postuma et al. 2010a).

Idiopathic RBD predicts development of PD, but is the

presence of RBD predictive of a particular subtype of PD?

With respect to motor manifestations, patients with PD and

RBD are less likely to have tremor predominant PD, and

more likely to have freezing and falls (Postuma et al.

2008b; Romenets et al. 2012). PD patients with RBD were

more likely to have signs and symptoms of orthostatic

hypotension (Postuma et al. 2008a). A systolic blood

pressure drop of[10 from supine to after 1 min of standing

was both sensitive (81 %) and specific (86 %) for identi-

fication of PD patients with RBD (Romenets et al. 2012).

Cognition was more likely to be affected in PD patients

with RBD. A prospective study of PD patients with and

without RBD showed that within 4 years, half of the

patients with PD ? RBD developed dementia compared to

none in the PD only group (Postuma et al. 2012a). Psy-

chiatric disorders including psychosis (delusions and hal-

lucinations) (Pacchetti et al. 2005) and depression

(Romenets et al. 2012) were increased in frequency in

those PD patients with RBD. Color vision dysfunction

(Postuma et al. 2008a) was also increased in frequency in

PD patients with RBD compared to PD alone. These results

show that not only can RBD predict future development of

PD, but also the presence of RBD in PD patients can

identify both the motor type [i.e., postural instability/gait

disorder (PIGD) subtype] and the non-motor manifesta-

tions (more autonomic, visual, cognitive and psychiatric

disturbances) within that particular patient.

Other nocturnal sleep disorders

Restless leg syndrome is characterized by an uncomfort-

able sensation that causes an urge to move the legs. This

urge is relieved by movement and is typically worst in the

evening when at rest. The presence of RLS is largely

determined by history or questionnaire and is estimated to

have a prevalence in the general population of between 5

and 10 % (7.2 % in RLS Epidemiology, Symptoms and

Treatment general population study) (Allen et al. 2005). In

several cross-sectional, case–control studies, RLS has a

higher prevalence in PD patients than controls (Nomura

et al. 2006; Loo and Tan 2008; Calzetti et al. 2009). In a

large, cross-sectional epidemiological study of over 23,000

men in the US, men with RLS had a threefold higher

prevalence of PD than those without RLS (Gao et al. 2010).

The presence of RLS symptoms preceding the diagnosis of

PD is highly varied from 0.6 % (Nomura et al. 2006) to

50 % (Loo and Tan 2008; Calzetti et al. 2009).

There have been no prospective studies of RLS to

determine if this particular sleep disorder is a pre-motor

manifestation of PD. While symptoms of RLS do respond

to dopaminergic medications similar to PD, imaging

studies suggest distinct pathologic processes. Transcranial

ultrasound showed hypoechogenicity of the substantia

nigra in RLS (Godau and Sojer 2010) and MRI measure-

ments suggested reduced substantia nigra iron concentra-

tion (Allen et al. 2001), the opposite of what is seen in PD.

Brain imaging studies of the central dopamine system

using SPECT or PET in patients with RLS have yielded

varied results. Presynaptic PET studies with [18F] dopa

have alternatively shown reduced uptake in the striatum

(Turjanski et al. 1999) or no difference (Trenkwalder et al.

1999) in RLS patients versus controls. Studies of radioli-

gand binding to D2-receptors as a measure of postsynaptic

function have demonstrated discrepant results. PET studies

Early diagnosis of Parkinson’s disease

123

using [11C]raclopride or SPECT scans using [123I] IBZM

have shown reduced binding (Turjanski et al. 1999), no

difference (Eisensehr et al. 2001) or increased binding

(Cervenka et al. 2006) in the striatum of RLS patients

compared to controls. Neuropathological analysis of four

patients with idiopathic RLS showed absence of Lewy

bodies and alpha-synuclein pathology (Pittock et al. 2004).

PD can decrease pain threshold, and may be associated

with RLS mimics such as cramping. Therefore, it is con-

ceivable that some patients may manifest RLS-like symp-

toms very proximate to diagnosis; whether this would

reflect a true pathophysiologic relationship is highly

uncertain, given the important differences in pathophysi-

ology of the two disorders. More research is required

before consideration of the use of RLS in a composite

measure of biomarkers for pre-motor diagnosis of PD.

