Nonmotor signs and symptoms of Parkinson’s disease [23, 24, 25].
\r\n\tWith this goal in mind, together with the US Prof. John M. Ballato and the InechOpen publishing house since 2011 we have published in 2011, 2013, 2015 and 2017 4 books of our serial “Optoelectronics” and the book “Excitons”, edited in 2018 by Prof. Sergei L. Pyshkin. Publishing the new book “Luminescence” we are pleased to note the growing number of countries participating in this undertaking as well as for a long time fruitfully cooperating scientists from the United States and the Republic of Moldova.
\r\n\tSpecialists from all over the world have published in edited by us books their works in the field of research of the luminescent properties of various materials suitable for use in optoelectronic devices, the development of new structures and the results of their application in practice.
In this chapter, we will discuss some important topics about Parkinson’s disease (PD), a progressive and neurodegenerative disease, that is characterized by many motor and nonmotor symptoms and with wide-reaching implications for patients and their families [1, 2]. It is neuropathologically characterized by nigrostriatal cell loss and the presence of intracellular a-synuclein-positive inclusions called Lewy bodies [3].
\nIt is the most common movement disorder with approximately 1–2% of the population over 65 years of age suffering from PD. This percentage increases in people of 85 years of age and older, about 3–5% [3]. According to the World Health Organization, 6.1 million individuals have Parkinson’s disease globally [4]. Some authors have shown that the burden of Parkinson’s disease has more than doubled over 26 years worldwide, from 2.5 million patients in 1990 to 6.1 million patients in 2016. So, we can expect that the trend will continue in the next 30 years having approximately more than 12 million individuals suffering from PD [5]. In 2016, there were 211,296 estimated deaths caused by Parkinson’s disease [4].
\nPD is characterized mainly by four motor symptoms: resting tremor, bradykinesia, rigidity, and postural instability [1] with balance decrements and gait disruption [2]. It may present problems in performing personal activities of daily living, such as eating, drinking, cutting food, walking in the neighborhood, and writing [6].
\nThe diagnosis of PD is based on medical history and a neurological examination since there are no blood tests, laboratory tests, or imaging examinations that have been proven to help in diagnosing PD [7], and its treatment is based on a pharmacological approach. The main therapy is based on levodopa and dopamine agonists and is very successful in the early stages of the disease, when dopaminergic symptoms and signs are predominant and long-term motor complications still have not developed [8].
\nThe traditional classification and disease progression of Parkinson’s disease (PD) orient toward disease milestones that can be most obviously followed along motor domains. However, diverse nonmotor domains, quality of life, psychosocial burden, and stigma have been used as important domains for the course of PD and the outcome parameters of clinical trials [9].
\nAt present, there is no cure for PD, but a variety of medications provide relief from the symptoms. Individuals who are affected usually are given levodopa combined with carbidopa. Levodopa helps in at least three-quarters of Parkinsonian cases; however, not all symptoms respond equally to the drug. Bradykinesia and rigidity respond best, while tremor may be only marginally reduced. Problems with balance and other symptoms may not be alleviated at all [7].
\nIn this scenario, physiotherapy has a significant importance in a multidisciplinary team focused on the rehabilitation of individuals with PD, with the purpose of maximizing functional ability and minimizing secondary complications through movement rehabilitation within a context of education and to support the person as a whole [10].
\nThe main focuses of physiotherapy for individuals with PD are transfers, posture, upper limb function, balance (and falls), gait, and physical capacity and activity. Physiotherapy also uses cueing strategies, cognitive movement strategies, and exercises to maintain or to increase independence, safety, and quality of life. The traditional and new strategies will be addressed in this chapter [10].
\nPhysiologically, the symptoms associated with Parkinson’s disease are the result of the loss of a number of neurotransmitters, most notably dopamine. It is characterized neuropathological by nigrostriatal cell loss and the presence of intracellular a-synuclein-positive inclusions called Lewy bodies [3, 11]. All these alterations change the function of the basal ganglia system, resulting in Parkinson’s main movement disorders.
\nCell loss in the substantia nigra occurs in a region-specific manner, with the lateral ventral tier of the pars compacta being most affected. It is estimated that at least 50% of the nigral neurons must degenerate to produce symptoms, and, at autopsy, most cases show more than 80% reduction [8].
\nThe basic basal ganglia circuitry and the balance between the direct and indirect striatal pathways provide a simple heuristic model for PD’s main signs. According to this model, the pathophysiological hallmark of PD, hypokinetic signs are the prevalence of the indirect pathway over the direct one, consequently, resulting in increased neuronal firing activity in the output nuclei of the basal ganglia and leading to excessive inhibition of thalamocortical and brainstem motor systems, interfering with normal speed of onset movement and execution. On the other hand, overactivity in the direct pathway and imbalance with the indirect one may cause reduced inhibitory basal ganglia output and result in reduced basal ganglia filtering and parallel facilitation of multiple movement fragments. (See \nFigure 1\n) [8].
\nA schematic view of the functional anatomy of the basal ganglia. There are the normal direct and indirect pathways (panel a) and the alteration of direct and indirect pathways in Parkinson’s disease (panel b). Modified from Magrinelli et al. [8] and Nitrini and Bacheschi [12].
Another important region that has been linked to physiopathology of PD is the cerebellum. Its reciprocal connections with basal ganglia, especially with striatum and external segment of the globus pallidus, strengthens the hypothesis that it plays a role in the pathogenesis of some PD symptoms and signs [8].
\nHistopathology alterations can be described in this pathophysiological situation. There usually can be seen some histological characteristics not just in nerve tissue. The most important marker is called Lewy bodies. They are made of a protein called alpha-synuclein, which, in a healthy brain, plays a number of important roles in neurons, especially at synapses [13].
\nLewy bodies can be found in many regions of the brain and some reports have suggested that the substantia nigra is not the first place where they form in Parkinson’s disease [14].
\nNeither cell loss nor the formation of Lewy bodies is absolutely specific for PD, but both are required for a diagnosis of PD under current definitions. Additionally, it’s necessary to consider that not all affected neurons in PD are dopaminergic. An example to be cited is the cholinergic neurons from the dorsal vagal nucleus. This variety of regions has been suggested to be responsible for the complex clinical picture in PD [13].
\nThis pathophysiological situation seems to be multifactorial. It can be considered by genetic factors, inflammation, immune response, and environmental elements [14].
\nWhile having a family member with PD may increase a person’s risk, PD is not normally considered a genetic disease. Variants in three genes (SNCA, UCHL 1, and LRRK 2) have been reported in familial PD. Mutations in three other genes (PARK 2, PARK 7, and PINK 1) have been found in sporadic PD [14, 15].
\nOn the other hand, large population studies have suggested that individuals taking nonsteroidal anti-inflammatory drugs (NSAIDs) have less risk of developing idiopathic PD, which suggests that anti-inflammatory drugs may be a promising disease-modifying treatment for Parkinsonian patients [16].
\nSome reports have provided direct evidence of interactions between α-synuclein and environmental agents. Some options described in the literature are heavy metals (iron, copper, manganese, lead, and mercury), pesticides (including insecticides and herbicides), and illicit substances (amphetamine, methamphetamine, and cocaine) [17].
\nIn a review, Di Monti et al. [18] describe some possibilities of multiple events and interactive mechanisms possibly responsible for alpha-synuclein alterations. These may include (i) the synergistic action of endogenous and exogenous toxins, (ii) the interactions of toxic agents with endogenous elements (e.g., the protein α-synuclein), (iii) the tissue response to an initial toxic insult, and (iv) the effects of environmental factors on the background of genetic predisposition and aging.
\nIt’s important to explain that the symptoms of Parkinson’s disease sometimes can be seen outside the disease itself. In these cases, we call this clinical condition of parkinsonism, also known as “atypical Parkinson’s,” “secondary Parkinson’s,” or “Parkinson’s syndrome.” Parkinsonism often has an identifiable cause, such as exposure to toxins, methamphetamine, trauma, multiple strokes, other nervous system disorders, or illness. Generally, Lewy bodies are not seen in parkinsonism [14].
\nThe three clinical motor cardinal signs of PD, a-/hypo-/bradykinesia, rest tremor, and rigidity, are directly related to the degeneration of dopaminergic neurons. However, other motor symptoms and signs, secondary to degeneration of nondopaminergic pathways, can be described such as loss of postural control, postural stability/balance, and gait disturbance. In addition, the most well-known nonmotor characteristic motor symptoms have also been described. There can be additional psychiatric and autonomic features found, as well as cognitive impairment, sleep disorders, olfactory dysfunction, and pain.
\n\n
A-/hypo-/bradykinesia: These terms are defined, collectively, as slowed voluntary movement. Separately, akinesia indicates the absence of voluntary movement, while hypokinesia means smaller movements, and bradykinesia refers to slowness of movement. They usually determine any impairment in fine motor movements, facial expression (hypomimia), monotonic and hypophonic speech with a reduction of speed, and general motion amplitude. This can have an important impact in functional skills like arm swinging when walking, raising from a chair, handwriting, and general gesturing [14, 19].
This cardinal sign is one of the best that emerges from its origin of dysfunction, which is cited in this chapter (see \nFigure 1\n). It has been determined especially by a characteristic involving the movement programming of the cerebral cortex, in particular the supplementary motor area [8, 19].
\nIt is possible to find two modulations of this cardinal sign of Parkinson’s disease: freezing phenomenon and kinesia paradoxa. In the first one, the individual presents a sudden and transient motor block, mainly in the lower limbs during walking. This may include start hesitation, hesitation, or inability to move through the presence of contradictory visual cues (floors with different colors and small steps), when there is a need to change direction of gait or be still in open spaces. The second one, kinesia paradoxa, occurs under certain emotional circumstances where the patient is able to exhibit a sudden brief period of mobility (walking or even running and catching a ball). This phenomenon shows that, even though individuals with Parkinson’s disease have their motor programs intact, the disease prevents them from accessing them in the correct way, requiring external stimuli for this to happen even if done poorly [19, 20].
2. Rest tremor: this sign is usually asymmetric, consisting of alternate contractions of agonist and antagonist muscles, including flexors, extensors, pronators, and supinators of the wrists and arms, resulting in the “pill rolling” movement of the hand. It has a medium frequency (3 to 6 Hz) and tends to disappear with action. The legs, lower jaw, or head may also be involved, resulting in an adduction-abduction movement of the lower limbs and yes-yes or no-no motion in the head [8, 21].
