Lectures 7-10

Question 1

Parkinson’s: defintion

Answer 1

• Progressive neurodegenerative disease
  Clinically: characterised by motor impairments such as resting tremor, muscle-rigidity and a range of non motor impairments
  Pathologically: characterised by a loss of dopamenergic neurons (DA) in the substantia nogra pas compacta (SNpc) and presence of lewy bodies

Question 2

Parkison’s: prevalence

Answer 2

• second most common neurodegenerative disease
• men more than females before menopause
• onset usually 50-80

Question 3

Parkison’s: Motor symptoms

Answer 3

• Tremor at rest
• Rigidity
• Akinesia (impaired movement)
• Bradykinesia (slowed/abnormal movements)
• Postural instability/gait change
• must have at least two, with at least on being bradykinesia or resting tremor

Question 4

Parkinson’s: Premotor symptoms

Answer 4

• Hyposmia
• Depression
• Constipation
• Sleep disturbances

Question 5

Parkinson’s: Cognitive Changes

Answer 5

• Executive function
• Visuospatial function
• Can progress to Parkinson’s Disease-Dementia

Question 6

Parkinson’s: Diagnosis

Answer 6

• No definitive test
• Relies on clinical symptoms (mainly motor), ruling out other potential disorders and levadopa response
• Presents a significant problem as by the time patients present with symptoms, they have already lost 80% of their dopamine neurons

Question 7

Parkinson’s: Risk factors

Answer 7

• Age
• 5-10% familial
• 90% idiopathic
• Likely to be combination of genetic and environmental factors

Question 8

PD: Environment factors

Answer 8

• History of TBI
• Industrial chemicals
• Pesticide and herbicide exposure
• Tea/coffee and smoking have been reported to be protective

Question 9

PD Aetiology

Answer 9

• learn table

Question 10

Basal Ganglia

Answer 10

• Two main pathways: indirect and direct
• Direct: promotes execution of a planned motor action by exciting cortical neurons
• Indirect: inhibits motor action by inhibiting cortical neurons
• These pathways are balanced for smooth execution of movement

Question 11

Dopamine and the Basal Ganglia

Answer 11

Dopamine facilitates movement:
- Released from the dopamine neurons located in the SN
- Binds to dopamine receptors in the striatum
Reinforces the activity of the direct pathway:
- Promotes execution of movement
Reverses the activity of the indirect pathway:
- Counters the inhibition of movement
Results in excitation of cortical neurons and movement

Question 12

Alpha-Synuclein

Answer 12

• Protein
• thought to be involved in synaptic transmission normally
• Deposits are a hallmark of PD

Question 13

Lewy Bodies

Answer 13

• Abnormal intracellular deposits of a-synuclein
• Appear as dense core surrounded by clear halo
• Believed to: disrupt homeostasis, induce neurotoxicity, cause synaptic dysfunction
• Appear in SN spread throughout the cortex

Question 14

Braak staging of Lewy Bodies

Answer 14

• Stage 1 and 2: autonomic and olfactory disturbances (just in brainstem)
• Stage 3 and 4: sleep and motor disturbances (starts spreading)
• Stage 5 and 6: emotional and cognitive disturbances (spread throughout)

Question 15

PD: degeneration of other neuronal populations

Answer 15

• NA neurons in the locus coeruleus
• ACh neurons in the nucleus basalis of Meynery
• 5HT neurons

Question 16

PD: Treatment

Answer 16

• Cannot cure or reverse
• Slow and treat progression of symptoms
• Increase striatal dopamine by either replacing lost dopamine or reducing its breakdown
• Levodopa
• Dopamine agonists
• COMT inhibs
• MAO inhibs

Question 17

Levodopa

Answer 17

• Current gold standard treatment
• Pro-drug: dopamine can’t cross BBB - therefore give Ldopa (precurose of Dopamine) - allowing CNS to convert
• Overtime becomes less effective
• SE: schizophrenia like syndrome, dyskinesias (abnormal movements)

Question 18

HD

Answer 18

• Hyperkinesia disorder
• Inherited condition - autosomal dominant
• Usually ‘late onset’ - late 30s/early 40s
• Characterised predominantly through involuntary movements, but also intellectual, emotional and behavioural problems

Question 19

HD: Prevalence

Answer 19

• 5-10 per 100,000
• Rare in Japan
• Men and women equally
• Death usually occurs within 15-20 years of neurological onset

Question 20

HD: Cause

Answer 20

• All humans have 2 copies of the Huntingtin gene (HTT), which codes for the protien Hutingtin (HTT)
• Part of this gene includes a repeated section called a trinucleotide repeat
• When the length og this repeat reaches a certain threshold it produces an altered form of the protein called mutant Hutingtin protein (mHTT) - differing functions of these proteins cause the pathological changes seen in HD individuals

Question 21

Genetic Basis of HD

Answer 21

• HTT gene found on exon 1 of the short arm of chromosome 4
• mHTT is autosomal dominant, meaning mutation of either copy of the HTT alleles will result in disease
• Gene contains sequence of 3 DNA bases (CAG), healthy gene = 10 - 26 repeats, HD gene = 37 - 80 repeats (40+ will be effected)
• CAG codes for glutamate -> repeated CAG codon results in a polyglutamine tract (polyQ tract), and the repeated part of the gene is known as PolyQ region

Question 22

HD: Symptoms

Answer 22

• Progresses in 3 stages: early, middle and late, each with differing symptoms
• The longer the polyQ region, the earlier symptom onset

Question 23

HD: Physical Symptoms

Answer 23

• Chorea: jerky, random, involuntary movements
• Loss of coordination and balance
• difficulty speaking/slurred speech
• continual muscle contractions
• sleep disturbances

Question 24

HD: Behavioural Symptoms

Answer 24

• irritability and hostility
• apathy/disinterest
• anxiety
• depressed mood

Question 25

HD: Psychological symptoms

Answer 25

- Delusions - Hallucinations - Paranoia

Question 26

HD: Cognitive symptoms

Answer 26

- impairments to executive functioning - planning, abstract thinking etc - forgetfulness - difficulty making decisions - ultimately dementia

Question 27

HD: pathology - macroscopic

Answer 27

- Most prominent region effected is the basal ganglia - widespread loss of medium spiny neurons in the striatum - progressive atrophy of striatum, particularly the caudate - ventricular enlargement - widespread cortical atrophy and thinning

Question 28

HD: pathology - microscopic

Answer 28

- Huntingtin proteins with long PolyQ regions (>36 repeats) are prone to misfolding and will cause neurotoxic insoluble protein aggregates that enter the nucleus Hallmark feature of HD pathology: - microscopic aggregates called inclusion bodies or intraneuclear inclusions (INIs) - theory that this may be a coping mechanism to isole the toxic misfolded protein

Question 29

HD: Treatment options

Answer 29

- No treatment to halt disease progression - Pharmacological agents can only reduce the symptoms (benzodiazepines - muscle relaxes, antidepressants) - Tetrabenazine approved as treatment for chorea associated with HD

Question 30

HD: Future therapies

Answer 30

- Many genetic diseases involving mutations like HD could benefit from gene silencing (stop the making of the HTT protein from RNA) - Biggest problem: it doesnt change the mutant gene, it only stops the making of the mutant protein - CRISPR Cas9: gene editing technology