Excessive daytime sleepiness

While not a nocturnal manifestation, excessive daytime

sleepiness (EDS) has long been recognized as a sleep

disorder associated with PD (Hobson et al. 2002) and is

typically evaluated through validated scales [e.g., Epworth

sleepiness scale (Hagell and Broman 2007)] or question-

naire. Excessive daytime sleepiness was evaluated as a risk

factor for PD in the Honolulu-Asia Aging Study, a study of

3,078 men between the ages 71 and 93 years with 7 years

follow-up. Excessive daytime sleepiness was assessed

through the use of a questionnaire, and men who reported

being sleepy most of the day were defined as having EDS.

During the follow-up period, 43 men developed PD. After

age adjustment, men with EDS had a threefold increased

risk of developing PD compared to men without EDS. This

relationship was maintained after adjustments for con-

founders (e.g., cigarette smoking, depression) (Abbott et al.

2005). A similar finding was reported by Gao et al.; in this

study, patients who reported [1 h of daytime napping,

were at an approximately 1.5-fold increased risk of

developing PD (Gao et al. 2011). Other sleep features

examined including insomnia, shortened sleep duration or

frequent nocturnal awakening showed no relation to the

risk of PD (Abbott et al. 2005; Gao et al. 2011).

One of the major neurotransmitters promoting wake-

fulness is hypocretin (orexin) produced by hypothalamic

cells. The potential role of EDS as a pre-motor manifes-

tation of PD is supported by neuropathological findings of

both alpha-synuclein deposition and neuronal loss in the

hypocretin producing cells of the hypothalamus (Fronczek

et al. 2007). Hypocretin (orexin) producing cells were

decreased in early clinical stage PD and continued to

decline with advancing stage. Similarly, alpha-synuclein

deposition was found in hypocretin producing cells in early

clinical stages of PD and deposition increased with

advancing clinical stage (Thannickal et al. 2007). CSF and

prefrontal cortex levels of hypocretin were reduced in post-

mortem brains of PD patients when compared to controls

(Fronczek et al. 2007). Reports of CSF levels of hypocretin

in PD patients have been variable, with some reports sug-

gesting lower levels in PD patients (Drouot et al. 2003) and

others showing no difference in levels when compared to

controls (Compta et al. 2009). Note, also, that many neu-

ronal systems in the reticular activating system also

degenerate in PD, including the locus coeruleus, median

raphe, and basal forebrain; these may be important sub-

strates of somnolence, particularly in prodromal stages (De

Cock et al. 2008).

While EDS is likely a prodromal feature of PD, it is also

very common in the general population, has heterogeneous

causes and is unlikely to be useful alone as a predictive tool

for pre-motor diagnosis of PD. It may be useful in a

composite measure with other pre-motor features (e.g.,

hyposmia, dysautonomia, imaging changes).

Discussion

There is an increasing need within the field of PD, as well

as many other neurodegenerative disorders, to diagnose the

disease early in the time course, since by the time of

classical motor symptom onset there has already been

significant neuronal loss. It is also increasingly recognized

that the motor manifestations, which constitute the diag-

nosis of PD, are likely symptoms that occur at a midpoint

in a disease process beginning years earlier. The need and

urgency to find early, non-motor manifestations of PD that

are highly specific to the disorder is great, both for

development and testing of neuroprotective strategies and

eventually for routine treatment of PD with neuroprotective

agents to prevent significant neurodegeneration.

REM sleep behavior disorder is recognized as an early,

non-motor manifestation of PD and other synucleinopa-

thies. It is an easily recognized syndrome, with specific

diagnostic criteria. Over 80 % of patients will eventually

convert to a neurodegenerative phenotype, and even those

remaining clinically disease-free may convert to a neuro-

degenerative disease diagnosis. Effectively, specificity of

true iRBD for the prediction of subsequent development of

PD or related synucleinopathy approaches 100 %.

While a potential biomarker with a specificity of 100 %

for predicting development of a disorder is outstanding,

this population of pre-motor PD is not without challenges.

First, RBD is not a specific predictor of development of

PD, but rather a predictor of the development of a neuro-

degenerative synucleinopathy. Therefore, iRBD patients

would be ideal to test future neuroprotective strategies

E. J. Slow et al.

123

targeting synucleinopathies in general, not specifically PD.

