Neurodegenerative disorders 1: Parkinson's Disease Flashcards
1
Q
A
2
Q
Who published a description of the symptoms of a disorder termed paralysis agitans in 1817?
A
James Parkinson
This article is now considered the first thorough description of this disorder.
3
Q
What does the term paralysis agitans literally translate to?
A
Agitated paralysis
The term reflects the symptoms associated with the disorder.
4
Q
How long after James Parkinson’s publication did the term Parkinson’s disease come into common usage?
A
More than 40 years
This indicates a delay in the acceptance of the term in the medical community.
5
Q
What is the second most common neurodegenerative disorder?
A
Parkinson’s Disease (PD)
It follows Alzheimer’s Disease.
6
Q
According to a 2018 report by Parkinson’s UK, how many people are living with Parkinson’s Disease in the UK?
A
Approximately 137,000 people
This statistic is based on a report from the charity Parkinson’s UK.
7
Q
At what age does the prevalence of Parkinson’s Disease increase significantly?
A
Around 80 years old
The prevalence increases approximately 100-fold in patients aged 80 and older.
8
Q
What is the prevalence rate of Parkinson’s Disease in men compared to women?
A
1.5 times higher in men
This indicates a gender disparity in the prevalence of PD.
9
Q
Fill in the blank: The youngest patients with Parkinson’s Disease can be in their _______.
A
20s
10
Q
True or False: The prevalence of Parkinson’s Disease is equal among men and women.
A
False
Men have a higher prevalence rate than women.
11
Q
things that increase risk of PD
A
- male gender
- age
- hispanic heritage
- head trauma
- rural living
- genetics
- melanoma
12
Q
things that decrease risk of PD
A
- smoking
- caffeine use
- high serum urate
- female gender
- physical activity
- NSAID use
- urban living
some of the things considered bad for you actually decrease the risk
13
Q
post mortem studies of PD patients
A
- evidence for loss of dopaminergic neurons in specific brain regions including substantia nigra
- appearace of lewy bodies
SN appears less dark in PD patients due to loss of SNpc( pars compacta) dopaminergic neurons
14
Q
what are lewy bodies
A
- intracellular inclusions
- of the protein α-synuclein
found in substantia nigra
15
Q
What is the primary characteristic of the majority of Parkinson’s disease cases?
A
Idiopathic, with no family history in 85% of cases
Idiopathic means the cause is unknown.
16
Q
What percentage of Parkinson’s disease cases have a family history?
A
15%
Indicates a potential genetic component.
17
Q
How does familial Parkinson’s disease differ from idiopathic forms?
A
Familial forms tend to have earlier onset than idiopathic forms
Familial forms can develop in middle age.
18
Q
how many genes have been linked to PD
A
more than 20
19
Q
what are the 4 main genes linked to PD
A
- SNCA
- PRKN
- PINK1
- PARK7
20
Q
what is the protein name for the gene SNCA
A
alpha-synuclein
21
Q
What is the function of alpha-synuclein?
A
Involved in synaptic function and may play a role in DNA repair
- Major component of Lewy bodies.
22
Q
What are Lewy bodies?
A
Aggregates of misfolded alpha-synuclein protein
Present in both familial and idiopathic Parkinson’s disease.
23
Q
what is PRKN
A
- parkin protein
- important in proteasome and mitochondrial function
24
Q
What role do proteasomes play in the context of Parkinson’s disease?
A
organelles which break down misfolded proteins
Dysfunction can lead to accumulation of toxic proteins.
25
what is PINK1
- PTEN induced putative kinase 1
- imporant in mitochondrial function
26
What is the function of the Parkin gene?
Important in proteasome function and mitochondrial function
## Footnote
Mutations can lead to Parkinson's disease.
27
What does PINK1 stand for?
PTEN induced putative kinase 1
## Footnote
Involved in mitochondrial function.
28
what protein is PARK7 coded for
DJ-1 protein
29
What is the role of the DJ-1 protein?
