FACULTY Treatment 5. Conclusion 1. Introduction Parkinson’s disease

FACULTY OF
ENGINEERING

DEPARTMENT
OF BIOMEDICAL ENGINEERING

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NEUROSCIENCE

PWADUBASHIYI
COSTON PWAVODI(MSC)

(20175356)

ASSIGMENT
ON

 

PARKINSON’S DISEASE

 

 

 

3RD
DECEMBER,2017

 

 

 

 

 

CONTENTS

1.     
Introduction

2.      Literature
Summary

3.      Neurotransmitter
Hypothesis

4.      Material
and Method

•      Where
are the receptors located in the brain

•      Diagnosis

•      Treatment

5.      Conclusion

 

 

 

 

 

 

 

 

 

 

 

1.     
Introduction

Parkinson’s disease is known to be
progressive disease with neurodegenerative effect on a person. It causes effects
to the brain, muscles, coordination and movement of a person. Parkinson’s (PD) has affected millions of people throughout the world from different cultures and races. This
disorder was named after the doctor James Parkinson who first described it in
1817. PD usually starts around the age of 60, but it can be detected 20years
earlier with diagnosis carried on. Early onset of the disorder is when it
begins before the age of 50 and these accounts for 5 to 10 percent of people
with PD. These forms of Parkinson’s are often inherited, eventhough they are
not related to genetic mutations. The disease
affects more men than women; however younger people
can be diagnosed with Parkinson’s too. This is referred to as Young Onset
Parkinson’s and also which is called juvenile Parkinsonism. It runs in families
and related to genetic mutation. Symptoms
of Parkinson’s disease are caused by the progressive degeneration of nerve
cells in the middle area of the brain. This causes a lack of
dopamine, a chemical messenger necessary for smooth, controlled movements. These
symptoms appear when 70 percent of these cells producing dopamine are damaged.
Parkinson’s disease cannot be cured, but the symptoms can be managed.

 

 

http://janeshealthykitchen.com/wp-content/uploads/2016/04/02-201251parkinson-full.gif?x59486

 

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What
Causes Parkinson’s?

Presently there is no known cause
Parkinson’s disease develops in a person. There are many theories
as to the causes and it is generally
thought that multiple factors are responsible for it. But Medical experts are not yet sure what destroys these nerve cells that produce dopamine or what conditions predisposes people to this
disease. Many other researchers think that this could be as a result of combination
of genetic and environmental factors and it may vary from person to person.

Genetics: This
cause of Parkinson’s disease is still unclear even though genetic mutations
increase a person’s risk of having the disease and passing it down to the children
through a faulty gene.

Environmental factors: Environmental factors also increase the chances of a person
having the Parkinson’s disease. Factors such as exposure to chemicals, like
pesticides, herbicides, industrial pollution and others.

Other causes of Parkinsonism: Parkinsonism’ is the umbrella term used to describe the
symptoms of tremors, muscle rigidity and slowness of movement. Parkinson’s
disease is the most common type of Parkinsonism, but there are also some rarer
types where a specific cause can be
identified. These include Parkinsonism caused
by:

Medication
(Drug induced Parkinsonism): Drugs such as
antipsychotic medication, when the intake is stopped, the condition improves.

Other progressive brain conditions: This condition of PD is
caused by other brain damage such as progressive supranuclear palsy, multiple
systems atrophy and corticobasal degeneration.

Cerebral
infarction: This case of PD is caused by a severe
stroke which causes several parts of the brain to die.

 

What
Causes Parkinson’s Symptoms Neurologically?

Parkinson’s disease (PD) also can be
seen as motor system disorders, which is as a result of the loss of brain cells
producing dopamine in the part of the brain called substantia nigra. This area
of the brain is able to communicate with the nerves and send messages down to
the muscles and also controlling them. They do these through chemicals called
the neurotransmitters. The Dopamine is the main neurotransmitter that is
produced by these cells in the substantia nigra
and also plays a vital role in regulating
and coordinating the movement of the body. The lack of the dopamine or
reduction in the amount leads to PD.

http://media.clinicaladvisor.com/images/2016/04/29/featureparkinsonsfig3150d_968815.png

 

https://mayfieldclinic.com/Images/PE-Parkinson_Figure1.jpg

 

 

 

PARKINSON’S
SYMPTOMS

Parkinson’s consists of many types of
symptoms which can be motor and non – motor. There are basically four important
motor symptoms and there are many other non-motor symptoms which are
also considered in the diagnostic process of this disease. They include symptoms such as pain,
depression, impaired memory, sleep disorders.