The pathophysiology of rest tremor is largely unknown. Clinical-pathological studies have demonstrated that patients with PD and prominent tremor have dysfunction of a subgroup of midbrain (A8) neurons and its magnitude seems to not be related to dopamine deficiency [8, 19].
3. Rigidity: it is a type of increase in muscle tone (also called plastic hypertonia), generally defined as an increased resistance to passive movement of a joint. Rigidity is more evident in the flexor muscles of the trunk and limbs and may be enhanced by voluntary movement. However, its presence usually determines a characteristic of stooped posture. Two types of rigidity can be described: cogwheel rigidity refers to resistance that stops and starts at the limb, the limb is moved through its range of motion, and it is the result of coexisting rigidity and tremor; lead-pipe rigidity is defined as a constant resistance to motion throughout the entire range of movement [8, 14].
It is unclear how rigidity is associated with dopamine deficiency and basal ganglia dysfunction. Nevertheless, evidence suggests that this cardinal sign has its pathogenesis in the passive mechanical properties of joints, tendons, and muscles, and spinal and supraspinal reflexes, which together determine an increased response to peripheral stimulation and an increased muscle elongation response [8].
\n\n
\nPosture disturbances: individuals with Parkinson’s disease usually develop abnormal axial postures as a result of bradykinesia, rigidity, and resting tremor. This abnormality leads to a flexed general posture, with hip and knee flexion, accompanied by shoulder and even elbow flexion. In the long term, this posture disturbance can determine severe postural deformities such as antecollis, scoliosis, camptocormia, and Pisa syndrome. Little is known about the cause of these deformities, which makes it unresponsive to most treatments [8, 19].
\nPostural instability balance and gait disturbances: postural instability and gait disturbances usually occur during the course of PD, generally being manifestations of the late stages of the disease. They represent a therapeutic challenge, since they show little change through traditional pharmacological treatment using dopaminergic drugs. These two impairments, especially if associated with the freezing phenomenon, are the most common cause of falls and fractures in Parkinsonians [19, 22].
One of the most important causes for these signs is the poor ability to integrate visual, vestibular, and proprioceptive inputs associated with a failure to activate central motor programs and their interaction with the mechanisms of sensitive feedback. Postural instability and gait disturbances have been associated with an akinetic-rigid syndrome, as well as an increased incidence of nonmotor features [8, 22].
3. Other signs and symptoms: in addition to the most important signs of Parkinson’s disease, some other motor signs can be found, such as dysarthria, hypophonia, dysphagia, and sialorrhea. These signs occur as a result of bulbar dysfunction and as a result of orofacial-laryngeal bradykinesia and rigidity. We can still find some neuro-ophthalmological signs such as a decreased blink rate and blepharospasm, among others. Other important disturbances are linked with the respiratory system and usually contribute strongly to morbidity and mortality in PD. The obstructive or restrictive respiratory complications are probably due to the presence of the rigidity present in the trunk area [19].
The current literature suggests there is a prodromal or premotor stage of Parkinson’s disease before the onset of motor symptoms. Nonmotor signs and symptoms of Parkinson’s disease include cognitive, neuropsychiatric, sleep, autonomic, and sensory dysfunctions, which are typically not treated by the dopaminergic therapy. Patients who go on to develop Parkinson’s disease commonly have experienced depression, constipation, anosmia, and rapid eye movement sleep behavior disorder in the years preceding their diagnosis. So, the presence of nonmotor features has contributed during the diagnosis process of Parkinson’s disease. However, if these nonmotor signs were not evaluated well enough during the diagnostic process, they may delay the diagnosis [23, 24].
\nMore specifically, there can be subtle cognitive deficits found affecting attentional, executive, visuospatial, and memory functions. Neuropsychiatric symptoms are also common and include depression, anxiety, apathy, and psychosis. Autonomic dysfunction can manifest as urinary frequency or urgency, constipation, orthostatic hypotension, drooling, erectile dysfunction, or abnormal sweating. These clinical manifestations can have a substantial impact on the patient’s quality of life [25]. We can see a long list of nonmotor signs and symptoms in \nTable 1\n.
\nNeuropsychiatric symptoms | \nDepression | \n
Dementia | \n|
Anxiety | \n|
Anhedonia | \n|
Apathy | \n|
Psychosis (hallucination and delusion) | \n|
Cognitive dysfunction | \n|
Attention deficit | \n|
Off-period–related panic attacks | \n|
Confusion | \n|
Sleep disorders | \nInsomnia | \n
Excessive daytime sleepiness | \n|
Nonrapid eye movement sleep-related movement disorders | \n|
Sleep-disordered breathing | \n|
Periodic limb movement disorder | \n|
Rapid eye movement sleep behavior disorder | \n|
Vivid dreaming | \n|
Restless legs syndrome | \n|
Autonomic symptoms | \nUrgency | \n
Frequency | \n|
Orthostatic hypotension | \n|
Nocturia | \n|
Erectile dysfunction | \n|
Sweating | \n|
Gastrointestinal symptoms | \nDribbling of saliva | \n
Ageusia | \n|
Nausea | \n|
Dysphagia | \n|
Reflux and vomiting | \n|
Constipation | \n|
Diarrhea | \n|
Fecal incontinence | \n|
Unsatisfactory voiding of bowel | \n|
Sensory symptoms | \nPrimary pain | \n
Secondary pain | \n|
Fluctuation-related pain | \n|
Paresthesia | \n|
Olfactory disturbance | \n|
Visual dysfunction | \n|
Other symptoms | \nFatigue | \n
Ankle swelling | \n|
Nonmotor fluctuations | \n|
Blurred vision | \n
Some of the most important nonmotor signs and symptoms for physiotherapists, which require special attention, are fatigue, pain, urinary bladder control, and anal sphincter control. We will discuss how physical therapy functions with these aspects of the disease later in this chapter.
\nDuring the diagnostic process of Parkinson’s disease, one of the first components to be established is the presence of “parkinsonism.” This clinical condition is established by the presence of the cardinal signs of the disease, of which bradykinesia is an indispensable criterion jointly with one of the other two signs [25], associated and exclusionary symptoms, atypical features in the history and on examination, and response to levodopa.
\nThe presence of nonmotor features is important, as these may be prominent even early in the disease’s course. Some diagnostic criteria have been developed by some organizations like the UK Parkinson’s Disease Society Brain Bank, the National Institute of Neurological Disorders and the Stroke (NINDS), and Movement Disorder Society. All of them ask for the presence of the cardinal signs, the application of exclusion criteria and some supportive criteria [25, 26]. They can be consulted in \nTable 2\n.
\n\n | United Kingdom Parkinson’s Disease Society Brain Bank’s | \nNational Institute of Neurological Disorders and Stroke (NINDS) | \nMovement Disorder Society | \n
---|---|---|---|
Step 1 | \n\n | Group A features (characteristic of Parkinson’s disease) | \n1. Diagnosis of parkinsonism | \n
\n | Bradykinesia | \nResting tremor | \n\n
| \n
\n | At least one of the following criteria: | \nRigidity | \n\n
| \n
\n | Rigidity | \nAsymmetric onset | \n\n
| \n
\n | 4–6 Hz rest tremor | \nGroup B features (suggestive of alternative diagnoses) | \n2. Exclusion criteria | \n
\n | Postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction | \nFeatures unusual early in the clinical course | \n\n
| \n
Step 2 | \n\n | Prominent postural instability in the first 3 years after symptom onset | \n\n
| \n
\n | Exclude other causes of parkinsonism | \nFreezing phenomenon in the first 3 years | \n\n
| \n
Step 3 | \n\n | Hallucinations unrelated to medications in the first 3 years | \n\n
| \n
\n | At least one of the following supportive (prospective) criteria: | \nDementia preceding motor symptoms or in the first year | \n\n
| \n
\n | Unilateral onset | \nSupranuclear gaze palsy (other than restriction of upward gaze) or slowing of vertical saccades | \n\n
| \n
\n | Rest tremor | \nSevere, symptomatic dysautonomia unrelated to medications | \n\n
| \n
\n | Progressive disorder | \nDocumentation of condition known to produce parkinsonism and plausibly connected to the patient’s symptoms (such as suitably located focal brain lesions or neuroleptic use within the past 6 months) | \n\n
| \n
\n | Persistent asymmetry primarily affecting side of onset | \nCriteria for definite Parkinson’s disease | \n\n
| \n
\n | Excellent response (70–100%) to levodopa | \nAll criteria for probable Parkinson’s are met and | \n3. Supportive criteria | \n
\n | Severe levodopa-induced chorea (dyskinesia) | \nHistopathological confirmation of the diagnosis is obtained at autopsy | \n\n
| \n
\n | Levodopa response for 5 years or more | \nCriteria for probable PD | \n\n
| \n
\n | Clinical course of 10 years or more | \nAt least three of the four features in group A are present and | \n\n
| \n
\n | \n | None of the features in group B is present (note: symptom duration ≥ 3 years is necessary to meet this requirement) and | \n\n
| \n
\n | \n | Substantial and sustained response to levodopa or a dopamine agonist has been documented | \n4. Red flags | \n
\n | \n | Criteria for possible Parkinson’s disease | \n\n
| \n
\n | \n | At least two of the four features in group A are present; at least one of these is tremor or bradykinesia and | \n\n
| \n
\n | \n | Either none of the features in group B is present or symptoms have been present ≤ 3 years and none of the features in group B is present and | \n\n
| \n
\n | \n | Either substantial and sustained response to levodopa or a dopamine agonist has been documented or the patient has not had an adequate trial of levodopa or a dopamine agonist | \n\n
| \n
\n | \n | \n | \n
| \n
\n | \n | \n | \n
| \n
\n | \n | \n | \n
| \n
\n | \n | \n | \n
| \n
\n | \n | \n | \n
| \n
\n | \n | \n | \n
| \n
\n | \n | \n | For the diagnosis of clinically established Parkinson’s disease | \n
\n | \n | \n | \n
| \n
\n | \n | \n | \n
| \n
\n | \n | \n | \n
| \n
\n | \n | \n | For the diagnosis of clinically probable Parkinson’s disease | \n
\n | \n | \n | \n
| \n
\n | \n | \n | \n
| \n
\n | \n | \n | \n
| \n
Options of diagnostic criteria for Parkinson’s disease.
