An analysis of Parkinson’s disease (PD) on Physical and Mental Health

Analysis of Parkinson’s disease (PD)
on Physical and Mental Health
STRESS AND MENTAL HEALTH TERM ESSAY
Arian Bashtar | 100943949 | NEUR 3403 | December 8, 2017

NEUR 3403 Essay Carleton University FA 2017
PAGE 1
1. Introduction
1.1. Introduction to Characteristics and Symptomology
It was as early as 1817 when Parkinson’s disease (PD) was first formally characterized
and described; yet, early records of its physical symptomology remain from ancient artifacts
dating back to biblical times.1
First clinically described by James Parkinson, Parkinson’s
disease is a neurological syndrome that is characterized by overall muscle weakness,
involuntary tremulous motion in body parts-even when they are supported or not in use-and
a tendency to arch the trunk forward (stooped posture).2,4
Further characterizations were
added to the definition of Parkinson’s disease,2
however, 4 fundamental movement
symptoms constitute the basis for its diagnosis.4
These symptoms are collectively referred
to as parkinsonism: Tremors, Rigidity, Bradykinesia (paucity) and postural instability.4
Parkinsonism can be either direct or indirect; the latter referring to symptoms caused by a
disease other than PD.3
Above all, PD is a neurodegenerative disease, which signifies that it
follows a sequential pattern of worsening symptoms.3
The first symptoms include shakiness-
mainly manifesting as “resting tremors” as opposed to tremors observed when a body part
is moved-and slowness in movement (bradykinesia). As the disease progresses, widespread
rigidity of muscles and problems with balance (postural instability) ensue in the latter
stages.3
In addition to being a movement disease, PD is also characterized by many
psychiatric and non-movement disturbances.6
Neuropsychiatric symptoms include anosmia
(an inability to smell or taste), cognitive disturbances (such as impairment of attention,
confusion or misinterpretation of speech) and mood disturbances (such as depression and
anxiety).6
Moreover, the autonomous nervous system is also affected by PD, producing
symptoms such as constipation (lack peristaltic movement regulation), dysregulation of
blood pressure and dysregulation of body temperature (causing sweating).6
1.2. Prevalance
In general, Parkinson’s Disease is a common neurological disease affecting ethnic groups
from around the world. About 300 people per 100,000 will develop Parkinson’s Disease at
some point in their life; it globally affected 6.2 million and killed 117,400 people in 2015. 3,
5
The proportion of PD amongst the elderly indicates that PD prevalence steadily increases
with age (see Figure 1).3
In a world where life expectancy is expected to increase globally, it
is also expected that Parkinson’s rates will increase.3
Along with age, there appears to be a
predilection in gender, whereby men are slightly more prone to developing PD than are
women.3

PAGE 2
2. Etiology
With regards to any neurodegenerative disease, it may be argued that anyone will develop
a neurodegenerative disease should they live long enough. This is mainly because neurons
are non-replicating cells and their counts naturally decrease with age. However, the question
is, rather: what determines if one develops ALS or Alzheimer’s disease (AD) over PD?
Parkinson’s disease is the byproduct of the death of dopaminergic neurons in the brain,
particularly in the area where they are normally highly concentrated: the substantia nigra pars
compacta (SNpc).8
Dopaminergic neurons are very fascinating and are currently researched
more than any other neuron.7
They constitute less than 1% of all neurons in the brain, produce
almost the entirety of the brain’s supply of the neurotransmitter dopamine (DA), and they are
found in the harshest cellular environment in the brain for supporting neuron life (i.e. are
under high oxidative stress from large concentrations of iron and mitochondria).7
As with
any disease, neurodegenerative diseases have some sort of trigger or cause, yet the triggers
of Parkinson’s disease are in fact idiopathic (largely unknown).3
Risk factors have been
identified, including age, genetics, gender, environmental toxins, history of head trauma
(concussions), and inhalation of heavy metals (namely lead, copper and manganese particles
which are found in high concentration in industrial areas).3
Specific genes have been
identified and are thought to either directly cause PD or to predispose the individual to
developing PD.3
Considering that about only 15% of PD patients have family history,
genetics does not seem to be the biggest consideration.3
As mentioned previously, age is a
key risk factor in determining the development of PD and this risk steeply increases past the
age of 60 (see Figure 1).3
In fact, humans are the only known organisms that lose over half
of their dopaminergic neurons as they age.7
Figure 1. Frequency distribution of Parkinson’s Disease at various ages
(courtesy of Khan Academy).3

