**Long-Term Multimodal Exercise Program Improves Motor and Non-Motor Parameters of People with Parkinson's Disease**

L.T.B. Gobbi, F.A. Barbieri, R. Vitório, M.P. Pereira, C. Teixeira-Arroyo, P.C.R. Santos, L.C. Morais, P.H.S. Pelicioni, L. Simieli, D. Orcioli-Silva, J. Lahr, A.Y.Y. Hamanaka, A.C. Salles, A.P.T. Alves, C.B. Takaki, E. Lirani-Silva, F.A. Cezar, F. Stella, M.D.T.O. Ferreira, M.J.D. Caetano, N.M. Rinaldi, P.M. Formaggio, R.A. Batistela and V. Raile

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57104

## **1. Introduction**

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146 A Synopsis of Parkinson's Disease

Parkinson's disease (PD) is a neurodegenerative pathology characterized by progressive death of the dopamine-containing neurons in the *substantia nigra pars compacta*. Although motor symptoms (i.e. resting tremor, postural instability, rigidity and gait impairment) are more commonly described in the literature, people with PD can also show cognitive symptoms (i.e. deficits in executive function, depression and dementia). Furthermore, these clinical charac‐ teristics of PD negatively impact functional capacity (Barbieri et al., 2012) and tend to get worse progressively (Karlsen et al., 2000).

Physical exercise has been described to benefit both clinical symptoms (motor and cognitive symptoms) and functional capacity of people with PD. In this concern, our research group has published a couple of studies demonstrating the benefits offered by a long-term multimodal exercise program on executive functions (Tanaka et al., 2009), balance (Gobbi et al., 2009), gait parameters (Vitório et al., 2011), and mobility (Pereira et al., 2012).

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The aim of current chapter is to discuss the effects of long-term multimodal exercise program on motor and cognitive symptoms, as well as on function capacity in people with PD. To reach this objective, this chapter is going to revisit the findings of our research group.

**Phases Coordination Muscular Resistance Balance**

**<sup>3</sup>** Head movements instead of trunk Exercises with barbells, ankle,

limbs Exercises without weights Recreational activities stimulating

Long-Term Multimodal Exercise Program Improves Motor and…

Exercises with hoops, ropes, and batons

weights, and medicine balls

Increase in intensity or repetitions (volume increment)

Gym exercises: leg press, pulley, seated cable rows, peck deck, and bench press. Two series with 15 repetitions

Increase in load and volume: addition of series of 15 repetitions

**Table 1.** Phases of the multimodal exercise protocol with progressive increments in volume, intensity and complexity.

Participants were tested before commencing the multimodal program (pretest) and upon completion (posttest). All assessments were carried out in the morning, in the "on-medication" state, 1 hour after participants' first morning dose of medication. The assessments included

Unified Parkinson's Disease Rating Scale (UPDRS; Fahn & Elton, 1987) was used to follow the longitudinal course of Parkinson's disease and assessed the impairments in psychological, functional and motor functions. This scale ranges from 0 to 176 points (I- psychological: 16

Hoehn and Yahr Scale (Hoehn & Yahr, 1967; Goetz et al., 2004) was used for describing how the stages of Parkinson's disease progress. This scale ranges from 1 to 5 stages: stage 1 - Unilateral involvement only; stage 1.5 - Unilateral and axial involvement; stage 2 - Bilateral involvement without impairment of balance; stage 2.5 - Mild bilateral disease with recovery

the vestibular system

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149

Recreational activities stimulating the vestibular system

> Stimulation of visual and somatosensory systems

Integration of visual, somatosensory, and vestibular systems

Activities including static balance, and half-turn and complete turn (all with visual cues)

Addition of tactile cues

**<sup>1</sup>** Movements of upper, and lower

**<sup>2</sup>** Movements of trunk, upper, and lower limbs

**<sup>4</sup>** Head, trunk, upper, and lower limb movements

> Four different movement sequences: two with same movements for upper and lower limbs and two alternating movements

> Four different movement sequences: two alternate movements for upper and lower limbs and two with different movements

clinical, cognitive and motor standard instruments.

points, II-functional: 52 points, III-motor: 108 points).

**5**

**6**

**2.1. Evaluations**

**2.2. Clinical evaluations**

## **2. Intervention**

Although promising, studies of exercise in PD have been limited in scope (program duration and specificity). Most have addressed the effects of short-term (over 4 to 12 weeks) specific exercise programs. The benefits of longer and nonspecific exercise intervention remain poorly understood. The cardinal clinical manifestations of PD are resting tremor, rigidity, bradyki‐ nesia, and gait dysfunction (Damier, Hirsch, Agid & Graybiel, 1999; Olanow; Stern & Sethi, 2009). However, it is known that PD is also associated with many non-motor features, including autonomic dysfunction, pain and sensory disturbances, mood disorders and sleep and cognitive impairment (Olanow; Stern & Sethi, 2009). In this way, a specific physical activity program may not be efficient in achieving many of these symptoms, and consequently to improve the quality of life of these patients. Furthermore, studies have shown that the annual rate of clinical decline in people with PD is between 3.5% (Alves, Wentzel-Larsen, Aarsland & Larsen, 2005) and 11.2% (García-Ruiz, Meseguer, Del Val & Vazquez, 2004), indicating the importance of knowing the effects of exercise are opposed to the advancement of the disease in the long term.

In this context, all the studies reviewed and included in this chapter used the same training protocol, characterized by a long duration multimodal program. Our multimodal exercise program aimed to develop the patients' functional capacities and to improve their quality of life. In contrast to specific programs, this one targeted a holistic improvement of PD patients.

The multimodal program took place over a 6-month period (72 sessions, 3 times a week and 60 minutes per session). Each session consisted of five parts (warm-up, pre-exercise stretching, exercise session, cool down and post-exercise stretching). The main exercise session lasted 40 minutes. The program was structured into six phases; each phase was composed of 12 sessions, each lasting approximately one month. At the end of each phase there was a progressive load increment. In each session, exercise intensity (remained between 60% and 80% of maximum heart rate, 220 minus the participant's age in years) was controlled by a heart rate monitor (Polar®).

