J Neurol (2014) 261:382–391
DOI 10.1007/s00415-013-7207-5
ORIGINAL COMMUNICATION
Association between fatigue and other motor and non-motor
symptoms in Parkinson’s disease patients
Paolo Solla • Antonino Cannas • Cesare Salvatore Mulas
Silvia Perra • Andrea Corona • Pier Paolo Bassareo •
Francesco Marrosu
Received: 7 August 2013 / Revised: 15 November 2013 / Accepted: 3 December 2013 / Published online: 28 December 2013
Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Although fatigue is a common non-motor
symptom in patients affected by Parkinson’s disease (PD),
its association with motor and other non-motor symptoms
is still largely unclear. We assessed fatigue in PD patients
studying the possible association with motor and non-
motor symptoms. Eighty-one PD patients were included in
the study. The PD Fatigue Scale (PFS) and the Fatigue
Severity Scale (FSS) scale were used to measure fatigue.
Non-motor symptoms were assessed with the Non-Motor
Symptoms Scale (NMSS). Motor impairment was assessed
using the modified Hoehn and Yahr (HY) staging and the
Unified PD Rating Scale (UPDRS) part-III and IV.
Bivariate tests comparing all independent variables
between patients with our without fatigue were used. Sig-
nificant predictors of presence and severity of fatigue were
determined with different models of logistic regression
analyses. Fatigue severity was significantly higher in
female patients. Bivariate test showed significant higher
NMSS score in fatigued patients according to PFS
(p \ 0.00001) and FFS (p \ 0.001), while HY was higher
only in fatigued patients according to FSS (p \ 0.022).
P. Solla (&)
A. Cannas
C. S. Mulas
A. Corona

