Dementia Flashcards
What differences between a dementia and a non dementia brain can be seen on a PET scan?
Neuronal loss
Hypometabolism
Loss of grey matter
Ligher
In which 3 areas of function is there a progressive decline in ability in dementia
- Decline in memory and reasoning
- Decline in communication skills
- Inability to carry out daily activities
What behavioural and psychological symptoms are seen in dementia
Agitation Aggression Wandering Shouting Repeated questioning Sleep disturbance Depression
4 non-modifiable risk factors for dementia
- Age
- Genetic predisposition
- Family history
- Downs syndrome
4 modifiable risk factor for dementia
- Vascular risk factor
- Cognitive inactivity
- Environment
- Depression
What 2 structures can be seen in the brain in dementia
Plaques
Tangles
What protein is present in senile plaques and cerebral vessels in alzheimers disease
Beta-amyloid peptide
What protein is present in neurofibrillary tangles
Hyperphosphorylated tau protein
Do cholinergic cells increase or decrease in number in AD
Decrease significantly
What % of AD cases are classified as early onset
<5%
Name the 3 genes identified to be involved in early onset AD
Amyloid precursor protein (APP) Presenilin 1 (PSEN1) Presenilin 2 (PSEN2)
What kind of protein is amyloid precursor protein
Single transmembrane protein
Where is APP expressed normally (4)
Neurones
Glial cells
Endothelial cells
SMC
What is APP cleaved to form
Amyloidogenic A-beta peptides
What are mutations in APP associated with
Familial forms of early onset Alzheimers
Cerebral amyloid angiopathy
What does A673T mutation do
Decreases a-beta production and it protective of AD
What does PSEN1 encode for
PSEN1 encoding presenilin-1
This is a subunit of gamma secretase
How much mutations have been reported in
a) PSEN1
b) PSEN2
c) APP
a) 189
b) 24
c) 29
What does PSEN2 encode for
Gamma sacretase- aspartyl protease responsible for A-beta generation
What enzymes cleave APP (transmembrane polypeptide)
alpha, beta and gamma secretase
Describe the APP processing pathway that is non-pathogenic
- Alpha and gamma secretase cleave APP
- Derives P3 and C83
- No AD
Describe APP processing pathway that is pathogenic
- Beta and gamma secretase and generates a beta amyloid peptide (39-43)
- This is a pathogenic peptide
What 2 explanations have been suggested to explain amyloid proteins involvement in AD
- Overproduction of amyloid and oligomers
- Inability to remove amyloid
What are the sequence of steps that result in familial forms of AD (10)
- Genetic missence mutations in APP, PS1, PS2
- Increased proteolysis and production of APP
- Progressive accumulation of a-beta in brain interstitial fluid
- Deposition of aggregated A-beta40/ a-beta42 as plaques
- Inflammatory response
- Progressive neuritic injury within amyloid plaques
- Disruption of neuronal metabolism and ionic homeostasis
- Altered kinase/ phosphatase activity– hyperphosphorylated tau
- Formation of hyperphosphorylated tau protein
- Widespread neuronal/ neuritic dysfunction and death in hippocampus and cerebral cortex
What is the inflammatory response seen in familial forms of AD
microglial activation
astrocytosis and acute phase protein release
What gene is the strongest genetic risk factor for late onset AD
Apolipoprotein E
What is apolipoprotein E
Secreted lipoprotein involved in cholesterol metabolism
What are the 3 isoforms of ApoE and which is the greatest risk
ApoE2, E3 and E4
Where is ApoE4 polymorphorphism located
Chromosome 19
What does ApoE4 protein do
Decreases clearance of extracellular a beta
What is the normal function of Tau protein
Stabilises microtubules through 4 tubulin binding domains in case of the longer isoform
What is the effect of phosphorylating tau
- Binding of tau to microtubules normally maintained in equilibrium by kinases and phosphatases
- Phosphorylation regulates activity to bind to microtubules and can affect axonal transport
What is MAPT
Encodes microtubule associated protein Tau
What form of dementia are MAPT mutations related to
Frontotemporal dementia
How do amyloid csf levels change as disease progresses and why
They decrease because all amyloid goes into the plaques
How do tau csf levels change as disease progresses
Increases
3 blood based biomarkers seen in AD
Protein
DNA/ RNA
Lipids
What are MRI used for in AD?
See things such as hippocampal loss
Ruling out of other causes
Which cholinergic pathways degenerate in AD
Forebrain pathways innervating cortical and limbic structures
Effect of blocking acetylcholinesterase
Increases failing cholingeric signal
2 categories of drugs used to treat AD
Acetylcholinesterase inhibitors
NMDA receptor antagonists
Name 3 acetylcholinesterase inhibitors
When are they used
Donepezil, galantamine and rivastigmine
Used for management for mild to moderate Alzheimers disease
Name a NMDA receptor antagonist
When is it used
Memantine
Moderate Alzheimer’s disease who are intolerant/ contraindication to AChE inhibitors
Name some examples of disease modification therapies
Anti-fibrillation Secretase inhibitors Increased clearance Immunisation GSK3 inhibitors