The exercise program execution was supervised by at least three physical education profes‐ sionals and one physiotherapist each time. The multimodal program was composed of a variety of activities that simultaneously focus on the components of functional capacity, such as muscular resistance (specific exercises for gastrocnemius, quadriceps femoralis, hamstrings, rectus abdominalis, and trunk dorsal muscles), motor coordination (rhythmic activities), and balance (recreational motor activities on different surfaces and obstacles) (Table 1).


**Table 1.** Phases of the multimodal exercise protocol with progressive increments in volume, intensity and complexity.

#### **2.1. Evaluations**

The aim of current chapter is to discuss the effects of long-term multimodal exercise program on motor and cognitive symptoms, as well as on function capacity in people with PD. To reach

Although promising, studies of exercise in PD have been limited in scope (program duration and specificity). Most have addressed the effects of short-term (over 4 to 12 weeks) specific exercise programs. The benefits of longer and nonspecific exercise intervention remain poorly understood. The cardinal clinical manifestations of PD are resting tremor, rigidity, bradyki‐ nesia, and gait dysfunction (Damier, Hirsch, Agid & Graybiel, 1999; Olanow; Stern & Sethi, 2009). However, it is known that PD is also associated with many non-motor features, including autonomic dysfunction, pain and sensory disturbances, mood disorders and sleep and cognitive impairment (Olanow; Stern & Sethi, 2009). In this way, a specific physical activity program may not be efficient in achieving many of these symptoms, and consequently to improve the quality of life of these patients. Furthermore, studies have shown that the annual rate of clinical decline in people with PD is between 3.5% (Alves, Wentzel-Larsen, Aarsland & Larsen, 2005) and 11.2% (García-Ruiz, Meseguer, Del Val & Vazquez, 2004), indicating the importance of knowing the effects of exercise are opposed to the advancement of the disease

In this context, all the studies reviewed and included in this chapter used the same training protocol, characterized by a long duration multimodal program. Our multimodal exercise program aimed to develop the patients' functional capacities and to improve their quality of life. In contrast to specific programs, this one targeted a holistic improvement of PD patients.

The multimodal program took place over a 6-month period (72 sessions, 3 times a week and 60 minutes per session). Each session consisted of five parts (warm-up, pre-exercise stretching, exercise session, cool down and post-exercise stretching). The main exercise session lasted 40 minutes. The program was structured into six phases; each phase was composed of 12 sessions, each lasting approximately one month. At the end of each phase there was a progressive load increment. In each session, exercise intensity (remained between 60% and 80% of maximum heart rate, 220 minus the participant's age in years) was controlled by a heart rate monitor

The exercise program execution was supervised by at least three physical education profes‐ sionals and one physiotherapist each time. The multimodal program was composed of a variety of activities that simultaneously focus on the components of functional capacity, such as muscular resistance (specific exercises for gastrocnemius, quadriceps femoralis, hamstrings, rectus abdominalis, and trunk dorsal muscles), motor coordination (rhythmic activities), and

balance (recreational motor activities on different surfaces and obstacles) (Table 1).

this objective, this chapter is going to revisit the findings of our research group.

**2. Intervention**

148 A Synopsis of Parkinson's Disease

in the long term.

(Polar®).

Participants were tested before commencing the multimodal program (pretest) and upon completion (posttest). All assessments were carried out in the morning, in the "on-medication" state, 1 hour after participants' first morning dose of medication. The assessments included clinical, cognitive and motor standard instruments.

#### **2.2. Clinical evaluations**

Unified Parkinson's Disease Rating Scale (UPDRS; Fahn & Elton, 1987) was used to follow the longitudinal course of Parkinson's disease and assessed the impairments in psychological, functional and motor functions. This scale ranges from 0 to 176 points (I- psychological: 16 points, II-functional: 52 points, III-motor: 108 points).

Hoehn and Yahr Scale (Hoehn & Yahr, 1967; Goetz et al., 2004) was used for describing how the stages of Parkinson's disease progress. This scale ranges from 1 to 5 stages: stage 1 - Unilateral involvement only; stage 1.5 - Unilateral and axial involvement; stage 2 - Bilateral involvement without impairment of balance; stage 2.5 - Mild bilateral disease with recovery on pull test; stage 3 - Mild to moderate bilateral disease; some postural instability; physically independent; stage 4 - Severe disability; still able to walk or stand unassisted; and stage 5 - Wheelchair bound or bedridden unless aided.

tape. The cans are located at 10-in intervals. The participants were seated at the table with the line of cans well within their grasp and they were then asked to place each can top-side-down in a space adjacent to its original position. Then they returned the cans to their original topside-up position. Each attempt consisted of performing these movements twice, and the raw

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151

Modified Timed "Up and Go" test (TUG; Schilling et al., 2009; Gobbi et al., 2009) consisted of the participant stand up from a sitting position in an armless chair with a seat height of 46.5 cm, walk a 3-m distance, pass around a cone, return, and sit back down in the chair. Each participant was instructed to perform the task as quickly as possible, but without running. At least one practice attempt was offered to the participants at the beginning of the procedure so that they could become familiar with it. Three attempts were performed for testing purposes, and the time to perform the task was measured in seconds. Time was recorded from the instant the person's buttocks left the chair until the next contact with the chair. The mean value of the

Berg's Functional Balance Scale (FBS; Scalzo et al., 2009), measured the static and dynamic balance abilities by 14 simple balance related tasks, ranging from standing up from a sitting position, to standing on one foot. For each task this test ranged from 0 (unable) to 4 (inde‐ pendent). The better score is 56 points with the increased risk of falls below a score of 45 and

Postural-Locomotor-Manual Test (PLM; Hong & Steen, 2007) was designed to assess move‐ ment patterns. The test movement is a compound movement involving a postural phase (rising up), a locomotion phase (walking), and a manual phase (pendulous arm movement and positioning of a test object on a pedestal). The PLM test consisted of a complex motion during which the patients moved an object from the floor 1.5-m forward and positioned it on a stand

Kinematic gait parameters: the walking task required participants to walk, at a self speed, on an 8m long pathway. Three attempts were performed. For the kinematic data recording, two passive markers (reflective, adhesive Styrofoam) were attached to the following anatomic landmarks: lateral face of the right calcaneus and medial face of the left calcaneus. The images of the right sagittal plane of one stride at center of the pathway were recorded with a frequency of 60Hz by one digital camcorder (JVC, GR-DVL 9800), generating 2D kinematic data. Markers

The multimodal exercise program improved several aspects related to quality of life of patients with PD. First, we showed the benefits of six months of the exercise program on clinical parameters. Exercise program improved the UPDRS-II (functional aspects) score. After exercise program patients with PD decreased the score (Table 2). The exercise program seems

at their chin height, as fast as possible. The time to complete the test was record.

were digitized automatically on Digital Video for Windows (DVIDEOW) software.