Protects cells against oxidative stress
## Footnote
.
30
What happens when alpha-synuclein misfolds?
Forms oligomers
31
what can get rid of oligomers ?
protesomes
32
how can oligomers become lewy bodies ?
- protesome dysfunction (PRKN mutation)
- SNCA mutations
## Footnote
these lead to more misfolding and formation of lewy bodies
33
What are the two proposed mechanisms by which Lewy bodies cause cell death?
* Neuroinflammation
* Mitochondrial dysfunction (PRKN, PINK1, PARK7 mutations)
34
How can environmental toxins contribute to Parkinson's disease?
They can cause oxidative stress and mitochondrial dysfunction
- exacerbated by mutations in DJ-1 as cannot protect cell (PARK7)
## Footnote
Examples include MPTP and pesticides such as rotenone.
35
What is the relationship between neuronal loss in the substantia nigra and Parkinson's disease?
Natural loss occurs with age and still have sufficient to allow basal ganglia to function, but familial mutations or environmental insult can accelerat loss and leads to symptoms
36
what is environmental insult
exposure to a toxin over a long period of time or a high concentration
37
True or False: Parkinson's disease is a homogeneous disorder.
False
## Footnote
There are various genetic and environmental factors involved.
38
What symptoms were exhibited by the six Californian drug addicts in the early 1980s?
Symptoms that strongly resembled Parkinson's Disease
39
What was a key difference in the symptoms of the drug addicts compared to typical Parkinson's cases?
Symptoms had a sudden onset
40
Which treatment did the symptoms of the drug addicts respond to?
L-DOPA
## Footnote
suggests illness may be connected to PD
41
What designer drug did the six addicts take that was contaminated?
MPPP - a synthetic opioid
contaminated with MPTP
42
MPTP vs MPP+
43
What is MPTP classified as?
A uniquely selective toxin
44
What type of cells metabolize MPTP into MPP+?
Glial cells
45
What does MPP+ interfere with in neurons?
Mitochondrial electron transport
46
Which neurons are particularly sensitive to MPP+?
Dopaminergic neurons of the substantia nigra
- killed by the build up of free radicals
47
What is produced by the loss of dopaminergic neurons due to MPP+?
Parkinson's Disease like symptoms
48
What is MPTP used for today in research?
To produce animal models of Parkinson's Disease
49
Why are non-human primates used instead of rodents for MPTP research?
Rodents are almost immune to the toxin
50
What have MPTP-lesioned animals contributed to Parkinson's Disease research?
They are important as a test bed for treatments
51
What potential environmental factor has been suggested to contribute to Parkinson's Disease?
Exposure to environmental toxins with MPTP-like effects
52
What similarity do several widely used pesticides share with MPTP?
Similar toxic mechanisms
53
What happened to several scientists who worked with MPTP before its recognition as a contaminant?
They developed Parkinson's Disease
54
Fill in the blank: MPTP is metabolized in glial cells to _______.
MPP+
55
what are the 4 cardinal features of PD ?
- bradykinesia
- resting trmeor
- ridgidity
- postural instability
## Footnote
all but postural symptoms are ue to loss of dopaminergic neurons
56
what does it mean for PD to be progessive ?
symptoms become more severe and more numerous with time
57
what is bradykinesia
slowed movement
- loss of movement amplitude
## Footnote
main feature and major case of disability in PD
58
how can bradkinesia present ?
- reduced performance in walking
- reduced facial expression
- decreased voice volume (hoarse or breathy)
- micrographia (reduction in writing size)
59
resting tremour
- most visible sign of PD
- 'shaking palsy'
- hand first
- 'pill rolling tremour'
60
rigidity
- in arms, back, neck, legs
- lead pipe type (smooth resistance to movement)
- cogwheel type (resistance that momentarily gives way)
61
postural instability
- loss of postural reflexes and balance
62
non-motor symptoms of PD
Depression
Apathy
Cognitive dysfunction (including dementia)
Anxiety
Psychosis (due to disease itself, rather than treatments)
Loss of sense of smell
Sleep disorders
Autonomic dysfunction
## Footnote
not dopamine based
63
what is the basal ganglia?
a group of cell bodies/subcortical nuclei in peripheral nervous sytem
64
what is the role of the basal ganglia
- control movement
- learning
- cognition
- emotion
65
what does the basal ganglia work with and why?
