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Pathophysiology 2 > April 6 - Parkinson's Disease > Flashcards

April 6 - Parkinson's Disease Flashcards

1
Q

What is parkinsonism?

A

The clinical syndrome that arises from the degeneration of the basal ganglia
First described as a “shaking palsy” in 1817 by British physician, James Parkinson
It is a progressively deteriorating neurological disorder
It is a hypokinetic or akinetic disease

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2
Q

What is Parkinson’s Disease?

A

Idiopathic neurodegenerative condition caused by the loss of dopaminergic neurons in the substantia nigra
It is characterized by asymmetrical resting tremor, bradykinesia, rigidity, postural instability

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3
Q

What is akinesia?

A

Akinesia is the slowness or loss of normal motor function, resulting in impaired muscle movement; literally “without movement” or without much movement

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4
Q

What is bradykinesia?

A

It means slow movements

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5
Q

Describe the epidemiology of Parkinson’s

A

Estimated 4 million people are living worldwide with Parkinson’s disease
It affects about 1 in 100 people over 65
Incidence increases as people age with the average age of onset being around 65

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6
Q

How does smoking and caffeine consumption affect idiopathic parkinson’s disease?

A

Development of IPD is inversely correlated with cigarette smoking and caffeine

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7
Q

Explain the synthesis of dopamine?

A

Tyrosine is taken up from the blood to the brain’s extracellular fluid then into the dopaminergic substantia nigra neurons via specific enzyme transporters (the substantia nigra is the only place functional dopamine is found)
Tyrosine is hydroxylated into L-dopa, the dopamine prescursor
L-dopa is decarboxylated into dopamine

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8
Q

Describe synaptic transmission in the substantia nigra neurons

A

Action potential (AP) are produced via depolarization. The produced AP propagates down the axon towards the pre-synaptic terminal. The arrival of the AP at the pres-synpatic terminal opens Ca+ channels. Ca+ triggers exocytosis of the vesicles containing dopamine. Dopamine enters the presynaptic cleft and binds to D1 and D2 receptors on the post-synaptic putamine neurons, located in the striata

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9
Q

What does the basal ganglia do?

A

It controls complex movements and has a part in motor learning

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10
Q

Where is the basal ganglia located?

A

At the base of the forebrain

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11
Q

What composes the basal ganglia?

A

The substantia nigra, the striatum and the subthalamic nucleus

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12
Q

Where is the substantia nigra located?

A

Located in the midbrain

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13
Q

What does the substantia nigra do?

A

It has an important role in reward, addiction and movement. Input from all over the brain relayed via dopaminergic neurons to striatum

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14
Q

What composes the striatum?

A

It is composed of putamen and caudate nucleus

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15
Q

Where is the striatum located?

A

Below the cortex and the cerebrum

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16
Q

What is the role of the striatum?

A

Major input site of the basal ganglia system. Putamen neurons have both D1 and D2 neuron receptors

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17
Q

What is the ventrolateral thalamus (VLT)?

A

Integration centre for basal-ganglionic and cerebellar impulses. The VLT is brought to the corticospinal system. The VLT sends fibres to the precentral and supplementary motor cortices to initiate body movement

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18
Q

What is the role of the sub-thalamic nucleus?

A

It is involved in the indirect motor pathway (inhibitory in the motor pathway)

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19
Q

What is the role of the motor cortex?

A

Input signals are changed to output signals which leads to movement. It receives input from the VLT

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20
Q

What are the three major neurotransmitters involved in Parkinson’s disease?

A

Dopamine
Acetylcholine
GABA

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21
Q

How is dopamine important?

A

It is important in many brain functions including: motivation, cognition, learning, mood, attention, reward, sleep and voluntary movement

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22
Q

How does dopamine work?

A

It works via the indirect pathway and direct pathway within the basal ganglia to initiate movement

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23
Q

What happens if there is not enough dopamine?

