A SEMINAR PRESENTATION

ON

CURRENT TRENDS IN ETIOLOGY, PROGNOSIS AND THERAPEUTIC ASPECTS

OF PARKINSON’S DISEASE

BY

BABALOLA OPEYEMI OLUWAPELUMI

(183402)

IN PARTIAL FULFILLMENT OF THE

REQUIREMENTS FOR THE AWARD OF BACHELOR OF TECHNOLOGY

(B.TECH) IN ANATOMY.

TO

DEPARTMENT OF ANATOMY,

FACULTY OF BASIC MEDICAL SCIENCES,

LADOKE AKINTOLA UNIVERSITY OF TECHNOLOGY

P.M.B 4000, OGBOMOSO, OYO STATE.

JANUARY, 2024.
 TABLE OF CONTENTS

TITLE PAGE I

TABLE OF CONTENT II

CHAPTER ONE

1.1 INTRODUCTION 1

CHAPTER TWO

2.1 PARKINSON’S DISEASE (PD) 3

2.1.1 EPIDEMIOLOGY 4

2.1.2 RISK FACTORS 5

2.1.3 NEUROPATHOLOGY 5

2.1.4 CLINICAL MANIFESTATIONS 5

2.2 MOTOR NEURON AND DOPAMINE CONTROLS 7

2.2.1 MOTOR SYMPTOMS 7

2.2.2 NON-MOTOR SYMPTOMS 10

2.3 TREATMENT 14

2.3.1 DRUGS AND THE TREATMENTS 15

2.4 RECENT THERAPY 17

2.4.1 ACTIVE IMMUNIZATION THERAPY 18

2.4.2 REHABILITATION 18

CHAPTER THREE

CONCLUSION 20

REFERENCE
 CHAPTER ONE

INTRODUCTION

1.1 BACKGROUND OF STUDY

Parkinson’s disease (PD) is a complex progressive neurodegenerative disease characterized

by tremor, rigidity, and bradykinesia, with postural instability appearing in some patients as

the disease progresses. It was first described by James Parkinson in 1817 and further

characterized by Jean-Martin Charcot, and our knowledge of PD is continuing to expand.

PD is the second most common neurodegenerative disease after Alzheimer’s disease (AD)

(Kalia and Lang, 2015), with a prevalence of approximately 0.5–1% among those 65–69

years of age, rising to 1–3% among persons 80 years of age and older (Tanner and Goldman,

1996; Nussbaum and Ellis, 2003). With an aging population, both the prevalence and

incidence of PD are expected to increase by more than 30% by 2030 (Chen et al., 2001),

which will result in both direct and indirect costs on both society and the economy as a

whole.

PD is pathologically characterized by the loss of nigrostriatal dopaminergic innervation,

although neurodegeneration is not limited to only the nigral dopaminergic neurons but also

involves cells located in other regions of the neural network. Such a widespread pathology

makes PD a very heterogeneous disorder, and a reliable diagnostic test is not yet available.

Currently, diagnosis is based on clinical symptoms with the criteria for a diagnosis requiring

the presence of two of the following clinical features: resting tremor, bradykinesia, rigidity

and/or postural instability. Clinical criteria, however, can only lead to a diagnosis of probable

PD, while a definitive diagnosis requires histopathological assessment, with the identification

of α-synuclein-containing Lewy bodies (LBs) or Lewy neurites.Treatment predominantly

focuses on symptomatic relief with drugs aiming to either restore the level of dopamine in the

striatum or to act on striatal post-synaptic dopamine receptors. However, as dopamine is not

1
the only neurotransmitter involved in PD, many other drugs are also being used to target

specific symptoms, such as depression or dementia. Yet, further investigation on novel

therapies to reduce the rate of neurodegeneration or even to replenish the loss of

dopaminergic cells remains in the research setting, with some in the early stages of clinical

trials. As our understanding of the pathogenesis of PD increases and more is learned about

new therapeutic targets, the potential for the development of disease-modifying therapies is

promising.

PD is a multifactorial disease, with both genetic and environmental factors playing a role.

Age is the biggest risk factor for PD, with the median age of onset being 60 years of age

(Lees et al., 2009). The incidence of the disease rises with age to 93.1 (per 100,000 person-

years) in age groups between 70 and 79 years (de et al., 1995; Bower et al., 1999).

