BRAINA JOURNAL OF NEUROLOGY

Cerebrospinal hypocretin, daytime sleepiness andsleep architecture in Parkinsons disease dementiaYaroslau Compta,1 Joan Santamaria,2 Luca Ratti,2 Eduardo Tolosa,1 Alex Iranzo,2

Esteban Munoz,1 Francesc Valldeoriola,1 Roser Casamitjana,3 Jose Ros4 and Maria J. Marti1

1 Parkinson disease and Movement Disorders Unit, Neurology Service, Institut Clnic de Neurocie`ncies (ICN), Institut dInvestigacions Biome`diques

August Pi i Sunyer (IDIBAPS), Centro de Investigacion en Red de Enfermedades Neurodegenerativas (CIBERNED), Hospital Clnic, c./Villarroel

170, 08036, Barcelona, Catalonia, Spain

2 Multidisciplinary Sleep Disorders Unit and Neurology Service, ICN, IDIBAPS, CIBERNED, Hospital Clnic, Barcelona, Catalonia, Spain

3 Biochemistry and Molecular Genetics Laboratory, Centre de Diagno`stic Biome`dic (CDB), IDIBAPS, Hospital Clnic, Barcelona, Catalonia, Spain

4 Statistics and Methodologic Support Unit, Unitat dAvaluacio, Suport i Prevencio (UASP), Hospital Clnic, IDIBAPS, Barcelona, Catalonia, Spain

Correspondence to: Maria J. Marti, MD, PhD,

Movement Disorders Unit,

ICN, IDIBAPS, CIBERNED,

Hospital Clnic, c./Villarroel 170,

08036, Barcelona,

Spain

E-mail: mjmarti@clinic.ub.es

Excessive daytime sleepiness is common in Parkinsons disease and has been associated with Parkinsons disease-related

dementia. Narcoleptic features have been observed in Parkinsons disease patients with excessive daytime sleepiness and

hypocretin cell loss has been found in the hypothalamus of Parkinsons disease patients, in association with advanced disease.

However, studies on cerebrospinal fluid levels of hypocretin-1 (orexin A) in Parkinsons disease have been inconclusive. Reports

of sleep studies in Parkinsons disease patients with and without excessive daytime sleepiness have also been disparate,

pointing towards a variety of causes underlying excessive daytime sleepiness. In this study, we aimed to measure cerebrospinal

fluid hypocretin-1 levels in Parkinsons disease patients with and without dementia and to study their relationship to dementia

and clinical excessive daytime sleepiness, as well as to describe potentially related sleep architecture changes. Twenty-one

Parkinsons disease patients without dementia and 20 Parkinsons disease patients with dementia, along with 22 control

subjects without sleep complaints, were included. Both Epworth sleepiness scale, obtained with the help of the caregivers,

and mini-mental state examination were recorded. Lumbar cerebrospinal fluid hypocretin-1 levels were measured in all indivi-

duals using a radio-immunoassay technique. Additionally, eight Parkinsons disease patients without dementia and seven

Parkinsons disease patients with dementia underwent video-polysomnogram and multiple sleep latencies test. Epworth sleep-

iness scale scores were higher in Parkinsons disease patients without dementia and Parkinsons disease patients with dementia

than controls (P50.01) and scores410 were more frequent in Parkinsons disease patients with dementia than in Parkinsonsdisease patients without dementia (P = 0.04). Cerebrospinal fluid hypocretin-1 levels were similar among groups (con-

trols = 321.15 47.15 pg/ml; without dementia = 300.99 58.68 pg/ml; with dementia = 309.94 65.95 pg/ml; P = 0.67), andunrelated to either epworth sleepiness scale or mini-mental state examination. Dominant occipital frequency awake was

slower in Parkinsons disease patients with dementia than Parkinsons disease patients without dementia (P = 0.05). Presence

of slow dominant occipital frequency and/or loss of normal non-rapid eye movement sleep architecture was more frequent

among Parkinsons disease patients with dementia (P = 0.029). Thus, excessive daytime sleepiness is more frequent in

Parkinsons disease patients with dementia than Parkinsons disease patients without dementia, but lumbar cerebrospinal

doi:10.1093/brain/awp263 Brain 2009: 132; 33083317 | 3308

Received May 13, 2009. Revised August 25, 2009. Accepted August 27, 2009. Advance Access publication October 25, 2009

The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.For Permissions, please email: journals.permissions@oxfordjournals.org

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fluid hypocretin-1 levels are normal and unrelated to severity of sleepiness or the cognitive status. Lumbar cerebrospinal fluid

does not accurately reflect the hypocretin cell loss known to occur in the hypothalamus of advanced Parkinsons disease.

Alternatively, mechanisms other than hypocretin cells dysfunction may be responsible for excessive daytime sleepiness and

the sleep architecture alterations seen in these patients.

Keywords: Parkinsons disease; dementia; excessive daytime sleepiness; hypocretin-1; sleep architecture

Abbreviations: EDS = excessive daytime sleepiness; ESS = Epworth sleepiness scale; MMSE = mini-mental state examination;MSLT = multiple sleep latency test; RBD = REM sleep behaviour disorder; REM = rapid eye movement; UPDRS = Unified ParkinsonDisease Rating Scale; vPSG = video-polysomnography

IntroductionExcessive daytime sleepiness (EDS) is frequent in Parkinsons

disease and its presence has been associated with longer disease

duration and dementia in epidemiological and case-series studies

(Gjerstad et al., 2002; Boddy et al., 2007). In addition, EDS is

currently part of the proposed criteria for Parkinsons disease-

related dementia as a supporting feature (Emre et al., 2007).

However, studies specifically addressing EDS in Parkinsons

disease-related dementia are lacking.

The ultimate cause of EDS in Parkinsons disease is unknown,

although factors such as dopaminergic medications, motor disabil-

ity or the neurodegenerative process itself have been implicated

(Arnulf et al., 2002; Gjerstad et al., 2006). The presence in some

Parkinsons disease patients of narcolepsy-like features, such as

daytime rapid eye movement (REM) sleep intrusions

associated with visual hallucinations and sleep onset REM periods

in the multiple sleep latency test (MSLT), has led some authors to

suggest that a mechanism similar to that of narcolepsy might under-

lie EDS in Parkinsons disease (Arnulf et al., 2000). However,

cerebrospinal fluid (CSF) levels of hypocretin-1, which are typically

low in narcolepsy (Nishino et al., 2001), have been normal in all

available studies in Parkinsons disease (Overeem et al., 2002;

Baumann et al., 2005; Yasui et al., 2006), except for one using

ventricular CSF (Drouot et al., 2003). All of these studies, however,

either included a small number of patients or evaluated patients with

only mild to moderate disease severity, without much information

on EDS or sleep architecture characteristics. In contrast, two recent

pathological studies have reported significant hypocretin cell loss in

the hypothalamus of Parkinsons disease patients (Fronczek et al.,

2007; Thannickal et al., 2007), with one of them showing a

significant association between hypocretin cell loss and disease

severity (Fronczek et al., 2007). Hence, the possibility that

neurodegeneration of the hypocretin system is related to EDS in

advanced disease cannot be excluded.