F. Marrosu
Department of Neurology, Movement Disorders Center,
University of Cagliari, SS 554 Bivio per Sestu,
09042 Monserrato (Cagliari), Italy
e-mail: paosol29@yahoo.it
S. Perra
Department of Mathematics and Computer Science,
University of Cagliari, Cagliari, Italy
P. P. Bassareo
Department of Medical Sciences ‘‘Mario Aresu’’,
University of Cagliari, Cagliari, Italy
123
•
Significant correlations between severity of fatigue and HY
stage (p \ 0.002) and UPDRS-III score (p \ 0.001) were
found, while, among specific non-motor symptoms, anhe-
donia presented with the most significant correlation
(p \ 0.003). Binary logistic regression confirmed NMSS as
the main variable predicting presence of fatigue, while HY
was significant as predicting variable only in the FSS
model. Strongest non-motor symptoms predictors of
severity were those included in Domain 3 (mood/anxiety)
and Domain 2 (sleep disorders) of the NMSS. A significant
increase in severity of fatigue related to the burden of non-
motor symptoms (mainly affective and sleep disorders) was
observed. Our findings indicate a moderate discrepancy in
the ratings of the two fatigue scales, with PFS principally
directed towards the burden of non-motor symptoms.
Finally, the accurate individuation of the factors underlying
fatigue, assessed with the systematic administration of
holistic evaluation scales such as the NMSS, might
improve current strategies used in the treatment of this
disabling condition.
Keywords Parkinson’s disease
Fatigue
Non-motor
symptoms
Introduction
Parkinson’s disease (PD), classically characterized by the
triad of resting tremor, rigidity, and bradykinesia, has tra-
ditionally been considered as a motor disturbance and
therefore included in the field of movement disorders.
However, parkinsonism probably represents only the tip of
an iceberg where non-motor disorders, often submerged,
strongly impact patients’ disability and, at the same time,
undermine their quality of life [1].
J Neurol (2014) 261:382–391
Moreover, the attention of the clinician has not been
specially trained to observe this peculiar category of
symptoms which are still poorly evaluated in comparison
to classic motor function disturbances [2]. Among non-
motor symptoms, fatigue is a common symptom in Par-
kinson’s disease with prevalence rates ranging widely from
37 to 56 % of patients [3], due to different definitions of
fatigue and populations tested. In this context, the corre-
lations of fatigue with motor and other non-motor symp-
toms of Parkinson’s disease are still largely unclear.
The main objective of our study was to assess fatigue in
Sardinian PD patients studying the possible association
with motor and non-motor symptoms, and to evaluate the
impact of fatigue on quality of life.
Patients and methods
Eighty-one consecutive patients with a diagnosis of PD
according to Gelb criteria [4] participated in the study.
Patients were excluded if they had dementia [Mini-Mental
State Examination (MMSE) B 23 points] or any other
medical disorder that could potentially be associated with
fatigue, such as heart diseases, pulmonary diseases, renal
failure, hepatic failure, or cancer. Medical history and
pharmacological treatment were collected in a structured
interview, and neurological examination was performed.
Each patient included in the study underwent a clinical
evaluation including: demographic data, gender, current
medications and dosage, age at onset, type and location of
presenting symptoms. Presenting symptoms and age at onset
were retrieved from the patient’s history, taken during the
first visit. Age at onset was determined as the age at which
the patient had first observed any parkinsonian motor
symptoms. Motor impairment and disability were assessed
using the Modified Hoehn and Yahr (HY) staging [5] and
the Unified PD Rating Scale (UPDRS) part III [6]. All
patients affected by motor fluctuations were examined dur-
ing the on-period. In addition, the following sub-scores
obtained from specific items of UPDRS-III were calculated:
tremor (items 20–21), rigidity (item 22), bradykinesia (items
23–26, 31) and postural/gait impairments (27–30).
Levodopa-related complications (dyskinesias and motor
fluctuations) were evaluated by using UPRDS part IV.
Fatigue was assessed using both the Parkinson’s disease
Fatigue Scale (PFS) [7] and the Fatigue Severity Scale
(FSS) [8]. While the FSS represents a not-specific scale
used in multiple disorders, PFS was designed to assess
fatigue exclusively associated with PD.
The FSS consists of nine questions that are answered
along a Likert scale ranging from 1 (completely disagree)
to 7 (completely agree). Although not explicitly recom-
mended in the original study, a cut-off of 4 has been used
383
in this study and subjects who had a score superior to this
value at the FSS were classified as fatigued.
The PFS is a self-report questionnaire consisting of 16
items and, for each question, subjects were asked to rate
how accurately each item described their personal fatigue
levels on a scale ranging from 1 (strongly disagree) to 5
(strongly agree). The overall PFS score was calculated as
the mean response across all items (range 1.0–5.0).
According to the original paper [7], an average score of 3.3
or greater optimally identified patients who perceived
fatigue as a problem with a sensitivity of 84.7 % and a
specificity of 82.1 %. In the present study, a cut-off point
of 3.3 was used.
The total burden of non-motor symptoms was assessed
with the Non-Motor Symptoms Scale (NMSS) [9]. NMSS
is a 30-item scale developed for the assessment of NMS in
PD and contains nine dimensions (domains): cardiovascu-
lar, sleep/fatigue, mood/cognition, perceptual problems,
attention/memory, gastrointestinal, urinary, sexual func-
tion, and miscellany. Patients were evaluated for levels of
depression using the Beck Depression Inventory (BDI)
[10]. Quality of life of PD patients was evaluated with the
Parkinson’s disease quality of life 8 questions (PDQ-8)
[11].
All subjects gave written informed consent and the study
was approved by the Local Ethics Committee.
Calculation of a levodopa equivalent daily dose (LEDD)
for each patient was based on theoretical equivalence to
levodopa, as described in previous reports [12].
Statistical analysis
Demographic, clinical characteristics and pharmacological
treatments of the groups of patients, separated by gender,
were reported. Student’s t test was used for comparisons of
normally distributed continuous data; ordinal type vari-
ables were compared using the Mann–Whitney U Test,
