International Journal of Gerontology 11 (2017) 171e175

Contents lists available at ScienceDirect

International Journal of Gerontology

journal homepage: www.ijge-online.com

Original Article

The Relationship Between Fatigue and Other Non-Motor Symptoms in

Parkinson's Disease in Chinese Population
Jian Ding a, Si-Ming Jiang a, Yong-Sheng Yuan a, Qing Tong, Li Zhang, Qin-Rong Xu,
Ke-Zhong Zhang*
Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

a r t i c l e i n f o s u m m a r y

Article history: Background: The aim of our study was to explore in detail the relationship between fatigue and other
Received 20 February 2016 non-motor symptoms in Parkinson's disease (PD).
Received in revised form Methods: One hundred and four PD patients took part in our study. The Fatigue Severity Scale (FSS) was
17 May 2016
used to measure the severity of fatigue and a cut-off of 4 was used to define the presence of fatigue.
Accepted 27 May 2016
Patients who scored more than 4 were divided into the “fatigue group” while the other patients were
Available online 24 August 2017
allocated to the “no fatigue group”. The Non-motor Symptoms Scale (NMSS) was used to screen other
non-motor symptoms. The Parkinson's disease Sleep Scale (PDSS), Rapid Eye Movement Sleep Behavior
Keywords:
fatigue,
Disorders Scale (RBD) and Epworth Sleepiness Scale (ESS) were used to measure different kinds of sleep
non-motor symptoms, disorders, and the affective sphere were measured with the Hamilton Anxiety Scale (HAMA) and the
Parkinson's disease Hamilton Depression Scale (HAMD).
Result: Patients with fatigue in PD had higher levels in domain 2 (sleep disorders) (p < 0.001) and
domain 3 (mood/anxiety) (p < 0.05) of the NMSS. The severity of fatigue was positively associated with
excessive daytime sleepiness (rs ¼ 0.254, p ¼ 0.009), anxiety (rs ¼ 0.268, p ¼ 0.006) and depression
(rs ¼ 0.264, p ¼ 0.007).
Conclusion: Forty patients (42.4%) showed notable complaints of fatigue with FSS scores > 4. Among the
patients with fatigue, the severity of fatigue in PD patients was related to sleep and affective disorders. Of
the disorders, excessive daytime sleepiness, anxiety and depression were particularly linked to fatigue in
PD.
Copyright © 2017, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier
Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).

1. Introduction
The characteristic symptoms that develop in patients with Par-
kinson's disease (PD) are traditionally considered to be motor
symptoms.1 However, more recently, the important contribution of
non-motor symptoms (NMS) has drawn a great deal of attention.2 A
study of 92 PD patients showed that almost all patients suffered
from at least one type of non-motor symptoms.3 Non-motor
symptoms constitute the main source of adversity to patients and
have a negative impact on their quality of life (QoL).4,5
Fatigue can be defined as “a sense of tiredness, lack of energy,
and a feeling of total exhaustion” and consists of mental fatigue and
* Corresponding author. Department of Neurology, The First Affiliated Hospital of
Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, China.
E-mail address: kezhong_zhang1969@126.com (K.-Z. Zhang).
a
The first three authors contributed equally to this work.
physical fatigue in PD.6,7 The prevalence ranges from 33% to 58%in
patients with PD, contrast to a prevalence of only 20% in the general
population.8e10 It is likely to be one of the most troublesome
symptoms for patients and limits their ability to enjoy social ac-
tivities. Despite this, it is often overlooked during routine follow-
up.7 Previous studies have reported that fatigue in PD patients is
related to sex, disease duration, anxiety and depression.11e14
Although several previous studies have shown a relationship be-
tween fatigue and other non-motor symptoms in PD patients, the
nature of the relationship has not been systemically examined and
its associations with other non-motor symptoms are unclear. Only
one study reported by Solla et al. showed that among all other non-
motor symptoms, sleep disorders and affective sphere were
thought to contribute to the severity of fatigue.15
Therefore, the aim of our study was to evaluate the prevalence of
fatigue in Chinese PD patients, and explore its relationship with
other non-motor symptoms in details.