Other potential contributors to EDS in Parkinsons disease are

night time sleep disorders (Arnulf et al., 2002) or impairment of

sleep architecture. Few studies using video-polysomnography

(vPSG) have reported altered sleep architecture in Parkinsons

disease (Emser et al., 1988), in association with disease duration

rather than disease severity (Diederich et al., 2005), with no

mention of its relation with cognitive impairment or dementia.

In this study, we aimed to explore the hypothesis that CSF

hypocretin-1 levels are lower in subjects with Parkinsons

disease-related dementia than in Parkinsons disease patients

with no dementia, and to assess their relationship with clinically

defined EDS. As a secondary objective, we tried to evaluate the

relationship between presence of dementia and EDS and the find-

ings of sleep tests with the secondary hypothesis that a variety of

abnormalities in sleep tests may constitute additional factors con-

tributing to EDS in Parkinsons disease patients.

Methods

PatientsAs a part of an ongoing project on biomarkers of dementia in

Parkinsons disease, 46 Parkinsons disease patients from the

Parkinson Disease and Movement Disorders Unit were asked to

participate in this study between February 2007 and December

2007. Forty-one agreed. All patients were diagnosed according to

United Kingdom Parkinson Disease Society Brain Bank diagnostic

criteria (Hughes et al., 1992). At the time of inclusion, 20 of the

Parkinsons disease patients fulfilled the Movement Disorder Society

diagnostic criteria for Parkinsons disease-related dementia as well as

the Diagnostic and Statistical Manual of Mental Disorders revised

fourth edition criteria for dementia (American Psychiatric Association,

2000; Emre et al., 2007). The control group included 22 subjects

admitted for knee surgery with intradural anaesthesia during the

recruitment period. These individuals were matched with patients

groups for age, and did not suffer from any known psychiatric or

neurodegenerative disease.

The study was approved by the Ethical Committee of our institution.

All subjects (or their caregiver in the case of patients) gave their

informed written consent, according to the Declaration of Helsinki

(Br Med J, 1991; 302; 1194), after full explanation of all the

procedures.

Procedures

Demographic and clinical variables

Age, gender, years of education and both Mini-Mental State

Examination (MMSE) (Folstein et al., 1975) and Epworth Sleepiness

Scale (ESS) (Johns, 1991) scores were obtained from all study subjects.

The interviews were always performed in the presence of the care-

givers, whose comments were taken into consideration when answer-

ing the ESS, particularly in Parkinsons disease patients with dementia,

but also in Parkinsons disease patients without dementia. Subjects

with an ESS score 410 were considered to have EDS (Johns, 1991).

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Years of disease duration, presence of visual hallucinations but not

during changes in dosage of anti-parkinsonian drugs or intercurrent

illness, motor severity assessed by Part III of the Unified Parkinson

Disease Rating Scale (UPDRS-III) (Fahn et al., 1987) in overnight-off

condition before the lumbar puncture, and disease stage by means of

Hoehn and Yahr classification (1967), were recorded from all

Parkinsons disease patients at their inclusion. Anti-parkinsonian and

psychotropic medications were obtained from all subjects, and the

equivalent L-dopa dose was calculated as reported elsewhere

(Wenzelburger et al., 2002).

Lumbar puncture

All patients and controls underwent lumbar puncture at L3L4 space

using a 22G needle. For Parkinsons disease patients, the lumbar punc-

ture was performed before the morning dose of the anti-parkinsonian

medications.

CSF hypocretin determination

The collected CSF was immediately centrifuged for 10 min at 4000g

and 4C, and subsequently stored at 80 in 400ml aliquots until finalanalysis. CSF hypocretin-1 levels were determined with commercially

available direct radio-immunoassay kit (Phoenix Pharmaceuticals,

Belmont, CA, USA) as described elsewhere (Nishino et al., 2001). In

order to minimize inter-assay variation, reference samples with internal

controls with known hypocretin-1 values were included in each assay

and the values were adjusted accordingly, as recommended (Nishino

et al., 2005).

Sleep studies

Sixteen of the Parkinsons disease patients (eight without and eight

with dementia) underwent a one-night vPSG, followed by MSLT

the following day. Reasons for rejection or exclusion from the

sleep studies were: (i) severe physical disability; (ii) nocturnal disorien-

tation and confusion and (iii) caregiver not available to accompany

the patient during the vPSG study. One Parkinsons disease patient

with dementia did not tolerate the procedure. The sleep studies were

evaluated by investigators unaware of the clinical features.

vPSG was performed with a digital polygraph (Deltamed, Paris,

France) including EEG (O1, O2, C3, C4 referred to A1+A2),

electrooculogram, surface electromyography from chin, bilateral

biceps brachii and bilateral tibialis anterior muscles, electrocardio-

gram, nasal and oral air flow, thoracic and abdominal effort and

oxygen saturation with synchronized audiovisual recording. Visual

scoring of sleep stages were according to the American Academy of

Sleep Medicine criteria (Iber et al., 2007), except for the fact that

frontal derivations were not used and REM sleep was scored even

without muscular atonia when the polygraphic features suggested

REM sleep behaviour disorder (RBD).

MSLTs were performed according to the standard procedures

(Littner et al., 2005) and started 23 h after finishing the nocturnal

vPSG study with nap times at 9:30, 11:30, 13:30, 15:30 and 17:30 h.

Statistical analysisAn a priori statistical power calculation was carried out for the first

hypothesis of this study using nQuery v4.0 software (MTT0-1

method). A sample size of 20 in each group was calculated to have

80% power to detect a difference of 70 pg/ml in CSF hypocretin-1

concentration means, assuming a common standard deviation of

76 pg/ml, with a 0.05 two-sided significance level. The difference in

means and the common standard deviation were defined considering

CSF hypocretin-1 levels in controls and other neurological diseases

from previous studies (Martinez-Rodriguez et al., 2003, 2007) in

order to identify clinically relevant rather than marginal differences.

As for the second objective of this study, no power calculation was

performed since it was an exploratory study of a subset of the original

sample.

