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'B33CNS - Pharmacology & Therapeutics > Alzheimer's and Other Dementias > Flashcards

Alzheimer's and Other Dementias Flashcards

1
Q

What is vascular dementia?

A
  • Dementia induced from avascular blood supply to brain

- Blood supply to brain is interrupted by blocked/diseased vascular system

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2
Q

What are the features (causes) of vascular dementia?

A
  • Reduced cerebral perfusion (strokes; ischaemia)
  • Thromboembolism (stroke)
  • Small blood vessel disease in brain
  • Bleeding into the brain
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3
Q

How difficult is it to diagnose vascular dementia? How is it diagnosed?

A
  • Easy diagnose, easily distinguishable from Alzheimer’s disease (vascular origin)
  • MRI or CT scans; used to confirm lesions caused by vascular disease
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4
Q

How is vascular dementia treated?

A

No approved treatment currently:
• Clinical trials - cholinergic stimulants, vasodilators (treating cause), platelet aggregation inhibitors
• Preventative measures

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5
Q

What is Dementia w/Lewy Bodies (DLB)?

A
  • Dementia as a result of Lewy body build-up (made up of α-synuclein)
  • Build-up/deposits in dopaminergic (DA) neurones of substantia nigra
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6
Q

How is DLB diagnosed/features?

A
  • Fluctuating cognition; varying attention and alertness (as w/most dementias)
  • Visual hallucinations; form of psychosis
  • Movement disorder (shared w/Parkinson’s Disease)
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7
Q

How is DLB distinguished from PDD (Parkinson’s disease dementia)?

A

• 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)
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8
Q

What is the three-pronged treatment approach to DLB?

A

• 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

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9
Q

What non-pharmacological treatments are associated w/DLB?

A
  • Memory prompts (e.g. logbook of daily activities, post-its)
  • Education of caregivers (debilitating condition; how to care for patient)
  • Mobility aids (motor symptoms)
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10
Q

How does Fronto-temporal dementia present? How is it diagnosed?

A
  • Loss of emotional warmth, apathy, selfishness etc. (frontal lobe affected)
  • Decline in language, and memory (main symptom)

Diagnosis:
• Neuropsychological evaluation (specialist required)

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11
Q

What are the frontal and temporal lobes responsible for?

A

• 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

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12
Q

What are the pathophysiology/features of Frontal-temporal dementia?

A
  • Mutation in tau protein

- Impact on neuronal processing, neuro-degeneration, normal nerve cell processes disrupted = cell death

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13
Q

What is the pathophysiology of Alzheimer’s disease?

A
  • Formation of beta-amyloid plaques (main)

- Neurofibrillary tangles (knock-on effects)

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14
Q

How do beta-amyloid plaques form WRT Alzheimer’s?

A
  • 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
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15
Q

How are neurofibrillary tangles implicated in the pathophysiology of Alzheimer’s disease?

A
  • 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
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16
Q

What is the main neurotransmitter are involved in Alzheimer’s disease?

A
  • Cholinergic (ACh) pathways; cognition and memory

- Thus research focus = manipulating ACh

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17
Q

What are the other NTs involved in Alzheimer’s disease, and what are they responsible for?

A

Other NTs (behavioural symptoms):

  • Glu; learning
  • 5-HT; mood and psychosis
  • GABA(a); anxiety + lethargy
  • NA; aggression
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18
Q

Why is Alzheimer’s hard to treat?

A
  • Neurotransmission is only impacted upon significant cell death
  • Thus treatment is difficult given symptoms do not present until there is already massive cell death
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19
Q

What genetic elements are involved in the aetiology of Alzheimer’s disease?

A

• 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)
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20
Q

What environmental factors are involved in the aetiology of Alzheimer’s disease?

A

• 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
21
Q

What are the cognitive and behavioral symptoms of Mild AD?

A

• 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

22
Q

What are the cognitive and behavioral symptoms of Moderate AD?

A

• 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
23
Q

What are the cognitive and behavioral symptoms of Late AD?

A
  • 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

24
Q

What are the symptoms of Advanced AD?

A
  • 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

25
Q

How is diagnosis/assessment of Alzheimer’s disease made?

A

• 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)
26
Q

What is the management strategy for the pharmacological treatment of AD?

A
  • Current drugs ‘improve symptoms’ but DO NOT treat underlying cause
    E.g. vascular dementia; can treat underlying cause
27
Q

What are the treatment challenges w/AD?

A
  • 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

28
Q

Where are cholinesterase inhibitors in AD treatment? Mechanism?

A
  • Effective to treat cognitive symptoms in mild - moderate dementia
  • Mechanism; slow down ACh breakdown/metabolism to acetate + choline (inhibiting acetylcholinesterase)
29
Q

What are some examples of cholinesterase inhibitors, and each one’s advantages?

A

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)
30
Q

How efficacious are cholinesterase inhibitors?

A
  • 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
31
Q

What are the S/Es associated w/cholinesterase inhibitors?

A
  • 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
32
Q

What is the duration of treatment w/cholinesterase inhibitors?

A
  • As long as benefits > S/Es
  • If no improvement/decline in function; consider higher dosage or swapping to alternative cholinesterase inhibitor
  • Discontinue therapy?
33
Q

Where is Memantine in AD therapy? Mechanism?

A
  • 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
34
Q

What S/Es are associated w/Memantine? Is it well tolerated?

A
  • Well tolerated and can be combined w/cholinesterase inhibitors

S/Es:

  • GI disturbances
  • Hypertension (central S/Es)
  • Dizziness
35
Q

What other treatments (non-pharmacological/non-approved) are availible for AD?

A
  • 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
36
Q

What is the management strategy WRT treating behavioural symptoms?

A

Only provided if the person is in distress or causing distress to others around.

37
Q

What are the treatment challenges w/behavioural symptoms?

A
  • 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?
38
Q

When are antipsychotic drugs used in AD?

A
  • Treats aggressive behaviour, agitation and other behavioural/psychological symptoms in dementia
39
Q

What are the treatment challenges in using antipsychotics in AD? How long are they used for?

A
  • 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

40
Q

Where are antidepressants in the treatment of AD? Give examples.

A
  • 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

41
Q

Where do the antiepileptic agents carbamazepine and sodium valproate have a place in AD therapy? S/Es?

A

Mood stabilising drugs
- Limited evidence of carbamazepine and sodium valproate displaying effectiveness treating aggressive behaviour

S/Es:
• Sedation
• LFTs (prior and during)

42
Q

How is anxiety/problems sleeping treated in AD?

A
  • 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?)
43
Q

What non-pharmacological treatments are availible for treating mild AD?

A

• 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

44
Q

What non-pharmacological treatments are availible for treating moderate AD?

A
  • 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.
45
Q

What are the next generation of therapeutic targets WRT diagnosis?

A

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)
46
Q

What are the next generation of therapeutic targets WRT neuroimaging?

A

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
47
Q

What are the next generation of therapeutic targets WRT pharmacological treatments?

A

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
48
Q

What would gene therapy involve WRT AD treatment?

A
  • 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
49
Q

What would stem cell grafts involve WRT AD treatment?

A

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

'B33CNS - Pharmacology & Therapeutics (13 decks)

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