http://dx.doi.org/10.1016/j.ijge.2016.05.011
1873-9598/Copyright © 2017, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier Taiwan LLC. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
172
2. Methods
2.1. Patients
One hundred and four PD patients who satisfied the UK PD Brain
Bank Criteria for the diagnosis of idiopathic PD were collected for
our study.16 Patients with Mini-Mental State Examination
(MMSE) < 24,17 as well as those who had corticobasal degeneration,
progressive supranuclear palsy, dementia with Lewy bodies,
vascular parkinsonism, or other forms of parkinsonism were
excluded from our study. Moreover, any patients with heart dis-
ease, pulmonary disease, renal failure, hepatic failure or cancer
were also excluded. The basic characteristics of PD patients
including age, disease duration, Unified Parkinson's disease Rating
Scale (UPDRS) I, II, III score, levodopa equivalent daily dose (LEDD),
etc. were also collected.18,19
Our study was approved by the ethics committee of the First
Affiliated Hospital of Nanjing Medical University and written
informed consent was obtained from each patient.
2.2. Defining fatigue in PD patients
The patients were divided into two groups: patients with and
without fatigue. As there is no recognized standard in the diagnosis
of fatigue in PD patients, we used the Fatigue Severity Scale (FSS) to
measure fatigue in our study.20 The FSS is widely used for its high
internal consistency and reliability. The FSS is a self-administered
9-item scale for measuring fatigue. Each answer is scored from
0 to 7, with a higher score meaning greater fatigue. Although it is
not a scale specifically designed for PD, a number of studies have
used the FSS to assess the severity of fatigue in patients with PD,
and a cut-off of 4 has been used to define the presence of fatigue.21
Patients who scored greater than four were allocated to the “fatigue
group” while the other patients were allocated to the “no fatigue
group”.
2.3. Primary screening tests
In the first phase, non-motor symptoms (NMS) were assessed
with the Non-Motor Symptoms Scale (NMSS).22 The NMSS is a
validated, 30-item self-reported questionnaire that has 9 domains:
cardiovascular, sleep disorders, mood/anxiety, perceptual prob-
lems, attention/memory, gastrointestinal, urinary, sexual function
and miscellaneous. Each domain has different items, which are
composed of two parts: severity (from 0 to 3) and frequency (from
1 to 4). The domains of this instrument can help us screen specific
aspects of non-motor disturbances, which may provide preliminary
clues for further exploration.
2.4. Tests for further exploration
After analyzing the NMSS between patients with and without
fatigue, our results highlighted domain 2 (sleep disorders) and
domain 3 (mood/anxiety) for further analysis. The symptoms of
anxiety and depression in patients with PD were assessed with the
Hamilton Anxiety Scale (HAMA) and the Hamilton Depression Scale
(HAMD), respectively.23 The Parkinson Disease Sleep Scale (PDSS),
Epworth Sleepiness Scale (ESS), and Rapid Eye Movement Sleep
Behavior Disorders Scale (RBD) were used to evaluate the different
kinds of sleep disorders in PD patients.24e26
2.5. Statistical analyses
Statistical analyses were performed with SPSS19.0 (SPSS Inc,
Chicago, IL, USA). All continuous variables are shown as the
J. Ding et al.
mean ± standard deviation and categorical variables are expressed
as percentages. Student's t-test or Mann-Whitney U test was
employed to compare groups. Spearman's Rho was used to evaluate
the correlations among the severity of fatigue with the clinical data
and other non-motor symptoms.
3. Results
3.1. Demographic and clinical characteristics
We collected data from a consecutive series of 104 patients with
a mean age of 62.02 ± 11.50 years, and mean disease duration of
2.89 ± 3.11 years. Forty patients (42.4%) showed notably complaints
of fatigue with FSS scores > 4. The demographic and clinical char-
acteristics are summarized in Table 1. No significant difference was
found in any of the demographic variables between the PD patients
with and without fatigue.
3.2. NMSS scores in PD patients with and without fatigue
Table 2 shows the descriptive results for NMS in PD patients,
illustrating the severity in each domain of the NMSS in the group.
According to the pre-defined FSS cut-off, we divided the PD pa-
tients into two subgroups: patients with fatigue and patients
without fatigue. Comparing the two subgroups, a significantly
higher total score of NMSS was found in the patients with fatigue
(40.75 ± 27.51 vs. 29.55 ± 30.81, p < 0.05) than that in the patients
without fatigue. Specifically, patients with fatigue, reported more
changes in the sleep disorders domain (8.16 ± 6.72 vs. 3.02 ± 6.31,
p < 0.001) and the mood/anxiety domain (11.10 ± 12.21 vs.
6.57 ± 9.22, p < 0.05) when compared with patients without fa-
tigue. Furthermore, we explored the correlation between NMSS
scores and fatigue. As summarized in Table 3, the severity of fatigue
positively correlated with the sleep disorders domain (rs ¼ 0.506,
p < 0.001) and the mood/anxiety domain (rs ¼ 0.358, p < 0.001).
3.3. Further assessments for sleep disorders and fatigue
To gain deeper understanding of the correlation between fatigue
and the sleep disorders domain, the ESS, PDSS and RBD scales were
used to represent the different kinds of sleep disorders and the
relationship between fatigue and sleep disorders was further
analyzed. Compared to the PD patients without fatigue, the PD
patients with fatigue had slightly more complaints about excessive
daytime sleepiness (EDS) at a marginal significance (4.89 ± 4.39 vs.
3.32 ± 3.05, p ¼ 0.054). Furthermore, the severity of fatigue posi-
tively correlated with excessive daytime sleepiness (rs ¼ 0.254,
p ¼ 0.009), as shown in Table 4.
3.4. Further details for affective sphere and fatigue
To obtain the relationship between fatigue and the mood/anx-
iety domain, more detailed analysis was performed. The HAMA and
HAMD scales were used to represent different aspects of the af-
fective sphere. When compared with PD patients without fatigue,
the PD patients with fatigue had significantly more complaints
about anxiety (8.68 ± 5.00 vs. 6.57 ± 4.89, p ¼ 0.02) and depression
(8.91 ± 7.03 vs. 6.43 ± 6.09, p ¼ 0.03). Moreover, the severity of
fatigue positively correlated with anxiety (rs ¼ 0.268, p ¼ 0.006)
and depression (rs ¼ 0.214, p ¼ 0.007), as shown in Table 4.
4. Discussion
The important results from our observational study are sum-
marized below:
Relationship Between Fatigue and Other Non-Motor Symptoms 173