However, the reliability and validity of them have not been clearly established. In this way, it is common to have a misdiagnosis of Parkinson’s disease. The most common causes of misdiagnosis that are described in literature are Alzheimer’s disease, essential tremor, and vascular parkinsonism. It should be remembered that rigidity, bradykinesia, and gait disturbance can be found during normal aging period or can be determined by other medical conditions of aging [25, 27, 28].
\nA rating scale is a means of providing information on a particular feature by assigning a value to it. Parkinson’s rating scales are a means of assessing the symptoms of the condition. They provide information on the course of the condition and/or assess quality of life. They may also help to evaluate treatment and management strategies, which can be useful to researchers, medical doctors, physiotherapists, and other healthcare professionals, as well as to people with Parkinson’s and their caregivers [29].
\nIn Parkinson’s disease, there are a number of rating scales used. Often, more than one scale is used to give a broader picture of symptoms. The most important and used rating scale for this disease is the Unified Parkinson’s Disease Rating Scale (UPDRS). The scale has three sections that evaluate key areas of disability, together with a fourth section that evaluates any complications of treatment, as shown below:
\nPart 1: Nonmotor experiences of daily living
\nPart 2: Motor experiences of daily living
\nPart 3: Motor examination
\nPart 4: Motor complications
\nThe UPDRS features sections that require independent completion by people affected by Parkinson’s and their caregivers, and sections to be completed by the clinician. The UPDRS is often used with two other Parkinson’s rating scales: The Hoehn and Yahr, and the Schwab and England Activities of Daily Living (ADL) scales [20, 30].
\nIn \nTable 3\n, there is a list of rating scales available and recommended by the European Parkinson’s Disease Association and by the International Parkinson and Movement Disorder Society [29, 30].
\nMDS-owned rating scales | \nThe European Parkinson’s Disease Association (EPDA) | \n
---|---|
Global assessment scale for Wilson’s disease | \nUnified Parkinson\'s disease rating scale (UPDRS) | \n
Global dystonia scale | \nHoehn and Yahr scale | \n
MDS-unified Parkinson’s disease rating scale (MDS-UPDRS) | \nSchwab and England activities of daily living (ADL) scale | \n
Modified bradykinesia rating scale | \nPDQ-39 | \n
Nonmotor symptoms scale (NMSS) | \nPD NMS questionnaire | \n
Nonmotor symptoms questionnaire (NMSQ) | \nNMS survey | \n
PKAN disease rating scale (PKAN-DRS) | \nParkinson’s disease composite scale | \n
Quality of life essential tremor questionnaire | \nKing\'s PD pain scale | \n
Rating scale for psychogenic movement disorders | \nParkinson\'s disease sleep scale‑PDSS-2 | \n
Rush dyskinesia rating scale | \nLindop Parkinson\'s assessment scale | \n
Rush video-based tic rating scale | \nShort-form 36 (SF-36) | \n
UFMG Sydenham\'s Chorea Rating Scale (USCRS) | \nSickness impact profile (SIP) | \n
Unified dyskinesia rating scale (UDysRS) | \nMini-mental state examination (MMSE) | \n
Unified dystonia rating scale (UDRS) | \nMontreal cognitive assessment scale (MoCa) | \n
Unified multiple system atrophy rating scale (UMSARS) | \nCaregiver strain index (CSI) | \n
It is important to note that many of these scales and questionnaires are owned and licensed by some organization. Hence, it is necessary to require a rating scales permission request form before working with them.
\nIn a nonclinical way, Braak and coworkers [31] proposed staging procedures of the pathology of Parkinson’s disease, based on central nervous system involvement. Their proposal has six stages:
\nStage 1: Premotor period in which typical pathological changes, Lewy neurites, and Lewy bodies spread from the olfactory bulb and vagus nerve to lower brainstem regions (medulla oblongata and pontine tegmentum).
\nStage 2: Additional lesions in the raphe nuclei and gigantocellular reticular nucleus of the medulla oblongata, locus coeruleus in the pontine tegmentum.
\nStage 3: The symptomatic period when pathological changes involve the midbrain including substantia nigra pars compacta, basal nuclei of Meynert. Structures affected in stages 1 and 2 develop more Lewy bodies.
\nStage 4: Severe dopaminergic cell destruction in the pars compacta with additional mesocortex and allocortex involvement, especially seen in amygdala and subnuclei of the thalamus.
\nStage 5: There are initial changes in neocortex (cortical lobes). Cellular death can be seen in the substantia nigra, the dorsal motor nucleus of the vagus nerve, the gigantocellular reticular nucleus, and the locus coeruleus.
\nStage 6: Neocortex entirely affected (motor and sensory areas).
\nThis kind of rate is totally based on histological development of the disease. It is important to remember that, historically, the definitive diagnosis of Parkinson’s disease is closed in a postmortem autopsy [32].
\n\nDrug treatment: traditionally, the drugs that have shown good effects on the motor signs and symptoms of Parkinson’s disease are the dopaminergic drugs.
\nAmong them, the most used in clinical practice is levodopa or levodopa plus dopa-decarboxylase inhibitors (DDC-I), designed to replace the dopamine in the depleted striatum, undoubtedly, the most efficient medication for Parkinson’s disease [33]. They improve motor functions in a cyclic way during the day period. When they reduce the motor impairment, the period is called “on time.” When the motor signs and symptoms start to return, the period is called “off time” or “wearing-off period.” However, during the “wearing-off period,” symptoms may not be related only to movement. It is also usual for patients to report increased anxiety, fatigue, mood changes, difficulty thinking, restlessness, and sweating [29].
\nInitially, levodopa offers a stable alleviation of PD symptoms so it is usual for it to be offered in low doses, being well-tolerated by patients. This period of treatment is called the “honeymoon.” However, as the disease becomes more advanced, the effect of the drug usually wears off quickly, and an increased frequency of dosing is often required. This marks the end of the “honeymoon” period. After some years (4–6 years), patients begin to experience, most strikingly, its intense side effects [33, 34].
\nThese long-term complications included many kinds of motor fluctuations. In addition to the on-off phenomenon, already described above, the patients may also experience delay on, when medication takes a longer period to take its effect; freezing phenomenon, which was already discussed during the motor signs presentation; and dyskinesia, which is determined by the presence of hyperkinetic involuntary movements, including twitches, jerking, twisting, or simple restlessness but no tremor, occurring when the drug is at its peak dose, during the wearing-off period or even during off-periods of the medication [29, 34]. Several new formulations of levodopa have been developed to provide a more stable levodopa plasma concentration, reducing some of the side effects, including dyskinesia. Among them, as aforementioned is a levodopa/carbidopa combination [33].
\nOther drugs on treatment of motor signs are dopaminergic agonists, amantadine, dopamine receptor agonists, catechol-O-methyltransferase (COMT), and monoaminoxidase (MAO) inhibitors. Recently, new pharmacological treatment has been studied such as the use of cannabis (to reduce mainly the three cardinal signs) and the angiotensin IV ligand-based compound, which influences motor and nonmotor signs (memory) [33].
\nSince Parkinson’s disease is not considered a pure movement disorder anymore, the treatment of nonmotor signs and symptoms is justified. However, the treatment of nonmotor symptoms is still an unsatisfactory field for patients and their families [35]. A cholinesterase inhibitor has been used for dementia treatment, while noradrenergic medications (like tricyclic antidepressants) have shown some effect in depression and serotoninergic agonists (like clozapine) in psychosis. Amantadine is used with some success in the management of levodopa-induced dyskinesia. For autonomic dysfunction, there are many options such as mineralocorticoid, fludrocortisone and adrenergic agents, the noradrenaline precursor for orthostatic hypotension, antimuscarinics for urinary urgency or incontinence, and prokinetic drugs to treat constipation [35].
\n\nSurgical treatment: lesioning procedures, such as pallidotomy and thalamotomy, were used to reduce the motor signs and symptoms of Parkinson’s disease. For a period, these procedures were abandoned because of good results with pharmacological treatment using dopaminergic drugs. However, nowadays, the surgical procedures are reviving as a result of the complications of pharmacological therapies.
\nThe technological advances in the area of medicine have led to the development of a new kind and nonablative surgical procedure: deep brain stimulation (DBS). It involves sending electrical impulses to certain parts of the brain by a neurostimulator device that is a brain implant known as a ‘brain pacemaker.’ The general procedure of this surgery is an intracranial electrode precisely implanted in the target area (see \nTable 4\n), followed by implantation of lead extension wires that connect the intracranial leads to a power-generating and programming source and, then finally, the implantation of an internal pulse generator (\nFigure 2\n). The main target areas can be seen in \nTable 4\n such as the signs/symptoms that are most prominently modulated by DBS [36, 38]. When PD symptoms are very severe and medications cannot moderate them, surgery and deep brain stimulation can be considered as the final options of treatment.
\nTypical deep brain stimulation setup. The electrode is placed in the brain and connected to a brain pacemaker permanently placed under the skin of the chest. Source: Shamir et al. [37] the use, distribution or reproduction in other forums is permitted.
\nOther treatments: other alternatives to Parkinson’s disease management include a group of therapies other than a pharmacological approach. There is a vast variety of techniques available for this purpose, such as tai chi, yoga, massage, acupuncture, dance, traditional herbs, and molecular targeted therapies, among others.
\nPhysical therapy shows a number of different strategies that has been frequently used in rehabilitation of Parkinson’s disease patients, having the most important goal to enhance the quality of life of these individuals.
\nPhysiotherapists are members within a multiprofessional team, which has the purpose of maximizing functions and abilities and minimizing secondary complications of several diseases. They use movement rehabilitation within a context of education and support for the person as a whole. In patients with Parkinson’s disease, physical therapy focuses on many functions such as transfer, posture, balance improvement and fall prevention, gait, upper limb functions, and physical capacity (including cardiorespiratory capacity) essential to carry out activities of daily life. All of these goals, worked together with cueing strategies, cognitive movement and exercises, increased independence, and safety, as a consequence, improve quality of life [10].
