doi:10.

1093/brain/awp263

Brain 2009: 132; 33083317

| 3308

BRAIN
A JOURNAL OF NEUROLOGY

Cerebrospinal hypocretin, daytime sleepiness and

sleep architecture in Parkinsons disease dementia
Yaroslau 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

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 individuals 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 sleepiness scale scores were higher in Parkinsons disease patients without dementia and Parkinsons disease patients with dementia
than controls (P50.01) and scores 410 were more frequent in Parkinsons disease patients with dementia than in Parkinsons
disease patients without dementia (P = 0.04). Cerebrospinal fluid hypocretin-1 levels were similar among groups (controls = 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), and
unrelated 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

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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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

CSF hypocretin and sleepiness in Parkinson dementia

Brain 2009: 132; 33083317

| 3309

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 Parkinson
Disease Rating Scale; vPSG = video-polysomnography

Introduction

Methods
Patients
As 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 caregivers, whose comments were taken into consideration when answering 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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Excessive 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 diseaserelated 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 disability 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 underlie 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 findings of sleep tests with the secondary hypothesis that a variety of
abnormalities in sleep tests may constitute additional factors contributing to EDS in Parkinsons disease patients.

3310

| Brain 2009: 132; 33083317

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 puncture was performed before the morning dose of the anti-parkinsonian
medications.

CSF hypocretin determination

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 disorientation 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, electrocardiogram, 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 analysis
An 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). Chisquare 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 analyses
were 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 the
dementia 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% confidence interval. Spearmans correlation coefficient between quantitative
variables was also calculated.
Level of statistical significance was established at P 4 0.05
(two-tailed). Due to the presence of a priori hypotheses and the
exploratory nature of the neurophysiological sleep sub-study, the significant results shown are uncorrected for multiple comparisons (Begg
et al., 1996; Perneger, 1998).

Results
Demographic and basic clinical data
The 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 versus
10.15  6.9, respectively). Parkinsons disease patients with
dementia 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 scores

Both Parkinsons disease patients with and without dementia
had higher ESS scores than controls (Parkinsons disease patients
without dementia = 10.34  5.60; Parkinsons disease patients
with dementia = 13.25  5.00; controls = 5.32  2.73) (global
comparison:
P50.001;
pair-wise
comparisons
between

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

and 4 C, and subsequently stored at 80 in 400 ml aliquots until final
analysis. 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).

Y. Compta et al.

CSF hypocretin and sleepiness in Parkinson dementia

Brain 2009: 132; 33083317

| 3311

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

Age
Gender (females)
Disease duration
Time to dementia
Visual hallucinations
UPDRS III off
Hoehn and Yahroff
Equivalent L-dopa dose
Dopamine agonists
MMSE
ESS score
Altered ESS (= EDS)

Controls (n = 22)

PDND (n = 21)

PDD (n = 20)

P-value

70.4  9
12 (55%)

0 (0%)

29.23  1.1
5.32  2.73
None (0%)

68.8  6.9
9 (42%)
10.19  4.5

9 (42.9%)
32.65  16.12
III
1046.5  399.53
8 (38%)
27.9  1.6
10.34  5.60
8 (34%)

72.5  7.14
11 (55%)
10.15  6.8
8.65 (6.71)
20 (100%)
36.00  9.35
IV
739.75  295.60
6 (30%)
17.75  4.75
13.25  5.00
14 (70%)

0.20
0.1
0.50
NA
50.001a
0.09
0.02
0.01
0.74
50.001b
50.005b,c
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 within
parentheses, 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

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Parkinsons disease patients with and without dementia with controls: P50.01). ESS scores did not differ between Parkinsons
disease patients with and without dementia (P = 0.063), despite
somewhat higher scores among Parkinsons disease patients with
dementia. Abnormal ESS scores (410) were significantly more
frequent 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 criterion
was used in this case as none of the controls scored 410).
The proportion of subjects with ESS scores 510 was smaller in
the control group than in both groups of Parkinsons disease
patients (with and without dementia) (P50.001), with
Parkinsons disease patients without dementia having a lower
proportion groups of Parkinsons disease patients (with and without dementia) ESS scores 510 than Parkinsons disease patients
with 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 differences 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