while the v2 test or, alternatively, the Fisher’s exact test
were used for the other group differences. Bivariate tests
were used to compare all independent variables between
male and female patients and between patients with or
without fatigue, according to PFS or FSS assessment.
Spearman’s rho was used for correlative analyses. All
statistical tests were corrected with a Bonferroni adjust-
ment for multiple comparisons.
Binary logistic regression was used to determine which
variable was the better predictor of the presence of fatigue.
The following independent variables (Hoehn and Yahr,
disease duration, NMSS score and gender) were entered
into bivariate logistic regression. Binary logistic regression
was also used to determine which items of BDI (excluding
the item 17, fatigue) were the better predictors of the
presence of fatigue. Possible predictors of severity of
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fatigue were determined with different models of ordinal
regression analyses, with the two scales of severity of
fatigue (FSS or PDQ) acting as dependent variable and
other clinical/demographic data (age, gender, NMSS score,
UPDRS-III score) as independent variables of fatigue.
Besides, among non-motor disorders, as individuated by
NMSS domains, peculiar symptoms were determined as
possible predictors of severity of fatigue with two ordinals
models of multiple regression analyses, with the same
scales of severity of fatigue acting as dependent variables.
Logically, when examining NMSS Domain 2 (sleep/fati-
gue), fatigue scores were deleted. Data were analyzed
using SPSS 16.0 for Windows (SPSS Inc., USA). The level
of statistical significance in this study was set at 0.05.
Results
The demographic, clinical characteristics and pharmaco-
logical treatments of the groups of patients, separated by
gender, are summarized in Table 1. The 81 PD patients
included 48 men and 33 women [mean age at assessment,
67.9 years ± standard deviation (SD) of 10.6], with a
mean disease duration of 5.9 ± 3.4 years. Mean age in
male patients was 67.9 ± 9.2 years, while in female pop-
ulation was 67.8 ± 12.5 years. Mean duration of disease in
male patients was 6.5 ± 3.4 years, while in female popu-
lation was 5.0 ± 3.1 years (p \ 0.044). The results
revealed no differences between male and female gender in
general clinical characteristics including Hoehn and Yahr
staging, UPDRS motor (part III) score, tremor dominant or
rigid-akinetic form, presence of motor fluctuations and
dyskinesias, pharmacological treatment, with the exception
of mean postural subscore at UPDRS III which was sig-
nificantly higher in female patients compared to males
(respectively, 3.7 ± 3.2 vs 1.6 ± 2.2; p \ 0.001), and
higher use of benzodiazepine drugs in female patients
compared to males (14 vs 4, p \ 0.016).
Mean PFS score was 2.9 ± 1.2, with significant higher
scores in female patients compared to males (respectively,
3.3 ± 1.2 vs 2.6 ± 1.2; p \ 0.007), while mean FSS score
was 3.9 ± 1.9, with significant higher scores in female
patients compared to males (respectively, 4.5 ± 1.9 vs
3.4 ± 1.8; p \ 0.008).
According to suggested cut-off, fatigue determined at
PFS (with a score higher than 3.3) was present in 32
(39.5 %) patients, with no significant difference of fre-
quency between males/females, while fatigue determined at
FSS (score higher than 4.0) was present in 41 (50.6 %)
patients, with significant higher frequency in female patients
compared to males (respectively, 22 vs 19; p \ 0.017).
Comparisons of PD patients with or without fatigue,
according to PFS or FSS, are summarized in Table 2.
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J Neurol (2014) 261:382–391
Fatigued patients (according to PFS scale) had higher total
NMSS scores (p \ 0.00001), higher NMSS Domain 2
(without the item fatigue) scores (p \ 0.0001) and higher
NMSS Domain 3 scores (p \ 0.039), while fatigued
patients (according to FFS scale) had higher Hoehn and
Yahr staging (p \ 0.022), higher UPDRS-III bradykinesia
(p \ 0.021) and postural subscores (p \ 0.009), higher
total NMSS scores (p \ 0.001), higher NMSS Domain 2
(without fatigue) scores (p \ 0.032) and higher NMSS
Domain 3 scores (p \ 0.043) than non-fatigued patients.
BDI scores significantly differed between patients with or
without fatigue (p \ 0.02, both according to PFS and FSS),
as well fatigued patients had higher PDQ-8 scores than
non-fatigued patients.
Correlation study among severity of fatigue with clinical
data and motor symptoms (Table 3) revealed a significant
correlation between the PFS score and Hoehn and Yahr
stage (r = 0.335; p \ 0.002), UPDRS III score (r = 0.374;
p \ 0.001), bradykinesia UPDRS III subscore (r = 0.368;
p \ 0.001), postural UPDRS III subscore (r = 0.493;
p \ 0.000), and a significant correlation between the FSS
score and age (r = 0.257; p \ 0.020), Hoehn and Yahr
stage (r = 0.374; p \ 0.001), UPDRS III score (r = 0.410;
p \ 0.000), bradykinesia UPDRS III subscore (r = 0.422;
p \ 0.000), postural UPDRS III subscore (r = 0.546;
p \ 0.000). There were no significant correlations between
fatigue scores and duration of PD, tremor or rigidity
UPDRS III subscores.
Correlation study among severity of fatigue detected at
PFS and non-motor symptoms assessed with the single
items of NMSS (Table 4) revealed significant correlations
between the PFS score and anhedonia (r = 0.450;
p \ 0.001), anxiety (r = 0.444; p \ 0.001), lost interest in
surroundings (r = 0.395; p \ 0.008), apathy (r = 0.398;
p \ 0.007), and difficulty in concentration (r = 0.374;
p \ 0.017), difficulty falling asleep (r = 0.365; p \
0.024), and day time sleep (r = 0.360; p \ 0.029).
Correlation study among severity of fatigue detected at
FFS and non-motor symptoms assessed at NMSS (Table 4)
revealed a significant correlations between the FFS score
and anhedonia (r = 0.415; p \ 0.003), lost interest in
surroundings (r = 0.384; p \ 0.012), apathy (r = 0.344;
p \ 0.049).
A significant correlation between severity of fatigue and
NMSS total score was observed both for PFS (r = 0.560;
p \ 0.000002), and for FSS (r = 0.520; p \ 0.00002).
Among other evaluation scales used in this study, other
significant correlations were found between severity
of fatigue and BDI score both for PFS (r = 0.371;
p \ 0.001), and for FSS (r = 0.328; p \ 0.003). Binary
logistic regression used to determine which items of BDI
were the better predictors of the presence of fatigue showed
that item 15 (work) and item 3 (failure) were the most
J Neurol (2014) 261:382–391 385

