Abstract
This paper is about the investigation of Parkinson’s disease, and in particular is involved with the examination of its symptoms, stages, causes, prevalence, diagnosis and treatment, and social impacts. Finally, the paper analyzes and evaluates two ongoing on Parkinson’s disease researches, which are also examined in respect to their impact on Parkinson’s disease patients.
Key words: Parkinson disease, Parkinson disease causes and impacts, Parkinson disease symptoms and prevalence, Parkinson disease diagnosis, and Parkinson disease ongoing research.
Idiopathic Parkinson disease (PD) is a progressively evolving disease with main manifestations resting tremor, muscle stiffness, slow movement and loss of reflective attitudes. Practically, there should be at least two of these symptoms for the disease’s diagnosis (Pfeiffer, Wszolek and Ebadi, 2012).
PD symptoms
Though PD is primarily a motor disease, it also presents a large number of non-motor symptoms. In other words, PD is characterized by a wide range of symptoms, which reflect the dissimilar and diffused pathology within the brain, as well as outside it (Zigmond, Coyle and Rowland, 2015).
The clinical heterogeneity of PD is determined by a variety of symptoms, due to the different age and form of the symptomatology’s onset, the different course of the clinical condition, the different degree of functional disability that is caused to each patient, and the different response in the treatment or the different side-effects each patient may experience (Rosenbaum, 2006). In the “puzzle” of the disease’s clinical condition, the symptoms-effects of medication are subsequently added, resulting in the triple combination of symptoms (motor, non-motor and side effects) (Pfeiffer, Wszolek and Ebadi, 2012):
Primary motor symptoms make their appearance when the degenerative process has destroyed much of the neurons in the substantia nigra and has greatly reduced the dopamine in the striatum. They includes resting tremor, stiffness, bradykinesia (with stillness and freezing in the latter disease’s stages), and balance disorders (Nuytemans et al., 2010).
Other motor symptoms: difficulty in swallowing, and speech disorders among others (Nuytemans et al., 2010).
Non-motor symptoms include mental disorders, and disorders of the autonomic nervous system among others (Chaudhuri et al., 2014).
Other non-motor symptoms: numbness, sleep disorders, olfactory dysfunction and hyposmia or rhinorrhea, fatigue, and excessive sweating (Chaudhuri et al., 2014).
Symptoms due to drugs’ side effects: both motor type and non-motor type symptoms (Stokes, 2004).
PD stages
Five stages are distinguished starting from the presymptomatic disease period (Rosenbaum, 2006).
In the 1960s, Hoehn and Yahr published a detailed description of the progression of PD and a scale, which has been widely used since then (yet modified since 1967) (Rosenbaum, 2006).
The modified scale of Hoehn and Yahr is as follows: Stage 0: no sign of the disease; Stage 1: unilateral disease; Stage 1, 5: one-sided attack on the torso; Stage 2: bilateral disease without disequilibrium; Stage 2, 5: slightly bilateral disease; Stage 3: slight to moderate disease but with the ability for daily care; Stage 4: severe disability but with the ability to move without assistance; and Stage 5: wheelchair, and need for help from others (Rosenbaum, 2006).
Subsequently, Schwab and England presented an additional scale to quantify the stages of the disease. Their scale of daily activities is as follows: 100 %: capacity for all; 90 %: capacity for all but in a somewhat slow and difficult manner; 80 %: capacity for most activities; 70 %: partial capacity with greater difficulty in minor activities; 60 %: most minor activities are done with greater fatigue and sluggishness; 50 %: relative dependence on others, while assistance is needed for at least half of the daily activities; 40 %: high dependence, while assistance is needed in almost all minor activities; 30 %: some minor activities are done or started with great effort, while assistance is again needed; 20 %: severe disability, while nothing can be done without help; and finally, 10 %: complete disability (Freed, 2000).
PD causes
Pathological-anatomical factors
Pathologically, PD is attributed to the loss of the dopaminergic neurons from the pars compacta of the substantia nigra, resulting in the dopaminergic deficiency in the striatum (Zigmond, Coyle and Rowland, 2015).
