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Objective sleep measures between patients with Parkinson's disease and community-based older adults
Journal Pre-proof Objective Sleep Measures between Patients with Parkinson’s Disease and Community-Based Older Adults Hiroshi Kataoka, Keigo Saeki, Norio Kurumatani, Kazuma Sugie, Kenji Obayashi PII:
S1389-9457(19)30322-3
DOI:
https://doi.org/10.1016/j.sleep.2019.09.010
Reference:
SLEEP 4190
To appear in:
Sleep Medicine
Received Date: 13 July 2019 Revised Date:
18 September 2019
Accepted Date: 19 September 2019
Please cite this article as: Kataoka H, Saeki K, Kurumatani N, Sugie K, Obayashi K, Objective Sleep Measures between Patients with Parkinson’s Disease and Community-Based Older Adults, Sleep Medicine, https://doi.org/10.1016/j.sleep.2019.09.010. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier B.V. All rights reserved.
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Objective Sleep Measures between Patients with Parkinson’s Disease and Community-Based Older Adults Running title: Objective sleep measures in PD
Hiroshi Kataoka1*, Keigo Saeki2, Norio Kurumatani2, Kazuma Sugie1, Kenji Obayashi2* 1 Department of Neurology, Nara Medical University School of Medicine, Nara, Japan. 2 Department of Epidemiology, Nara Medical University School of Medicine, Nara, Japan.
*
Corresponding author
Kenji Obayashi, MD, PhD 840 Shijocho, Kashiharashi, Nara, 634-8521, Japan Department of Epidemiology, Nara Medical University School of Medicine, Nara, Japan E-mail: [email protected] Phone: +81-744-29-8841, Fax: +81-744-29-0673 Hiroshi Kataoka, MD, PhD 840 Shijocho, Kashiharashi, Nara, 634-8521, Japan Department of Neurology, Nara Medical University School of Medicine, Nara, Japan E-mail: [email protected] Phone: +81-744-22-3051, Fax: +81-744-24-6065
Word count: abstract (2650), text (235) Number of tables: 2, Number of figures: 1, Number of supplemental files: 0
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Abstract
Objectives: Previous studies comparing objective sleep measures between patients with Parkinson’s disease (PD) and control participants were limited by their small sample size. The purpose of this study was to compare objective sleep measures between large-scale cohorts of PD outpatients and community-based older adults. Methods: In this cross-sectional study, we measured sleep parameters for 157 PD patients using an actigraph on the non-dominant wrist for six consecutive nights (95 Hoehn–Yahr stage I/II; 62 Hoehn–Yahr stage III–V). Moreover, two consecutive nights of actigraphy were performed on 1101 community-based control participants aged ≥60 years. Results: In multivariable analysis, sleep efficiency (SE) was significantly lower in patients with late-stage PD by 17.5% [95% confidence interval: 15.3%–19.7%] and early-stage PD by 9.4% [7.6%–11.1%] compared to the controls (67.1% and 75.3% vs. 84.6%, respectively). Similar results were observed for wake after sleep onset (WASO) and fragmentation index (FI). Total sleep time and sleep onset latency (SOL) were significantly shorter in patients with late- and early-stage PD stage compared to the controls. Among PD patients, significant association trends between advancement of individual Hoehn–Yahr stages and worsened sleep measures of SE, WASO, and FI were observed independently of age, gender, levodopa equivalent dose, and motor function parameter. Conclusion: This study demonstrated significant and quantitative differences in objective sleep quality and quantity between PD patients and control participants. Furthermore, with advancement of disease stages, objectively measured sleep quality worsened in PD patients.
Keyword: Actigraphy, sleep, older adult, Parkinson’s disease, objective measures.
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INTRODUCTION Sleep problems are one of the most common non-motor symptoms in Parkinson's disease (PD) patients; more than 40% of patients suffer from problems related to the initiation and maintenance of sleep [1–3]. These problems are influenced by various conditions, including neuronal loss in the dopaminergic systems [4]. Several previous studies have reported a significant decrease in sleep quality, even in early PD. Currently, polysomnography (PSG) is the gold standard method for sleep measurement in laboratory settings. However, studies with PD patients have shown good correlations between actigraphy and PSG sleep measures [5]. A PSG study showed a 7% decrease in sleep efficiency (SE) in 29 patients with early PD compared to 15 age/gender-matched controls [6]. Another found 17.2% decreases in SE and 21.1 min increases in sleep onset latency (SOL) in the PD patients (n = 56), including 34 early-stage and 22 late-stage PD patients, compared to 68 controls [7]. Regarding studies using actigraphy, a study reported a 10.4% decrease in SE and a 48.4 min decrease in total sleep time (TST) in PD patients (n = 30) compared to controls (n = 14) [8]. Another found 9.6% and 17.6% decreases in SE and 43.4 min and 77.0 min increases in wake after sleep onset (WASO) in patients with early-stage PD (n = 9) and late-stage PD (n = 18), respectively, compared to 30 controls [9]. However, a PSG study reported no significant differences in sleep measures between PD patients (n = 16) and controls (n = 10) [10]. An actigraphy study has also reported no significant differences in sleep measures between early-stage PD patients (n = 18) and controls (n = 18) [11]. Other studies have found conflicting results, possibly due to small numbers of cases and controls in these studies [12–14]. The purpose of the present study was to quantitatively compare objective sleep measures using actigraphy between large-scale cohorts of PD outpatients and community-based older adults.
