Corrected by: Erratum Arq Neuropsiquiatr 2018; 76(12): 1-1
DOI: 10.1590/0004-282x20180071err
Keywords: resistance training - anxiety - Parkinson disease - randomized controlled trial
Palavras-chave: treinamento resistido - ansiedade - doença de Parkinson - ensaio randomizado controlado
Parkinson's disease (PD) is a neurodegenerative disorder that affects approximately
7 to 10 million individuals worldwide, and is characterized by the degeneration of
neurons of the substantia nigra pars compacta[1 ]. Individuals with PD present mainly with clinical motor findings: tremor, stiffness,
progressive bradykinesia and postural instability. In addition, nonmotor symptoms
are frequent before and after the PD diagnosis: sleep disorders, behavioral or mood
changes, apathy, depression and anxiety[2 ].
Anxiety affects approximately 25% to 49% of PD patients, with a higher prevalence
in this population than in non-PD populations[3 ],[4 ]. The etiology of anxiety in PD has not yet been defined, but it may be a reaction
secondary to motor and nonmotor symptoms. Studies have shown that anxiety symptoms
may contribute to morbidity and are correlated with decreased quality of life in patients
with PD[2 ],[5 ].
Previous studies have shown positive effects of resistance training on the physical
aspects of PD patients, improving balance[6 ], speed and spatial features of gait[7 ], reaction time, functional capacity[8 ], muscle strength and power[7 ],[6 ].
It is known that physical training, such as resistance training, is able to reduce
anxiety symptoms in adults and in people with other chronic diseases[9 ],[10 ]. Studies have shown that resistance training and other forms of physical exercise
are beneficial for central nervous system functions[11 ] and are important for the control of motor and nonmotor symptoms of PD[12 ].
To the best of our knowledge, there are no studies evaluating the anxiety symptoms
of individuals with PD undergoing a resistance training protocol. Thus, the main aim
of this study was to evaluate the effects of resistance training on anxiety symptoms
and quality of life of patients with PD. We hypothesized that resistance training
decreases the symptoms of anxiety, improving the quality of life and symptoms of PD.
METHODS
Trial design and ethics
We conducted an open-label randomized parallel group controlled clinical trial. The
study was approved by the ethics committee of the University of the Amazon (43624015.6.0000.5173).
The trial was registered in the Brazilian Registry of Clinical Trials (http://www.ensaiosclinicos.gov.br/):
RBR-36cw3y. The study was conducted at the Laboratory of Resistance Training and Health,
Universidade do Estado do Pará, August 2016 - December 2016.
Eligibility and trial procedures
Initially, 70 individuals from the Parkinson's Association in the State of Pará were
selected. Eligibility criteria included: 1) the diagnosis of PD by a neurologist specialized
in movement disorders, according to the clinical criteria proposed by Gelb[13 ]; 2) age ≥ 60 years; 3) stage 1–3 on the Hoehn and Yahr scale; 4) stable use of medication;
5) participants could not have participated in any exercise protocol in the previous
three months. Participants were excluded if: 1) they had a Mini-Mental State Examination
score of < 24[14 ]; 2) suffered from unstable cardiovascular disease; 3) suffered from other uncontrolled
chronic conditions that would interfere with the participant's safety, or our conducting
of the training and testing protocol and interpretation of the results; 4) the patient's
ability to walk independently; 5) or other neurological, cardiopulmonary, or orthopedic
disease.
Participants and randomization
After assessing the inclusion and exclusion criteria, 35 patients (aged over 60 years,
of both genders, with a clinical diagnosis of idiopathic PD and staging between 1
and 3 on the Hoehn and Yahr scale) were randomly divided into two groups: 1) control
group (CG) with 17 individuals and 2) resistance training group (RTG) with 18 individuals.
The CG continued with their standard pharmacological treatment for PD and the RTG,
in addition to pharmacological treatment, participated in a resistance training protocol
([Figure 1 ]). Both groups were followed up by a neurologist throughout the study. The individuals
in the sample (n = 35) did not present with other chronic disease (e.g. diabetes mellitus
and/or hypertension).
Figure 1 Flow diagram of study.
Participants were assigned a number between 1 and 35, and distributed to their group
by a research analyst, who was not involved in the study, by the implementation of
a publicly-accessible official website designed for research randomization (https://www.randomizer.org).
Randomization was stratified using the results of the Beck's Anxiety Inventory (BAI)
at baseline and outcome assessors were masked to group allocation. Randomization resulted
in a parallel group design with a 1:1 allocation ratio.