Additionally, there are cross-cultural variations, with higher prevalence reported in Europe,

North America, and South America compared with African, Asian and Arabic countries

(Kalia and Lang, 2015).

2
 CHAPTER TWO

LITERATURER REVIEW

2.1 PARKINSON’S DISEASE(PD)

Parkinson’s disease (PD) is a chronic disorder of the central nervous system with symptoms

appearing gradually with the increase in age. PD was first described by James Parkinson in

1817 and he explained in an essay titled as “shaking palsy”. In the late nineteenth century, the

description of the disease was further refined by Charcot based on the cardinal clinical

features (Josephs et al., 2006).Loss of nerve cells in the brain leading to PD is known as

substantia nigra. These nerve cells make up the neurochemical messenger of dopamine,

which is responsible for all messages that coordinate normal movement. The lack of

dopamine in a PD patient’s brain cells, leads to motor complications and the progress turns

out to be slow, gradually expanding over years. Commonly occurring cardinal motor

symptoms in PD patients, includes resting Tremor, Rigidity Akinesia and Postural instability

(TRAP) (Ene et al., 2008). Assessments of PD manifestations are done using foot pressure

analysis, finger motion analysis and the Unified Parkinson’s Disease Rating Scale (UPDRS)

are (Kostek et al., 2012). Treatment options for PD patients are limited and primarily focused

to reduce the disease symptoms (Tian et al.,2011. In near future, this disease will in course

occupy a dominant place in research, due to its treatment modality and medical expenditures

involved (Gil et al.,2009). Recently, researchers have been focusing on the non-motor

symptoms (NMS) of PD which are not documented and thereby ineffectively cured through

physicians. Non-motor symptoms (NMS) include depression, social phobias, low blood

pressure, apathy, loss of sense of smell, fear and anxiety, panic attacks, which are due to the

mild lesions of the meso-limbic and meso-cortical pathways (Janakiraman et al.,2016). PD

patients generally are seen to have NMS, observed much before motor symptoms, and it

3
would really help if we recognize these symptoms as a part of PD symptoms and address to

it. It is hard to choose the right medication and treatment as PD patients with NMS do not

respond to medication prescribed for NMS (ModugnoN et al.,2013). Stress is considered to

be another cause of PD, but the mechanism is still unknown (Swaab et al.,2005). Various

studies have concluded that stress induced neural effects are progressive to various

neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease and

Parkinson’s disease. Psychological stress in humans due to depression, anxiety and impaired

cognition is the primary cause of PD. About 40-50% of all PD cases are caused due to

depression (Aarsland et al., 2009) and it has been reported that acute or chronic stress might

lead to an earlier onset of this disease (Goetz et al., 1990; Treves et al., 1990; Smith et al.,

2002). Recently Hemmerle et al. (2014), demonstrated that chronic stress-induced depression

potentially impairs the behavioral dysfunction and dopaminergic degeneration of nigrostriatal

system, rather than neurotoxin-induced neurodegeneration.

2.1.1 EPIDEMIOLOGY

PD normally affects about 1-2% of the world population, where the estimated incidence rate

is found to be 20/100,000 and approximate prevalence rate is about 150/100,000. The current

estimation shows 1.5 million people being affected by this disease in US (Booby and Beal,

2007; Schapira, 1999). Men are one and half times more prone to have this disease. European

survey reported the rate of prevalence between 100 and 200 per 100,000 inhabitants (Dawson

et al., 2003). In Norwegian Park West survey, they calculated the age-standardized incidence

to be 12.6 per 100,000 (Betarbet et al., 2000). Most studies reported the incidence of PD to be

more common in rural population (Warner et al., 2003). Overall male to female ratio was

found to be 1.58 based on published prevalence studies, reported by the Norwegian Park

West

4
2.1.2 RISK FACTORS

The two types of risk factors include genetic and non-genetic risk factors. There is no reverse

linkage between smoking and this disease and also consumption of coffee was found to

decrease the risk of PD. Even the dietary factors like fatty acids and antioxidants are under

investigation. A presence of genetic mutation is stipulated to show a risk for developing PD

(Deet al., 2006). A recent study has also showed some results where risk of PD was increased

after a stroke. Thus, ischemia plays a role in the development of cognitive decline (De Lau et

al., 2006).

