Dementia Flashcards
Why is memory loss the first symptom of dementia?
cells in the hippocampus are often the first to be damaged
What are the 2 main risk factors of dementia?
age (over 65) and family history
What are the main causes of dementia?
- 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)
What are the most important dementing disorders?
- 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
What is AD?
a progressive neurodegenerative disease
What are the 4 stages of AD?
- preclinical
- early-stage (mild cognitive impairment)
- mid-stage
- late-stage
Aside from memory, what else is affected over the course of AD?
visuospatial, executive and language skills
What are the pathological hallmarks of AD?
- neuritic amyloid plaques
- neurofibrillary tangles
- synaptic and neuronal loss
- oxidative stress
What are the causes of AD pathology?
- misfolded proteins (plaques) → Aβ-amyloid protein
- disintegrated MTs in neurons → collapse into twisted neurofibrillary tangles due to Tau
By which mechanisms do Aβ and tau induce neuronal dysfunction and death?
- direct impairment of synaptic transmission and plasticity
- excitotoxicity
- oxidative stress
- neuroinflammation
What happens to APP in AD?
it is abnormally processed, leading to the formation of Aβ peptides that aggregate into plaques
How do ApoE mutations increase the risk of developing AD?
they interfere with clearance of Aβ and tau-mediated neurodegeneration
What are the 3 steps of AD pathology?
- Aβ -amyloid plaques
- tau-neurofibrillary triangles
- loss of cholinergic neurons
What drugs are used to treat AD cognitive symptoms?
- cholinesterase inhibitors
- NMDA antagonists
- amyloid immunotherapy
What drugs are used to treat AD non-cognitive symptoms?
- antipsychotics
- SSRIs
- BZDs
What are the first line treatment of AD?
cholinesterase inhibitors
What is the MOA of cholinesterase inhibitors?
they inhibit ACh esterase enzymes which prevents breakdown of ACh and increases ACh synaptic availability; they boost cholinergic neurotransmission and enhance memory and learning
What are disadvantages of cholinesterase inhibitors?
they have no effect on disease progression and no improvement in psychological and behavioural symptoms
Which cholinesterase inhibitor is competitive?
galantamine
What are side effects of cholinesterase inhibitors?
- GI symptoms
- bradycardia
What do NMDA antagonists do?
block NMDA receptors and inhibit excitotoxicity
What are NMDA antagonists used for?
moderate and severe AD dementia for modest cognitive improvement
What are side effects of NMDA antagonists?
- headache
- dizziness
- constipation
- shortness of breath
- hypertension
Give examples of disease modifying drugs
anti-amyloid immunotherapy drugs e.g. lecanemab and donanemab
What is the MOA of anti-amyloid immunotherapy drugs?
they bind to Aβ aggregates and cause phagocytosis and therefore reduction of the amyloid plaques
How are anti-amyloid immunotherapy drugs administered?
monthly by intravenous infusion for mild cognitive impairment (require MRI monitoring for ARIAs at 6 months interval)
What are ARIAs?
side effects of aducanumab drugs
Give examples of ARIAs
- localised areas of cerebral oedema (ARIA-E)
- microhaemorrhages (ARIA-H)
Why are amyloid immunotherapies more effective in earlier stages of AD?
amyloid plaques begin depositing approximately 15 years before symptom onset
Give examples of newer therapeutic approaches for AD
- neurotransmitter regulation
- gut microbiota regulators
- anti-inflammatory drugs
- lipid metabolism regulators
- autophagic modifiers
- circadian rhythm regulators
- natural compounds
- gene and cell therapies
- nonpharmacological interventions
Give examples of behavioural and psychiatric symptoms of dementia
- irritability
- agitation
- paranoia and delusional thinking
- wandering
- anxiety and depression
Why are atypical antipsychotics not commonly used for agitation and psychosis in AD?
- 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
Describe benzodiazepine treatment of AD
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
How may the typical antipsychotic haloperidol be useful for AD?
treatment of aggression in acute episodes only
