Dementia Flashcards
What is dementia?
a syndrome consisting of progressive impairment in two or more areas of cognition:(memory; language; visuospatial & perceptual ability; thinking & problem-solving; personality)
sufficient to interfere with work, social function or relationships”
What is the prevalence of dementia in the UK?
2019 - 850,000
Predicted 1m by 2025, 1.5m in 2040
> 40,000 people with early-onset dementia (onset before 65 years)
Total in over 65’s is 7.1% (2019)
One in every 79 of the entire UK population, and 1 in every 14 of the population aged 65 years and over.
What is the prevalence of different types of dementia?
Alzheimer’s - 62%
Vascular - 17%
Mixed dementia - 10%
Lewy Body - 4%
Fronto-temporal - 2%
Parkinson’s - 2%
Other - 2%
What are the financial implications of dementia?
The total cost of dementia in the UK is £26.3 billion.
The NHS picks up £4.3 billion of the costs and social care £10.3 billion.
The remaining £11.6 billion is picked up by those living with dementia or their carers.
What is the pathophysiology of Alzheimer’s?
Amyloid hypothesis – accumulation of amyloid-beta triggers a cascade ultimately leading to the pathological hallmarks of AD – amyloid plaques and neurofibrillary tangles
However, treatments targeting amyloid-beta are performing poorly in clinical trials
What is the clinical presentation of Alzheimers?
Insidious onset
Gradual deterioration
Defined stages of disease progression
Disease of exclusion
What are the signs and symptoms of early stage alzheimers?
Forgetting recent events, difficulty following or recalling conversations
Misplace items
Impaired judgement
Decrease in flexibility, less willing to try new things
Mood – anxious, irritable, depressed
What are the signs and symptoms of mid stage alzheimers?
Increasing confusion and disorientation
Behaviour – obsessive, compulsive and/or repetitive
Difficulty with spatial tasks e.g. judging distances
Dysphasia - using wrong words
Mood – blunted emotions, sudden mood changes
What are the signs and symptoms of end stage alzheimers?
Fragmented and incoherent thoughts and language
Double incontinence
Dysphagia – swallowing and eating problems
Weight loss, often severe
Mood – unresponsive to stimuli (other than pain)
What are the causes of vascular dementia?
Interruption of the brain’s blood supply
Ischaemia leads to neuronal cell death and loss of function
Risk factors – family history, hypertension, male sex, history of strokes/TIAs, diabetes, smoking, AF
Preventable? Statins, aspirin
What are the symptoms of clinical dementia?
Usually a sudden onset and step-wise progression (unlike AD)
Focal neurological signs & symptoms
Agnosia – loss of a sense, hearing, taste, smell, touch or sight
Dysarthria – difficult or unclear articulation of speech
Dizziness and problems with balance
Relative preservation of personality and insight
Difficulty with planning and understanding
Feeling disorientated and confused (especially at night)
What are the causes of Lewy Body dementia?
Lewy bodies are circular aggregates of protein that form inside brain cells. Can be identified by histology.
First identified by Fritz Lewy in 1910
Dopaminergic and cholinergic neurotransmission affected by Lewy bodies in the cortex
Some crossover with Parkinson’s. 4-6% of UK dementias
What are the signs and symptoms of LB dementia?
Three core features of Lewy Body Dementia:
1) Fluctuating concentration and attention
2) Spontaneous Parkinson’s-like motor symptoms
3) Recurring visual hallucinations
Progressive but shifting course
Memory impairment is less pronounced than other dementias, especially in early stages.
Other psychotic symptoms are common
How can you tell the difference between types of dementia?
Alzheimers
- progressive onset and decline
- usually presents as memory loss
Vascular
- Sudden onset, stepwise progression
- history of CV events
- preserved insight
Lewy body
- impaired attention and visuospatial
- preserved recent memory
- visual hallucinations
-
How is dementia diagnosed?
NICE (June 2018) recommend that an initial assessment takes place in a non-specialist setting
Ideally a person who knows the patient well will also be present. Cognitive, behavioural and psychological symptoms are assessed, including their impact on everyday life.
If dementia is still suspected then a physical examination is conducted, cognitive testing is undertaken and appropriate blood and urine tests are performed to rule out other, reversible, causes of cognitive decline
What are the types of cognitive tests?
The 10-point cognitive screener (10-CS)
The 6-item cognitive impairment test (6CIT)
The 6-item screener
The Memory Impairment Screen (MIS)
The Mini-Cog
Test Your Memory (TYM)
What are the alternative causes of cognitive decline?
D - Drugs/medication
E - Emotional problems, ears, eyes
M - Metabolic
E - Endocrine
N - Nutritional deficiency
T - Tumour
I - Infection
A - Anaemia or alcohol
S - Systemic disease
How all differential diagnoses ruled out in dementia?