2.1.3 NEUROPATHOLOGY

Gliosis and cell loss in nigrostriatal neurons are interestingly the gold standard for the

diagnosis of PD. In 2003, Braak and colleagues hypothesized that disease concerned

pathology develops in a logical sequence. The Primary stage consists of levels-I & II, where

lesions occur in the anterior olfactory nucleus, the dorsal motor nucleus of the IX/X nerves,

the raphe nuclei and the reticular formation. In later stages three and four, the pathology is

restricted to the brainstem and anteromedial temporal mesocortex. The chief characteristic of

this stage is that the substantia nigra gets affected. Stage five and six is consists of the acute

involvement of the brain including most of the neocortical areas (Braak et al., 2003).

2.1.4 CLINICAL MANIFESTATIONS

The four cardinal signs of Parkinson’s disease are tremor, rigidity, bradykinesia and postural

instability (Smith et al., 2008). Postural instability may be the most debilitating feature (Tien

et al., 2010) and leads to further disability. Mostly it can be defined as the disability to

maintain the body’s centre of gravity over the base of support during standing and also during

movement (Nocera et al., 2009) and is essential for any locomotors activity. Further, patients

lack the coordination of biomechanical, sensory, motor and the central nervous systems

5
 Mask like
facial Front bent
Drooling expression head

Rigidity Tremor
CLINICAL
(head)
SYMPTOMS OF
PARKISON’S
DISEASE
Shuffling and
propulsive gait Weight loss

Demineraliza Loss of
tion of bone postural
instability

Fig 2.1.4. Clinical Symptoms of Parkinson’s Disease.

6
2.2 MOTOR NEURON AND DOPAMINE CONTROLS

The motor disability symptoms of Parkinson’s disease result from the loss of dopamine -

secreting (dopaminergic) pigmented cells, in the pars compacta region of the substantia nigra

(literally “black substance”). The substantia nigra is a very small area located deep within the

brain and in PD patients these dopaminergic neural cells of substantia nigra degenerates and

dies, only few live neurons in this region are observed in PD brain tissues than in the normal

brain tissue. The loss of dopaminergic neurons leads to the loss of dopamine and dopamine is

the major neurotransmitter which relays neuronal signals from the brain to other motor

centers. The lack of dopamine in PD patients disturbs the movement control of the patients

(motor symptoms) and mood, behavior, thinking and sensation of the patients (non – motor

symptoms).

2.2.1 MOTOR SYMPTOMS

Tremor

Tremor is one of the common symptoms and moreover first symptom of Parkinson’s disease

which is observed in >70% of the PD patients. Typically the tremor in PD patients starts at

one limb and may spread to another on the same side of the body before proceeding to the

other side. The progression of tremor is gradual which could affect the arms, legs, feet, lips

and head. These tremors, or shakes most likely occur in the resting condition and this

symptom could disappear when the patient is actually moving. For many PD patients tremor

is one of the most distressing symptoms due to its psychological impact when exposed to the

society and also this symptom can become worse if a patient is anxious or excited.Tremors in

PD patients are unilateral which normally occurs at a frequency between 4 and 6 Hz, and

most of the time they are prominent in the distal part of the extremity. Some PD patients have

a history of postural tremor for many years before the onset of parkinsonian tremor or other

7
PD related features and this postural tremor is symptomatically identical to essential tremor

(Kara et al., 2012).

Stiffness (rigidity)

Rigidity or resistance to movement affects most of the Parkinson’s disease patients. The

principle behind the body movement is coordinated by two muscles where one will be an

opposing muscle. Hence the movement is achieved by one muscle that becomes active and

the opposing muscle relaxes. In Parkinson’s disease, the rigidity originates due to the

disturbed response to signals from the brain, which leads to the disturbance of the balance of

opposing muscle during the muscular coordination. The relaxation of the muscle during a

movement is disturbed, which makes the muscles to remain constantly tensed and contracted

and hence the patient arches or feels stiff or weak. The rigidity turns out to be a noticeable

one when another person tries to move the patient’s arm, which will display a ratchet – like or

short, jerky movement known as “cogwheel” rigidity.

Reinforcing maneuvers (e.g. Voluntary movements of the contralateral limb), known as the

froments maneuver (Shahed et al., 2007) usually increases rigidity and are particularly useful

in detecting mild cases of rigidity. Rigidity may be associated with pain, and painful

shoulder, although it is commonly misdiagnosed as arthritis, bursitis or rotator cuff injury

(Broussolle et al., 2007).

