Alzheimer's and Other Dementias Flashcards
What is vascular dementia?
- Dementia induced from avascular blood supply to brain
- Blood supply to brain is interrupted by blocked/diseased vascular system
What are the features (causes) of vascular dementia?
- Reduced cerebral perfusion (strokes; ischaemia)
- Thromboembolism (stroke)
- Small blood vessel disease in brain
- Bleeding into the brain
How difficult is it to diagnose vascular dementia? How is it diagnosed?
- Easy diagnose, easily distinguishable from Alzheimer’s disease (vascular origin)
- MRI or CT scans; used to confirm lesions caused by vascular disease
How is vascular dementia treated?
No approved treatment currently:
• Clinical trials - cholinergic stimulants, vasodilators (treating cause), platelet aggregation inhibitors
• Preventative measures
What is Dementia w/Lewy Bodies (DLB)?
- Dementia as a result of Lewy body build-up (made up of α-synuclein)
- Build-up/deposits in dopaminergic (DA) neurones of substantia nigra
How is DLB diagnosed/features?
- Fluctuating cognition; varying attention and alertness (as w/most dementias)
- Visual hallucinations; form of psychosis
- Movement disorder (shared w/Parkinson’s Disease)
How is DLB distinguished from PDD (Parkinson’s disease dementia)?
• Severity of movement disorder:
- DLB; dementia precedes onset of movement disorder by 1 year (can have symptoms of movement problems but not established in 1st year)
- PDD; dementia occurs in the presence of existing movement disorder, pronounced bradykinesia (slowness of movement)
What is the three-pronged treatment approach to DLB?
• Cognitive:
- Cholinesterase inhibitors e.g. donepezil and rivastigmine (prevent ACh breakdown in cleft)
- NMDA receptor blocker; memantine (blocking Glu - implicated in DLB)
• Motor:
- Levodopa
- DA agonists (as per Parkinson’s)
• Psychiatric:
- Antipsychotics CONTRAINDICATED (exacerbate motor symptoms
What non-pharmacological treatments are associated w/DLB?
- Memory prompts (e.g. logbook of daily activities, post-its)
- Education of caregivers (debilitating condition; how to care for patient)
- Mobility aids (motor symptoms)
How does Fronto-temporal dementia present? How is it diagnosed?
- Loss of emotional warmth, apathy, selfishness etc. (frontal lobe affected)
- Decline in language, and memory (main symptom)
Diagnosis:
• Neuropsychological evaluation (specialist required)
What are the frontal and temporal lobes responsible for?
• Frontal:
- Part of cerebral cortex
- Personality; man impaled in frontal lobe and survived = completely different after, (reasoning, judgement) some motor coordination
• Temporal:
- Speech, language, memory
What are the pathophysiology/features of Frontal-temporal dementia?
- Mutation in tau protein
- Impact on neuronal processing, neuro-degeneration, normal nerve cell processes disrupted = cell death
What is the pathophysiology of Alzheimer’s disease?
- Formation of beta-amyloid plaques (main)
- Neurofibrillary tangles (knock-on effects)
How do beta-amyloid plaques form WRT Alzheimer’s?
- Normally, at the neuronal cell, gamma secretase and alpha secretase enzymes are implicated in the cutting/snipping of amyloid precursor protein (APP), which is embedded in the nerve cell membrane
- This usually produces a harmless P3 protein fragment as a result
- However, in Alzheimer’s; through mutation, alpha-secretase enzyme is replaced by beta-secretase (whilst gamma-secretase still remains)
- Thus when APP is cut now, a beta-amyloid fragment is produced instead of a harmless P3 protein fragment
- These beta-amyloid fragments clump up, eventually forming plaques
- Causing neurodegeneration and death of neurones, hence Alzheimer’s
How are neurofibrillary tangles implicated in the pathophysiology of Alzheimer’s disease?
- Affects microtubules; which have role in cell stability and the permitting of nutrient movement in the CNS
- Tau proteins in microtubules facilitate and support this process
- However, in Alzheimer’s: Tau protein becomes phosphorylated
- Leads to formation of neurofibrillary tangles
- These affect nutrient movement across microtubules; impeding movement
- Thus resulting in neurodegeneration of neuronal cells
»> Knock-on effect of beta-amyloid plaque formation
What is the main neurotransmitter are involved in Alzheimer’s disease?