Aerobic resistance: an 880-yd walk, at the participant's maximum speed.

score reflected the faster of two attempts.

three attempts was considered for statistical analysis.

a significant increase below 40 points.

**3. Results**

#### **2.3. Cognitive evaluations**

Mini-Mental State Examination (MMSE) (Folstein, Folstein, & Mchugh, 1975; Brucki et al., 2003), a brief 30-point questionnaire test was used to screening cognitive impairment. This test evaluates orientation, memory, arithmetic and visuo-constructive praxis. For Brazilian population the cutoff score for cognitive impairment considers the educational level (illiterate people - 19 points; from 1 to 4 years of schooling - 24 points; from 5 to 8 years of schooling - 26 points; from 9 to 11 years of schooling - 28 points and educational level ≥ 12 years - 29 points).

Wisconsin Card Sorting Test (WCST; Heaton, Chelune, Talley, Kay, & Curtiss, 1993; Paolo, Troster, Axelrod, & Koller, 1995) specifically assessed abstraction, mental flexibility and attention respectively by the subtests ''Categories Completed", ''Perseverative Errors" and ''Failure to Maintain Set".

Wechsler Memory Scale – Revised (WMS-R; Wechsler, 1997), a neuropsychological test designed to measure different memory functions. Subtests used in reviewed studies were logical memory, for short-term memory (logical memory I) and episodic declarative memory (logical memory I I), and Symbol Search, for attention capacity.

State-Trait Anxiety Inventory (STAI; Spielberger, Gorsuch, & Lushene, 1979; Gorenstein & Andrade, 1996), a psychological inventory based on a 4-point Likert scale and consisted in 2 self-report questionnaires that measured two types of anxiety: state anxiety (anxiety about an event) and trait anxiety (anxiety level as a personal characteristic). Higher scores represent higher levels of anxiety.

#### **2.4. Motor evaluations**

Functional capacity was assessed by means of AAHPERD tests (flexibility, muscle strength, agility, coordination and aerobic endurance; Osness et al., 1990). Flexibility test: a standard sitand-reach test in which participants were seated, with their heels 12-in apart and over a line that runs perpendicular to a measuring tape. They were asked to reach with both hands as far along the measuring tape as they comfortably can while keeping both knees straight. The score was their highest tape measure mark in three attempts.

Muscular strength: requires female participants to lift a 4-lb object, and male participants to lift an 8-lb object, using a biceps curl motion, as many times as possible in 30-s.

Agility: patients started from a seated position and were asked to rise from a chair, walk to the right around a cone, and return to the seat and sit down, stand again, walk to the left around a cone, return to their seat and sit down, and then repeat the entire procedure. Two attempts were given to the participants, and the raw score represented the faster of the two.

Coordination: involved the movement of three 12-oz soda cans, using the dominant hand. The cans are placed on a table, topside-up and on a line indicated by a 30-in length of masking tape. The cans are located at 10-in intervals. The participants were seated at the table with the line of cans well within their grasp and they were then asked to place each can top-side-down in a space adjacent to its original position. Then they returned the cans to their original topside-up position. Each attempt consisted of performing these movements twice, and the raw score reflected the faster of two attempts.

Aerobic resistance: an 880-yd walk, at the participant's maximum speed.

Modified Timed "Up and Go" test (TUG; Schilling et al., 2009; Gobbi et al., 2009) consisted of the participant stand up from a sitting position in an armless chair with a seat height of 46.5 cm, walk a 3-m distance, pass around a cone, return, and sit back down in the chair. Each participant was instructed to perform the task as quickly as possible, but without running. At least one practice attempt was offered to the participants at the beginning of the procedure so that they could become familiar with it. Three attempts were performed for testing purposes, and the time to perform the task was measured in seconds. Time was recorded from the instant the person's buttocks left the chair until the next contact with the chair. The mean value of the three attempts was considered for statistical analysis.

Berg's Functional Balance Scale (FBS; Scalzo et al., 2009), measured the static and dynamic balance abilities by 14 simple balance related tasks, ranging from standing up from a sitting position, to standing on one foot. For each task this test ranged from 0 (unable) to 4 (inde‐ pendent). The better score is 56 points with the increased risk of falls below a score of 45 and a significant increase below 40 points.

Postural-Locomotor-Manual Test (PLM; Hong & Steen, 2007) was designed to assess move‐ ment patterns. The test movement is a compound movement involving a postural phase (rising up), a locomotion phase (walking), and a manual phase (pendulous arm movement and positioning of a test object on a pedestal). The PLM test consisted of a complex motion during which the patients moved an object from the floor 1.5-m forward and positioned it on a stand at their chin height, as fast as possible. The time to complete the test was record.

Kinematic gait parameters: the walking task required participants to walk, at a self speed, on an 8m long pathway. Three attempts were performed. For the kinematic data recording, two passive markers (reflective, adhesive Styrofoam) were attached to the following anatomic landmarks: lateral face of the right calcaneus and medial face of the left calcaneus. The images of the right sagittal plane of one stride at center of the pathway were recorded with a frequency of 60Hz by one digital camcorder (JVC, GR-DVL 9800), generating 2D kinematic data. Markers were digitized automatically on Digital Video for Windows (DVIDEOW) software.