A

Insufficient dopamine biosynthesis causes Parkinson’s disease where a person loses the ability to execute smooth controlled movements. Parkinson’s disease manifests when approximately 80% of dopamine function has been lost

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24
Q

What is the relationship between acetylcholine and dopamine in Parkinson’s disease?

A

Acetylcholine and dopamine are antagonistic neurotranstmitters; acetylcholine is excitatory where dopamine is inhibitory. If dopaminergic cells are destroyed, no dopamine is released to compete and acetylcholine runs unchecked.

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25
Q

What happens if there is too much acetylcholine?

A

Too much acetylcholine causes over activity of cholingeric neurons. This leads muscles to contract but as there is excess acetylcholine, muscles cannot repolarize and will remain contracted

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26
Q

What is the relationship between GABA and dopamine in Parkinson’s disease?

A

GABA is the main inhibitory neurotransmitter
In normal motor systems GABA release is regulated by the binding of dopamine to receptors
In Parkinson’s disease, the release of GABA will increase and decrease in the incorrect portions of the nigro-striatal pathway
A reduction in dopamine causes an increase GABA resulting the individual to be partially or fully paralyzed

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27
Q

How is movement initiated?

A

Information from different parts of the brain is sent to the substantia nigra to stimulate dopamine synthesis.
Dopamine is released from the substantia nigra neurons where is binds to D1 and D2 receptors (direct and indirect pathways, respectively) on the putamen neurons in the striatum

28
Q

What happens when dopamine binds to D1 receptors?

A

Dopamine binds to D1 receptors of substance P-producing putamen neurons in the striatum. Dopamine binding causes an increase in GABA levels which inhibits the firing of D1 putamen neurons. These putamen neurons are responsible for the production of GABA, so their inhibition causes a reduction in GABA production. This reduces the inhibition of the VLT, which allows the VLT to send signal to the premotor and motor cortices of the brain which leads to bodily movement

29
Q

What is the overall result of the direct and indirect motor pathways?

A

Both the direct and indirect pathways produce movement by decreasing inhibition of the VLT
GABA is either up or down regulated to facilitate necessary inhibition to propel the pathway

30
Q

Describe the pathophysiology of the direct motor pathway leading to Parkinson’s disease

A

In Parkinson’s disease, dopamine becomes deficient due to problems with synpatic transmission or death of neurons that produce it. Dopamine doesn’t activate D1 receptors, so no substance P is released to decrease GABA, firing of D1 neurons will increase in the putamen as they are not inhibited by GABA and thus D1 neurons release GABA upon firing to the VLT inhibiting the VLT from transmitting the signal to the motor cortex

31
Q

What is the overall result of the pathophysiology of the direct and indirect pathways?

A

VLT becomes inhibited in both the direct and indirect pathways by an excess of GABA
D1 and D2 receptors become inactive due to a complete or partial reduction in dopamine levels
Net inhibition occurs in the system, which stops the motor cortex from being activated resulting in no movement

32
Q

Describe idiopathic Parkinson’s disease (IPD)

A

Aka primary Parkinson’s
Degeneration of pigmented dopaminergic neurons in the substantia nigra (results in loss of dopamine)
Remaining dopaminergic neurons contain Lewy Bodies

33
Q

Describe the etiology of IPD

A

True etiology is unknown

Possible factors: genetic factors (alpha-synuclein and parkin genes), oxidative stress, excitotoxicity

34
Q

How is oxidative stress involved in the etiology of IPD?

A

Substantia nigra is a region of characterized by high levels of oxidative stress
Free radicals generated from dopamine metabolism
Healthy individuals have several anti-oxidative molecules in the substantia nigra to limit damage
IPD: free radical attack damages neurons because antioxidant defenses are not present

35
Q

How is excitotoxicity involved in the etiology of IPD?

A

Pathological process where nerve cells are damaged or killed from excess glutamate
In IPD, inhibitory effects of dopamine are not present, resulting in excessive glutaminergic stimulation

36
Q

In secondary Parkinsonism, Parkinsonian signs may be due to what?