Table 1
Demographic and clinical features of PD patients with and without fatigue.

No fatigue (n ¼ 60) Fatigue (n ¼ 44) P

Age (years), mean ± SD 62.42 ± 10.79 61.48 ± 12.50 0.631

Male: females 33: 27 22: 22 0.614
Disease duration (years), mean ± SD 3.00 ± 3.40 2.74 ± 2.68 0.873
LEDD (mg/day), mean ± SD 146.26 ± 26.16 199.84 ± 37.14 0.340
H-Y stage, mean ± SD 1.82 ± 0.66 1.95 ± 0.79 0.330
UPDRS I score, mean ± SD 2.57 ± 1.91 2.95 ± 2.21 0.421
UPDRS II score, mean ± SD 10.55 ± 5.13 11.63 ± 5.82 0.353
UPDRS III score, mean ± SD 18.84 ± 11.32 18.89 ± 11.12 0.929
HAMD score, mean ± SD 6.43 ± 6.09 8.91 ± 7.03 0.035
HAMA score, mean ± SD 6.57 ± 4.89 8.68 ± 5.00 0.022
PDSS score, mean ± SD 135.38 ± 202.60 132.20 ± 246.37 0.614
ESS score, mean ± SD 3.32 ± 3.05 4.89 ± 4.39 0.054
RBD score, mean ± SD 2.83 ± 3.26 3.64 ± 3.69 0.340
FSS score, mean ± SD 2.18 ± 0.94 5.35 ± 0.95 <0.001

PD, Parkinson's disease; SD, Standard deviation; H-Y stage, Hoehn and Yahr stage; LEDD levodopa-equivalent daily dose; UPDRS, Unified Parkinson's disease rating scale;
HAMD, Hamilton Depression Scale; HAMA, Hamilton Anxiety Scale; PDSS, Parkinson's disease Sleep Scale; ESS, Epworth Sleepiness Scale; RBD, Rapid Eye Movement Sleep
Behavior Sleep Disorders Scale; FSS, Fatigue Severity Scale.
Bold values indicate p < 0.05.