Table 1 Characteristics, assessment scores and pharmacological treatments of patients included in this study, subdivided by gender
All patients Male patients Female patients p\

Gender, N (%) 81 (100) 48 (59.2) 33 (40.7)

Age, mean years ± SD 67.9 (10.6) 67.9 (9.2) 67.8 (12.5) NS
Duration of PD, mean years ± SD 5.9 (3.4) 6.5 (3.4) 5.0 (3.1) 0.044
Hoehn and Yahr stage, mean ± SD 2.0 (0.7) 2.0 (0.8) 1.9 (0.5) NS
UPDRS III score, mean ± SD 31.9 (18.9) 29.4 (15.3) 35.5 (22.9) NS
Tremor subscore UPDRS III, mean ± SD 4.9 (3.8) 4.8 (3.3) 4.9 (4.4) NS
Rigidity subscore UPDRS III, mean ± SD 4.1 (3.6) 4.6 (3.6) 3.5 (3.5) NS
Bradykinesia subscore UPDRS III, mean ± SD 10.7 (7.1) 9.8 (6.2) 12.0 (8.2) NS
Postural subscore UPDRS III, mean ± SD 2.5 (2.8) 1.6 (2.2) 3.7 (3.2) 0.001
PFS, mean (SD) 2.9 (1.2) 2.6 (1.1) 3.3 (1.2) 0.007
FSS, mean (SD) 3.9 (1.9) 3.4 (1.8) 4.5 (1.9) 0.008
NMSS, mean (SD) 69.9 (4.2) 61.8 (38.4) 81.7 (46.8) 0.039
Patients with PFS score [ 3.3, N (%) 32 (39.5) 15 (31,2) 17 (51,5) NS
Patients with FSS score [ 4.0, N (%) 41 (50.6) 19 (39.6) 22 (66.7) 0.017
BDI, mean (SD) 9.0 (5.4) 7.4 (5.0) 11.3 (5.5) 0.002
PDQ8, mean (SD) 9.0 (6.3) 6.9 (4.8) 12.1 (7.0) 0.000
LEDD—levodopa, mean mg ± SD 349.6 (251.1) 382.2 (286.9) 302.0 (181.1) NS
LEDD—dopamine agonist, mean mg ± SD 101.8 (105.5) 111.2 (117.0) 88.1 (86.0) NS
LEDD total, mean mg ± SD (range) 478.5 (297.2) 526.8 (347.4) 408.2 (187.3) NS
Patients on levodopa, N (%) 67 (82.7) 39 (81.2) 28 (84.8) NS
Patients on dopamine agonists, N (%) 51 (62.9) 29 (60.4) 22 (66.7) NS
Patients on COMT inhibitors, N (%) 9 (11.1) 5 (10.4) 4 (12.1) NS
Patients on MAO B inhibitors, N (%) 22 (27.2) 16 (33.3) 6 (18.2) NS
Patients on antidepressants, N (%) 8 (9.9) 4 (8.3) 4 (12.1) NS
Patients on benzodiazepine, N (%) 18 (22.2) 4 (8.3) 14 (42.4) 0.016
Patients on anticholinergics, N (%) 6 (7.4) 4 (8.3) 2 (6.1) NS
Statistically significant data (p \ 0.05) are highlighted in bold
PD Parkinson’s disease, N number of patients, SD standard deviation, NS not significant, UPDRS unified Parkinson’s disease rating scale, NMSS
nonmotor symptom scale, PFS Parkinson’s disease fatigue scale, FSS Fatigue Severity Scale; BDI Beck Depression Inventory, PDQ-8 Par-
kinson’s disease Quality of life 8 questions, LEDD levodopa equivalent daily dose, COMT Catechol-O-methyltransferase, MAO-B monoamine
oxidase B

significant according to both fatigue scale (item 15:
p \ 0.001, according to PFS and also to FSS; item 3:
p \ 0.019, according to FSS, and p \ 0.029, according to
PFS).
Besides, severity of fatigue was in strong correlation
with PDQ-8 both for PFS (r = 0.602; p \ 0.001), and for
FSS (r = 0.577; p \ 0.001).
The correlation between the two different scales used in
the assessment of fatigue was strongly significant (Fig. 1).
On binary logistic regression analyses (dependent vari-
able: presence of fatigue), NMSS score was the only sig-
nificant predictors of fatigue (p \ 0.001) in PFS model,
while NMSS scores (p \ 0.002) and Hoehn and Yahr
stages (p \ 0.004) were both significant in FSS models
(Table 5). The first ordinal regression model, constructed
on analyses between severity of fatigue and other clinical,
motor and non-motor variables (see Table 6), identified
three variables explaining 39.3 and 35.7 % of the variance
in fatigue scores detected, respectively, at PFS and FSS.
The strongest predictors were the overall load of non-motor
symptoms (p \ 0.000; in both models), higher disability at
Hoehn and Yahr stage (p \ 0.005 in PFS model and
p \ 0,002 in FSS model), and female gender (p \ 0.045 in
PFS model and p \ 0,040 in FSS model).
The second stepwise linear regression model, con-
structed on analyses between severity of fatigue and single
non-motor variables (see Table 7), identified the same four
variables in both scales. The strongest predictors in both
model were Domain 3 (PFS: p \ 0.010, FFS: p \ 0.011),
Domain 2 (PFS: p \ 0.014, FFS: p \ 0.024), Domain 8
(PFS: p \ 0.020, FFS: p \ 0.030), and Domain 6 (PFS:
p \ 0.021, FFS: p \ 0.043).

