Parkinson's Disease

Question 1

Symptoms of PD?

Answer 1

Bradykinesia
Resting tremor
Rigidity (cogwheel/lead pipe)
Sleep disturbances (flailing out)
Excessive salivation
Shuffling gait
Falls
Freezing of gate
Masked faces
Impaired swallowing 
Anosmia
Micrographics

Question 2

Risk factors?

Answer 2

Family history
Smoking
pesticide exposure
Age (17.4 per 100,000 person years between 50 and 59 increases to 93 per 100,000 person years between 70-79)

Question 3

What compensatory changes mean PD only manifests when a significant proportion of neurons have been lost in the nigrostiatal pathway?

Answer 3

Increase in TH activity

Increase in postsynaptic dopamine receptors in the striatum

Question 4

What other dopaminergic pathway may degenerate in PD?

Answer 4

Those from the VTA (mesolimbic may degenerate up to 50%)

Question 5

What other neurons may degenerate other than dopaminergic ones?

Answer 5

Noradrenergic (locus coeruleus)
Cholinergic (basal forebrain)

These may be responsible for the non motor symptoms of PD

Question 6

What are the cognitive dysfunctions in PD?

Answer 6

Mood disturbances
Cognitive defects
Dementia

Question 7

What mood disturbances are seen in PD?

Answer 7

Depression (increases risk of developing dementia)
May be organic or reactionary

Could be due to morphological changes in NA and 5-HT pathways in locus coeruleus and dorsal rap he nucleus

Question 8

What are the cognitive defects seen in PD?

Answer 8

Degeneration of the mesolimbic pathway

Disturbed processes under frontal lobe control

Question 9

What factors in PD increase th risk of developing dementia in PD?

Answer 9

Depression
Prominent gait and speech disordered
Poor L-dopa response

Question 10

What dementias may be associated with PD?

Answer 10

Lewy body dementia

Alzheimer’s (degeneration of the basal nucleus of meynert)

Question 11

What is psychosis?

Answer 11

The inability to distinguish between the subjective experience and external reality

Question 12

How many PD patients develop psychoso due to l-dopa treatment?

Answer 12

20-30%

Those with preexisting cognitive defects are at increased risk

Question 13

How do you treat PD psychosis without making the PD worse?

Answer 13

Reassess patients medication
Pimavanserin (selective serotonin inverse agonist)
Quitiapine

Question 14

What are Lewy bodies?

Answer 14

The hallmark of PD
Insoluble aggregates of alpha Synuclein
Which stain heavily for eosin

Question 15

Wha factor determines LB morphology

Answer 15

The neuroanatomical location

Question 16

Where else can LB be found?

Answer 16

DwLB
multiple system atrophy
Incidental LB pathology (patient who do not have PD…will they have gone on to develop PD?)

Question 17

What did Braak et al suggest?

Answer 17

LB disseminates throughout the brain affecting specific neuroanatomical areas in various stages. Not all PD cases show this progression though

Question 18

What is hypothesised to be the toxic species of PD?

Answer 18

Alpha Synuclein oligomers

Question 19

What might LB do?

Answer 19

May have a neuroprotective role acting as an aggresome for misfolded proteins which causes neurodegenration

Question 20

What are the aetiologcal theories of PD?

Answer 20

Familial (hereditary)
Viral
Pesticides and chemicals
MPTP (MPP+)
Industrial exposure

Question 21

What genes are associated with monogentic variants of PD

Answer 21

SNCA
LRRK
DJ-1
PARKIN
PINK1

Question 22

How may SNPs are associated with PD

Answer 22

~28 (over 20)

Found via genome wide association studies

Question 23

What viral aetiology is associated with a parkinsonian like syndrome?

Answer 23

Encephalitis lethargia

Question 24

Why is MPTP useful?

Answer 24

Provides a animal model for PD as is selective for mono amino neurons, particularly those in the SN

Question 25

What industrial chemicals cause degeneration of striatum and its outputs producing a PD like syndrome?

Answer 25

Manganese | Carbon disulphide

Question 26

Ultimately, do we know what causes Parkinson's disease?

Answer 26

No. However RNAi studies have indicated that several genes involve din protein trafficking are genetic modifiers for this disease e.g. The RabGTPases

Question 27

How can we treat PD with medications?

Answer 27

``` Dopamine therapy (give L-DOPA as dopamine cannot cross BBB) + carbidopa Dopamine agonists MAO-B inhibitors COMT inhibitor Anticholingerics Amantidine ```

Question 28

What are the problems with L-Dopa?

Answer 28

ADRS (psychosis, dyskinesia, N+V, hypotension) Effect decrease overtime Deietary considerations ?neurotoxic

Question 29

What are the different types of dopamine agonists? Give an example

Answer 29

Ergot derived - Bromocryptine Non ergot - ropinirole Subcutaneous - apomorphine

Question 30

What are the disadvantages of dopamine agonists?

Answer 30

Increased risk of psychosis Less efficacious than L-Dopa Impulse control disordered i.e. Pathological gambling

Question 31

name a MAO-B inhibitor

Answer 31

Selegiline

Question 32

How do MAO-B inhibitors work?

Answer 32

Bloc dopamine break down in DOPAC | Can be used alone or in combination with LDopa to prolong its effects

Question 33

name come COMT inhibitors

Answer 33

``` Tolcapone Entacapone (does not cross BBB) ```

Question 34

How does entacapone work?

Answer 34

Breaks peripheral break down of Ldopa to a compound which competes with it for entry into the CNS Thus needs to be even with L-Dopa Prolongs L dopa effects and helps eliminate wearing off

Question 35

What is procyclidine useful for?

Answer 35

Anticholingeric good for treating tremor

Question 36

What does Amantadine do?

Answer 36

Increases dopamine release ?inhibits uptake Unclear mechanism

Question 37

where can graft to treat PD come from?

Answer 37

Stem cells and the adrenal medulla

Question 38

What do grads from the adrenal medulla show?

Answer 38

Variable results and graft do not survive well

Question 39

What do graft from foetal stem cells show?

Answer 39

Short lived improvements | May accumulate alpha Synuclein themselves over time

Question 40

What surgical interventions are there for PD?

Answer 40

Lesions (thalamus, STN, globus pallidus) | Deep brain stimulation (electrodes often placed in subthalamic nucleus to cause depolarisation block of Gpi)