Lectures 7-10 Flashcards
1
Q
Parkinson’s: defintion
A
- 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
2
Q
Parkison’s: prevalence
A
- second most common neurodegenerative disease
- men more than females before menopause
- onset usually 50-80
3
Q
Parkison’s: Motor symptoms
A
- 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
4
Q
Parkinson’s: Premotor symptoms
A
- Hyposmia
- Depression
- Constipation
- Sleep disturbances
5
Q
Parkinson’s: Cognitive Changes
A
- Executive function
- Visuospatial function
- Can progress to Parkinson’s Disease-Dementia
6
Q
Parkinson’s: Diagnosis
A
- 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
7
Q
Parkinson’s: Risk factors
A
- Age
- 5-10% familial
- 90% idiopathic
- Likely to be combination of genetic and environmental factors
8
Q
PD: Environment factors
A
- History of TBI
- Industrial chemicals
- Pesticide and herbicide exposure
- Tea/coffee and smoking have been reported to be protective
9
Q
PD Aetiology
A
- learn table
10
Q
Basal Ganglia
A
- 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
11
Q
Dopamine and the Basal Ganglia
A
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
12
Q
Alpha-Synuclein
A
- Protein
- thought to be involved in synaptic transmission normally
- Deposits are a hallmark of PD
13
Q
Lewy Bodies
A
- 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
14
Q
Braak staging of Lewy Bodies
A
- 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)
15
Q
PD: degeneration of other neuronal populations
A
- NA neurons in the locus coeruleus
- ACh neurons in the nucleus basalis of Meynery
- 5HT neurons
16
Q
PD: Treatment
A
- 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
17
Q
Levodopa
A
- 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)
18
Q
HD
A
- 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
19
Q
HD: Prevalence
A
- 5-10 per 100,000
- Rare in Japan
- Men and women equally
- Death usually occurs within 15-20 years of neurological onset
20
Q
HD: Cause
A
- 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
21
Q
Genetic Basis of HD
A
- 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
22
Q
HD: Symptoms
A
- Progresses in 3 stages: early, middle and late, each with differing symptoms
- The longer the polyQ region, the earlier symptom onset
23
Q
HD: Physical Symptoms
A
- Chorea: jerky, random, involuntary movements
- Loss of coordination and balance
- difficulty speaking/slurred speech
- continual muscle contractions
- sleep disturbances
24
Q
HD: Behavioural Symptoms
A
- irritability and hostility
- apathy/disinterest
- anxiety
- depressed mood
25
Q
HD: Psychological symptoms
A
- Delusions
- Hallucinations
- Paranoia
26
Q
HD: Cognitive symptoms
A
- impairments to executive functioning - planning, abstract thinking etc
- forgetfulness
- difficulty making decisions
- ultimately dementia
27
Q
HD: pathology - macroscopic
A
- 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
28
Q
HD: pathology - microscopic
A
- 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
29
Q
HD: Treatment options
A
- 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
30
Q
HD: Future therapies
A
- 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