- Cholinergic (ACh) pathways; cognition and memory
- Thus research focus = manipulating ACh
What are the other NTs involved in Alzheimer’s disease, and what are they responsible for?
Other NTs (behavioural symptoms):
- Glu; learning
- 5-HT; mood and psychosis
- GABA(a); anxiety + lethargy
- NA; aggression
Why is Alzheimer’s hard to treat?
- Neurotransmission is only impacted upon significant cell death
- Thus treatment is difficult given symptoms do not present until there is already massive cell death
What genetic elements are involved in the aetiology of Alzheimer’s disease?
• Coding variant on amyloid precursor protein gene
- Icelandic study; found in elderly w/this variant are protected against Alzheimer’s
• Familial Alzheimer’s
- Autosomal dominant mutations in chromosome 1, 14 and 21 in families displaying the disease
- Info. on CHR 21 derived from persons w/Down’s
• Late onset Alzheimer’s
- Isolated gene; apolipoprotein E (APOE)
- Synthesised in brain and liver, involved in lipid metabolism and tissue repair
- Allele APOε4 associated w/lower cognitive performance and mild cognitive impairment; progresses to dementia (Alzheimer’s)
What environmental factors are involved in the aetiology of Alzheimer’s disease?
• Head trauma:
- Survivors of head trauma observed to overexpress amyloid precursor protein (protective role)
- Increases probability of forming amyloid plaques
• Diet and malnutrition:
- Rabbits fed high cholesterol diet formed amyloid plaques
- Greater vitamin B12 deficiency observed in families w/AD and amyloid precursor mutation
What are the cognitive and behavioral symptoms of Mild AD?
• Cognitive (worsen w/AD stages):
- Short term memory impairment e.g. names of relatives
- Aphasia; inability to communicate in speech (start forgetting words, vocabulary decreases)
• Behavioural (common across AD stages):
- Reversal changes; previously social person may become introverted
- Depression (common across all stages of AD)
- Acute episodes of confusion, disorientation, hallucinations, agitation
> > > Person still able to day-to-day stuff
What are the cognitive and behavioral symptoms of Moderate AD?
• Cognitive (worse than mild)
- Poor retention of recent memories (short-term memory) but can be triggered by visual cues e.g. photo of family member for names
- Chronology of events severely affected; e.g. think they were married before they were born
- Effects on language; language learned most recently eroded first (short-term)
- Effects on comprehension
- Executive and intellectual function diminishes
- Reduced capacity for self-care; hygiene diminishes etc.
• Behavioural (similar to mild but slightly worse)
- Neurological alterations in brain
- 5-HT, DA, and NA implicated in aggression, agitation, psychoses
- Reduced function in frontal lobes impacts personality; apathy, depression, psychosis
- Sleep disturbance due to changes/detachment to the brainstem (medulla, pons, midbrain); pons involved in sleep/waking
What are the cognitive and behavioral symptoms of Late AD?
- Full-time care required
- Common stage of death e.g. pneumonia
- Almost irreversible (hard to treat)
• Cognitive:
- Memory function severely impaired ‘gone’
- Language skills; lost, speech is impoverished - can’t vocalise, child-like close to forming words
- Executive/intellectual function lost (can’t make decisions)
- Incontinence; self-care assistance/pads required
- Dysphagia (swallowing challenges; tube?); could inhale food into lungs instead - pneumonia risk
- Mobility diminishes; bed or chairbound
• Behavioural (similar to moderate):
- Aggression
- Agitation
- Sleep disturbance
- Psychoses
- Depression
> > > As functional impairment increases, physical function declines and eventually diminishes
What are the symptoms of Advanced AD?
- Most do not get to this stage; pass away at Late AD
- Completely dependent
- Mute
- Dysphagia; can’t swallow (pneumonia/flu)
- Incontinence; pads
- Cardiac
- Stroke
> > > Will die
How is diagnosis/assessment of Alzheimer’s disease made?