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Table 2 Comparison of patients with Parkinson’s disease with and without fatigue, according to Parkinson’s disease Fatigue Scale and to
Fatigue Severity Scale
Characteristics PFS FFS
PD patients PD patients p\ PD patients PD patients p\
with without with without
fatigue (32) fatigue (49) fatigue (41) fatigue (40)

Age, mean years ± SD 69.6 (10.3) 66.7 (10.8) NS 70 (9.7) 65.6 (11.1) NS
Disease duration, mean years ± SD 5.6 (3.5) 6.4 (3.2) NS 6 (3.6) 6 (3) NS
Hoehn and Yahr staging, mean ± SD 2.1 (0.7) 1.9 (0.6) NS 2.2 (0.6) 1.7 (0.5) 0.022
UPDRS-III score, mean ± SD 38.1 (19.7) 27.8 (17.3) NS 38.1 (20.2) 25.4 (15) NS
UPDRS-III Tremor subscore, mean ± SD 5.2 (4.4) 4.7 (3.3) NS 5.2 (4.1) 4.4 (3.3) NS
UPDRS-III rigidity subscore, mean ± SD 4.1 (3.6) 4.2 (3.6) NS 4.1 (3.7) 4.1 (3.4) NS
UPDRS-III Bradykinesia subscore, mean ± SD 13.3 (8.2) 9.0 (5.8) NS 13.3 (7.6) 8 (5.4) 0.021
UPDRS-III postural subscore, mean ± SD 3.5 (3.0) 1.8 (2.6) NS 3.5 (3) 1.3 (2.1) 0.009
NMSS total score, mean ± SD 97.0 (41.4) 52.2 (34.0) 0.00001 88.4 (40.5) 50.8 (36.8) 0.001
Domain 1 score (cardiovascular), mean ± SD 3.0 (3.7) 2.3 (3.6) NS 2.8 (3.6) 2.4 (3.7) NS
Domain 2 score (sleep disorders, without fatigue), 13.8 (9.1) 5.8 (6.8) 0.0001 11.6 (9.8) 6.2 (6.5) 0.032
mean ± SD
Domain 3 score (mood/anxiety), mean ± SD 18.2 (14.1) 9.1 (14.0) 0.039 17.0 (14.7) 8.2 (13.4) 0.043
Domain 4 score (perceptual problems), mean ± SD 1.7 (3.6) 0.6 (2.1) NS 1.3 (3.2) 0.7 (2.3) NS
Domain 5 score (attention/memory), mean ± SD 12.8 (11.9) 7.0 (8.4) NS 10.8 (11.5) 7.7 (8.7) NS
Domain 6 score (gastrointestinal), mean ± SD 10.0 (7.4) 5.6 (6.9) NS 9.5 (7.8) 5.1 (6.2) NS
Domain 7 score (urinary), mean ± SD 18.5 (13.0) 12.7 (12.5) NS 17.8 (12.7) 12.1 (12.6) NS
Domain 8 score (sexual dysfunction), mean ± SD 1.1 (3.3) 0.4 (1.8) NS 1.2 (3.2) 0.2 (1.3) NS
Domain 9 score (miscellaneous), mean ± SD 7.4 (8.4) 6.6 (6.8) NS 7.3 (8.8) 6.6 (5.8) NS
BDI score, mean ± SD 10.8 (4.4) 7.9 (5.9) 0.02 10.4 (5) 7.5 (5.6) 0.02
PDQ-8 score, mean ± SD 12.4 (6.4) 6.8 (5.1) 0.002 11.9 (5.6) 6.0 (5.4) 0.001
LEDD—Levodopa, mean mg ± SD 333.9 (232.9) 359.8 (264.1) NS 389.9 (265.2) 308.3 (231.7) NS
LEDD—Dopamine Agonist, mean mg ± SD 84.5 (90.4) 113.0 (113.8) NS 80.4 (99.1) 123.7 (108.5) NS
LEDD total, mean mg ± SD (range) 430.9 (263.0) 509.6 (316.4) NS 484.8 (322.0) 471.9 (273.5) NS
Patients on Levodopa, N (%) 29 (90.6) 38 (77.6) NS 37 (90.2) 30 (75.0) NS
Patients on dopamine agonists, N (%) 20 (62.5) 31 (63.3) NS 24 (58.5) 27 (67.5) NS
Statistically significant data (p \ 0.05) are highlighted in bold
PD Parkinson’s disease, N number of patients, SD standard deviation, NS not significant, UPDRS unified Parkinson’s disease rating scale, NMSS
nonmotor symptom scale, BDI Beck Depression Inventory, PDQ-8 Parkinson’s disease Quality of life 8 questions