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PARTICIPANTS AND METHODS Participants Between October 2014 and June 2015, 161 PD outpatients were recruited from the Nara Medical University Hospital and related hospitals in the Parkinson’s disease and the relationships with circadian biological rhythms and sleep (PHASE) study. PD was diagnosed according to the UK Parkinson’s Disease Society Brain Bank criteria [15]. Demographic and medical information was collected via a standardized questionnaire. Of 161 PD outpatients, 157 patients completed home actigraphy measurements, kept a sleep diary for six consecutive days, and underwent basic neurological examinations. All patients were on stable medication doses for at least one-month pre-study and none had multiple system atrophy, progressive supranuclear palsy, dementia with Lewy bodies, any other atypical Parkinsonian syndrome (eg, vascular Parkinsonism, large vessel disease, cerebral infarction, brain tumor) or a history of cranial surgical intervention, including deep brain stimulation surgery. The control participants were from the Housing environments and health investigation among Japanese older people in Nara, Kansai region: a prospective community-based cohort (HEIJO-KYO) study of 1127 community-dwelling individuals aged ≥60 years, assembled with the cooperation of local residents’ associations and elderly residents’ clubs between September and April in the years 2010–2014 [16]. Of these, anyone diagnosed with PD or who did not complete home actigraphy measurements and sleep diary was excluded, leaving 1101 participants. All the participants provided written informed consent. Nara Medical University’s ethics committee approved the study protocol.
Sleep Measures Physical activity was measured at 1-min intervals using an actigraph (Actiwatch 2; Respironics Inc., PA, USA) worn on the non-dominant wrist during six nights by the PD
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patients and two nights by the control participants. The participants recorded their bedtime and rising time in standardized sleep diaries. Sleep status at each epoch, sleep onset, and sleep termination were automatically determined by Actiware v5.5 software (Respironics Inc.) using the following algorithm. Awake epochs were defined by activity counts >10 counts/min (PD patients) or >40 counts/min (controls) because of lower activity thresholds suggesting better correlations with PSG data in PD patients [5]. Sleep onset was defined as the first minute followed by an immobility period lasting at least 5-min in PD patients and 10-min in controls. Similarly, sleep termination was defined as the last-minute after an immobility period lasting at least 5-min in PD patients and 10-min in controls [5,17]. Five objective sleep parameters were determined from actigraphic and self-reported data of bedtime and rising time: SE, the time spent sleeping as a percentage of the total time between bedtime and rising time; WASO, the time spent awake between sleep onset and offset; SOL, the time between bedtime and sleep onset; TST, time between bedtime and rising time × SE; and the fragmentation index (FI), the number of 1-min immobile epochs as a percentage of the total number of immobile epochs between bedtime and rising time. For subjective sleep measure, the scores of Pittsburg Sleep Questionnaire Index (PSQI) were measured. Subjective sleep disturbances were defined as the PSQI score of ≥6 [18].
Other Variables Body mass index (BMI) was calculated from body weight and height and information regarding smoking, drinking, and socioeconomic status was obtained from a self-administered questionnaire. Hypertension and diabetes were established from the participants’ current therapy. Sleep drugs included prescription pills, such as benzodiazepine receptor agonists, non-benzodiazepine hypnotics, melatonin receptor agonists, and orexin antagonists. PD stage in the “ON” state was rated according to the Hoehn–Yahr stage as early
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(I and II) or late (III–V) [19]. The daily dose of anti-parkinsonian agents at study entry was converted into the levodopa equivalent dose, as follows [20)]: (regular levodopa dose × 1) + (levodopa-controlled release dose × 0.75) + (entacapone or stalevo × 0.33) + (pramipexole dose × 100) + (ropinirole dose × 20) + (rotigotine dose × 30) + (pergolide dose and cabergoline dose × 67) + (bromocriptine dose × 10) + (selegiline dose × 10) + (amantadine dose × 1). The Unified Parkinson’s Disease Rating Scale (UPDRS) III score was assessed and REM sleep behavior disorder (RBD) was defined as a score ≥5 in the RBD screening questionnaire [21].
Statistical Analysis Variables were expressed as the mean ± standard deviation (SD) if normally distributed, or as the median with interquartile range (IQR) otherwise. SOL was log-transformed for the analyses. Sleep measures were averaged over the measurement days. Means and medians were compared between groups using unpaired t-tests and Mann–Whitney U tests, respectively, and categorical data using chi-square or Fisher’s exact tests. Multivariable linear regression models to compare sleep parameters between PD patients (early and late disease stage) and controls were adjusted for age (per year), gender, BMI (per kg/m2), current smoking, drinking status (daily or not), education period (≥13 years or less), household income (≥4 million Japanese yen/year or less), hypertension, diabetes, and sleeping drug administration. In the analysis by detailed disease stage among PD patients, the models were adjusted for age, gender, levodopa equivalent dose, and UPDRS-III score. In addition, odds ratios (ORs) for subjective sleep disturbances in PD patients compared with controls were estimated using multivariable logistic regression models. The number of missing data in PD patients was BMI (n = 2), household income (n = 13), and diabetes (n = 2); that in control participants was household income (n = 84). These missing data were substituted with the
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mean, median, or proportion values. The statistical analyses were performed using SPSS version 24.0 for Windows (IBM SPSS Inc., IL, USA). Statistical significance was assigned to a two-sided P-value < 0.05.