Assessments
All assessments were made by a single evaluator who was unable to distinguish participants
from either group (blind evaluation). All patients were analyzed when they were in
the “on” state of medication (1–1.5 hours after taking medication). During the study
period, it was recommended that all patients maintain their medication schedules.
Assessment of anxiety symptoms
The anxiety symptoms of patients with PD were evaluated by the BAI. This inventory
was translated and validated in Brazil by Cunha[15 ] in 2001 and is an anxiety measure that has been carefully designed to avoid confusion
with depression. The BAI consists of 21 self-reported items that highlight somatic,
affective and cognitive signs of anxiety symptoms. Each item has four possible answers
with scores from 0 to 3: 0 = Not at all; 1 = Mild, but it didn't bother me much; 2
= Moderate, it wasn't pleasant at times; 3 = Severe, it bothered me a lot. The total
score is 63 points[15 ].
Quality of Life Assessment and Unified Parkinson's Disease Rating Scale
The quality of life (QoL) assessment was performed using Parkinson's Disease Questionnaire
(PDQ-39), which is a validated and reliable tool for assessing PD patients[16 ]. The PDQ-39 has eight domains: mobility, activities of daily living, emotional well-being,
stigma, social support, cognition, communication and bodily discomfort. Each item
can be answered according to five predetermined answers: never; rarely; sometimes;
often; and always. The score of each item ranges from 0-4 points. The total score
is 0-100 points, and a lower score reflects a higher QoL. The PD symptoms were evaluated
using the Movement Disorders Society – Unified Parkinson's Disease Rating Scale (UPDRS)[17 ]. The UPDRS can be divided into four parts: 1) nonmotor experiences of daily living,
2) motor experiences of daily living, 3) motor examination and 4) motor complications.
Anthropometry
Body weight was measured on an analog scale (Filizola, Brazil) with 100 g accuracy
and capacity up to 150 kg. Height was measured using the stadiometer coupled to the
scale with 1 mm increments. To estimate subcutaneous fat, a skinfold caliper (Harpenden,
London, UK) was used according to standards established by the Siri equation using
a body density regression model (g.mL-1 ) for three skinfolds. To measure the waist, hip and abdomen circumference, a flexible
metal tape with 0.1 cm accuracy was used (Sanny, São Paulo, Brazil). All measurements
were performed in triplicate by a single, experienced evaluator.
Hand grip strength
The participant held the dynamometer in the hand to be tested, with their arm at right
angles and elbow by the side of their body. The handle of the dynamometer was adjusted
if required—the base should rest on the first metacarpal (heel of palm), while the
handle should rest on the middle of four fingers. When ready, the participant squeezed
the dynamometer with maximum isometric effort, which was maintained for about five
seconds. No other body movement was allowed. The participant was encouraged to give
maximum effort.
Training protocol
The six-month intervention exercise program consisted of resistance training sessions
lasting 30–40 minutes, on two nonconsecutive days per week, under the supervision
of an exercise specialist. The resistance training program comprised two sets of 8–12
submaximal repetitions for each of the following exercises: bench press, deadlift,
unilateral rowing, standing calf raise, and lower abdominal exercise. The interval
between sets and exercises was 1–2 minutes. During the first two weeks, the participants
became familiar with the exercises. After this phase, training loads were adjusted
following the recommendations of the American College of Sports Medicine[18 ]. In addition, the following characteristics were observed: tendency to concentric
failure, rhythm reduction, apnea, isometry and difficult effort on the OMINI-RES scale.
Statistical analysis
An a priori sample size calculation using G*Power showed that a total sample across both groups
of 34 participants would be sufficient to detect effect sizes of 0.5 from F tests
(p > 0.05) with a statistical power of 0.80. Data were analyzed using the SSPS v.20
statistical software. The α level for significance was p < 0.05 and all tests were
one-tailed. To analyze data normality, the Shapiro-Wilk test was used. Due to the
normal distribution, anxiety symptom, quality of life, hand grip strength and anthropometry
results were reported as mean ± standard deviation. The Hoehn and Yahr scale and UPDRS
results were presented as median and 25th −75th percentile), as they did not show normal distribution. The magnitudes of effect from
pre-intervention to post-intervention tests for each group were estimated using calculations
of effect size (ES).
The differences between groups at baseline were analyzed using the Mann-Whitney test
(variables with non-normal distribution) and the t-test (variables with normal distribution).
Groups were compared using factorial mixed-model 2 × 2 ANOVA [group (RTG x CG) x moment
(baseline x after 24 weeks)]. When necessary, multiple comparisons with confidence
adjustment using the Bonferroni procedure were used for post-hoc analysis. In the RTG, the Spearman's correlation was used to evaluate the association
between the BAI and the UPDRS and Pearson's correlation was used to evaluate the association
between the BAI and the PDQ-39.
