2. Parkinson's Disease

Question 1

who first described PD

Answer 1

James parkinson
- described it as a shaking palsy

Question 2

what is the mean age of onset

Answer 2

65 years

Question 3

what percentage of people are diagnosed before the age of 40

Answer 3

4%

Question 4

how many people does PD affect worldwide

Answer 4

10 million

Question 5

describe the clinical features of PD

Answer 5

rigidity
bradykinesia
tremor at rest
impaired gait
mask-like face
cramped handwriting

Question 6

what are the pathological features of PD

Answer 6

degeneration of DA neurons in the substantial nigra or caudate-putamen

presence of Lewy bodies

Question 7

what are Lewy bodies composed of

Answer 7

aggregated alpha-synucleiun protein

Question 8

where are Lewy bodies found

Answer 8

in the cell body and axons of neurons in the basal ganglia

Question 9

what dark substance from the substantia nigra is lost in PD

Answer 9

neuromelanin

Question 10

what is the difference between PD and dementia with lewy bodies

Answer 10

in DLB - cognitive symptoms appear either at the same time or before the onset of motor problems

in PD- motor problems arise at least a year before cognitive symptom

Question 11

what is the direct pathway of the motor circuit responsible for

Answer 11

increased movement

Question 12

describe the processes occurring in the direct pathway:

Answer 12

1. motor cortex releases excitatory glutamate into the caudate putamen

1b. substantia nigra releases dopamine to the caudate putamen, it stimulates the caudate pathway

2. caudate putamen releases GABA to the substantial nigra and globus pallidus
3. GABA binding to the globus pallidus and substantial nigra means less GABA is released to the thalamus
4. this means glutamatergic neurons of the thalamus can fire and stimulate increased movement

Question 13

what does dopamine bind to in the caudate putamen

Answer 13

d1 receptors

Question 14

what additional structure is featured in the indirect pathway

Answer 14

the sub thalamic nucleus

Question 15

describe the indirect pathway of motor movement.

Answer 15

1. glutamate release from the motor cortex
2. GABA is released from the caudate putamen to the globus pallidus. this creates an internal feedback within the globus pallidus whereby the pars internal and subthalamic nucleus are disinhibited
3. glutamate release from the sub thalamic nucleus to the substantia nigra and the pars interna of the globus pallidus
4. increases the GABA release from the globus pallidus and substantia nigra to the thalamus = decreased activation of the motor cortex

Question 16

what happens when the substantia nigra releases dopamine in the indirect pathway

Answer 16

binds to D2 receptors to inhibit the caudate pathway
GABA neurons are inhibited - and less GABA is released onto the thalamus = increased movement

Question 17

what happens to the direct and indirect pathways in PD

Answer 17

there is a loss of dopamine - this shifts the balance towards the indirect pathway, where stronger inhibition of the system reduces voluntary movement

Question 18

name 3 non-modifiable risk factors for PD

Answer 18

age
sex
genetics

Question 19

what is the sex ration for PD

Answer 19

male bias
male to female = 1.5:1

Question 20

what percentage of cases does genetics account for

Answer 20

~10%

Question 21

how many regions does alpha-synuclein protein have

Answer 21

3

Question 22

what are the 3 regions of a-synuclein

Answer 22

1. ampiphatic region
2. the non-amyloid component
3. acidic tail

Question 23

which region is associated with familial PD

Answer 23

the ampiphatic region

Question 24

which region confers aggregation properties

Answer 24

the non-amyloid component

Question 25

what mutation is a relatively common cause of autosomal dominant PD in caucasians

Answer 25

G2019S

Question 26

describe the G2019S mutation

Answer 26

elevates LRKK2 activity - a large protein kinase

Question 27

what % of cases does the g2019S mutation account for

Answer 27

4% of familial PD cases

Question 28

describe the evidence proving a role of LRKK2 in PD

Answer 28

anti-LRKK2 antibodies strongly label brainstem and cortical levy bodies - could play a role in alpha-synuclein and levy body formation

Question 29

what is Parkin part of

Answer 29

the ubiquitin E3 ligase complex

Question 30

what does UCH-L1 encode

Answer 30

a de-ubiquitinating enzyme

Question 31

what does a point mutation to UCH-L1 cause

Answer 31

late-onset PD - as there is a build up of aggregating proteins

Question 32

name 2 more mutations that cause early-onset PD

Answer 32

DJ-1 and PINK1

Question 33

what is the role of DJ-1

Answer 33

a mitochondrial protein that acts as a sensor for oxidative stress

Question 34

how many DJ-1 mutations have been identified in PD

Answer 34

19

Question 35

what is the role of PINK1

Answer 35

a protein kinase that protects cells from stress-induced mitochondrial dysfunction

Question 36

how many PINk1 mutations found in PD

Answer 36

70

Question 37

what do PINk1 and DJ-1 mutations elude to?

Answer 37

the role of mitochondrial dysfunction and oxidative damage in the pathogenesis of PD

Question 38

name 3 modifiable risk factors that increase the risk of PD

Answer 38

traumatic brain injury heavy metals pesticides

Question 39

name 2 things that can decrease risk of PD and by what % compared to non-users

Answer 39

smoking - 60% lower compared to non-smokers caffeine - 30% lower compared to non-caffeine drinkers

Question 40

describe the case study in 1982 where heroin users developed irreversible parkinsons

Answer 40

7 young people (aged 20-40) injected synthetic heroin containing MPTP. this molecule crossed the blood brain barrier where it was converted into MPP+ MPP+ gets transported into DA neurons where it can impair the electron transport chain and result in cell death

Question 41

what molecule converts MPTP into MPP+

Answer 41

glial cells

Question 42

what did the 1982 heroin fiasco suggest

Answer 42

could PD be caused by an environmental trigger similar to MPTP

Question 43

describe how a 1/3 of the Chamorro tribe came to be affected by PD

Answer 43

they indirectly ingested BMAA from flying foxes who had consumed the dangerous chemical from cycad palm nuts BMAA is a glutamate agonist - causes excitotoxicity and neurodegeneration = deficits

Question 44

during 1915-1926, an outbreak of which disease triggers Parkinsonism in 50% of its survivors

Answer 44

encephalitis lethargica

Question 45

what is L-dopa

Answer 45

a precursor to dopamine

Question 46

why can't you just inject dopamine into the brain

Answer 46

it cannot pass the BBB unlike L-dopa

Question 47

how long does L-dopa effects last for? why?

Answer 47

last for approx 5 years this is because neurons are continuing to die, so the relief will only last so long

Question 48

what is the effect of administrating carbidopa

Answer 48

its is a dopa decarboxylase inhibitor - so it prevents premature conversion into dopamine

Question 49

what can also be given to inhibit dopamine degradation

Answer 49

COMT and MAO-B inhibitors

Question 50

name a non-pharmaceutical option of managing PD

Answer 50

deep brain stimulation

Question 51

describe how deep brain stimulation works in PD

Answer 51

electrode is imparted into the pars interna of the globus pallidus, this attempted to increase input to the subthalamic nucleus (the idea is that it bypasses the substantial nigra

Question 52

name 3 drugs in the pipeline for PD

Answer 52

antioxidants immunotherapy inhibiting alpha-synuclein aggregation