Though there is a physiological loss of dopamine with the progress of age (calculated at a rate of 5-8 % per decade) this loss is profound in PD. A loss of about 80 % of the dopamine is required for the symptoms of the disease to be manifested (Zigmond, Coyle and Rowland, 2015).
Hereditary factors
Concerning hereditary predisposition, it is considered that first-degree relatives of patients with PD present 3-4 times greater risk of developing the disease (Zigmond, Coyle and Rowland, 2015).
Environmental factors
In 1979, an environmental neurotoxin toxin, MPTP (1-methyl 1-4-phenyl 1-1, 2, 3, 6-tetrahydropyridine) was found, which by means of conversion into a metabolite, selectively destroys the dopaminergic neurons of the substantia nigra (Zigmond, Coyle and Rowland, 2015).
Genetic factors
While most patients exhibit the disease sporadically, it is now known that there are familial forms of the disease with autosomal dominant or recessive inheritance. Six genes are implicated to date in the pathogenesis of the disease (α-synuclein (SNCA), parkin (PARK2), UCHL1 (PARK5), DJ-1 (PARK7), PTEN-induced putative kinase 1 (PINK1), and leucine-rich repeat kinase 2 (LRRK2) (Nuytemans et al., 2010).
It is interesting that the proteins encoded by the first three genes are directly related to the function of the proteasome either as active parts (parkin and ubiquitin) or as degradable by it as popia (a-synuclein). This discloses the involvement of the ubiquitin-proteasome system in the pathogenesis of PD (Klein and Westenberger, 2012).
A-synuclein, a protein consisting of 140 amino acids, is as a gene located on the long arm of chromosome 4 (4q21). An over-expression of a- synuclein may cause PD due to a triplication of a-synuclein gene. Particular features of PD due to the mutations in the a-synuclein gene constitute the autosomal dominant inheritance of the disease (Nuytemans et al., 2010).
Parkin, on the other hand, is an E3-ligase consisting of 465 amino acids. Mutations in the parkin gene cause the autosomal recessive juvenile PD form. The main features of this PD form are the juvenile age onset (during the second decade of life), the brief appearance of dyskinesia due to treatment with L-DOPA and the absence of Lewy bodies in the substantia nigra (Klein and Westenberger, 2012; Nuytemans et al., 2010).
Genetic linkage studies have also revealed PD’s association with other loci. One of them is the DJ-1 gene (PARK7), whose mutations are linked with PD’s autosomal recessive form at an early onset (Klein and Westenberger, 2012; Nuytemans et al., 2010).
Gene PINK1 (located at locus PARK6) is associated to patients with an autosomal dominant form of hereditary PD and small age of onset. It encodes a protein with the serine-threonine kinase activity, which is normally found in the mitochondria (Klein and Westenberger, 2012; Nuytemans et al., 2010).
The LRRK2 gene, located at locus PARK8, encodes protein LRRK2 or DARDARIN, a kinase, which lies mutated in about 1.6 % of the patients with idiopathic PD and in 5-6.6 % of the patients with familial PD. The heritability of the disease in patients with the LRRK2 gene mutations follows the autosomal dominant type. Its clinical picture is characterized by typical disease manifestations and a satisfactory response to L-DOPA treatment. Characteristic are the diverse pathologist conditions with or without the presence of Lewy bodies and the occasional presence of Tau protein (neurofilament) accumulations (Klein and Westenberger, 2012).
Additionally, other regions of the genome that may comprise of genes associated with the disease (chromosomes 5,8,9,10,16 and 17), while several polymorphisms in genes (e.g. NR4A2, Tau, SYNPHILIN 1) have been found, which serve as genetic risk factors in PD’s sporadic forms (Klein and Westenberger, 2012).