## **3. Results**

on pull test; stage 3 - Mild to moderate bilateral disease; some postural instability; physically independent; stage 4 - Severe disability; still able to walk or stand unassisted; and stage 5 -

Mini-Mental State Examination (MMSE) (Folstein, Folstein, & Mchugh, 1975; Brucki et al., 2003), a brief 30-point questionnaire test was used to screening cognitive impairment. This test evaluates orientation, memory, arithmetic and visuo-constructive praxis. For Brazilian population the cutoff score for cognitive impairment considers the educational level (illiterate people - 19 points; from 1 to 4 years of schooling - 24 points; from 5 to 8 years of schooling - 26 points; from 9 to 11 years of schooling - 28 points and educational level ≥ 12 years - 29 points). Wisconsin Card Sorting Test (WCST; Heaton, Chelune, Talley, Kay, & Curtiss, 1993; Paolo, Troster, Axelrod, & Koller, 1995) specifically assessed abstraction, mental flexibility and attention respectively by the subtests ''Categories Completed", ''Perseverative Errors" and

Wechsler Memory Scale – Revised (WMS-R; Wechsler, 1997), a neuropsychological test designed to measure different memory functions. Subtests used in reviewed studies were logical memory, for short-term memory (logical memory I) and episodic declarative memory

State-Trait Anxiety Inventory (STAI; Spielberger, Gorsuch, & Lushene, 1979; Gorenstein & Andrade, 1996), a psychological inventory based on a 4-point Likert scale and consisted in 2 self-report questionnaires that measured two types of anxiety: state anxiety (anxiety about an event) and trait anxiety (anxiety level as a personal characteristic). Higher scores represent

Functional capacity was assessed by means of AAHPERD tests (flexibility, muscle strength, agility, coordination and aerobic endurance; Osness et al., 1990). Flexibility test: a standard sitand-reach test in which participants were seated, with their heels 12-in apart and over a line that runs perpendicular to a measuring tape. They were asked to reach with both hands as far along the measuring tape as they comfortably can while keeping both knees straight. The score

Muscular strength: requires female participants to lift a 4-lb object, and male participants to

Agility: patients started from a seated position and were asked to rise from a chair, walk to the right around a cone, and return to the seat and sit down, stand again, walk to the left around a cone, return to their seat and sit down, and then repeat the entire procedure. Two attempts

Coordination: involved the movement of three 12-oz soda cans, using the dominant hand. The cans are placed on a table, topside-up and on a line indicated by a 30-in length of masking

lift an 8-lb object, using a biceps curl motion, as many times as possible in 30-s.

were given to the participants, and the raw score represented the faster of the two.

(logical memory I I), and Symbol Search, for attention capacity.

was their highest tape measure mark in three attempts.

Wheelchair bound or bedridden unless aided.

**2.3. Cognitive evaluations**

150 A Synopsis of Parkinson's Disease

''Failure to Maintain Set".

higher levels of anxiety.

**2.4. Motor evaluations**

The multimodal exercise program improved several aspects related to quality of life of patients with PD. First, we showed the benefits of six months of the exercise program on clinical parameters. Exercise program improved the UPDRS-II (functional aspects) score. After exercise program patients with PD decreased the score (Table 2). The exercise program seems be able to improve clinical parameters, agreeing with the benefits to functional capacity components, mobility and locomotion, which are aspects relate to functional activities. Therefore, the improvement in the clinical parameters is important for quality of life for this population.

**FUNCTIONAL CAPACITY**

**Dependent Variables Pre exercise Post exercise p values**

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153

balance (score) 52.86 ± 4.15 53.57 ± 2.71 0.19

flexibility (cm) 47.56 ± 12.10 50.14 ± 10.53 0.17

coordination (s) 18.50 ± 7.58 15.89 ± 6.84 0.01

agility (s) 28.82 ± 12.37 30.74 ± 11.54 0.64

strength (rep) 19.79 ± 6.57 23.50 ± 5.33 0.01

TUG (s) 10.10 ± 4.32 8.46 ± 2.16 0.01

PLM (s) 4.03 ± 1.42 3.58 ± 0.76 0.01

aerobic resistance (min) 10.08 ± 2.45 10.13 ± 2.90 0.83

**GAIT PARAMETERS**

**Dependent Variables Pre exercise Post exercise p values**

Stride Length (cm) 95.1 ± 14.8 102.4 ± 15.5 0.01

Stride duration (s) 1.06 ± 0.17 0.97 ± 0.11 0.06

Stride velocity (cm/s) 92.7 ± 21.1 105.7 ± 15.5 0.01

Cadence (strides/s) 0.97 ± 0.13 1.04 ± 0.12 0.07

Swing phase (%) 36.5 ± 4.1 37.2 ± 2.3 0.93

Single support (%) 37.5 ± 3.7 38.3 ± 2.3 0.83

Double support (%) 26.0 ± 7.3 24.5 ± 4.0 0.86

**Table 3.** Means and standard deviations for each functional capacity component and gait dependent variables at

Third, even though it was not the purpose of the multimodal exercise program, the individuals with PD improved the non-motor symptoms (Table 4). Patients with PD improved short-term memory (logical memory I), episodic declarative memory (logic memory II), abstraction capacities (categories completed) and mental flexibility (perseverative errors) after the enrolment in the multimodal exercise program. Again, these findings indicated an improve‐ ment of quality of life for patients with PD. So, the multimodal exercise program seems to

TUG: Timed Up and Go Test; PLM: Posture-Locomotor-Manual Test.

before (pre) and after (post) the multimodal exercise program.

improve cognitive function.


H&Y: Hoehn & Yahr Stage; UPDRS: Unified Parkinson's Disease Rating Scale; MMSE: Mini-Mental State Examination.

**Table 2.** Means and standard deviations for the demographic characteristics and clinical dependent variables at before (pre) and after (post) the multimodal exercise program.