The statistical analysis was performed using Statistical package for

the Social Sciences 15.0 software (SPSS Inc, Chicago, Ill, USA). Chi-

square test or Fishers exact test was used for comparison between

qualitative variables, with data being expressed as percentages or

number of cases. Comparison of quantitative variables among all

three groups was established by KruskalWallis test followed by

MannWhitney test for pair-wise comparisons, with data presented

as mean SD except where otherwise stated. Comparative analyseswere performed between the groups of Parkinsons disease patients

with and without dementia, and between Parkinsons disease subjects

with ESS scores 410 and those with scores 410, regardless of thedementia classification. Differences in proportion of patients with

high ESS between groups were estimated, applying a general linear

model with a binomial distribution of the dependent variable, and

where the post hoc pair-wise comparisons (control versus Parkinsons

disease patients without dementia; control versus Parkinsons disease

patients without dementia; and Parkinsons disease patients without

dementia versus Parkinsons disease patients with dementia) were

assessed by means of the least significant difference method. The

results of this analysis consist of means of estimation of the proportion

of patients with high ESS score with the corresponding 95% confi-

dence interval. Spearmans correlation coefficient between quantitative

variables was also calculated.

Level of statistical significance was established at P4 0.05(two-tailed). Due to the presence of a priori hypotheses and the

exploratory nature of the neurophysiological sleep sub-study, the sig-

nificant results shown are uncorrected for multiple comparisons (Begg

et al., 1996; Perneger, 1998).

Results

Demographic and basic clinical dataThe three study groups did not differ in age or gender. Disease

duration was not different between Parkinsons disease patients

with or without dementia (mean SD: 10.2 4.5 versus10.15 6.9, respectively). Parkinsons disease patients withdementia were at a more advanced stage of the disease, as

measured by Hoehn and Yahr (1967) staging, despite similar

UPDRS-III scores, had more visual hallucinations and were on a

lower average equivalent L-dopa dose (Table 1; Supplementary

Table 1). There were no significant differences in either

demographic or clinical features of the patients who underwent

sleep studies and those who did not, except for a smaller

proportion of females among the former group (Supplementary

Table 2).

Epworth sleepiness scale scoresBoth Parkinsons disease patients with and without dementia

had higher ESS scores than controls (Parkinsons disease patients

without dementia = 10.34 5.60; Parkinsons disease patientswith dementia = 13.25 5.00; controls = 5.32 2.73) (globalcomparison: P50.001; pair-wise comparisons between

3310 | Brain 2009: 132; 33083317 Y. Compta et al.

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Parkinsons disease patients with and without dementia with con-

trols: P50.01). ESS scores did not differ between Parkinsonsdisease patients with and without dementia (P= 0.063), despite

somewhat higher scores among Parkinsons disease patients with

dementia. Abnormal ESS scores (410) were significantly morefrequent in Parkinsons disease patients with dementia than

those without (P= 0.04) (Table 1). In order to assess the gradation

from less to more sleepiness, according to ESS scores, through the

three study groups (controls, Parkinsons disease patients without

and those with dementia), pair-wise comparisons between groups

were conducted applying a general linear model for the proportion

of subjects with ESS 510 (this more conservative criterionwas used in this case as none of the controls scored 410).The proportion of subjects with ESS scores 510 was smaller inthe control group than in both groups of Parkinsons disease

patients (with and without dementia) (P50.001), withParkinsons disease patients without dementia having a lower

proportion groups of Parkinsons disease patients (with and with-

out dementia) ESS scores 510 than Parkinsons disease patientswith dementia (P= 0.022) (Fig. 1; Supplementary Table 3). ESS

scores were not significantly related to any other demographic or

clinical variables, except for higher scores in patients with visual

hallucinations (P= 0.047). There was no correlation between ESS

and any of the quantitative demographic and clinical variables,

except for a weak negative correlation between MMSE and ESS

scores in the analysis of all Parkinsons disease patients (r= 0.33;

P= 0.053; Supplementary Table 4).

When classifying Parkinsons disease patients as having high or

normal ESS scores, those with high scores were significantly older,

had more visual hallucinations, scored less on the MMSE and were

on a lower equivalent L-dopa dose. However, there were no dif-

ferences regarding the intake of dopamine agonists between these

two ESS-defined groups (Table 2).

ESS scores were not higher among Parkinsons disease patients

taking psychotropic drugs known to be potentially sedative

(benzodiazepines, anti-depressants or neuroleptics) (n= 24 versus

17; P= 0.45). The set of Parkinsons disease patients who under-

went sleep studies and were taking such drugs (two out of eight

Parkinsons disease patients without dementia and five out of

seven Parkinsons disease patients with dementia) did not have

the highest ESS scores.

CSF levels of hypocretin-1There were no differences in CSF hypocretin-1 levels among

the three groups (in pg/ml: controls = 321.15 47.15;

Table 1 Comparison of demographic and clinical data, including MMSE and ESS scores, across the three study groups

Controls (n = 22) PDND (n = 21) PDD (n = 20) P-value

Age 70.4 9 68.8 6.9 72.5 7.14 0.20Gender (females) 12 (55%) 9 (42%) 11 (55%) 0.1

Disease duration 10.19 4.5 10.15 6.8 0.50Time to dementia 8.65 (6.71) NA

Visual hallucinations 0 (0%) 9 (42.9%) 20 (100%) 50.001a

UPDRS III off 32.65 16.12 36.00 9.35 0.09Hoehn and Yahroff III IV 0.02

Equivalent L-dopa dose 1046.5 399.53 739.75295.60 0.01Dopamine agonists 8 (38%) 6 (30%) 0.74

MMSE 29.23 1.1 27.9 1.6 17.75 4.75 50.001bESS score 5.32 2.73 10.34 5.60 13.25 5.00 50.005b,cAltered ESS (= EDS) None (0%) 8 (34%) 14 (70%) 0.04

All data are expressed as mean SD except gender, presence of visual hallucinations and use of dopamine agonists, as number of subjects with percentage withinparentheses, and Hoehn and Yahr as mean only. All temporal data are expressed in years.a Significant differences between PDD and PDND.

b Significant differences between PDD and controls and between PDND and controls.c Non-significant trend between PDD and PDND (P= 0.063). PDD = Parkinsons disease patients with dementia; PDND = Parkinsons disease patients without dementia

Figure 1 Proportion of subjects with ESS scores410 in thethree study groups. Standard error bar diagram, where dots

represent mean and bars represent two times the SE of the

proportion of subjects with ESS scores410 in each study group(controls = 0.05 0.21; PDND = 0.52 0.51;PDD = 0.80 0.41). The pair-wise differences (with the 95%confidence interval within parentheses) in this proportion were

significant: PDNDcontrols = 0.48 (0.250.71), P50.001;PDDcontrols = 0.75 (0.520.99), P50.001; PDDPDND = 0.28 (0.510.04), P= 0.022. PDD = Parkinsons disease

patients with dementia; PDND = Parkinsons disease patients

without dementia

CSF hypocretin and sleepiness in Parkinson dementia Brain 2009: 132; 33083317 | 3311

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Parkinsons disease patients without dementia = 300.99 58.68;Parkinsons disease patients with dementia = 309.94 65.95;P= 0.67) (Fig. 2). There was also no difference when comparing

Parkinsons disease patients with ESS scores410 with those whoscored 410 (300.60 57.48 versus 309.46 66.20, respectively;P= 0.49), or those with and without visual hallucinations

(304.53 68.15 versus 302.76 49.90, respectively; P= 0.72).There were no significant correlations between CSF hypocretin-1

levels and ESS (r= 0.02; P= 0.8) or MMSE scores (r= 0.08;

P= 0.6) in Parkinsons disease patients.

