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?
850,000 cases
Predicted 1M by 2025, 1.5M in 2040
> 40,000 people with early-onset dementia
Over 65’s is 7.1%
One in every 79 of the entire UK population, and 1 in every 14 65 years and over.
What is the prevalence of the 7 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
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
What are the risks of developing vascular dementia?
Family history
hypertension
male
history of strokes/TIAs
diabetes
smoking
AF
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
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?
Its recommend that 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
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.
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
Improve cognitive function
Long-term studies 4 to 7 years continued benefit
NNT of 3 to 7 at low dose
What are the 6 procholinergic effects?
Lacrimation (crying)
Salivation
Pupillary constriction (miosis)
Bradycardia
Urination
Increased GI secretions and smooth muscle contraction
What are the 6 anticholinergic 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?
Related to pharmacology
Nausea, vomiting, diarrhoea
Leg cramps, excess mucus production
Bradycardia – monitor pulse (also 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.
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
LogP – ca. 2
Inhibits both acetylcholinesterase and butylcholinesterase
Twice daily dosing, also available as daily patch
Low side effect profile, especially with patch
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
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.
NMDA channel blockers - Memantine
NMDA-receptor antagonist
Protects the neurone from excessive calcium ion influx
Significant improvement in cognition, function and global outcome
Useful in behavioural problems
Licensed for moderate to severe AD
Dose 5mg day increased by 5mg per week until 20mg dose
Half life is 80 hours
Reduce dose in moderate renal impairment (40-60ml/min/1.73m2)
Avoid if eGFR less than 5ml/min/1.73m2
Renal excretion probably relies on cation-transport proteins. Increasing the urinary pH can dramatically affect the elimination of the drug (by a factor of 7-9)
Monitor if changes in diet
What are the potential pharmacist inputs for dementia care?
Establish links with Alzheimer’s Soc and any local charities
Make it clear that pharmacies are dementia friendly. Posters, DF badges etc.
Recognition of possible symptoms of dementia (e.g. poor short term memory; forgetfulness etc) especially when responding to symptoms and refer as appropriate
Awareness of medicines that can exacerbate or cause confusion – mainly anticholinergic agents.
Early access to – information, treatment, care and support networks
Reversible causes can be eliminated or treated
Make the most of remaining abilities
Explain to family and friends – plan for the future
Easier to determine subtype at early stages and treat accordingly
Show empathy, offer privacy, signpost to support
Advice around behaviour changes and aggravating factors eg. Constipation, pain, infection, physical/psychosocial factors
What are the classifications of memory?
Declarative - daily episodes, words and meanings, history
Emotional - preferences and aversions
Procedural - motor skills, associations, priming clues, puzzle solving
What is Hebbs law?
Donald Hebb (1949) - when two neurones are active, so that one repeatedly releases neurotransmitter at the same time as its postsynaptic partner is firing action potentials, then that synapse will become stronger.
“cells that fire together, wire together”
Synapses strengthened by intense activity
memory depends on populations of interacting neurones
pattern of strengthened synapses defines memory
How does a synapse get stronger?
Increase in the strength after repeated stimulation is called Long Term Potentiation (LTP)
How is long term potentiation manifested?
Postsynaptic
- More AMPAr
- More sensitive AMPAr
- More synapses
Presynaptic
- Increased release
- More release sites
- More vesicles
What are the long-term potentiation induction mechanisms?
Phosphorylation of AMPAr by PKC
Insertion of new receptors by CaMKII. Also synthesis of new receptors
Retrograde messenger - nitric oxide - presynaptic changes
What is NMDAr?
The NMDAr is a glutamate receptor that plays a role in synaptic plasticity, learning, and memory.
It is an ion channel that allows calcium, sodium, and potassium to flow into or out of neurons upon activation by glutamate, but excessive activation can lead to cell damage and neurodegenerative diseases.