PAGE 3
The vulnerability of DA neurons to pathology is because DA neurons have a high
metabolic demand and therefore require lots of support from surrounding glia to maintain
their microenvironments.7
Evidently, head trauma is not beneficial to neural or glial cells in
the brain as this lyses cells, disrupts cellular environments, thus promoting pathogensis.3, 8
With regards to gender, it is uncertain why men are slightly more predisposed, but it may be
that males age faster since they have an overall higher metabolism.8, 9
As for the remaining
risk factors, the environmental toxin hypothesis was particularly popular in the 20th
century,
whereby chemicals that increase oxidative stress in the brain were thought to be involved in
PD pathogenesis.8
These oftentimes include pesticides and cleaning chemicals found in our
day to day environments.3
In summary, the field of PD research proposes two main leading
pathogenesis theories: i) the mitochondrial dysfunction hypothesis and ii) the misfolding of
proteins that lead to α-synuclein aggregate accumulations in the DA neurons in the SNpc.8
3. Mechanisms of Pathology
3.1 Protein Aggregation
As described in the final portion of Section 2, the theory of protein misfolding is a major
hypothesis contemporary PD research, but neither hypothesis is mutually exclusive.8
In other
words, both mechanisms are believed to be at play simultaneously and the goal of current PD
research is to understand the interaction and sequences implicated in both mechanisms that
lead to the demise of SNpc DA neurons.8
α-synuclein is a protein aggregate that, in relation
to all other neurodegenerative diseases, appears most prominently in PD.10
Other protein
aggregates including tau and Aβ proteins are also found in lower quantities.10
It is believed
that oxidative stress promotes the formation of misfolded proteins, resulting in intracellular
aggregates that cause toxicity.10
Furthermore, reactive oxidative species in and of themselves
cause toxicity.8
Aggregates of α-synuclein form the basis of Lewy bodies, which can be
observed postmortem in the DA neurons of the nigrostriatal pathway.11
In transgenic mice,
the overexpression of α-synuclein has been observed to engender toxicity and dopaminergic
neurodegeneration.8
However, ablation of α-synuclein in these mice was not associated with
any neuropathological changes, suggesting that mutations causing PD operate via a toxic
gain of function mechanism.8
Ultimately, the role that Lewy bodies play in development of
PD remains unknown.8,11
It could be either an etiologic agent or a neuroprotective adaptation.
It works either to promote protein aggregation, directly causing toxicity, or conversely, to
protect the cell from the harmful effects of misfolded proteins by sequestering them in an
isolated cellular compartment.8
The cascade of genetic mutations, protein misfolding,
toxicity, mitochondrial dysfunction and energy crisis (i.e. the depletion of ATP) are thought
to be the events that provoke natural cell death (apoptosis) in DA neurons of the nigrostriatal
pathway.8

PAGE 4
3.2. Concepts of the Direct Pathway of the Basal Ganglia
In order to understand the mechanism for generation of Parkinson’s symptoms, it is
necessary to put into perspective the role of the basal ganglia in the brain, which follow two
main functional pathways. Both pathways along with neuroanatomical components are
illustrated in Figure 2.13
The first functional pathway is required for generating voluntary
movement, referred to as the direct pathway of the basal ganglia. 13
Initiation of movement
in this pathway occurs in the motor cortex (see Figure 2 on the next page). For the motor
cortex to be able to send a motor command to corresponding motor neurons, the thalamus
must be liberated from its default state of inhibition. 12
The thalamus is by default inhibited
by the Globus Pallidus internal segment (GPi).12
The motor cortex first sends an excitatory
message via glutamate projecting fibers into the striatum, a component that is comprised of
the caudate putamen and the caudate nucleus.12
Inhibitory GABA fibers then convey IPSPs
(inhibitory post-synaptic potentials) to the GPi, resulting in its inhibition. When the GPi is
sufficiently inhibited, transmission of IPSPs from the GPi to the thalamus stops, thalamic
activity increases, and EPSPs (excitatory post-synaptic potentials) transmit from the
thalamus to the motor cortex. 12
The ultimate result is increased motor cortex activity, which
then allows motor commands to be sent directly to the muscles via spinal tract pathways.12,
13
Two more components are also at play and help modulate the pathway described above:
the substantia nigra (SN) and the subthalamic nucleus (STN). 13
The SN projects to the
striatum via the nigrostriatal pathway: a connection of dopaminergic fibers that excite
inhibitory GABA neurons in the striatum 11, 12
Indeed, the inhibitory fibers of the striatum are
not under sufficient stimulation from the motor cortex so as to fully inhibit the GPi.
Therefore, the SN conveys powerful EPSPs to the striatum by releasing dopamine binding to
D1 receptors, further activating GABA neurons that convey IPSPs to the GPi. 12
When about
80% of DA neurons in this pathway are lost, the full range of PD symptoms begins to
manifest. 11
Lastly, the STN is responsible for stimulating the SN, which modulates dopamine
release into the striatum. The SN is able to modulate the STN itself via its own connection
of inhibitory fibers.12
3.3. Concepts of the Indirect Pathway of the Basal Ganglia
The indirect pathway works to make sure that unwanted movements do not spontaneously
arise from the activity of the motor cortex via the direct pathway.12
As mentioned previously,
the thalamus is in a default state of inhibition. 12
This is because the thalamus, if not inhibited,
will uncontrollably overstimulate the motor cortex, resulting in unwanted movements
(dyskinesia).14
The indirect pathway starts from the motor cortex, where EPSPs are projected
to the striatum.

