Lecture 10

Question 1

Parkinson’s Disease

Answer 1

2nd most common neurodegenerative disease affecting 1% of people <60 years. Fastest growing neurological disorder where increase is thought to be cause die to increase in lifespan and increase in population. Burden of disease is increasing, costing $8.9B in 2014 in Australia. No cure or disease-modifying treatment. Diagnosis based off clinical observation

• Rigidity (jerky movement)
• Resting tremor
• Bradykinesia (slow movement)

Question 2

Neuropathology

Answer 2

1. Progressive death of dopamine neurons in substantia Nigra
2. Deposition of abnormal form of protein (alpha-synuclein, superoxide dimutase 1, tau)

alpha-synuclein forms Lewy Bodies in Parksinson’s brain.

Question 3

Cause of Parkinson’s

Answer 3

~90% of cases are idiopathic, ~10% caused by mutations in alpha-synuclein protein genes/other mutations. In healthy brain, alpha-synuclein is solubule found in axon terminals and is involved in synapses. In P, it becomes insoluble and is linked to decreasing mitochondrial activity, autotrophy, decrease golgi activity, ER and lysosome function. They form Lewy Bodies in Substantia Nigra

Question 4

Risk factors

Answer 4

Age, REM sleep disorder, male gender, pesticide/chemical exposure, genetic predisposition, rural living

Question 5

Motor circuitry in health and Parkinson’s

Answer 5

Basal Ganglia consists of different interconnected regions of the brain. Substantia Niagra compacta houses the soma of dopaminergic neurons which project to striatum. Dopamine released in striatum modifies two different motor pathways (direct and indirect). Balance exists between pathways where direct facilitates movement while indirect inhibits it. Decrease dopaminic neurons = decrease dopamine = decrease in direct pathway but increase of indirect pathway = classic symptoms.

Question 6

Direct

Answer 6

Striatum -> globus pallidus internus and substantia nigra pars reticulata -> thalamus -> motor cortex

Question 7

Indirect

Answer 7

striatum -> globus pallaidus externus -> subthalamic nucleus -> globus pallaidus -> thalamus -> motor cortex

Question 8

Death of neurons

Answer 8

Unknown. Changes interlinked molecular pathways create a self-perpetuating neurodegenerative cascade

Question 9

treatment

Answer 9

Goal to prevent/ slow dopamine death, but, it is so complex. By the time movement symptoms arise, patient has had disease for ~20 yrs, just non-motor symptoms and theyve lost 60% neurons.

Question 10

alpha-synuclein biomarker

Answer 10

alpha-synuclein seed amplification assay uses blood/CSF to determine whether aggregated alpha-synuclein is present. You can produce Lewy Bodies where rate of amplification can be quantified. Increase ROA = Parkinson’s where it is above threshold. Accuracy unknown or early stage diagnosis.