Second, the exercise program affected motor aspects. The multimodal exercise program was efficient to improve the functional parameters, such as functional capacity (some components), mobility and locomotion. For functional capacity components, the coordination and muscle strength (Table 3) improved after the multimodal exercise program, which indicates a control of the motor symptoms effects. Moreover, the exercise program maintained the other compo‐ nents, which was an important finding since PD and ageing decreases progressively the functional capacity. For functional mobility, patients with PD were faster in TUG and PLM (Table 3) after the enrolment in the multimodal exercise program. The exercise seems to act on bradykinesia symptom revealing that patients PD were able to perform functional tasks faster. In addition, our results for locomotion corroborated with functional mobility. Patients with PD increased gait velocity after exercise program (Table 3). Still, the multimodal exercise program improved stride length (Table 3), indicating a positive change for hypometria symptom. Therefore, the exercise program seems to be an important aspect for PD patients, improving the quality of life and decreasing the dependency.


be able to improve clinical parameters, agreeing with the benefits to functional capacity components, mobility and locomotion, which are aspects relate to functional activities. Therefore, the improvement in the clinical parameters is important for quality of life for this

**DEMOGRAPHIC CHARACTERISTICS**

**CLINICAL PARAMETERS**

UPDRS - Functional (score) 11.07 ± 6.36 9.73 ± 6.04 0.02

UPDRS - Motor (score) 20.13 ± 12.26 21.00 ± 14.53 0.72

UPDRS – Total (score) 34.87 ± 18.89 34.07 ± 20.71 0.45

H&Y: Hoehn & Yahr Stage; UPDRS: Unified Parkinson's Disease Rating Scale; MMSE: Mini-Mental State Examination.

Second, the exercise program affected motor aspects. The multimodal exercise program was efficient to improve the functional parameters, such as functional capacity (some components), mobility and locomotion. For functional capacity components, the coordination and muscle strength (Table 3) improved after the multimodal exercise program, which indicates a control of the motor symptoms effects. Moreover, the exercise program maintained the other compo‐ nents, which was an important finding since PD and ageing decreases progressively the functional capacity. For functional mobility, patients with PD were faster in TUG and PLM (Table 3) after the enrolment in the multimodal exercise program. The exercise seems to act on bradykinesia symptom revealing that patients PD were able to perform functional tasks faster. In addition, our results for locomotion corroborated with functional mobility. Patients with PD increased gait velocity after exercise program (Table 3). Still, the multimodal exercise program improved stride length (Table 3), indicating a positive change for hypometria symptom. Therefore, the exercise program seems to be an important aspect for PD patients,

**Table 2.** Means and standard deviations for the demographic characteristics and clinical dependent variables at

MMSE (score) 26.20 ± 3.47 25.90 ± 4.35 0.77

**Dependent Variables Pre exercise Post exercise p values**

H&Y (stage) 1.47 ± 0.72 1.53 ± 0.72 0.15

Age (years) 67.77 ± 7.28

Body height (cm) 161.00 ± 8.74

Body mass (kg) 70.70 ± 15.87

before (pre) and after (post) the multimodal exercise program.

improving the quality of life and decreasing the dependency.

population.

152 A Synopsis of Parkinson's Disease

**Table 3.** Means and standard deviations for each functional capacity component and gait dependent variables at before (pre) and after (post) the multimodal exercise program.

Third, even though it was not the purpose of the multimodal exercise program, the individuals with PD improved the non-motor symptoms (Table 4). Patients with PD improved short-term memory (logical memory I), episodic declarative memory (logic memory II), abstraction capacities (categories completed) and mental flexibility (perseverative errors) after the enrolment in the multimodal exercise program. Again, these findings indicated an improve‐ ment of quality of life for patients with PD. So, the multimodal exercise program seems to improve cognitive function.


we demonstrate that enrolling into our exercise program allowed the patients to improve

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155

Considering functional capacity, PD patients showed improvements on muscular strength, motor coordination, dynamic balance and functional mobility (Orcioli-Silva et al., 2013, submitted for publication). Muscular strength is a function of length and velocity (Winter, 1990), where its gain can leads to an improvement of both stride velocity and length. Motor coordination is a motor act that requires the control of body segments in an integrated way, with the aim to create a successful movement pattern. In this way, both improvements of strength and coordination could drive patients to increase their gait velocity and stride length. This is reinforced by the results of some studies which demonstrated that gait is highly influenced by coordination in PD patients (Plotnik, Giladi & Hausdorff, 2008). Due to the improvement of these both motor capacities, a more stable level was acquired, thus reflecting

Lower limbs muscular strength decrease, a reduction of stride length and velocity, and poor levels of balance and functionality can lead to higher risk of falling in PD patients (Cole et al., 2010; Kerr et al., 2010; Latt et al., 2009; Vitório, Lirani-Silva & Pelicioni, 2013). In this way, even without assessing the number of falls during our exercise program, we can suggest that the enrolment on our multimodal exercise program leads to a reduction of patients' risk of falls. Also, since patients increased their self-judgment about their functionality (increase in UPDRS II scores), this could also result in a falling risk reduction. This is based on the study of Vellas et al. (1997), which indicates that fear of falling (and therefore a reduction of own judgment

Beyond the benefits in patients' quality of life, we cannot forget to mention another important aspect of our motor results. The improvement of both strength and coordination after a 6 month multimodal exercise program show us that peripheral benefits observed in healthy elderly, from exercise enrolment, can be transferred, at least in part, to PD patients. Also, the improvement on coordination leaves an open window to discuss the maintenance of learning

Finally, about the motor benefits of our multimodal exercise program, we need to discuss the maintenance of UPRDS III score. Someone can argue that our program did not reduced motor impairments and therefore, is not so attractive. However, since a decrease of 3.2% in HY stage score per year is expected (Alves et al., 2005), the maintenance of UPRDS III score is an important result. We must remember that our program has a long lasting period and the maintenance of motor impairments after 6 months has important effects on patients' quality

However, the most exciting results are those related to cognitive aspects. The improvement in executive functions (responsible to successfully plan, select and execute motor plans) could also be responsible to higher performance of gait. This is based on the study of Yogev et al. (2005), which relates the gait performance to cognitive status in PD patients. Furthermore, a higher cognitive performance can also leads to a better self-perception of functional state,

on functional mobility, measured through TUG and PLM tests.

about functional capacity) is direct related to the number of falling episodes.

different aspects of their life.

capacity in PD patients.

increasing the UPDRS II score.

of life.

WCST: Wisconsin Card Sorting Test; STAI: State-Trait Anxiety Inventory; HAD: Hospital Anxiety and Depression Scale.

