PD I

Question 1

Voluntary movement originates in the ___ cortex and are mediated abd nodulated by the ______ and _____ systems

Answer 1

Motor (frontal) cortex; pyranidal and extrapyramidal systems

Question 2

The 2 tracts of the pyramidal system

Answer 2

Corticospinal tract

Corticobulbar tract

Question 3

Structures of the extrapyramidal system

Answer 3

Basal ganglia (Caudate, putamen, globus pallidus, substantia nigra, subthalamic nucleus)
Thalamus,
Cerebellum

Question 4

Structures that make up the Basal ganglia

Answer 4

Caudate, putamen, globus pallidus,

substantia nigra, subthalamic nucleus

Question 5

The _____ is a major target in the pharmacology of movement

disorders

Answer 5

basal ganglia–at the core if movement control

Question 6

The activity of the motor cortex is increased by ________

Answer 6

excitatory (glutamatergic) thalamo-cortical connections

Question 7

Excitatory motor control by _____ neurons is regulated by ______

Answer 7

excitatory (glutamatergic) thalamo-cortical connections;

GABAergic inhibitory neurons in the Gpi and SNr

Question 8

BG Output neurons are…

Answer 8

GABAergic inhibitory neurons in the GPi and SNr

Question 9

Role of ‘output neurons’

Answer 9

exert a tonic inhibitory effect on the thalamo-cortical neurons

Question 10

The ‘output” neurons are regulated by

Answer 10

by the coordinated activity of neurons located in the basal ganglia, which form two major pathways (indirect and direct)

Question 11

2 pathways of BG

Answer 11

Indirect and direct; regulate ‘output’ neuron firing

Question 12

Both the indirect and direct pathways originate with ____ neurons with ___ receptors

Answer 12

medium spiny GABAergic neuron; dopamine receptors (D1 or D2

Question 13

Dopamine receptors– __ receptors, __ types

Answer 13

5 receptors, in 2 types

Question 14

2 DA receptor types

Answer 14

D1-like

D2-like

Question 15

D1-like receptors

Answer 15

D1 and D5

Question 16

D2-like receptors

Answer 16

D2, D3, D4

Question 17

D1R mechanism

Answer 17

activates adenylate cyclase and production of cAMP –> stimulatory

Question 18

D2R mechanism

Answer 18

inhibits adenylate cyclase and decreases cAMP –> inhibitory

Question 19

D1Rs are _____ since they ___ neuronal excitability and D2Rs are ____ as they ____ neuronal exciatbility

Answer 19

D1Rs– Activating; Increase

D2Rs–inhibitory; decrease

Question 20

Other contributions of D1 and D2Rs

Answer 20

D1R and D2R also modulate the activity of various ion channels resulting in opposite effects on neuronal excitability

Question 21

Thalamocortical connects role

Answer 21

Stimulate motor activity (stim motor cortex)

Question 22

Striatal medium spiny GABAergic neurons: modulation/role

Answer 22

Role: integrate information from many sources
Receive excitatory synapses from cortical neurons, as well as stimulation from cholinergic striatal interneurons and dopaminergic modulation from the substantia nigra

Question 23

Activation of the ____ pathway
results in reduced activation of the
motor cortex. Overall ____ effect on movement

Answer 23

Activation of the INDIRECT pathway
results in reduced activation of the
motor cortex.
Overall INHIBITORY effect on movement

Question 24

Activation of indirect pathway

Answer 24

ACh –> excites GABA neurons –> inhibit GPe
1) –> less inhibition on GPi and SNr
2) –> inhibit STN –> less excitation of GPi and SNr
= can’t disinhibit movement (thalamus inhibited = no movement)

Question 25

Output neurons w/ activation of indirect pathway

Answer 25

Over-excitation of output neurons --> can't disinhibit thalamus = no movement

Question 26

Activation of Direct Pathway

Answer 26

Activate D1 receptor on GABA neurons--> inhibit GPi and SNr --> disinhibition of thalamus --> increase movement

Question 27

Output neurons w/ activation of direct pathway

Answer 27

Output neurons Inhibited --> thalamus disinhibited --> increased movement

Question 28

Net effect of activation of Direct pathway

Answer 28

results in increased excitation of the motor cortex (overall stimulatory effect on movement)

Question 29

Striatal neurons are densely innervated by _____ afferent fibers from the _____

Answer 29

Striatal neurons are densely innervated by DOPAMINERGIC afferent fibers from the SUBSTANTIA NIGRA PARS COMPACTA

Question 30

__ released in the striatum activates D1 and D2 receptors

Answer 30

Dopamine

Question 31

Binding to D1 receptors in the striatum ___ the ___ pathway

Answer 31

Binding to D1 receptors (activating receptors) activates the direct pathway

Question 32

Binding to D2 receptors in the striatum ___ the ___ pathway

Answer 32

Binding to D2 receptors (inhibitory receptors) inhibits the indirect pathway

Question 33

Overall effect of DA on movement

Answer 33

dopaminergic transmission in the striatum overall facilitates movement BY inhibiting indirect pathway and exciting direct pathway