Slowness of the movement (bradykinesia)

Due to the lack of Dopamine, the signals from the brain to the muscles slowdown, that leads

to Bradykinesia (slowness of the movement) Bradykinesia slows down day to day activities

of the patient, such as walking, bathing or dressing etc, and this is very disabling as it

interferes routine life style. The patient may begin to shuffle (called festination) and their

walking steps become shorter and shorter and more likely they will have problems like

starting and stopping and turning while walking and some patients may feel to be falling

8
forward. All these walking complications are known as “Parkinson’s gait.” Bradykinesia is

considered to be a hallmark of basal ganglia disorders, and it includes difficulties with

planning, initiating and executing movement and with performing sequential and

simultaneous tasks (Riley et al.,1989).

Loss of balance (postural instability)

The posture and balance maintaining ability would be disturbed, which could lead to

instability while walking, turning, standing or when performing actions such as rising from a

chair or bending over. These unsteady movements lead to a fall, which is a major cause of

injury in PD patients. Several other parkinsonian symptoms such as orthostatic hypotension,

age related sensory changes and the ability to integrate visual, vestibular and proprioceptive

sensory input (kinesthesia) (Berardelli et al., 2001; Bronte-Stewart et al., 2002).

Speech and facial expression

PD patients have reduced facial expression that can lead to communication difficulties,

disinterest, or as a lack of understanding, vocal change including speedy or rough speech.

Fatigue

Fatigue resulting from physical or mental tiredness is very common. Fatigue can be caused

by one or more factors, including drug treatment, disturbed sleep or depression. Alternatively,

fatigue may be caused directly by the chemical changes that occur in the brain of PD patients.

If it is found to be associated with depression, the depression should be treated; if it is caused

by sleeping problems, then that should be assessed and treated.

2.2.2 NON-MOTOR SYMPTOMS

Mood/Depression

Mood change or depression is a natural feedback, commonly diagnosed due to lower level of

signals in the PD brain that control the mood. Signs of depression include: a negative view of

9
oneself, the environment and the future, loss of motivation, energy and interests (including

social and sexual), poor sleep and memory, and a decreased hunger. Depression is one of the

most common non-motor symptoms of PD, affecting over 40 percent of the patients (Adkin

et al., 2003). Depression is difficult to be characteristically identified in the clinical practice

as it overlaps with many other signs and symptoms of PD. The depression in the PD patients,

may cause major interference with the quality of life, but often might involve less severe

symptoms with more understated features for which the clinician should be prepared.

Pain

Most of the patients develop muscle and joints pain. Mostly pain seems to increase with

duration of disease, severity, depression or dopaminergic therapy. PD is directly related to

pain (e.g. dystonia when ‘off1) or pain can also be unrelated to PD (e.g. osteoarthritis or

neuropathic pain) (Shulman et al.,2002).

Sleep problems

Sleep problems being a preclinical marker in PD (Ha et al., 2012) includes difficulty staying

asleep at night, restless sleep, nightmares, emotional dreams and drowsiness or sudden sleep

onset during the day. Rapid eye movement (REM) sleep behavior disorder is characterized by

loss of muscle atonia allowing patients to physically act out their dreams. Injury to the patient

or bed partner is not unknown.

Difficulty with swallowing and chewing

Muscles used in swallowing may work less efficiently and food and saliva may collect in the

mouth and the back of the throat, which can result in choking or drooling. These chewing and

swallowing difficulties may lead to malnutrition to the patient.

Skin problems

In PD, improper functioning of autonomic nervous system, causes oily skin specifically on

the T region surrounding forehead, and nose and also causes dandruff as well.

10
Urinary problems or constipation

Due to the improper functioning of the nervous system, bladder and bowel problems can

occur in some patients and also experience problems with urinating and others might become

incontinent. As the intestinal tract operates more slowly, poor diet or less fluid intake are the

major factors for constipation. Sometimes medications are also used to treat PD and

contribute to constipation. If the problem is serious and persistent, then the patients require

hospitalization in rare cases. Constipating patients are encouraged to consume more fluid and

fiber intake for stool softness, macrogel 3350 and electrolytes for consumption (Chaudhuri et

al., 2003).