Discussion context, in accordance to indications of Movement Disor-

The present study, exploring the presence and severity of
fatigue in Sardinian patients affected by PD, has evidenced
significant correlations both with motor symptoms and,
mainly, with those of non-motor type.
This result has been determined by the contemporary
evaluation of fatigue with two different scales and the
assessment of the total load of non-motor symptoms with
the NMSS, which has offered the opportunity to assess the
possible correlations of fatigue with every specific group of
NMS. Although a previous study addressed clinical pre-
dictors of fatigue using NMSS in PD [13], the assessment
of fatigue was limited by the evaluation carried out with
the administration of a simple visual analogue scale. In this
ders Society task force on rating scales for Parkinson’s
disease [14], we decided to administer two more complex
validated scales, such as FFS (‘‘recommended’’ for
screening and severity rating of fatigue) and the PFS
(‘‘recommended’’ for screening and ‘‘suggested’’ for
severity) [14].
In general, fatigue is a frequent non-motor symptom in
parkinsonian patients, affecting 40–50 % of the population
in our study. This frequency of fatigue is consistent with
previous reports [15–19]. In this regard, other studies
showed how this condition was more common in individ-
uals with PD compared to normal subjects [20, 21].
However, fatigue represents a major disabling condition
also in other diseases both neurological, such as multiple

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Table 3 Correlations among severity of fatigue assessed at PFS and Table 4 Correlations among severity of fatigue detected at PFS and
FSS with clinical data and motor symptoms FSS and non-motor symptoms assessed at NMSS
Clinical data or motor symptoms PFS FSS Items NMSS PFS FSS
r p r p r p r p

Age 0.181 \0.105 0.257 <0.020 Light-headedness 0.180 NS 0.117 NS

Duration of PD 0.106 \0.344 0.067 \0.550 Fainting 0.233 NS 0.252 NS
Hoehn and Yahr stage 0.335 <0.002 0.374 <0.001 Daytime sleep 0.360 <0.029 0.265 NS
UPDRS III score 0.374 <0.001 0.410 <0.000 Difficulty falling asleep 0.365 <0.024 0.341 NS
Tremor subscore UPDRS III 0.028 \0.804 0.101 \0.370 Restless legs 0.238 NS 0.159 NS
Rigidity subscore UPDRS III 0.074 \0.510 0.076 \0.500 Lost interest in 0.395 <0.008 0.384 <0.012
Bradykinesia subscore UPDRS III 0.368 <0.001 0.422 <0.000 surroundings
Postural subscore UPDRS III 0.493 <0.000 0.546 <0.000 Apathy 0.398 <0.007 0.344 <0.049
Anxiety 0.444 <0.001 0.322 NS
Statistically significant data (p \ 0.05) are highlighted in bold
Sadness 0.335 NS 0.274 NS
PFS Parkinson’s disease fatigue scale, FSS, Fatigue Severity Scale,
r correlation, PD Parkinson’s disease, UPDRS-III Unified Parkinson’s Flat mood 0.068 NS 0.139 NS
disease rating scale part III Anhedonia 0.450 <0.001 0.415 <0.003
Hallucinations 0.098 NS 0.037 NS
sclerosis [22], and chronic diseases and/or cancer [23–26]. Delusions 0.091 NS 0.148 NS
In our study female patients presented with significant Double vision 0.248 NS 0.198 NS
higher severity of fatigue compared to males, while pre- Concentration 0.374 <0.017 0.330 NS
sence of fatigue investigated with the FSS was significant Forget things or events 0.130 NS 0.089 NS
higher in women compared to men. Forget to do things 0.052 NS -0.004 NS
These data are somewhat in agreement with a previous Saliva 0.108 NS 0.074 NS
Norwegian research [3], although other two studies [17, 27] Swallowing 0.250 NS 0.270 NS
did not report any difference between fatigue and gender Constipation 0.300 NS 0.222 NS
difference. Urgency 0.167 NS 0.226 NS
Although this was not a priority of the present study, the Frequency 0.164 NS 0.199 NS
significant gender differences detected both at the BDI Nocturia 0.224 NS 0.257 NS
score and in the total score of NMSS confirms how gender Interest in sex 0.137 NS 0.234 NS
differences in PD patients can play a key role in the largest Problems having sex 0.116 NS 0.085 NS
expression of clinical symptoms [28, 29], representing a Pains 0.145 NS 0.121 NS
scarcely exploited field of research in neurodegenerative
Taste of small -0.051 NS -0.067 NS
diseases. Although these findings might suggest a possible
Weight change 0.204 NS 0.125 NS
dose dependent relationship between fatigue and depres-
Excessive sweating 0.067 NS 0.076 NS
sive symptoms in female patients, it should be highlighted
NMS total score 0.560 <0.000002 0.520 <0.00002
that depressive symptoms, as evidenced by multiple
regression analyses, cannot be considered the unique pre- Statistically significant data (p \ 0.05) are highlighted in bold
dictors of presence and severity of fatigue. PFS Parkinson’s disease fatigue scale, FSS Fatigue Severity Scale,
NMSS Non Motor Symptoms Scale
In line with this assumption, the two fatigue scales used
in this study were in agreement in the indication of the total
burden of non-motor symptoms as the most significant with a different sensibility regard to PFS is not surprising.
factor in predicting the presence of fatigue in PD patients. In fact, several items of FSS are more focused on the
However, despite the fact that the analysis of the correla- evaluation of motor correlates of fatigue rather than PFS.
tion involving PFS and FFS showed a significant rela- Moreover, it seems of interest the fact that the proposed
tionship between these different scales, both bivariate tests cut-off for the FFS suggests a higher frequency of PD
and binary logistic regression evidenced how presence of patients with fatigue compared to the one proposed for the
fatigue was conditioned by motor symptoms according to PFS.
FFS evaluation but not according to PFS. These results A necessary comment on the use of two different scales
confirm as different scales could detect different aspects of is due to the lack of ‘‘gold standards’’ for assessing the
fatigue, concluding that PFS and FSS, although similar, did ‘‘fatigue’’ symptom, as already previously suggested by
not appear to assess identical features of fatigue. However, other papers [3], while other objective assessment methods
the fact that FSS could reflect motor symptoms of fatigue are not available. On the contrary, both PFS and FSS did