A

The inability of dopamine to be produced
The inability of dopamine to be secreted
The inability of dopamine to bind to receptors on the post synaptic putamen neurons in the striatum

37
Q

What are causal factors of secondary Parkinsonism?

A

Drugs
Toxins
Infections
Head trauma

38
Q

Describe drug-induced Parkinsonism

A

Dopamine antagonists block dopamine receptors and output by the substantia nigra cells
They cause Parkinsonian signs such as rigidity, hypokinesia and resting tremor
Onset is abrupt, symptoms symmetrical
Symptoms tend to disappear after use of the drug is disontinued
Examples: antipsychotics, calcium channel blockers

39
Q

Describe toxin-induced Parkinsonism

A

Environmental factors such as pesticides and exposure to heavy metals such as iron and manganese irreversibly damage the dopaminergic neurons in the substantia nigra
Example: MPTP, carbon monoxide poisoning

40
Q

Describe infection-induced Parkinsonism

A

Post-encephalitic syndrome:
Due to a viral illness which results in degeneration of nerve cells in the substantia nigra
Disease follows a condition called encephalitis lethargica, which causes inflammation (encephalitis) of the brain
Leaves the patient speechless and statue-like

41
Q

Describe trauma-induced Parkinsonism

A

Repeated head trauma makes a person 4x more likely to develop Parkinson’s than individuals who have never experienced a head injury
Lesions to the substantia nigra and/or striatum can cause hematoma
Obstructs ventricular outflow resulting in pressure on the brain
Lesions and pressure affect dopaminergic cells causing Parkinsonian signs

42
Q

What are the clinical features of Parkinson’s disease

A

In the normal aging process, neurons of the substantia nigra degenerate at a rate of 0.5% per year
In IPD, neurons of the substantia nigra degenerate at a rate of 1% per year (around 45% are lost in the first decade after diagnosis
Threshold for clinically detectable PD occurs after 70-80% loss of dopaminergic neurons in the substantia nigra

43
Q

What are the primary symptoms of Parkinson’s disease?

A

Resting tremor
Bradykinesia
Cogwheel rigidity
Postural instability

44
Q

Describe the resting tremor

A

Present in 2/3rds of patients with PD
Most common in the hands (accompanied with characteristic “pill rolling” motion)
Less common in the jaw, legs and toes
Begins unilaterally but becomes bilateral as the disease progresses
Tremor amplitude and severity increase under stress and in emotional situations
Absent in sleep

45
Q

Describe bradykinesia

A

Slowness of movement - movement are often slow throughout and intended action
Trouble initiating moves
Unconscious associative movements occur in a series in a series of discontinuous steps rather than in a smooth and coordinated manner
They freeze in place (around doorways, initiating turns)
Festinating gait

46
Q

Describe cogwheel rigidity

A

Increased rigidity to passive movement of a limb
Ratchet like interruptions in tone that is seen when limb is bent
Thought that cogwheel rigidity is thought of as rigidity with a superimposed tremor
Usually begins unilaterally, but becomes bilateral as PD progresses

47
Q

Describe postural instability

A 
Stooped posture contributes to shuffling gait
Most common in advanced stages of IPD
Most disabiling to the patient
Increases the risk of falling
Least amenable to pharmacotherapy
48
Q

What are the secondary motor symptoms of PD?

A 
Decrease in spontaneous blink rate
Hypomania
Monotonous voice
Speech hurried, slurred
Microphagia
Drooling
49
Q

What are the secondary autonomic symptoms of PD?

A 
Uncontrolled sweating
Excess salivation (drooling)
Lacrimation
Impaired thermal regulation
Constipation
Urinary incontinence
Impotence
Sexual dysfunction
50
Q

What are the psychological symptoms of PD?

A

Dementia (affects about 20% of persons with PD)
Anxiety
Depression (endogenous due to biochemical changes in the basal ganglia, exogenous due to frustration with their condition)
Psychosis (paranoia, hallucinations)
Sleep disturbances

51
Q

What is Huntington’s disease

A

Autosomal dominant neurodegenerative condition
Hyperkinetic movement disorder
Progressive atrophy of the striatal neurons of the indirect pathway and abnormalities in all 4 domains of the basal ganglia
Usual age of onset is between 30 and 50 years
Physical symptoms: fidgety movements, tics, chorea

52
Q

Since there is no current diagnostic test for IPD, how is diagnosis made?