Figure 1 Proportion of subjects with ESS scores 410 in the

three study groups. Standard error bar diagram, where dots
represent mean and bars represent two times the SE of the
proportion of subjects with ESS scores 410 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; PDD
PDND = 0.28 (0.510.04), P = 0.022. PDD = Parkinsons disease
patients with dementia; PDND = Parkinsons disease patients
without dementia

17; P = 0.45). The set of Parkinsons disease patients who underwent 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-1

There were no differences in CSF hypocretin-1 levels among
the three groups (in pg/ml: controls = 321.15  47.15;

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| Brain 2009: 132; 33083317

Y. Compta et al.

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

Age
Gender (females)
Disease duration
Visual hallucinations
UPDRSoff
Hoehn and Yahroff
Equivalent L-dopa dose
Dopamine agonists
MMSE

Parkinsons disease with ESS 410 (n = 19)

Parkinsons disease with ESS 410 (n = 22)

P-value

68.21  6.87
10 (52%)
9.83  4.49
10 (52%)
33.50  16.52
III
1043.33  423.24
6 (31%)
25.11  4.96

72.68  6.99
10 (45%)
11.00  6.66
19 (86%)
35.00  9.86
III.5
770.23  296.84
8 (36%)
21.05  6.63

0.033 a
0.76
0.53
0.037 a
0.21
0.49
0.017 a
1.00
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 within
parentheses, 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 three

vPSG results
Of 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 criteria, due to an altered non-REM sleep architecture. The abnormalities 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 posterior-dominant alpha/theta activity at least 1 Hz slower than the dominant occipital rhythm during wakefulness (eight patients) and (iv)
absence of well-defined sleep spindles or K-complexes, the hallmarks of stage N2 (8 and all 10 cases, respectively).
Altered non-REM sleep and/or slow dominant occipital frequency 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:

study 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 concentration: 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

8.3 Hz (percentile 2575: 79.3) Hz; P = 0.05]. REM sleep was present 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  106.2
versus 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 per
hour of sleep (26.2  20.1 versus 31.9  16.7) were also not significant (P = 0.34 and 0.3, respectively).

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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 scores 410 with those who
scored 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).

a-freq

a- in S

sp freq

P
P

18
19
Summary

6.0
6.5
6 [67.5]

9.0

+
+
71%
12.0 
1.4

11
1

RNR
RNR
100%

RNR
RNR
+
+

+
+
4

+
RNR

RBD

+
+
+
+
71%

+
+

308
179
240.6 
106.2

403

163
84
264
284

172
228
331
388
473
432
255
398
334.6 
106.6

TST

55
20
29.6 
25.2

26
73
21
5

15
28
21
31
3
7
30
14
18.6 
10.6

AW 41

48
15.4
26.2 
20.1

28.5

52
5.5

36.7
52.0
18.0
20.1
5.4
50.2
28.8
44.3
31.9 
16.7

Arousal
index

29.3
43.8
14.5 
17.9

24.8

0.4
0.7
0.2
2.3

35.0
0.0
7.8
0.0
1.3
38.1
22.2
40.0
18.0 
17.8

AHI

1200

318
84
330
484.5 
387.1

1
1
0

0
1

2
0
0
0

258
606
408
384
481.0 
361.9
600
375

0
1

SOREMP

1134
96

MSLT
mean lat

0
0
43.6
0

20
0
0
0
0
0
0
0

PLMS

8
21
14.7 
4.4

11

15
17
18
13

18
10
9
6
14
9
22
15
12.9 
5.4

ESS

196.75
296.57
292.78 
79.48

298.92

368.85
241.47
419.19
227.75

315.20
371.87
305.89
341.69
115.93
388.97
314.41
262.61
302.07 
84.97

CSF
hypocr-1

QTP 0-0-25
QTP 0-0-100 DPZ 0-0-10
DPZ 0-0-10
RVT 4.5-0-3 VFX 75-075 CNZ 0.5-0-0-1 APZ
0.25-0.25-0
PX 20-0-0 QTP 0-0-50
CNZ 0-0-0.5
RVT 3-0-3

