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PMCOL 412 > PD I > Flashcards

PD I Flashcards

1
Q

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

A

Motor (frontal) cortex; pyranidal and extrapyramidal systems

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2
Q

The 2 tracts of the pyramidal system

A

Corticospinal tract

Corticobulbar tract

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3
Q

Structures of the extrapyramidal system

A

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

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4
Q

Structures that make up the Basal ganglia

A

Caudate, putamen, globus pallidus,

substantia nigra, subthalamic nucleus

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5
Q

The _____ is a major target in the pharmacology of movement

disorders

A

basal ganglia–at the core if movement control

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6
Q

The activity of the motor cortex is increased by ________

A

excitatory (glutamatergic) thalamo-cortical connections

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7
Q

Excitatory motor control by _____ neurons is regulated by ______

A

excitatory (glutamatergic) thalamo-cortical connections;

GABAergic inhibitory neurons in the Gpi and SNr

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8
Q

BG Output neurons are…

A

GABAergic inhibitory neurons in the GPi and SNr

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9
Q

Role of ‘output neurons’

A

exert a tonic inhibitory effect on the thalamo-cortical neurons

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10
Q

The ‘output” neurons are regulated by

A

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

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11
Q

2 pathways of BG

A

Indirect and direct; regulate ‘output’ neuron firing

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12
Q

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

A

medium spiny GABAergic neuron; dopamine receptors (D1 or D2

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13
Q

Dopamine receptors– __ receptors, __ types

A

5 receptors, in 2 types

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14
Q

2 DA receptor types

A

D1-like

D2-like

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15
Q

D1-like receptors

A

D1 and D5

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16
Q

D2-like receptors

A

D2, D3, D4

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17
Q

D1R mechanism

A

activates adenylate cyclase and production of cAMP –> stimulatory

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18
Q

D2R mechanism

A

inhibits adenylate cyclase and decreases cAMP –> inhibitory

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19
Q

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

A

D1Rs– Activating; Increase

D2Rs–inhibitory; decrease

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20
Q

Other contributions of D1 and D2Rs

A

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

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21
Q

Thalamocortical connects role

A

Stimulate motor activity (stim motor cortex)

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22
Q

Striatal medium spiny GABAergic neurons: modulation/role

A

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

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23
Q

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

A

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

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24
Q

Activation of indirect pathway

A

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)

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25
Q

Output neurons w/ activation of indirect pathway

A

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

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26
Q

Activation of Direct Pathway

A

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

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27
Q

Output neurons w/ activation of direct pathway

A

Output neurons Inhibited –> thalamus disinhibited –> increased movement

28
Q

Net effect of activation of Direct pathway

A

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

29
Q

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

A

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

30
Q

__ released in the striatum activates D1 and D2 receptors

A

Dopamine

31
Q

Binding to D1 receptors in the striatum ___ the ___ pathway

A

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

32
Q

Binding to D2 receptors in the striatum ___ the ___ pathway

A

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

33
Q

Overall effect of DA on movement

A

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

34
Q

Damage to the BG causes

A

altered balance between direct and

indirect pathways leading to motor disorders

35
Q

2 types of movement disorders

A

1) hypokinetic

2) Hyperkinetic

36
Q

In Hypokinetic disorders, the ___ pathway dominates causing ___ output

A

Indirect pathway dominates causing increased inhibitory output
ex. PD

37
Q

In Hyperkinetic disorders, the ___ pathway dominates causing ___ output

A

Direct Pathway dominates causing decreased inhibitory output
ex. HD

38
Q

Most common neurodegenerative disorder after AD

A

PD

39
Q

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

A

1%; 95%

40
Q

Characteristic symptoms of PD

A
  • tremor
  • bradykinesia
  • rigidity
41
Q

T/F PD also has non-motor symptoms

A

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

42
Q

The most affected neurons in PD are

A

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

43
Q

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

A

80%

44
Q

Loss of dopaminergic neurons in PD causes…

A

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

45
Q

Control of D2 neurons (afferents)

A

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

46
Q

T/F There is a cure for PD

A

There is no cure for PD, nor disease-modifying treatments.

The only approved drugs for PD treat symptoms, not the underlying pathogenic process

47
Q

Environmental factors affecting PD

A

Rotenone
Paraquat
MPTP/MPP+

48
Q

genetic actors affecting PD

A 
Alpha-synuclein
Parkin PINK1
DJ1 LRRK2
VPS35 ATP13A2
GBA
49
Q

Neuronal dysfunction in PD

A

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

50
Q

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

A

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

51
Q

3 cases for PD etiology

A

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

52
Q

Most PD likely of ___ complex etiology

A

Complex

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

53
Q

Genetics in PD

A

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

54
Q

Enviro factors in PD that increase risk

A
  • concussion (head injury)
  • pesticides
    BUT coffee and tobacco DECREASE risk
55
Q

MPTP/MPP+

A

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

56
Q

Rotenone, paraquat

A

Rotenone (pesticide), paraquat (herbicide)

both inhibitors of mitochondrial respiratory complec I

57
Q

Heavy metals

A

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

58
Q

Commonalities b/t environmental toxin

A

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

59
Q

Drug-induced Parkinson–which drugs

A

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

60
Q

T/F Drug-induced PD is reversible

A

TRUE

61
Q

Cause of drug-induced PD

A

Caused by D2 receptor antagonism

62
Q

Those more likely to develop drug-induced PD

A

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

63
Q

Drug-induced PD timeline

A

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

64
Q

Goal in treating PD

A

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

65
Q

Strategies in treated PD (pharmacologically)

A
  • 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)

PMCOL 412 (35 decks)

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