Introduction Parkinson’s disease

Introduction
Parkinson’s disease (PD) affects 6.3 million people worldwide (1), as it is one of the most common neurodegenerative disorders. Between 1990 and 2015 PD was the only neurological disorder with increasing age-standardized rates of deaths (2). The incidence and prevalence of PD peaks in the age-group 80-89 years old (3, 4). For instance, the prevalence in the age group 40-49 years old was 41 per 100 000, but in the age group of 80 years and older was 1903 per 100 000.

Clinical presentation
PD can be divided into three phases. The first phase, also known as the prodromal period, includes the non-motor symptoms, such as constipation, rapid eye movement sleep behavior disorder and depression (5, 6). The duration of this phase is approximately between the 10 and 20 years. When the patient is diagnosed with PD, the patient transitions into the second phase (early PD). The symptomatology of this phase is predominantly characterized by motor features (7): bradykinesia, muscular rigidity and rest tremor. Bradykinesia in PD is defined as slow movement and an impaired ability to move the body (progressive hesitations) as movements are continued. Muscular rigidity refers to resistance to passive movement, while rest tremor refers to an involuntary, oscillatory movement in a resting limb, which is put to an end during the onset of movement (8). This tremor is asymmetrical and usually located in the hands. During the progression of the disease into the final phase (advanced PD) the motor symptoms worsen, often leading to dysphagia, freezing of gait and postural impairment (9). Freezing of gait is a clinical phenomenon characterized by “brief, episodic absence or marked reduction of forwarding progression of the feet despite the intention to walk” (10). Postural impairment is associated with the patient’s sensation of imbalance and can thus exacerbate the risk of falls. The non-motor symptoms progress as well during advanced PD. The usual non-motor symptoms in this stage include pain syndrome, lethargy, urinary symptoms and cognitive decline (11). As the disease progresses further, motor complications, such as dyskinesia and response fluctuations, start to arise due to the reduced responsiveness to levodopa (12). This will be discussed in more detail below.
The most common tool that is assessed in research to evaluate the progression of motor features in PD is the Hoehn and Yahn scale (13). This scale uses clinical features of PD to describe the motor function (table 1). The advantage of the Hoehn and Yahn scale is that it is not complex to use. Progression in the Hoehn and Yahn scale is associated with a decline in QoL and motor function. However, due to its simplicity, not all motor nor non-motor features are evaluated (14). It is for example possible that a patient is suffering from disabling unilateral motor symptoms. This patient will be classified in stage 1 according to the Hoehn and Yahn scale, even though these symptoms could occur in more advanced phases of PD as well.

Etiology
The exact cause of PD is unknown. It is assumed that the multidimensional development of PD is related to an interaction between specific genes and toxic environmental factors. A few genes have been discovered with mutations, such as Parkin, PINK1 and VPS35. These mutations create a genetic susceptibility to PD (15). Environmental risk factors, for example, include exposure to pesticides and head injuries (16, 17).

Pathogenesis
The clinical features of PD develop due to loss of dopaminergic neurons in various parts of the brain, which are primarily concentrated in the substantia nigra in the mesencephalon. The substantia nigra can be subdivided into the substantia nigra pars reticulata (SNpr) and the substantia nigra pars compacta (SNpc). Both SNpr and SNpc are part of the basal ganglia.
The neurons in the SNpc are projecting on the dorsal putamen of the striatum with dopamine as the neurotransmitter (nigrostratial pathway). This pathway stimulates the cerebral cortex and initiates movement. Therefore, the reduction of the dopaminergic neurons in SNpc is related to the motor features of PD (18). However, the basal ganglia are involved in the regulation of emotion and cognition as well. They thereby contribute to the non-motor features too. Another explanation for the occurrence of non-motor symptoms is the loss of dopaminergic neurons in other parts of the brain, such as substantia innominata and raphe nuclei (19).
The degenerating neurons are often aggregated with cytoplasmic inclusions of the ?-synuclein protein, also known as Lewy bodies (20). During the prodromal phase, the Lewy bodies develop at the anterior olfactory nucleus or the dorsal nucleus of the vagus nerve in the brainstem. However, by means of trans-synaptic transport they are mobilized through the medulla oblongata, pontine tegmentum, midbrain and basal forebrain to the telencephalic cortex (21, 22). It might be possible that the Lewy bodies are contributing to the loss of dopaminergic neurons (23).

Treatment
When taking the therapeutic options of PD into consideration, a lot of progress has been made in the past few decades (24). The current therapeutic options, which can be categorized into medical and surgical procedures, are able to improve the clinical motor features of PD.
Drug treatments are usually initiated during early PD, when the patient is experiencing impairment in functioning from the symptoms (disability and/or discomfort). The goal of the initial symptomatic treatment is to increase the intracerebral concentration of dopamine or the susceptibility of neurons to dopamine. Hence the motor symptoms, which predominate early PD, can be treated. The first choice of drug is usually levodopa, a dopamine precursor, as it is the most effective treatment for motor symptoms in early PD (25). It is combined with carbidopa or benserazide, both of which are able to inhibit the peripheral metabolism of levodopa. Alternatives include dopamine agonists (DA) and monoamine oxidase type B (MOA-B) inhibitors (26). Dopamine agonists are able to activate dopamine receptors, while MOA-B inhibitors impede the MOA-B. This enzyme is responsible for breaking down the dopamine neurotransmitter.
As the disease progresses from early PD to advanced PD, the duration of action of levodopa decreases, which contributes to the motor complications. Moreover, the reponse to levodopa modifies, causing patients to have to deal with response fluctuations. When the dose of levodopa is high, patients are suffering from dyskinesia; when the dose is low, patients are suffering from hypokinesia (27). This fluctuating response pattern is also known as “on-off”-periods, with the off-time referring to hypokinesia. The on-time can be associated with both non-impairing and debilitating dyskinesias. A possible explanation for this phenomenon is the pulsatile stimulation of the dopamine receptors. If the motor symptoms are susceptible for levodopa, but fluctuations and dyskinesia are becoming disabling, Deep Brain Stimulation (DBS) is an option for treatment. During this procedure an operation will be conducted to insert stimulating electrodes in the nucleus subthalamicus (28). A lot of patients, however, do not meet the requirements for this treatment. Alternatives include subcutaneous infusion of apomorphine, which is a non-selective DA, and duodenal infusion of levodopa. Because of the duodenal infusion, the dose of levodopa can be kept stable.
Patients who are suboptimally treated with levodopa and are dealing with levodopa-induced motor complications will be treated with adjunctive drugs instead. A variety of adjunctive oral medication exist, including DA, MOA-B inhibitors and Catechol-O-methyl transferase (COMT) inhibitors (26). COMT inhibitors prevent the degradation of levodopa. According to international consensus of the European evidence-based guidelines, the American Academy of Neurology evidence-based guidelines and the International Parkinson and movement disorder society evidence-based medicine review for treating PD, DAs could be used as an adjunctive therapy to levodopa in patients with advanced PD suffering with motor fluctuations (26, 29, 30).
Nevertheless, PD remains an incurable and slowly progressive neurodegenerative disease. Furthermore, the clinical features have a great impact on the Quality of Life (QoL) of patients (31-34). QoL uses subjective and multidisciplinary components to assess the general well-being of the patient (35). Especially the non-motor features and motor complications contribute to the low QoL, which progress significantly during advanced PD. We therefore need to know whether DAs, one of the adjunctive drugs used in the later phases of PD, are an effective adjunctive therapy to levodopa in patients with advanced PD and motor complications.