Association of daytime sleepiness with nigrostriatal dopaminergic ...

J Neurol (2007) 254:1037–1043 DOI 10.1007/s00415-006-0483-6

Svenja Happe Paul Christian Baier Kathrin Helmschmied Johannes Meller Klaus Tatsch Walter Paulus

Received: 10 July 2006 Received in revised form: 18 September 2006 Accepted: 17 October 2006 Published online: 12 March 2007

S. Happe, MD Æ P. C. Baier, MD K. Helmschmied, MD Æ W. Paulus, MD Dept. of Clinical Neurophysiology University of Go¨ttingen Robert-Koch-Str. 40 37075 Go¨ttingen, Germany S. Happe, MD (&) Dept. of Clinical Neurophysiology Klinikum Bremen-Ost University of Go¨ttingen Zu¨richer Straße 40 28325 Bremen, Germany Tel.: +49-421/408-2370 Fax: +49-421/408-2375 E-Mail: [email protected] J. Meller, MD Dept. of Nuclear Medicine University of Go¨ttingen Robert-Koch-Str. 40 37075 Go¨ttingen, Germany K. Tatsch, MD Dept. of Nuclear Medicine Ludwig-Maximilians-University Marchioninistr. 15 81377 Munich, Germany

ORIGINAL COMMUNICATION

Association of daytime sleepiness with nigrostriatal dopaminergic degeneration in early Parkinson’s disease

j Abstract Introduction Many

patients with Parkinson’s disease (PD) report daytime sleepiness. Its etiology, however, is still not fully understood. The aim of this study was to examine if the amount of nigrostriatal dopaminergic degeneration is associated with subjective daytime sleepiness in patients with PD. Patients and methods We investigated 21 patients with PD clinically and by means of [123I] FP-CIT-SPECT (DaTSCANR). Each patient filled in the Epworth sleepiness scale (ESS), the Parkinson’s Disease Sleep Scale (PDSS), and the self-rating depression scale according to Zung (SDS) to assess sleepiness, sleep quality, and depressive symptoms. Results The mean specific dopamine transporter binding in the 21 PD patients (60.8 ± 10.4 years, nine females, median Hoehn and Yahr stage 2.0) was decreased. Nine patients were in Hoehn and Yahr stage 1 (58.7 ± 6.6 years, four females; ESS score 7.4 ± 4.5; PDSS score 105.1 ± 30.9), the other 12 patients were in Hoehn and Yahr

Introduction

j Key words Parkinson’s disease Æ sleepiness Æ Epworth sleepiness scale (ESS) Æ SPECT Æ dopamine transporter

disorders with a subsequently impaired quality of life [1]. A recent study described that excessive daytime sleepiness (EDS) may even be associated with an increased risk of developing PD [2]. However, the frequent sleep and wake complaints in PD have so far

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During the course of the disease, almost all patients with Parkinson’s disease (PD) develop sleep-wake

stage 2 (62.4 ± 12.6 years, five females; ESS score 6.7 ± 4.7, PDSS score 97.1 ± 25.6). Age, gender, ESS, and PDSS scores were not significantly different in both groups. However, ESS scores showed an inverse correlation with mean DAT binding in the striatum (r = )0.627, p = 0.03), the caudate nucleus (r = )0.708, p = 0.01), and the putamen (r = )0.599, p = 0.04) in patients with Hoehn and Yahr stage 2. There was no correlation of the ESS score with age, disease duration, UPDRS motor score, PDSS score, or depression score. Conclusion Subjective daytime sleepiness seems to be associated with dopaminergic nigrostriatal degeneration in early PD.

