Parkinson's (DONE)

Question 1

Parkinson’s disease

Answer 1

Disease of aging
Typical onset in 60s
Incidence in the UK of 1 in 500; 10,000 diagnosed each year; 1 in 20 will be under 40 (early onset)

Question 2

Diagnosed by

Answer 2

3 of 4 cardinal symptoms for diagnosis: begins with tremor, develops into bradykinesia (slowness of movement), rigidity, postural instability
Classic: micrographia, altered posture, shuffling gait

Question 3

Pathology

Answer 3

PD brains have <10% of normal DA levels
Corresponding neuronal loss of the dopaminergic nigrostriatal pathway, also of serotonergic and noradrenergic pathways but to a lesser extent
Lewy bodies- present in CNS and PNS, protein inclusions that contain a-synuclein, tau

Question 4

The basal ganglia- control

Answer 4

The cortex is controlled by the thalamus (inhibited by GABA) and the thalamus is controlled by output nuclei
Striatum (acted on by glutamate from cortex) has D1 and D2 receptors, D1 innervate GP and SN reticula, D2 inhibitory

Question 5

The basal ganglia- direct pathway

Answer 5

Direct pathway inhibits output nuclei, less inhibition of thalamus, more activity in cortex

Question 6

The basal ganglia- indirect pathway

Answer 6

Indirect pathway also GABA but controlled by D2 (inhibitory) so DA suppresses pathway, reduces activity, excitatory at output nuclei
Balance regulates output- amount of GABA going to thalamus

Question 7

The basal ganglia in PD

Answer 7

Lose DA pathway from substantia nigra, less activation of direct pathway
Indirect pathway no longer inhibited
More excitation at output nuclei means too much GABA at thalamus, so not enough glutamate to cerebral cortex

Question 8

Symptoms onset once the critical balance of dopamine in the brain is lost

Answer 8

Can lose over 50% of SN neurons before experience Parkinson’s
By the time symptoms happen, the brain can no longer compensate, so intervention is difficult

Question 9

Genetic and environmental factors both play a role

Answer 9

5% of cases are familial, rest are sporadic or idiopathic
Environmental factors: herbicide/insecticide
Autosomal dominant: looks same as sporadic, develops at same age, genes involved are risk factors for general population
Autosomal recessive: earlier onset

Question 10

Toxin-induced Parkinson’s

Answer 10

MPTP causes severe Parkinson’s very quickly, discovered by accident

Question 11

Environmental causes of PD

Answer 11

MPTP administration
Pesticide/herbicide exposure
Well water
Head injury
Virus- sleep sickness following viral encephalitis
Antipsychotics- dopamine receptor antagonists
Food and water- aluminium content
NB: decreased risk with smoking or caffeine intake

Question 12

The first genetic link: a-synuclein

Answer 12

Family identified in Greece with mutation
Found in Lewy bodies
Known to interact with DA system
Spreading hypothesis, Lewy bodies found throughout brain in sequential patterning
Additional mutations in the SNCA gene identified

Question 13

Other symptoms

Answer 13

Combination of symptoms can be indicator of Parkinson’s developing in 5-10 years
Cardinal symptoms
Mental changes
Sensory phenomena
Motor
Sleep disturbances- fragmentation, apnoea, REM behaviour disordered, restless leg syndrome
Autonomic nervous system dysfunction- constipation, sexual dysfunction, urinary problems, sweating

Question 14

LRRK2/Park 8

Answer 14

Multiple mutations cause familial PD
Mutations looked for in general PD population
1-7% of idiopathic PD in western populations have a single mutation
Increased proportions in selected populations
May contribute to both tau and a-synuclein inclusions, mitochondrial toxicity and cytoskeletal dysfunction

Question 15

How do the cells die?

Answer 15

Genes and environment point to:
Mitochondrial dysfunction (mitophagy)
Propagation
Lysozomes
Evidence of increased levels of Par-4 in animal models (increased sensitivity to apoptosis)
Reduced growth factors