RESULTS Of the 157 PD patients, 95 had early-stage PD (30 Hoehn–Yahr stage Ⅰ and 65 stage II) and 62 late-stage PD (25 stage III and 37 stages IV/V). The median duration after PD diagnosis was 57 months (IQR, 33, 102) and the mean daily levodopa-equivalent dose was 487.8 ± 375.9 mg. Mean age did not differ significantly between the PD patients and controls, but the PD patients had significantly lower BMIs and a lower prevalence of habitual drinking and hypertension (Table 1). The prevalence of RBD symptoms was 40.8%. Objective sleep measures were poorer in the late-stage and early-stage PD groups than in the control group (Table 2). In the unadjusted analyses, mean SE was significantly lower, WASO significantly longer, and TST significantly shorter in the late-stage and early-stage PD groups than in the control group (SE: 67.4% and 75.3% vs. 84.6%; WASO: 121.4 and 93.8 min vs. 49.8 min; TST: 324.8 and 356.0 min vs. 420.1 min). FI was significantly higher in the late-stage group than the control group (4.4 vs. 3.0). In contrast, median SOL was significantly shorter in the late-stage and early stage PD groups than in the control group (10.0 and 12.2 min vs. 18.5 min). Sensitivity analysis excluding individuals administering sleep drugs (n = 140) suggested consistent result regarding all parameters (data not shown). In the adjusted multivariable models, the late-stage and early-stage groups showed the following significant results compared to the control group: lower SE, by 17.5% [95% CI, 15.3%–19.7%] and 9.4% [7.6%–11.1%], respectively; longer WASO, by 71.2 [62.8–79.7] min and 43.8 [36.9–50.7] min; shorter TST, by 101.1 [82.5–119.8] min and 62.5 [47.3–77.7] min; but shorter SOL, by 0.5 [0.2–0.7] log min and 0.4 [0.2–0.6] log min. FI was
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significantly higher in the late-stage group than the control group by 1.4 [0.5–2.3]. Objective sleep measures in PD group by individual disease stage (Hoehn–Yahr stage I, II, III, and IV/V) were shown compared with control group (Figure 1). Among PD group, significant association trends between the advancement of individual disease stage (Hoehn–Yahr stages I, II, III, and IV/V) and sleep measures (SE, WASO, and FI) were observed (SE, P for trend = 0.034; WASO, P for trend = 0.007; and FI, P for trend = 0.013). These were consistent in the analysis adjusting for age, gender, levodopa equivalent dose, and UPDRS-III score (mean, 24.4; SD, 14.9). Regarding subjective sleep measures, the median score of PSQI was significantly higher in PD group (median, 5; IQR, 3, 8) than that in control group (median, 4; IQR, 3, 7; P <0.001). The OR for subjective sleep disturbances was significantly higher in the late-stage group than control group after adjustment for same parameters in table 2 (adjusted OR, 2.63; 95% CI, 1.51, 4.58; P = 0.001) but not the early-stage group (adjusted OR, 1.46; 95% CI, 0.93, 2.31; P = 0.10).
DISCUSSION The present study suggested quantitative differences in objectively measured sleep quality and quantity between PD patients and control participants, including significantly decreased SE (by about 17% and 9% in the late and early PD stages compared with controls) and shorter TST (by about 100 min and 62 min). To the best of our knowledge, this is the first study to report objective sleep measures based on large samples of PD patients and non-PD controls, which enabled the construction of statistical models adjusted for multiple potential confounding factors. Our results were consistent with previous evidence of differences in objective sleep measures between PD patients and controls. An actigraphy study found a 10.4% decrease in
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SE and 48.4 min shorter TST in 30 PD patients compared with 14 controls [8]. Another reported a 17.6% decrease in SE and a 77.0 min increase in WASO in 18 late-stage PD patients compared with 30 controls [9]. Other actigraphy studies have reported conflicting results [11–13]. However, these studies were limited by their small numbers of participants and by not using validated analytic methods for actigraphic data. Our results were based on actigraphic data from 157 PD outpatients and 1101 community-based older adults and used previously validated algorithms and thresholds for actigraphic sleep measures in PD patients and control participants. Even the patients with early-stage PD in our study showed decreased sleep quality and shortened sleep time compared with the controls, including SE lower by 9.4% and WASO increased by 43.8 min. These results were consistent with a previous actigraphy study that reported a 9.6% decrease in SE and a 43.4 min increase in WASO in nine patients with early-stage PD compared with 30 controls [9]. The decrease in actigraphy-measured TST for early-stage PD patients was also similar between the two studies (62.5 min and 58.5 min, respectively). In addition, our data showed possible decreased sleep quality and shortened sleep time even in patients with Hoehn–Yahr stage Ⅰ (as can been in Figure 1). However, only 30 patients were at Hoehn–Yahr stage Ⅰ; further large-scale studies are needed to confirm this. A recent advance in understanding the pathophysiology of PD has suggested potential mechanisms underlying sleep problems in PD. Over 40% of PD patients have a problem related to sleep initiation and maintenance [1–3]. Moreover, PD-related sleep problems can be influenced by multiple conditions, including neuronal loss in the dopaminergic systems, RBD symptoms, and nocturia [3,4,22,23]. A recent study revealed neuropathologic involvements of Lewy bodies and Lewy neurites in the suprachiasmatic nucleus and pineal gland of PD patients that regulate circadian biological rhythms and sleep [24]. Furthermore,
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increased sleep fragmentation was reportedly related to the presence of Lewy body pathology in older adults without PD that was independent of the motor features of parkinsonism, depression, urinary incontinence, and other symptoms and medical comorbidities [25]. Our results suggested that FI was markedly higher in patients at Hoehn–Yahr stage III or above than in those at stages I and II. In addition, our analysis among PD patients suggested that the significant associations between advancement of disease stage and worsened sleep measures were independent of levodopa equivalent dose and UPDRS-III score, potentially suggesting that sleep problems in PD could not be explained only as dopamine- and motor-responsive symptoms. Strengths of the present study included measuring objective sleep measures with the same actigraph in large samples; earlier studies were limited in their ability to adjust for potential confounding factors because of the small sample sizes. However, this study had several potential limitations. First, the PD diagnosis was not supported by meta-iodobenzylguanidine myocardial scintigraphy, although no prompt mistakes were observed during the follow-up period. Second, while sleep measures in PD were determined using a method that had been validated against PSG, significant wrist tremor and dyskinesia may have influenced the actigraphic data; however, as yet there are no analytic methods to compensate for these involuntary movements. Third, the sleep parameters were measured only over two nights for the control participants, potentially leading to misclassification, although a previous study reported a moderately high correlation in the average data obtained over two and 14 nights [26]. Fourth, the control participants were not randomly selected, possibly leading to selection bias, although BMI and estimated glomerular filtration rate data were similar to those from a nationwide survey [27]. In addition, the control group did not include anyone diagnosed with PD, although they have not been examined by neurologists. Thus, there might be some early stage PD patients, although this may lead to underestimation
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of the detected differences in objective sleep measures. Finally, we did not measure UPDRS-III score in control participants, this parameter could not be entered in the multivariable analysis. In conclusion, our findings, based on large sample sizes, indicated quantitative differences in objective sleep quality and quantity between PD patients and control participants. Significant decreases in sleep quality and sleep time were observed even in patients with early-stage PD.