PAGE 5
This time the striatum projects IPSPs to the Globus Pallidus external segment (GPe), via
inhibitory GABA fibers. 14
The GPe in turn projects IPSPs to the STN, which results in
excitatory stimulation of the GPi by the STN. 13, 14
As seen previously, the inhibition of the
GPi promotes thalamic activity; therefore, its excitatory stimulation via the indirect pathway
results in inhibition of thalamus.14
The question then becomes: what then is the role of the
SN in the indirect pathway? As with the direct pathway, the SN promotes thalamic activity
by inhibiting the GPi. In the indirect pathway, the SN excites the striatum via dopamine
release targeting D2 receptors, which results in inhibition of the GPe.14
By inhibiting the GPe,
the STN is inhibited, the GPi is less excited and thalamic activity increases.
Figure 2. A) Coronal section of the midbrain illustrating the direct and indirect
pathways of the basal ganglia seen in a healthy individual and B) an individual with
Parkinson’s disease. Declining activity resulting from the death of excitatory
dopaminergic tracts projecting from SNpc to the striatum are visualized with a dashed
arrow. Schematic figure borrowed from Calabresi & colleagues. 13

PAGE 6
3.4 Conclusions on the Direct and Indirect Pathways
Therefore, it is observed that in both the direct and the indirect pathways, the ultimate
goal of the SN is to promote thalamic activity and to promote muscle movement. The DA
neurons in the SN appear to modulate stimulation of the striatum independently, as they may
inhibit the STN. With the death of the nigrostriatal pathway, the main symptoms seen are
bradykinesia and rigidity of muscles. In PD, the activity of the indirect pathway (D2) is in
excess and the activity of the direct pathway (D1) is deficient.
3.5 Genetics
For the overwhelming majority of patients with PD (85%), the cause is said to idiopathic.
However, for 15%, mutations in at least one gene are thought to have either directly caused
Parkinson’s disease in those patients or increased their likelihood for developing Parkinson’s.
These gene mutations are autosomal, meaning that they are found in the non-sex
chromosomes and can be either recessive or dominant. An autosomal dominant inheritance
signifies that only one copy of the gene is required for the expression of that gene (the
phenotype) to manifest. Conversely, in autosomal recessive inheritance, both copies from
mother and father containing the mutant gene must be present in the offspring for its
expression to occur. In PD genetics research, five main genes have been identified and are
thought to be commonly implicated, although there are more known genes described in
literature. The first gene, PARK7 (Parkinson Disease protein 7) is implicated in familial early
onset PD. 15
It is situated on autosomal chromosome 1 and transcribes for DJ-1.15
DJ-1 is a
neuroprotective chaperone protein that is involved in many different processes, including
protein folding, protection against oxidative stress, as well as transcriptional, mitochondrial,
and protease regulation.16
Ultimately, it functions to prevent the aggregation of α-synuclein.16
The mutation of PARK7 is a direct cause for PD and follows an autosomal recessive
inheritance pattern.15, 16
The next gene found on autosome 6 is the PARK2 gene, which is
one of the largest genes in the human genome and encodes for the protein Parkin.15
Parkin
is responsible for tagging damaged or misfolded proteins for ubiquitination (protein
degradation) in the cytosol of cells.15,17
PARK2 also follows autosomal recessive inheritance
and is implicated in juvenile onset PD (i.e. extremely early: before the age of 20) as well as
late onset PD (after the age of 50).15
Interestingly, over 200 possible mutations in the PARK2
exist that can render Parkin defective.15
Another noteworthy gene is LRRK 2, which is found
in autosome 12 and encodes for the protein Dardarin.15
The function of Dardarin is not
completely understood, yet it is thought to be involved in cell-cell communication in the
brain and the ability to turn cellular activity on and off.15, 18
LRRK 2 is a large gene with 51
exons and 50 possible mutations have been identified to date.17

