Dementia

Question 1

Why is memory loss the first symptom of dementia?

Answer 1

cells in the hippocampus are often the first to be damaged

Question 2

What are the 2 main risk factors of dementia?

Answer 2

age (over 65) and family history

Question 3

What are the main causes of dementia?

Answer 3

• protein deposition
• infections and immune disorders
• metabolic or endocrine problems
• low levels of certain nutrients e.g. vitamin B1, B6, B12, copper or vitamin E
• medicine side effects
• normal-pressure hydrocephalus (abnormal buildup of CSF in the brain)

Question 4

What are the most important dementing disorders?

Answer 4

• AD (most common)
• dementia with Lewy bodies (second most common and includes dementia associated with PD)
• frontotemporal dementia
• progressive supranuclear palsy
• vascular cognitive impairment
• normal pressure hydrocephalus

Question 5

What is AD?

Answer 5

a progressive neurodegenerative disease

Question 6

What are the 4 stages of AD?

Answer 6

1. preclinical
2. early-stage (mild cognitive impairment)
3. mid-stage
4. late-stage

Question 7

Aside from memory, what else is affected over the course of AD?

Answer 7

visuospatial, executive and language skills

Question 8

What are the pathological hallmarks of AD?

Answer 8

• neuritic amyloid plaques
• neurofibrillary tangles
• synaptic and neuronal loss
• oxidative stress

Question 9

What are the causes of AD pathology?

Answer 9

• misfolded proteins (plaques) → Aβ-amyloid protein
• disintegrated MTs in neurons → collapse into twisted neurofibrillary tangles due to Tau

Question 10

By which mechanisms do Aβ and tau induce neuronal dysfunction and death?

Answer 10

• direct impairment of synaptic transmission and plasticity
• excitotoxicity
• oxidative stress
• neuroinflammation

Question 11

What happens to APP in AD?

Answer 11

it is abnormally processed, leading to the formation of Aβ peptides that aggregate into plaques

Question 12

How do ApoE mutations increase the risk of developing AD?

Answer 12

they interfere with clearance of Aβ and tau-mediated neurodegeneration

Question 13

What are the 3 steps of AD pathology?

Answer 13

1. Aβ -amyloid plaques
2. tau-neurofibrillary triangles
3. loss of cholinergic neurons

Question 14

What drugs are used to treat AD cognitive symptoms?

Answer 14

• cholinesterase inhibitors
• NMDA antagonists
• amyloid immunotherapy

Question 15

What drugs are used to treat AD non-cognitive symptoms?

Answer 15

• antipsychotics
• SSRIs
• BZDs

Question 16

What are the first line treatment of AD?

Answer 16

cholinesterase inhibitors

Question 17

What is the MOA of cholinesterase inhibitors?

Answer 17

they inhibit ACh esterase enzymes which prevents breakdown of ACh and increases ACh synaptic availability; they boost cholinergic neurotransmission and enhance memory and learning

Question 18

What are disadvantages of cholinesterase inhibitors?

Answer 18

they have no effect on disease progression and no improvement in psychological and behavioural symptoms

Question 19

Which cholinesterase inhibitor is competitive?

Answer 19

galantamine

Question 20

What are side effects of cholinesterase inhibitors?

Answer 20

• GI symptoms
• bradycardia

Question 21

What do NMDA antagonists do?

Answer 21

block NMDA receptors and inhibit excitotoxicity

Question 22

What are NMDA antagonists used for?

Answer 22

moderate and severe AD dementia for modest cognitive improvement

Question 23

What are side effects of NMDA antagonists?

Answer 23

• headache
• dizziness
• constipation
• shortness of breath
• hypertension

Question 24

Give examples of disease modifying drugs

Answer 24

anti-amyloid immunotherapy drugs e.g. lecanemab and donanemab

Question 25

What is the MOA of anti-amyloid immunotherapy drugs?

Answer 25

they bind to Aβ aggregates and cause phagocytosis and therefore reduction of the amyloid plaques

Question 26

How are anti-amyloid immunotherapy drugs administered?

Answer 26

monthly by intravenous infusion for mild cognitive impairment (require MRI monitoring for ARIAs at 6 months interval)

Question 27

What are ARIAs?

Answer 27

side effects of aducanumab drugs

Question 28

Give examples of ARIAs

Answer 28

- localised areas of cerebral oedema (ARIA-E) - microhaemorrhages (ARIA-H)

Question 29

Why are amyloid immunotherapies more effective in earlier stages of AD?

Answer 29

amyloid plaques begin depositing approximately 15 years before symptom onset

Question 30

Give examples of newer therapeutic approaches for AD

Answer 30

- neurotransmitter regulation - gut microbiota regulators - anti-inflammatory drugs - lipid metabolism regulators - autophagic modifiers - circadian rhythm regulators - natural compounds - gene and cell therapies - nonpharmacological interventions

Question 31

Give examples of behavioural and psychiatric symptoms of dementia

Answer 31

- irritability - agitation - paranoia and delusional thinking - wandering - anxiety and depression

Question 32

Why are atypical antipsychotics not commonly used for agitation and psychosis in AD?

Answer 32

- their use is often limited by adverse effects including parkinsonism, sedation and falls - use has been associated with a higher risk of stroke and overall mortality

Question 33

Describe benzodiazepine treatment of AD

Answer 33

can be used for occasional control of acute agitation but not recommended for long-term management because of their adverse effects on cognition and other risks in the elderly population

Question 34

How may the typical antipsychotic haloperidol be useful for AD?

Answer 34

treatment of aggression in acute episodes only