Tremor: This
is the most common symptom of Parkinson’s disease and its effects is seen affecting
body parts unilaterally, mostly common in the upper parts of the body and
progresses to other parts where there is tremor at rest. This is an early
symptom but also seen in about 70 Percent of people with the disease. Tremor is related to an imbalance of
neurotransmitters, dopamine and acetylcholine in the brain and in the body.

Slowness of movement (bradykinesia): Bradykinesia is a symptom that refers to slowness band
decreased movement, dysrhythmia and imbalanced gait. This affects everyday
activities and makes movements difficult.

Muscles
stiffness (rigidity): This symptom causes greater tension
in the tendon leading to the stiffness of the tendon. The stiffness can be
diagnosed by the doctor and sometimes not noticed by the patient. This makes
movement of muscles difficult and also causes muscle cramps.

Postural Instability: This symptom affects the posture of an individual thereby
causing flexion of the neck and leaning to one side. And this occurs in the
late phase of the disease.

Other Symptoms: They include: Anosmia, Anxiety, Constipation, Depression, Fatigue,
Festination of speech, Postural hypotension and Micrographia.1

 

http://www.easynotecards.com/uploads/980/56/_c65d1b7_157762adae7__8000_00000044.jpeg

 

https://skrischer.files.wordpress.com/2016/10/4884e7c347f2b13936d46ca87475e3b61.jpg?w=207&h=274

 

 

 

 

2.     
The Different Hypothesis of
Parkinsons Disease

André X. C. N.V.  et al.,2010 put forward a hypothesis in their
publication titled ‘A stem-cell ageing hypothesis on the origin of Parkinson’s
disease’ where they stated that parkinson disease also has a genetic origin
eventhough the cause of the disease is still unknown. This led them to
postulating a hypothesis from a mathematical framework named ‘The
hypothesis-rich framework” which they used in analyzing, profiling and
interpreting the PD blood gene expression of the data sets previously reported
(like the biological variables which are in the 22 283 gene expression probe
readings sample). They were able to construct a composite biomarker based on
the data to distinguish PD individuals form non-PD individuals. The biomarker
result that was analysed across the board presence of was able to show which genes
were known to play a role in  PD and
neurodegenerative processes. This led them to propose an integral presence of
PD in the blood and thus hematopoietic stem-cell defect can be the origin of
sporadic PD.2

Naomi P.V et al.,2013
in their paper titled ‘The prion hypothesis in Parkinson’s disease: Braak to the future’ reported on the Braak staging of Parkinson’s
disease. How Parkinson disease starts and also how it spreads from the origin
to the brain and manifesting with different symptoms. This hypothesis states
that the disease starts in the lower part of the brainstem and also in the
motor nucleus of the vagus nerve as well in the anterior olfactory structures.
The disease now moves upwards from the dorsal vagus nerve through the regions
of the part of the brain like the medulla, pontine tegmentum, midbrain and
basal forebrain and then finally reaches the cerebral cortex. The movement of
this disease is a nonrandom. progressive process with specific nuclei and
neuronal types involved and then develops into the lewy pathology which happens
in a stereotypic pattern. The severity and clinical manifestations of the
Parkinson disease increases as the disease continues to move upwards into the
brain through the brainstem. The idea of the Braak hypothesis is that the lewy
pathology that involves the movement of the disease into the brain is not random.
The cell types and neurons affected share common features and they are the
projection neurons which have long thin unmyelinated or poorly myelinated
axons. The neurons that are heavily myelinated are not affected because they
are resistant to the pathology. Eventhough
the brainstem is affected but that is not the site of the initial disease
starting. This affects also the peripheral nervous system and also the enteric
nervous system. This was observed from both the nonmotor and motor symptoms the
people develop. Braak and his friends stated that the whole process of the
pathogenic disease begins when substances from the environment gains access
into the body and gradually moves into the central nervous system where it the
spreads and affects the brain. This pathogens enter through the nasal route and
the gastric route which explains the early symptoms experienced PD in the early
phase where the olfactory structures are affected and the gastric structures
affected in the mid and late phase of the disease 3.

