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MD1 Neuroscience > Pathogenesis of Dementia > Flashcards

Pathogenesis of Dementia Flashcards

1
Q

What do all neurodegenerative diseases associated with abnromal protein conformations involve?

A

Toxic gain of function of gene product

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2
Q

What do all neurodegenerative diseases associated with abnromal protein conformations involve?

A

Toxic gain of function of gene product

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3
Q

What is the incidence rate of Alzheimer’s disease?

A

1 in 300

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4
Q

What is the overall incidence rate of Alzheimer’s disease?

A

> 90%

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5
Q

What is the incidence rate of Parkinson’s disease?

A

1 in 5 000

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6
Q

What is the incidence rate of Creutzfeldt-Jakob disease?

A

1 in 1 000 000

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7
Q

What sort are most risk factors of AD?

A

Genetic

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8
Q

What is the most relevant genetic risk factor in AD?

A

Apolipoprotein E on chromosome 19

Determines age of onset

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9
Q

Which genetic risk factor relates to mutations in the aberrant protein in AD?

A

APP mutations on chromosome 21

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10
Q

Which genetic risk factors are associated with autosomal dominant AD?

A

PS1 on chromosome 14

PS2 on chromosome 1

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11
Q

Why are people with Down’s syndrome far more likely to develop early onset AD?

A

Have extra copy of chromosome 21 > carries APP gene > make too much APP

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12
Q

What is the median age at which people with Down syndrome develop AD?

A

45

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13
Q

What is the relationship between age and prevalence in AD?

A

Exponential doubling of prevalence with each decade after 50

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14
Q

What is the mean age of onset of AD in autosomal dominant cases?

A

Less than 45

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15
Q

What is the mean age of onset of AD in sporadic cases?

A

80

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16
Q

What are the environmental risk factors of AD?

A
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17
Q

What is the relative influence of environmental risk factors in AD?

A

All carry some risk
Relative risks of each quite small
Also share risk factors with vascular disease

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18
Q

What are the basic types of AD?

A

Amnestic (temporal)
Visuospatial
Aphasic
Frontal

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19
Q

What is the classic type of AD?

A

In medial temporal lobe (amnestic)
Problems with memory - especially STM
Lost in space and time because of hippocampal damage

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20
Q

What is the classic type of AD?

A

In medial temporal lobe (amnestic)
Problems with memory - especially STM
Lost in space and time because of hippocampal damage

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21
Q

What is the incidence rate of Alzheimer’s disease?

A

1 in 300

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22
Q

What is the overall incidence rate of Alzheimer’s disease?

A

> 90%

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23
Q

What is the incidence rate of Parkinson’s disease?

A

1 in 5 000

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24
Q

Describe the amyloid cascade hypothesis

A

Alpha or beta cleavage of APP by alpha/beta secretases
Gamma secretase cleaves further in transmembrane domain of APP
Toxic gain of function when APP cleaved by beta and gamma secretases
Product = amyloid beta monomer ~42 AAs long = cell junk
In sporadic disease: failure to cleare amyloid beta monomers
Monomers > oligomers > plaques - self assemble
Amyloid plaque + inflammation
Neuronal loss and AD

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25
Q

What sort are most risk factors of AD?

A

Genetic

How well did you know this?
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26
Q

What is the most relevant genetic risk factor in AD?

A

Apolipoprotein E on chromosome 19

Determines age of onset

27
Q

Which genetic risk factor relates to mutations in the aberrant protein in AD?

A

APP mutations on chromosome 21

28
Q

Which genetic risk factors are associated with autosomal dominant AD?

A

PS1 on chromosome 14

PS2 on chromosome 1

29
Q

Why are people with Down’s syndrome far more likely to develop early onset AD?

A

Have extra copy of chromosome 21 > carries APP gene > make too much APP

30
Q

What is the median age at which people with Down syndrome develop AD?

A

45

31
Q

What is the relationship between age and prevalence in AD?

A

Exponential doubling of prevalence with each decade after 50

32
Q

What is the mean age of onset of AD in autosomal dominant cases?

A

Less than 45

33
Q

What is secondary prevention of AD?

A

Give therapy to slow down/delay onset of AD in pre-clinical AD population

34
Q

What are the environmental risk factors of AD?

A 
Less than 7 years of school
Head trauma
Smoking
Vascular disease
Diabetes
35
Q

What is the relative influence of environmental risk factors in AD?

A

All carry some risk
Relative risks of each quite small
Also share risk factors with vascular disease

36
Q

What are the basic types of AD?

A

Amnestic (temporal)
Visuospatial
Aphasic
Frontal

37
Q

What are the types of AD defined by?