CNZ 0-0-0.5
CNZ 0-0-0.5

Drugs

Brain 2009: 132; 33083317

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S = sleep pattern type (N = normal; P = pathologic); -freq = dominant occipital frequency (Hz);  in S = persistence of alphatheta activity during sleep; sp freq = sleep spindles frequency (Hz); K = presence of well-recognizable Kcomplexes; RBD = presence of REM sleep behaviour disorder; TST = Total sleep time (in minutes); AW41 = number of awakenings of at least 1 min in duration; AHI = apnoeahypopnoea index; PLMS = periodic leg movements in
sleep index; MSLT mean lat = mean latency at MSLT (seconds); SOREMP = number of Sleep-onset REM Periods; ESS = Epworth sleepiness scale score (out of 24 items); CSF hypocr-1 = levels of CSF hypocretin-1 expressed in pg/ml;
+ = yes;
= no; RNR = REM sleep episodes not recorded; CNZ = clonazepam; QT = quetiapine; DPZ = donepezil; RVT = rivastigmine; VFX = venlafaxine; APZ = alprazolam; PX = paroxetine. The patient number corresponds to the
order of recruitment for the CSF study. All drugs doses expressed in mg. All data expressed as: mean  SD, median [percentile 2575], number of cases, or %.

16

disease patients without dementia

P
6.0
P
8.5
+
N 10.5
15
N 9.0
15
P
7.0
+
12
P
7.0
+
N 9.5
13
N 8.0
13
8.3 [79.3] 38%
13.6 
1.3
Parkinsons disease patients with dementia
6
P
6.0
+
7
P
6.0
+
10
P
7.5
+
15
N 6.0
13

Parkinsons
1
3
11
12
14
18
19
20
Summary

Patient #

Table 3 Findings of vPSG and MSLT recordings in patients with Parkinsons disease, with and without dementia

CSF hypocretin and sleepiness in Parkinson dementia

| 3313

3314

| Brain 2009: 132; 33083317

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 results

Discussion
In 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 patients
with 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 frequency 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 nondemented 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 patients
with 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 is 570%, even in advanced
disease 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 narcoleptic-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 dementia. RBD occurred in all the Parkinsons disease patients with
dementia where REM sleep could be identified. Previous studies

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There 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 disease
with ESS 410 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 correlation 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 dementia, 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).

Y. Compta et al.

CSF hypocretin and sleepiness in Parkinson dementia

| 3315

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 individuals 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 hypocretin-1 in Parkinsons disease. Moreover, the study was statistically 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 convenience sample and the referral centre setting. ESS is an autoadministered scale, however, since the caregivers often contributed to completion of the ESS in Parkinsons disease patients with
dementia, they could have mistaken situations frequently associated with advanced Parkinsons disease (e.g. fluctuating attention) as sleep (Rye, 2003). Conversely, non-demented patients
may have also underestimated sleep episodes, although the opinion of their caregiver was also taken into account when discrepancies 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 responsible 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 neurodegenerative process might account for EDS in advanced Parkinsons
disease. The loss of normal non-REM and REM sleep architecture

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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 hallucinations, 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), cholinergic 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 fragmentation, 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
scores 410, were on lower equivalent L-dopa doses. Even though
L-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

Brain 2009: 132; 33083317

3316

| Brain 2009: 132; 33083317

in the subset of Parkinsons disease patients with dementia who

underwent sleep studies would support this notion.

Acknowledgements
The 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 SanchezEtayo (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).

Funding
Post-residency grant from the Spanish Neurology Society (SEN to
Y.C.). Fundacio la Marato de TV3 2006 (N-2006-TV060510,
partial).

Supplementary material
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