 Staging of Lewy
pathology according to the Braak model. Picture showing the progression of Parkinson’s disease
 

 

     

 

 

Ketil Berstad and
Johanna E.R. Berstad in 2017 in their publication titled “Parkinson’s disease;
the hibernating spore hypothesis” stated that Breckenridge et al.recently found out that cigarette
smoking is associated inversely to PD and also the kind of lifestyle such as
rural living, consumption of well water, farming, exposure to pesticides and
other environmental factors could be the cause of PD. The abnormality
along the ‘gut-brain’ pathway is a possible explanation of the model for  PD, 
which favors the idea of PD being caused by an environmental factor. These
environmental factors are been picked through nasal routes or taken through the
mouth, later mixed with saliva and moved to the guts from there to then to
brain. Most of these causative agents are; toxins, metals, pesticides, bacteria, viruses. These hypothesis also
involves the presence of the alpha synuclein protein in the bodies and neuritis
been aggregated or misfolded which is related to Parkinson disease
pathogenesis. The misfoldings of the alpha synuclein is caused by different
factors and these factors also determine the conformations of the misfoldings. These
misfoldings also increases the disease in a prion like manner. The aggregation
of these protein occur to neurons that have long unmyelinated axons and also
the disease follow the gut-brain axis for its spreading to the brain4.

Diagram showing the Braaks Hypothesis
of the Parkisons Disease caused by spores

https://www.frontiersin.org/files/Articles/232637/fneur-08-00037-HTML/image_t/fneur-08-00037-g001.gif

 

https://plus.google.com/106010668250647143671/posts/DUivLYGTYHj

 

 

 

3.     
Neurotransmitter Hypothesis.

Dopamine

Movement
control is achieved through several coomunications between groups of nerve
cells in the central nervous system. One of such important group of neurons is
the one located in the substantia nigra in the ventral midbrain. The Nigral
neurons form an extensive network of axonal processes which innervate the basal
ganglia, establishing predominantly symmetrical synapses with the dendritic
spines and also with the shafts of medium spiny projection neurons. Neurons
that are located in the substantia nigra communicate with neurons that are
located in the basal ganglia by liberating the neurotransmitter dopamine (DA).
This is the communication that leads to the formation and release of the
dopamine and also the stable coordination of movements in the body. Once the
neurons of the substantia nigra is affected and the secretion of dopamine is
low,coordination of movement is affected and the symptoms of PD is
manifested.The symptoms continue to increase as the neurons continue to
degenerate.This biochemical imbalance is what manifests the clinical symptoms
that include resting tremor, rigidity, bradykinesia(slowness of movement), and
loss of postural reflexes, poor balance and motor coordination.5

https://mayfieldclinic.com/Images/PE-Parkinson_Figure2.jpg
 

 

https://www.ncbi.nlm.nih.gov/books/NBK6271/bin/ch735f1.gif

 

 

In
Parkinson’s disease, dopamine depletion blocks autoinhibition of acetylcholine
release through muscarinic autoreceptors, leading to excessive acetylcholine
release which eventually prunes spines of the indirect-pathway projection
neurons of the striatum and thus interrupts information transfer from motor
command centers in the cerebral cortex.

The
imbalance between cholinergic activity and dopaminergic activity in the
striatum part of the brain causes a variety of neurological disorders, such as
the Parkinson’s disease. During sensorimotor learning, when a stimulus arrives
reporting reward,it evokes the active cholinergic interneurons in targeted
areas of the striatum, whereas the same stimulus triggers an increase in the
firing frequency of the dopaminergic neurons in the substantia nigra pars
compacta. The pause response of the cholinergic interneurons begins with an
initial depolarizing phase followed by a pause in spike firing and ensuing
rebound excitation. The timing of the pause phase coincides well with the surge
in dopaminergic firing, indicating that a dramatic rise in dopamine (DA)
release occurs while nicotinic receptors remain unbound by acetylcholine. The
pause response begins with dopamine D5 receptor-dependent synaptic plasticity
in the cholinergic neurons and an increased GABAergic IPSP, which is followed
by a long pause in firing through D2 and D5 receptor-dependent modulation of
ion channels. Inactivation of muscarinic receptors on the projection neurons
eventually yields endocannabinoid-mediated, dopamine-dependent long-term
depression in the medium spiny projection neurons. Breakdown of
acetylcholine-dopamine balance hampers proper functioning of the cortico-basal
ganglia-thalamocortical loop circuits.6

http://emersonblognews.blogspot.com.cy/2013/08/
 

 

 

 

 

 

4.     
Materials
And Method

 

Location of the Receptors

The
five different dopamine receptors can be grouped as thus, Dopamine receptors 1
and 5 are regarded to be D1-like receptors, while Dopamine receptors
2,3 and 4 are regarded to be D2-like receptors. Through these receptors, the
dopamine is able to exert its effect on the different activities of the brain, especially
motor co-ordination.