\nSome evidence presented in the literature supported that therapeutic exercises applied in individuals with Parkinson’s disease were effective in improving both the motor and nonmotor impairments [39, 40]. This improvement may be linked to a number of plasticity-related physiological events including synaptogenesis, angiogenesis, and neurogenesis. This process can be mediated by use-dependent expression of endogenous neurotrophic factors. In an unedited systematic review and meta-analysis, Hirsch and his coworkers show aggregated evidence that physical exercise training increases brain-derived neurotrophic factor (BDNF) blood levels in individuals with Parkinson’s disease. This BDNF increase results in concomitant reduction in motor signs and symptoms, measured by UPDRS, confirming possible effects on dopaminergic pathways [41].
\nTogether with neuroplasticity, there is some evidence pointing to the participation of motor modules (coordinated patterns of muscle activity that combine to produce functional motor behaviors) like a physiological theory for good results of physical therapy in Parkinson’s disease. For this purpose, it is proposed to consider five neuromechanical principles: motor abundance, which means that for any given task, many equivalent motor solutions are possible; motor structure, which means that motor modules reflect biomechanical task relevance; motor variability, which means that variations on motor modules are higher as much as the motor output is lower; individuality, which means that different motor repertory must be considered among different individuals; and multifunctionality, which means that muscle activity can generate a large number of different actions. It is important to emphasize that in Parkinson’s disease the basal ganglia dysfunction supposedly leads to inappropriate selection of motor modules [8].
\nIt is still important to remember that motor rehabilitation is a motor relearning practice and training where it is essential to reacquire motor skills. Although individuals with Parkinson’s disease show preserved motor learning abilities, the basal ganglia dysfunction may impair the consolidation of them. Therefore, the basic rules of neural plasticity practice must be used to be successful in the rehabilitation process. It includes intensity, repetition, specificity, difficulty, and complexity of practice [8, 42].
\nSeveral rehabilitative approaches have been proposed in Parkinson’s disease.
\nIn the last two decades, exercise, such as resistance training, has shown to be beneficial for the improvement of both motor and nonmotor signs and symptoms. It increases low strength determined by hypokinesia and disuse, besides playing a neuroprotective effect in individuals with Parkinson’s disease. Its effect is probably determined by an increase of mitochondrial respiration and of neuroplasticity mechanisms, improving the recruitment of motor unit and generating selective activation of the muscles [14, 43, 44].
\nHowever, there is no consensus about the parameters for resistance training prescription for individuals who have Parkinson’s disease [43]. In a systematic review and meta-analysis, Saltychev and his coworkers [45] concluded that there is no evidence on the superiority of progressive resistance training compared with other treatments to support the use of this approach in rehabilitation procedures.
\nOn the contrary, it is possible to find successful directions to use this therapeutic strategy in rehabilitation of individuals with Parkinson’s disease from other systematic reviews, meta-analysis, and clinical research. Studies shows that low (2 times per week over 12 weeks) to moderate (2–3 times per week over 8–10 weeks) intensity resistance training appears to be effective in people with early, mild-to-moderate Parkinson’s disease. They still show that this specific approach resulted in gaining muscle strength, balance, Parkinson’s motor symptoms, and quality of life, with low or no improvement in gait performance, freezing phenomenon, and the number of falls [43, 44, 46, 47]. The load of the exercises can be chosen using the test of maximal strength (1-RM). The number of sets may vary between 2 and 3 during initial periods. The retest of 1-RM can provide additional information to adjust the load and sets along the rehabilitation period. The resting time between the sets can be controlled by cardiovascular parameters and can vary from 30 seconds up to 3 or 4 minutes [43, 44].
\nThere are numerous ways to work with resistance training, and it is up to the physiotherapists to choose the most appropriate one for the individual under their care. In resistance training, the following examples of exercises can be used: bench press, lat pulldown, military press, seated row, leg 45o, barbell squat, leg curl, leg extension, calf raises, lower abdominal exercises, and manual or external (theraband, barbell, ankle-weight, and pulley system) resistance in active movement. Treadmill and bicycle intervention can be used when performing against resistance [43, 44, 45, 47]. Da Silva and her coworkers [48] suggest a long-term effect in nonmotor signs and symptoms of Parkinson’s disease, especially in cognitive aspects, in individuals performing treadmill training, just as Ferreira and her coworkers [49] showed that resistance training was an effective intervention in the reduction of anxiety symptoms and improved the quality of life in this population.
\nEven if the treatment of Parkinson’s disease tremor focuses on medication, and there is indication to deep brain stimulation for those patients with tremor recalcitrant using oral medication, electrotherapy has been shown to be beneficial to control this special cardinal sign.
\nFew studies have been performed to provide further evidence on the effects of electrotherapy on Parkinson’s tremor reduction. The theory supporting the use of this strategy is based on evidence revealing that propriospinal neurons in the C3–4 spinal cord mediate voluntary commands from the motor cortex (in Parkinson’s disease, these commands are oscillating and give rise to resting tremor) and project directly to forelimb motor neurons. This proposal assumes the importance of propriospinal neurons to interfere in tremor signal transmission, especially because there are a rich variety of afferents, including cutaneous afferents [6].
\nBased on this concept, Xu and coworkers [50] hypothesize that cutaneous afferents evoked by surface stimulation could produce an inhibitory effect on propriospinal neurons, which in turn could suppress tremor signals passing through the propriospinal neurons.
\nAdditionally, evidence shows benefits of electrical stimulation, especially when applied to the superficial cutaneous radial nerve area, in reduction refractory resting tremor. This effect is possibly mediated by cutaneous reflex via premotor neuron interneurons, through a disynaptic inhibitory postsynaptic potential. Some initial research was performed to confirm this theory using transcutaneous electrical nerve stimulation (TENS), with good results [6, 52]. The position of the electrodes can be verified in \nFigure 3\n.
\nUse of transcutaneous electrical nerve stimulation to reduce resting tremor in Parkinson’s disease. The figure brings cutaneous superficial radial nerve area and electrodes position for transcutaneous electrical nerve stimulation (TENS). Source: Modified from Gray [56]. Picture is public domain.
The parameters used for TENS stimulation were 200 μs pulse width at 250 Hz pulse frequency. The pulse amplitude of stimuli must be adjusted during the stimulation period. First, it is necessary to discover the radiating threshold of the patient. It occurs when the patient refers to a radiating sensation, such as a paresthesia, running from the dorsal skin to the fingers. This radiating threshold has been used as a sensory marker because it indicates that the superficial radial nerve is actually activated by electrical stimulation. After detecting the radiating threshold, the intensity of electrical stimulation must be adjusted to 1.5–1.75 times radiating threshold to produce better effects on tremor control [6].
\nNowadays, researchers have been studying a way to detect the tremors and control them simultaneously and automatically by electrostimulation. They already developed and tested a closed-loop system for tremor suppression by transcutaneous electrical nerve stimulation (TENS) using EMGs of the forearm muscles. Through this record, when a tremor is detected, a command signal triggers a stimulator to output TENS pulses to a pair of surface electrodes positioned just as described in \nFigure 3\n. The preliminary results showed that a closed-loop system can detect tremor properly and suppress significantly the tremor, by electrical stimulation of cutaneous afferents, in Parkinson’s disease patients. Within this new concept, a tremor’s glove was developed reaching also good results [50, 51, 52].
\nIt’s known that aerobic exercises can reduce inflammation, suppress oxidative stress, and stabilize calcium homeostasis in the brain. So, it has been prescribed as an important activity for the elderly. The form of aerobic exercise used may be adapted to the capability of the individual. In individuals with Parkinson’s disease, these exercises show important functions, once they can trigger plasticity-related changes, including synaptogenesis, enhanced glucose utilization, and neurogenesis [2, 53].
\nIn general, aerobic training has been reported to improve both motor and nonmotor signs and symptoms of Parkinson’s disease. The motor effects are extensively known and have been studied the most so far, showing the most unequivocal benefits on health across the life span. Furthermore, the neural mechanisms involving dopaminergic pathways are studied and suggest a significant preservation of nigrostriatal neuronal connections as well as striatal dopamine levels in experimental models. As a result, exercise-dependent plasticity following aerobic exercises acts on the brain in a similar manner as dopaminergic-derived treatments, using the same pathways to produce symptomatic relief [54].
\nIn nonmotor signs and symptoms, aerobic training promotes positive and significant effects on global cognitive function, processing speed, sustained attention and mental flexibility, memory, and mood disorder aspects (anxiety and depression) in patients who are considered in a moderate stage of Parkinson’s disease [49]. In sleep disorder, present in Parkinson’s disease, aerobic exercise has been shown to have small-to-moderate effects. The mechanism involved in these effects evolved increased dopaminergic signaling and a wide variety of effects on nondopaminergic neurotransmitter systems, including serotonergic, noradrenergic, and GABAergic systems, which is relevant for depression, anxiety, and sleep [53, 54].
\nThe most common and studied form of aerobic training is using a treadmill. In some systematic reviews, the majority of articles considered in analyses use treadmills for aerobic training. This approach can be used with or without a body-weight-support system, depending on the motor difficulties of the individual with Parkinson’s disease. It may be related with improvement in motor signs like motor action, balance, and gait, although the evidence is not so strong [2, 48].
\nIn the same way, free walking and Nordic walking (a total body version of walking performed with specially designed walking poles similar to ski poles) also have good effects on motor and nonmotor domains of Parkinson’s disease and must be stimulated and used in physical therapy practice in rehabilitation of individuals with Parkinson’s disease [55].
\nSimilar to the aerobic training used on the treadmill, moderate intensity of interval training for cycling has shown several beneficial effects on the DA-dependent motor and nonmotor signs that compromise Parkinson’s disease patients. Researchers have reported improvement on bimanual motor control, automatic interlimb coordination, executive functions, and neurological (UPDRS) symptoms [56].
\nAn interval protocol template that can be used can be the following: from 8 to 12 weeks of training, 3 times per week, 1-hour session training with 10 minutes of warm-up, 40 minutes of aerobic training, and 10 minutes of cooldown). During the 40 minutes of aerobic training, the patient can perform 8 sets of 3 minutes of cycling or treadmill at 60–80 rpms and 2 minutes of less than 60 rpms. The heart rate also can be used as a parameter to improve effort during the training period. Hence, the physiotherapist may adjust the resistance to ensure the patient is cycling at 60–75% of his/her maximal heart rate. This effort can increase gradually during the training period [56]. A guideline with some exercise modes to be used in Parkinson’s disease was provided by Meng and coworkers in a systematic review and meta-analysis [57].
