Abstract
Parkinson’s disease is a multifaceted illness that requires interdisciplinary approach to be fully addressed. The etiology of the disease is not completely understood, but genetic and environmental cues play important roles. Histological hallmarks of the disease are the accumulation of alpha-synuclein aggregates, mitochondrial changes and loss of dopaminergic neurons in the substantia nigra. The dopaminergic shortage leads to many motor and non-motor symptoms that affect patient quality of life. Current treatments are symptomatic only, for none can stop disease progression or cure it. Among them are intense physical exercise, dopaminergic drug intake, deep brain stimulation and the use of medical cannabis. Dopaminergic drugs help increase the levels of dopamine in the synaptic cleft or stimulate dopamine receptors directly. Intense physical exercise has been proved beneficial and safe. Deep brain stimulation is done by surgically implanting electrodes and has shown immediate improvements. Medical cannabis is being used mostly to fight non-motor symptoms, such as pain, anxiety, appetite loss and depression. Exciting researches are being done with stem cells, animal models and wearable technology, which might answer many current doubts, but finding early markers to detect and stop the disease progression remains a challenge
Keywords
Parkinson disease, Deep brain stimulation, Physical exercise, Medical cannabis, Dopaminergic drugs, Dopaminergic circuitry, Substantia nigra, Nigrostriatal dopaminergic circuitry, Stem cells, Dementia
Introduction
Parkinsonism is a syndrome characterized by dysfunction of specific brain circuitry. The clinical condition of each patient characterizes one among the many forms of the syndrome: post-encephalic, drug related, vascular, just to name a few examples. The presence of one such cause leading to the development of parkinsonian symptoms is present in secondary parkinsonism, and its different clinical developments help guide diagnose and treatment [1,2]. The most common presentation of parkinsonism, however, is its idiopathic and age-related form, called Parkinson’s disease (PD). The neural dysfunction typical of this clinical entity is caused by neurotransmitter deficiency and death of neurons, which triggers neurological signs that ultimately impairs patients’ quality of life [3,4].
PD affects millions of people worldwide and is the second most prevalent neurodegenerative condition, next to Alzheimer disease, and has chronic, continuous, and disabling nature. There are several treatment options, but none capable of stopping or reversing the disease’s progression. Diagnosis is still also a hindrance, for there is no molecular marker exam to perform in vivo. Therefore, PD keeps posing challenges to the scientific community, in many fields and fronts.
History of PD
Its first description is from 1817, on the monograph “An Essay on the Shaking Palsy”, by British physician James Parkinson [3,4]. He described his subjects’ resting tremor, shuffling gait, stooped posture, sleep problems, and constipation. He also noted the degenerative nature of the disease, with its ever-growing disability, and called it paralysis agitans. A few years later, bradykinesia and rigidity were added to the list of symptoms [3,4], and the syndrome was renamed PD, in honor of its first describer. Thereafter, many more studies described motor and non-motor features (Table 1), and detailed neuropathological, neurochemical, neurophysiological, and neuroimaging characteristics of PD [5]. Favorable treatment results were first achieved in the 1950s with levodopa, a dopamine (DA) precursor which, when paired with carbidopa (Figure 1), became the mainstay of medical therapy and remains so to this day [6,7].
