The progressive death of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc) located in the midbrain, more precisely in the Basal Ganglia (BG), promotes a significant decrease in the levels of the neurotransmitter dopamine, and as a consequence the functional impairment of the neural circuits (motor, executive and limbic) [26]. The chronic reduction in dopamine levels gives rise to the manifestation of the motor symptoms that characterize this disease. However, the pathophysiology of PD is not limited to the dopaminergic system, that is, neuronal degeneration of other areas of the brain such as the brainstem and cortex competes and even precedes neuronal death in BG. Thus, other neurotransmitter systems (cholinergic, serotonergic and adrenergic) are compromised, thus making PD a multisystemic pathology manifested by a series of motor and non-motor symptoms [2] (Fig. 1).

The cardinal motor signs of PD are: resting tremor, plastic-type muscular rigidity, bradykinesia (akinesia or hypokinesia), and postural instability. This set of symptoms associated or not, forges characteristic clinical signs in patients with the disease such as gait and balance disorders, mask facies and dysarthria. In addition to these symptoms, a set of sensory (anosmia, pain, paresthesia) autonomic (dysphagia, constipation, urinary incontinence) and cognitive-behavioral symptoms (depression, apathy, dementia) may manifest during the course of the disease [27].

PD has five stages divided according to the impairment caused by the symptoms. The Hoehn & Yahr Scale (H & Y) is the most common clinical instrument used to evaluate the stages of the disease [28]. This scale classifies patients into patients into five stages of disease severity according to signs and symptoms (tremor, stiffness, bradykinesia and postural instability), thus assessing the degree of disability. From stage I to stage III, the patients present mild to moderate disability, and in stages IV and V, severe disability.

Fig. (1). Examples of experimental tests showing a high (a) and a low (b) data dispersion.

Pharmacological treatment of PD is based on the replacement of dopamine levels in the brain, which generally promotes the temporary improvement of physical disability and control of some of the symptoms. The medication considered gold standard in the treatment of PD motor symptoms is Levodopa (L-dopa), a metabolic precursor of dopamine that crosses the blood-brain barrier easily. Once in the Central Nervous System, L-Dopa is metabolized basally by DOPA decarboxylase, leading to dopamine. L-Dopa is marketed in association with a decarboxylase inhibitor drug (benserazide, carbidopa), preventing the peripheral synthesis of dopamine and ensuring the drug's arrival in the brain [29]. Other drugs are available, in most cases in association with L-dopa, and are divided according to the mechanism of action in order to increase the concentration of dopamine levels such as Monoamine Oxidase-B (MAO-B), Catechol-O-Methyl Transferase (COMT) inhibitors, or dopaminergic agonists such as Pramipexole (Amantadine) [30]. However, pharmacological treatment for PD has limitations ranging from possible drug interactions and side effects (nausea, sleep disorders, hallucinations), to decrease in its efficacy with years of use and the appearance of secondary symptoms such as dyskinesias and fluctuations (wearing off), due to the lack of effectiveness of the treatment of non-motor symptoms of the disease [27, 31]. The choice of drug or association that will be administered to the patient depends on factors such as age, stage of the disease, type of activity performed by the patient, and their mental state.

Other therapeutic strategies have been evaluated clinically and scientifically in recent years in the search for an action to reduce clinical problems of PD, such as, non-pharmacological interventions like physiotherapy and physical exercise [32, 33]. Rehabilitation through physical therapy has a variety of goals and methods that generally promote benefits in parkinsonian mobility, posture, and balance. However, some limitations have been observed in a consensual way by some researchers in two topics: in relation to the benefits that seem to be more immediate (acute), and the variety and low methodological quality of the studies [23-25]. Other nonpharmacological approaches to rehabilitation in Parkinson's disease are the practice of different modalities of physical exercises such as walking, running, strength training, whole body vibration and functional exercises, which are related to the reduction in the risk of falls, decreased motor symptoms, motor performance improvements, balance and gait improvements, positive repercussions in quality of life and executive functions [34-39].

For 50 years, physical exercise has been considered as a form of treatment for PD [40]. Recent literature reviews agree on the benefits of physical exercise in improving functional capacity, gait, balance, and strength in patients with PD [24, 41, 42]. Studies on animal models have shown very promising results on the effect of exercise on PD, especially treadmill aerobic training. Lau et al. (2011) examined the effects of treadmill exercise on rats, assessing the the coordination of movements and balance, changes in biomarkers of dopaminergic neurons, mitochondrial function and the activity of neurotrophic factors such as Brain-Derived Neurotrophic Factor (BDNF) in the nigrostriatal system, and their results demonstrated that the neuronal and behavioral recovery produced by exercise in the parkinsonian rats was associated with an improvement in mitochondrial function and an increase in BDNF in the nigrostriatal region of the brain [43]. Other animal model studies point to the hypothesis that physical exercise influences brain plasticity favoring neuroregenerative, neuroadaptive and neuroprotective responses mediated by the release of neurotrophic factors such as the Glial cell line-Derived Neurotrophic Factor (GDNF) and the Vascular Endothelial Growth Factor (VEGF) [43-45], and by the reduction of oxidative stress and the production of Reactive Oxygen Species (ROS) [46]. The expression of these trophic factors is closely related to the activation of certain biomolecular signaling cascades. The expression of BDNF in the hippocampus is generally due to the increase in the activation of β-CaMKII (Calmodulin-dependent Protein Kinase II) promoted by aerobic exercise, whereas the increase of central Insulin-like growth factor 1 (IGF-1) in strength training through the greater activation of the Akt pathway (Protein Kinase B) [47].