\nOther forms of aerobic exercises have been stimulated in the rehabilitation process in Parkinson’s disease. Several data have shown that dance can provide increased activation of the reward system, determining better mood aspects in people. In patients with Parkinson’s disease, practicing dance has induced better responses and a substantial relevant improvement in motor symptoms (such as static and dynamic balance, freezing phenomenon, and gait) and functional mobility. This improvement determines also a better quality of life in performers. It probably occurs because rhythmic stimulation leads to time-perception compensation due to the synchronization of movement with rhythm [58, 59].
\nTo get these effects, a dance program must include visual and auditory cues, rhythm tasks, and recreational activities that motivate socialization. Another important aspect is to reach the ideal heart rate during practice, just as discussed previously in the aerobic training protocol [58].
\nOriental martial arts, such as tai chi, have been successfully used in treatment of individuals with Parkinson’s disease. Tai chi combines deep breathing and slow movements and studies have provided moderate evidence that tai chi improves balance and functional mobility, reducing the number of falls, but with no significant effect in gait velocity, step length, and gait endurance improvement [33, 60, 61]. A systematic review and meta-analysis showed that tai chi, plus medication, showed greater gains than medication alone or another therapy plus medication in motor function and balance. Presumably, these gains were due to the development of new motor programs, which allow faster reactions responding to postural challenge promoting better behavioral recovery through new synaptic connections [62]. It is necessary to know and practice this technique before using it on patients.
\nThe aim of the multimodal exercise program is to develop the patients’ functional capacity, cognitive functions, posture, and locomotion. It’s comprised of a variety of activities that simultaneously focus on the components of functional capacity, such as muscular resistance, motor coordination, and balance [14]. It’s a 6-month program, performed 3 times per week, 1 hour per session. Each session consists of five parts (warm-up, pre-exercise stretching, the exercise session, the cooldown, and postexercise stretching). The program is divided into six phases with different uses of coordination, muscular resistance, and balance strategies [63, 64]. A description of each phase can be seen in \nTable 5\n.
\n\nSubthalamic nucleus | \nDisabling motor symptoms | \n
Dyskinesia | \n|
Motor fluctuations | \n|
Globus pallidus internus | \nImprovement of motor symptoms in general | \n
Ventral intermediate thalamic nucleus | \nTremor | \n
Pedunculopontine nucleus | \nGait instability | \n
Gait freezing phenomenon | \n
Main target areas for deep brain stimulation (DBS) in Parkinson’s disease.
Note: Based on Dallapiazza et al [36].
Phases | \nCapacities | \n||
---|---|---|---|
Coordination | \nMuscular resistance | \nBalance | \n|
Phase 1 | \nUpper and lower limb movements. | \nExercises without weights. | \nRecreational activities that stimulated the vestibular system. | \n
Phase 2 | \nTrunk movements were added to upper and lower limb movements. | \nLight-weight equipment (hoops, ropes, and batons). | \nRecreational activities that stimulated the visual and vestibular systems. | \n
Phase 3 | \nTrunk movements were substituted by head movements. | \nHeavier equipment (barbells, ankle weights, and medicine balls). | \nRecreational activities that stimulated the visual and somatosensorial systems. | \n
Phase 4 | \nHead, trunk, and upper and lower limb movements. | \nLoad was again increased with heavier equipment for resistance training (increase of intensity) or increased repetitions (increased volume). | \nRecreational activities integrated the vestibular, visual, and somatosensorial systems. | \n
Phase 5 | \nFour different movement sequences, two of which were the same for upper and lower limbs and two other sequences that alternated movements for upper and lower limbs in place and in movement. | \nExercises were done with weights: leg press, pulley, seated cable rows, peck deck, and bench press. Load was adjusted according to patients\' convenience (in two series of 15 repetitions). | \nRecreational activities included static balance, dynamic balance, half-turn, and complete turn (all with visual cues). | \n
Phase 6 | \nFour sequences of different movements, two sequences of alternating movement for upper and lower limbs, and two sequences of different movement for upper and lower limbs, with or without trunk movement and equipment (balloons, balls, hoops, and rope). | \nThe same exercises with load increase. Series of 15 repetitions were added. | \nRecreational activities were composed of activities with tactile cues. | \n
Multimodal exercise program in Parkinson´s disease.
Note: Based on Vitório and coworkers [63].
The little data that are available in the literature point to improvement in some kinematic gait parameters of mild-to-moderate idiopathic PD patients using multimodal exercise programs [63, 64].
\nSeveral data show acupuncture and electroacupuncture (still performed on animal models) as beneficial strategies in Parkinson’s disease treatment, used either isolated or combined with other treatments. It has been described as showing improvement in the UPDRS total score and in its subsections after an acupuncture session. So, even motor and nonmotor signs and symptoms, including pain, can be improved with the use of acupuncture [65, 66, 67]. However, the most important source of data that proves the beneficial effects of acupuncture in treatment of signs and symptoms in Parkinson’s disease is provided from functional neuroimaging studies. These studies have shown huge modifications in neural functions after acupuncture sessions [68, 69].
\nAs tai chi use was previously discussed, acupuncture requires previous academic training so that it can be used in an accurate way in the treatment of Parkinsonian individuals.
\nHydrotherapy has been widely used to treat individuals with Parkinson’s disease. It has been proven to be effective for different gait rehabilitation programs, as well as to improve balance and quality of life, and reduce pain and falls. The warm property of water used for hydrotherapy potentially also reduces rigidity [70, 71].
\nIn water, innumerable forms of exercises can be performed including warm-up exercises (like jumping and walking), stretching exercises, gait training, cooldown exercises, trunk mobility, balance, coordination and proprioceptive exercises, the Halliwick method, posture exercises, the Ai Chi method, aerobic exercise, the Bad Ragaz method, motor dexterity exercises, and swimming exercises, among others [71].
\nVirtual reality potentially optimizes motor learning in a safe environment, and by replicating real-life scenarios, it could help to improve functional activities of daily living in individuals with Parkinson’s disease. However, the use of commercially available devices makes this tool contiguous to many other physical therapy instruments, leading to low evidence in the results [72]. Despite this, several studies have reported greater improvement in many signs and symptoms such as balance, gait, functional capacity, and self-confidence, improving quality of life and reducing the risk of falling [73, 74, 75].
\nAs an example of specific virtual reality developed for Parkinson’s disease rehabilitation, Gomez-Jordana and coworkers [76] developed visual cues that could be presented in an immersive, interactive virtual reality environment. With this, they created different forms of spatial and temporal information where black footprints presented at a prespecified distance apart could recreate different step lengths (spatial cues), and by controlling when the black footprints changed color to red, they could convey information about the timing of the foot placement (temporal cues). With this device, they could get significantly improved gait performance in participants.
\nAdditionally, exercise-based video gaming (exergaming), a form of physical training that is delivered through virtual reality technology, facilitates motor learning and is efficacious in improving balance in aged populations. This approach can use commercial devices such as Nintendo Wii Fit System®, X-box 360o with Kinect®, or rehabilitation-specific software program like Jintronix® [70, 74, 77].
\nThese devices usually combine automated game instructions as well as visual and auditory and tactile inputs to correct performance and sustain motivation levels during and following game play. Therefore, exergames employ visual and auditory feedback techniques to create a quasi-immersive environment that can facilitate motor and cognitive learning. Since individuals with Parkinson’s disease are dependent on sensory cues to maintain postural stability and show difficulties with long-term consolidation of new motor skills, this sensorial integration provided by using exergames may help to upregulate neuroplasticity and facilitate motor skill acquisition and retention [77].
\nThese resources can be used isolated or associated in a clinical approach or in a telerehabilitation program like a home-based virtual reality or home-based exergame [74].
\nGroups are used in physical therapy to improve global health status and bring relief from typical disability symptoms of several diseases, competing with individual rehabilitation at least in short-term follow-up. Therapeutic groups have been beneficial to the health care system by decreasing the cost and time spent on rehabilitation.
\nSimilar to other techniques, group therapy can use several kinds of exercise goals such as general mobility, using muscular strength, free movement, and relaxation exercises; trunk control, using trunk displacement and rotation during dynamic exercises performed in a sitting posture; static balance, using the same strategies for trunk control but in a standing position; dynamic balance and gait, using free gait; and gait with obstacles, stairs, ramp, uneven ground, performed in and outside the room. The use of hearing and visual cues during the procedure provides several stimulus associations for the patients. This approach was reported to improve gait, balance, and activity of daily life performance in patients with PD [78].
\nMental imagery is the cognitive process of creating visual, auditory, or kinesthetic experiences in the mind with or without overt physical execution. In many people, this procedure can help or improve motor performance. This strategy has the potential to increase the function of both the motor cortex and the spinal neurons, resulting in improved muscle function [79, 80]. Thus, it is an important technique in motor learning and control, and although it has its origin in sports science, it has been introduced into the field of neurorehabilitation.
\nIn a few sources about mental imagery in Parkinson’s disease rehabilitation, some data show a better muscle recruitment measured by electromyography or other form or neurophysiologic register. But available data are, sometimes, contradictory [80, 81].
\nSpecifically in individuals with Parkinson’s disease, this approach has shown to be beneficial to motor (measured by UPRDS-III‑motor signs) and cognitive functions [79].
\nSince smartphones became popular, numerous health-related apps have been developed for professionals, patients, and the general population. However, many of these apps are not validated, so their efficacy may be not satisfactory. Nowadays, this resource still has been used as a complementary treatment [82].
\nIt is a well-known fact that it is important to emphasize that apps are a democratic source of information and rehabilitation, since they maintain the main principles of usability, accessibility, and equal opportunities for healthcare professionals, patients, relatives, and caregivers [82].
\nFor Parkinson’s disease, there are a few apps available, and just one with some data partially published. On the Parkinson’s UK webpage, we can find a list of apps reviewed and recommended for individuals with Parkinson’s disease. There are apps for sleep, volume of voice, mood, swallowing, memory (recording stories of patients), mobility, speech, and dexterity [83].
\nAnother source from the International Parkinson’s Community recommended eight extra apps. They focus on measurement and tracking the patient’s symptoms, give information about Parkinson’s disease, record and measure the magnitude of tremor and speech, and manage and track the individual’s health condition. The only one that has some physical approach is the Parkinson’s home exercise [84].