One form of memory depends on NMDAr
- induced by NMDAr activation
- expressed by AMPA receptors
- maintained by changes in number/sensitivity of postsynaptic AMPAr and structural changes
- also maintained by presynaptic alterations of glutamate release
What are the 6 cognition enhancing drugs?
anticholinesterases - donepezil (Aricept), galantamine
agonists - nicotine, arecoline
Stimulants - amphetamine, methylphenidate, modafanil, caffeine
5HT drugs – particularly 5HT6 antagonists
GABAA receptor blockers - inverse agonists – suritozole
AMPAkines - positive AMPAr modulators - piracetam, IDRA-21
mGluR drugs – particularly mGluR5 positive allosteric modulators
What the two categories of memory disorders?
Amnesia
drug induced
head trauma - temporary or permanent
Retrograde or anterograde
Dementias
Loss of multiple memory categories
Inability to form new memories
Associated with general cognitive decline
Memory impairment first presenting symptom
What is the cellular pathology of alzheimers?
Neuritic plaques (NP) - extracellular - amyloid--protein
Neurofribrillary tangles (NFT) - intracellular - abnormal cytoskeletal protein Tau
Primarily affect glutamate and acetylcholine neurones and terminals
Aberrant function - synapse loss - neuronal death - brain shrinkage
What is abnormal APP processing?
90 % of AD cases are sporadic
-secretase may be enhanced - environmental, disease, inflammation
Genetic mutations identified in early onset AD (< 65 years)
In presenilin genes - excess -secretase activity – make more A42 which is MOST likely to form plaques
Genetic risk factor in late onset
ApoE4 mutations - increased aggregation
How do we treat alzheimers symptomatically?
Cholinesterase inhibitors - cholinergic neurones damaged early
donepezil, rivastigmine, galantamine
Enhance ACh at nicotinic and muscarinic receptors
Small improvements in cognition
Memantine
Non-competitive NMDA receptor blocker
slight improvements in cognition
How do we treat disease progression alzheimers?
Secretase inhibitors - in trials
Anti-amyloid-beta vaccine / monoclonal antibodies – in trials
Anti-tau vaccine / monoclonal antibodies – in trials
Copper and zinc chelators - metal ions promote plaque formation – toxic
Growth factors - not feasible for routine therapy
Antioxidants – limited evidence – eg. Vitamin C, flavinoids
Statins – some epidemiological evidence
- cholesterol promotes amyloid deposition
What is the motor control hierarchy?
High - sensory and association neocortex, basal ganglia - for planning strategy
Medium - motor cortex, cerebellum - for tactics, prep and direction
Low - brain stem, spinal cord - execution
What is the motor cortex?
The motor cortex is located in the frontal lobe of your brain. It generates electrical signals that control movement.
Primary Motor Cortex: Directly controls specific muscles for voluntary movements.
Premotor Cortex: Plans movements and coordinates muscle groups.
What is the Corticospinal Tract/lateral pathway?
This is the major pathway for voluntary movement of the limbs.
Upper motor neurons originate in the motor cortex, and most of them cross over at the level of the medulla in the brainstem.
This means that the left motor cortex controls muscles on the right side of the body and vice versa.
These neurons descend through the lateral column of the spinal cord and synapse with lower motor neurons in the spinal cord, which then send signals to the muscles.
Fine motor control
What is the Corticobulbar Tract?
Controls movements of the face, head, and neck. These neurons end in the brainstem rather than the spinal cord.
How do spinal reflexes work?
The signals from the motor cortex travel down the spinal cord and exit through nerves that connect to muscles.
Sometimes, spinal reflexes occur before the signal even reaches the brain, like if you touch something hot and pull away quickly.
What is the basal ganglia?
The basal ganglia are a group of structures deep within the brain that play a crucial role in the regulation and coordination of movement.
They help initiate, modulate, and fine-tune voluntary movements, ensuring they are smooth, purposeful, and properly executed.
The basal ganglia are involved in various functions, including motor control, habit formation, learning, and even emotions.
Helps initiate and regulate movements (think of it as the “brake” and “gas” for movement control
What is the Cerebellum?