The CSF levels of hypocretin-1 did not differ between the subset

of Parkinsons disease patients with and without dementia who

underwent sleep studies and those that did not (in pg/ml:

292.78 79.48 versus 302.07 84.97; P= 0.45).

vPSG resultsOf the 15, 10 patients studied with vPSG (four Parkinsons disease

patients without dementia: Patients 1, 3, 14, 18; and six with

dementia: Patients 6, 7, 10, 16, 18 and 19), sleep could not be

scored using standard American Academy of Sleep Medicine cri-

teria, due to an altered non-REM sleep architecture. The abnorm-

alities detected consisted of at least two of the following findings: (i)

slow dominant occipital frequency awake that made it difficult to

identify the onset of stage-1 non-REM sleep (eight patients); (ii)

irregular, continuous or almost continuous, medium-amplitude

delta activity during the whole sleep recording (all 10 cases),

which did not allow for the different non-REM sleep stages to be

distinguished; (iii) persistence during behavioural sleep of a poster-

ior-dominant alpha/theta activity at least 1 Hz slower than the dom-

inant occipital rhythm during wakefulness (eight patients) and (iv)

absence of well-defined sleep spindles or K-complexes, the hall-

marks of stage N2 (8 and all 10 cases, respectively).

Altered non-REM sleep and/or slow dominant occipital fre-

quency was more frequent in Parkinsons disease patients with

dementia than in those patients without (P= 0.029). Parkinsons

disease patients with dementia had significantly slower dominant

occipital frequency than Parkinsons disease patients without

dementia [median: 6 Hz (percentile 2575: 67.5) versus median:

8.3 Hz (percentile 2575: 79.3) Hz; P= 0.05]. REM sleep was pre-

sent in all but one of the eight Parkinsons disease patients without

dementia. In five of these patients, RBD was present, three of them

with visual hallucinations. Four Parkinsons disease patients with

dementia (n= 7) did not have REM sleep and the other three had

RBD. Presence of RBD in these patients was not associated with the

presence of visual hallucinations (data not shown).

Parkinsons disease patients with dementia had shorter total

sleep time than those patients without dementia (240.6 106.2versus 334.6 106.6); however, this difference was non-significant(P= 0.18). Differences in the number of awakenings longer than

1 min (29.6 20.1 versus 18.6 10.6) or number of arousals perhour of sleep (26.2 20.1 versus 31.9 16.7) were also not signif-icant (P= 0.34 and 0.3, respectively).

Table 2 Comparison of demographic and clinical data between Parkinsons disease patients with ESS scores410 andthose with scores 410

Parkinsons disease with ESS 410 (n = 19) Parkinsons disease with ESS410 (n = 22) P-value

Age 68.21 6.87 72.68 6.99 0.033 aGender (females) 10 (52%) 10 (45%) 0.76

Disease duration 9.83 4.49 11.00 6.66 0.53Visual hallucinations 10 (52%) 19 (86%) 0.037 a

UPDRSoff 33.50 16.52 35.00 9.86 0.21Hoehn and Yahroff III III.5 0.49

Equivalent L-dopa dose 1043.33423.24 770.23 296.84 0.017 aDopamine agonists 6 (31%) 8 (36%) 1.00

MMSE 25.11 4.96 21.05 6.63 0.039 a

All data expressed as mean SD except gender, presence of visual hallucinations and use of dopamine agonists, as number of subjects with percentage withinparentheses, and Hoehn and Yahr as mean only. All temporal data expressed in years.

a Significant differences.

Figure 2 Box diagrams of CSF hypocretin-1 levels in the threestudy groups. Global and pair-wise comparison of the means

resulted in no significant differences (see text and Table 2). The

two outsiders showing the lowest levels had: two sleep onset

REM periods (subject PDND 14; CSF hypocretin-1 concentra-

tion: 115.93 pg/ml), and the shortest sleep latency of the

sample (subject PDD 18; CSF hypocretin-1 concentration:

196.75 pg/ml), respectively. PDD = Parkinsons disease patients

with dementia; PDND = Parkinsons disease patients without

dementia

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Tab

le3

Findin

gs

of

vPSG

and

MSL

Tre

cord

ings

inpat

ients

wit

hPar

kinso

ns

dis

ease

,w

ith

and

wit

hout

dem

enti

a

Pat

ient

#S

a-f

req

a-

inS

spfr

eqK

RB

DTST

AW4

1A

rousa

lin

dex

AH

IPLM

SM

SLT

mea

nla

tSO

REM

PES

SC

SFhyp

ocr

-1D

rugs

Par

kinso

ns

dis

ease

pat

ients

without

dem

entia

1P

6.0

+

172

15

36.7

35.0

20

18

315.2

0

3P

8.5

+

R

NR

228

28

52.0

0.0

01134

010

371.8

7

11

N10.5

15

+

331

21

18.0

7.8

096

19

305.8

9

12

N9.0

15

+

388

31

20.1

0.0

06

341.6

9

14

P7.0

+12

+

473

35.4

1.3

0258

214

115.9

3C

NZ

0-0

-0.5

18

P7.0

+

+

432

750.2

38.1

0606

09

388.9

7C

NZ

0-0

-0.5

19

N9.5

13

++

255

30

28.8

22.2

0408

022

314.4

1

20

N8.0

13

++

398

14

44.3

40.0

0384

015

262.6

1

Sum

mar

y8.3

[79

.3]