• Mini Mental State Examination (MMSE)
- Assess mental impairment rather than diagnosing dementia
- Accuracy; influenced by person’s education
E.g.
1) Orientation to time; What is the date?
2) Registration; assessor says 3 words which are to be repeated back
3) Naming; what is this?
4) Reading; Read this and do what it says (close your eyes)
- Clock drawing test; draw clock face and indicate time
- Blood test; rule out organic disease
- Scans (MRI/CT); structural changes in brain (enlarged ventricles and shrinking of brain tissue - cell loss)
What is the management strategy for the pharmacological treatment of AD?
- Current drugs ‘improve symptoms’ but DO NOT treat underlying cause
E.g. vascular dementia; can treat underlying cause
What are the treatment challenges w/AD?
- AD is indistinguishable between the different forms of dementia
- Main S/E of drugs is increased confusion (as well as a behavioural symptom)
- Delay in efficacy; and then improvement may be short-term also
> > > If drug causes big S/Es before positive effect observed; discontinue drugs
Where are cholinesterase inhibitors in AD treatment? Mechanism?
- Effective to treat cognitive symptoms in mild - moderate dementia
- Mechanism; slow down ACh breakdown/metabolism to acetate + choline (inhibiting acetylcholinesterase)
What are some examples of cholinesterase inhibitors, and each one’s advantages?
Equivalent efficacies:
- Donepezil (Aricept); most suitable drug; first line, been around for 20 years, best understood
- Rivastigmine; availible as transdermal patch (good for tolerability/compliance)
- Galantamine; availible as extended release formulation (compliance)
How efficacious are cholinesterase inhibitors?
- 1/3; temporary improvement in cognition - better concentration and alertness, improved short term memory and behavior (12-18 months; can monitor efficacy by doing MMSE test again)
- 1/3; stabilise for same time
- 1/3; little if any benefit
What are the S/Es associated w/cholinesterase inhibitors?
- GI disturbances; elevated levels of ACh = additional binding to muscarinic receptors e.g. M3 = constipation
- Cardiac receptors; activate M2 receptors (cardiac inhibition), decreases heart rate
What is the duration of treatment w/cholinesterase inhibitors?
- As long as benefits > S/Es
- If no improvement/decline in function; consider higher dosage or swapping to alternative cholinesterase inhibitor
- Discontinue therapy?
Where is Memantine in AD therapy? Mechanism?
- NMDA receptor blocker
- Treats moderate-severe AD
• Mechanism:
- Damaged neuronal cells release Glutamate in XS in AD
- Thus protects brain nerve cells against xs Glu
What S/Es are associated w/Memantine? Is it well tolerated?
- Well tolerated and can be combined w/cholinesterase inhibitors
S/Es:
- GI disturbances
- Hypertension (central S/Es)
- Dizziness
What other treatments (non-pharmacological/non-approved) are availible for AD?
- Gingko biloba; Chinese herb thought to improve circulation, approved in Germany, better than placebo for improving cognitive function
- Vitamin E; modest evidence that Vit E slows down progression
- Selegiline (MAO B inhibitor); treatment for PD w/evidence of modest effects on memory, mood and behaviour in AD
- Huperzine A; moss extract w/similar properties to cholinesterase inhibitors
What is the management strategy WRT treating behavioural symptoms?
Only provided if the person is in distress or causing distress to others around.
What are the treatment challenges w/behavioural symptoms?
- Legal consent required
- Ethical issues with using psychotropic (antipsychotics) drugs; are they being used for therapy of the problem or as a means of sedating the person?
When are antipsychotic drugs used in AD?
- Treats aggressive behaviour, agitation and other behavioural/psychological symptoms in dementia
What are the treatment challenges in using antipsychotics in AD? How long are they used for?
- Atypicals are CI in elderly w/AD due to evidence of increased cerebrovascular stroke
- Best avoided avoided in dementia w/Lewy bodies due to induction of severe parkinsonism even at very low doses
Rx duration:
• Benefit vs. risk ratio
• Longer the use of antipsychotics, the greater the risk of adverse effects inc. increased mortality
Where are antidepressants in the treatment of AD? Give examples.