Acknowledgements We would like to thank Naomi Takenaka, Sachiko Sogahara, and Keiko Nakajima for their valuable help with data collection and analysis. This work was supported by research funding from JSPS KAKENHI (grant numbers: 15K09356). The funder had no role in the study design, data collection and analysis, decision to publish, and preparation of the manuscript.
Conflict of interest
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Drs. Obayashi and Saeki received research grant from YKK AP Inc., Ushio Inc., Tokyo Electric Power Company; EnviroLife Research Institute Co., Ltd.; and Sekisui Chemical Co., Ltd.; LIXIL Corp.; and KYOCERA Corp. The other authors reported no conflict of interest.
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Figure Legend
Figure 1. Objective sleep measures in Parkinson’s disease patients by individual disease stage (Hoehn–Yahr stage I, II, III, and IV/V) compared with control participants. Solid bars indicate unadjusted mean values of sleep measures.
Table 1. Basic and clinical characteristics between PD patients and control group PD
Control
Characteristics
( n = 157 )
( n = 1101 )
P
Age, mean (SD), years
71.4 (7.7)
71.9 (7.1)
0.44
86 (54.8%)
515 (46.8%)
0.06
Body mass index, mean (SD), kg/m
22.2 (3.6)
23.1 (3.1)
<0.001
Current smoker, number
9 (5.7%)
55 (5.0%)
0.69
Habitual drinker, number
20 (12.7%)
266 (24.2%)
0.001
Past education (≥13 years), number
47 (29.9%)
294 (26.7%)
0.39
Household income (≥4 million JPY), number
52 (36.1%)
437 (43.0%)
0.12
Hypertension, number
51 (32.5%)
489 (44.4%)
0.005
Diabetes, number
20 (12.9%)
105 (9.5%)
0.19
Sleep drug administration, number
22 (14.0%)
118 (10.7%)
0.44
PD duration, median (IQR), month
57 (33, 102)
-----
Levodopa equivalent dose, mean (SD), mg/day
487.8 (375.9)
-----
64 (40.8%)
-----
Gender, male 2
RBD symptoms (score ≥5), number
SD, standard deviation; IQR, interquartile range; PD, Parkinson's disease; JPY, Japanese Yen; RBD, REM sleep behavior disorder.
Table 2. Objective sleep parameters in PD patients compared with control group PD Hoehn-Yahr Stage Unadjusted Sleep efficiency, mean (SD), % difference (95% CI) P WASO, mean (SD), min difference (95% CI) P SOL, median (IQR), min mean (SD), log min difference (95% CI) P FI, mean (SD) difference (95% CI) P TST, mean (SD), min difference (95% CI) P Adjusted* Sleep efficiency, mean (SE), % difference (95% CI) P WASO, mean (SE), min difference (95% CI) P SOL, mean (SE), log min difference (95% CI) P FI, mean (SE) difference (95% CI) P TST, mean (SE), min difference (95% CI) P
Control ( n = 1101 ) 84.6 (7.7) reference 49.8 (29.1) reference 18.5 (9.5, 36.5) 3.0 (1.0) reference 3.0 (3.5) reference 420.1 (69.6) reference
84.6 (0.3) reference 49.8 (1.0) reference 3.0 (0.03) reference 3.0 (0.1) reference 420.3 (2.2) reference
Early ( n = 95 ) 75.3 (10.8) -9.4 (-11.2, -7.6) <0.001 93.8 (44.5) 44.1 (37.1, 51.1) <0.001 12.2 (6.0, 20.0) 2.5 (0.9) -0.5 (-0.7, -0.3) <0.001 2.9 (2.5) -0.1 (-0.8, 0.6) 0.81 356.0 (98.9) -64.1 (-79.8, -48.5) <0.001
Late ( n = 62 ) 67.4 (15.9) -17.3 (-19.5, -15.1) <0.001 121.4 (69.1) 71.7 (63.1, 80.2) <0.001 10.0 (5.6, 19.1) 2.4 (0.8) -0.5 (-0.8, -0.3) <0.001 4.4 (4.2) 1.4 (0.5, 2.3) 0.002 324.8 (109.4) -95.3 (-114.4, -76.2) <0.001
75.3 (0.9) -9.4 (-11.1, -7.6) <0.001 93.7 (3.4) 43.8 (36.9, 50.7) <0.001 2.5 (0.10) -0.4 (-0.6, -0.2) <0.001 2.8 (0.4) -0.1 (-0.9, 0.6) 0.72 319.2 (9.2) -62.5 ( -77.7, -47.3) <0.001
67.1 (1.1) -17.5 (-19.7, -15.3) <0.001 121.0 (4.2) 71.2 (62.8, 79.7) <0.001 2.5 (0.12) -0.5 (-0.7, -0.2) <0.001 4.4 (0.4) 1.4 (0.5, 2.3) 0.002 357.8 (7.4) -101.1 (-119.8, -82.5) <0.001
CI, confidence interval; SD, standard deviation; IQR, interquartile range; SE, standard error; WASO, wake after sleep onset; SOL, sleep onset latency; FI, fragmentation index; TST, total sleep time. Early and late PD stages indicate the Hoehn–Yahr stage I/II and stage III–V, respectively. *Adjusted for age, gender, body mass index, current smoking, habitual drinking, past education, household income, hypertension, diabetes, and sleep drug administration.
Figure 1.
(%) 90
SE
(min) 150
WASO
(log min) 4
5
(min) 500
TST
4
3 80
FI
SOL
100
400 3 2
70
2
50
300
1 1 60
0
C Ⅰ ⅠⅠ ⅠⅠⅠ Ⅳ/Ⅴ
0
0
C Ⅰ ⅠⅠ ⅠⅠⅠ Ⅳ/Ⅴ
C Ⅰ ⅠⅠ ⅠⅠⅠ Ⅳ/Ⅴ
C Ⅰ ⅠⅠ ⅠⅠⅠ Ⅳ/Ⅴ
200
C Ⅰ ⅠⅠ ⅠⅠⅠ Ⅳ/Ⅴ
Highlights
This study suggested objective sleep measures based on large samples of PD patients and non-PD controls. Early-stage PD showed decreased sleep quality and shortened sleep time compared with controls. These associations were independent of several potential confounding factors.