38%

13.6

1.3

471%

334.6

106.6

18.6

10.6

31.9

16.7

18.0

17.8

481.0

361.9

12.9

5.4

302.0

7

84.9

7Par

kinso

ns

dis

ease

pat

ients

with

dem

entia

6P

6.0

+

R

NR

163

26

80.4

0600

15

368.8

5Q

TP

0-0

-25

7P

6.0

+

R

NR

84

73

0.7

0375

217

241.4

7Q

TP

0-0

-100

DPZ

0-0

-10

10

P7.5

+

+264

21

52

0.2

43.6

18

419.1

9D

PZ

0-0

-10

15

N6.0

13

++

284

55.5

2.3

01200

013

227.7

5R

VT

4.5

-0-3

VFX

75-0

-75

CN

Z0.5

-0-0

-1A

PZ

0.2

5-0

.25-0

16

P9.0

+

403

728.5

24.8

1318

011

298.9

2PX

20-0

-0Q

TP

0-0

-50

CN

Z0-0

-0.5

18

P6.0

+11

R

NR

308

55

48

29.3

184

08

196.7

5R

VT

3-0

-3

19

P6.5

+

RN

R179

20

15.4

43.8

0330

121

296.5

7

Sum

mar

y6

[67

.5]

71%

12.0

1.4

1100%

240.6

106.2

29.6

25.2

26.2

20.1

14.5

17.9

484.5

387.1

14.7

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CSF hypocretin and sleepiness in Parkinson dementia Brain 2009: 132; 33083317 | 3313

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The apnoeahypopnoea index and the periodic leg movement

index were not different between Parkinsons disease patients with

and without dementia (Table 3). None of the quantitative vPSG

variables correlated with the ESS scores, except for a mild negative

correlation with total sleep time, indicating that the longer the

sleep duration at night the lower the sleepiness (r= 0.55;

P= 0.041) (Supplementary Table 5). We were not able to associate

any of these features with the use of psychotropic drugs (data not

shown). We found no correlation between any of the vPSG

variables and the ESS.

Multiple sleep latencies test resultsThere were no differences in mean sleep latency between

Parkinsons disease patients with and without dementia (in seconds:

481.0 361.9 versus 484.5 387.1; P= 0.81) or Parkinsons diseasewith ESS410 versus Parkinsons disease with ESS410 (in seconds:480.50 498.76 versus 484.12 306.15; P= 0.73) (Table 3).

Sleeep onset REM periods were observed in two Parkinsons

disease patients without dementia (one with a normal and one

with an abnormal sleep pattern) and two Parkinsons disease

patients with dementia (both with abnormal sleep pattern).

There was no relation between the apnoeahypopnoea index or

periodic leg movement in sleep index or sleep fragmentation

and the MSLT latency.

The mean sleep latency in the MSLTs did not show any corre-

lation with either the ESS scores (Spearman test: r= 0.19; P= 0.54)

(Supplementary Table 5) or the CSF hypocretin-1 levels (Spearman

test: r= 0.49; P= 0.10). However, in the two patients with the

lowest CSF hypocretin levels (Parkinsons disease without demen-

tia, Patient 14: 115.93 pg/ml; Parkinsons disease with dementia,

Patient 18: 196.75 pg/ml) one had two sleep onset REM periods

and the other had the shortest sleep latency (Table 3).

DiscussionIn this study, lumbar CSF hypocretin-1 levels were similar in

Parkinsons disease patients and controls and were not associated

with the cognitive status, presence of visual hallucinations, ESS

scores or vPSG and MSLT results. However, ESS scores were

higher in the Parkinsons disease patients (with and without

dementia) than in the control group, and EDS defined as

ESS410 was more frequent in the Parkinsons disease patientswith dementia subgroup. In the subset of patients who underwent

sleep studies, Parkinsons disease patients with dementia showed

a slower dominant occipital frequency awake and a more frequent

loss of the normal sleep architecture.

In a population-based study, EDS in Parkinsons disease was

related to disease progression and subsequent dementia

(Gjerstad et al., 2002). In addition, EDS has recently been included

in the clinical diagnostic criteria for Parkinsons disease patients

with dementia (Emre et al., 2007). However, the relative fre-

quency of EDS in Parkinsons disease patients with and without

dementia has seldom been assessed. In one study, where EDS was

shown to be more frequent in Parkinsons disease patients with

dementia than in controls or Alzheimers disease patients,

differences in ESS between Parkinsons disease patients without

and those with dementia were not significant, despite somewhat

higher scores in the latter group (Boddy et al., 2007). In other

studies, EDS has been linked to disease duration, advanced disease

and older age, as well as to cognitive impairment in non-

demented Parkinsons disease patients (Tandberg et al., 1999;

Ondo et al., 2001; Arnulf et al., 2002; Gjerstad et al., 2006).

Recently, the Sydney Multicenter Study of Parkinsons disease

has shown that after 20 years of follow-up, 83% of the patients

have dementia and 70% EDS (Hely et al., 2008). In contrast,

other studies have not found any link between EDS and cognition

in Parkinsons disease, probably due to the study design being

focused on EDS rather than cognitive impairment (Arnulf et al.,

2002; Gjerstad et al., 2006; Shpirer et al., 2006). In our study,

both non-demented and demented Parkinsons disease patients

had higher ESS scores than controls, and the number of patients

with ESS scores 410 was higher in Parkinsons disease patientswith dementia than those patients without. The weak, borderline

significant correlation between MMSE and ESS scores would also

be in line with the notion that cognitive impairment and sleepiness

are associated in Parkinsons disease.

We found CSF levels of hypocretin-1 in Parkinsons disease to

be in a similar range to a large and neurologically unimpaired

control group, with no significant associations with ESS, MMSE

or disease duration. Normal CSF hypocretin levels in our sample

agreed with all previous studies assessing lumbar CSF levels of

hypocretin-1 (Overeem et al., 2002; Baumann et al., 2005;

Yasui et al., 2006). The only two studies showing low CSF

hypocretin levels in Parkinsons disease measured hypocretin-1 in

ventricular CSF (Drouot et al., 2003; Fronczek et al., 2007).

Therefore, it is possible that lumbar CSF levels of hypocretin-1

may not accurately reflect the hypocretin cell loss shown in

pathology studies (Fronczek et al., 2007; Thannickal et al.,

2007). Another reason may be that CSF hypocretin-1 levels only

drop when hypothalamic hypocretin neurons decrease above 70%

(Gerashchenko et al., 2003), whereas the hypocretin cell loss

shown to occur in Parkinsons disease is570%, even in advanceddisease stages (Thannickal et al., 2007). Since a widespread

neurodegeneration occurs in advanced Parkinsons disease,

impairment of sleep-related structures other than the hypocretin

system may account for EDS in Parkinsons disease (Arnulf et al.,

2002; Baumann et al., 2007; Fronczek et al., 2008 Thannickal

et al., 2008).

