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Neurological Diseases > Lectures 7-10 > Flashcards

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
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2
Q

Parkison’s: prevalence

A
  • second most common neurodegenerative disease
  • men more than females before menopause
  • onset usually 50-80
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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
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4
Q

Parkinson’s: Premotor symptoms

A
  • Hyposmia
  • Depression
  • Constipation
  • Sleep disturbances
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5
Q

Parkinson’s: Cognitive Changes

A
  • Executive function
  • Visuospatial function
  • Can progress to Parkinson’s Disease-Dementia
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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
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7
Q

Parkinson’s: Risk factors

A
  • Age
  • 5-10% familial
  • 90% idiopathic
  • Likely to be combination of genetic and environmental factors
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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
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9
Q

PD Aetiology

A
  • learn table
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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
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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

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12
Q

Alpha-Synuclein

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

Neurological Diseases (24 decks)

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