In research on humans, the results are more controversial, mainly due to the methodological quality of the studies available in the literature, but no less important. Several reviews show that it is evident the great variability of interventions adopted in the treatment of PD with exercise [30, 41, 48]. Many of these studies combine more than one type of intervention in their treatments, demonstrating favorable results in some of their main outcomes, but making it difficult to interpret the role of each type of intervention in improving patients.

Nevertheless, there are good studies available in the literature on the effect of aerobic exercise and strength training in PD patients. Cakit et al. (2007) investigated the effects of eight weeks of aerobic training on a treadmill with load bearing for 30 minutes in the symptoms of PD, balance, speed, and distance walked on treadmill and fear of falls. At the end of the study, the authors presented positive results in the group that underwent the intervention in all variables evaluated in comparison to the control group [49].

Kurtais et al. (2008) investigated the effects of six weeks of supervised treadmill walking, three times a week for 40 minutes in patients with mild to moderate PD, and observed significant improvements in lower limb functional parameters such as walking, balance, and agility, and in related parameters, the adaptations promoted by aerobic exercise as increase of peak VO₂ and caloric expenditure in METs [50].

Other authors suggest that forced aerobic exercise (the patient is led to train at a given intensity by another participant) promotes more benefits than voluntary training [51, 52]. Ridgel et al. (2009) compared two groups submitted to aerobic training on the cycle ergometer for one hour, three times a week, for eight weeks. One of the groups pedaled at an intensity between 60% and 80% of maximal heart rate which was called a voluntary exercise (EV), the other group pedaled on a double bicycle, assisted by a trainer who maintained a 30% higher HR intensity group EV. According to the authors, the group that did the forced training had a 35% improvement in the motor symptoms of PD, and the same result was not found in the EV group [51]. Recently Alberts et al. (2011) in a study with the same methodology corroborated the results found by Ridgel et al. (2009), demonstrating that patients who underwent forced training had an improvement of 41% in stiffness, 38% in tremor and 28% in bradykinesia evaluated by a specific clinical instrument. In this same study, Alberts et al. (2011) also demonstrated through magnetic functional resonance (fMRI) that aerobic exercise was able to promote increased activity in cortical and subcortical areas, with responses similar to those observed under the effect of antiparkinsonian medication [52].

Studies on strength training in patients with PD are more recent, only in the last 10 years this type of intervention has been investigated [53]. In general, the health benefits provided by strength training (increased strength and muscle mass, bone mineral density) are useful to the needs of patients with PD, especially with regard to functionality and independence related to daily life. For example, Scandalis et al. (2001) investigated the effect of eight weeks of strength training with lower limb emphasis twice weekly in 14 patients with moderate PD. The authors demonstrated that in addition to gait improvement, patients with PD increased strength similar to the control group composed of volunteers without the disease [54]. Dibble et al. (2006) demonstrated that patients with PD submitted to 12 weeks of high-intensity strength training had increased muscle strength and volume, as well as improvements in mobility [55]. Although in clinical practice, strength training is related to a possible worsening of PD symptoms, as can be observed, there is no evidence in the literature for this association [53].

Few studies have evaluated the effects of physical exercise on non-motor symptoms of PD. Tanaka et al. (2008) investigated the effect of combined exercise training (strength, balance, and coordination) on 10 patients with mild to moderate PD in executive functions, and found improvements in focused attention and inhibitory control [38]. Ridgel et al. (2011) observed an improvement in the executive functions of patients with PD assessed by the Trail-Making Test (TMT) A and B acutely, that is, immediately after two groups pedal for 40 minutes on a voluntary or forced basis [56]. Physical activity through active video games (Exergames), looks like a potentially useful tool in the field of neurorehabilitation able to offer motor and cognitive improvements in people with neurodegenerative diseases, including PD [57].

It is possible to assume that patients with Parkinson's disease should benefit in the majority of cases with different strategies, which should be prescribed based on a careful clinical evaluation, functional capacity, mental health and cardiorespiratory function. With these data in hand, the physical education or physiotherapy professional will be able to choose the type of training, duration, intensity and other variables to be worked out in order to promote the benefits of exercise to the patients.

The American College of Sports Medicine (ACSM) has published recommendations for the prescription of exercises for parkinsonians [58]. These recommendations are a good guide on what exercises to prescribe for this population and how to do it. One of the key information in this guide is that exercise recommendations for adult health fitness can be applied to parkinsonians, with caveats to the condition and physical limitations that the person presents. Adults with Parkinson's disease may present improvements similar to those of healthy adults in the variables of physical fitness (strength, muscular and aerobic resistance, balance and flexibility) [54], with direct impact on improving functional capacity (Board 1).

Most of these recommendations apply to those patients who are between the early stage (stage 1 of the Hoehn & Yahr scale) to moderate (stage 3). In stage 4, the patient usually needs ancillary devices for balance and gait, which requires an adaptation of the exercises to the presented physical limitations. While in stage 5, the patient is usually bedridden and with many limitations, requires a palliative approach with emphasis on the prevention of deformities.