Helps with balance and coordination, ensuring the movement is smooth.
What is the Rubrospinal Tract?
This is another smaller pathway that also helps control limb movements, particularly in the upper limbs.
It starts in the red nucleus (a structure in the midbrain) and crosses over to the opposite side of the body in the brainstem.
It plays a role in coordination of motor actions, often complementing the corticospinal tract.
What are the ventromedial pathways?
Vestibulospinal Tract
Reticulospinal Tract
Tectospinal Tract
The ventromedial pathways control more gross movements and movements involving posture, balance, and coordination. These pathways mainly influence the muscles of the trunk and proximal (closer to the body) muscles of the limbs, helping with activities like walking, standing, or maintaining balance.
What is the Vestibulospinal Tract?
This pathway originates in the vestibular nuclei in the brainstem, which receive information from the inner ear (about balance and head position).
It helps control muscles that keep you upright and maintain balance, especially in response to changes in body position or movement.
It does not decussate and influences both sides of the body equally.
What is the Reticulospinal Tract?
The reticulospinal tract originates in the reticular formation, a network of neurons in the brainstem that is involved in arousal, attention, and motor control.
It helps regulate posture, muscle tone, and automatic movements, such as those required for walking.
The reticulospinal pathway also plays a role in anticipatory adjustments to posture in response to changes in the environment.
What is the Tectospinal Tract?
This tract originates in the superior colliculus of the midbrain, which is involved in visual processing and coordinating head and eye movements.
It is particularly important for orienting the body toward visual or auditory stimuli.
Like the vestibulospinal tract, it helps with coordinating movements of the head and neck in response to sensory stimuli.
What are the 4 key structures in the basal ganglia?
Striatum
Globus Pallidus
Substantia Nigra
Subthalamic Nucleus
What is the striatum made up of?
Caudate nucleus: Involved in cognitive functions, learning, and memory.
Putamen: Primarily involved in motor control and movement coordination.
What is the Globus Pallidus made up of?
External segment (GPe): Involved in modulating signals between the basal ganglia and other brain regions.
Internal segment (GPi): Plays a more direct role in motor control, sending inhibitory signals to the thalamus, which then influences movement.
What does the Substantia Nigra do?
This is a small structure in the midbrain that is critical for movement control.
The pars compacta of the substantia nigra produces dopamine, which is crucial for facilitating movement by promoting activity in the striatum.
The pars reticulata of the substantia nigra also sends inhibitory signals to the thalamus, helping regulate movement.
What does the Subthalamic Nucleus do?
Located beneath the thalamus, the subthalamic nucleus plays an important role in modulating the output of the basal ganglia, particularly through its connections with the globus pallidus.
It is involved in generating and controlling movement, particularly in the initiation of voluntary actions.
What is the pathway through the basal ganglia?
The direct pathway promotes movement by disinhibiting the thalamus.
When the striatum receives input from the cortex, it sends inhibitory signals to the internal segment of the globus pallidus (GPi).
This inhibits the GPi’s usual inhibitory signals to the thalamus.
The thalamus becomes more active, which then sends excitatory signals to the motor cortex, leading to movement initiation.
What is the indirect pathway through the basal ganglia?
The indirect pathway works to suppress unwanted movements or inhibit excessive movement.
The striatum, upon receiving input from the cortex, inhibits the external segment of the globus pallidus (GPe).
This leads to disinhibition of the subthalamic nucleus, which sends excitatory signals to the GPi.
The GPi, in turn, increases inhibition to the thalamus, reducing the thalamic signals to the motor cortex and preventing unwanted movements.
What motor disorders are associated with basal ganglia?
Parkinson’s Disease: Degeneration of dopamine-producing neurons in the substantia nigra leads to difficulty initiating movement (akinesia), tremors, and rigidity. Hypokinetic.
Huntington’s Disease: A genetic disorder that causes damage to the striatum, leading to involuntary movements (chorea), impaired coordination, and cognitive decline. Hyperkinetic.
