Pathogenesis of Dementia Flashcards Preview

MD1 Neuroscience > Pathogenesis of Dementia > Flashcards

Flashcards in Pathogenesis of Dementia Deck (64):
1

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

Toxic gain of function of gene product

2

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

Toxic gain of function of gene product

3

What is the incidence rate of Alzheimer's disease?

1 in 300

4

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

>90%

5

What is the incidence rate of Parkinson's disease?

1 in 5 000

6

What is the incidence rate of Creutzfeldt-Jakob disease?

1 in 1 000 000

7

What sort are most risk factors of AD?

Genetic

8

What is the most relevant genetic risk factor in AD?

Apolipoprotein E on chromosome 19
Determines age of onset

9

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

APP mutations on chromosome 21

10

Which genetic risk factors are associated with autosomal dominant AD?

PS1 on chromosome 14
PS2 on chromosome 1

11

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

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

12

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

45

13

What is the relationship between age and prevalence in AD?

Exponential doubling of prevalence with each decade after 50

14

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

Less than 45

15

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

80

16

What are the environmental risk factors of AD?

17

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

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

18

What are the basic types of AD?

Amnestic (temporal)
Visuospatial
Aphasic
Frontal

19

What is the classic type of AD?

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

20

What is the classic type of AD?

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

21

What is the incidence rate of Alzheimer's disease?

1 in 300

22

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

>90%

23

What is the incidence rate of Parkinson's disease?

1 in 5 000

24

Describe the amyloid cascade hypothesis

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

25

What sort are most risk factors of AD?

Genetic

26

What is the most relevant genetic risk factor in AD?

Apolipoprotein E on chromosome 19
Determines age of onset

27

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

APP mutations on chromosome 21

28

Which genetic risk factors are associated with autosomal dominant AD?

PS1 on chromosome 14
PS2 on chromosome 1

29

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

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

30

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

45

31

What is the relationship between age and prevalence in AD?

Exponential doubling of prevalence with each decade after 50

32

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

Less than 45

33

What is secondary prevention of AD?

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

34

What are the environmental risk factors of AD?

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

35

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

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

36

What are the basic types of AD?

Amnestic (temporal)
Visuospatial
Aphasic
Frontal

37

What are the types of AD defined by?

Neuropathologies in certain brain areas that then spread

38

What is the classic type of AD?

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

39

What is the amyloidcentric pathway of AD?

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

Where are APCs found?

In EC space and around small blood vessels

41

What are the proteins that form NFTs?

Different proteins

42

Why is amyloid beta problematic?

Buildup causes damage to nerve cells especially at synapses

43

Describe the amyloid cascade hypothesis

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

How does the amyloid plaque cause damage?

Tetramer sits on neuronal cell membrane and interrupts synapse

45

What is the order of damage in AD?

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

46

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

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

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

10 years

48

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

20 years

49

What are the therapies available for AD?

No effective disease modifying therapy
All drugs today boost general arousal of system by boosting cholinergic systems

50

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

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

51

What is primary prevention of AD?

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

What is secondary prevention of AD?

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

53

Describe CJD

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

54

What is kuru disease?

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

55

Why did kuru disease dramatically affect women?

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

56

What is the spongiform change histologically in prion diseases?

Small vacuoles in neurons
Pathological response to toxin in neurons - not mediated by astrocytes

57

What happens to the protein in a prion disease?

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

What is vCJD?

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

59

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

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

60

What is the protein affected in Parkinson's disease?

Alpha synuclein

61

What is the damage to the brain in PD?

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

What are Lewy bodies?

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

63

How does alpha synuclein become toxic?

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

64

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

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

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