\nThe Parkinson’s Home Exercise®, promoted by the European Foundation for Health and Exercise, was easy-to-use and designed to be used by patients and physiotherapists. It provides advice and instructions for daily exercises and movements through over 50 videos and text instructions. It has a cost involved [85]. There are no references in literature about its efficacy.
\nAnother app, developed by TEVA Pharmaceutical Industries, named Parkinsounds®, is a free app that helps patients with Parkinson’s disease to find their gait rhythm using music and rhythmic beats (like a metronome). They use a predetermined music list or one that can be linked to Spotify®. Once the rhythm is chosen, Parkinsounds is able to find music that combines with the preselected rhythm adding beats in the music. The physiologic base for this strategy is centered on the synchronic activation of neurons provided by the music and the rhythmic stimulus, added to an increase of dopamine liberation [86].
\nOur group has been developing research using this specific app in rehabilitation of gait in Parkinson’s disease. The partial data were already presented at the World Confederation of Physical Therapy Conference (research data are not still available). However, a huge acute effect could be seen in the gait of Parkinsonians using Parkinsounds, even in a long-term period of rehabilitation. We could see an improvement in width and length of gait, with a reduction of base and number of steps, which were measured in a 10 meters’ route, after 10 weeks of treatment. It is important to emphasize that the walking test was performed with and without Parkinsounds® use for patients at the moment of evaluation (initial and final), and in both cases, the improvement was significant. So, it can be considered an important feature for gait rehabilitation in Parkinson’s disease.
\nAccording to the literature data, there is no apparent consistency in the effect of whole body vibration shown on mobility, balance, and gait in individuals with Parkinson’s disease [87]. However, the majority of the studies point to a favorable effect of this therapeutic strategy [87, 88].
\nDisregarding the differences between the various types of equipment, a lot of research has proposed some parameters that are useful in improving mobility and balance in individuals with Parkinson’s disease. The majority recommend orthostatic position and 7 to 14 mm amplitude with a frequency ranging between 3 and 25 Hz, in cycles of 5 bouts of 1 minute each. Until now, there is no consensus about which frequency in better [87]. So, it is recommended that the physical therapist evaluate these functions constantly after using this resource.
\nThe effect of whole body vibration on tremor is less prominent [87]. Moreover, it also does not appear to lead to better cardiovascular conditions reducing the feeling of fatigue when compared to treadmill training [89].
\nThe physiological mechanism involved in the effects of whole body vibration on reducing some of the motor signs of Parkinson’s disease remains elusive. Some theories suggest that whole body vibration provides tactile and proprioceptive stimulus to the whole body originated from the vertical oscillating mechanical movement or the movement along the horizontal axis, which through neuromuscular activation and metabolic mechanism may bypass dysfunctional basal ganglia, resulting in better adjustments for postural stability and gait [88, 90].
\nIn this chapter, we can notice how profound the discussions about Parkinson’s disease are, especially about treatment. Physical therapy has increased its participation in Parkinson’s disease treatment. However, research is still lacking to substantiate its real effectiveness. It is imperative that further research be done to strengthen performance and the excellent results obtained with physical therapy in treating individuals with Parkinson’s disease.
\nI would like to thank Pontifical University of Minas Gerais for funding the research cited in this chapter: PROBIC PUC Minas 95/35 {80}; Parkinsounds Project PROBIC PUC/FAPEMIG 2018/1510.
\nInflammatory myopathies, also called idiopathic inflammatory myopathy or myositis, are rare conditions characterized by the involvement of various organs in addition to muscle tissue. These changes can lead to severe impairments and adversely impact the quality of life of affected individuals [1, 2].
\nThe diagnosis and treatment of inflammatory myopathies involve the participation of an interdisciplinary team, due to the complexity of the disease and the high variety of possible signs and symptoms. The integration of subspecialties, such as rheumatologist, neurologist, dermatologist, pulmonologist, cardiologist, and physiotherapist, among others, is necessary to achieve the ideal treatment plan. Diagnosis of inflammatory myopathies involves several steps and often requires autoantibody testing and histological evaluation of a muscle tissue biopsy in addition to several other tests, including muscle magnetic resonance imaging and electromyography. Typical symptoms of inflammatory myopathies include muscle weakness in the arms and legs, which may manifest in a few days or even several weeks. Muscular weakness is reflected in difficulties in performing daily activities such as walking, climbing stairs, or lifting an object above the head. In addition to muscle weakness, it is observed that pain is also a frequent detectable symptom in a patient with inflammatory myopathies. Laboratory tests usually show a significant increase of creatine kinase and elevation in the concentration of liver enzymes that suggest the occurrence of damage to muscle cells [1, 3].
\nThe adverse impact on quality of life highlights the importance of performing an accurate and reliable diagnosis from the combination of clinical and laboratory findings to establish the appropriate treatment for each individual [1, 2].
\nIn this chapter we will discuss the epidemiology and subtypes of inflammatory myopathies. Next, we will discuss the existence of crosstalk between inflammatory processes in the oral cavity and their consequences on skeletal muscle.
\nAll myositis subtypes can be considered rare diseases due to their relatively low prevalence. Studies indicate that overlap myositis represents the subtype of the disease that affects the largest number of people, comprising about half of the cases registered. Dermatomyositis accounts for more than a third of the cases of the disease and presents a prevalence of approximately 1–6 patients per 100,000 people in the United States [4, 5, 6].
\nIt is important to emphasize that obtaining accurate epidemiological data is extremely difficult due to the different diagnostic criteria adopted in each study. Therefore, the information provided by the publications should be examined and evaluated with caution and attention [7].
\nA large study conducted from the analysis of 3067 patients from Belgium, China, Czech Republic, Hungary, Italy, Mexico, Norway, Sweden, Switzerland, the United Kingdom (UK), and Vietnam who were registered in the Euromyositis Registry demonstrated that the dermatomyositis was the most common disorder with 31% of the cases [7].
\nData on the prevalence of necrotizing myopathy suggest that this subtype of the disease accounts for approximately one-fifth of the reported cases of inflammatory muscle diseases [4, 5, 6].
\nThe information regarding the epidemiology of polymyositis varies and depends on the methodology and location of the study ranging from the largest fraction with prevalence of approximately 10 cases per 100,000 people in the United States [1, 2, 3], 27% in the Euromyositis Registry [7], to the rarest subtype that should be diagnosed only by exclusion [4, 5, 6].
\nCurrently there is some consensus that overlap myositis, necrotizing myopathy, and dermatomyositis represent about 90% of the cases of inflammatory muscle diseases [4, 5, 6]. It is estimated that the inclusion body myositis occurs with a prevalence of up to 14 per million people [8].
\nDermatomyositis is typically characterized by the development of proximal muscle weakness and cutaneous manifestations that may arise over a period of weeks to months. However, there are cases in which muscular impairment is not significant without signs and symptoms of muscle weakness, elevated muscle enzymes or changes in electromyography, magnetic resonance imaging (MRI), and muscle biopsy [9].
\nSkin signs frequently seen in dermatomyositis include an exacerbated periorbital rash with edematous features and erythematous lesions involving the extensor surfaces of the joints. In some cases, myalgia and pruritus may also be observed as important symptoms of the disease. Muscle enzyme concentrations tend to be elevated, and electromyography commonly shows a myopathic pattern [10]. Intramuscular T2 hyperintensities resulting from inflammation or muscle necrosis can be observed on MRI. Dermatomyositis may present a characteristic less frequently observed in other types of inflammatory myopathies, which involves the presence of T2 hyperintensities around individual muscles due to fascial involvement [11].
\nMuscular biopsies in patients with dermatomyositis have perifascicular atrophy as a feature of high specificity [12]. Evidences show that the expression of perifascicular human myxovirus resistance protein 1 and retinoic acid-inducible gene 1 have higher diagnostic sensitivity than perifascicular atrophy with equivalent specificity [13]. Muscular biopsies of dermatomyositis patients usually present cellular infiltrates composed of plasmacytoid dendritic cells, B cells, CD4 T cells, and macrophages. These cells usually involve medium-sized blood vessels and invade the perimysium [14]. However, it is possible that dermatomyositis biopsy does not present this cellular infiltrate. Predominantly, necrotic pathologically indistinguishable from immune-mediated necrotizing myopathy may be observed. Some early features of dermatomyositis involve deposition of membrane attack complex and presence of microtubular inclusions on intramuscular capillaries [11]. In addition, like other inflammatory myopathies, class-1 major histocompatibility complex (MHC) is generally upregulated in the sarcolemma of muscle fibers. In patients with dermatomyositis, class-1 MHC upregulation and other pathological findings may be characteristically prominent in perifascicular regions [14].
\nStudies have shown that dermatomyositis autoantibody can be found in a considerable proportion of patients with dermatomyositis [15]. Typical features of dermatomyositis, including proximal muscle weakness and prominent cutaneous manifestations have been associated with the presence of autoantibodies recognizing the nuclear antigen Mi2 [16]. Patients with dermatomyositis and autoantibodies that recognize nuclear matrix protein (NXP) 2 are more predisposed to be affected by proximal and distal muscular weakness, subcutaneous edema, and dysphagia [17].
\nPatients with dermatomyositis who are positive for anti-NXP2 or anti-transcription intermediary factor (TIF)-1 autoantibodies are at increased risk for malignancy development; thus making comprehensive cancer screening 13–15 or positron emission tomography–computed tomography (PET-CT) scans is extremely important in these cases [18]. In cases of dermatomyositis patients who have autoantibodies recognizing the small ubiquitin-like modifier activating enzyme or melanoma differentiation-associated gene 5 (MDA5), it is observed that cutaneous tissue impairment is more prominent than in muscle. In addition to most commonly present cutaneous manifestations, these patients may develop ulcerous lesions on the flexor surface of the fingers and palm [19, 20].
\nMost patients with anti-MDA5 autoantibodies are hypomyopathic or amyopathic. In addition, it should be noted that unlike patients with other autoantibodies of dermatomyositis, those who are anti-MDA5 positive often develop an aggressive form of interstitial lung disease, reinforcing the importance of assessment through periodic lung function tests and high-resolution computed tomography [20, 21, 22].
