Pathophysiology of Parkinson's Disease

Question 1

Parkinson’s disease is a

Answer 1

PROGRESSIVE and NEURODEGENERATIVE disorder with INSIDIOUS onset

Question 2

Four Cardinal Signs of PD are:

Answer 2

Resting Tremor
Muscular rigidity
Bradykinesia
Postural impairment

Question 3

As the disease progress, you could see

Answer 3

Issues arise with swallowing and speech

Insomnia and incontience

Question 4

Declining NE levels can lead to

Answer 4

visual and heart disturbances + orthostatic hypotension

Question 5

Mean age of onset

Answer 5

~60 years

Question 6

The brain of a Parkinson’s patient shows

Answer 6

Dramatic loss of dopamine-containing neurons in the substantia nigra pars compacta

Question 7

The SNpc sends axons to the

Answer 7

caudate adn putamen/striatum which is a part of the basal ganglia and involve din control of movement

Question 8

The degree of functional impairment is correlated with

Answer 8

the loss of nigral neurons

Symptoms aren’t seen until 80% neuronal loss is approached

Question 9

Basal ganglia regulates

Answer 9

size and volume of movement that occurs through the primary motor neurons

Question 10

Define Lewy Bodies

Answer 10

Abnormal filamentous aggregates of the protein alpha-synuclein
Not specific for AD

Question 11

Lewy bodies can be seen through

Answer 11

silver stain or eosin and are located in the presynaptic bouton where it regulates the function of synaptic vesicles

Question 12

Lew bodies in PD

Answer 12

They precipitate into filaments and accumulate in the brain

Question 13

Common theme of neurdegenerative disorders?

Answer 13

Selective neuronal vulnerability - something about the disease affects one type of neuron more than others

Question 14

Substantia nigra has

Answer 14

Neuromelanin which is made from oxidized dopamine
High levels of FE which may enhance the oxidation of DA
Migroglial cells which produce ROS

Question 15

Heritability for PD

Answer 15

0.17

Question 16

Gene mutation in PD are

Answer 16

Mendelian and polygenic risk factors

Question 17

Two Risk Factor Genes

Answer 17

GBA-acid beta-glucosidase

UbiquitinC-terminal esterase L1 (UCHL1

Question 18

Other genetics in PD

Answer 18

SNCA
PARK2
PARK7
PINK1
LRRK2

Question 19

SNCA

Answer 19

Mutation in the gene encoding alpha-synuclein which is a major protein in lewy bodies

Question 20

PARK2

Answer 20

Encodes Parking an E3 ubiquitin ligase that recognizes damage and defective proteins and tags them for distruction
Also involved in mitophagy or removal of damaged mitochondria

Question 21

PARK 7

Answer 21

Encodes DJ1, a chaperone protein that protects damage proteins from misfolding
Function as a regulator of oxidant defenses

Question 22

PINK1

Answer 22

Recruits Parkin to damaged mitochondria to do its job

Question 23

LRRK2

Answer 23

Known to associate with Parkinson’s but unknown how

Leucine Rick Repeat Kinase-2 (dardarin)

Question 24

Environmental Toxins associated with PD

Answer 24

6- hydroxydopamine

MPTP

Question 25

6-hydroxydopamine

Answer 25

Produces ROS and is taken up by DA transporters into the neurons and wreck havoc

Question 26

MPTP

Answer 26

Once ingested, MAOB converts MPTP to MPP which does not cross the BBB but MPTP. It uses DA transpoter to get inside the cell and inhibits Mitochondrial Complex 1 No ATP then no cell

Question 27

Drug Induced PD

Answer 27

Antipsychotics (haldol) Reserpine Metoclopramide Tetrabenzine

Question 28

Other disease that induced PD

Answer 28

``` Progressive supranuclear palsy Corticobasal degeneration Shy-Drager syndrome Alzheimer's Wilson's disease Creutzfeldt-Jakob Striatonigral degeneration Encephalitis (WW1) ```

Question 29

Toxin Induced PD

Answer 29

Flour made from cycad seed has beta-methylaminoalanie | Manganese, carbon disulfide, CO

Question 30

Trauma Induced PD

Answer 30

Dementia pugilistica (punch drunk)

Question 31

Tyrosine hydroxylase dose what

Answer 31

Tyrosine to DOPA with oxygen

Question 32

High levels of Fe(III) in SN neurons leads to

Answer 32

Reaction with neuromelanin to form Fe(II) which reacts spontaneously with H2O2 to from OH- (destorys SNA and crosslinking lipids)

Question 33

3-nitrotyrosine is seen when

Answer 33

NO reacts with OH- producing ONOO- which reacts with tyrosine in proteins = oxidative stress

Question 34

BG receives input from where and does what with it

Answer 34

Cerebral cortex, processes it and sends it back to premotor and motor cortex to modulate activity of cortical neurons which send signals to motor neurons in the ventral horn of the spinal cord

Question 35

Net effect of basal ganglia output neurons in the internal globus pallidus (IGP) is

Answer 35

INHIBITION of motor activty

Question 36

Direct Pathway

Answer 36

Acts on the output neurons of the IGP to reduce inhibition of the motor pathway

Question 37

Indirect Pathway

Answer 37

Sends axons from the stiatum to the EGP which is in the subthalamic nucleus which then sends axons to the output neurons in the IGP/SNR to reinforces inhibition of motor activity

Question 38

Direct pathway is characterized by

Answer 38

D1, substance P and dynorphin

Question 39

Indirect pathway is characterized by

Answer 39

D2 and enkephalin

Question 40

Basal ganglia sends innervation where else?

Answer 40

Frontal and limbic cortex for a role in cognitive and emotional behavior

Question 41

DA in the circult

Answer 41

DA neurons are pacemaker neurons that require lots of ATP | They cause a rise in Ca which further increases the ATP need so you need good mitochondria

Question 42

DA + Direct

Answer 42

Facilitates direct so increases motor activity | Through D1

Question 43

DA + Indirect

Answer 43

Inhibits indirect so increases motor activity through inhibition of indirect Through D2

Question 44

Loss of DA in PD leads to

Answer 44

no thalamic activation of motor coretex

Question 45

ACh in the circut

Answer 45

Dopamine prevents the overactivation of cholinergic inhibitory neurons With the loss of DA, these inhibitory neurons are hyperactive leading to overactivity of the indirect pathway = bradykinesia and muscle rigidity

Question 46

Nucleus Accumbus Function

Answer 46

Reward and Reinforcement and motivation

Question 47

Too much DA =

Answer 47

Psychosis -- so correct DA deficiency in PD can lead to psychosis