Second, not every patient with PD has onset of RBD before

motor symptom onset, and some may never develop any

symptom of RBD throughout the entire disease course. In

addition, iRBD predicts a distinct clinical phenotype with

more PIGD features and greater cognitive, psychiatric and

autonomic disturbances. Therefore, targeted therapeutics

that prevent neurodegeneration in patients with iRBD, may

not be generalizable to all PD patients. Finally, there is a

long and highly variable time course between the onset of

symptoms of RBD and conversion to a neurodegenerative

disorder, in one case 50 years (Claassen et al. 2010),

making the planning of therapeutic trials challenging.

In planning for therapeutic trials, it will be necessary

to identify which patients with iRBD will convert to a

neurodegenerative disorder within a defined time period.

Research has shown that those patients with abnormal

color vision, olfactory abnormalities, mild motor dys-

function, transcranial ultrasound hyperechogenicity and

decreased putaminal DAT uptake are more likely to

convert to a neurodegenerative condition. It is likely

that a composite measure of these features will be able

to minimize both the number of patients required for

therapeutic trials and also the amount of time necessary

to determine efficacy of a given therapeutic agent.

RBD is a nocturnal manifestation of PD with increasing

evidence that it represents a prodromal or pre-motor form

of PD. This highlights the need to redefine PD (Berg et al.

2013). Within this definition, there is a need for the

development of diagnostic criteria for ‘‘prodromal’’ or

‘‘pre-motor’’ PD for at least research, if not clinical pur-

poses. RBD will be a key part of this new diagnostic par-

adigm. Prodromal criteria for PD will be essential in

moving forward into the realm of therapeutics which target

neuroprotection.

References

Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb

JD, Grandinetti A, Blanchette PL, Popper JS, Ross GW (2001)

Frequency of bowel movements and the future risk of Parkin-

son’s disease. Neurology 57(3):456–462

Abbott RD, Ross GW, White LR, Tanner CM, Masaki KH, Nelson

JS, Curb JD, Petrovitch H (2005) Excessive daytime sleepiness

and subsequent development of Parkinson disease. Neurology

65(9):1442–1446. doi:10.1212/01.wnl.0000183056.89590.0d

Albin RL, Koeppe RA, Chervin RD, Consens FB, Wernette K, Frey

KA, Aldrich MS (2000) Decreased striatal dopaminergic inner-

vation in REM sleep behavior disorder. Neurology 55(9):

1410–1412

Allen RP, Barker PB, Wehrl F, Song HK, Earley CJ (2001) MRI

measurement of brain iron in patients with restless legs

syndrome. Neurology 56(2):263–265

Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ,

Ferini-Strambi L (2005) Restless legs syndrome prevalence and

impact: REST general population study. Arch Intern Med

165(11):1286–1292

Berg D, Godau J, Walter U (2008) Transcranial sonography in

movement disorders. Lancet Neurol 7(11):1044–1055. doi:10.

1016/S1474-4422(08)70239-4

Berg D, Lang AE, Postuma RB, Maetzler W, Deuschl G, Gasser T,

Siderowf A, Schapira AH, Oertel W, Obeso JA, Olanow CW, Poewe

W, Stern M (2013) Changing the research criteria for the diagnosis of

Parkinson’s disease: obstacles and opportunities. Lancet Neurol

12(5):514–524. doi:10.1016/S1474-4422(13)70047-4

Biousse V, Skibell BC, Watts RL, Loupe DN, Drews-Botsch C,

Newman NJ (2004) Ophthalmologic features of Parkinson’s

disease. Neurology 62(2):177–180

Boeve BF (2013) Idiopathic REM sleep behaviour disorder in the

development of Parkinson’s disease. Lancet Neurol 12(5):