Normal CSF hypocretin-1 levels, along with the lack of narco-

leptic-like findings in MSLT studies, do not support the view that

EDS in Parkinsons disease patients has a narcoleptic basis (Arnulf

et al., 2000). However, the two Parkinsons disease cases with the

lowest CSF hypocretin levels, despite being higher than the

diagnostic cut-off for narcolepsy (110 pg/ml) (Mignot et al.,

2002), had two sleep onset REM periods and the shortest sleep

latency, respectively. Therefore, elements of a narcoleptic-like

phenotype may occasionally be seen in Parkinsons disease

(Maeda et al., 2006).

The sleep architecture in both REM and non-REM sleep was

particularly abnormal in Parkinsons disease patients with demen-

tia. RBD occurred in all the Parkinsons disease patients with

dementia where REM sleep could be identified. Previous studies

3314 | Brain 2009: 132; 33083317 Y. Compta et al.

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have found that RBD is associated with cognitive impairment in

non-demented Parkinsons disease patients (Vendette et al.,

2007). Five of our eight Parkinsons disease patients without

dementia had RBD, and three of them also had visual hallucina-

tions, which have also been linked to progression to dementia in

Parkinsons disease (Ramirez-Ruiz et al., 2007).

Our finding of slower dominant occipital frequency awake in

Parkinsons disease patients with dementia when compared to

those without dementia is in agreement with previous awake

EEG studies in Parkinsons disease with dementia and dementia

with Lewy bodies, two entities sharing clinical and pathological

features (Neufeld et al., 1998; Domitrz et al., 1999; Bonanni

et al., 2008; Roks et al., 2008). Slowing of the dominant occipital

frequency also occurs in Alzheimers disease, where a cholinergic

deficiency has been implicated in such awake EEG abnormalities

(Riekkinen et al., 1991). Since a cholinergic deficiency is also

prominent in Parkinsons disease patients with dementia (Hilker

et al., 2005) and treatment with acetylcholinesterase inhibitors

increases the EEG frequency awake (Fogelson et al., 2003), cho-

linergic dysfunction might underlie these abnormalities. Posterior

cortical impairment shown in a perfusion SPECT study in

Parkinsons disease patients with dementia could also be linked

with slower dominant occipital frequency (Mito et al., 2005).

To date, polysomnographic studies in Parkinsons disease have

shown abnormalities in sleep architecture such as sleep fragmen-

tation, increase of stage 1 sleep and reductions in the REM sleep

amount (Emser et al., 1988). However, the pattern of changes in

non-REM sleep we have described, and its higher frequency in

Parkinsons disease patients with dementia as compared with

those without dementia, have not been reported previously. It is

uncertain, however, whether these changes can be explained by

the above mentioned cholinergic deficit or not.

The mean sleep latency on the MSLT was not correlated with

any vPSG variable, reflecting in part the difficulties in detecting

sleep onset with conventional criteria in these patients. Sleepiness

measured with the ESS was only negatively associated with the

amount of nocturnal sleep in the vPSG. That is, the longer the

sleep time at night, the lower the daytime sleepiness, suggesting

that advanced Parkinsons disease patients might be sleep

deprived, either by motor problems at night, alerting effects of

medications or degeneration of sleep related structures. The lack

of association between daytime sleepiness and the apnoea

hypopnoea index suggests that EDS in this group of Parkinsons

disease patients has a complex origin (Arnulf et al., 2002).

Our study did not show a relationship between EDS and higher

equivalent L-dopa dose or intake of dopamine agonist (Gjerstad

et al., 2006). In fact, we found that both Parkinsons disease

patients with dementia and Parkinsons disease patients with ESS

scores410, were on lower equivalent L-dopa doses. Even thoughL-dopa has been associated with improved subjective alertness in

Parkinsons disease (Molloy et al., 2006), we interpreted such

lower equivalent L-dopa doses as a consequence of the common

clinical practice of reducing anti-parkinsonian medications in

patients prone to confusion and hallucinations, such as in patients

with dementia, rather than the cause of their EDS.

Since Parkinsons disease patients with dementia received more

hypnotic, anti-depressant and neuroleptic medications than

Parkinsons disease patients without dementia, we cannot exclude

that EDS and the above discussed vPSG abnormalities could be

related to these medications (Parrino et al., 1996; Bell et al., 2003;

Cohrs et al., 2004). We could not find a clear relationship

between drug treatment and presence of sleep alterations or

EDS. Although quetiapine or paroxetine decrease the amount of

REM sleep and could be responsible for the absence of REM sleep

in three of the studied Parkinsons disease patients with dementia

(Parrino et al., 1996; Schlosser et al., 1998; Bell et al., 2003;

Cohrs et al., 2004; Barbanoj et al., 2005), this feature was also

present in patients not taking any of these drugs. Furthermore,

benzodiazepines increase, rather than decrease, the number of

sleep spindles and thus are unlikely to be responsible for the

lack of sleep spindles in Parkinsons disease patients with dementia

(Rye, 2003). Finally, all the pathologic features described above

were also found in the only Parkinsons disease patient with

dementia taking no psychotropic medications.

Our study has both strengths and limitations. The strengths are

that the patients were classified according to currently accepted

criteria for Parkinsons disease and Parkinsons disease with

dementia. Presence or absence of EDS was not used to select

the patients of the study. The control group, consisting of indivi-

duals not suffering from any known neurodegenerative disease or

serious psychiatric illness, wasto our knowledgethe largest

control group included to date in a study of CSF levels of hypo-

cretin-1 in Parkinsons disease. Moreover, the study was statisti-

cally powered to assess differences in CSF hypocretin-1

concentrations between the study groups. As limitations, we

have to acknowledge a potential selection bias due to the conve-

nience sample and the referral centre setting. ESS is an auto-

administered scale, however, since the caregivers often contribu-

ted to completion of the ESS in Parkinsons disease patients with

dementia, they could have mistaken situations frequently asso-

ciated with advanced Parkinsons disease (e.g. fluctuating atten-

tion) as sleep (Rye, 2003). Conversely, non-demented patients

may have also underestimated sleep episodes, although the opin-

ion of their caregiver was also taken into account when discrepan-

cies were detected. Finally, the fact that sleep studies were only

available for a subset of Parkinsons disease patients, and none of

the controls, could have led to underpowered analysis for this part

of the results. Should this be the case, however, a larger sample

might have lent more robustness to our already significant findings

of slower dominant occipital frequency and abnormal non-REM

sleep. Furthermore, there were no significant clinical differences

between patients who underwent sleep studies and those who did

not other than gender distribution, which is unlikely to be responsi-

ble for the observed vPSG findings. Further studies including larger

samples are warranted to eventually replicate such findings.