**Table 4.** Means and standard deviations for the cognitive functions at before (pre) and after (post) the multimodal exercise program.

In summary, a multimodal exercise program of six months seems to improve motor and nonmotor symptoms of PD. Aspects related to functional activity, mobility and cognition showed benefits with exercise program, which is a relevant finding for functionality and quality of life of PD patients.

## **4. Final considerations**

The aim of this chapter was to discuss the effects of long-term multimodal exercise program on motor and cognitive symptoms, as well as on functional capacity in people with PD. To reach this aim, we reviewed the published data of our group and as main results we found improvements in four different domains: clinical aspects, gait parameters, functional capacity and cognitive status. All these improvements certainly increased patients' independency, mobility, functional aspects and quality of life. For functional aspects, this is clear according to the improvement of UPDRS II score. Since the UPRDS II is a self-related scale, this is also important to the patients' quality of life: patients self-perceived their own functional aspects as better after the enrolment in our program. This certainly increases patients' quality of life. However, the benefits did not only rely on PD clinical aspects, but also on peripheral gains (as strength) and improvements in brain functions, as memory and executive function. We show during this section that there is not a main cause as responsible for our results. In another way, we demonstrate that enrolling into our exercise program allowed the patients to improve different aspects of their life.

**COGNITIVE FUNCTIONS**

**Dependent Variables Pre exercise Post exercise p values**

STAI - Trait 50.40 ± 8.01 48.70 ± 5.39 0.58 STAI - State 49.20 ± 6.95 48.50 ± 6.67 0.27

HAD 5.40 ± 2.59 5.40 ± 3.13 0.35

Logic memory I (score) 15.50 ± 3.60 19.50 ± 5.00 0.04 Logic memory II (score) 8.6 ± 5.95 13.8 ± 6.38 0.01

Symbol Search 22.50 ± 7.73 24.20 ± 9.12 0.60

Categories Completed (WCST) 2.80 ± 1.68 4.10 ± 1.37 0.04 Perserverative Errors (WCST) 4.00 ± 3.49 0.30 ± 0.94 0.04 Failure to Maintain Set (WCST) 6.00 ± 2.40 5.20 ± 2.34 0.64

WCST: Wisconsin Card Sorting Test; STAI: State-Trait Anxiety Inventory; HAD: Hospital Anxiety and Depression Scale.

**Table 4.** Means and standard deviations for the cognitive functions at before (pre) and after (post) the multimodal

In summary, a multimodal exercise program of six months seems to improve motor and nonmotor symptoms of PD. Aspects related to functional activity, mobility and cognition showed benefits with exercise program, which is a relevant finding for functionality and quality of life

The aim of this chapter was to discuss the effects of long-term multimodal exercise program on motor and cognitive symptoms, as well as on functional capacity in people with PD. To reach this aim, we reviewed the published data of our group and as main results we found improvements in four different domains: clinical aspects, gait parameters, functional capacity and cognitive status. All these improvements certainly increased patients' independency, mobility, functional aspects and quality of life. For functional aspects, this is clear according to the improvement of UPDRS II score. Since the UPRDS II is a self-related scale, this is also important to the patients' quality of life: patients self-perceived their own functional aspects as better after the enrolment in our program. This certainly increases patients' quality of life. However, the benefits did not only rely on PD clinical aspects, but also on peripheral gains (as strength) and improvements in brain functions, as memory and executive function. We show during this section that there is not a main cause as responsible for our results. In another way,

exercise program.

154 A Synopsis of Parkinson's Disease

of PD patients.

**4. Final considerations**

Considering functional capacity, PD patients showed improvements on muscular strength, motor coordination, dynamic balance and functional mobility (Orcioli-Silva et al., 2013, submitted for publication). Muscular strength is a function of length and velocity (Winter, 1990), where its gain can leads to an improvement of both stride velocity and length. Motor coordination is a motor act that requires the control of body segments in an integrated way, with the aim to create a successful movement pattern. In this way, both improvements of strength and coordination could drive patients to increase their gait velocity and stride length. This is reinforced by the results of some studies which demonstrated that gait is highly influenced by coordination in PD patients (Plotnik, Giladi & Hausdorff, 2008). Due to the improvement of these both motor capacities, a more stable level was acquired, thus reflecting on functional mobility, measured through TUG and PLM tests.

Lower limbs muscular strength decrease, a reduction of stride length and velocity, and poor levels of balance and functionality can lead to higher risk of falling in PD patients (Cole et al., 2010; Kerr et al., 2010; Latt et al., 2009; Vitório, Lirani-Silva & Pelicioni, 2013). In this way, even without assessing the number of falls during our exercise program, we can suggest that the enrolment on our multimodal exercise program leads to a reduction of patients' risk of falls. Also, since patients increased their self-judgment about their functionality (increase in UPDRS II scores), this could also result in a falling risk reduction. This is based on the study of Vellas et al. (1997), which indicates that fear of falling (and therefore a reduction of own judgment about functional capacity) is direct related to the number of falling episodes.

Beyond the benefits in patients' quality of life, we cannot forget to mention another important aspect of our motor results. The improvement of both strength and coordination after a 6 month multimodal exercise program show us that peripheral benefits observed in healthy elderly, from exercise enrolment, can be transferred, at least in part, to PD patients. Also, the improvement on coordination leaves an open window to discuss the maintenance of learning capacity in PD patients.

Finally, about the motor benefits of our multimodal exercise program, we need to discuss the maintenance of UPRDS III score. Someone can argue that our program did not reduced motor impairments and therefore, is not so attractive. However, since a decrease of 3.2% in HY stage score per year is expected (Alves et al., 2005), the maintenance of UPRDS III score is an important result. We must remember that our program has a long lasting period and the maintenance of motor impairments after 6 months has important effects on patients' quality of life.

However, the most exciting results are those related to cognitive aspects. The improvement in executive functions (responsible to successfully plan, select and execute motor plans) could also be responsible to higher performance of gait. This is based on the study of Yogev et al. (2005), which relates the gait performance to cognitive status in PD patients. Furthermore, a higher cognitive performance can also leads to a better self-perception of functional state, increasing the UPDRS II score.