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not been sufficiently acknowledged and understood. Sleep-wake disturbances in PD are caused by many different factors, including psychological and physical alterations with disease specific and treatment specific contributions. Reports of EDS with sudden sleep onset, so-called ‘‘sleep attacks’’, have drawn attention on impaired sleep as an additional important symptom of PD patients during the last years [3]. The neurodegenerative process itself with disturbances of, e.g., the reticular activating system, the dorsal raphe nucleus and the locus coeruleus, separate sleep disorders such as sleep apnea syndrome and narcolepsy, REM sleep behaviour disorder (RBD), mood disorders, as well as various drugs could contribute to EDS [4]. Studies in the last years described an increased risk for causing motor vehicle accidents by sudden sleep onset, so-called ‘‘sleep attacks’’, in PD patients. Those episodes were primarily attributed to the intake of non-ergot dopamine receptor agonists [3]. It was suggested that the sedating effect of non-ergot dopamine receptor agonists may be due to their stronger D3 receptor activity as compared to other dopamine receptor agonists [3, 5]. However, reports from more recent studies suggest that sedation may be rather a class effect of dopaminergic medication in general, since EDS was generally more frequent in patients taking dopaminergic drugs [6, 7]. Sleepiness does not result only from pharmacotherapy or sleep abnormalities but is also related to the pathology of the disease itself [8]. Dopaminergic medication may exacerbate sleepiness in a subset of patients, but the primary pathology seems to be the greatest contributor to the development of EDS. However, these associations have never been shown to date. A variety of neurodegenerative, psychological, and pharmacological factors could lead to disturbances of sleep in patients with parkinsonism: First, sleep disruption may be a consequence of the neurodegenerative process in the neurophysiological and neurochemical system that is responsible for sleep regulation itself. According to the six progressive stages described by Braak and co-workers, the neurodegenerative process starts in the lower brainstem areas, where sleep-wake regulation gains important input [9, 10]. The first signs of sleep-wake disruption may occur when Lewy bodies, the neuropathological equivalent of PD, intrude those brainstem areas relevant for sleep-wake regulation. Second, symptoms commonly associated with PD such as breathing-difficulties, akinesia, and depression can lead to nocturnal sleep problems. Third, the medication can induce new symptoms such as nightmares, psychosis, and nightly movements, or can increase wakefulness. The aim of this study was therefore to systematically investigate a possible association of subjective

daytime sleepiness as measured by the Epworth Sleepiness Scale (ESS) [11] with the degree of nigrostriatal dopaminergic degeneration as measured by [123I] FP-CIT-SPECT in patients with early PD.

Patients and methods j Patients Twenty-one consecutive PD patients who were either de novo (n = 14) or pre-treated with levodopa (n = 7) were recruited from the specialized outpatient clinics for PD and movement disorders at the Department of Clinical Neurophysiology, University of Go¨ttingen. All patients were examined by means of [123I] FP-CIT-SPECT (DaTSCANR). The clinical classification was made by experienced neurologists who were blinded for the SPECT results according to the UK Brain Bank criteria [12–14]. Magnetic resonance imaging or – when this was not possible – computer tomography was performed to exclude relevant vascular lesions and atrophy. Patients’ severity was assessed with Hoehn and Yahr staging [15] and the Unified Parkinson’s Disease Rating Scale motor score (UPDRS, Part III) [16]. Patients with a positive history of sleep disorders possibly associated with daytime sleepiness, such as sleep apnea syndrome, REM sleep behavior disorder, and narcolepsy were not included. Before participating in the study, all patients gave informed consent. The experimental protocol was approved by the local ethics committee of the Medical Faculty of the University of Go¨ttingen, Germany. j [123I] FP-CIT-SPECT Single photon emission computed tomography (SPECT) was performed 3.5 hours after intravenous injection of approx. 100 MBq 123 I-Ioflupane ([123I]FP-CIT) (DaTSCANR, Nycomed Amersham, GE Healthcare, UK) with a triple headed gamma camera (Philips, PRISM 3000) fitted with LEUHR fan-beam collimators (360 circular orbit, 60 seconds per view, 60 projections, 128 · 128 matrix). The projection data was checked visually for patient motion using the cine display and sinograms provided by the software of the camera manufacturer (Odyssey-FX software, Philips Medical Systems). Data were reconstructed by filtered back projection and filtered using a Butterworth filter (5th order, 0.22 cut-off). Attenuation correction was performed according to Chang’s method (l = 0.11/cm) with separate contours for each slice (manually placed ellipses). Semi-quantification was performed objectively using a modified version of the Brain Analysis Software (BRASS, version 3.4.4) running on a Hermes workstation (Nuclear Diagnostics, Sweden). The software automatically registers individual patient studies to a SPECT template of healthy controls (aligned according the Talairach space) and subsequently applies a standardized 3-D VOI (volume of interest) map, which is automatically fine-adjusted to compensate for individual anatomical variation. The standardized VOI map is based on an MRI scan (matching the SPECT template) of a healthy control and consists of separate regions for striatum, caudate, putamen, as well as an occipital reference region [17]. From the average counts/voxel values within 1 volume of interest, specific radiotracer binding within the respective striatal areas was calculated according to the formula [specific binding] = ([counts striatum])[counts occipital reference region])/ [counts occipital reference region]. SPECT data were analyzed with respect to the mean of the right and left striatum, caudate, and putamen, and also separately for the side with the more respectively less pronounced symptomatic side of PD (ipsilateral/contralateral).