|
Motor-symptoms |
|
|
Bradykinesia |
Impairment of voluntary movements that afflicts arms, hands, face and legs. |
|
Hypokinesia |
Decrease in body movement. |
|
Akinesia |
Loss of movement, like loss of arm swing. |
|
Freezing |
Sudden but temporary inability to move; a stiff feeling in arms, legs, and torso area, such as walking or getting up from a chair. |
|
Resting tremor |
It is the classic rhythmic tremor of PD. Initially starts in one hand, foot or leg of one side of the body and eventually hits both sides. It can also occur in the jaw, chin, mouth, or tongue and provoke a feeling of internal tremor. It does not directly cause muscle force loss. |
|
Postural instability |
Trouble maintaining balance. |
|
Rigidity |
Stiffness or inflexibility of muscles. |
|
Non-motor symptom |
|
|
Sleep abnormalities |
Ex: moving while in REM sleep, insomnia, daytime sleepiness. |
|
Depression |
Mood disorder that involves a persistent feeling of sadness and loss of interest. |
|
Cognition problems |
Difficulty in learning new material, problem solving, memory and concentration, disorientation and confusion. |
|
Autonomic dysfunction |
Orthostatic hypotension, constipation, fecal incontinence, bladder disturbances, olfactory dysfunction, sweating and sexual dysfunction. |
|
Mood changes |
Irritability, impatience, aggression. |
|
Hallucinations |
Hearing or seeing things others do not. |
|
Dementia |
Common neurodegenerative condition that presents itself with a wide range of neuropsychiatric, cognitive, sleep, motor, and autonomic symptoms. |
|
Paranoia |
Feeling suspicious or distrustful of others. |
|
Weight Loss |
Accompanied by appetite loss, weight loss is more likely in later phases of the disease and could lead to malnutrition or exacerbate motor and non-motor symptoms. |
|
Delusions |
False, unrealistic or strange beliefs. |
|
Anosmia |
Lack of the senses of taste and smell. |
Figure 1: A) DA: neurotransmitter associated with motor function, reward and addiction. B) Levodopa: molecular precursor of DA capable of penetrating the blood-brain barrier, increasing DA production in the brain and manage symptoms. C) Carbidopa: this molecule slows degradation of levodopa by decreasing its peripheral conversion to DA, reducing gastrointestinal side effects and increasing levodopa’s bioavailability in the central nervous system [8,9] (Source: Public Domain [10–12]).
Continuous advances have been made regarding the physiologic mechanisms and genetic causes of PD, and additional treatment options were developed [13,14]. DA agonists, monoamine oxidase type B inhibitors and catechol-O-methyltransferase inhibitors have been added to the pharmacological arsenal. But even the rise of new pharmacological options is insufficient, and the prevalence of patients, either harmed by persistent symptoms or afflicted by severe side effects of the medication, has pressed scientists towards the search of new techniques. One of the currently available interventions is the surgically implanted deep brain stimulation [15-19]. Another is the prescription of medical cannabis, which is gaining more adherence of physicians, as regulation reaches several countries and beneficial effects are consistently demonstrated in trials. In more recent developments, stem cell research brings hope to physicians and patients, with its focus on neuroprotection and neurorestorative therapies [20-29], therapeutic benefits not observed in any of the previously available methods.
Epidemiology of PD
Epidemiology of PD
PD is a common neurological disorder in older adults, with a prevalence of approximately 1% of individuals over 60 years of age, 2% of those over 65, and 4% of the population older than 85 in the United States [30]. Its average annual incidence is 14 per 100,000 inhabitants of the total population, and 160 per 100,000 inhabitants over 65 years of age in high-income countries. The number of affected patients is predicted to double worldwide by 2030 [3,31].
The risk of developing the pathology is estimated at 2% for men and 1.3% for women aged 40 years and older [30,31]. Data on incidence according to race and ethnicity are few and inconsistent, but it appears to affect all ethnic groups and socioeconomic classes. Prevalence is low before the age of 50, but increases sharply with senescence [32].
The risk of dementia in patients of PD varies among research, with incidences ranging from 30 to 80%, a sharp contrast to the incidence of this condition in the overall population, in which it goes from 5 to 8%. Dementia is a major cause of permanent disability, for currently there are no restorative treatments. Depression is also an important factor to be taken into account, with 47% of PD patients also showing evidence of this pathology [30,33,34].
PD can be hard to diagnose since there is no laboratorial test able to identify it. This lack of molecular or histological diagnosis, therefore, renders it mistakable for other health conditions. Healthcare providers must then stick to medical and family histories, physical examinations, and body imaging. Magnetic resonance imaging and computed tomography scan, for instance, can identify other problems and discard other diseases [31,32].
