Parkinson's disease

Question 1

Clinical features

Answer 1

Muscle stiffness
Slow movement (bradykinesia)
Tremor at rest
Sometimes dementia in later stages

Question 2

Pathological features

Answer 2

Degeneration of dopaminergic (DA) neurons in substantia nigra
Loss of DA in caudate-putamen
Lewy bodies are located in cell body and axons of neurons in basal ganglia
Lewy bodies composed of aggregated alpha-synuclein

Question 3

DLB

Answer 3

Dementia with Lewy bodies
Third most common dementia form
Distinct from Parkinson’s disease dementia (PDD)
Shared clinical symptoms
Lewy bodies accumulate in neurons in cortex and basal ganglia

Question 4

Non-modifiable risk factors

Answer 4

Age (median onset of 65 years)
Males
10% of cases due to mutation in genes (alpha-synuclein, Parkin)

Question 5

Alpha-synuclein mutations

Answer 5

6 missense mutations associated with familial PD including A30P
Causes formation of toxic alpha-synuclein aggregates
H50Q may influence metal binding (Cu2+ induces aggregation)

Question 6

LRKK2 mutations

Answer 6

Leucine-rich repeat kinase 2
G2019S is relatively common cause of autosomal dominant PD
Anti-LRRK2 antibodies strongly label brainstem and cortical LBs

Question 7

Parkin

Answer 7

Part of the ubiquitin E3 ligase complex involved in degrading abnormal proteins (26s proteasome)
Parkin deletions and point mutations cause juvenile PD

Question 8

UCH-L1

Answer 8

Ubiquitin carboxy-terminal hydrolase L1
De-ubiquitinating enzyme
Missense mutation causes familial PD

Question 9

DJ-1 and PINK1

Answer 9

Both cause early onset AD PD
DJ-1 is mitochondrial protein that senses oxidative stress
Encoded by PARK7 gene
PTEN-induced putative kinase 1 (PINK1) is mitochondrial serine-threonine kinase
Protects cells from stress-induced mitochondrial dysfunction

Question 10

Modifiable PD risk factors

Answer 10

Traumatic brain injury, heavy metals and pesticides increase risk
Smoking and caffeine may decrease risk

Question 11

MPTP

Answer 11

7 people developed parkinsonism after injecting synthetic heroin containing MPTP
Crosses BBB and converted to MPP+ by glial cells
MPP+ transported to dopaminergic neurons and impairs mitochondrial electron transport
MPP+ structurally similar to pesticide paraquat

Question 12

PD treatment

Answer 12

Motor symptoms alleviated with L-dopa (converted to dopamine in brain)
COMT and MAO-B inhibitors prevent dopamine degradation