RESULTS
Thirty-five patients participated in the study and, at baseline, there were no differences
between the groups (RTG x CG) in any demographic, anthropometric, clinical and outcome
characteristics ([Table 1 ]). At baseline, the groups showed no differences in the Hoehn and Yahr scale [RTG
= 1 (1–2) and CG = 1 (1–2); U = 0.322; p = 0.273]. All RTG patients completed the
training and no adverse events were reported during the trial. At the end of the study,
there was a significant decrease in part I of the UPDRS (p = 0.003) and UPDRS total
(p = 0.002) in the RTG. The CG showed a significant decrease only in part I of UPDRS
(p = 0.038) ([Table 2 ]).
Table 1
Characteristics of participants at baseline.
Characteristics
CG (n = 17)
RTG (n = 18)
95% CI
t
p-value*
Mean
SD
Mean
SD
Age (years)
67.6
8.9
64.1
7.0
3.53 (-1.97–9.04)
1.306
0.201
Time since PD diagnosis (years)
4.5
4.0
6.4
2.7
-1.9 (-4.23–0.43)
-1.740
0.091
PDQ-39 (score)
47.4
17.3
38.1
20.2
9.3(-3.67–22.27)
1.471
0.151
Symptoms of anxiety (score)
21.3
7.2
18
7.1
3.3 (-1.62–8.22)
1.381
0.177
Height (cm)
156.7
11.4
156.7
8.8
0 (-6.98–6.98)
2.043
0.447
Weight (kg)
66.9
8.3
67.8
11
-0.9 (-7.63–5.83)
-0.854
0.398
BMI (kg/m2 )
27.6
4.7
27.6
3.7
0 (-2.90–2.90)
2.030
0.972
Fat weight (kg)
15.6
2.6
16.4
4.6
-0.8 (-3,39–1.79)
-1.241
0.223
Lean weight (kg)
52.7
5.8
52.8
11.5
-0.1 (-6.42–6.22)
-0.100
0.920
Body fat (%)
23.1
1.9
24.5
7
-1.4 (-4.97–2.17)
-1.945
0.060
Waist (cm)
93.1
9.4
91.9
9.6
1.2 (-0.92–3.32)
2.055
0.777
Hip (cm)
99.6
6.5
97.8
7.7
1.8 (-2.83–6.43)
1.994
0.054
Abdomen (cm)
101.9
9.8
100.7
9.4
1.2 (-5.40–7.80)
1.145
0.260
Drugs (mg)
Levodopa + Carbidopa
5
0
5
0
–
–
NA
Prolopa
100
0
100
0
–
–
NA
Benserazide
25
0
25
0
–
–
NA
Sifrol
0.19
0.06
0.18
0.06
–
–
NA
Biperiden
157.4
33.1
146.3
25.5
–
–
NA
CG: control group; RTG: resistance training group; SD: standard deviation; PD: Parkinson
disease; BMI: body mass index;
*Test t samples independents; DM: difference between mean; NA: not available.
Table 2
Scoring on the UPDRS of the resistance training group and control group.
UPDRS
RTG
Δ%
CG
Δ%
Pre
Post
Pre
Post
Median
25th 75th
Median
25t −75th
Median
25th 75th
Median
25t −75th
UPDRS - Part I
11.5
(8-17.3)
6.5
(5-8.5)*
-43.5
13.5
(7.7-18.5)
8.5
(6-16.2)*
-37
UPDRS - Part II
19
(15.3-20.8)
19
(10-21.5)
0
18
(14-20.7)
17
(12.5-20)
-12.5
UPDRS - Part III
30
(28.5-39.8)
29
(22.8-48)
-3.3
29
(23.75-39)
34
(26.2-34)
17.2
UPDRS - Part IV
2
(0-4.5)
0
–
-100
4.5
(1-7)
6
(5.2-6)
33.3
UPDRS – Total
65.5
(57-74.8)
54.5
(42.5-73.3)*
-16.8
66.5
(56.5-75.7)
69.2
(60-72.2)
4
RTG: resistance training group; CG: control group; median (first quartile–third quartile);
UPDRS: Unified Parkinson's Disease Rating Scale; Part I: nonmotor experiences of daily
living; Part II: motor experiences of daily living; Part III: motor examination; Part
IV: motor complications; *statistically significant; Δ%: percentage difference.