Basis of the Disease
The etiopathogenesis PD is complex, with environmental and genetic both playing important roles in its development [35-40]. Its motor manifestations are due to discontinuity of the nigrostriatal dopaminergic circuitry (Figure 2A). Another pathological hallmark of PD are the Lewy bodies. These round eosinophilic intracytoplasmic proteinaceous inclusion bodies, structures composed of fibrillar alpha-synuclein (Figure 2B), are present in surviving neurons [39,41]. It is not yet clear if the protein alpha-synuclein is a cause or a compensatory protection.
Figure 2 : A) High magnification of human adu lt midbrain post-mortem tissue, with highlight to the substantia nigra and to the dark pigment neuromelanin. Black scale bar: 1mm. Red scale bar: 200 μm [28]. B) Alpha-synuclein immunostaining (red) of stem cell derived dopaminergic neurons (green) generated from arm adipose tissue. Nuclei (blue). White scale bar: 10 μm [42]. Motor symptoms appear when 60% to 80% of dopaminergic neurons of the substantia nigra die [43]. (Source: Public Domain).
Some light begins to be shed over this pathogenesis puzzle. Parkinsonism observed in users of contaminated heroin [44] led to the verification of mitochondria abnormalities. Post-mortem tissue of PD patients, as well as animal models of the disease (fly, zebrafish and mouse) also presented decrease in mitochondrial activity and energy production [45-47], and mitochondrial diseases are more prone to damage tissues with bigger energy demands, such as nervous and cardiac tissues [48,49]. The oxidative stress, resultant of this mitochondrial breakdown, harms the neuron’s integrity and signals pathways that lead to cell death [35,50-52], and demonstrate the importance of defective mitochondrial activity in PD pathogenesis [27,37,39,51,53,54].
Genetics also plays an important role in PD [4,37,39,55,56]. Two sets of genes are associated with mitochondrial function: mitochondrial DNA (mtDNA) and chromosomal DNA, the latter responsible for mtDNA regulation. The circular mtDNA has 37 genes [57], responsible for encoding 13 proteins essential for the energy machinery (electron transport chain) to work [58]. Mutations can cause changes in the organelle function [38,59], and these accumulate over life, which explains their growing relevance as the patients age.
The best-known gene group associated with PD are PARK genes, because of their importance in the regulation of mitochondrial activity, protein activity, alpha-synuclein production and, consequently, vesicle traffic and neurotransmitter release. This field receives ever more attention. The mechanisms underlying these organelles dysfunction, particularly in familial PD, require further research, making PARK genes a potential target for the development of PD biomarkers for help with diagnosis, and even a target for new treatment alternatives [28,37,49,51,60].
Treatments
Intense physical exercise
High-intensity exercise might modify disease progression [61]. It improves clinical symptoms: pain, mobility, standing balance, posture, has a positive effect in the associated depression and decreases the risk of falls [62-64]. It produces benefits across many body systems, presents few risks, is inexpensive, and showed good adherence with minimal supervision. In rodent PD models, exercise has been shown to not only decrease symptoms but also to reduce underlying disease processes [65]. A high-intensity multimode exercise program tested in PD patients produced more improvement than low-intensity exercise, which also suggests a link between these results and an improved anti-inflammatory profile [66].
These perceived benefits could be consequence of the synthesis and expression of monoaminergic neurotransmitters. DA, together with the brain-derived neurotrophic factor (a growth factor that promotes proliferation and maturation of new neurons), activates the striatum and positively influence motor disorders and neuronal plasticity [63,64,67,68]. This factor is also related to increased dendritic arborization in cortical areas and mitochondrial biogenesis [69], and its role in the regulation of the serotoninergic system [70,71] shows how important adequate amounts of physical exercise are, playing parts both in increasing resilience against PD and helping maintain physical and mental health [63].
Dopaminergic drugs
PD treatment is anchored on pharmacological substitution of striatal DA and non-dopaminergic approaches, addressing both motor and non-motor symptoms. Levodopa, a medication classified as a central nervous system agent, works by being converted to DA, reducing its cerebral deficit. It manages motor symptoms but its conversion in the digestive tract might cause nausea or vomiting. Because of that, it is usually associated with carbidopa (Figure 1C), a decarboxylase inhibitor. This prevents the levodopa degradation that occurs before it reaches the brain, lowering its effective dose and lessening side effects [8,9].