- motor cortex
- for regulation of desired motor patterns
66
What are the primary disorders focused on in this module?
Parkinson's disease and Huntington's disease
## Footnote
both have motor symptoms as a result of dysfunction of structures in the brain known as the basal ganglia
67
What brain structures are collectively known as the basal ganglia?
Striatum, globus pallidus, substantia nigra, subthalamic nucleus
68
What is the main function of the basal ganglia?
Regulate cortical output
## Footnote
also learning, mood and emotion
69
How do the basal ganglia function in relation to the cerebral cortex?
- links cerebral cortex back to cerebral cortex through thalamus which links spinal output
70
motor loops
- cerebral cortex
- into basal ganglia
- into thalamus
- back to cerebra cortex
## Footnote
regulate output of cortex to motor targets
- (or instead of basal ganglia into cerebellum but we won't focus on this)
71
What are the two main components of the dorsal striatum?
Putamen and caudate nucleus
## Footnote
ventral striatum on the ottom
72
Fill in the blank: The putamen and caudate nucleus together form the _______.
Dorsal striatum
73
What are the two subdivisions of the globus pallidus?
Globus pallidus externus (GPe) and globus pallidus internus (GPi)
## Footnote
near midline of the brain
74
What structure is located just above the substantia nigra?
Subthalamic nucleus
75
What type of functions also have similar looping circuits through the basal ganglia?
## Footnote
cortical-basal ganglia circuits
Ocular motor functions, executive and associative functions, emotion and motivation
## Footnote
use different areas of the cortex, striatum and globus pallidus
76
True or False: The ventral striatum is primarily focused on motor functions.
False
77
What is the role of the thalamus in the basal ganglia circuit?
Acts as a relay point for information between the cortex and basal ganglia
78
What is the loop structure that regulates cortical output?
Cortex → Basal ganglia → Thalamus → Cortex
79
80
What is the primary function of the basal ganglia?
To regulate motor actions and integrate cortical plans
81
What is meant by 'motor loops'?
Circuits that regulate cortical plans during initiation, execution, and after execution
82
normal circuit with no dopamine
- cortex -> basal ganglia -> thalamus -> cortex
* if excitatory at thalamus then facilitates cortical movement plan (glutamatergic)
83
What neurotransmitter is vital for the functioning of the basal ganglia?
Dopamine
84
What is the role of excitatory neurons in the basal ganglia circuitry?
They facilitate the cortical movement plan
85
What neurotransmitter do excitatory neurons in the basal ganglia release?
Glutamate
86
What is the role of inhibitory neurons in the basal ganglia circuitry?
They inhibit signals and regulate movement
87
What neurotransmitter do inhibitory neurons in the basal ganglia release?
GABA
88
What is the role of the 'direct pathway' in the basal ganglia?
A pathway that facilitates movement by sending excitatory signals from cortex to thalamus
## Footnote
through the basal ganglia
89
what is the route of the 'direct pathway'
- excitatory output from cortex to striatum
- from striatum inhibitory (GABAergic neuron) into globus pallidus internus (GPi)
- GPi inhibitory neurons go to thalamus
- overall excitatory (positive) influence over thalamocortical input
## Footnote
indicated by dashed lines (think of it as + x - x - so overall positive)
90
What is the output of the direct pathway from the thalamus?
Excitatory, which facilitates movement
91
What is the 'indirect pathway' in the basal ganglia?
A pathway that inhibits movement through multiple inhibitory connections
92
What effect does the indirect pathway have on movement?