The results of the PDQ-39 showed that the RTG patients had an improvement in QoL (ES
= −0.156; p = 0.009), while CG patients had no significant difference in QoL (ES =
−0.0043; p = 0.959) ([Table 3 ]). Before starting the exercise protocol, the RTG patients presented with an anxiety
level of 18 ± 7.1 and, after performing resistance training, these patients reported
a significant decrease of these symptoms, presenting with a score of 12.2 ± 5.5 (ES
= −0.415; p = 0.0001) ([Table 3 ] and [Figure 2 ]). Initially, the CG showed an anxiety level of 21.3 ± 7.2 and after six months,
with the maintenance of pharmacological treatment, the anxiety level was 19.9 ± 9.5.
This difference was not significant (ES = −0.082; p = 0.37).
Table 3
Anxiety symptoms and quality of life in elderly people with Parkinson's disease.
Variable
RTG
CG
Mean
SD
95% CI
Δ%
Mean
SD
95% CI
Δ%
BAI
Pre
18
7.1
14.5–21.5
-32.8%
21.3
7.2
17.60–25
-6.6%
Post
12.2
5.5
9.5–14.9
19.9
9.5
15.0–24.8
PDQ-39
Pre
38.06
20.16
28.03–48.09
-16.7%
47.41
17.27
38.5–56.3
-0.4%
Post
31.72
19.75
21.9–41.54
47.24
21.34
36.3–58.2
RTG: resistance training group; CG: control group; 95% CI: 95% confidence interval;
SD: standard deviation; Δ%: percentage difference; BAI: Beck Anxiety Inventory; PDQ-39:
Parkinson's Disease Questionnaire – 39
Figure 2 Levels of anxiety in the study groups.
The correlation of anxiety symptoms with age (p = 0.228) and time of PD diagnosis
(p = 0.269) was not significant. However, there was a positive correlation between
anxiety symptoms with the UPDRS and QoL ([Figure 3 ]). At the end of the intervention, there was an increase in training load (Kg) in
all exercises ([Table 4 ]). The hand grip strength increased significantly in the RTG (pre = 24.9 ± 7.4; post
= 29.4 ± 6.4; ES = 0.31; t = −2.59; p = 0.004). However, in the CG there was a significant
decrease in hand grip strength (pre = 25 ± 5.6; post = 23.3 ± 5; ES = −0.16; t = 5.146;
p = 0.16).
Figure 3 Correlation between the parts of the UPDRS and the symptoms of anxiety. A: Spearman's
correlation of the BAI vs UPDRS I. B: Spearman's correlation of the BAI vs UPDRS III.
C: Spearman's correlation of the BAI vs UPDRS total. D: Pearson's correlation of the
BAI vs PDQ-39.BAI: Beck Anxiety Inventory; UPDRS: Unified Parkinson's Disease Rating
Scale; PDQ-39: Parkinson's Disease Questionnaire-39
Table 4
Progression of the load in the exercises of the intervention protocol.
Exercise
Pre-intervention
Post-intervention
Mean (kg)
SD (kg)
Min–Max (kg)
Mean (kg)
SD (kg)
Min–Max (kg)
Bench Press
13.6
5.15
4–24
27.5
11.56
10–48
Unilateral rowing – Right
14.2
5.65
2–20
28.8
10.36
6–40
Unilateral rowing - Left
17.5
3.54
15–20
27.5
10.61
20–35
Deadlift
18.4
11.78
4–45
32.1
13.75
10–60
Standing calf raise
24.5
11.17
5–45
43.5
15.1
15–65
Lower abdominal exercise
1
1.05
0–2
4.6
2.32
2–8
SD: standard deviation; Min: minimum; Max: maximum
DISCUSSION
The main finding of our study showed a significant reduction in the anxiety level
of patients with PD after the regular resistance training; however, the CG did not
show any changes in this symptom. In previous studies, it had been observed that physical
exercise (e.g. resistance training) had potential benefits in the control and reduction
of anxiety symptoms in different populations[9 ],[12 ],[19 ],[20 ].
Anxiety is associated with increased motor symptoms in PD and decreased QoL of these
patients. Therefore, our main explanation for the reduction of anxiety symptoms in
the RTG was the reduction of the symptoms of the disease as evaluated through the
UPDRS and the consequent improvement in QoL of patients with PD. In addition, a positive
association between the BAI and UPDRS and between the BAI and PDQ-39 was found. It
is currently known that patients with PD who practice resistance training have significant
improvements in motor and nonmotor symptoms[1 ],[12 ],[21 ].
Unlike the localized action of the drug, chronic exercise promotes crosstalk among
tissues, providing metabolic, structural and functional adaptations in various cells
and organ systems at the same time, improving the ability to gain in the presence
of stress[22 ]. This may explain the response of reduction of anxiety symptoms in virtually all
RTG subjects.