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Table 1 Clinical and demographic data of all investigated patients with early Parkinson’s disease (PD) (n = 21) differentiated by Hoehn and Yahr stage

Age, years (range) Female, n (percentage) Duration of disease, months UPDRS motor score, part III ESS score PDSS score SDS score L-dopa dose

PD patients Hoehn and Yahr stage 1 (n = 9)


p-value

58.7 ± 6.6 (48–68) 4 (44.4) 27.1 ± 17.5 8.8 ± 8.6 7.4 ± 4.5 (0–16) 105.1 ± 30.9 (54–139) 35.9 ± 10.9 (25–52) 90.3 ± 150.2 (0–375) (3 pts. treated)

62.4 ± 12.6 (34–76) 5 (41.7) 33.8 ± 18.5 16.9 ± 10.9 6.7 ± 4.7 (1–13) 97.1 ± 25.6 (53–140) 40.7 ± 10.4 (23–53) 125.0 ± 196.3 (0–500) (4 pts. treated)

0.247 0.899 0.345 0.023 0.624 0.427 0.427 0.808

Values are given with mean ± SD unless otherwise specified. p-values according to Mann–Whitney-U-test for the non-parametric parameter age and Chi-square test/Fisher’s exact test for the qualitative parameter gender

No antiparkinsonian drugs were allowed for at least 16 hours prior to the SPECT scan. All SPECT scans were performed at the Department of Nuclear Medicine, University of Go¨ttingen, Germany. The semi-quantitative analysis was done by experienced analyzers (including K.T.), Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Germany.

lower UPDRS motor score (p = 0.023), whereas all other clinical and demographical data including levodopa dose were not different between the two groups (see Table 1). Follow-up showed that all included patients (also the initially untreated de-novo patients) responded to dopaminergic therapy.

j Scales

j [123I]FP-CIT-SPECT

All patients filled in the Epworth Sleepiness Scale (ESS) [11] to assess daytime sleepiness. The Parkinson’s disease sleep scale (PDSS) [18] was used to assess sleep disorders. Depressive symptoms were measured using the self-rating depression scale (SDS) by Zung [19]. j Statistics We used Spearman’s rank test to correlate the ESS and PDSS scores with the mean nigrostriatal dopamine transporter binding (DAT). Wilcoxon test was carried out to find whether there was a difference in specific DAT binding between the ipsi- and contralateral regions of interest related to the clinically affected side. We used Mann– Whitney-U-test for non-parametric parameters and Chi-square test/Fisher’s exact test for the qualitative parameter gender between the groups.

Results

The mean of the left and the right specific DAT binding was 1.50 ± 0.56 in the striatum, 1.20 ± 0.59 in the putamen, and 1.76 ± 0.59 in the caudate nucleus (see Table 2). In patients with Hoehn and Yahr stage 1, the dopamine transporter binding contralateral to the clinically more affected side of PD was significantly lower than ipsilateral in the striatum (p = 0.008) and the putamen (p = 0.008), but not in the caudate nucleus (p = 0.260), overall resulting in a significant asymmetry of the putamen/caudate nucleus ratio (p = 0.035). Contralateral versus ipsilateral specific DAT binding was not statistically different in patients with Hoehn and Yahr stage 2 (p ‡ 0.108). The specific binding ratios are in detail presented in (Table 2).

j Correlation of the ESS with dopamine transporter binding

j Clinical characteristics and demographics Twenty-one patients with early PD (60.8 ± 10.4 years, nine females, median Hoehn and Yahr stage 2.0, range 1.0–2.5), mean duration of the disease 30.9 ± 18.0 months) were included in this study. Patients were analyzed separately according to Hoehn and Yahr stage 1 and Hoehn and Yahr stage 2. Patients with Hoehn and Yahr stage 1 showed a significantly