It inhibits movement
93
what is the route of the 'indirect pathway'
* cortex to striatum is excitatory
* synapses with inhibtory neuron in GPe (externus)
* 2 branches from GPe: one to GPi and one to STN (subthalamic nucleus)
* upper pathway: GPe->GPi is inhibitory - GPi -> thalamus inhibitory
* lower pathway GPe -> STN inhibitry, STN -> GPi excitatory, GPi-> thalamus inhibitory
## Footnote
both upper and lower pathways inhibt movement as overall negative
94
What is the 'hyper direct pathway'?
A pathway that bypasses the striatum and globus pallidus externus, inhibiting movement
* direct from cortex to STN (excitatory)-> (excitatory) GPi -> (inhibitory) thalamus
## Footnote
think of + x + x -
95
What are medium spiny neurons?
GABAergic neurons in the striatum that form the first synapse with cortical output - lots of dendritic spines
96
What are the two populations of medium spiny neurons based on dopamine receptors?
Dopamine D1 receptors and dopamine D2 receptors
97
Which dopamine receptors are associated with the direct pathway?
Dopamine D1 receptors
98
Which dopamine receptors are associated with the indirect pathway?
Dopamine D2 receptors
99
What is the effect of dopamine acting on D1 receptors?
It facilitates movement by strengthening the direct pathway
## Footnote
D1 are excitatory
100
What is the effect of dopamine acting on D2 receptors?
It inhibits the indirect pathway, thereby promoting movement
| remmeber indirect pathway inhibits movement/ so if we inhibit it we prom
## Footnote
inhibitory neurons
101
What happens to dopaminergic neurons in Parkinson's disease?
There is a degeneration of these neurons from substantia nigra (pc), leading to less dopamine release into striatum
| hence movement becomes more difficult with a loss of dopamine
## Footnote
therefore if less dopaminergic neurons in direct pathway = less movement, less in indirect pathway = strengthened inhibtion of movement, less movement
102
What is bradykinesia?
A symptom of Parkinson's disease characterized by slowed movement
## Footnote
as a result of low dopamine
103
What is the activity pattern of neurons in the GPi of a normal animal?
A constant level of activity
104
How does the activity pattern of GPi neurons change in Parkinson's disease?
It becomes bursty with high activity followed by periods of quiet
105
What does the bursting activity in the GPi disrupt?
The cortical function and execution of movement plans
106
Fill in the blank: The excitatory output from the cortex to the striatum is classified as _______.
Glutamatergic
107
True or False: The indirect pathway promotes movement.
False
108
what brain region is not part of the basal ganglia ?
- thalamus
## Footnote
it is connected but not a part of the basal ganglia
109
where do medium spiny neurons expressing dopamine D1 receptors project from ?
striatum to globus pallidus internus
110
The loss of neurons from which brain region causes the main motor deficits in Parkinson's disease?
substantia nigra pars compacta
## Footnote
as these project ot striatum and effect excitation
111
Neurons projecting from the thalamus to the cortex release which neurotransmitter?
excitatory, so glutamate
112
113
What is the primary deficit in Parkinson's disease?
A dopaminergic deficit in the basal ganglia.
114
Which neurons are lost in Parkinson's disease?
Dopaminergic neurons from the substantia nigra pars compacta.
115
Biosynthesis of dopamine
116
What is the immediate precursor of dopamine?
L-DOPA.
117
What enzyme converts L-DOPA into dopamine?
DOPA decarboxylase.
118
Why can't we simply give dopamine to patients with Parkinson's?
Dopamine has peripheral side effects and cannot cross the blood-brain barrier.
119
What is the mainstay of Parkinson's therapy?
L-DOPA.
## Footnote
as it can be taken across the BBB,
120
L-DOPA (levodopa) for PD treatment
- across BB
- converted into dopamine by DOPA decarboxylase
- increases CNS dopamine levels
121
Why is L-DOPA almost never used alone?
Because it is metabolized in the periphery where there is lots of DOPA decarboxylase, reducing its availability in the CNS.