Patients benefit from dopaminergic therapy in the early period after diagnosis. However, as the disease progresses, motor complications and therapeutic fluctuations appear, consequence of an uneven response to levodopa. This hindrance in efficacy is partly due to the loss of the endogenous DA-synthesizing enzyme, L-amino acid decarboxylase. Consequently, patients require higher doses of levodopa and additional therapies to maintain motor function, even though clinical research suggests it does not worsen disease progression [72,73].
One additional therapy is the use of inhibitors of catechol-O-methyltransferase, commonly used as an adjunct to levodopa for the amelioration of wearing-off symptoms. These inhibitors reduce the breakdown of levodopa and increase its plasma half-life, although they may increase dyskinesia [74-76].
Monoamine oxidase B inhibitors block DA degradation and are used to increase its synaptic concentration. There is evidence that monoamine oxidase B inhibitors do exert some neuroprotective properties in the PD models. They are recommended as monotherapy in the early stages of the disease, and as complementary therapy to levodopa in advanced PD [77-79].
DA agonists are another option. They directly stimulate DA receptors, bypassing degenerating dopaminergic neurons in the brain. They help to decrease the frequency of levodopa intake (they possess longer half-life, of 6 hours), but their use has more psychiatric side effects, like somnolence, hallucination, and impulse control disorders [77,80]. DA agonists can be ergoline (first generation) or non-ergoline. The latter are considered a better option, since they bond only to specific receptors, and preserve other pathways for additional pharmacodynamic interventions [3].
Deep brain stimulation
In some cases, symptoms of PD persist despite pharmacologic optimal treatment and, in others, too heavy are the side effects of the medication [3]. In both cases, innovative surgical therapies may be used. One of these therapies is deep brain stimulation. It consists of a pacemaker like device that uses electrical stimulation to alleviate symptoms, reducing tremor significantly. A new generation of brain implants might become available as research groups around the world develop more efficient technology [19,81,82].
Deep brain stimulation implants are surgically inserted. The targeted areas are thalamus and basal ganglia [15]. Placement of electrodes (Figure 3) is done with help of imaging technology, and by real time checking of the stimulation’s effect, both precise methods. The United States Food and Drug Administration has already approved indications of deep brain stimulation for essential tremor, PD, obsessive compulsive disorder, and trials are on their way to evaluate its contributions in other disorders, such as depression [83-85]. So great is its success, that it is becoming a viable choice for younger patients, and results have been positive. The implants diminish the need of the medication, softening its side effects [16,86,87].
Figure 3: Electrode positioning in deep brain stimulation [88]. (Source: Public Domain).
Medical cannabis
PD non-motor symptoms are not responsive to DA replacement therapy. Among them are pain, anxiety, appetite loss and depression [89]. They usually appear even before the first motor symptoms, and have a dramatic impact on the patients’ quality of life.
Opioids are often used to treat neuropathic pain, but over-prescription and addiction associated to this treatment is a worldwide crisis, affecting public health and quality of life [90,91].
Medical cannabis is already one of the strategies used to fight opioid addiction, as well as treating chronic pain, with particular success in neuropathic, surgical and cancer related pains, and shows reduction in opioid consumption [92-94]. Cannabis induced a significant reduction on reported pain intensity, improved assessments of quality of life, was not associated with serious adverse events and was characterized by improvement in treatment perception and low discontinuation rate [95].
Cannabis mostly know components are cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) (Figure 4). An advantage to its prescription is its historical use by humanity and demonstrated safety: death by cannabis overdose has never been recorded. Heavy and chronical users, particularly those who begin its use in adolescence, have shown cognition and memory impairment, and long-term effects on DA signaling. Nevertheless, its most common side effects are dizziness, dry mouth and somnolence, and even these are reported by less than 10% of patients. Although dizziness should increase the risk of falls, these have been less frequent during treatment with cannabis [95].