These are exciting results since they demonstrate that exercise cannot benefits only healthy adult brain, but also mental function of PD patients. Some studies had demonstrated that the practice of moderate and intense physical exercise can result in compensatory changes on the dopaminergic neurotransmission (Petzinger et al., 2007). In addition, some studies had shown that exercise could also be responsible to neural adaptations as the increase of blood flow (Hirsch & Farley, 2009) and to an increase of metabolic and neurochemical function in the brain (Petzinger et al., 2010). Other results point to an increase of neuroprotection and even to an increase of neural growth factors (Zigmond et al., 2009) in the brain after exercise programs. These results were seen mainly on animal models and at this time, we cannot assure that our exercise program promoted these adaptations. However, even without assessing these morphological and physiological aspects of physical exercise (and this is not the objective of our group), the improvement in memory and executive function point to some adaptations in brain levels. The PD brain also shows a high capacity to redesign itself in response to physical activity, providing a plausible argument related to the neuroplasticity mechanism in PD patients after physical exercises (Hirsch & Farley, 2009).

**Author details**

M.D.T.O. Ferreira2

, F.A. Barbieri1

, P.H.S. Pelicioni1

, A.P.T. Alves2

2 The PROPARKI Group, Brazil

*rology*, 65, 1436-1441.

, R. Vitório1

, C.B. Takaki2

, M.J.D. Caetano1

*teoria à prática*. Curitiba, PR: CRV, 325-339.

*Neuro-Psiquiatria*, 61(3B), 777-781.

*ment Disorders*, 5(14), 2369 – 2378.

231-238.

22(3), 226-233.

severity." *Archives of Gerontology and Geriatrics*, 54, e83-e88.

1 UNESP Univ Estadual Paulista, Rio Claro, Brazil

, L. Simieli1

, M.P. Pereira1

, E. Lirani-Silva2

[1] Alves, G.; Wentzel-Larsen, T.; Aarsland, D. & Larsen, J. P. (2005) Progression of mo‐ tor impairment and disability in Parkinson disease: a population-based study. *Neu‐*

[2] Barbieri, F. A.; Simieli, L.; Orcioli-Silva, D. & Gobbi, L. T. B. (2013). Benefícios do ex‐ ercício físico para pacientes com doença de Parkinson. In. Coelho, F. G. M.; Gobbi, S.; Costa, J. L. R. & Gobbi, L. T. B. *Exercício físico no envelhecimento saudável e patológico: da*

[3] Barbieri, F.A.; Rinaldi, N.M.; Santos, P.C.R.; Lirani-Silva, E; Vitório, R.; Teixeira-Ar‐ royo, C.; Stella, F.; Gobbi, L.T.B. (2012) "Functional capacity of Brazilian patients with Parkinson's disease (PD): Relationship between clinical characteristics and disease

[4] Brucki, S. M. D., Nitrini, R., Caramelli, P., Bertolucci, P. H. F., & Okamoto, I. H. (2003) Suggestions for utilization of the mini-mental state examination in Brazil. *Arquivos de*

[5] Burini, D.; Farabollini, B.; Iacucci, S.; Rimatori, C.; Riccardi, G.; Capecci, M.; Provin‐ ciali, L. & Ceravolo, M. G. (2006). A randomized controlled cross-over trial of aerobic training versus qigong in advanced Parkinson's disease. *Europa Medicophysica*, 42(3),

[6] Canning, C. G; Ada, L; Woodhouse, E. (2008). Multiple-task walking training in peo‐ ple with mild to moderate Parkinson's disease: a pilot study. *Clinical Rehabilitation*,

[7] Cole, M. H.; Silburn, P.A.; Wood, J.M.; Worringham, C. J. & Kerr, G.K. (2010). Falls in Parkinson's disease: kinematic evidence for impaired head and trunk control. *Move‐*

, N.M. Rinaldi2

, D. Orcioli-Silva1

, C. Teixeira-Arroyo1

Long-Term Multimodal Exercise Program Improves Motor and…

, J. Lahr1

, F.A. Cezar2

, P.M. Formaggio1

, P.C.R. Santos1

http://dx.doi.org/10.5772/57104

, A.Y.Y. Hamanaka2

, R.A. Batistela2

,

, F. Stella1

,

157

,

and

L.T.B. Gobbi1

L.C. Morais1

A.C. Salles2

**References**

V. Raile2

It is believed that these adaptations are due to our program design and to the exercises intensity level. High intensity exercises have shown more positive effects in PD patients when compared to low intensity exercises (Burini et al., 2006; Fisher et al., 2008). Also, physical activity programs lasting longer than 10 weeks, with a frequency more than 3 days a week and with 45-60minutes of duration per session can lead to higher benefits to PD patients (Barbieri et al., 2013). Also, it is indicated that activities with intensity between moderate to high (Barbieri et al., 2013). Our multimodal exercise program fully respected all these statements as well as it had a continuous progression during each phase, whereas the intensity of physical exercises was kept between moderate to high. It is believed that this exercise design is better for PD patients than others since it results in compensatory changes in the dopaminergic neurotrans‐ mission (Petzinger et al., 2007; Petzinger et al., 2010).

It is also important to consider that patients enrolled in our multimodal exercise program were in between the mild to moderate stages of disease. Since these patients have a better physical condition than those on severe stages, possibly these last could not be able to execute the exercises properly. Also, patients in mild to moderate disease stages are still able to learn new motor skills (Canning, Ada & Woodhouse, 2008).

In resume, the results of our group clearly show that a 6-months multimodal exercise program was feasible and improved patients' physical and cognitive status (Gobbi et al., 2011). After 6 months, patients enrolled in our exercise program maintained their motor impairments and, moreover, improved their independency and functionality. We can state that our exercise program increased patient's mobility, with the reduction of two main symptoms: bradikynesia and hypometria. At this time is not possible to state if the positive results found after our program are mainly due to a reduction in the physiological aging process, to neural adapta‐ tions or to a combination of both. However, these improvements are not only result of motor aspects but they are also related to improvement on cognitive domain. Finally, after reviewing our results we can properly affirm that our 6-months multimodal exercise program increased patients' independency, which certainly, improved their quality of life.