PAGE 7
Interestingly, LRRK 2 is the most common genetic trigger for PD and it follows an
autosomal dominant inheritance pattern.15
Other common genes in PD are fundamentally
subtypes of the previous three mentioned (ex. PARK 1, LRRK 8 and etc.).18
The SNCA gene
(encoding PARK1-4) was the first autosomal dominant genetic mutation that was reported
in literature.18
The study PD genetics is extremely important, as PD tends to be
individualized. That is, response to medication and surgical treatment greatly varies between
individuals by function of the patient’s genetics, physiology and psyche.18
Each type of
genetic trigger renders a different type of prognosis, although patterns of progression have
been observed in certain genetic forms of PD.18
In summary, the genetics of PD appears to
be extremely complex and the origins of the genetic mutations that are steadily implicated
are unknown.
3.6 Other Considerations
Although PD has an evident neurological basis, many patients with PD experience their
diagnosis as a major life stressor, which has the potential to worsen with stress associated
with motor and psychiatric symptoms of PD. 19
Neurologists and medical staff spend minimal
time beyond the first visit, to ensure that the patient understands the course of the illness and
its management.19
Managing stress associated with PD is very important, as psychological
support promote resiliency in the course of the disease. More emphasis on psychosocial
factors is required, as PD patients, unless specifically asked by their doctors, have a tendency
to omit psychosocial issues related to their health.19
Another consideration is the gut
microbiome and its association with PD. As previously mentioned, PD directly affects the
autonomic nervous system, particularly the enteric and parasympathetic nervous systems.3, 20
These nervous systems have been shown to be in interaction with the gut microbiome, as
they control peristalsis.20
Scheperjans and colleagues found that the gut microbiome in PD
patients slightly differed in composition relative to the normal gut microbiome, which may
potentially have a protective or detrimental impact on the progression of the disease.20
4. Summary
Parkinson’s disease affects a large group of people per annum, and the course of each
illness is unique. Treatment options include dopamine agonists, MAO B inhibitors, L-DOPA
(dopamine precursor) and other drugs for the various psychiatric facets of the disease
(Clozapine, Modafinil, etc.), including dementia and psychosis. In general, I believe that a
wide variety of treatment options are available, yet a great number of them are
unconventional and should be studied with scrutiny before being prescribed to patients. One
example, is for instance, marijuana, which works to alleviate the symptoms in some PD
patients, yet what are long-term considerations for its use?

PAGE 8
Although treatment options are more or less effective at managing the symptoms of PD,
no current medication can completely abolish the symptoms.21
Furthermore, the efficacy of
these medications diminishes as the disease progresses. For example, L-DOPA was
revolutionary in its ability to manage Parkinson’s disease, and for many recently diagnosed
patients, L-DOPA therapy is enough to manage symptoms. However, the caveat is once
enough DA neurons in the SNpc are lost, the margins of the gap between the effective dose
and the overdose (non-lethal) narrows.21
The patient himself must discern how much L-
DOPA to take, and if he takes too much, then undesired symptoms will result (i.e. chorea,
dyskinesia, insomnia, etc.).21
My opinion is that more emphasis must be placed on potential stem-cell implant therapies
for DA neurons, as this area of research appears to be the most promising in alleviating or
completely abolishing the symptoms of PD.7
This is because DA progenitor implants have
potential to boost existing DA neuron circuits by forming self-sustaining
microenvironments.7
I also believe that emphasis should be put into searching means of
preventing PD. In a day and age where humans are bombarded with so much technological
stimuli, it is sure that we are asking more from our brains than in previous generations. I
believe in the future, human brains are going to evolve to become more advanced than they
are now. They may feature more dopaminergic neurons and will likely have greater capacity
for working memory and cognitive processing. Indeed, this means more time spent behind
computer screens, less time exercising and more time tackling complicated ideas. Therefore,
what can be done to protect the invaluable DA neurons we are born with? 15 years of genetic
research has identified many different genes involved, but none of the known gene mutations
have been linked to a definite cause.17
As such, the interaction of epigenetics also remains
crudely elucidated.