Table 2 Table 4
NMSS domains scores of PD patients with and without fatigue. Correlations among severity of fatigue with clinical data and non-motor symptoms.

Items (mean ± SD) No fatigue (n ¼ 60) Fatigue (n ¼ 44) P Items (mean ± SD) FSS

Cardiovascular 1.48 ± 4.36 0.23 ± 0.64 0.340 rs p

Sleep disorders 3.82 ± 6.31 8.16 ± 6.72 <0.001
Age (years) 0.096 0.332
Mood/anxiety 6.57 ± 9.22 11.09 ± 12.21 0.031
Disease duration (years) 0.019 0.850
Perceptual problems 0.47 ± 1.43 1.23 ± 2.92 0.117
LEDD (mg/day) 0.129 0.190
Attention/memory 4.55 ± 6.11 5.91 ± 6.70 0.226
H-Y stage 0.063 0.523
Gastrointestinal 3.15 ± 5.00 3.61 ± 4.36 0.349
UPDRS I scores 0.082 0.407
Urinary 4.78 ± 8.46 5.23 ± 7.10 0.665
UPDRS II scores 0.048 0.629
Sexual dysfunction 0.03 ± 0.26 0.27 ± 1.81 0.814
UPDRS III scores 0.053 0.593
Miscellaneous 4.70 ± 7.17 5.02 ± 5.63 0.261
HAMD scores 0.264 0.007
NMSS total 29.55 ± 30.81 40.75 ± 27.51 <0.001
HAMA scores 0.268 0.006
PD, Parkinson's disease; NMSS, Non-motor Symptoms Scale. PDSS scores 0.198 0.044
Bold values indicate p < 0.05. ESS scores 0.204 0.009
RBD scores 0.155 0.155

LEDD, levodopa-equivalent daily dose; H-Y stage, Hoehn and Yahr stage; UPDRS,
Table 3 Unified Parkinson's disease rating scale; HAMD, Hamilton Depression Scale; HAMA,
Correlations among severity of fatigue and the different domains of non-motor Hamilton Anxiety Scale; PDSS, Parkinson's disease Sleep Scale; ESS, Epworth
symptoms scale. Sleepiness Scale; RBD, Rapid Eye Movement Sleep Behavior Sleep Disorders Scale;
Items (mean ± SD) FSS FSS, Fatigue Severity Scale; rs: Spearman's rho.
Bold values indicate p < 0.05.
rs p