122
What are the two drugs that inhibit DOPA decarboxylase in the periphery?
* Carbidopa
* Benserazide
| peripheral inhibitors / doesn't work in CNS
## Footnote
can't cross blood brain barrier
123
What is the combined formulation of L-DOPA and carbidopa called?
Cocareldopa.
124
What is the combined formulation of L-DOPA and benserazide called?
Cobeneldopa.
125
What is the enzyme that can metabolize L-DOPA in the periphery?
Catechol-O-methyl transferase (COMT).
126
what does COMT convert levodopa (L-DOPA) into?
3-O-methyldopa
127
What are the main COMT inhibitors used in the periperhy for Parkinson's therapy and what do they do?
* Entacapone
* Tolcapone
| increase L-DOPA available to CNS
128
what are the two main pathways dopamine can be broken down through in the CNS ?
- COMT
- MAO
129
Which form of monoamine oxidase primarily catabolizes dopamine in the CNS?
Monoamine oxidase B.
130
what can tolcapone do that entacapone can't?
cross BBB
- perserves L-DOPA in periphery and increases dopamine availability in CNS
131
What are the selective inhibitors of monoamine oxidase B used in Parkinson's?
* Selegiline
* Rasagiline
| both increase dopamine availability
132
what are the problems with selegiline ?
amphetamine derivatives in CNS which can cause behavioural issues
133
What is a common side effect associated with long-term L-DOPA treatment?
Dyskinesias.
| involuntary writhing movements seen around 2 years after levodopa treatm
134
what is the cause of dyskinesia ?
upregulation of protein called RASGRP1
135
What can cause rapid changes in clinical status in Parkinson's patients?
The loss of dopaminergic neurons from SN.
| HYPOKINESIA/DYSKINESIA reappears for short periods
136
What is a common acute side effect of L-DOPA therapy?
Nausea and postural hypertension
137
What medication can be used to treat nausea caused by L-DOPA?
Domperidone.
| DA antagonist
138
What psychiatric effects can occur as side effects of L-DOPA therapy?
* schizophrenia like symptoms: delusion/ hallucinations as a result of hyperdopaminergic neurons
* Confusion
* Insomnia
* Nightmares
139
What are dopamine agonists used for in Parkinson's disease?
They stimulate dopamine receptors directly.
| don't rely on DA neurons
140
what are common side efects of DA agonists ?
- compulsive behaviours e.g. gambling or hyper-sexuality realted to dopamine reward circuits
- cardiovasucalr effects (periphreal DA effects)
141
what are some older DA agonists ?
- bromocriptine
- pergolide
- apomorphine
## Footnote
less selective for dopamine subtypes
142
What are common side effects of older dopamine agonists?
* Vomiting
* Lung fibrosis
143
What newer dopamine agonists are better tolerated?
* Pramipexole
* Ropinirole
## Footnote
more active at D2 and D3 receptors
144
what is another name for dopamine release enhancers ?
mAChR antagonists
145
What is the role of muscarinic antagonists in Parkinson's treatment?
They help regulate transmission in the basal ganglia.
146
examples of mAChR antagonists?
- benztropine
- procyclidine
## Footnote
but they are non-selective so difficult to manage side effects/ more recent at M4 drugs
147
What is the mechanism of action of amantadine?
It is a non-competitive inhibitor of NMDA receptors and increases dopamine release.
148
What is the on-off effect in Parkinson's disease?
Fluctuations between good therapeutic effects ('on') and periods of bradykinesia (too low L-DOPA) or dyskinesia (too much L-DOPA) were not enough theraputic effect ('off')
## Footnote
typically, those in early stage PD spend more time in theraputic effect zone, but as it goes on the window of theraputic effect gets smaller - due to continuing loss of neurons in SN
149
What are some strategies to manage the on-off effect?