469–482. doi:10.1016/S1474-4422(13)70054-1

Boeve BF, Molano JR, Ferman TJ, Smith GE, Lin SC, Bieniek K, Haider

W, Tippmann-Peikert M, Knopman DS, Graff-Radford NR, Lucas

JA, Petersen RC, Silber MH (2011) Validation of the Mayo Sleep

Questionnaire to screen for REM sleep behavior disorder in an aging

and dementia cohort. Sleep Med 12(5):445–453

Boeve BF, Silber MH, Ferman TJ, Lin SC, Benarroch EE, Schmei-

chel AM, Ahlskog JE, Caselli RJ, Jacobson S, Sabbagh M, Adler

C, Woodruff B, Beach TG, Iranzo A, Gelpi E, Santamaria J,

Tolosa E, Singer C, Mash DC, Luca C, Arnulf I, Duyckaerts C,

Schenck CH, Mahowald MW, Dauvilliers Y, Graff-Radford NR,

Wszolek ZK, Parisi JE, Dugger B, Murray ME, Dickson DW

(2013) Clinicopathologic correlations in 172 cases of rapid eye

movement sleep behavior disorder with or without a coexisting

neurologic disorder. Sleep Med 14(8):754–762. doi:10.1016/j.

sleep.2012.10.015

Booij J, Tissingh G, Boer GJ, Speelman JD, Stoof JC, Janssen AG,

Wolters EC, van Royen EA (1997) [123I]FP-CIT SPECT shows

a pronounced decline of striatal dopamine transporter labelling

in early and advanced Parkinson’s disease. J Neurol Neurosurg

Psychiatry 62(2):133–140

Boot BP, Boeve BF, Roberts RO, Ferman TJ, Geda YE, Pankratz VS,

Ivnik RJ, Smith GE, McDade E, Christianson TJ, Knopman DS,

Tangalos EG, Silber MH, Petersen RC (2012) Probable rapid eye

movement sleep behavior disorder increases risk for mild

cognitive impairment and Parkinson disease: a population-based

study. Ann Neurol 71(1):49–56. doi:10.1002/ana.22655

Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak

E (2003) Staging of brain pathology related to sporadic

Parkinson’s disease. Neurobiol Aging 24(2):197–211

Calzetti S, Negrotti A, Bonavina G, Angelini M, Marchesi E (2009)

Absence of co-morbidity of Parkinson disease and restless legs

syndrome: a case-control study in patients attending a movement

disorders clinic. Neurol Sci 30(2):119–122. doi:10.1007/s10072-

009-0037-7

Cervenka S, Palhagen SE, Comley RA, Panagiotidis G, Cselenyi Z,

Matthews JC, Lai RY, Halldin C, Farde L (2006) Support for

dopaminergic hypoactivity in restless legs syndrome: a PET

study on D2-receptor binding. Brain 129(Pt 8):2017–2028

Claassen DO, Josephs KA, Ahlskog JE, Silber MH, Tippmann-Peikert

M, Boeve BF (2010) REM sleep behavior disorder preceding other

aspects of synucleinopathies by up to half a century. Neurology

75(6):494–499. doi:10.1212/WNL.0b013e3181ec7fac

Compta Y, Santamaria J, Ratti L, Tolosa E, Iranzo A, Munoz E,

Valldeoriola F, Casamitjana R, Rios J, Marti MJ (2009)

Cerebrospinal hypocretin, daytime sleepiness and sleep archi-

tecture in Parkinson’s disease dementia. Brain 132(Pt

12):3308–3317. doi:10.1093/brain/awp263

De Cock VC, Vidailhet M, Arnulf I (2008) Sleep disturbances in

patients with parkinsonism. Nat Clin Pract Neurol 4(5):254–266.

doi:10.1038/ncpneuro0775

Early diagnosis of Parkinson’s disease

123

Drouot X, Moutereau S, Nguyen JP, Lefaucheur JP, Creange A, Remy

P, Goldenberg F, d’Ortho MP (2003) Low levels of ventricular

CSF orexin/hypocretin in advanced PD. Neurology 61(4):540–543

Eisensehr I, Wetter TC, Linke R, Noachtar S, von Lindeiner H,

Gildehaus FJ, Trenkwalder C, Tatsch K (2001) Normal IPT and

IBZM SPECT in drug-naive and levodopa-treated idiopathic

restless legs syndrome. Neurology 57(7):1307–1309

Fronczek R, Overeem S, Lee SY, Hegeman IM, van Pelt J, van

Duinen SG, Lammers GJ, Swaab DF (2007) Hypocretin (orexin)

loss in Parkinson’s disease. Brain 130(Pt 6):1577–1585. doi:10.