PD prevalence
PD’s overall prevalence ranges from 70 to 180 cases per 100,000 people (about 0.2 % of the population). PD increases with the lapse of ages, affecting about 0.5-2 % of persons aged over 70 (Rosenbaum, 2006). An epidemiological study conducted on London patients, showed that the disease’s prevalence has remained stable over the last 30 years, despite the reduction in the mortality of patients aged below 75 years (Pfeiffer, Wszolek and Ebadi, 2012).
PD affects about 1 % of Americans over the age of 50 years and is uncommon in people younger than 40 years. The number of patients with PD in the United States is estimated at 1 million (about 1 in 272 or 0.37 %), while each year 50,000 new case are diagnosed (Pfeiffer, Wszolek and Ebadi, 2012).
Prevalence varies in different regions from 14 people per 100,000 in China to 328 people per 100,000 in Mumbai, India. Asians and Africans are impacted to a lesser extent in relation to African-Americans, and especially whites (Rosenbaum, 2006). In the past, it was considered that the disease affected almost exclusively whites, but recent studies have shown similar prevalence rates among African-Americans and Whites living in the same geographical area. The variations in the disease’s prevalence in the same tribal groups living in different geographical regions have formulated the hypothesis that people, who are located in rural areas, have a higher risk of disease due to their exposure to pesticides and insecticides (Pfeiffer, Wszolek and Ebadi, 2012).
The disease’s incidence is approximately 20 new cases per 100,000 people annually. Undiagnosed early symptoms are present in a proportion of about 10 % of people over 60 years. Therefore, the disease remains undiagnosed for an estimated of 10-20 % of all patients (Pfeiffer, Wszolek and Ebadi, 2012).
On the other hand, PD’s early onset, which occurs under the age of 40 years, is rare and affects about 5 % of all cases. Idiopathic PD that starts before the age of 21 is extremely rare and includes two separate and distinct situations: juvenile Parkinsonism and DOPA-responsive dystonia. Juvenile Parkinsonism occurs more frequently in Japan (Pfeiffer, Wszolek and Ebadi, 2012).
Regarding gender, men are affected more frequently than women (3:2). Before the discovery of levodopa, the disease was associated with a high mortality rate with an average life expectancy of 10 years (Rosenbaum, 2006). After the discovery of levodopa and other anti-Parkinson drugs, life expectancy has increased significantly almost approaching normal limits (Pfeiffer, Wszolek and Ebadi, 2012).
PD’s epidemiology and death rate world maps are presented below:
Figure 1. Age-standardized disability-adjusted life year (DALY) rates from Parkinson disease by country (per 100,000 inhabitants) in 2010 (Wikimedia Commons, 2010)
Figure 2. Age-standardized death rate from Parkinson disease by country (per 100,000 inhabitants) in year 2014 (World Life Expectancy, 2016)
PD diagnosis and treatment
Parkinson’s diagnosis is mainly clinical and is based on the person’s medical history and on their physical examination. Positron emission tomography (PET) is used to determine the concentration of dopamine in the striatum, which serves as an indication of an increased probability of presymptomatic PD. This finding, however, of a reduced concentration of dopamine is not an exclusive PD feature (Pfeiffer, Wszolek and Ebadi, 2012).
Since the first description of PD until today, specialists insist on publishing new data, surveys and contemporary data for its treatment, as for example with medication, surgery with various stimuli, brain stimulation and gene therapy via genes’ implantation to the brain. Finally, alternative treatments exists, though with low success rates, and mainly for the relief of some of PD’s symptoms (Pfeiffer, Wszolek and Ebadi, 2012).
PD social impacts
PD is a serious disease which evolves for a long time. Its social impact is significant and painful. The world, for the patient and their family environment, changes. The daily activities are limited and interpersonal relationships are tested. The patient and their family need information, guidance and support on many levels. For this reason, in all developed countries, diverse organizations have been established by patients and their relatives or other interested parties at national level and on a voluntary basis, giving information in relation to the disease via brochures, videos, and publications in the media and on the Internet (Belgum, 2008).