S1389-9457(19)30322-3
DOI:
https://doi.org/10.1016/j.sleep.2019.09.010
Reference:
SLEEP 4190
To appear in:
Sleep Medicine
Received Date: 13 July 2019 Revised Date:
18 September 2019
Accepted Date: 19 September 2019
Please cite this article as: Kataoka H, Saeki K, Kurumatani N, Sugie K, Obayashi K, Objective Sleep Measures between Patients with Parkinson’s Disease and Community-Based Older Adults, Sleep Medicine, https://doi.org/10.1016/j.sleep.2019.09.010. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier B.V. All rights reserved.
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Objective Sleep Measures between Patients with Parkinson’s Disease and Community-Based Older Adults Running title: Objective sleep measures in PD
Hiroshi Kataoka1*, Keigo Saeki2, Norio Kurumatani2, Kazuma Sugie1, Kenji Obayashi2* 1 Department of Neurology, Nara Medical University School of Medicine, Nara, Japan. 2 Department of Epidemiology, Nara Medical University School of Medicine, Nara, Japan.
*
Corresponding author
Kenji Obayashi, MD, PhD 840 Shijocho, Kashiharashi, Nara, 634-8521, Japan Department of Epidemiology, Nara Medical University School of Medicine, Nara, Japan E-mail: [email protected] Phone: +81-744-29-8841, Fax: +81-744-29-0673 Hiroshi Kataoka, MD, PhD 840 Shijocho, Kashiharashi, Nara, 634-8521, Japan Department of Neurology, Nara Medical University School of Medicine, Nara, Japan E-mail: [email protected] Phone: +81-744-22-3051, Fax: +81-744-24-6065
Word count: abstract (2650), text (235) Number of tables: 2, Number of figures: 1, Number of supplemental files: 0
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Abstract
Objectives: Previous studies comparing objective sleep measures between patients with Parkinson’s disease (PD) and control participants were limited by their small sample size. The purpose of this study was to compare objective sleep measures between large-scale cohorts of PD outpatients and community-based older adults. Methods: In this cross-sectional study, we measured sleep parameters for 157 PD patients using an actigraph on the non-dominant wrist for six consecutive nights (95 Hoehn–Yahr stage I/II; 62 Hoehn–Yahr stage III–V). Moreover, two consecutive nights of actigraphy were performed on 1101 community-based control participants aged ≥60 years. Results: In multivariable analysis, sleep efficiency (SE) was significantly lower in patients with late-stage PD by 17.5% [95% confidence interval: 15.3%–19.7%] and early-stage PD by 9.4% [7.6%–11.1%] compared to the controls (67.1% and 75.3% vs. 84.6%, respectively). Similar results were observed for wake after sleep onset (WASO) and fragmentation index (FI). Total sleep time and sleep onset latency (SOL) were significantly shorter in patients with late- and early-stage PD stage compared to the controls. Among PD patients, significant association trends between advancement of individual Hoehn–Yahr stages and worsened sleep measures of SE, WASO, and FI were observed independently of age, gender, levodopa equivalent dose, and motor function parameter. Conclusion: This study demonstrated significant and quantitative differences in objective sleep quality and quantity between PD patients and control participants. Furthermore, with advancement of disease stages, objectively measured sleep quality worsened in PD patients.
Keyword: Actigraphy, sleep, older adult, Parkinson’s disease, objective measures.
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INTRODUCTION Sleep problems are one of the most common non-motor symptoms in Parkinson's disease (PD) patients; more than 40% of patients suffer from problems related to the initiation and maintenance of sleep [1–3]. These problems are influenced by various conditions, including neuronal loss in the dopaminergic systems [4]. Several previous studies have reported a significant decrease in sleep quality, even in early PD. Currently, polysomnography (PSG) is the gold standard method for sleep measurement in laboratory settings. However, studies with PD patients have shown good correlations between actigraphy and PSG sleep measures [5]. A PSG study showed a 7% decrease in sleep efficiency (SE) in 29 patients with early PD compared to 15 age/gender-matched controls [6]. Another found 17.2% decreases in SE and 21.1 min increases in sleep onset latency (SOL) in the PD patients (n = 56), including 34 early-stage and 22 late-stage PD patients, compared to 68 controls [7]. Regarding studies using actigraphy, a study reported a 10.4% decrease in SE and a 48.4 min decrease in total sleep time (TST) in PD patients (n = 30) compared to controls (n = 14) [8]. Another found 9.6% and 17.6% decreases in SE and 43.4 min and 77.0 min increases in wake after sleep onset (WASO) in patients with early-stage PD (n = 9) and late-stage PD (n = 18), respectively, compared to 30 controls [9]. However, a PSG study reported no significant differences in sleep measures between PD patients (n = 16) and controls (n = 10) [10]. An actigraphy study has also reported no significant differences in sleep measures between early-stage PD patients (n = 18) and controls (n = 18) [11]. Other studies have found conflicting results, possibly due to small numbers of cases and controls in these studies [12–14]. The purpose of the present study was to quantitatively compare objective sleep measures using actigraphy between large-scale cohorts of PD outpatients and community-based older adults.
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PARTICIPANTS AND METHODS Participants Between October 2014 and June 2015, 161 PD outpatients were recruited from the Nara Medical University Hospital and related hospitals in the Parkinson’s disease and the relationships with circadian biological rhythms and sleep (PHASE) study. PD was diagnosed according to the UK Parkinson’s Disease Society Brain Bank criteria [15]. Demographic and medical information was collected via a standardized questionnaire. Of 161 PD outpatients, 157 patients completed home actigraphy measurements, kept a sleep diary for six consecutive days, and underwent basic neurological examinations. All patients were on stable medication doses for at least one-month pre-study and none had multiple system atrophy, progressive supranuclear palsy, dementia with Lewy bodies, any other atypical Parkinsonian syndrome (eg, vascular Parkinsonism, large vessel disease, cerebral infarction, brain tumor) or a history of cranial surgical intervention, including deep brain stimulation surgery. The control participants were from the Housing environments and health investigation among Japanese older people in Nara, Kansai region: a prospective community-based cohort (HEIJO-KYO) study of 1127 community-dwelling individuals aged ≥60 years, assembled with the cooperation of local residents’ associations and elderly residents’ clubs between September and April in the years 2010–2014 [16]. Of these, anyone diagnosed with PD or who did not complete home actigraphy measurements and sleep diary was excluded, leaving 1101 participants. All the participants provided written informed consent. Nara Medical University’s ethics committee approved the study protocol.
