Pathogenesis of Dementia

Question 1

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

Answer 1

Toxic gain of function of gene product

Question 2

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

Answer 2

Toxic gain of function of gene product

Question 3

What is the incidence rate of Alzheimer’s disease?

Answer 3

1 in 300

Question 4

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

Answer 4

> 90%

Question 5

What is the incidence rate of Parkinson’s disease?

Answer 5

1 in 5 000

Question 6

What is the incidence rate of Creutzfeldt-Jakob disease?

Answer 6

1 in 1 000 000

Question 7

What sort are most risk factors of AD?

Answer 7

Genetic

Question 8

What is the most relevant genetic risk factor in AD?

Answer 8

Apolipoprotein E on chromosome 19

Determines age of onset

Question 9

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

Answer 9

APP mutations on chromosome 21

Question 10

Which genetic risk factors are associated with autosomal dominant AD?

Answer 10

PS1 on chromosome 14

PS2 on chromosome 1

Question 11

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

Answer 11

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

Question 12

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

Answer 12

45

Question 13

What is the relationship between age and prevalence in AD?

Answer 13

Exponential doubling of prevalence with each decade after 50

Question 14

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

Answer 14

Less than 45

Question 15

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

Answer 15

80

Question 16

What are the environmental risk factors of AD?

Question 17

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

Answer 17

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

Question 18

What are the basic types of AD?

Answer 18

Amnestic (temporal)
Visuospatial
Aphasic
Frontal

Question 19

What is the classic type of AD?

Answer 19

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

Question 20

What is the classic type of AD?

Answer 20

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

Question 21

What is the incidence rate of Alzheimer’s disease?

Answer 21

1 in 300

Question 22

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

Answer 22

> 90%

Question 23

What is the incidence rate of Parkinson’s disease?

Answer 23

1 in 5 000

Question 24

Describe the amyloid cascade hypothesis

Answer 24

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

Question 25

What sort are most risk factors of AD?

Answer 25

Genetic

Question 26

What is the most relevant genetic risk factor in AD?

Answer 26

Apolipoprotein E on chromosome 19 | Determines age of onset

Question 27

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

Answer 27

APP mutations on chromosome 21

Question 28

Which genetic risk factors are associated with autosomal dominant AD?

Answer 28

PS1 on chromosome 14 | PS2 on chromosome 1

Question 29

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

Answer 29

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

Question 30

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

Answer 30

45

Question 31

What is the relationship between age and prevalence in AD?

Answer 31

Exponential doubling of prevalence with each decade after 50

Question 32

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

Answer 32

Less than 45

Question 33

What is secondary prevention of AD?

Answer 33

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

Question 34

What are the environmental risk factors of AD?

Answer 34

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

Question 35

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

Answer 35

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

Question 36

What are the basic types of AD?

Answer 36

Amnestic (temporal) Visuospatial Aphasic Frontal

Question 37

What are the types of AD defined by?

Answer 37

Neuropathologies in certain brain areas that then spread

Question 38

What is the classic type of AD?

Answer 38

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

Question 39

What is the amyloidcentric pathway of AD?

Answer 39

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

Question 40

Where are APCs found?

Answer 40

In EC space and around small blood vessels

Question 41

What are the proteins that form NFTs?

Answer 41

Different proteins

Question 42

Why is amyloid beta problematic?

Answer 42

Buildup causes damage to nerve cells especially at synapses

Question 43

Describe the amyloid cascade hypothesis

Answer 43

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

Question 44

How does the amyloid plaque cause damage?

Answer 44

Tetramer sits on neuronal cell membrane and interrupts synapse

Question 45

What is the order of damage in AD?

Answer 45

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

Question 46

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

Answer 46

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

Question 47

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

Answer 47

10 years

Question 48

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

Answer 48

20 years

Question 49

What are the therapies available for AD?

Answer 49

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

Question 50

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

Answer 50

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

Question 51

What is primary prevention of AD?

Answer 51

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

Question 52

What is secondary prevention of AD?

Answer 52

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

Question 53

Describe CJD

Answer 53

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

Question 54

What is kuru disease?

Answer 54

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

Question 55

Why did kuru disease dramatically affect women?

Answer 55

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

Question 56

What is the spongiform change histologically in prion diseases?

Answer 56

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

Question 57

What happens to the protein in a prion disease?

Answer 57

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

Question 58

What is vCJD?

Answer 58

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

Question 59

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

Answer 59

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

Question 60

What is the protein affected in Parkinson's disease?

Answer 60

Alpha synuclein

Question 61

What is the damage to the brain in PD?

Answer 61

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

Question 62

What are Lewy bodies?

Answer 62

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

Question 63

How does alpha synuclein become toxic?

Answer 63

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

Question 64

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

Answer 64

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