In conclusion, our study shows that lumbar CSF hypocretin-1

levels in advanced Parkinsons disease patients with dementia and

EDS are normal. Subjective EDS was, however, more frequent in

demented than non-demented Parkinsons disease patients. Thus,

causes other than dysfunction of the hypocretin system, such as

involvement of other sleep-related structures by the neurodegen-

erative process might account for EDS in advanced Parkinsons

disease. The loss of normal non-REM and REM sleep architecture

CSF hypocretin and sleepiness in Parkinson dementia Brain 2009: 132; 33083317 | 3315

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in the subset of Parkinsons disease patients with dementia who

underwent sleep studies would support this notion.

AcknowledgementsThe authors are grateful to the patients, their families, and control

subjects for their support. We also acknowledge the invaluable help

of Dr Misericordia Basora, Dr Fatima Salazar, Dr Gerard Sanchez-

Etayo (Anesthesiology Service), Dr Ferran Macule (Knee Surgery

Unit), Mrs Ana Camara (Parkinsons disease and Movement

Disorders Unit research nurse) and Mrs Rosa Page`s (technician

from the Biochemistry and Molecular Genetics Laboratory).

FundingPost-residency grant from the Spanish Neurology Society (SEN to

Y.C.). Fundacio la Marato de TV3 2006 (N-2006-TV060510,

partial).

Supplementary materialSupplementary material is available at Brain online.

ReferencesAmerican Psychiatric Association.edn. Diagnostic and statistical manual

of mental disorders. 4th edn., Washington: American Psychological

Association; 2000.Arnulf I, Konofal E, Merino-Andreu M, Houeto JL, Mesnage V,

Welter ML, et al. Parkinsons disease and sleepiness: an integral part

of PD. Neurology 2002; 58: 101924.

Arnulf I, Bonnet AM, Damier P, Bejjani BP, Seilhean D, Derenne JP, et al.

Hallucinations, REM sleep, and Parkinsons disease: a medical

hypothesis. Neurology 2000; 55: 2818.Baumann C, Ferini-Strambi L, Waldvogel D, Werth E, Bassetti CL.

Parkinsonism with excessive daytime sleepiness: a narcolepsy-like

disorder? J Neurol 2005; 252: 13945.

Baumann CR, Scammell TE, Bassetti CL, . Parkinsons disease, sleepiness

and hypocretin/orexin. Brain 2007; 131: e91.

Barbanoj MJ, Romero S, Morte A, Gimenez S, Lorenzo JL, et al. Sleep

laboratory study on single and repeated dose effects of paroxetine,

alprazolam and their combination in healthy young volunteers.

Neuropsychobiology 2005; 51: 13447.

Begg C, Cho M, Eastwood S, Horton R, Mother D, Olkin I, et al.

Improving the quality of reporting of randomized controlled trials:

the CONSORT statement. JAMA 1996; 276: 6379.

Bell C, Wilson S, Rich A, Bailey J, Nutt D. Effects on sleep architecture of

pindolol, paroxetine and their combination in healthy volunteers.

Psychopharmacology 2003; 166: 10210.

Boddy F, Rowan EN, Lett D, OBrien JT, McKeith IG, Burn DJ.

Subjectively reported sleep quality and excessive daytime somnolence

in Parkinsons disease with and without dementia, dementia with Lewy

bodies and Alzheimers disease. Int J Geriatr Psychiatry 2007; 22:

52935.

Bonanni L, Thomas A, Tiraboschi P, Perfetti B, Varanese S, Onofrj M.

EEG comparisons in early Alzheimers disease, dementia with Lewy

bodies and Parkinsons disease with dementia patients with a 2-year

follow-up. Brain 2008; 131: 690705.

Cohrs S, Rodenbeck A, Guan Z, Pohlmann K, Jordan W, Meier A, et al.

Sleep-promoting properties of quetiapine in healthy subjects.

Psychopharmacology 2004; 174: 4219.

Diederich NJ, Vaillant M, Mancuso G, Lyen P, Tiete J. Progressive sleep

destructuring in Parkinsons disease. A polysomnographic study in 46

patients. Sleep Med 2005; 6: 3138.Domitrz I, Friedman A. Electroencephalography of demented and

non-demented Parkinsons disease patients. Parkinsonism Relat

Disord 1999; 5: 3741.

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

et al. Low levels of ventricular CSF orexin/hypocretin in advanced PD.

Neurology 2003; 61: 5403.

Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, et al.

Clinical diagnostic criteria for dementia associated with Parkinsons

disease. Mov Disord 2007; 22: 1689707.Emser W, Brenner M, Stober T, Schimrigk K. Changes in nocturnal

sleep in Huntingtons and Parkinsons disease. J Neurol 1988; 235:

1779.

Fahn S, Elton RL. members of the UPDRS Development Committee

Unified Parkinsons Disease rating Scale. Unified Parkinsons Disease

rating Scale. In: Fahn S, Marsden CD, Calne DB, Lieberman A, editors.

Recent developments in Parkinsons disease. Florham Park, NJ:

McMillan Health Care Information; 1987. p. 1533.Folstein MF, Folstein SE, McHugh PR. Mini-Mental state. A practical

method for grading the cognitive state of patients for the clinician.

J Psychiatr Res 1975; 12: 18998.

Fogelson N, Kogan E, Korczyn AD, Giladi N, Shabtai H, Neufeld MY.

Effects of rivastigmine on the quantitative EEG in demented

Parkinsonian patients. Acta Neurol Scand 2003; 107: 2525.

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

Duinen SG, et al. Hypocretin (orexin) loss in Parkinsons disease.

Brain 2007; 130: 157785.Fronczek R, Overeem S, Lee SY, Hegeman IM, van Pelt J, van

Duinen SG, et al. Hypocretin (orexin) loss and sleep disturbances in

Parkinsons Disease. Brain 2008; 131: e88.

Gerashchenko D, Murillo-Rodriguez E, Lin L, Xu M, Hallett L, Nishino S,

et al. Relationship between CSF hypocretin levels and hypocretin

neuronal loss. Exp Neurol 2003; 184: 10106.

Gjerstad MD, Aarsland D, Larsen JP. Development of daytime somno-

lence over time in Parkinsons disease. Neurology 2002; 58: 15446.

Gjerstad MD, Alves G, Wentzel-Larsen T, Aarsland D, Larsen JP.

Excessive daytime sleepiness in Parkinson disease: is it the drugs or

the disease? Neurology 2006; 67: 8538.Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. The Sydney

multicenter study of Parkinsons disease: the inevitability of dementia

at 20 years. Mov Disord 2008; 23: 83744.

Hilker R, Thomas AV, Klein JC, Weisenbach S, Kalbe E, Burghaus L, et al.

Dementia in Parkinson disease: functional imaging of cholinergic and

dopaminergic pathways. Neurology 2005; 65: 171622.

Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality.

Neurology 1967; 17: 42742.

Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of

idiopathic Parkinsons disease: a clinico-pathological study of 100

cases. J Neurol Neurosurg Psychiatry 1992; 55: 1814.Iber C, Ancoli-Israel S, Chesson A, Quan SF, for the American Academy

of Sleep Medicine.The AASM Manual for the Scoring of Sleep and

Associated Events. Rules, Terminology and Technical Specifications.

Westchester, IL: American Academy of Sleep Medicine; 2007.

Johns MW. A new method for measuring daytime sleepiness: the

Epworth sleepiness scale. Sleep 1991; 14: 5405.

Littner MR, Kushida C, Wise M, Davila DG, Morgenthaler T, Lee-

Chiong T, et al. Practice parameters for clinical use of the multiple

sleep latency test and the maintenance of wakefulness test. Sleep

2005; 28: 11321.

Maeda T, Nagata K. Parkinsons disease comorbid with narcolepsy

presenting low CSF hypocretin/orexin level. Sleep Med 2006; 7: 662.

Martinez-Rodriguez JE, Lin L, Iranzo A, Genis D, Mart MJ, Santamaria J,

et al. Decreased hypocretin-1 (Orexin-A) levels in the cerebrospinal

3316 | Brain 2009: 132; 33083317 Y. Compta et al.

by guest on June 29, 2015D

ownloaded from

fluid of patients with myotonic dystrophy and excessive daytimesleepiness. Sleep 2003; 26: 28790.

Martinez-Rodriguez JE, Seppi K, Cardozo A, Iranzo A, Stampfer-

Kountchev M, Wenning G, et al. SINBAR (Sleep Innsbruck

Barcelona) group. Cerebrospinal fluid hypocretin-1 levels in multiplesystem atrophy. Mov Disord 2007; 22: 18224.

Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S,

et al. The role of cerebrospinal fluid hypocretin measurement in the

diagnosis of narcolepsy and other hypersomnias. Arch Neurol 2002;59: 155362.

Mito Y, Yoshida K, Yabe I, Makino K, Hirotani M, Tashiro K, et al. Brain

3D-SSP SPECT analysis in dementia with Lewy bodies, Parkinsonsdisease with and without dementia, and Alzheimers disease. Clin

Neurol Neurosurg 2005; 107: 396403.

Molloy SA, Rowan EN, OBrien JT, McKeith IG, Wesnes K, Burn DJ.

Effect of levodopa on cognitive function in Parkinsons disease withand without dementia and dementia with Lewy bodies. J Neurol

Neurosurg Psychiatry 2006; 77: 13238.

Neufeld MY, Inzelberg R, Korczyn AD. EEG in demented and non-

demented parkinsonian patients. Acta Neurol Scand 1988; 78: 15.Nishino S, Ripley B, Overeem S, Nevsimalova S, Lammers GJ, Vankova J,

et al. Low cerebrospinal fluid hypocretin (Orexin) and altered

energy homeostasis in human narcolepsy. Ann Neurol 2001; 50:

3818.Nishino S, Kanbayashi T. Symptomatic narcolepsy, cataplexy and

hypersomnia, and their implications in the hypothalamic hypocretin/

orexin system. Sleep Med Rev 2005; 9: 269310.Ondo WG, Dat Vuong K, Khan H, Atassi F, Kwak C, Jankovic J. Daytime

sleepiness and other sleep disorders in Parkinsons disease. Neurology

2001; 57: 13926.

Overeem S, van Hilten JJ, Ripley B, Mignot E, Nishino S, Lammers GJ.Normal hypocretin-1 levels in Parkinsons disease patients with

excessive daytime sleepiness. Neurology 2002; 58: 4989.

Parrino L, Terzano MG. Polysomnographic effects of hypnotic drugs.

A review. Psychopharmacology 1996; 126: 116.Perneger TV. Whats wrong with Bonferroni adjustments. Br Med J

1998; 316: 12368.

Ramirez-Ruiz B, Junque C, Marti MJ, Valldeoriola F, Tolosa E. Cognitive

changes in Parkinsons disease patients with visual hallucinations.

Dement Geriatr Cogn Disord 2007; 23: 2818.

Riekkinen P, Buzsaki G, Riekkinen P Jr, Soininen H, Partanen J. The

cholinergic system and EEG slow waves. Electroencephalogr Clin

Neurophysiol 1991; 78: 8996.

Roks G, Korf ESC, van der Flier WM, Scheltens P, Stam CJ. The use of

EEG in the diagnosis of dementia with Lewy bodies. J Neurol

Neurosurg Psychiatry 2008; 79: 37780.

Rye D. Sleepiness and unintended sleep in Parkinsons disease. Curr Treat

Options Neurol 2003; 5: 2319.

Schlosser R, Roschke J, Rossbach W, Benkert O. Conventional and

spectral power analysis of all-night sleep EEG after subchronic

treatment with paroxetine in healthy male volunteers. Eur

Neuropsychopharmacol 1998; 8: 2738.

Shpirer I, Miniovitz A, Klein C, Goldstein R, Prokhorov T, Theitler J, et al.

Excessive daytime sleepiness in patients with Parkinsons disease: a

polysomnography study. Mov Disord 2006; 21: 14328.

Tandberg E, Larsen JP, Karlsen K. Excessive daytime sleepiness and sleep

benefit in Parkinsons disease: a community-based study. Mov Disord

1999; 14: 9227.

Thannickal TC, Lai YY, Siegel JM. Hypocretin (orexin) cell loss in

Parkinsons disease. Brain 2007; 130: 158695.Thannickal TC, Lai YY, Siegel JM. Hypocretin (orexin) and melanin con-

centrating hormone loss and the symptoms of Parkinsons disease.

Brain 2008; 131: e87.Vendette M, Gagnon JF, Decary A, Massicotte-Marquez J, Postuma RB,

Doyon J, et al. REM sleep behavior disorder predicts cognitive impairment

in Parkinson disease without dementia. Neurology 2007; 69: 18439.Wenzelburger R, Zhang BR, Pohle S, Klebe S, Lorenz D, Herzog J, et al.

Force overflow and levodopa-induced dyskinesias in Parkinsons

disease. Brain 2002; 125: 8719.Yasui K, Inoue Y, Kanbayashi T, Nomura T, Kusumi M, Nakashima K.

CSF orexin levels of Parkinsons disease, dementia with Lewy bodies,

progressive supranuclear palsy and corticobasal degeneration. J Neurol

Sci 2006; 250: 1203.

CSF hypocretin and sleepiness in Parkinson dementia Brain 2009: 132; 33083317 | 3317

by guest on June 29, 2015D

ownloaded from