Sleep Measures Physical activity was measured at 1-min intervals using an actigraph (Actiwatch 2; Respironics Inc., PA, USA) worn on the non-dominant wrist during six nights by the PD
5
patients and two nights by the control participants. The participants recorded their bedtime and rising time in standardized sleep diaries. Sleep status at each epoch, sleep onset, and sleep termination were automatically determined by Actiware v5.5 software (Respironics Inc.) using the following algorithm. Awake epochs were defined by activity counts >10 counts/min (PD patients) or >40 counts/min (controls) because of lower activity thresholds suggesting better correlations with PSG data in PD patients [5]. Sleep onset was defined as the first minute followed by an immobility period lasting at least 5-min in PD patients and 10-min in controls. Similarly, sleep termination was defined as the last-minute after an immobility period lasting at least 5-min in PD patients and 10-min in controls [5,17]. Five objective sleep parameters were determined from actigraphic and self-reported data of bedtime and rising time: SE, the time spent sleeping as a percentage of the total time between bedtime and rising time; WASO, the time spent awake between sleep onset and offset; SOL, the time between bedtime and sleep onset; TST, time between bedtime and rising time × SE; and the fragmentation index (FI), the number of 1-min immobile epochs as a percentage of the total number of immobile epochs between bedtime and rising time. For subjective sleep measure, the scores of Pittsburg Sleep Questionnaire Index (PSQI) were measured. Subjective sleep disturbances were defined as the PSQI score of ≥6 [18].
Other Variables Body mass index (BMI) was calculated from body weight and height and information regarding smoking, drinking, and socioeconomic status was obtained from a self-administered questionnaire. Hypertension and diabetes were established from the participants’ current therapy. Sleep drugs included prescription pills, such as benzodiazepine receptor agonists, non-benzodiazepine hypnotics, melatonin receptor agonists, and orexin antagonists. PD stage in the “ON” state was rated according to the Hoehn–Yahr stage as early
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(I and II) or late (III–V) [19]. The daily dose of anti-parkinsonian agents at study entry was converted into the levodopa equivalent dose, as follows [20)]: (regular levodopa dose × 1) + (levodopa-controlled release dose × 0.75) + (entacapone or stalevo × 0.33) + (pramipexole dose × 100) + (ropinirole dose × 20) + (rotigotine dose × 30) + (pergolide dose and cabergoline dose × 67) + (bromocriptine dose × 10) + (selegiline dose × 10) + (amantadine dose × 1). The Unified Parkinson’s Disease Rating Scale (UPDRS) III score was assessed and REM sleep behavior disorder (RBD) was defined as a score ≥5 in the RBD screening questionnaire [21].
Statistical Analysis Variables were expressed as the mean ± standard deviation (SD) if normally distributed, or as the median with interquartile range (IQR) otherwise. SOL was log-transformed for the analyses. Sleep measures were averaged over the measurement days. Means and medians were compared between groups using unpaired t-tests and Mann–Whitney U tests, respectively, and categorical data using chi-square or Fisher’s exact tests. Multivariable linear regression models to compare sleep parameters between PD patients (early and late disease stage) and controls were adjusted for age (per year), gender, BMI (per kg/m2), current smoking, drinking status (daily or not), education period (≥13 years or less), household income (≥4 million Japanese yen/year or less), hypertension, diabetes, and sleeping drug administration. In the analysis by detailed disease stage among PD patients, the models were adjusted for age, gender, levodopa equivalent dose, and UPDRS-III score. In addition, odds ratios (ORs) for subjective sleep disturbances in PD patients compared with controls were estimated using multivariable logistic regression models. The number of missing data in PD patients was BMI (n = 2), household income (n = 13), and diabetes (n = 2); that in control participants was household income (n = 84). These missing data were substituted with the
7
mean, median, or proportion values. The statistical analyses were performed using SPSS version 24.0 for Windows (IBM SPSS Inc., IL, USA). Statistical significance was assigned to a two-sided P-value < 0.05.