## Footnote
to stabalise the plasma L-DOPA levels in theraputic window
* Small frequent doses of L-DOPA
* Extended release formulations e.g. intestinal gel pump (Duopa)
* using add on medications like entacapone
150
What happens to the patient's dopamine buffer as Parkinson's disease progresses?
It decreases due to the loss of dopaminergic neurons.
151
What is the purpose of add-on drugs in the treatment of Parkinson's disease?
To stabilize the L-DOPA levels
## Footnote
Add-on drugs are used to complement the effects of L-DOPA and improve patient outcomes.
152
What does a positive change in disease status indicate in a clinical study?
A benefit to the patient
## Footnote
A positive number on the y-axis indicates improvement in the patient's condition.
153
What were the three drug combinations used in the clinical study?
* Co-beneldopa alone
* Co-beneldopa plus selegiline
* Bromocriptine
## Footnote
These combinations were compared over a six-year study period.
154
Which drug combination performed best in the first three years of the study?
Co-beneldopa plus selegiline
## Footnote
This combination provided the greatest benefit to patients compared to others.
155
What happens to the patient's function after three years of treatment with bromocriptine and co-beneldopa?
It dips below their starting score
## Footnote
This indicates that the treatment was becoming less effective over time.
156
What does the decline in patient function during the study suggest about Parkinson's disease?
It is neurodegenerative in nature
## Footnote
Patients lose neurons from the substantia nigra as the disease progresses.
157
What surgical approach was initially used for treating Parkinson's disease?
Ablation therapy targeting the globus pallidus internus
| - which removes inhibitory drive on thalamus
## Footnote
This approach involved destroying parts of the basal ganglia.
158
What has largely replaced ablation surgery in the treatment of Parkinson's disease?
Deep brain stimulation (DBS)
## Footnote
DBS is a less invasive method that involves implanting electrodes in the brain.
159
Which part of the brain is most often targeted in deep brain stimulation?
Subthalamic nucleus (STN)
## Footnote
Sometimes the globus pallidus internus is targeted, but STN is the most common.
160
What is the purpose of stimulating the subthalamic nucleus in DBS?
To modify its abnormal firing pattern
## Footnote
This alteration can lead to significant improvements in motor function. (good for dyskineasias)
161
What are some risks associated with deep brain stimulation?
* Further motor problems
* Cognitive issues
* Mood disturbances
* Behavioral problems
## Footnote
DBS does not improve non-dopamine related issues of Parkinson's disease.
162
What is the main limitation of deep brain stimulation?
It does not improve the non-dopamine problems of Parkinson's disease
## Footnote
Patients may still experience other symptoms not addressed by DBS.
163
summary of PD drug therapies
164
NICE guidelines of PD treatment
## Footnote
DDCi = DOPA decarboxylase inhibitor (e.g. carbidopa, benserazide); MAOi = monoamine oxidase B inhibitor (e.g. selegiline, rasagiline) DA agonist: NICE only recommends newer drugs such as pramipexole and ropinirole as first choice drugs.
165
what are first line treatments for PD?
- co-benaldopa
- rasagline
- tolcapone
166
what are 'last resort' drugs for PD ?
- ergot-derived dopamine agonists e.g. bromocriptine
167
what is the first choice drug if patients are experiencing significant motor problems ?
co-benaldopa
168
what drugs may be suggested if motor problems are not interfering with a pateint's life ?
- rasagline (MAOBi)
- tolcapone (COMTi)
169
what is the mechanism of action for benztropine ?
- MAChR
## Footnote
targets muscarinic receptors that regulate transmission in basal ganglia
170
L-DOPA intestinal gel formulation
duopa
171
COMT inhibitor that acts in the periphery only
entacapone
172
dopamine precursor
L-DOPA
173
dopamine agonist
pergolide
174
COMT inhibitor that acts centrally and in the periphery
tolcapone
175
DOPA decarboxylase inhibitor
benserazide
176
dopamine receptor antagonist
domperiode
177
Dopamine release enhancer, NMDA receptor antagonist
amantidine