## **Author details**

These are exciting results since they demonstrate that exercise cannot benefits only healthy adult brain, but also mental function of PD patients. Some studies had demonstrated that the practice of moderate and intense physical exercise can result in compensatory changes on the dopaminergic neurotransmission (Petzinger et al., 2007). In addition, some studies had shown that exercise could also be responsible to neural adaptations as the increase of blood flow (Hirsch & Farley, 2009) and to an increase of metabolic and neurochemical function in the brain (Petzinger et al., 2010). Other results point to an increase of neuroprotection and even to an increase of neural growth factors (Zigmond et al., 2009) in the brain after exercise programs. These results were seen mainly on animal models and at this time, we cannot assure that our exercise program promoted these adaptations. However, even without assessing these morphological and physiological aspects of physical exercise (and this is not the objective of our group), the improvement in memory and executive function point to some adaptations in brain levels. The PD brain also shows a high capacity to redesign itself in response to physical activity, providing a plausible argument related to the neuroplasticity mechanism in PD

It is believed that these adaptations are due to our program design and to the exercises intensity level. High intensity exercises have shown more positive effects in PD patients when compared to low intensity exercises (Burini et al., 2006; Fisher et al., 2008). Also, physical activity programs lasting longer than 10 weeks, with a frequency more than 3 days a week and with 45-60minutes of duration per session can lead to higher benefits to PD patients (Barbieri et al., 2013). Also, it is indicated that activities with intensity between moderate to high (Barbieri et al., 2013). Our multimodal exercise program fully respected all these statements as well as it had a continuous progression during each phase, whereas the intensity of physical exercises was kept between moderate to high. It is believed that this exercise design is better for PD patients than others since it results in compensatory changes in the dopaminergic neurotrans‐

It is also important to consider that patients enrolled in our multimodal exercise program were in between the mild to moderate stages of disease. Since these patients have a better physical condition than those on severe stages, possibly these last could not be able to execute the exercises properly. Also, patients in mild to moderate disease stages are still able to learn new

In resume, the results of our group clearly show that a 6-months multimodal exercise program was feasible and improved patients' physical and cognitive status (Gobbi et al., 2011). After 6 months, patients enrolled in our exercise program maintained their motor impairments and, moreover, improved their independency and functionality. We can state that our exercise program increased patient's mobility, with the reduction of two main symptoms: bradikynesia and hypometria. At this time is not possible to state if the positive results found after our program are mainly due to a reduction in the physiological aging process, to neural adapta‐ tions or to a combination of both. However, these improvements are not only result of motor aspects but they are also related to improvement on cognitive domain. Finally, after reviewing our results we can properly affirm that our 6-months multimodal exercise program increased

patients' independency, which certainly, improved their quality of life.

patients after physical exercises (Hirsch & Farley, 2009).

156 A Synopsis of Parkinson's Disease

mission (Petzinger et al., 2007; Petzinger et al., 2010).

motor skills (Canning, Ada & Woodhouse, 2008).

L.T.B. Gobbi1 , F.A. Barbieri1 , R. Vitório1 , M.P. Pereira1 , C. Teixeira-Arroyo1 , P.C.R. Santos1 , L.C. Morais1 , P.H.S. Pelicioni1 , L. Simieli1 , D. Orcioli-Silva1 , J. Lahr1 , A.Y.Y. Hamanaka2 , A.C. Salles2 , A.P.T. Alves2 , C.B. Takaki2 , E. Lirani-Silva2 , F.A. Cezar2 , F. Stella1 , M.D.T.O. Ferreira2 , M.J.D. Caetano1 , N.M. Rinaldi2 , P.M. Formaggio1 , R.A. Batistela2 and V. Raile2

1 UNESP Univ Estadual Paulista, Rio Claro, Brazil

2 The PROPARKI Group, Brazil

## **References**


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**Chapter 7**

**The Potential of Targeting LRRK2 in Parkinson's Disease**

Parkinson's disease (PD) is the second most common neurodegenerative disease that affects more than 5 million people, accounting to 1-2 % of the population worldwide. It is character‐ ized by the loss of dopaminergic neurons in the substantia nigra associated with the formation of fibrillar aggregates that are composed of α-synuclein and other proteins [1]. PD is clinical characterized by four major symptoms; tremor, bradykinesia, rigidity and postural instability. Initially PD was considered sporadic, however genetic studies in patients families revealed mutations that are segregating with PD. Nowadays, in addition to environmental factors, mutations within 6 loci (SNCA, LRRK2, PRKN, DJ1, PINK1 and ATP13A2) have been clearly demonstrated to be causative to familial PD [2-4]. Among them, SNCA and LRRK2 mutations cause autosomal dominant forms of PD [5]. Human leucine-rich-repeat kinase 2 (LRRK2) has been found to be thus far the most frequent cause of late-onset PD [6, 7]. The identification of missense mutations in LRRK2 has redefined the role of genetic variation in PD susceptibility. The mutations are found in 5-6 % of patients with familial PD, and also have been implicated with sporadic PD [8]. LRRK2 mutations initiate a penetrant phenotype with complete clinical and neurochemical overlap with idiopathic PD (IPD). Penetrance is age-related, around 75 % mutation carriers showed PD symptoms at the age of 80 [9, 10]. Tremor is more commonly observed in LRRK2 mediated PD compared to IPD [11]. Although dementia and cognitive defects are not frequently present in patients with mutations in LRRK2, LRRK2 does associate

LRRK2 belongs to the Roco family of proteins, which constitute a novel family of Ras-like Gproteins that have an unique domain architecture [15]. LRRK2 is a large and complex protein with multiple domains; Armadillo repeats (ARM), Ankyrin repeats (ANK), leucine-rich repeats (LRR), a Ras of complex (Roc), a C-terminal of Roc (COR), kinase domain and WD40 repeats (Fig. 1). Most of the PD mutations are accumulated around the central core of the protein, one is found in the LRR, two in the Roc domain (with multiple substitutions), one in

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

F.Y. Ho, K.E. Rosenbusch and A. Kortholt

with Lewy bodies in IPD and dementia [12-14].

http://dx.doi.org/10.5772/57362

**1. Introduction**

Additional information is available at the end of the chapter

