April 6 - Parkinson's Disease

Question 1

What is parkinsonism?

Answer 1

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

Question 2

What is Parkinson’s Disease?

Answer 2

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

Question 3

What is akinesia?

Answer 3

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

Question 4

What is bradykinesia?

Answer 4

It means slow movements

Question 5

Describe the epidemiology of Parkinson’s

Answer 5

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

Question 6

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

Answer 6

Development of IPD is inversely correlated with cigarette smoking and caffeine

Question 7

Explain the synthesis of dopamine?

Answer 7

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

Question 8

Describe synaptic transmission in the substantia nigra neurons

Answer 8

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

Question 9

What does the basal ganglia do?

Answer 9

It controls complex movements and has a part in motor learning

Question 10

Where is the basal ganglia located?

Answer 10

At the base of the forebrain

Question 11

What composes the basal ganglia?

Answer 11

The substantia nigra, the striatum and the subthalamic nucleus

Question 12

Where is the substantia nigra located?

Answer 12

Located in the midbrain

Question 13

What does the substantia nigra do?

Answer 13

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

Question 14

What composes the striatum?

Answer 14

It is composed of putamen and caudate nucleus

Question 15

Where is the striatum located?

Answer 15

Below the cortex and the cerebrum

Question 16

What is the role of the striatum?

Answer 16

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

Question 17

What is the ventrolateral thalamus (VLT)?

Answer 17

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

Question 18

What is the role of the sub-thalamic nucleus?

Answer 18

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

Question 19

What is the role of the motor cortex?

Answer 19

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

Question 20

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

Answer 20

Dopamine
Acetylcholine
GABA

Question 21

How is dopamine important?

Answer 21

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

Question 22

How does dopamine work?

Answer 22

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

Question 23

What happens if there is not enough dopamine?

Answer 23

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

Question 24

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

Answer 24

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.

Question 25

What happens if there is too much acetylcholine?

Answer 25

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

Question 26

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

Answer 26

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

Question 27

How is movement initiated?

Answer 27

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

Question 28

What happens when dopamine binds to D1 receptors?

Answer 28

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

Question 29

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

Answer 29

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

Question 30

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

Answer 30

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

Question 31

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

Answer 31

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

Question 32

Describe idiopathic Parkinson's disease (IPD)

Answer 32

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

Question 33

Describe the etiology of IPD

Answer 33

True etiology is unknown | Possible factors: genetic factors (alpha-synuclein and parkin genes), oxidative stress, excitotoxicity

Question 34

How is oxidative stress involved in the etiology of IPD?

Answer 34

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

Question 35

How is excitotoxicity involved in the etiology of IPD?

Answer 35

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

Question 36

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

Answer 36

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

Question 37

What are causal factors of secondary Parkinsonism?

Answer 37

Drugs Toxins Infections Head trauma

Question 38

Describe drug-induced Parkinsonism

Answer 38

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

Question 39

Describe toxin-induced Parkinsonism

Answer 39

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

Question 40

Describe infection-induced Parkinsonism

Answer 40

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

Question 41

Describe trauma-induced Parkinsonism

Answer 41

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

Question 42

What are the clinical features of Parkinson's disease

Answer 42

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

Question 43

What are the primary symptoms of Parkinson's disease?

Answer 43

Resting tremor Bradykinesia Cogwheel rigidity Postural instability

Question 44

Describe the resting tremor

Answer 44

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

Question 45

Describe bradykinesia

Answer 45

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

Question 46

Describe cogwheel rigidity

Answer 46

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

Question 47

Describe postural instability

Answer 47

``` 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 ```

Question 48

What are the secondary motor symptoms of PD?

Answer 48

``` Decrease in spontaneous blink rate Hypomania Monotonous voice Speech hurried, slurred Microphagia Drooling ```

Question 49

What are the secondary autonomic symptoms of PD?

Answer 49

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

Question 50

What are the psychological symptoms of PD?

Answer 50

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

Question 51

What is Huntington's disease

Answer 51

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

Question 52

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

Answer 52

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)

Question 53

What are pharmcological treatment options for PD?

Answer 53

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

Question 54

How does dopamine replacement work?

Answer 54

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

Question 55

What are the main side effects of dopamine replacement?

Answer 55

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

Question 56

How do MAO-B inhibitors work?

Answer 56

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

Question 57

How do COMT inhibitors work?

Answer 57

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

Question 58

How do dopamine agonists work?

Answer 58

The drug bypasses presynpatic neuron and acts directly on dopaminergic receptors

Question 59

What are the side effects of dopamine agonists?

Answer 59

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)

Question 60

How do anticholinergics work?

Answer 60

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

Question 61

What are side effects of anticholinergics?

Answer 61

``` Urinary retention Blurred vision (loss of accomodation) Constipation Tachycardia Confusion Memory loss Restlessness Hallucinations ```

Question 62

How does Amantidine work to treat PD?

Answer 62

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

Question 63

What are non-pharmacological treatment options for PD?

Answer 63

``` Education Support groups Therapies (occupation, physical) Diet and nutrition Deep brain stimulation ```

Question 64

When do we use deep brain stimulation?

Answer 64

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

Question 65

How does deep brain stimulation work?

Answer 65

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

Question 66

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

Answer 66

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

Question 67

How does deep brain stimulation treat debilitating symptoms of PD?

Answer 67

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