Tourette Syndrome: Characterized by repetitive, involuntary movements and vocalizations (tics), Increased activity in nigro-striatal pathway
Treated with dopamine D2 receptor-antagonists
Dystonia: A movement disorder caused by abnormal activity in the basal ganglia, resulting in muscle spasms and abnormal postures.
Obsessive-compulsive disorder: Lesions in caudate/putamen - repetitive motor responses, Treated with SSRIs
What is the prevalence of parkinsons?
1817 - James Parkinson – shaking palsy
Progressive - dementia - cognitive decline
0.1% of population, disease of the elderly
Rare at < 40 yrs
> 50 yrs - 1%
Increased risk with head trauma
Genetic susceptibility?
Environmental and drug induced
Survival time ~10yrs
Drugs do not alter progression
What are the symptoms of parkinsons?
akinesia - the absence or reduction of movement
bradykinesia - slowness of movement
rigidity - resistance to passive movement
tremor - pill rolling
poor balance
speech problems
progressively
depression, anxiety, sleep disturbance, cognitive dysfunction
What is the pathology of parkinsons?
Primary - loss of DA cells from SNc
Degeneration of nigro-striatal pathway
Genetic mutations
Mutant synaptic proteins (-synuclein) - aggregation
Mutant Parkin (ligase) - prevents proteolysis
Protein aggregation - inclusion (Lewy) bodies
Oxidative stress - mitochondrial dysfunction
Cell death
Parkinsonism - drug induced
Neuroleptics
MPTP
What are the knock-on consequences of SNc degeneration?
Loss of DA neurones - imbalance in direct and indirect pathways
increases activation of Gpi via indirect
Decreases inhibition via direct
Increases inhibition of thalamus
Switches off thalamo-cortical pathways
Loss of cortico-spinal output
Decreased movement, rigidity etc
How do we treat Parkinson’s disease?
Increase DA synthesis
Oral L-DOPA - first line
Converted to DA by DOPA-decarboxylase
Combined with peripheral decarboxylase inhibitors (carbidopa, benserazide).
DA receptor agonists
bromocriptine, pramipexole, apomorphine
COMT inhibitors - entacapone
MAO inhibitors - selegiline
DA release
Combination therapy with L-DOPA
Deep brain stimulation
STN
Disruption of GPi
What is huntingtons disease?
1872 - George Huntington - “On Chorea”
Progressive degenerative
Cognitive decline before motor
Low incidence 0.01%
Appears between 30 and 50yrs
Inherited disorder - 50% chance of defective gene
What are the symptoms of huntingtons?
Chorea - involuntary jerking
Grimacing
Balance and gait problems
Cognitive decline, memory loss, depression
Swallowing and speech
Death 10-20 years following diagnosis
What is the pathology of huntingtons?
Primary - cell death in caudate/putamen
Impaired striatal-nigral and striato-pallidal transmission
Nigro-striatal preserved
progressive - degeneration of GP
Huntingtin protein - normal function unclear
Mutant huntingtin - genetic defect
Expanded repeats of codon for glutamine
Dense protein aggregates migrate to nucleus
Apoptosis - cell death
What are the knock-on consequences of striatal degeneration?
Loss of caudate neurones
decreased inhibition of GPe
increased inhibition of STN
Decreased excitation of GPi/SNc
Decreased inhibition of thalamus
Increased thalamo-cortical activity
Increase in cortico-spinal output
Hyperkinesia, facial tics etc
How do we treat Huntington’s disease?
No cure
Baclofen (antispasticity)
D2 antagonists (e.g. chlorpromazine)
Treat symptoms e.g. depression
What is Cerebellar dysfunction?
Ataxia
Fine motor control, gait and co-ordination
Multiple types and causes - genetic, trauma, stroke, alcohol and drugs
Degeneration of cerebellar cortex, spino-cerebellar pathways, ponto-cerebellar pathways, deep cerebellar nuclei, cerebellar-cortico pathways
No cure - treat the symptoms
