Alzheimer's Flashcards
What populations are affected by Alzheimer’s?
LD, Parkinson’s, BME
What is the mortality of Alzheimer’s?
Terminal condition, 5-8 years from diagnosis.
Aphasia, Apraxia, Agnosia, Disturbance of executive functioning, depression, psychosis, behavioural and personality changes are all symptoms of what?
Alzheimer’s disease / dementia
Early stages (year 1-3) of Alzheimer’s include what symptoms?
Learning difficulties
Depression
Losing direction when out
Recent memory impairment and forgetting names
Increased number of accidents whilst driving
Impaired activity of daily living
Mid stages (year 2-7) of Alzheimer’s include what symptoms?
Aphasia, Amnesia, Inability to bath, eat, toilet, or dress without help. Behavioural and Psychiatric changes, Inability to calculate solutions and problem solve!
Late stages (7+ years), of Alzheimer’s include what symptoms?
Seizures, Short and long term memory loss, double incontinence, Mutism or nonsensical speech, complete dependence on others, rigid posture
What type of Dementia is caused by increasing age, family history, down syndrome, ApoE4, Low IQ, Previous head injury, Cerebrovascular disease, depression, diabetes, obesity?
Alzheimer’s!
What type of Dementia has a sudden onset in late 60’s-70’s?
Vascular disease
What type of dementia is caused by an infarct, hypertension, stroke, TIA, family history, male, smoking or AF?
Vascular dementia
What type of dementia has the symptoms of; Emergent of emotional and personality changes including depression and memory impairment, apraxia, agnosia, dysarthria, dizziness, gait walk, weakness of extremities, extensor plantar response, pseudobulbar palsy, exaggeration of deep tension reflexes?
Vascular
What type of dementia have these symptoms; repeated falls, syncope, transient loss of consciousness, systemised delusions, non-visual hallucinations, REM sleep behaviour disorder, depression, extremely sensitive to side effects of antipsychotics?
Lewy body dementia
What type of dementia is caused by: related to Parkinson’s disease, and family history?
Lewy body dementia
What type of dementia has an onset of 45-70 years of age and doesn’t follow the conventional therapy?
Frontotemporal lobar degeneration / Frontotemporal dementia
Frontal lobal dementia is responsible for what change in a person?
Behaviour and personality
Temporal lobe dementia is responsible for what change in a person?
Language disorders
The following symptoms are related to what type of dementia?: Insidious onset, slow progression, early loss of insight, early signs of disinhibition, distractibility, impulsivitiy, language features (repeating!), affective features (depression, emotional blunting, apathy)
Frontotemporal lobar degeneration / Frontotemporal Dementia
The causes of what type of dementia are primarily unknown, but can be associated with mutations in progranulin (GRN), TAU linked to chromosome 17, TDP-43 and C90RF72 genes?
Frontotemporal lobar degeneration / Frontotemporal Dementia
What investigates are done in primary care to rule out differential diagnosis?
Alzheimers**
- FBC
- U&E’s
- LFT’s
- CRP
- Calcium and Phosphate
- Thyroid function
- Vitamin B12 and Folate
- Urine dipstick
- Blood Glucose
Temperature
What investigations are done in secondary care to rule out differential diagnosis?
Alzheimer’s**
- MRI and CT scan
- Urinalysis
- HIV status
- Neuropsychological assessment
EEG
What MMSE score means a patient is initiated on treatment? Alzheimers*
21-25 ‘Mild AD’
What agents are proven to prevent dementia?
Antihypertensives, Beer, Oestrogen,
What agents are proven to be helpful at the onset of dementia ?
Ginseng
What medication group is used at the onset of Dementia?
AChEI’s
What is first line AChEI?
Donepezil
What AChEI can be used for Lewy body dementia off license?
Rivastigmine
What type of AChEI is a selective reversible inhibitor?
Donepezil
What type of AChEI is a selective reversible AChE inhibitor, and enhances the response of nAchR to Ach?
Galantamine
What type of AChEI is a non-selective reversible AChE inhibitor, non-competitive?
Rivastigmine
What is a common side effect of Donepezil and when can it be dangerous?
!!Bradycardia!! (Dangerous in certain heart diseases, or if taking heart-slowing drugs such as Digoxin, Beta blockers, or CCB!)
What type of drug is used in the later stages of dementia?
Memantine - NMDA receptor antagonist
Dose of Memantine?
5mg OD for one week then increased by 5mg per week until at 20mg,
What is Memantine cautioned in?
Epilepsy and seizures!
Examples of Anti-amyloid antibodies?
Aducanumab, and Lecanemab
What medications can cause cognitive decline?
○ Antihistamines: Diphenhydramine
○ Tricyclic antidepressants
○ Antipsychotics: Quetiapine
○ Drugs used in urinary incontinence: Solfienacin
○ Hyoscine
○ Painkillers: Morphine
Some Asthma and COPD medications
Unlicensed use for mild to moderate dementia with lewy bodys?
Donepezil or Rivastigmine
Unlicensed use When is Galantamine considered in mild to moderate dementia with Lewy bodies?
When Donepezil and Rivastigmine aren’t tolerates
Unlicensed use Severe dementia with Lewy Bodies, what medication?
Consider Donepezil or Rivastigmine
Unlicensed use Vascular dementia + suspected comorbid Alzheimer’s disease, Parkinson’s disease dementia or dementia with Lewy Bodies, what medication should be considered?
AChEi or Memantine
What should not be offered for Frontotemporal Dementia?
AChE inhibitors or Memantine!
Why are Benzodiazepines avoided in dementia?
Increase the falls risk by 8!
How much does anti-psychotics increase a falls risk?
x2
What dose of risperidone is used for Schizophrenia?