Delirium – characterised by an acute onset of fluctuating changes in mental states and changing levels of consciousness and inattentiveness
Onset of symptoms are often associated with physical illness (common in intensive care patients)
Symptoms include impaired attention, memory disturbance, emotional disturbance, disorientation
How is it different from dementia? – Rapid onset, short duration, fluctuation between agitation and lethargy
What happens when dementia is suspected?
If reversible causes of cognitive decline have been ruled out and dementia is still suspected then referral to a specialist setting is recommended
Memory clinic or Community Old Age Psychiatry Service ideally
Further cognitive tests to confirm diagnosis and diagnose a dementia subtype if possible
Other tests only recommended if it would help diagnose a dementia subtype AND this would change the management of the condition
MRI – damage to specific areas of brain or vascular damage. AD temporal lobe.
CT – Tumour/stroke
Does acetylcholinesterase affect the CNS?
Neurotransmission in cholinergic neurones in the CNS and at the neuromuscular junction is mediated via acetylcholine. The neurotransmitter is usually rapidly hydrolysed by acetylcholinesterase and recycled. Inhibition of AChE will result in the accumulation of acetylcholine, biological effect of inhibition will depend on site of action (CNS or periphery) and nature of inhibition (reversible or irreversible). Irreversible inhibition at neuromuscular junction will lead to paralysis. Think of drugs which inhibit AChE essentially as cholinergics.
What was considered when designed cholinesterase inhibitors?
Kill = irreversible inhibition
Cure = reversible inhibition
Also consider potency, IC50 against acetylcholinesterase. Sarin has a single digit nanomolar IC50 malathion – in millimolar range, one million times less potent.
Selectivity? Butyryl-/actetyl-cholinesterase
Route of administration? Consider LogP 0=equal affinity for oil/water, higher the values, the more lipophilic the drug.
Oral? LogP 1-2 Mucous membranes? Higher LogP >5
Volatility?
Efficacy of ChEIs
3 drugs currently licensed in UK – donepezil, rivastigmine and galantamine
No response with one does not mean with all
Linear dose pharmacokinetics (i.e. pharmacokinetic parameters of drug are unchanged by multiple/changed doses)
Improve cognitive function
Global rating (as measured by cognitive testing instruments), or
Activities of Daily Living’s (eating, drinking, washing etc)
Long-term studies 4 to 7 years continued benefit
NNT of 3 to 7 at low dose
What are procholinergic effects?
Lacrimation (crying)
Salivation
Pupillary constriction (miosis)
Bradycardia
Urination
Increased GI secretions and smooth muscle contraction
What are anti cholinergic effects?
Dry eyes
Dry mouth
Pupillary dilation (mydriasis)
Tachycardia
Urinary retention
Decreased GI secretions and smooth muscle contraction
CNS – antiemetic
What are the side effects of ChEIs?
Unsurprisingly related to pharmacology
Cholinergic especially GI (nausea, vomiting, diarrhoea)
Leg cramps, excess mucous production
Bradycardia – monitor pulse (also consider increased risk of falls)
Side effects with one does not mean with all
What is the PK of donepezil?
Licensed for mild to moderate dementia in Alzheimer’s disease.
NICE – LBD
LogP 5 (low water-solubility)
Greater selectivity acetylcholinesterase
Once daily dosing
Low side effect profile
Peak concentration 3 to 4 hours
T1/2 = 70 hours
Linear pharmacokinetics
Food does not affect absorption
93 to 96% protein bound
Metabolised in liver CYP450
Renal excretion
Few clinically significant interactions, consider bradycardia and CYP inhibitors/inducers
What is the PK of rivastigmine?
Licensed for AD and mild to moderate dementia in Parkinson’s disease
NICE – LBD
LogP – ca. 2
Inhibits both acetylcholinesterase and butylcholinesterase
Twice daily dosing (a problem?), also available as daily patch
Low side effect profile, especially when patch is used
Monitoring – patient’s body weight should be monitored whilst being treated with rivastigmine
T1/2 approximately 2 hours
Inhibition lasts 10 hours
Renal excretion
No hepatic metabolism
Little protein binding
What is the PK of galantamine?
Licensed for mild to moderately severe dementia in Alzheimer’s disease
Enhances response of nicotinic receptors to Ach (unlike donepezil and rivastigmine)
T1/2 approximately 7-8h
Starting dose is 8mg/day, titrating to max of 24mg/day
Twice daily dosing liquid or once daily modified release capsules
Low side effect profile
Avoid if eGFR is less than 9mL/minute/1.73 m2
Long term efficacy of ChEIs?
As the disease progresses the amount of Ach
produced will be less than at pre-treatment and
individual patient performance will decline,
eventually to a stage where the agent will seem
to have little clinical effect.