Diagnosis

Diagnosis of PD is the main challenge for the scientists and the clinicians. The disease is

sometime underdiagnosed (Emre, 2003) while misdiagnosis occurs owing to drugs, Wilson’s

disease and other neurological disorders. Due to misdiagnosis, approximately 10-20% of

people suffer from PD. The data for the diagnosis of PD is usually made with the help of the

patient’s history and physical examination of the patient. Early onset of Parkinson’s disease

in patients may include slowness in walking, tremor, imbalance even when the neurological

examination is normal (de Rijk et al., 1997). The infrequent occurrence of tremor at rest is 4-

6 Hz. but it is also absent in up to one quarter of cases.. Initially 90% of patients have a

response to levodopa drug, whereas the remaining 10%, serve to be the main lead to opt for

alternative diagnosis. To date, there are no biological markers available to confirm the

diagnosis of the PD. The presymptomatic patients are undergoing irrelevant treatment

because of inaccurate diagnosis of PD. To overcome this problem, it is of prime importance

to find biomarkers, imaging techniques and laboratory based clinical assays. Routine imaging

studies of brain, PET, single photon emission tomography (SPECT) and functional imaging

11
techniques are helpful in differentiating Parkinsonism with 95% accuracy (Van Laar et al.,

2004).

One of the potent features of the diagnosis is dementia and its presence shows that survival

rate lessens in PD patient. Based on the large population based survey in Norway population,

28% of the patients encountered dementia (Suchowersky et al.,2006). These results have high

sensitivity, but care should be taken while distinguishing the idiopathic PD. In another study,

65% of the surviving cohorts experienced dementia. The diagnosis was also strengthened by

the assessment of The Unified Parkinson’s Disease Rating Scale assessment which in turn

strengthened the PD diagnosis. The physical and mental symptoms are the major criteria for

diagnosis, which have an influence on the quality of life (QoL) of patients with PD (Marek et

al., 2003). One of the physical symptoms of PD is also called “Parkinson’s mask” (Mayeux et

al., 1990).

12
Fig 2.2. Parkinson disease symptoms.

13
2.3 TREATMENT

Pharmacotherapy

The standard treatment approach is oral based pharmacotherapy and recently they focussed

on the surgical alteration of the brain region associated with PD. Surgical treatments are

proceeds only on selected patients with approximately 8-10% of success (Thacker et al.,

2008). Generally, pharmacotherapies are related to monoamine neurotransmitter imbalances.

There are several drugs available to treat motor impairments in PD like, carbidopa/levodopa

and pramipexole and ropinirole (Weiner et al., 2008; Stephenson et al., 2009). These drugs

are able to modify the imbalances in dopamine producing neurons in PD patients.

Pharmacotherapies are very effective within short course time, along with side effect like

levodopa induced dyskinesias (LIDs) (Tarazi et al., 2014) and additionally optimized dosage

of individual patient might lead to increasing motor fluctuations resulting in “wearing off”

periods (Kalinderi et al., 2011). Upper and lower limbs will respond to the dopomeric

treatment where there is limited response from axial symptoms. There are significant

responses to levodopa for axial and appendicular rigidity in PD patients. Besides levodopa

executes significant effect on appendicular system (knees, arms, wrists) and on the other hand

exerted insignificant effect on rigidity in the axial system (trunk, torso) (Poewe et al., 2009;

Wright et al., 2007).

During the early stage of disease progression, appendicular symptoms and non-dopaminergic

axial symptoms occur. In extended stages non-dopaminergic systems (frontal cortex and

cerebellum) are further affected (Connolly et al., 2014; Maillet et al., 2012; Ferrara et al.,

2010). For better understanding novel interventions and replacement of oral medication for

betterment of quality of life are needed. One of the studies reported 21 PD participants who

underwent STN-DBS surgery, established that there were major improvements in the energy

14
levels, and possible relief for a yearpost-operation, mainly due to the lesser dose of

medication with neurostimulation (Horstink et al., 2006)

2.3.1 DRUGS AND THE TREATMENTS

Currently, no permanent treatment against PD is available. Only medication and surgery will

provide relief from the PD symptoms. Thirty years ago, approximately about 50,000 people

were diagnosed with PD per year. The only drug that was available at that time was