\nAlthough the etiology of dermatomyositis is not fully elucidated, it is suggested that a combination of genetic risk factors and exposure to environmental factors may trigger the disease. In this sense, several immunogenetic risk factors, including certain class-2 human leukocyte antigen (HLA) alleles, have been implicated in dermatomyositis pathogenesis [23]. Studies suggest that exposure to ultraviolet light may also be considered an important risk factor for the development of dermatomyositis [24].
\nRegardless of the origin of dermatomyositis, it is not known which mechanisms are involved in the development of muscle damage and weakness. Studies suggest that muscle damage may result from hypoperfusion due to endothelial destruction [14]. In addition, the presence of plasmacytoid dendritic cells, along with the increase in expression of type-1 interferon-inducible proteins in the perifascicular area, suggests that interferon may mediate perifascicular atrophy [12, 25].
\nOverlap myositis is being recognized as an individual form of myositis. This myositis manifests itself without a rash typical of dermatomyositis, with prominent pathologic changes in the perifascicular, interfascicular, and perimysial regions, and is frequently associated with anti-synthetase antibodies [2].
\nLaboratory evaluation shows a significant elevation of muscle enzymes including creatine kinase (CK), which is generally present [3]. Approximately 30% of patients with myositis were positive for Jo-1O antibody (most common of the eight anti-synthetase antibodies) [26].
\nPolymyositis is a rare disease, which belongs to the various idiopathic inflammatory myopathies. It is estimated that the incidence of polymyositis is 5% of all cases of myositis [2, 5, 27]. Polymyositis consists of muscle weakness, elevated creatine phosphokinase concentrations, and myopathic electromyography features [2]. However, rash or other signs of skin inflammation do not occur in polymyositis. Therefore, its diagnosis is by exclusion [3].
\nHistopathological hallmarks of polymyositis include invasion of endomysial cytotoxic CD8 T cells and widespread upregulation of class I MHC in muscle fibers [2, 24]. Polymyositis is a chronic, degenerative disease that has no cure. The treatment consists in the relief of the symptoms with the use of corticosteroids, such as prednisone, intravenous glucocorticoids (when weakness at onset is severe or rapidly worsening), azathioprine, methotrexate, mycophenolate, cyclosporine, and intravenous immune globulin [3].
\nInclusion body myositis is a very common disease among inflammatory myopathies affecting mainly men from the age of 50. The disease begins insidiously and develops over a period of years, sometimes asymmetrically; it may begin with unilateral affection of a leg or arm, progress steadily, and lead to deep muscular atrophy [2]. Laboratory evaluation shows that an elevated CK is much blander. Skin changes are not present [3].
\nThere is a higher mortality rate in patients with inclusion body myositis, since muscle weakness (long flexors of the fingers, quadriceps, anterior tibial, and, to a lesser extent, all other muscles of the arms and legs) usually leads to harmful falls and dysphagia can cause aspiration pneumonia [3].
\nThe antibody, identified a few years ago, that is present in inclusion body myositis is cN1A (5NT1A/5NTC1A) [3]. The frequency of this antibody is about 30%; other forms of myositis such as dermatomyositis and other conditions such as Sjögren’s syndrome and systemic lupus erythematosus (SLE) were also positive even in the absence of any muscle symptoms [3, 28, 29]. Study suggested that the presence of cN1A is associated with a more severe course of disease, dysphagia [3, 30], and increased mortality [3, 31]. However, in another study in German patients, the presence of cN1A did not correlate with the severity of dysphagia or muscle impairment [3, 32].
\nIn the histopathological hallmarks, the distribution and the immunophenotypic profile of the inflammatory cells are similar to those seen in polymyositis macrophages and CD8+ T cells which invade nonnecrotic muscle fibers that express MHC class I antigen on the sarcolemma [33], signs of protein accumulation by detection of amyloid (Congo red, thioflavin S, immunohistochemistry for p62 or TDP-43), detection of tubulofilaments on EM, vacuoles and signs of mitochondrial damage as evidenced by histochemical proof of COX-deficient muscle fibers, and paracrystalline inclusions [3, 34, 35].
\nImmune-mediated necrotizing myopathy is an acute or subacute proximal weakness of the arms and legs, most prominent in the lower limbs [3]. It often affects adults, but it can also occur in children [3]. The progression of the disease is constantly more rapid and severe compared to other myopathies (dermatomyositis and polymyositis) [3]. Laboratory evaluation shows very high muscle enzymes, with an elevated CK of 20–50 times [3]. Neck muscle weakness and dysphagia are common [3].
\nApproximately 10–20% of patients with immune-mediated necrotizing myopathy have anti-signal recognition particle (SRP); however its detection varies from 0 to 54% [36]. This antibody may be associated with cardiomyopathy and a severe disease with muscle atrophy, interstitial lung disease, and dysphagia [37, 38]. Another antibody that has been identified is reductase (HMGCR) antibody; its detection in certain cohorts was 60% [39].
\nHistopathological hallmarks in necrotizing myopathy show dispersed necrotic myofibers of varying degrees; moderate and predominantly MHC class I focal regulation, particularly in areas with necrotic fibers; and complement binding to the sarcolemma [2, 3, 40, 41, 42]. Some inflammatory T cells and other immune cells may be present around these focal points, but there are no primary inflammatory lesions. Necrotic fibers typically exhibit a secondary invasion by macrophages to clean the cell debris [3].
\nIn addition to these inflammatory muscular diseases mentioned above, a localized inflammation at a distance from the skeletal muscle may promote change in this tissue. Recent study proposed the existence of crosstalk between oral cavity and skeletal muscle [43]. The researchers induced oral inflammation in rats and observed that the skeletal muscle was affected by increased infiltration of macrophages, which was suggested by the authors as an explanation for the glucose intolerance shown in animals with oral inflammation [43].
\nResearch conducted over the last 15 years has investigated possible mechanisms that cause changes in macrophages polarization and the effects of these changes on insulin signaling in metabolic organs [44]. These cells exhibit a high degree of functional plasticity, so that the nature of an inflammatory trigger, as well as the cytokines present, can determine their polarization and their functional status [44]. In analogy to the nomenclature T-helper cells (Th), Th1 Th2, macrophages can be classified into two distinct phenotypes: type 1 (M1) classically activated and type 2 (M2) alternatively activated [45].
\nIn vitro, these subsets can be induced by stimulation with interferon gamma (IFN-γ) and lipopolysaccharides (LPS) for M1 or interleukin-4 (IL-4) for M2 [46]. The M1/M2 dichotomy is often used to classify macrophages into pro-inflammatory (M1) or anti-inflammatory (M2) [44]. Among the functions performed by the M1 macrophages, tumor necrosis factor-alpha (TNF-α) production is outstanding [47]. Saghizadeh [48] and collaborators observed that diabetic or insulin-resistant patients have increased expression of TNF-α in skeletal muscle when compared to normoglycemic individuals, suggesting that cytokine plays an important role in the pathogenesis of insulin resistance. TNF-α impairs the insulin signal by decreasing the phosphorylation of insulin receptor substrate 1 (IRS-1) in tyrosine residues [49]. In addition, TNF-α can stimulate some serine kinases including IκB kinase (IKK) and c-Jun amino-terminal kinase (JNK), which promote IRS-1 phosphorylation in serine residues, resulting in insulin signal attenuation [50]. On the other hand, M2 macrophages are associated with tissue repair, angiogenesis, reduction of inflammation, and the improvement of insulin signaling in adipose tissue [45, 51]. In addition to the studies that relate obesity to insulin resistance, there are studies in the literature that demonstrate a correlation between this hormonal resistance and inflammatory processes, such as rheumatoid arthritis and oral inflammations [52, 53, 54]. In this context, the apical periodontitis (AP), an oral inflammation, stands out. AP occurs as a consequence of various aggressions to the dental pulp, including physical, iatrogenic, infectious, and endodontic traumas. This inflammatory picture can cause a wide variety of immunological responses, in order to protect the dental pulp and periapical regions. The regulation of periapical inflammation is extremely complex, as it involves host mediators, including immunological components such as antibodies, cytokines, arachidonic acid metabolites, and neuropeptides [55]. The characteristic inflammatory process of AP presents different types of gram-negative anaerobic bacteria [56] with LPS in the cell wall [57]. Studies have reported that bacteria which are present in the oral cavity can release LPS into the systemic circulation [58]. This substance has the ability to activate toll-like receptors (TLRs), a cell surface receptor that activates innate immunity and induces inflammatory responses. LPS is a specific ligand for TLR2 and TLR4 but has a higher specificity for TLR4 [59, 60]. When released by gram-negative bacteria, LPS binds to a soluble plasma protein called LPS binding protein. LPS or LPS binding protein [61, 62] binds to the CD14 co-receptor via lipopolysaccharide binding protein (LPB), forming the LPS-CD14 complex. This complex, in turn, is recognized by the TLR4-MD-2 complex, present on the cell surface, which is capable of promoting intracellular recruitment of adapter molecules with N-terminal TIR domain, such as myeloid differentiation primary response 88 (MYD88). This molecule can activate the serine kinases JNK and IKKα/β, which promote activation of the activating proteins-1 (AP-1) and factor nuclear kappa B (NF-κB) transcription factors, respectively [63, 64]. NF-κB regulates the expression of several genes involved in different cellular processes such as inflammatory and immune responses and cell growth and development. In the absence of an NF-κB-activating stimulus, this protein is present in the cytoplasm inactive with an inhibitory protein, IκB [65]. Activation of NF-κB can occur not only by exposure of the cells to LPS but also by the action of inflammatory cytokines (TNF-α and IL-1), activation of T and B lymphocytes, UV radiation, and expression of products [66]. After stimulation, the IKK is phosphorylated and activated. The IKK complex consists of two catalytic subunits, IKK-α and IKK-β, in addition to the NF-kappa-B essential modulator (NEMO) or IKK-γ [67]. After activation, IKK recruits and phosphorylates the IκB that is recognized by the ubiquitin ligase machinery, which leads to its polyubiquitination and consequent degradation. In this way, the NF-κB dimers translocate to the nucleus, binding at specific sites of the deoxyribonucleic acid (DNA) and promoting the transcription of a large number of genes [65, 67].