1093/brain/awm090

Gagnon JF, Vendette M, Postuma RB, Desjardins C, Massicotte-

Marquez J, Panisset M, Montplaisir J (2009) Mild cognitive

impairment in rapid eye movement sleep behavior disorder and

Parkinson’s disease. Ann Neurol 66(1):39–47. doi:10.1002/ana.

21680

Gagnon JF, Bertrand JA, Genier Marchand D (2012) Cognition in

rapid eye movement sleep behavior disorder. Front Neurol 3:82.

doi:10.3389/fneur.2012.00082

Gao X, Schwarzschild MA, O’Reilly EJ, Wang H, Ascherio A (2010)

Restless legs syndrome and Parkinson’s disease in men. Mov

Disord 25(15):2654–2657. doi:10.1002/mds.23256

Gao J, Huang X, Park Y, Hollenbeck A, Blair A, Schatzkin A, Chen H

(2011) Daytime napping, nighttime sleeping, and Parkinson

disease. Am J Epidemiol 173(9):1032–1038. doi:10.1093/aje/

kwq478

Godau J, Sojer M (2010) Transcranial sonography in restless legs

syndrome. Int Rev Neurobiol 90:199–215. doi:10.1016/S0074-

7742(10)90015-9

Haehner A, Boesveldt S, Berendse HW, Mackay-Sim A, Fleischmann

J, Silburn PA, Johnston AN, Mellick GD, Herting B, Reichmann

H, Hummel T (2009) Prevalence of smell loss in Parkinson’s

disease—a multicenter study. Parkinsonism Relat Disord

15(7):490–494. doi:10.1016/j.parkreldis.2008.12.005

Hagell P, Broman JE (2007) Measurement properties and hierarchical

item structure of the Epworth sleepiness scale in Parkinson’s

disease. J Sleep Res 16(1):102–109

Hobson DE, Lang AE, Martin WR, Razmy A, Rivest J, Fleming J

(2002) Excessive daytime sleepiness and sudden-onset sleep in

Parkinson disease: a survey by the Canadian Movement

Disorders Group. JAMA 287(4):455–463

Iranzo A, Molinuevo JL, Santamaria J, Serradell M, Marti MJ,

Valldeoriola F, Tolosa E (2006) Rapid-eye-movement sleep

behaviour disorder as an early marker for a neurodegenerative

disorder: a descriptive study. Lancet Neurol 5(7):572–577.

doi:10.1016/S1474-4422(06)70476-8

Iranzo A, Lomena F, Stockner H, Valldeoriola F, Vilaseca I,

Salamero M, Molinuevo JL, Serradell M, Duch J, Pavia J,

Gallego J, Seppi K, Hogl B, Tolosa E, Poewe W, Santamaria J,

Sleep Innsbruck Barcelona Group (2010) Decreased striatal

dopamine transporter uptake and substantia nigra hyperechog-

enicity as risk markers of synucleinopathy in patients with

idiopathic rapid-eye-movement sleep behaviour disorder: a

prospective study corrected. Lancet Neurol 9(11):1070–1077.

doi:10.1016/S1474-4422(10)70216-7

Iranzo A, Valldeoriola F, Lomena F, Molinuevo JL, Serradell M,

Salamero M, Cot A, Ros D, Pavia J, Santamaria J, Tolosa E

(2011) Serial dopamine transporter imaging of nigrostriatal

function in patients with idiopathic rapid-eye-movement sleep

behaviour disorder: a prospective study. Lancet Neurol

10(9):797–805. doi:10.1016/S1474-4422(11)70152-1

Iranzo A, Tolosa E, Gelpi E, Molinuevo JL, Valldeoriola F, Serradell

M, Sanchez-Valle R, Vilaseca I, Lomena F, Vilas D, Llado A,

Gaig C, Santamaria J (2013) Neurodegenerative disease status

and post-mortem pathology in idiopathic rapid-eye-movement

sleep behaviour disorder: an observational cohort study. Lancet

Neurol 12(5):443–453. doi:10.1016/S1474-4422(13)70056-5

Iwanami M, Miyamoto T, Miyamoto M, Hirata K, Takada E (2010)

Relevance of substantia nigra hyperechogenicity and reduced

odor identification in idiopathic REM sleep behavior disorder.