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Fig. 1 Correlation between Parkinson’s disease fatigue scale (PFS) and Fatigue Severity Scale (FSS)

Table 5 Binary logistic

Characteristics T SE Wald df p Exp (B)
regression models for clinical,
motor and non-motor variables PFS model (dependent variable)
predicting presence of fatigue in
PD Constant -2.451 1.135 4.664 1 0.031 0.086
NMSS 0.032 0.008 15.175 1 0.000 1.033
PD duration -0.164 0.096 2.949 1 0.086 0.849
Hoehn and Yahr 0.405 0.447 0.821 1 0.365 1.499
Gender -0.262 0.572 0.210 1 0.647 0.770
FSS model (dependent variable)
Statistically significant data
Constant -3.372 1.173 8.269 1 0.004 0.034
(p \ 0.05) are highlighted in
bold NMSS 0.023 0.008 9.243 1 0.002 1.023
FSS Fatigue Severity Scale; Hoehn and Yahr 1.541 0.538 8.207 1 0.004 4.670
PFS, Parkinson’s disease PD duration -0.118 0.091 1.671 1 0.196 0.888
Fatigue Scale; NMSS, Non Gender -0.782 0.602 1.689 1 0.194 0.457
Motor Symptoms Scale

not significantly diverge on the identification of a signifi-
cant relationship among both non-motor and motor symp-
toms and severity of fatigue.
In this scenario, the correlations of severity of fatigue
with the UPDRS-III, as well with the HY scale, closely link
the motor deterioration with an increased sensation of
fatigue.
Thus, the feeling of increased sensation of fatigue might
share a common pathophysiologic basis with the one
underlying the deterioration of physical condition. At the
same time, our findings suggests how different scales used
in previous studies could have not found a clear relation-
ship between fatigue and PD motor severity as measured
by the UPDRS scores or Hoehn and Yahr stage [20, 30, 31]
while other reports have found a relationship between
fatigue and severity of disease [3, 18, 27, 32]. Moreover,
our results are in agreement with a previous study which
detected an increase in severity of fatigue at stage III of
Hoehn and Yahr scale [17].
Another intriguing correlation, detected within the
motor symptoms, concerns the relationship between fatigue
and the specific UPDRS III subscores for bradykinesia and
postural instability/posture. In this regard, fatigue was
previously reported as more severe in patients with postural
instability and gait disorders [17]. The detection of higher
levels of fatigue in PD patients with worsening of the

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Table 6 Ordinal regression models for clinical motor and non-motor variables predicting severity of fatigue in PD
Independent variables Estimate SE Wald df p Interval of confidence 95 %
Lower bound Upper bound

PFS Model (dependent variable)

NMSS 0.024 0.005 19.029 1 0.000 0.013 0.034
UPDRS-III 0.023 0.011 4.029 1 0.045 0.001 0.045
Gender 0.654 0.411 2.534 1 0.111 -0.151 1.460
Age 0.017 0.019 0.805 1 0.370 -0.020 0.054
FSS model (dependent variable)
NMSS 0.019 0.005 13.282 1 0.000 0.009 0.030
UPDRS-III 0.024 0.011 4.357 1 0.037 0.001 0.046
Gender 0.686 0.412 2.777 1 0.096 -0.121 1.494
Age 0.031 0.019 2.683 1 0.101 -0.006 0.069
Statistically significant data (p \ 0.05) are highlighted in bold
FSS Fatigue Severity Scale, NMSS Non Motor Symptoms Scale, PFS Parkinson’s disease Fatigue Scale, UPDRS-III unified Parkinson’s disease
rating scale part III

Table 7 Ordinal regression model for NMSS domains predicting severity of fatigue in PD
Independent variables Estimate SE Wald df p Interval of confidence 95 %
Lower bound Upper bound

PFS model (dependent variable)