PD ongoing research
Research on PD’s diagnosis prior to its emergence
An expert group working under the auspices of International Parkinson and Movement Disorder Society (MDS), have developed a new tool for health professionals, which they hope will mark a breakthrough in PD’s diagnosis and treatment, namely, in the early stages. The study’s new tool, consisting of new diagnosis criteria, was published in the journal Lancet Neurology in 2016 (Postuma et al., 2016).
The new criteria originate from the data collected by experts on the movement disorder and are aimed at PD’s earlier diagnosis, and particularly in the early stages. The creation of this new criteria list for PD’s clinical diagnosis was enabled in light of the latest scientific knowledge and technological progress of the past 20 years (Postuma et al., 2016).
The goal was to develop a reference point, based on which the diagnostic procedure will be systematized. The focus was on identifying the characteristics that mark the disease’s presence at an early stage. The current goal is for this diagnosis to become officially accessible in Medical Centers and to allow for PD’s more accurate diagnosis by a wider range of non-specialists in PD doctors (Postuma et al., 2016).
It has to be noted that the diagnosis criteria include the already used synuclein deposition (which remains the basic PD arbiter), as well as genetic cases associated with PD (explained previously), which, however, have no synuclein deposition on autopsy, yet do not include dementia. This method’s innovation lies in its statistical approach, according to which the criteria incorporate the following steps: a) prodromal PD’s possibility of is estimated based on the person’s age; b) diagnostic information include environmental and genetic risk variables, biomarker testing or even prodromal symptoms and signs (likelihood ratios are applied to each variable); and c) if the variables’ multiplication, i.e. if their total likelihood ration exceeds the 80 % probability threshold, then the patient is diagnosed with prodromal PD (Postuma et al., 2016).
The first advantage of this new method is its positive impact on PD’s more effective diagnosis. The method’s second advantage lies in PD’s prodromal diagnosis, which has up to now been at a rather infant stage. Another advantage is that the method is evidence-based, since it allows for PD’s quantifiable diagnostic accuracy. Finally, the particular method serves as the basis upon which new diagnostic tests can be added as the research on PD progresses (Postuma et al., 2016).
Currently, PD’s diagnosis can only be demonstrated by the patient’s medical history and their neurological examination by a doctor with experience in movement disorders. There is no objective test for the particular disease, while and since PD’s symptoms often resemble symptoms of other neurological disorders, the rate of misdiagnosis is high, causing great discomfort to patients. This discomfort is to be, thus, greatly relieved by the establishment of the present diagnosis method (Postuma et al., 2016).
Research on a device administering medication via remote control
A group of researchers at the School of Medicine (in Washington University in St. Louis) and the University of Illinois at Urbana-Champaign have discovered a wireless device, the size of which is equal to the width of a human hair. This device can be implanted in the human brain and be activated by remote control, so as to administer the medication to the PD patient (Washington University in St. Louis, 2015).
This device technology was first demonstrated in mice, and its researchers claim that it can be used in the treatment of pain, depression, epilepsy and other neurological disorders by targeting specific brain circuits (Washington University in St. Louis, 2015).
The device’s base is derived from earlier optogenetics research. This optogenetics technology operated by making a single set of brain cells sensitive to light. Because it is still not easy and practical to modify and redesign the neurons of the brain, researchers have created the above explained tiny wireless devices that are capable of delivering the drug directly to the brain, with the simple push of a button (Washington University in St. Louis, 2015).
The above research is an important step in pharmacology’s evolution, while its application is expected to facilitate PD patients become less dependable on others for their medication’s administration. Thus, it is overall, it is expected to make PD patients’ daily routine easier (Washington University in St. Louis, 2015).
Conclusions
The more promising of the two researches seems to be the one on PD’s diagnosis prior to its emergence, since it will help treat the symptoms of PD prior to its actual manifestation, thus, allowing for its most severe symptoms never to evolve. This will provide relieve PD patients from having to depend on others in their daily chores, thus, potentially eliminating the need for the development of devices such as the one detailed in the second research. The overall impact on society is also expected to be profound, since both the incidences and death rate of PD patients will be decreased, while concurrently PD patients’ families will still see their beloved ones living a more normal and autonomous life.
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