- Studies in UK/USA found no overall beneficial effects over placebo in patients w/AD
- Brain damage/neurodegeneration inhibits actions of antidepressants
If prescribed:
• SSRIs as first line as before; citalopram as lowest drug interaction
• If SSRI ineffective, then SNRI venlafaxine considered
> > > If effective, minimum of 6 months treatment.
CBT may be better though
Where do the antiepileptic agents carbamazepine and sodium valproate have a place in AD therapy? S/Es?
Mood stabilising drugs
- Limited evidence of carbamazepine and sodium valproate displaying effectiveness treating aggressive behaviour
S/Es:
• Sedation
• LFTs (prior and during)
How is anxiety/problems sleeping treated in AD?
- Brain stem (particularly pons) may be affected in AD
- Thus hypnotics and anxiolytics potentially helpful - BDZs have limited use in dementia due to over-sedation
- Useful for treating acute anxiety though
- Sleep disturbances; short-acting BDZ temazepam, or melatonin (part of sleep cycle; preferential to BDZ cause fewer S/Es?)
What non-pharmacological treatments are availible for treating mild AD?
• Limited evidence, though popular:
Memory training:
- Use external memory aids e.g. diaries/memo books (short-term affected)
- Person forms habit of using memory aids, minimising the impact of short term impairment
Cognitive stimulation therapy:
- Recommended by NICE for mild Alzheimer’s disease
- Involves person attending multiple sessions at a center interacting w/others; games, food, current affairs etc
- Complements pharmacological therapy
> > > If new learning required, events should be outside from daily routine
What non-pharmacological treatments are availible for treating moderate AD?
- No approach more superior than other, can combine etc. complement pharmacological management
- Can also be used for mild AD
Validation therapy:
- Reassuring patient about their hallucinations; e.g. a masked intruder - ask patient and reassure how scary the situation could be (understanding their worry)
Reminiscence therapy:
- Triggers such as music, photos, videos etc.
- Evidence it reduces depression symptoms
Multisensory stimulation:
- Snoezelen room (for autistic too); wide room w/therapeutic music and wide beams of light (calming effect w/patients)
- Physical, music, pet, aromatherapy and touch therapy
- Behavioural management
- Physical restraints; ethics, but necessary if patient keeps yanking out bladder catheter etc.
What are the next generation of therapeutic targets WRT diagnosis?
Diagnostic blood tests:
- Beta amyloid protein biomarker; though difficult translating changes in blood to brain
- Use of blood test; monitor disease progression and treatment efficacy (easier than using for diagnosis)
Diagnostic CSF:
- Translatable to brain function
- Current analysis of CSF is to exclude infections (e.g. meningitis)
- Beta amyloid protein decreased in patient CSF; reduced levels as used up to make beta amyloid plaques in brain
- Tau protein increased in patient’s CSF (responsible for neurofibrillary tangles)
What are the next generation of therapeutic targets WRT neuroimaging?
Structural neuroimaging:
- 4-D brain map may help track anatomical changes over time
- Map brain’s degeneration associated with AD over time
Functional neuroimaging:
- Relevant in diagnosing early dementia
- Develop ability to detect amyloid plaques = monitor disease progression (neuropathological abnormality of AD) over time) = can start treatments earlier if detected earlier
What are the next generation of therapeutic targets WRT pharmacological treatments?
Secretase inhibitors:
- gamma or beta-secretase involved in production of beta-amyloid protein
- trials disappointing currently but ongoing
Beta amyloid vaccination:
- Aim; increase ‘removal’ of beta-amyloid protein
- Trials been peak currently
- Recommendation to use in combination therapy (cholinesterase inhibitors/memantine) if trial is effective
What would gene therapy involve WRT AD treatment?
- Determine whether NGF (nerve growth factor; isolated from fibroblasts and genetically modified etc) can prevents the death of some cells affected by AD
- Or enhance function of remaining brain cells
What would stem cell grafts involve WRT AD treatment?
Approach 1
- Undifferentiated/immature stem cells transplanted w/subsequent control cues (instruct to differentiate into ACh neurones etc.) derived from patient’s brain
Approach 2
- Grow stem cells in vitro (culture dish) to desired neuronal type
- Implant back into patient as neuronal graft
- Used in PD with okay-dece results