Figure 4: A) The THC molecule is responsible for the psychoactive effects and changes in pain perception, and requires heat to be activated. B) The CBD molecule, devoid of psychoactive euphoriant effects, has anti-inflammatory properties and relieves pain and anxiety [92,93,96-98]. For pain relief, an optimal rate of THC and CBD should be considered for each person, as well as a suitable form of consumption. Edibles containing THC have been associated to anxiety increase [99,100], already a common symptom in PD patients, so these might not be adequate for them. Herb-vaporizers seem to be a better alternative than joints for THC consumption, since they have controlled temperature and produce less residues [101,102] (Source: Public Domain [103]).
Cannabis compounds have been broadly studied since the 90’s. This led to the discovery of the endocannabinoid system and its composition: endocannabinoids (endogenous lipid-based retrograde neurotransmitters) and cannabinoid receptors (proteins present in the vertebrate nervous system). Its involvement in PD is being studied, but it is known that it functions as a neuromodulator, with important roles in the central nervous system, such as regulating development and synaptic plasticity, and orchestrating response to insults [104-109].
Treating pain and diminishing opioid consumption are but a few of the many applications of medical cannabis for PD. Changes of the endocannabinoid signaling have been implicated in other neurological diseases, such as Alzheimer's and multiple sclerosis [110,111]. Medicinal cannabis and its derivatives seem to also function as neuroprotectants, decreasing spasticity in multiple sclerosis [112], and reducing seizures in Lennox–Gastaut syndrome. Adverse events were reported by 86% of patients, mostly mild. It has also been found to improve patients’ scores in the Unified PD Rating Scale, particularly when assessing rigidity, bradykinesia and tremors [113,114].
It is therefore no surprise that the data regarding cannabis usage is increasing, along with regulation or judicial authorization in several countries: Canada, United States, Brazil and Uruguay, among others [115-117]. Epidemiological information show that the older population constitutes a growing segment of medical cannabis users, ranging from approximately 7% to more than a third, depending on the country [95,118]. Since the aging population constitutes a large parcel of neurological patients (with its worldwide number expected to double by 2025), cannabis use is predicted to increase among this demographic. [30].
Hyporexia and depression, both struggles for PD patients, might also be mitigated by cannabis therapeutics. These properties could be beneficial to many other pathologies, such as chemotherapy induced nausea and vomiting, Alzheimer's disease, anorexia nervosa, dementia, dystonia, Huntington's disease, post-traumatic stress disorder, psychosis, Tourette syndrome, epilepsy, and more [106,107,119,120].
Nevertheless, large randomized trials are still needed to confirm the utility of cannabis in chronic pain management and elucidate long-term adverse effects, in both young and elderly populations. Studies must also determine dosage and the best way of administrating these compounds, regarding the clinical aspects of each patient [96,121].
Conclusion
PD is a complex neurodegenerative disease with a heterogeneous aspect, requiring a multidisciplinary approach in order to be appropriately addressed [3,4,35]. Exciting research is being done on its etiology and pathogenesis, and wearable technologies [122,123] bring information for physicians and researchers in real time. As current treatments evolve and their precision improves, they help patients cope with motor and no motor symptoms, while reducing side effects. For now, treatments are symptomatic only, but animal models and in vitro investigation might accelerate drug discovery and help elucidate genetic and neuroprotectant mechanisms [124]. As more of the brain development and aging is understood, it becomes apparent that events thought to happen only in brain development remain in some parts of the developed brain, like neurotransmitter switching. Unveiling the role of neurotransmitter switching in PD pathogenesis could lead to a new front of research [125,126]. At the same time, stem cells slowly gain recognition as a viable therapy, not only in restoring lost cells, but also in modulating chronic neuroinflammation [127-135]. The results in these fronts could lead to the discovery of early biomarkers and even a stop or a reversion to PD.
Declarations
Authors have contributed to the manuscript elaboration, editing and reviewing, and declare no conflict of interest.
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