Cardiovascular 0.011 0.915

Sleep disorders 0.506 <0.001 which is consistent with previous findings in the range of
Mood/anxiety 0.358 <0.001 37%e56%.1 The clinical characteristics of PD patients with and
Perceptual problems 0.174 0.077 without fatigue, in terms of age, sex, disease duration and UPDRS I,
Attention/memory 0.139 0.159
II, and III scores, were similar between both groups. These data are
Gastrointestinal 0.134 0.176
Urinary 0.144 0.145 partly in agreement with a study reported by Solla et al. who found
Sexual dysfunction 0.012 0.902 that there were no differences between fatigue and non-fatigue
Miscellaneous 0.145 0.121 groups in age, disease duration and UPDRS III scores, while the
NMSS total scores 0.382 <0.001
level of fatigue was higher in women than that in men.15 Possible
NMSS: Non-motor Symptoms Scale; rs; Spearman's rho. reasons for the discrepancy may be attributed to differences in
Bold values indicate p < 0.05. methodology, demographics and cultural bias that may influence
questionnaire interpretation. Solla et al. reported that domain 3
1. Fatigue is a very common non-motor symptom present in 42.4% (sleep disorders) and domain 2 (mood/anxiety) were related with
of patients with PD in Chinese population; fatigue when the NMSS was used to measure the non-motor
2. Among all nine domains of the NMSS, domain 2 (sleep disor- symptoms in PD patients.15 However, in Solla et al.’s study, the
ders) and domain 3 (mood/anxiety) were associated with the definition of sleep disorders and the affective sphere were broad.
scores of fatigue; Our study aimed to address this with more tightly defined criteria.
3. The severity of fatigue in PD was positively correlated with In our study, we found that more sleep disorders were reported
excessive daytime sleepiness, anxiety and depression. in PD patients with fatigue. Correlation analysis suggested that the
severity of fatigue was strictly associated with sleep disorders.
Fatigue is a very common symptom in PD patients with an Accurately, the problems of fatigue and sleep disorders were closely
increasing occurrence rate in recent years. The prevalence of fatigue linked in PD. Fabbrini et al. reported that fatigue may be a comor-
in PD was 55.5% in 2004, while in 2013, it rose to 77.6%.27,28 Our bidity of sleep disorders.29 When we did further explore, we found
study showed that fatigue was present in 42.4% of PD patients, that although the EDS scores in PD patients with fatigue was not
174
significantly higher than that in PD patients without fatigue
(p ¼ 0.054), a significant correlation was found between EDS and
fatigue (rs ¼ 0.254, p ¼ 0.009). EDS is a common symptom in PD
patients with a prevalence ranging from 20% to 50%.30 Our finding
was somewhat in agreement with some previous studies although
there are some contrary views. In a study reported by Havlikova
et al., fatigue was not related to the quality of sleep or excessive
daytime sleepiness.31 Hagell et al. even revealed that fatigue cannot
be attributed to excessive daytime sleepiness or poor sleep in a
multiple logistic regression analysis.12 However, in a study by Alves
et al., with a sample of 233 PD patients, fatigue was correlated to
excessive daytime sleepiness.27 A report studied by Kurtis et al.
showed that both excessive daytime sleepiness and poor sleep
were related to fatigue in PD patients.32 The disparity of the rela-
tionship between excessive daytime sleepiness and fatigue in PD
may be attributed to differences in the methods, diagnostic crite-
rion of fatigue in PD, and sample size, in addition to diversity.
Another intriguing correlation detected among fatigue and
other non-motor symptoms was between fatigue and affective
sphere. Correlation analysis suggested that the severity of fatigue
was strictly associated with the affective sphere, which was
consistent with the results of Solla et al., who found that fatigue in
PD patients was significantly correlated with the affective sphere.15
We preformed further exploration and found that the severity of
fatigue was significantly associated with anxiety and depression. A
study reported by Saez-Francas et al. also showed that patients
with fatigue scored higher in both the anxiety and depression traits,
in line with our results.33 In addition, Shulman et al. suggested that
fatigue was associated with anxiety while Marsh et al. held the
opinion that fatigue was related to depression in PD.13,14 The rela-
tionship between depression and fatigue is controversial as fatigue