A

Clinically probable IPD can be diagnosed when the patient show 2 of the following sypmtoms: muscle rigidity, bradykinesia, resting tremor, postural instability
Rule out secondary parkinsonism (infections, toxins, drug-induced, trauma-induced)
Test to see if patient responds to L-dopa treamtent (IPD responds positively, other forms do not respond)

53
Q

What are pharmcological treatment options for PD?

A 
Dopamine replacement (levodopa, dopa decarboxylase inhibitor)
COMT Inhibitors
MAO-B Inhibitors
Dopamine agonists
Amantidine
Anticholingerics
54
Q

How does dopamine replacement work?

A

Levodopa (the precursor to dopamine) replaces depleted dopamine. Administration of dopa decarboxylase inhibitor mitigates the catabolism of levedopa in the periphery and promotes levodopa absorption across the BBB

55
Q

What are the main side effects of dopamine replacement?

A

Usually present within 5 years of treatment
Dyskinesia (abnormal or involuntary movements)
Wearing off (presentation of PD symptoms between doses; becomes longer as desensitization occurs)
“On - off” fluctuations (sporadic fluctuation of motor states)
Motor side effects may be due to periodic L-dopa administration, erratic absorption and a short half life producing pulsatile stimulation of dopaminergic receptors

56
Q

How do MAO-B inhibitors work?

A

Inhibition of MAO-B increases the amount of dopamine that is recycled and stored within protective vesicles

57
Q

How do COMT inhibitors work?

A

Inhibition of COMT peripherally increases the L-dopa available to cross the BBB

58
Q

How do dopamine agonists work?

A

The drug bypasses presynpatic neuron and acts directly on dopaminergic receptors

59
Q

What are the side effects of dopamine agonists?

A

Dyskinesia (reduced compared to L-dopa therapy)
Motor fluctuations (reduced compared to L-dopa therapy)
Confusion
Hallucinations
Sleep disorders (sleep attacks)
Leg oedema
Postural hypotension (sudden drop in blood pressure upon standing)
Impulsive behaviors (gambling, sex, shopping)

60
Q

How do anticholinergics work?

A

They decrease acetylcholine levels to restore dopamine/acetylcholine balance
Effective in treating involuntary resting tremors

61
Q

What are side effects of anticholinergics?

A 
Urinary retention
Blurred vision (loss of accomodation)
Constipation
Tachycardia 
Confusion
Memory loss
Restlessness
Hallucinations
62
Q

How does Amantidine work to treat PD?

A

It was an originally an antiviral
Presynaptically, it increases release of dopamine and it blocks reuptake of dopamine
Postsynpatically, it upregulates D2 receptors

63
Q

What are non-pharmacological treatment options for PD?

A 
Education
Support groups
Therapies (occupation, physical)
Diet and nutrition
Deep brain stimulation
64
Q

When do we use deep brain stimulation?

A

When patients sypmtoms cannot be adequately controlled by medications to stimulate release of dopamine from substantia nigra neurons

65
Q

How does deep brain stimulation work?

A

A neurostimulator delivers electrical stimulation to targeted areas of the brain that control movement (thalamus, subthalamic nucleus, globus pallidus)

66
Q

What are the three components of deep brain stimulation systems? How do they work together?

A

Neurostimulator
Extension
Lead (electrodes)
Electrical impulses are passed from the neurostimulator, up the extension and released from the leads into the targeted brain areas

67
Q

How does deep brain stimulation treat debilitating symptoms of PD?

A

Three theories:
DBS stimulates neurons that initiate movement
DBS blocks inhibitory neurons, thereby allowing brain signals to resume
DBS influences the flow of information along axons

Pathophysiology 2 (15 decks)

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