Sleep Med 11(4):361–365. doi:10.1016/j.sleep.2009.12.006

Leentjens AF, Van der Akker M, Metsemakers JF, Lousberg R,

Verhey FR (2003) Higher incidence of depression preceding the

onset of Parkinson’s disease: a register study. Mov Disord

18(4):414–418

Loo HV, Tan EK (2008) Case-control study of restless legs syndrome

and quality of sleep in Parkinson’s disease. J Neurol Sci

266(1–2):145–149. doi:10.1016/j.jns.2007.09.033

Miyamoto T, Miyamoto M, Inoue Y, Usui Y, Suzuki K, Hirata K

(2006) Reduced cardiac 123I-MIBG scintigraphy in idiopathic

REM sleep behavior disorder. Neurology 67(12):2236–2238.

doi:10.1212/01.wnl.0000249313.25627.2e

Miyamoto T, Miyamoto M, Iwanami M, Hirata K (2010) Olfactory

dysfunction in Japanese patients with idiopathic REM sleep behavior

disorder: comparison of data using the University of Pennsylvania

smell identification test and odor stick identification test for

Japanese. Mov Disord 25(10):1524–1526. doi:10.1002/mds.23170

Mollenhauer B, Trautmann E, Sixel-Doring F, Wicke T, Ebentheuer

J, Schaumburg M, Lang E, Focke NK, Kumar KR, Lohmann K,

Klein C, Schlossmacher MG, Kohnen R, Friede T, Trenkwalder

C, DeNoPa Study Group (2013) Nonmotor and diagnostic

findings in subjects with de novo Parkinson disease of the

DeNoPa cohort. Neurology 81(14):1226–1234. doi:10.1212/

WNL.0b013e3182a6cbd5

Nomura T, Inoue Y, Miyake M, Yasui K, Nakashima K (2006)

Prevalence and clinical characteristics of restless legs syndrome

in Japanese patients with Parkinson’s disease. Mov Disord

21(3):380–384. doi:10.1002/mds.20734

Pacchetti C, Manni R, Zangaglia R, Mancini F, Marchioni E,

Tassorelli C, Terzaghi M, Ossola M, Martignoni E, Moglia A,

Nappi G (2005) Relationship between hallucinations, delusions,

and rapid eye movement sleep behavior disorder in Parkinson’s

disease. Mov Disord 20(11):1439–1448. doi:10.1002/mds.20582

Parkinson J (2002) An essay on the shaking palsy. 1817. J Neuropsy-

chiatry Clin Neurosci 14(2):223–236 (Discussion 222)

Pittock SJ, Parrett T, Adler CH, Parisi JE, Dickson DW, Ahlskog JE

(2004) Neuropathology of primary restless leg syndrome:

absence of specific tau- and alpha-synuclein pathology. Mov

Disord 19(6):695–699. doi:10.1002/mds.20042

Postuma RB, Lang AE, Massicotte-Marquez J, Montplaisir J (2006)

Potential early markers of Parkinson disease in idiopathic REM

sleep behavior disorder. Neurology 66(6):845–851. doi:10.1212/

01.wnl.0000203648.80727.5b

Postuma RB, Gagnon JF, Vendette M, Charland K, Montplaisir J

(2008a) Manifestations of Parkinson disease differ in association

with REM sleep behavior disorder. Mov Disord 23(12):

1665–1672. doi:10.1002/mds.22099

Postuma RB, Gagnon JF, Vendette M, Charland K, Montplaisir J

(2008b) REM sleep behaviour disorder in Parkinson’s disease is

associated with specific motor features. J Neurol Neurosurg

Psychiatry 79(10):1117–1121. doi:10.1136/jnnp.2008.149195

Postuma RB, Gagnon JF, Vendette M, Fantini ML, Massicotte-

Marquez J, Montplaisir J (2009a) Quantifying the risk of

neurodegenerative disease in idiopathic REM sleep behavior

disorder. Neurology 72(15):1296–1300. doi:10.1212/01.wnl.000

0340980.19702.6e

Postuma RB, Gagnon JF, Vendette M, Montplaisir JY (2009b)

Markers of neurodegeneration in idiopathic rapid eye movement

sleep behaviour disorder and Parkinson’s disease. Brain 132(Pt

12):3298–3307. doi:10.1093/brain/awp244

E. J. Slow et al.

123

Postuma RB, Gagnon JF, Rompre S, Montplaisir JY (2010a) Severity

of REM atonia loss in idiopathic REM sleep behavior disorder

predicts Parkinson disease. Neurology 74(3):239–244. doi:10.