Question 34

Damage to the BG causes

Answer 34

altered balance between direct and | indirect pathways leading to motor disorders

Question 35

2 types of movement disorders

Answer 35

1) hypokinetic | 2) Hyperkinetic

Question 36

In Hypokinetic disorders, the ___ pathway dominates causing ___ output

Answer 36

Indirect pathway dominates causing increased inhibitory output ex. PD

Question 37

In Hyperkinetic disorders, the ___ pathway dominates causing ___ output

Answer 37

Direct Pathway dominates causing decreased inhibitory output ex. HD

Question 38

Most common neurodegenerative disorder after AD

Answer 38

PD

Question 39

__% of population over 65 is affected by PD and __% of cases are sporadic

Answer 39

1%; 95%

Question 40

Characteristic symptoms of PD

Answer 40

- tremor - bradykinesia - rigidity

Question 41

T/F PD also has non-motor symptoms

Answer 41

TRUE Non-motor features, including cognitive impairment and psychiatric symptoms, are also frequently present.

Question 42

The most affected neurons in PD are

Answer 42

DA neurons in the substantia nigra, which progressively die. Up to 80% of DA neurons might be lost at the time of diagnosis

Question 43

Up to __% of DA neurons in the SNr may be lost at time of PD diagnosis

Answer 43

80%

Question 44

Loss of dopaminergic neurons in PD causes...

Answer 44

... a neurotransmitters imbalance in the striatum, over-activation of the indirect pathway, decreased stimulation of the direct pathway and reduced movement (bradykinesia)

Question 45

Control of D2 neurons (afferents)

Answer 45

The activity of D2 neurons in the striatum is regulated by the balanced activity of inhibitory dopaminergic and excitatory cholinergic afferents

Question 46

T/F There is a cure for PD

Answer 46

There is no cure for PD, nor disease-modifying treatments. | The only approved drugs for PD treat symptoms, not the underlying pathogenic process

Question 47

Environmental factors affecting PD

Answer 47

Rotenone Paraquat MPTP/MPP+

Question 48

genetic actors affecting PD

Answer 48

``` Alpha-synuclein Parkin PINK1 DJ1 LRRK2 VPS35 ATP13A2 GBA ```

Question 49

Neuronal dysfunction in PD

Answer 49

Neuronal dysfunction may start at synaptic terminal w/ neurons then atrophying Only ~30% of DA neurons are lost but 50-60% of terminals are lost

Question 50

Sporadic PD is due to ___, but monogenic PD is also possible (but rarer)

Answer 50

Environmental factors such as Rotenone, Paraquat, MPTP/MPP+

Question 51

3 cases for PD etiology

Answer 51

Case 1 (complex): distinct genotype and environemental factors (onset ~65) Case 2: one monogenic event (early onset ~35-40) Case 3: Enviro event in young age (ex. exposure to toxins MPTP/injury)--onset before 30 yrs

Question 52

Most PD likely of ___ complex etiology

Answer 52

Complex | mix of genetics and enviro (~95% of cases)

Question 53

Genetics in PD

Answer 53

genetic risk factors are usually many polymorphisms in many genes --> predispose one to PD as they age

Question 54

Enviro factors in PD that increase risk

Answer 54

- concussion (head injury) - pesticides BUT coffee and tobacco DECREASE risk

Question 55

MPTP/MPP+

Answer 55

MPTP converted to MPP+ which is a cation that enters Da neurons --> inhibits mitochondrial respiratory complex I

Question 56

Rotenone, paraquat

Answer 56

Rotenone (pesticide), paraquat (herbicide) | both inhibitors of mitochondrial respiratory complec I

Question 57

Heavy metals

Answer 57

Probable risk Mn, Fe Cause mitochondrial dysfunction, oxidative stress, impaired protein degradation

Question 58

Commonalities b/t environmental toxin

Answer 58

All toxins affect the mitochondria--may tell ys that it function may play an important role in PD pathogenesis

Question 59

Drug-induced Parkinson--which drugs

Answer 59

Typical antipsychotic drugs (chlorpromazine etc.) and neuroleptic agents may induce parkinsonism

Question 60

T/F Drug-induced PD is reversible

Answer 60

TRUE

Question 61

Cause of drug-induced PD

Answer 61

Caused by D2 receptor antagonism

Question 62

Those more likely to develop drug-induced PD

Answer 62

Most common among elderly patients, probably due to smaller reserve of dopaminergic neurons A genetic component predisposes to drug-induced parkinsonism

Question 63

Drug-induced PD timeline

Answer 63

Symptoms usually appear within days to months after drug use and disappear over weeks or months after cessation of the drug.

Question 64

Goal in treating PD

Answer 64

to decrease the activity of the indirect pathway, by increasing dopaminergic transmission or inhibiting cholinergic activity in the basal ganglia

Question 65

Strategies in treated PD (pharmacologically)

Answer 65

- Supplementation with L-DOPA (DA does not cross the BBB) - Inhibition of dopamine catabolism (decreased DA breakdown) - Use of dopamine receptor (D2R) agonists (inhibit indirect pathway) - Muscarinic antagonists (balance Ach and DA activity to modulate indirect pathway)