The
D1 receptor subfamily is expressed in multiple brain regions, including the
cortex, hippocampus, amygdala, and most intensively, the striatum, olfactory
bulb, and substantia nigra. In the cortex and hippocampus, D1 receptors are
expressed in a subpopulation of interneurons, but are primarily expressed in
pyramidal neurons, with a predominant subcellular localization in the spines of
apical dendrites. D5 receptors coexpresses with D1 receptors in cortical
pyramidal neurons, and are predominately localized in shafts. D2 receptors, the
predominant subtype of this class, are expressed in the pituitary gland and
basal ganglia (striatum and substantia nigra) and localized in both pre- and
postsynaptic structures. D2 receptors are concentrated in shafts and spines of
both cortical pyramidal neurons and striato pallidal neurons. D3 receptors are
expressed in the olfactory tubercle, nucleus accumbens, striatum, and
substantia nigra. Importantly, D3 receptors are also found in limbic system
such as hippocampus, septum, or mammillary nuclei of the hypothalamus. The D4
receptors are localized in the frontal cortex, medulla, amygdala, hypothalamus,
mesencephalon, and nucleus accumbens. It has been shown that lower level of D4
receptor expression is detected in the basal ganglia 7.

https://scienceofparkinsons.com/tag/sexuality/

 

 

 

 

 

The
Different Receptors and their Location in the brain

 

 

https://mayfieldclinic.com/Images/PE-Parkinson_Figure2.jpg

 

Diagnosis

The diagnosis of Parkinson Disease can be done by Physical examinations and
imaging methods using the biomarkers in the brain to see the areas affected in
the brain.

The cardinal physical features of the Parkinson disease, includes tremor
at rest, bradykinesia, rigidity, postural instability. The presence of tremor
at rest is a pathophysiology of Parkinson disease. Other diagnosis on other
symptoms might be done such as in the table below.

The diagnosis that involves Imaging thereby using the biomarkers of the
disease has led to imaging procedures and clinical laboratory based assays.
Brain imaging studies using PET and single photon emission computed tomography
(SPECT),MRI,trascranial ultrasound are used to be able to differentiate those
people with PD from normal people that don’t have PD .8

Paul F W.(2013). How to treat Parkinson’s disease Clinical Medicine , Vol 13, No 1: 93–6
 

 

 

 

TREATMENT

Parkinson’s disease can’t be cured,
but medications and other therapies can help to control the symptoms. And when
in advanced cases surgeries are carried out.

Medications

Medications may help you manage
problems with walking, movement and tremor. These medications increase or
substitute for dopamine, a specific signaling chemical (neurotransmitter) in
your brain.

·        
Carbidopa-levodopa. Levodopa, is the most effective medication of PD, It is a natural
medication that passes into the brain and is then converted to dopamine.It is
combined with carbidopa such as Rytary and Sinemet, which prevents the
conversion of the drug to dopamine outside the brain.Their side effects are nausea
or lightheadedness.

·        
Carbidopa-levodopa infusion. Doupa is a device used to administer l-dopa.It has been
approved by the US FDA in 2015 and is inserted into the body by a surgery so
that the drugs are infused into the body.It is used for pateints with advanced
PD.

·        
Dopamine agonists. Dopamine agonists don’t change into dopamine unlike the levodopa. They
mimic the effects of dopamine in the brain.They include pramipexole, ropinirole
and rotigotine. Their side effects is same as levodopa and also include hallucinations,
sleepiness,compulsive behaviors as hypersexuality, gambling and eating.

·        
MAO-B inhibitors. These inhibitors includes selegiline and rasagiline. They prevent the
breakdown of dopamine in the brain by inhibiting the enzyme monoamine oxidase B
(MAO-B) in the brain. Because this enzyme metabolises dopamine in the brain.The
side effects may include nausea or insomnia.

·        
Catechol-O-methyltransferase (COMT) inhibitors. . This inhibitors  prolong the effect of levodopa in the brain
by blocking enzymes that breakdown dopamine in the brain.There is increased
risk of involuntary movements (dyskinesias) as their side effects.Also causes
liver damage and liver failure.