2mg = Should not be stopped, if pt has dementia!
What does the ABC approach stand for?
Antecedents - trigger
Behaviour - what it was
Consequence - what happens after
If a patient is on psychotropics when should it be reviewed?
At least every 3 months
When anti-psychotics are initiated when should they be reviewed?
Every 6 weeks
When would using Amitriptyline be a good idea?
Sedating antidepressant for agitation, depression and sleep disturbance
When should antipsychotics be given to a dementia patient?
-Persistent aggression
-Moderate to severe Alzheimer’s dementia
Unresponsive to non-drug approaches
-Risk of harm to self or others
What is the starting dose of Risperidone for Alzheimer’s?
0.25mg TWICE daily
How should the dose of Risperidone be altered for Dementia?
Adjust by increments of 0.25mg twice daily, not more frequently than every other day, if needed.
What is the optimum dose for most patients on Risperidone for Dementia?
0.5mg twice daily
When does most BPSD resolve?*Dementia
4-6 weeks
What is first line for BPSD? *Dementia
Non-drug psychosocial interventions
In severe aggression in dementia we should use what drug?*Dementia
Risperidone
What drug’s should be avoided in dementia?
Haloperidol, Quetiapine and Benzodiazepines
What features in the brain indicate Alzheimer’s?
-Smaller brain
-Larger gaps between Juru
-Smaller surface area
-Less grey matter
-Neuronal loss
-Enlarged ventricles
-Hippocampus atrophy
-Extracellular plaques
What are the Intra-neuronal neurofibrillary tangles composed in in Alzheimer’s?
HYPERphosphorylated TAU protein
What percentage of atrophy is present in the hippocampus in mild-moderate Alzheimer’s disease?
15-20%
What functional losses are present in Alzheimer’s disease?
Cholinergic, GABAergic and monoaminergic transmitter systems *Specific and important!
What does APP stand for?
Amyloid Precursor Protein
Where is APP found?
Neuronal and non-neuronal cells
What cleaves APP?
a,b, and y secretases
What secretase forms soluble APP?
a-secretases = sAPP and then cleaved by y-secretase!
By cleaving b and y secretase what is produced?
B-amyloid (AB- which is toxic!!)
AB40 and AB42 are produced which is the most abundant?
AB40
AB42 is the most insoluble and most amyloidogenic, mutations in what increase the production of AB42?
APP mutations
A mutation in what increases y secretase activity?
Presenilin
What does an increase in B-amyloid mean?
More plaque!
What secretase does this path correspond to? Amyloid precursor protein cleaved by a secretases –> extracellular part forms SAPP Soluble = physiological roles in extracellular environment - rest of protein cleaved by y secretase
A
What secretase does this path correspond to? Forms plaques, peptide between two sies 40-42 amino acid sites - Amyloid B 42 most soluble and most likely to make more plaques. B40 most likely to be seen.
B
What secretase does this path correspond to? Within extracellular site, cleavage site is within transmembrane = c terminal liberated - cleavage of B next.
Y
What are the stayed of B-amyloid deposition?
1) Monomer hydrophobic regions
2) Oligomer interacts with other oligomers
3) Fibrils Amyloid B
4)Plaques (cell debri, astrocytes)
What is the role of Tau protein in neurons and how does its abnormal phosphorylation lead to neurofibrillary tangles and neuronal cell death?
1) Tau protein binds to microtubules in neurons, stabilizing them and facilitating axonal transport.
2) When Tau becomes hyperphosphorylated, it detaches from the microtubules, leading to their depolymerization.
3) Tau proteins aggregate to form paired helical filaments, which further aggregate to form neurofibrillary tangles.
4) Axonal transport is disrupted, leading to neuronal cell death
What is first to be changed in the ACh pathways in Alzheimer’s?
Nucleus basalis projects to cortex. Septal nuclei project to hippocampus (role in memory)
What gene is associated with down syndrome early onset Alzheimer’s?
Trisomy 21 - APP is on chromosome 21, more expression of amyloid protein = more B-amyloid - more plaques
What are the 3 key mutations found in early onset of Alzheimer’s?
APP - more plaques
Presenilin - Increases AB42 production
Tau mutation - Increased phosphorylation of Tau protein
What gene is involved with late onset (60+) of Alzheimer’s?
ApoE (ApoE1-4)
What is the role of ApoE4?
Linked with risk of developing Alzheimer’s as it is found in plaques
What is the role of ApoE2 in Alzheimer’s disease?
It reduces the risk as it plays a role in plaque clearance
What are the two classes of drugs used to treat Alzheimer’s Disease?
Anticholinesterases and NMDA antagonist’s
MOA of Acetylcholinesterase inhibitors?
They boost AcH, meaning the activity at cholinergic synapses to make up for the loss, this means it stays in the synapse for longer meaning the downstream effects can occur.
What is the significance of Galantamine binding to BuChE in the post pre membrane?
It boosts action further, it is also a positive allosteric modulator at the nicotinic receptors, enhancing the effect in the post pre membrane.
What is the significance of Galantamine binding to BuChE in the pre-synaptic receptor?
Positive feedback which causes more Acetylcholine to be released
What type of drug is Memantine?
Non-competitive NMDA antagonist
What does inhibiting the NMDA receptor do?
Limits excitability, meaning there is excess glutamate meaning downstream there is neuronal cell death and glutamate is released, this causes a 2nd cell death, which inhibits neuronal cell death in disease.
What can carbamates do and why are they important?
Carbonyl group is ‘deactivated’, Carbamate is stabilised by assed resonance from Nitrogen lone pair.
What is he chemical MOA for Rivastigmine?
‘Pseudo Irreversible’ - stable resonance, stays in active site increasing the half life! ‘Non-selective!!’