NMSS Domain 1 (cardiovascular) -0.021 0.062 0.113 1 0.736 -0.142 0.100
NMSS Domain 2 (sleep disorders without fatigue) 0.069 0.028 6.092 1 0.014 0.014 0.124
NMSS Domain 3 (mood/anxiety) 0.038 0.015 6.698 1 0.010 0.009 0.068
NMSS Domain 4 (perceptual problems) 0.021 0.075 0.082 1 0.775 -0.126 0.168
NMSS Domain 5 (attention/memory) 0.009 0.024 0.134 1 0.714 -0.038 0.056
NMSS Domain 6 (gastrointestinal) 0.074 0.032 5.290 1 0.021 0.011 0.137
NMSS Domain 7 (urinary) 0.006 0.017 0.122 1 0.727 -0.028 0.040
NMSS Domain 8 (sexual dysfunction) 0.209 0.084 5.428 1 0.020 0.045 0.373
NMSS Domain 9 (miscellaneous) -0.014 0.030 0.202 1 0.653 -0.073 0.046
FSS model (dependent variable)
NMSS Domain 1 (cardiovascular) -0.024 0.062 0.147 1 0.701 -0.145 0.098
NMSS Domain 2 (sleep disorders without fatigue) 0.063 0.028 5.098 1 0.024 0.008 0.118
NMSS Domain 3 (mood/anxiety) 0.038 0.015 6.536 1 0.011 0.009 0.067
NMSS Domain 4 (perceptual problems) -0.012 0.075 0.026 1 0.872 -0.159 0.135
NMSS Domain 5 (attention/memory) 0.003 0.024 0.021 1 0.885 -0.044 0.051
NMSS Domain 6 (gastrointestinal) 0.065 0.032 4.083 1 0.043 0.002 0.127
NMSS Domain 7 (urinary) 0.018 0.018 1.042 1 0.307 -0.016 0.052
NMSS Domain 8 (sexual dysfunction) 0.168 0.078 4.692 1 0.030 0.016 0.321
NMSS Domain 9 (miscellaneous) -0.021 0.030 0.453 1 0.501 -0.080 0.039
Statistically significant data (p \ 0.05) are highlighted in bold
FSS Fatigue Severity Scale, NMSS Non Motor Symptoms Scale, PFS Parkinson’s disease Fatigue Scale

postural control might suggest a possible inclusion of this
symptom in the spectrum of the motor symptoms [33]. A
further clue of fatigue as a motor symptom is represented
by previous neurophysiological data which correlated
fatigue and decreased motor performance during the
movements of finger-tapping, expression of increased
bradykinesia [34].
This involvement of non-motor disorders underlying the
clinical manifestation of fatigue in PD seems to suggest
also a key role played by extrastriatal areas.

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Indeed, fatigue severity was strictly correlated to NMSS
such as the presence and frequency of disturbances in the
affective sphere (anhedonia, loss of interest, apathy and
anxiety) and sleep disorders (daytime sleepiness and sleep
difficulties), followed by gastrointestinal and sexual dys-
functions. Therefore, both the affective sphere and sleep
disorders seem to be closely related to the appearance of
fatigue. With this regard, our results confirm the findings of
Metta et al. [13], who observed an association of fatigue
with sleep dysfunction and anxiety and depression. In
addition, several previous publications demonstrated a
comorbidity of affective symptoms with fatigue, [14, 31,
34–37]. In this scenario, it should be highlighted that PD
patients did not declare the mere symptom ‘‘sadness’’ as
associated with higher severity of fatigue, which appears
more related to an apathetic/anhedonic disorder. However,
the association with depression was confirmed by the
stringent correlation between the two scales of fatigue used
and the BDI scores. Interestingly, it is useful to recall that
the diagnostic criteria of major depression coded in the
DSM-5 require the presence of fatigue or lack of energy
[38].
In view of a relevant role played by affective symptoms,
it is pertinent to recall that the presence of fatigue associ-
ated with anxiety disorders was retrieved in previous
observations [17, 27], as well the association with sleep
disorders [18, 27, 30, 39–41].
Finally, it is worth remembering that the quality of life,
scored with the PDQ-8, shows a significantly impairment
correlated with the increased severity of fatigue symptom,
thus amplifying the negative impact of motor and non-
motor disabilities related to PD.
As other previous study, a possible limitation of the
present investigation is represented by the possible pitfall
in generalizing these data, partly because peculiarities
concerning this specific population and because the pur-
pose of this study ruled out fatigue in PD patients with
dementia or with other associated severe clinical condi-
tions. Another limitation is the fact that this study did not
include normal controls. However, the aim of this study
was to highlight the possible association of fatigue with
other symptoms associated with PD, and thus assessment
of normal controls was not deemed imperative.
In conclusion, with the aim to clarify the nature of
fatigue in PD, we investigated its relationship with motor
and non-motor symptoms and compared these variables
among a sample of Sardinian parkinsonian patients. Data
analyses revealed that both motor and non-motor symp-
toms together with gender differences were related to
severity of fatigue in PD, although non-motor symptoms,
and, mostly, affective conditions and sleep disturbances,
were the main factors influencing fatigue. The better
individuation of these factors underlying fatigue, also with
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J Neurol (2014) 261:382–391
the systematic administration of holistic evaluation scales,
such as the NMSS, may lead to the improvement of current
pharmacologic and not pharmacologic strategies used in
the treatment of this disabling condition.
Acknowledgment This work was not supported by funding
agencies
Conflicts of interest Nothing to report.
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