Pathogenesis of Dementia Flashcards
What do all neurodegenerative diseases associated with abnromal protein conformations involve?
Toxic gain of function of gene product
What do all neurodegenerative diseases associated with abnromal protein conformations involve?
Toxic gain of function of gene product
What is the incidence rate of Alzheimer’s disease?
1 in 300
What is the overall incidence rate of Alzheimer’s disease?
> 90%
What is the incidence rate of Parkinson’s disease?
1 in 5 000
What is the incidence rate of Creutzfeldt-Jakob disease?
1 in 1 000 000
What sort are most risk factors of AD?
Genetic
What is the most relevant genetic risk factor in AD?
Apolipoprotein E on chromosome 19
Determines age of onset
Which genetic risk factor relates to mutations in the aberrant protein in AD?
APP mutations on chromosome 21
Which genetic risk factors are associated with autosomal dominant AD?
PS1 on chromosome 14
PS2 on chromosome 1
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
What is the median age at which people with Down syndrome develop AD?
45
What is the relationship between age and prevalence in AD?
Exponential doubling of prevalence with each decade after 50
What is the mean age of onset of AD in autosomal dominant cases?
Less than 45
What is the mean age of onset of AD in sporadic cases?
80
What are the environmental risk factors of AD?
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
What are the basic types of AD?
Amnestic (temporal)
Visuospatial
Aphasic
Frontal
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
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
What is the incidence rate of Alzheimer’s disease?
1 in 300
What is the overall incidence rate of Alzheimer’s disease?
> 90%
What is the incidence rate of Parkinson’s disease?
1 in 5 000
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
What sort are most risk factors of AD?
Genetic
What is the most relevant genetic risk factor in AD?
Apolipoprotein E on chromosome 19
Determines age of onset
Which genetic risk factor relates to mutations in the aberrant protein in AD?
APP mutations on chromosome 21
Which genetic risk factors are associated with autosomal dominant AD?
PS1 on chromosome 14
PS2 on chromosome 1
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
What is the median age at which people with Down syndrome develop AD?
45
What is the relationship between age and prevalence in AD?
Exponential doubling of prevalence with each decade after 50
What is the mean age of onset of AD in autosomal dominant cases?
Less than 45
What is secondary prevention of AD?
Give therapy to slow down/delay onset of AD in pre-clinical AD population
What are the environmental risk factors of AD?
Less than 7 years of school Head trauma Smoking Vascular disease Diabetes
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
What are the basic types of AD?
Amnestic (temporal)
Visuospatial
Aphasic
Frontal
What are the types of AD defined by?
Neuropathologies in certain brain areas that then spread
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
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
Where are APCs found?
In EC space and around small blood vessels
What are the proteins that form NFTs?
Different proteins
Why is amyloid beta problematic?
Buildup causes damage to nerve cells especially at synapses
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
How does the amyloid plaque cause damage?
Tetramer sits on neuronal cell membrane and interrupts synapse
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
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
How much time does it take to go from absolute zero to a pre-clinical AD burden of amyloid beta?
10 years
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
What are the therapies available for AD?
No effective disease modifying therapy
All drugs today boost general arousal of system by boosting cholinergic systems
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
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
What is secondary prevention of AD?
Give therapy to slow down/delay onset of AD in pre-clinical AD population
Describe CJD
Infectious disease Protein behaves like that of AD Much faster Subacute progressive onset Progression over 3-6 months Global distribution
What is kuru disease?
Prion disease in Kuru region of PNG
Very high mortality rate
Dramatically affected women
Why did kuru disease dramatically affect women?
Endocannibalism = mortuary feasting to honour dead
Women and children prepare bodies
Infected at much higher rates
What is the spongiform change histologically in prion diseases?
Small vacuoles in neurons
Pathological response to toxin in neurons - not mediated by astrocytes
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
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
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
What is the protein affected in Parkinson’s disease?
Alpha synuclein
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
What are Lewy bodies?
Found in PD
Round little balls and concentric rings
Made of alpha synuclein
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
What are the effects of a synuclein aggregation in the neuron?
Disruption of dopamine vesicle function
Neurodegeneration and less dopamine released
Synaptic loss