is among the diagnostic criteria for depression. While there is some
overlap, they are two separate symptoms. What's more, about
43.5% patients without depression reported being fatigued.34 A
multiple logistic regression analysis found that depression was not
a strictly independent variable related to fatigue in PD, indicating
that fatigue may result from depression, but depression may not be
the only pathogenic factor.35
While fatigue is one of the most common non-motor symptoms
in PD patients, its etiology is not well understood. Previous study
has found that the existence of sleep disturbance and depression
may worsen the subjective experience of fatigue in PD.36 One hy-
pothesis indicated that all these three non-motor symptoms might
share the same pathology. In fact, recent studies suggest that one
neuronal hormonedserotonindis responsible for fatigue, sleepi-
ness, anxiety and depression in PD, which may partially explain the
pathophysiological mechanism of fatigue in PD. However, the
specific mechanism still requires further exploration.36e39
There are some limitations of our study. First, the definition of
fatigue in PD is controversial, and there are no specific recognized
methods to measure fatigue and NMS in PD. However, both the FSS
and NMSS are widely used for their outstanding consistency and
reliability. Second, the study did not include normal controls since
the purpose of study was to explore the possible correlation be-
tween fatigue and other non-motor symptoms among PD patients.
Third, our study was only concerned with clinical phenomena, the
biochemical and pathological mechanisms of fatigue in PD need to
be further explored.
5. Conclusion
In conclusion, our study showed that only sleep disturbances
and affective sphere were significantly related to the severity of
fatigue in PD patients among all non-motor symptoms. The main
factors that influenced fatigue the most were anxiety and excessive
J. Ding et al.
daytime sleepiness. Doctors in clinical may need to especial pay
attention to this, and provide appropriate treatment to alleviate
fatigue and improve the quality of life in PD patients.
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgments
This work was supported by the Natural science foundation of
Jiangsu Province (No.BK20141494), the Jiangsu Provincial Personnel
Department “the Great of Six Talented Man Peak” Project (No.2014-
WSN-013), the University Natural Science Research Project in
Jiangsu Province (No.13KJB32009), the Opening Project of Jiangsu
Key Laboratory of Neurodegeneration (No.SJ11KF01), and Project
Funded by the Priority Academic Program Development of Jiangsu
Higher Education Institutions (PAPD) and Science and Technology
Project of Jiangsu Bureau of Traditional Chinese Medicine
(No.YB2015163).
References
1. Beiske AG, Svensson E. Fatigue in Parkinson's disease: a short update. Acta
Neurol Scand Suppl. 2010;190:78e81.
2. Ziemssen T, Reichmann H. Non-motor dysfunction in Parkinson's disease. Park
Relat Disord. 2007;13:323e332.
3. Tong Q, Xu Q, Xia Q, et al. Correlations between plasma levels of amino acids
and nonmotor symptoms in Parkinson's disease. J Neural Transm (Vienna).
2015;122:411e417.
4. Chaudhuri KR, Yates L, Martinez-Martin P. The non-motor symptom complex
of Parkinson's disease: a comprehensive assessment is essential. Curr Neurol
Neurosci Rep. 2005;5:275e283.
5. Khedr EM, El Fetoh NA, Khalifa H, et al. Prevalence of non motor features in a
cohort of Parkinson's disease patients. Clin Neurol Neurosurg. 2013;115:
673e677.
6. Friedman JH, Chou KL. Sleep and fatigue in Parkinson's disease. Park Relat
Disord. 2004;10(Suppl. 1):S27eS35.
7. Herlofson K, Larsen JP. Measuring fatigue in patients with Parkinson's disease -
the fatigue severity scale. Eur J Neurol. 2002;9:595e600.
8. Falup-Pecurariu C. Fatigue assessment of Parkinson's disease patient in clinic:
specific versus holistic. J Neural Transm (Vienna). 2013;120:577e581.
9. Berardelli A, Conte A, Fabbrini G, et al. Pathophysiology of pain and fatigue in
Parkinson's disease. Park Relat Disord. 2012;18(Suppl. 1):S226eS228.
10. Adams MA, Dolan P. Could sudden increases in physical activity cause
degeneration of intervertebral discs? Lancet. 1997;350:734e735.
11. Song Y, Gu Z, An J, et al. Gender differences on motor and non-motor symp-
toms of de novo patients with early Parkinson's disease. Neurol Sci.
2014;35(12):1991e1996.
12. Hagell P, Brundin L. Towards an understanding of fatigue in Parkinson disease.
J Neurol Neurosurg Psychiatry. 2009;80:489e492.