RESULTS Of the 157 PD patients, 95 had early-stage PD (30 Hoehn–Yahr stage Ⅰ and 65 stage II) and 62 late-stage PD (25 stage III and 37 stages IV/V). The median duration after PD diagnosis was 57 months (IQR, 33, 102) and the mean daily levodopa-equivalent dose was 487.8 ± 375.9 mg. Mean age did not differ significantly between the PD patients and controls, but the PD patients had significantly lower BMIs and a lower prevalence of habitual drinking and hypertension (Table 1). The prevalence of RBD symptoms was 40.8%. Objective sleep measures were poorer in the late-stage and early-stage PD groups than in the control group (Table 2). In the unadjusted analyses, mean SE was significantly lower, WASO significantly longer, and TST significantly shorter in the late-stage and early-stage PD groups than in the control group (SE: 67.4% and 75.3% vs. 84.6%; WASO: 121.4 and 93.8 min vs. 49.8 min; TST: 324.8 and 356.0 min vs. 420.1 min). FI was significantly higher in the late-stage group than the control group (4.4 vs. 3.0). In contrast, median SOL was significantly shorter in the late-stage and early stage PD groups than in the control group (10.0 and 12.2 min vs. 18.5 min). Sensitivity analysis excluding individuals administering sleep drugs (n = 140) suggested consistent result regarding all parameters (data not shown). In the adjusted multivariable models, the late-stage and early-stage groups showed the following significant results compared to the control group: lower SE, by 17.5% [95% CI, 15.3%–19.7%] and 9.4% [7.6%–11.1%], respectively; longer WASO, by 71.2 [62.8–79.7] min and 43.8 [36.9–50.7] min; shorter TST, by 101.1 [82.5–119.8] min and 62.5 [47.3–77.7] min; but shorter SOL, by 0.5 [0.2–0.7] log min and 0.4 [0.2–0.6] log min. FI was
8
significantly higher in the late-stage group than the control group by 1.4 [0.5–2.3]. Objective sleep measures in PD group by individual disease stage (Hoehn–Yahr stage I, II, III, and IV/V) were shown compared with control group (Figure 1). Among PD group, significant association trends between the advancement of individual disease stage (Hoehn–Yahr stages I, II, III, and IV/V) and sleep measures (SE, WASO, and FI) were observed (SE, P for trend = 0.034; WASO, P for trend = 0.007; and FI, P for trend = 0.013). These were consistent in the analysis adjusting for age, gender, levodopa equivalent dose, and UPDRS-III score (mean, 24.4; SD, 14.9). Regarding subjective sleep measures, the median score of PSQI was significantly higher in PD group (median, 5; IQR, 3, 8) than that in control group (median, 4; IQR, 3, 7; P <0.001). The OR for subjective sleep disturbances was significantly higher in the late-stage group than control group after adjustment for same parameters in table 2 (adjusted OR, 2.63; 95% CI, 1.51, 4.58; P = 0.001) but not the early-stage group (adjusted OR, 1.46; 95% CI, 0.93, 2.31; P = 0.10).
DISCUSSION The present study suggested quantitative differences in objectively measured sleep quality and quantity between PD patients and control participants, including significantly decreased SE (by about 17% and 9% in the late and early PD stages compared with controls) and shorter TST (by about 100 min and 62 min). To the best of our knowledge, this is the first study to report objective sleep measures based on large samples of PD patients and non-PD controls, which enabled the construction of statistical models adjusted for multiple potential confounding factors. Our results were consistent with previous evidence of differences in objective sleep measures between PD patients and controls. An actigraphy study found a 10.4% decrease in
9
SE and 48.4 min shorter TST in 30 PD patients compared with 14 controls [8]. Another reported a 17.6% decrease in SE and a 77.0 min increase in WASO in 18 late-stage PD patients compared with 30 controls [9]. Other actigraphy studies have reported conflicting results [11–13]. However, these studies were limited by their small numbers of participants and by not using validated analytic methods for actigraphic data. Our results were based on actigraphic data from 157 PD outpatients and 1101 community-based older adults and used previously validated algorithms and thresholds for actigraphic sleep measures in PD patients and control participants. Even the patients with early-stage PD in our study showed decreased sleep quality and shortened sleep time compared with the controls, including SE lower by 9.4% and WASO increased by 43.8 min. These results were consistent with a previous actigraphy study that reported a 9.6% decrease in SE and a 43.4 min increase in WASO in nine patients with early-stage PD compared with 30 controls [9]. The decrease in actigraphy-measured TST for early-stage PD patients was also similar between the two studies (62.5 min and 58.5 min, respectively). In addition, our data showed possible decreased sleep quality and shortened sleep time even in patients with Hoehn–Yahr stage Ⅰ (as can been in Figure 1). However, only 30 patients were at Hoehn–Yahr stage Ⅰ; further large-scale studies are needed to confirm this. A recent advance in understanding the pathophysiology of PD has suggested potential mechanisms underlying sleep problems in PD. Over 40% of PD patients have a problem related to sleep initiation and maintenance [1–3]. Moreover, PD-related sleep problems can be influenced by multiple conditions, including neuronal loss in the dopaminergic systems, RBD symptoms, and nocturia [3,4,22,23]. A recent study revealed neuropathologic involvements of Lewy bodies and Lewy neurites in the suprachiasmatic nucleus and pineal gland of PD patients that regulate circadian biological rhythms and sleep [24]. Furthermore,
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increased sleep fragmentation was reportedly related to the presence of Lewy body pathology in older adults without PD that was independent of the motor features of parkinsonism, depression, urinary incontinence, and other symptoms and medical comorbidities [25]. Our results suggested that FI was markedly higher in patients at Hoehn–Yahr stage III or above than in those at stages I and II. In addition, our analysis among PD patients suggested that the significant associations between advancement of disease stage and worsened sleep measures were independent of levodopa equivalent dose and UPDRS-III score, potentially suggesting that sleep problems in PD could not be explained only as dopamine- and motor-responsive symptoms. Strengths of the present study included measuring objective sleep measures with the same actigraph in large samples; earlier studies were limited in their ability to adjust for potential confounding factors because of the small sample sizes. However, this study had several potential limitations. First, the PD diagnosis was not supported by meta-iodobenzylguanidine myocardial scintigraphy, although no prompt mistakes were observed during the follow-up period. Second, while sleep measures in PD were determined using a method that had been validated against PSG, significant wrist tremor and dyskinesia may have influenced the actigraphic data; however, as yet there are no analytic methods to compensate for these involuntary movements. Third, the sleep parameters were measured only over two nights for the control participants, potentially leading to misclassification, although a previous study reported a moderately high correlation in the average data obtained over two and 14 nights [26]. Fourth, the control participants were not randomly selected, possibly leading to selection bias, although BMI and estimated glomerular filtration rate data were similar to those from a nationwide survey [27]. In addition, the control group did not include anyone diagnosed with PD, although they have not been examined by neurologists. Thus, there might be some early stage PD patients, although this may lead to underestimation
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of the detected differences in objective sleep measures. Finally, we did not measure UPDRS-III score in control participants, this parameter could not be entered in the multivariable analysis. In conclusion, our findings, based on large sample sizes, indicated quantitative differences in objective sleep quality and quantity between PD patients and control participants. Significant decreases in sleep quality and sleep time were observed even in patients with early-stage PD.
Acknowledgements We would like to thank Naomi Takenaka, Sachiko Sogahara, and Keiko Nakajima for their valuable help with data collection and analysis. This work was supported by research funding from JSPS KAKENHI (grant numbers: 15K09356). The funder had no role in the study design, data collection and analysis, decision to publish, and preparation of the manuscript.