In patients with Hoehn and Yahr stage 2, there was a significant inverse correlation of the ESS score with mean DAT binding of both sides of the striatum (r = )0.627; p = 0.029), the putamen (r = )0.599; p = 0.040), and the caudate nucleus (r = )0.708; p = 0.010) (see Fig. 1), as well as with the binding ratios in the striatum (r = )0.683, p = 0.014), the putamen (r = )0.739; p = 0.006), and the caudate

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Table 2 Specific striatal DAT binding in all investigated patients with early Parkinson’s disease (PD) (n = 21) as measured by [123I]FP-CIT-SPECT (DaTSCANR). Ipsilateral and contralateral according to the more pronounced symptomatic side of PD

Striatum, mean ± SD (range)

Putamen, mean ± SD (range)

Caudate nucleus mean ± SD (range)

Putamen/Caudate nucleus, mean ± SD (range)



p-value

both sides 1.61 ± 0.57 (1.05–3.00) ipsilateral 1.79 ± 0.51 (1.31–3.01) contralateral** 1.44 ± 0.63 (0.78–2.98) both sides 1.32 ± 0.66 (0.84–3.01) ipsilateral 1.59 ± 0.69 (0.99–3.28) contralateral** 1.06 ± 0.70 (0.56–2.75) both sides 1.85 ± 0.49 (1.23–2.93) ipsilateral 1.90 ± 0.42 (0.1.34–2.67) contralateral 1.79 ± 0.60 (1.01–3.18) both sides 0.69 ± 0.15 (0.55–1.05) ipsilateral 0.82 ± 0.23 (0.54–1.23) contralateral* 0.56 ± 0.14 (0.42–0.86)

both sides 1.33 ± 0.51 (0.64–2.13) ipsilateral 1.42 ± 0.60 (0.60–2.40) contralateral 1.24 ± 0.45 (0.68–2.07) both sides 1.04 ± 0.46 (0.53–2.04) ipsilateral 1.16 ± 0.55 (0.44–2.16) contralateral 0.93 ± 0.44 (0.43–2.10) both sides 1.58 ± 0.62 (0.70–2.36) ipsilateral 1.63 ± 0.68 (0.73–2.47) contralateral 1.52 ± 0.58 (0.64–2.27) both sides 0.70 ± 0.18 (0.39–0.98) ipsilateral 0.72 ± 0.20 (0.43–1.05) contralateral 0.65 ± 0.25 (0.25–1.08)

0.247 0.169 0.382 0.169 0.082 0.754 0.554 0.464 0.651 0.702 0.345 0.382

Values are given with mean ± SD. p-values according to Wilcoxon test in between the individual group and Mann–Whitney-U-test between both groups. * = p < 0.05, ** = p < 0.01, *** = p < 0.001 comparing ipsilateral versus contralateral region of the more affected side

nucleus (r = )0.739, p = 0.006) contralateral to the clinically more affected side. There was no correlation of the ESS score with mean binding ratios in patients with Hoehn and Yahr stage 1 (p ‡ 0.081) and no correlation of the ESS score with age, duration, and clinically rated disease severity by UPDRS in both patient groups. Only one patient in the Hoehn and Yahr group stage 1 and four patients in the Hoehn and Yahr group stage 2 showed an increased ESS score superior to 10.

j Correlation of the PDSS score and the SDS score with dopamine transporter binding There were no correlations of binding ratios with the PDSS score (p ‡ 0.333) and the SDS score (p ‡ 0.082) in both patient groups.

Discussion Subjective daytime sleepiness as measured by the ESS but not subjective sleep quality and depressive symptoms correlated with the amount of nigrostriatal dopaminergic degeneration in patients with moderate PD. Altogether, our data support the hypothesis that the nigrostriatal dopaminergic deficit is associated with an increased subjective daytime sleepiness in moderately affected PD patients, and that EDS in PD is independent of age, pretreatment with levodopa, as well as duration of the disease in a homogenous group of patients with early PD. However, the mediation and the neurophysiological mechanisms of the dopaminergic control of daytime sleepiness are still not fully understood. Dopaminergic abnormalities in PD are not restricted

a

14

14

12

12

10

10 ESS score

Fig. 1 Inverse correlation of excessive daytime sleepiness as measured by Epworth Sleepiness Scale (ESS) and (a) mean putaminal binding ratios of both sides (r = )0.599, p = 0.04), (b) mean striatal binding ratios of both sides (r = )0.627, p = 0.03), and (c) mean caudate binding ratios of both sides (r = )0.708, p = 0.01) as measured by [123I] FP-CITSPECT in 12 patients with early Parkinson’s disease in Hoehn and Yahr stage 2