13. Shulman LM, Taback RL, Rabinstein AA, et al. Non-recognition of depression
and other non-motor symptoms in Parkinson's disease. Park Relat Disord.
2002;8:193e197.
14. Marsh L. Depression and Parkinson's disease: current knowledge. Curr Neurol
Neurosci Rep. 2013;13:409.
15. Solla P, Cannas A, Mulas CS, et al. Association between fatigue and other motor
and non-motor symptoms in Parkinson's disease patients. J Neurol. 2014;261:
382e391.
16. Hughes AJ, Daniel SE, Kilford L, et al. Accuracy of clinical diagnosis of idiopathic
Parkinson's disease: a clinicopathological study of 100 cases. J Neurol Neurosurg
Psychiatry. 1992;55:181e184.
17. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method
for grading the cognitive state of patients for the clinician. J Psychiatr Res.
1975;12:189e198.
18. Wenzelburger R, Zhang BR, Pohle S, et al. Force overflow and levodopa-induced
dyskinesias in Parkinson's disease. Brain. 2002;125(Pt 4):871e879.
19. Fahn S, Elton RL. In: Unified Parkinson’s disease rating scale. Recent developments
in Parkinson’s disease. 2. 1987:153e163.
20. Karlsen K, Larsen JP, Tandberg E, et al. Fatigue in patients with Parkinson's
disease. Mov Disord. 1999;14:237e241.
21. Friedman JH, Alves G, Hagell P, et al. Fatigue rating scales critique and rec-
ommendations by the Movement Disorders Society task force on rating scales
for Parkinson's disease. Mov Disord. 2010;25:805e822.
22. Chaudhuri KR, Martinez-Martin P, Brown RG, et al. The metric properties of a
novel non-motor symptoms scale for Parkinson's disease: results from an in-
ternational pilot study. Mov Disord. 2007;22:1901e1911.
Relationship Between Fatigue and Other Non-Motor Symptoms
23. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry.
1960;23:56e62.
24. Johns MW. Daytime sleepiness, snoring, and obstructive sleep apnea. The
Epworth Sleepiness Scale. Chest. 1993;103:30e36.
25. Chaudhuri KR, Pal S, DiMarco A, et al. The Parkinson's disease sleep scale: a
new instrument for assessing sleep and nocturnal disability in Parkinson's
disease. J Neurol Neurosurg Psychiatry. 2002;73:629e635.
26. Stiasny-Kolster K, Mayer G, Schafer S, et al. The REM sleep behavior disorder
screening questionnaireea new diagnostic instrument. Mov Disord. 2007;22:
2386e2393.
27. Alves G, Wentzel-Larsen T, Larsen JP. Is fatigue an independent and persistent
symptom in patients with Parkinson disease? Neurology. 2004;63:1908e1911.
28. Skorvanek M, Nagyova I, Rosenberger J, et al. Clinical determinants of primary
and secondary fatigue in patients with Parkinson's disease. J Neurol. 2013;260:
1554e1561.
29. Fabbrini G, Latorre A, Suppa A, et al. Fatigue in Parkinson's disease: motor or
non-motor symptom? Park Relat Disord. 2013;19:148e152.
30. Gjerstad MD, Alves G, Wentzel-Larsen T, et al. Excessive daytime sleepiness in
Parkinson disease: is it the drugs or the disease? Neurology. 2006;67:853e858.
31. Havlikova E, Rosenberger J, Nagyova I, et al. Clinical and psychosocial factors
associated with fatigue in patients with Parkinson's disease. Park Relat Disord.
2008;14:187e192.
175
32. Kurtis MM, Rodriguez-Blazquez C, Martinez-Martin P, et al. Relationship be-
tween sleep disorders and other non-motor symptoms in Parkinson's disease.
Park Relat Disord. 2013;19:1152e1155.
33. Saez-Francas N, Hernandez-Vara J, Corominas Roso M, et al. The association of
apathy with central fatigue perception in patients with Parkinson's disease.
Behav Neurosci. 2013;127:237e244.
34. Del Sorbo F, Albanese A. Clinical management of pain and fatigue in Parkinson's
disease. Park Relat Disord. 2012;18:S233eS236.
35. Miwa H, Miwa T. Fatigue in patients with Parkinson's disease: impact on
quality of life. Intern Med. 2011;50:1553e1558.
36. Metta V, Logishetty K, Martinez-Martin P, et al. The possible clinical predictors
of fatigue in Parkinson's disease: a study of 135 patients as part of international
nonmotor scale validation project. Park Dis. 2011;2011:125271.
37. Pavese N, Metta V, Bose SK, et al. Fatigue in Parkinson's disease is linked to
striatal and limbic serotonergic dysfunction. Brain. 2010;133:3434e3443.
38. Drevets WC, Thase ME, Moses-Kolko EL, et al. Serotonin-1A receptor imaging in
recurrent depression: replication and literature review. Nucl Med Biol. 2007;34:
865e877.
39. Sargent PA, Kjaer KH, Bench CJ, et al. Brain serotonin1A receptor binding
measured by positron emission tomography with [11C]WAY-100635: effects of
depression and antidepressant treatment. Arch Gen Psychiatry. 2000;57:
174e180.