·        
Anticholinergics. These medications are given to help control tremor. And they include
benztropine (Cogentin) or trihexyphenidyl.Their side effects are impaired
memory, confusion, hallucinations, constipation, dry mouth and impaired
urination.

·        
Other medications includes: Amantadine.

 

Paul F W.(2013). How to treat Parkinson’s disease Clinical Medicine , Vol 13, No 1: 93–6
 

 

 

 

 

 

 

 

Physical Therapies/ Lifestyle and home remedies

 

Healthy eating

Eating foods which are high in fiber
and also drinking an adequate amount of fluids can help prevent constipation
that is manifested in Parkinson’s disease. A balanced diet that provides
nutrients, such as omega-3 fatty acids, are also important in PD.

Exercise

Muscle strength may increase when
exercises are done, and likewise flexibility and balance. The exercise will
also reduce depression or anxiety and improve wellbeing. Exercises such as
walking, swimming, gardening, dancing, water aerobics or stretching

Alternative medicine

Some of the alternative medicines and
methods that could help PD patients include:

Coenzyme Q10. This is a
supplement that is beneficial for people in the early phases of PD.
Eventhough High doses of it must be taken for a longer period of time like
16months.Massage. This can reduce the tension
in the muscle and brings relaxation.Acupuncture. This involves the
insertion of tiny needles into many specific points on your body to reduce
pains.

·        
Tai chi. This
is an ancient form of exercise for the chinese, which involves slow, flowing
motions that improves flexibility, balance and muscle strength and may prevent
falls.

Yoga. This also improves flexibility and
balance.Alexander technique. This technique
reduces muscle tension and pain by focusing on muscle posture, balance and
thinking about how you use muscles.Meditation. This reduces stress and pain
and improve your sense of well-being.Music or art therapy.
This provides relaxation and may improve walking and speech in people with
PD. While participating in different arts improves mood.Pet therapy. This may increase
flexibility, movement and improve your emotional health.9

 

 

 

5.     
CONCLUSION

Parkinson’s disease is a disorder that
is incurable and has been so difficult to manage and treat with the current
methods.But with different modifications and ongoing research there has been
improvements in the managing of disorder and improving life and wellbeing.

 

References

1.      
Rewar S.(2015).A systematic review on
Parkinson Disease(PD) 3(2),
176-15 Indian Journal of Research in Pharmacy and Biotechnology. https://www.researchgate.net/publication/279181994

2.      
André X. C. N. Valente, Jorge A. B. Sousa, Tiago F. Outeiro, & Lino Ferreira.(2010). A stem-cell ageing hypothesis on the
origin of Parkinson’s disease. arXiv:1003.1993 q-bio.CB

3.      
Visanji N.P, Brooks P.L.,Hazrati L,N
& Anthony E Lang A.E.(2013). The prion hypothesis in Parkinson’s disease: Braak to the future.1:2,1-12.actaneuropathologica
communications. www.actaneurocomms.org/1/1/2

4.      
Berstad K., &
Berstad E.R.J. (2017). Parkinson’s disease; the hibernating spore hypothesis.
104 48–53.Medical Hypothesis. Elsevier http://dx.doi.org/10.1016/j.mehy.2017.05.022

5.      
Triarhou LC. Dopamine and Parkinson’s Disease.
In: Madame Curie Bioscience Database Internet. Austin (TX): Landes
Bioscience; 2000-2013. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK6271/

6.      
Aosaki, T., Miura, M., Suzuki, T., Nishimura, K.
and Masuda, M. (2010), Acetylcholine–dopamine balance hypothesis in the
striatum: An update. Geriatrics & Gerontology International, 10: S148–S157.
doi:10.1111/j.1447-0594.2010.00588.x

7.      
Shin H., and Shun S,.(2011). “Dopamine
Receptors and Parkinson’s Disease,” International Journal of Medicinal
Chemistry. 403039:16 doi:10.1155/2011/403039

8.      
Joseph M. S, Valina L. D, Ted M. D.
(2006).Diagnosis and treatment of Parkinson disease: molecules to medicine. 116(7):1744-1754. J Clin Invest doi:10.1172/JCI29178.

9.      
 https://www.mayoclinic.org/diseases-conditions/parkinsons-disease/diagnosis-treatment/drc-20376062

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