1212/WNL.0b013e3181ca0166

Postuma RB, Lanfranchi PA, Blais H, Gagnon JF, Montplaisir JY

(2010b) Cardiac autonomic dysfunction in idiopathic REM sleep

behavior disorder. Mov Disord 25(14):2304–2310. doi:10.1002/

mds.23347

Postuma RB, Gagnon JF, Vendette M, Desjardins C, Montplaisir JY

(2011) Olfaction and color vision identify impending neurode-

generation in rapid eye movement sleep behavior disorder. Ann

Neurol 69(5):811–818. doi:10.1002/ana.22282

Postuma RB, Bertrand JA, Montplaisir J, Desjardins C, Vendette M,

Rios Romenets S, Panisset M, Gagnon JF (2012a) Rapid eye

movement sleep behavior disorder and risk of dementia in

Parkinson’s disease: a prospective study. Mov Disord

27(6):720–726. doi:10.1002/mds.24939

Postuma RB, Lang AE, Gagnon JF, Pelletier A, Montplaisir JY

(2012b) How does parkinsonism start? Prodromal parkinsonism

motor changes in idiopathic REM sleep behaviour disorder.

Brain 135(Pt 6):1860–1870. doi:10.1093/brain/aws093

Romenets SR, Gagnon JF, Latreille V, Panniset M, Chouinard S,

Montplaisir J, Postuma RB (2012) Rapid eye movement sleep

behavior disorder and subtypes of Parkinson’s disease. Mov

Disord 27(8):996–1003. doi:10.1002/mds.25086

Schenck CH, Bundlie SR, Mahowald MW (1996) Delayed emergence

of a parkinsonian disorder in 38% of 29 older men initially

diagnosed with idiopathic rapid eye movement sleep behaviour

disorder. Neurology 46(2):388–393

Schenck CH, Boeve BF, Mahowald MW (2013) Delayed emergence

of a parkinsonian disorder or dementia in 81% of older men

initially diagnosed with idiopathic rapid eye movement sleep

behavior disorder: a 16-year update on a previously reported

series. Sleep Med 14(8):744–748. doi:10.1016/j.sleep.2012.10.

009

Shin HY, Joo EY, Kim ST, Dhong HJ, Cho JW (2013) Comparison

study of olfactory function and substantia nigra hyperechoge-

nicity in idiopathic REM sleep behavior disorder, Parkinson’s

disease and normal control. Neurol Sci 34(6):935–940. doi:10.

1007/s10072-012-1164-0

Siegel JM (2006) The stuff dreams are made of: anatomical substrates

of REM sleep. Nat Neurosci 9(6):721–722. doi:10.1038/nn0606-

721

Stiasny-Kolster K, Mayer G, Schafer S, Moller JC, Heinzel-Gutenb-

runner M, Oertel WH (2007) The REM sleep behavior screening

questionnaire—a new diagnostic instrument. Mov Disord

22(16):2386–2393

Stockner H, Iranzo A, Seppi K, Serradell M, Gschliesser V, Sojer M,

Valldeoriola F, Molinuevo JL, Frauscher B, Schmidauer C,

Santamaria J, Hogl B, Tolosa E, Poewe W, Sleep Innsbruck

Barcelona Group (2009) Midbrain hyperechogenicity in idio-

pathic REM sleep behavior disorder. Mov Disord

24(13):1906–1909. doi:10.1002/mds.22483

Thannickal TC, Lai YY, Siegel JM (2007) Hypocretin (orexin) cell

loss in Parkinson’s disease. Brain 130(Pt 6):1586–1595. doi:10.

1093/brain/awm097

Trenkwalder C, Walters AS, Hening WA, Chokroverty A, Antonini

A, Dhawan V, Eidelberg D (1999) Positron emission tomo-

graphic studies in restless legs syndrome. Mov Disord 14(1):

141–145

Turjanski N, Lees AJ, Brooks DJ (1999) Striatal dopaminergic

function in restless legs syndrome: 18F-dopa and 11C-raclopride

PET studies. Neurology 52(5):932–937

Early diagnosis of Parkinson’s disease

123