The origin of anxiety symptoms in PD has not been clearly explained, but many studies
support the hypothesis of sharing underlying biological mechanisms among these pathologies,
which involve abnormalities in the dopaminergic system and in other interacting systems
such as: noradenergics, serotonergics[2 ],[23 ]. In addition, a constant stress stimulus is an important determinant for the development
of excessive anxiety symptoms, and PD is a homeostatic disorder that causes this type
of stimulation in the central nervous system[24 ].
Excessive anxiety symptoms are linked to reduced activity of noradrenergic neurons
in the medulla oblongata - locus coeruleus, leading to reduced synthesis of the norepinephrine
level, as well as increased expression of 5-hydroxytryptamine (5-HT) and decreased
5-HT 1A and 5-HT 1B autoreceptors by serotonergic neurons of the dorsal raphe nucleus.
However, stress promoted by chronic exercise increases the tyrosine hydroxylase activity
that transforms the tyrosine into norepinephrine, increasing expression of this neurotransmitter.
Triggers in the dorsal raphe lead to greater expression of 5-HT1A autoreceptors, which,
when activated, regulate the release of 5-HT[24 ],[25 ].
According to Moteiro-Junior et al.[26 ], the exercises may have a neuroprotective potential in patients with PD, by the
stimulation of neurotrophic factors responsible for the neurogenesis, neuroplasticity
and angiogenesis processes, which are fundamental for mental health. Resistance exercise
increases central insulin-like growth factor (IGF1) by stimulating the expression
of the IGF1 receptor that activates the Akt pathway, which is critical for angiogenesis,
cell growth and proliferation, and neural survival[19 ]. In addition, it is known that muscle under vigorous contraction releases many endocrine-related
factors, such as brain-derived neurotrophic factor, which can cross the blood-brain
barrier and trigger neuroplasticity[22 ].
Another important mechanism is the mitochondrial turnover disorder that is related
to the increase of oxidative stress and consequent neuroinflammation. This process
is cyclic, and is responsible for neurodegeneration, which may explain the progression
of PD symptoms and psychological disturbances, but chronic exercise by mediated increase
in the co-activators of SIRT1 transcription and peroxisome proliferator-activated
1-alpha-receptor co-activator (PGC-1α) promotes mitochondrial biogenesis, increases
antioxidant enzyme activity and decreases reactive oxygen species, reducing the progression
of PD symptoms and improving mental health[26 ],[27 ].
The relationship between the patients’ age and the time of diagnosis of PD with symptoms
of anxiety is still unclear[28 ],[29 ], but studies have demonstrated that anxiety may precede the onset of PD motor symptoms
or may develop after PD diagnosis[2 ],[4 ]. In the present study, no relationship between the patients’ age and time of PD
diagnosis was found.
Patients with PD present with a high prevalence of anxiety symptoms[30 ], which cause excessive concern and difficulty in social relations, directly affecting
their QoL. Our findings have shown that these symptoms can be attenuated with participation
in resistance training programs and the maintenance of pharmacological treatment,
under the care of a neurologist.
However, the QoL of patients with PD is influenced by other aspects of the disease,
such as: depression, apathy, cognition, insomnia, tremor, rigidity, medication, age
and severity of PD[28 ]. Many patients with PD become confined and abandon social life due to the progression
of motor symptoms. This situation further increases the symptoms of depression and
anxiety in this population.
Therefore, it is important that therapies, such as resistance training, which are
capable of acting on both motor and nonmotor symptoms of PD are added to the treatment
of this disease[12 ]. It was observed that in the RTG, the decrease of the total UPDRS, as well as in
parts I and II of the UPDRS, correlated with lower BAI scores. However, parts II (motor
experiences of the daily living) and part IV (motor complications) were not correlated
with the BAI. This demonstrates that understanding the complexity of different PD
symptoms is important because they directly influence the patients’ anxiety status.
Future studies should specifically research this relationship and how much and how
it influences the quality of life.
In conclusion, the resistance training was effective in reducing anxiety symptoms
and improved quality of life in patients with PD. Therefore, resistance training may
be a very important therapeutic intervention in PD.
Limitations
There were some limitations of this trial. First, all patients were treated and tested
during the “on” phase of their medications and the effects of therapy when “off” awaits
confirmation. Second, only patients at stages 1-3 of the Hoehn and Yahr scale, without
chronic conditions at the study onset, were included. Thus, results cannot be generalized
to patients without these characteristics. Third, the level of transmitters associated
with anxiety was not investigated. Fourth, the sample size was modest, with 17 control
patients and 18 patients in the experimental group, but this was due to the inclusion
and exclusion criteria proposed in this study.
