Parkinson's disease - Pathophysiology

Question 1

What is Parkinson’s disease?

Answer 1

neurodegenerative disorder characterised with neurodegeneration of the dopaminergic (DAergic) neurones
- occurs in the nigrostriatal pathway projecting from the substantia nigra to the striatum
= dopamine deficit

Question 2

What is the basal ganglia/striatum?

Answer 2

refer to a large and functionally diverse set of neural structures embedded deep within the cerebral hemispheres

cordate
- starts in the frontal lobe (cell body) and ends in the temporal lobe (tail)

putamen

• located in the forebrain
• connected to the cordate

globus pallidus
- comprised of internal and external segments

Question 3

What is the function of the basal ganglia?

Answer 3

primarily involved in regulating movement
- initiation and maintenance of movement, inhibit antagonist movements

converts highly processed sensory information into motor programme

has many parallel circuits.loops within the basal ganglia
- some have non-motor functions:
= cognition, motivation, addiction

Question 4

What are the symptoms of Parkinson’s disease?

Answer 4

muscle rigidity, stiffness
tremor at rest

hypokinesia, bradykinesia (slow), motor activity difficult to initiate & stop
= partial or complete loss of muscle movement, movements are not as wide-ranging as they normally should be

Question 5

What is the difference between Parkinson’s disease and Huntington’s disease?

Answer 5

Parkinson’s disease
- not hereditary
- characterised by the loss of DAergic neurons in the nigrostriatal tract which leads to motor impairments
= e.g. hypokinesia

Huntington’s disease
- progressive, inherited disorder
- characterised by the loss of GABAergic neurons in striatum which leads to excitation
= e.g. hyperkinesia (jerky-like involuntary movement, dementia)

Question 6

How do DAergic neurons act? How is DA released? How is DA terminated?

Answer 6

release

• L-DOPA enters the neurone
• L-DOPA is converted to dopamine via enzyme DOPA decarboxylase
• DA is engulfed by a vesicle and gets released into the synaptic cleft
• acts on D1 and D2 receptors

termination

• reuptake of dopamine into the neurone via DAT (DA transporter)
• DA can bind to autoreceptors (D2) to inhibit release of DA
• broken down by MAOb which is selective for DA

Question 7

What is the neurochemical origin of Parkinson’s disease?

Answer 7

stage 1-2

• early degeneration
• sleep and olfaction (smell) disturbances

stage 3-4
- loss of 50-80% of nigrostriatal neurons
- emergence of motor symptoms
= e.g. bradykinesia, hypokinesia, tremors

stage 5-6
- emergence of psychiatric symptoms (could be due to compensatory upregulation in D1,D2 receptors, dementia)

presence of Lewy bodies is associated with protein misfolding (abnormal conformation)

• proteins can form aggregates as time passes
• in PD, protein alpha-synuclein leads to aggregates called lewy bodies

Question 8

How is Parkinson’s disease diagnosed? What cannot be used to diagnose it and why?

Answer 8

is diagnosed using DAT Scan (123)I-FP-CIT SPECT
- distinguishes between PD and drug induced PD

DAT scans identify and label dopamine transporters in living people
- a radiotracer is injected into the blood circulation and it binds selectively to DA transporters (DAT)

cannot be diagnosed with D2 receptor PET scan
- not used as diagnostic criteria as downregulation of D2 receptors is found in other CNS diseases
= e.g. addiction

Question 9

How does PD cause hypokinesia?

Answer 9

hypokinesia - suppression of voluntary movement

loss of DAergic inhibition of GABAergic cells

• increased activity of GABAergic neurons in globus pallidus leads to inhibition of motor function
• decreased activation of cortical areas leads to difficulty initiating movements

Question 10

How does PD cause tremor and rigidity?

Answer 10

imbalance of neurotransmitter systems
- ACh, NA, 5-HT and GABA

cholinergic interneurons in the striatum are typically strongly inhibited by DA
- deficit in DA leads to increase in acetylcholine hyperactivity

hyperactivity of cholinergic neurons linked to PD symptoms
- tremor, bradykinesia

Question 11

How does PD cause psychiatric symptoms?

Answer 11

pathological changes in other brain areas (at later stages)

= e.g. hallucinations, delusions, dementia

Question 12

What are non-motor symptoms of PD?

Answer 12

depression
- high co-morbidity due to loss of DA
dementia
- due to neurodegeneration of cholinergic (Ach) neurones 
dyskinesias
pain
REM sleep Behaviour Disorder
constipation 
urinary problems 
siallorrhoea (drooling)
postural Hypotension
daytime sleepiness due to hypodopaminergic state

Question 13

How can MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) cause PD?

Answer 13

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
- heroin metabolite

can selectively be transported into dopaminergic cells via DAT and be converted to 1-methyl-4-phenylpyridine (MPP+) via MAOB

MPP+ generates free radicals which induces reactive oxygen species (ROS) generation from the mitochondrion
- ROS damages the cell membrane causing cell death

degeneration of DAergic neurones in the nigrostriatal pathway