PAGE 9
References
1. García, R. P. (2004). Prehistory of Parkinson's disease. Neurologia (Barcelona,
Spain), 19(10), 735-737.
2. Goetz, C. G. (2011). The history of Parkinson's disease: early clinical descriptions and
neurological therapies. Cold Spring Harbor perspectives in medicine, 1(1), a008862.
3. Emma Giles. (2017). What is Parkinson’s Disease? Khan Academy. AAMC. n.d. Web.
06 Mar. 2017.
4. Emma Giles. (2017). Movement signs and Symptoms of Parkinson’s disease. Khan
Academy. AAMC. Web. 08 Dec. 2017.
5. Vos, T., Allen, C., Arora, M., Barber, R. M., Bhutta, Z. A., Brown, A., ... & Coggeshall,
M. (2016). Global, regional, and national incidence, prevalence, and years lived with
disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global
Burden of Disease Study 2015. The Lancet, 388 (10053), 1545-1602.
6. Emma Giles. (2017). Non-movement symptoms of Parkinson’s disease. Khan Academy.
AAMC. Web. 08 Dec. 2017.
7. Chinta, Shankar J., et Julie K. Andersen. Dopaminergic neurons. (2005) The
International Journal of Biochemistry & Cell Biology, Cancer and Aging at the
Crossroads, 37: 942-46.
8. Dauer, W., & Przedborski, S. (2003). Parkinson's disease: mechanisms and
models. Neuron, 39(6), 889-909.
9. Arciero, P. J., Goran, M. I., & Poehlman, E. T. (1993). Resting metabolic rate is lower in
women than in men. Journal of applied physiology.
10. Moussaud, S., Jones, D. R., Moussaud-Lamodière, E. L., Delenclos, M., Ross, O. A., &
McLean, P. J. (2014). Alpha-synuclein and tau: teammates in
neurodegeneration?. Molecular neurodegeneration, 9(1), 43.
11. Emma Giles. (2017). Putting it all together - Pathophysiology of Parkinson's disease.
Khan Academy. AAMC. Web. 08 Dec. 2017.
12. Emma Giles. (2017). The basal ganglia – The direct pathway. Khan Academy. AAMC.
Web. 08 Dec. 2017.
13. Calabresi, P., Picconi, B., Tozzi, A., Ghiglieri, V., & Di Filippo, M. (2014). Direct and
indirect pathways of basal ganglia: a critical reappraisal. Nature neuroscience, 17(8),
1022-1030.
14. Emma Giles. (2017). The basal ganglia – Details of the indirect pathway. Khan
Academy. AAMC. Web. 08 Dec. 2017.
15. Emma Giles. (2017). Genetics and Parkinson’s disease. Khan Academy. AAMC. Web.
08 Dec. 2017.
16. Ariga, H., Takahashi-Niki, K., Kato, I., Maita, H., Niki, T., & Iguchi-Ariga, S. M. (2013).
Neuroprotective function of DJ-1 in Parkinson’s disease. Oxidative medicine and cellular
longevity, 2013.
17. Klein, C., & Westenberger, A. (2012). Genetics of Parkinson’s Disease. Cold Spring
Harbor Perspectives in Medicine, 2(1).
18. Li, J.-Q., Tan, L., & Yu, J.-T. (2014). The role of the LRRK2 gene in Parkinsonism.
Molecular Neurodegeneration, 9, 47.
19. Reese, S. L. (2007). Psychosocial factors in Parkinson’s disease. Disease-a-Month, 53(5),
291-295.
20. Scheperjans, F., Aho, V., Pereira, P. A., Koskinen, K., Paulin, L., Pekkonen, E., ... &
Kinnunen, E. (2015). Gut microbiota are related to Parkinson's disease and clinical
phenotype. Movement Disorders, 30(3), 350-358.
21. Emma Giles. (2017). Managing Parkinson’s Disease with medications. Khan Academy.
AAMC. Web. 08 Dec. 2017.

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