Dementia Flashcards
What is dementia?
A term used to describe a syndrome that may be caused by a number of illnesses in which there is progressive decline in multiple areas of function.
In dementia, what are the three main symptoms?
Decline in memory and reasoning
Decline in communication skills
Inability to carry out daily activities
What are the behavioural and psychological symptoms of dementia? (8)
agitation aggression wandering shouting repeated questioning sleep disturbance depression psychosis
What accounts for 62% of dementia cases?
What other types of dementia are there?
Alzheimer's disease Vascular dementia (17%), mixed AD and vascular dementia (10%), Lewy body dementia (4%), frontal temporal (2%), PD (2%) and others (3%).
What are the non-modifiable risk factors for dementia? (4)
Age, genetic predisposition, family history, Downs syndrome
What are the modifiable risk factors for dementia? (4)
Vascular risk factors (high cholesterol, hypertension, diabetes)
Cognitive inactivity
Environment
Depression and other psychiatric diseases
What are the two classic histological signs seen in AD?
Extracellular depositions of amyloid protein forming plaques
Intraneuronal depositions of hyper-phosphorylated tau, forming neurofibrillary tangles in cell bodies and neurites
What peptide forms these senile plaques?
Where is it also deposited?
Beta-amyloid peptide
Cerebral vessels
In AD, there is significant loss of what type of neurotransmitter cell?
Cholinergic cells
In AD, there is neuritic dystrophy and synaptic loss, as well as selective neuronal cell loss. What does this all cause?
Neuronal dysfunction
What three genes are linked to early-onset AD? What chromosomes are they located on?
APP - chromosome 21
PSEN1 - chromosome 14
PSEN2 - chromosome 1
APP is a single transmembrane polypeptide.
Where is it expressed? (4)
Neurones
Glial cells
Endothelial cells
Smooth muscle cells
What does APP encode and what is this protein’s function?
Amyloid precursor protein
It is cleaved to form amyloidogenic A-beta peptides
What are mutations in APP associated with?
Early onset AD
Cerebral amyloid angiopathy
How many mutations have been found in APP? What do they generally do?
29
Increase A-beta production (there is one, A673T, that decreases production)
What is presenilin-1?
How many mutations have been reported?
A subunit of gamma-secretase, the aspartyl protease responsible for A-beta generation.
189
What is the most common cause of early onset AD?
PSEN1 mutation
How many mutations in PSEN2 have been identified? Are these a common cause of AD?
24
No - rare cause of early onset AD
APP is cleaved by three secretase enzymes. What are they?
Alpha, beta and gamma
What secretases are used for the non-amyloidogenic pathway?
Alpha and gamma
What secretases are used for the amyloidogenic pathway?
What does this pathway generate?
Beta and gamma
A-beta amyloid peptide (39-43)
What is the causal sequence of pathogenic steps of familial forms of AD? (10 steps)
- Genetic missense mutations in APP, PS1,PS2
- Increased proteolysis and production of APP
- Progressive accumulation of Aβ in brain interstitial fluid
- Deposition of aggregated Aβ40/Aβ42 as diffuse plaques
- “Inflammatory” response (microglial activation, astrocytosis and acute phase protein release)
- Progressive neuritic injury within amyloid plaques
- Disruption of neuronal metabolism and ionic homeostasis (oxidative stress)
- Altered kinase/phosphatase activity, which causes hyperphosphorylation of tau.
- Formation of neurofibrillary tangles
- Widespread neuronal/neuritic dysfunction and death in hippocampus and cerebral cortex and progressive neurotransmitter deficits
–> DEMENTIA
What gene is associated with late-onset AD?
Apolipoprotein E - chromosome 19
What is ApoE? How many isoforms are there?
Why are these different isoforms important?
A lipoprotein involved in cholesterol metabolism
3 isoforms (2, 3 and 4)
The isoforms determine your risk - ApoE4 has the greatest risk (it decreases clearance of extracellular A-beta) and ApoE2 is protective against AD.
What is the function of tau?
How is this maintained?
It stabilises microtubules through four tubulin binding domains.
This is maintained in equilibrium by the actions of kinases and phosphatases. The phosphorylation of tau regulates its ability to bind to microtubules and so affects axonal transport.
What happens when tau becomes hyper-phosphorylated?
It dissociates from microtubules and they disassemble, causing neuronal loss.
Hyperphosphorylated, aggregated tau forms the neurofibrillary tangles.
What does MAPT encode?
Whatt are mutations in this linked to?
Microtubule associated protein Tau
Frontotemporal dementia and other Tauopathies
What are the current established CSF markers?
Decreased amyloid-beta 40 and 42 in the CSF
Increased p-tau 181,231/total tau/phospho-tau in CSF
In the future, what blood based markers could be used to diagnose AD?
Protein
DNA/RNA
Lipids
On MRI in patients with AD, what can be seen?
Reduction in brain volume
Enlarged ventricles
What can be used in PET scans to visualise A-beta plaques?
What about tau?
C11 Pittsburgh Compound B
FDG
What pathways degenerate in AD?
Cholinergic forebrain pathways innervating cortical and limbic structures
Name three acetylcholinesterase inhibitors.
Who are they recommended for?
What are they modestly efficacious on?
Donepezil, galantamine and rivastigmine
Those with mild to moderate Alzheimer’s disease
Cognitive symptoms
Name a NMDA receptor antagonist.
Who is it recommended for?
What are they modestly efficacious on?
Memantine
Those with moderate AD who are intolerant to AChE inhibitors, and those with severe AD
What are the symptomatic treatments for AD?
Antidepressant drugs
Antipsychotic drugs
Mood stabilisers
What are the side effects of memantine?
Dizziness, headaches, tiredness, increased blood pressure and constipation.
AD may be associated with a slow form of excitotoxicity and increased glutamate. What can excessive calcium ions lead to?
Free radicals
ROS
Mitochondrial dysfunction
What are the potential future treatments for AD? (6)
β-secretase inhibitors
Notch-sparing γ-secretase inhibitors or modulators
Aβ vaccines and monoclonal antibodies
Aβ aggregation inhibitors
Tau lowering/anti aggregation compounds
Regulation of abnormal anti-inflammatory mechanisms