Levodopa – a chemical compound that the body can convert into dopamine. This helped

many of the PD patients to survive, but the long term use of this drug resulted in the

uncontrolled movements. Brain surgery of the destroyed regions also is an alternate mode of

available treatment other than the drug therapy. Recently several new drugs have been

introduced other than the Levodopa as a treatment outcome for PD patients. PD medications

fall under three distinct categories that help in controlling the disease and ease the effects of

PD. Drugs that work directly or indirectly to increase the level of dopamine in the brain that

include dopamine precursors like levodopa make up the first genre of PD drugs. It crosses the

blood brain barrier and triggers dopamine secretion. The second type of PD drugs affects

other neurotransmitters in the body in order to control the disease. Drugs like anticholinergic

agents are an excellent example that interferes with the production or uptake of the

neurotransmitter acetylcholine. These drugs help to reduce tremors and muscle stiffness,

which can result from having more acetylcholine than dopamine in the system. The third type

of drugs prescribed for PD includes medications that help control the non–motor

symptomatic effects of the disease. Other drugs mimic dopamine or prevent or slow its

breakdown.

15
Fig2.3.1. Current therapy for PD

16
2.4 RECENT THERAPY

Gene therapy

Gene therapy is one of treatment options where human gene therapy is implemented in

somatic cells. Generally with gene modifications by either over expressing or inhibiting

particular target genes can restore the normal function of these genes. Currently, there are two

types of vectors are used in gene therapy, such as viral mediated vectors, and nonviral

systems. In viral vectors, it can transport the genetic material to target cells. Non-viral vector

delivers the genes to the CNS by physical and chemical methods like a gene gun or

electrophoresis. Various kinds of vectors have been constructed with differing by their

packaging capacity, tropism, and immunogenicity. Adeno-associated virus (AAV) and

lentivirus derived vectors are under CNS gene therapy clinical trials.

Stem cell therapy

Dopamine modulates transmission of signals in the highly specialized areas of the brain, like

the basal ganglia, concerned with the body and limb movements, which leads to tremors,

rigidity, freezing and slurring of speech.

Recent advances in stem cell research involves administration of genetically modified stem

cells which are able to produce dopamine and also can convert dopamine producing cells to

treat PD patients. Furthermore, in stem cell research, the mesenchymal cells are infused into

the part of the brain, where these cells are multiplied into healthy cells in substantia nigra,

resuming normal production of dopamine that helps in retrieving much of the normal

functions.

17
2.4.1 ACTIVE IMMUNIZATION THERAPY

Vaccination is being scrutinized to be the prospective or possible treatment for Parkinson

disease. This vaccination found to be a better option for these neurological diseases because

of the unusual administration, less production costs for the huge amount of people, etc. In

preclinical animal models of previous decade, there was progress in the active immunization

against alpha-synuclein (Schneeberger et al., 2016).

2.4.2 REHABILITATION

Other than pharmacological and surgery treatments, rehabilitation act as an adjuvant for less

complications and maximize functional ability in Parkinson disease. When compared to

physiotherapy, virtual reality technology leads to much improvement. It is a new

rehabilitation tool where it revives the movement by computer based in a virtual reality

environment. (Kim et al., 2016) A recent meta-analysis report identified that rehabilitation

could instigate short-lasting, but significant benefits for gait and balance. But rehabilitation

program should be organized as goal-based, where number of variables has to be identified

and program should be made according to the individual’s characteristics (Abbruzzese et al.,

2016).

18
Fig 2.4 Administration of Drug And Management Of PD

19
 CHAPTER THREE

3.0 CONCLUSION

This review highlights that there is a paucity of information about PD worldwide. There are

very few research groups working on neurodegenerative type of disorders. Diagnosis is of

paramount importance for clinical manifestation and treatment strategies for PD. Medication

and routine exercise, is primary to treatment strategies for this neurodegenerative disease.

The social and psychological issues in PD affected patients should also be considered and

might vary in individual patients. Therapies, such as deep brain stimulation and surgical

lesioning ought to be explored. Further research should be encouraged for the better

understanding of the disease involving its characteristics and etiology. Future scientific

research involving Parkinson’s disease might enlighten our knowledge of disease onset and

progression and can deliver some added aspects/components to help find more effective

therapies to improve quality of life of patients with PD.

20
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