Conflict of interest
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Drs. Obayashi and Saeki received research grant from YKK AP Inc., Ushio Inc., Tokyo Electric Power Company; EnviroLife Research Institute Co., Ltd.; and Sekisui Chemical Co., Ltd.; LIXIL Corp.; and KYOCERA Corp. The other authors reported no conflict of interest.
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Figure Legend
Figure 1. Objective sleep measures in Parkinson’s disease patients by individual disease stage (Hoehn–Yahr stage I, II, III, and IV/V) compared with control participants. Solid bars indicate unadjusted mean values of sleep measures.
Table 1. Basic and clinical characteristics between PD patients and control group PD
Control
Characteristics
( n = 157 )
( n = 1101 )
P
Age, mean (SD), years
71.4 (7.7)
71.9 (7.1)
0.44
86 (54.8%)
515 (46.8%)
0.06
Body mass index, mean (SD), kg/m
22.2 (3.6)
23.1 (3.1)
<0.001
Current smoker, number
9 (5.7%)
55 (5.0%)
0.69
Habitual drinker, number
20 (12.7%)
266 (24.2%)
0.001
Past education (≥13 years), number
47 (29.9%)
294 (26.7%)
0.39
Household income (≥4 million JPY), number
52 (36.1%)
437 (43.0%)
0.12
Hypertension, number
51 (32.5%)
489 (44.4%)
0.005
Diabetes, number
20 (12.9%)
105 (9.5%)
0.19
Sleep drug administration, number
22 (14.0%)
118 (10.7%)
0.44
PD duration, median (IQR), month
57 (33, 102)
-----
Levodopa equivalent dose, mean (SD), mg/day
487.8 (375.9)
-----
64 (40.8%)
-----
Gender, male 2
RBD symptoms (score ≥5), number
SD, standard deviation; IQR, interquartile range; PD, Parkinson's disease; JPY, Japanese Yen; RBD, REM sleep behavior disorder.
Table 2. Objective sleep parameters in PD patients compared with control group PD Hoehn-Yahr Stage Unadjusted Sleep efficiency, mean (SD), % difference (95% CI) P WASO, mean (SD), min difference (95% CI) P SOL, median (IQR), min mean (SD), log min difference (95% CI) P FI, mean (SD) difference (95% CI) P TST, mean (SD), min difference (95% CI) P Adjusted* Sleep efficiency, mean (SE), % difference (95% CI) P WASO, mean (SE), min difference (95% CI) P SOL, mean (SE), log min difference (95% CI) P FI, mean (SE) difference (95% CI) P TST, mean (SE), min difference (95% CI) P
Control ( n = 1101 ) 84.6 (7.7) reference 49.8 (29.1) reference 18.5 (9.5, 36.5) 3.0 (1.0) reference 3.0 (3.5) reference 420.1 (69.6) reference
84.6 (0.3) reference 49.8 (1.0) reference 3.0 (0.03) reference 3.0 (0.1) reference 420.3 (2.2) reference
Early ( n = 95 ) 75.3 (10.8) -9.4 (-11.2, -7.6) <0.001 93.8 (44.5) 44.1 (37.1, 51.1) <0.001 12.2 (6.0, 20.0) 2.5 (0.9) -0.5 (-0.7, -0.3) <0.001 2.9 (2.5) -0.1 (-0.8, 0.6) 0.81 356.0 (98.9) -64.1 (-79.8, -48.5) <0.001
Late ( n = 62 ) 67.4 (15.9) -17.3 (-19.5, -15.1) <0.001 121.4 (69.1) 71.7 (63.1, 80.2) <0.001 10.0 (5.6, 19.1) 2.4 (0.8) -0.5 (-0.8, -0.3) <0.001 4.4 (4.2) 1.4 (0.5, 2.3) 0.002 324.8 (109.4) -95.3 (-114.4, -76.2) <0.001
75.3 (0.9) -9.4 (-11.1, -7.6) <0.001 93.7 (3.4) 43.8 (36.9, 50.7) <0.001 2.5 (0.10) -0.4 (-0.6, -0.2) <0.001 2.8 (0.4) -0.1 (-0.9, 0.6) 0.72 319.2 (9.2) -62.5 ( -77.7, -47.3) <0.001
67.1 (1.1) -17.5 (-19.7, -15.3) <0.001 121.0 (4.2) 71.2 (62.8, 79.7) <0.001 2.5 (0.12) -0.5 (-0.7, -0.2) <0.001 4.4 (0.4) 1.4 (0.5, 2.3) 0.002 357.8 (7.4) -101.1 (-119.8, -82.5) <0.001
CI, confidence interval; SD, standard deviation; IQR, interquartile range; SE, standard error; WASO, wake after sleep onset; SOL, sleep onset latency; FI, fragmentation index; TST, total sleep time. Early and late PD stages indicate the Hoehn–Yahr stage I/II and stage III–V, respectively. *Adjusted for age, gender, body mass index, current smoking, habitual drinking, past education, household income, hypertension, diabetes, and sleep drug administration.
Figure 1.
(%) 90
SE
(min) 150
WASO
(log min) 4
5
(min) 500
TST
4
3 80
FI
SOL
100
400 3 2
70
2
50
300
1 1 60
0
C Ⅰ ⅠⅠ ⅠⅠⅠ Ⅳ/Ⅴ
0
0
C Ⅰ ⅠⅠ ⅠⅠⅠ Ⅳ/Ⅴ
C Ⅰ ⅠⅠ ⅠⅠⅠ Ⅳ/Ⅴ
C Ⅰ ⅠⅠ ⅠⅠⅠ Ⅳ/Ⅴ
200
C Ⅰ ⅠⅠ ⅠⅠⅠ Ⅳ/Ⅴ
Highlights
This study suggested objective sleep measures based on large samples of PD patients and non-PD controls. Early-stage PD showed decreased sleep quality and shortened sleep time compared with controls. These associations were independent of several potential confounding factors.