A

Neuropathologies in certain brain areas that then spread

38
Q

What is the classic type of AD?

A

In medial temporal lobe (amnestic)
Problems with memory - especially STM
Lost in space and time because of hippocampal damage

39
Q

What is the amyloidcentric pathway of AD?

A

Environmental and pathogenic mutations create APP
Genetic and environmental risk factors > cleavage of APP to amyloid beta
Buildup of amyloid beta creates
- Amyloid plaque cores (APC)/amyloid cerebral angiopathy (ACA)
- Neurofibrillary tangles (NFT)
- Neurodegeneration

40
Q

Where are APCs found?

A

In EC space and around small blood vessels

41
Q

What are the proteins that form NFTs?

A

Different proteins

42
Q

Why is amyloid beta problematic?

A

Buildup causes damage to nerve cells especially at synapses

43
Q

Describe the amyloid cascade hypothesis

A

Alpha or beta cleavage of APP by alpha/beta secretases
Gamma secretase cleaves further in transmembrane domain of APP
Toxic gain of function when APP cleaved by beta and gamma secretases
Product = amyloid beta monomer ~42 AAs long = cell junk
In sporadic disease: failure to cleare amyloid beta monomers
Monomers > oligomers > plaques - self assemble
Amyloid plaque + inflammation
Neuronal loss and AD

44
Q

How does the amyloid plaque cause damage?

A

Tetramer sits on neuronal cell membrane and interrupts synapse

45
Q

What is the order of damage in AD?

A

Synapses lost
Neuronal cell death
Reactive changes in astrocytes trying to repair damage (throughout) but ultimately failing

46
Q

Is there a way of measuring the amount of amyloid plaques in a living person?

A

Yes, using a compound that crosses BBB and reversibly binds to amyloid beta
Detected by PET
Threshold determined for pre-clincal AD, and AD

47
Q

How much time does it take to go from absolute zero to a pre-clinical AD burden of amyloid beta?

A

10 years

48
Q

How much time does it take to go from a pre-clinical AD burden of amyloid beta to that of someone with AD?

A

20 years

49
Q

What are the therapies available for AD?

A

No effective disease modifying therapy

All drugs today boost general arousal of system by boosting cholinergic systems

50
Q

What is a potential therapy now in clinical trials that could modify disease?

A

Abs directed at amyloid beta proteins to decrease toxicity and/or increase clearance

51
Q

What is primary prevention of AD?

A

In populations that aren’t yet pre-clincal - meet prognostic algorith of “age x genes x PET” change over 3 years
Targeted with therapy
Currently trying to ID these people

52
Q

What is secondary prevention of AD?

A

Give therapy to slow down/delay onset of AD in pre-clinical AD population

53
Q

Describe CJD

A 
Infectious disease
Protein behaves like that of AD
Much faster
Subacute progressive onset
Progression over 3-6 months
Global distribution
54
Q

What is kuru disease?

A

Prion disease in Kuru region of PNG
Very high mortality rate
Dramatically affected women

55
Q

Why did kuru disease dramatically affect women?

A

Endocannibalism = mortuary feasting to honour dead
Women and children prepare bodies
Infected at much higher rates

56
Q

What is the spongiform change histologically in prion diseases?

A

Small vacuoles in neurons

Pathological response to toxin in neurons - not mediated by astrocytes

57
Q

What happens to the protein in a prion disease?

A

Normal form converted to abnormal form which is protease resistant
Alpha helices converted to beta sheets
Can amplify itself - causes normal protein to misfold
Same process in AD

58
Q

What is vCJD?

A

Variant of BSD that infects humans
Affects cerebellum
Occurs at much younger age
All cases were homozygous for susceptibility polymorphism in prion gene

59
Q

If you were exposed to BSD in its peak in the UK, why are you not allowed to donate blood?

A

Protein will probably mutate to become person-person infectious via blood

60
Q

What is the protein affected in Parkinson’s disease?

A

Alpha synuclein

61
Q

What is the damage to the brain in PD?

A

Specific degeneration of dopaminergic system in substantia nigra - blood cells shrink and disappear
Dopamine neurons in striatum disappear
Also affects cholinergic and noadrenergic pathways

62
Q

What are Lewy bodies?

A

Found in PD
Round little balls and concentric rings
Made of alpha synuclein

63
Q

How does alpha synuclein become toxic?

A 
Normally unfolded
Misfolds in oxidative environment - dopamine and metals in dopaminergic neurons
Oligomerises
Forms fibrils
Aggregates in substantia nigra
64
Q

What are the effects of a synuclein aggregation in the neuron?

A

Disruption of dopamine vesicle function
Neurodegeneration and less dopamine released
Synaptic loss

MD1 Neuroscience (55 decks)

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