ESS score

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8 6

8 6

4

4

2

2

0 ,4

,6 ,8 1,0 1,2 1,4 1,6 1,8 2,0 2,2 mean putaminal binding of both sides

0 ,6

b

,8 1,0 1,2 1,4 1,6 1,8 2,0 2,2 mean striatal binding of both sides

14 12

ESS score

10 8 6 4 2 0

c

,5

1,0

1,5

2,0

2,5

mean caudate binding of both sides

to the nigrostriatal tract. Additional dopamine depletion occurs in hypothalamic, mesolimbic, and mesocortical pathways, and a derangement of these systems, including receptor hypersensitivity in PD, has been reported [20]. A positron emission tomographic study using fluorodopa demonstrated an altered dopaminergic metabolism of extrastriatal structures in patients with PD compared to control. The annual loss of extrastriatal dopamine-D2-receptor availability in PD patients was up to three times faster than the rate previously measured in the putamen [21, 22]. In an animal model limited to striatal degeneration, unilateral lesioning of A9 nigro-striatal pathways did not affect circadian distribution of locomotor activity and indicated an intact sleepwake-regulation [23]. Therefore, it can be suggested that daytime sleepiness may be associated with an extrastriatal dopaminergic neurodegeneration in brain regions known to be involved in alertness. Particularly degeneration of the mesocorticolimbic dopaminergic neurons associated with the ascending reticular activating system, as well as degeneration of pathways arising from the dorsal raphe and locus coeruleus may contribute to impaired alertness during the day. Since the

neurodegenerative process in PD is known to start in the lower brainstem areas, where sleep-wake regulation gains important input [9, 10], this also explains why daytime sleepiness can precede motor symptoms and that it can be a risk factor for developing PD as previously shown [2]. The reduced striatal dopamine transporters in idiopathic REM sleep behavior disorder [24] and the correlation of increased muscle activity during REM sleep with the decrease of striatal presynaptic dopamine transporters [25], as measured by IPT SPECT, also suggests a direct association of the amount of striatal neurodegeneration with certain sleep disorders associated with parkinsonian syndromes. Interestingly, in our patient population the relationship of ESS scores with the extent of dopaminergic degeneration was confined to patients with Hoehn and Yahr stage 2 and was not detected in the less severely affected patients of Hoehn and Yahr stage 1. As a possible explanation it can be speculated that – as for motor symptoms – dopaminergic cell loss needs to fall below a certain threshold before clinical symptoms of EDS occur. We did neither find a correlation of the ESS score nor of the nigrostriatal DAT binding with duration and severity of the disease. Possibly, this was due to

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the fact that the group of patients in this study was in an early stage of the disease and did not cover the entire range up to severe cases. Possibly, a broader spectrum of PD patients also including more advanced stages of the disease (Hoehn and Yahr stage above 2.5) would have revealed such relations as previously shown for nigrostriatal DAT binding [26, 27] and might also be advantageous to further analyze possible correlations of the extent of EDS with duration and severity of the disease. Previous studies have shown an impact of levodopa and dopamine agonists on EDS in PD [3, 6, 7]. Dopaminergics may exacerbate sleepiness in a subset of patients in a dose-dependent fashion [28]. There might be an individual susceptibility to specific antiparkinsonian drugs, which may play a role in the

etiology of sleepiness in PD patients [29]. In this study, however, EDS scores and levodopa doses were not different in both patients groups. We hypothesize that the primary pathologies involved in parkinsonism appear to be the most important contributors to daytime sleepiness. Altogether, subjective daytime sleepiness seems to be associated with the dopaminergic nigrostriatal degeneration in moderate PD. Studies with a broader spectrum and more advanced PD patients and with objective measurements of daytime sleepiness are warranted to further confirm this finding. j Acknowledgements This study was partly supported by the Medical Faculty, University of Go¨ttingen, Germany (to S. H.)

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