\nIn addition to activating the IKKα/β/NF-κB pathway, TLRs are capable of activating the JNK pathway [68]. The serine/threonine kinase group called JNK (JNK-1, JNK-2, and JNK-3) belongs to the family of mitogen-activated protein kinase (MAPKs), responsible for the regulation of various cellular functions. This regulation occurs largely because of its ability to control the transcription of specific genes by AP-1 [69]. AP-1 is a transcription factor that, when activated, promotes the expression of genes related to innate immunity [70]. In addition to LPS, the signaling pathway of TLRs can be activated by heat shock proteins [71]. Heat shock proteins (HSP) are proteins characterized as chaperones because they have an important function in adaptation to stress and cellular protection, acting mainly in the synthesis and protein degradation, besides regulating fundamental cellular processes [72]. The family of HSPs is divided into subfamilies, classified according to the molecular mass, being small HSPs (8–27 kDa) and large HSPs (100–110 kDa), among which stand out HSP90, HSP70, and HSP60 [73]. In addition to its essential functions as a chaperone [74], HSP70 has an anti-inflammatory effect by inhibiting the activation of NF-KB when present in the intracellular environment [75]. However, stimuli such as cell necrosis and bacterial products such as LPS can cause the passage of HSP70 through the membrane into the extracellular environment [76, 77]. Studies have suggested that elevated serum levels of HSP70 may be correlated with cardiovascular disorder, pulmonary fibrosis, renal damage, oxidative stress, and inflammation [78]. The development of these conditions may occur due to the ability of HSP70 to bind to TLR2 and TLR4, promoting the activation of the NF-κB pathway which, as mentioned above, induces the expression of inflammatory mediators related to insulin resistance [79]. Studies suggest that insulin sensitivity may undergo regulatory action by the adaptive immune system [80, 81]. This system is composed of different types of cells, among which the B and T lymphocytes [82] stand out. T lymphocytes are classified into two main classes: helper T lymphocytes, also known as T helper (Th), and cytotoxic T lymphocytes. The “naïve” Th1 lymphocytes, when interacting with antigen presenting cells, undergo activation and can differentiate into different subtypes [83]. The Th1 subtype expresses proinflammatory cytokines, such as TNF-α and IFN-γ; Th2 expresses mainly anti-inflammatory cytokines, such as interleukin-4 (IL-4) and interleukin-13 (IL-13), and regulatory T cells secrete predominantly anti-inflammatory cytokine and transforming growth factor-β (TGF-β) [84]. Th1 cells play a central role in the recruitment of macrophages and induction of insulin resistance in obesity-induced diabetes models. These effects are counterbalanced by the function of Th2 and Treg cells that maintain an anti-inflammatory state and increase insulin sensitivity [85]. Appropriate regulation of Th cells is of extreme importance for the control and prevention of various diseases [86]. An increase or decrease in the Th1 or Th2 subtypes, as well as the cytokines produced by these cells, indicates an imbalance that may be one of the factors responsible for the development of insulin resistance [87]. It is known that insulin resistance is one of the main characteristics of diabetes mellitus [88]. This disease is also closely related to muscle weakness due to altered insulin action [89], standing out that insulin is an important anabolic hormone for protein metabolism [90].
\nThe study performed by Boon et al. [91] with healthy lean individuals observed that only 5 days of hyperlipidic diet promoted increased messenger ribonucleic acid (mRNA) expression of macrophage markers in skeletal muscle and reduced expression of the glucose transporter type 4 (GLUT-4) glucose transporter protein in this tissue. Similarly, Patsouris et al. [92] demonstrated increased macrophage content in skeletal muscle in diabetic patients independently of body mass index (BMI). An increased macrophage content (assessed by F4/80 protein detection) was observed in muscle tissue of rats with AP in the absence of obesity, highlighting the key role of these cells in the etiology of insulin resistance. It should be noted that only F4/80 detection is not able to provide details on M1-type and M2-type macrophage polarization although evidence demonstrates that under obesity conditions, macrophages infiltrated into muscle tissue exhibit phenotype characteristic of M1 polarization [92, 93, 94, 95]. The reprogramming of the M1 polarization toward the M2 polarization may represent a promising strategy for the treatment of glycemic homeostasis in patients with diabetes and insulin resistance [44].
\nAs previously reported, inflammation causes insulin resistance. According to Pereira et al., rats with AP had increased IKKα/β and JNK phosphorylation status in gastrocnemius muscle. These results are in agreement with the study of Yaspelkis et al. [96], who observed a higher IKKα/β phosphorylation status in the skeletal muscle of rats treated with a hyperlipidic diet for 12 weeks, and also the study by Todd et al. [97] that identified an increase in JNK activity in the skeletal muscle of rats subjected to 3 weeks of hyperlipidic diet. Kaneto et al. [98] reported that treatment of diabetic rats with JNK inhibitors improved the insulin sensitivity of the animals. Similarly, studies by Yuan et al. [99] and Hundal et al. [100] have reported that inhibition of IKK-β by the administration of salicylates improves insulin action in obese and diabetic human and rats. Furthermore, it has been demonstrated that genetically modified mice, which do not express IKK-β or JNK, are protected from obesity-induced insulin resistance [99, 101, 102, 103].
\nIn addition to stimulating inhibitory effects on insulin signal transduction, TNF-α may interact with tumor necrosis factor receptor 1 (TNFR1) in skeletal muscle [104] and thereby stimulate the NF-κB and/or MAPK pathway [105, 106], which are related to the phosphorylation of IKK and JNK and, in their turn, may impair insulin action. Pereira et al. [43] evaluated the plasma concentrations of LPS and HSP70 in AP models. Rats with AP showed a significant increase in both LPS and HSP70 when compared to the control group. Research on diabetes suggests that chronic elevation of LPS levels may play a key role in the development of insulin resistance [107, 108].
\nAmong the possible mechanisms involved in this alteration, we highlight the ability of LPS to bind to the TLR4 receptor, which may trigger the activation of inflammatory signaling pathways related to inhibition of the insulin signal [108]. Another mediator that plays an active role in the modulation of inflammation is the heat shock proteins. The study by Goodman et al. [109] reported higher expression of 44 HSP genes in periapical granulomas compared to healthy periodontal tissues. Elevation of HSP70 plasma concentrations observed in rats with AP may indicate that increased local HSP expression is associated with higher concentrations of this protein in serum [43]. Interestingly, studies have shown that serum concentrations of HSP70 are higher in diabetic patients [110, 111]. Asea et al. [79] reported that HSP70 can bind to the TLR4 receptor, suggesting a possible involvement of this protein in the development of insulin resistance. With regard to the adaptive immunity markers, animals from the AP groups showed an increase in the Th1 response represented by increased T-bet expression in the spleen and elevated plasma concentrations of INF-γ [43]. A study carried out with knockout animals for the T-bet gene treated with hypercaloric diet showed that even with weight gain and increased adiposity, the animals were protected from insulin resistance [112]. The authors attributed the lack of insulin resistance to reduced production of INF-γ. These results are consistent with studies that reported that IFN-γ deficiency may improve glycemic homeostasis under obesity conditions [113, 114, 115]. In addition, treatment of adipocytes (3 T3-L1) with interferon gamma (INF-γ) reduces insulin signal and glucose uptake [116]. The functions of Th1 cells are antagonized by the Th2 subpopulation presenting the transcription factor GATA3 and IL-4 as specific markers. The AP in rats promotes a reduction of IL-4 [43]. Chang et al. [117] reported that IL-4 treatment promotes improved insulin sensitivity and glucose tolerance and simultaneously reduces body weight in obese rats. These findings suggest that IL-4 plays beneficial effects on glycemic homeostasis. The role of Th2 cells in insulin sensitivity was demonstrated in the study by Gonzales et al. [118]. In this study, a model of inactivation of Th2 response was developed through the inhibition of the activator of transcription 6 (STAT6) protein, in which it was observed that animals with Th2 response deficiency were more prone to insulin resistance. Thus, the reduction of the Th2 response observed in rats with AP may contribute to the understanding of the mechanisms involved in insulin resistance observed in animals with AP [43, 54].
\nStudies suggest that TNF-α contributes to age-related muscle loss and that resistance exercise may attenuate this process by suppressing TNF-α expression in skeletal muscle [119]. Other findings demonstrate that decreased muscle strength in diabetic individuals is associated with elevated plasma concentrations of TNF-α and interleukin-6 (IL-6) [120]. Therefore, considering that oral inflammation, such as AP, may increase infiltration of macrophages in muscle tissue and this increase is related to the production of proinflammatory cytokines, it is possible to suggest that prevention of chronic inflammatory oral diseases contributes to the maintenance of muscle integrity.
\nThe main subtypes of inflammatory muscular diseases are polymyositis, dermatomyositis, necrotizing myopathy, overlap myositis, and myositis of inclusion bodies. The origin of these diseases is idiopathic, making it difficult to prevent them. As oral inflammation can increase infiltration of macrophages in muscle tissue and this increase is related to the production of proinflammatory cytokines in this tissue, these cytokines can cause muscle weakness. It is important to consider the prevention of chronic inflammatory processes in order to maintain muscle integrity or even prevent the worsening of the clinical condition of patients with inflammatory muscle diseases.
\nThe authors declare that there are no conflicts of interest.
This study was supported by the São Paulo Research Foundation (FAPESP) [grant #2016/24829-2] São Paulo, SP, Brazil.
\n\n apical periodontitis activating proteins-1 body mass index cluster of differentiation 14 cluster of differentiation 4 cluster of differentiation 8 creatine kinase cyclooxygenase deoxyribonucleic acid glucose transporter type 4 human leukocyte antigen 3-hydroxy-3-methylglutaryl-CoA reductase heat shock proteins interferon gamma IkB kinase interleukin-13 interleukin-4 interleukin-6 insulin resistance insulin receptor substrate 1 c-jun amino-terminal kinase lipopolysaccharide binding protein lipopolysaccharides M1-type macrophage polarization M2-type macrophage polarization mitogen-activated protein kinase melanoma differentiation-associated gene 5 major histocompatibility complex magnetic resonance imaging messenger ribonucleic acid myeloid differentiation primary response 88 NF-kappa-B essential modulator factor nuclear kappa B nuclear matrix protein positron emission tomography–computed tomography systemic lupus erythematosus signal recognition particle activator of transcription 6 transactive DNA-binding protein 43 transforming growth factor-β T-helper transcription intermediary factor toll-like receptors tumor necrosis factor receptor 1 tumor necrosis factor-alpha United Kingdom United States of America
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