Dementia (DONE) Flashcards
Types of dementia
Alzheimer’s disease (~60%)
Vascular dementia (~20%)
Dementia with Lewy bodies (~15%)
Frontotemporal dementia (<5%)
Dementia overview
Defined as the loss of mental processing ability, including communication, abstract thinking, judgment and physical abilities, such that it interferes with daily living
Acquired, chronic disorder which is usually progressive
Affects multiple parts of the brain:
Higher cognitive functions- memory, thinking, comprehension, learning capacity, language
Daily living activities/emotional behaviour- agitation, apathy, depression, anxiety, delusions, hallucinations, irritability, wandering
Alzheimer’s disease
Gross pathology: shrinkage due to death of cortical neurons and hippocampal neurons
Microscopic pathology: amyloid plaques- extracellular, contain B-amyloid; neurofibrillary tangles- intracellular, contain tau
Proteins involved in AD
Amyloid hypothesis- B-amyloid cleaved from amyloid precursor protein by sequential action of B and G secretases, build up of B-amyloid is crucial, drives AD
Tau accumulation- naturally occurring axonal protein, stabilises microtubules, abnormally phosphorylated in AD- forms neurofibrilliary tangles, results in cytoskeletal disruption, altered protein transport to and from dendrites
Build up of amyloid process
Normally monomeric and soluble
Oligomerises (soluble)- toxic form
Cellular stress (membrane, mitochondria, ER)
Synaptic changes (synaptic loss, possibly changes in tau)
Eventual neuronal death
Oligomers become insoluble, leading to fibrils and plaques
Disease progression
Pathology appears sequentially (AB, tau, cell death)
Good correlation between severity of dementia and NFTs
Early Alzheimer’s disease- decreased knowledge of recent/life events, changes in behaviour
Severe Alzheimer’s disease- no longer recognise family and friends, don’t understand language
Variations e.g. posterior cortical atrophy
Causes of AD
Two presentations: early onset/familial- strong genetic component (as early as 40)
Late onset- sporadic (>65)
Problem for diagnosis: AB levels (toxic) start to increase many years before memory symptoms become obvious
Genetic causes of AD
Familial disease- rare, autosomal dominant
Mutations in APP- copy number (Down’s syndrome), clustered around secretase cleavage sites, alter APP processing to AB
Mutations in presenilins
Genetics implicated in sporadic disease
Apolipoprotein E- modifies age of onset, molecular mechanism uncertain, may contribute to tau and AB pathology
Evidence for other new candidate genes uncertain
Causes of AD- environment
Age
Gender
Ethnicity
Lifestyle
Increased risk associated with vascular disease, mid or later life
Increased risk with depression, Parkinson’s disease, MS and HIV
Diagnosis/assessment
Scans- MRI/CT/PET
Cognitive tests- e.g. Mini Mental State Examination
Post mortem
Blood tests and CSF measurements of AB and tau being developed
Treatments
All symptomatic- do not affect underlying disease process
Treat cognitive symptoms- AChesterase inhibitors, NMDA receptor antagonist
NICE guidelines- cholinesterase inhibitors for mild to moderate AD, NMDA receptor antagonist for severe AD and moderate AD in some cases
Treat non-cognitive symptoms- behavioural and psychological symptoms of dementia
Acetylcholinesterase inhibitors I
Loss of cholinergic neurones
Substantial contribution to cognitive and non-cognitive symptoms
Counteract cholinergic deficits by inhibiting the breakdown of ACh
Acetylcholinesterase inhibitors II
Used for mild to moderate AD
Donepezil, galantamine and rivastigmine- oral and patches
Some improvement in daily living but large placebo effect
Generally well tolerated, side effects reflect dose related peripheral cholinergic stimulation
Caution in patients with hepatic and renal dysfunction
Caution in asthma, COPD, bladder and GI problems
No delay in disease progression
Excitotoxicity- NMDA receptor antagonists
Excessive glutamate release activates NMDA receptors and voltage operated calcium channels
Calcium influx results
Leads to the formation of reactive oxygen species and mitochondrial damage
Oxidative stress and the activation of proteases and endonucleases contribute to neuronal cell death
NMDA receptor antagonists
Memantine- uncompetitive antagonist, needs initial receptor activation by agonist
Does not affect normal NMDA receptor activity
May also be other mechanisms of action
Generally well tolerated, moderate and severe AD
Caution in epilepsy
Combination therapy with AChE inhibitors appears advantageous
No/little delay in disease progression
Psychiatric medications
Treatment of non-cognitive symptoms of Alzheimer’s disease
Anxiolytics- anxiety
Anti-psychotics- severe confusion, paranoia and hallucinations
Antidepressants- to treat depression
Vascular dementia overview
Affects about 150,000 people in the UK
Ischaemic or haemorrhagic stroke (stroke related dementia)
Post-stroke dementia
Single-infarct and multi-infarct dementia
Subcortical dementia
Mixed dementia (AD + vascular dementia)
Vascular dementia symptoms and treatment
Symptoms- reflect area of brain affected, abrupt onset or more slowly, executive dysfunction early sign- motivation, language, sequencing, memory, mood changes uncommon
Unusual/atypical behaviours seen with disease progression
Treatment: no specific treatment for vascular dementia, aim mostly to decrease risk factors for cerebro-vascular events, AChesterase inhibitors not recommended
Dementia with Lewy bodies- overview
Thought to be underdiagnosed
Alpha synucleinopathy (like PD)
Lewy bodies- round inclusion bodies in cytoplasm of neurons
Major protein deposited- alpha synuclein
Reduction in dopamine and ACh (more than AD)
Age only clear risk factor
Dementia with Lewy bodies- symptoms
Combination of AD and Parkinson’s disease symptoms
Problems with attention and alertness, later memory
Hallucinations and delusions
Features of Parkinsonism- rigidity and slowness of movement
Sleep disturbances
Other symptoms- lose sense of smell, constipation, urinary incontinence, fainting
Dementia with Lewy bodies- treatment
Try non-pharmacological approaches first
May respond better to cholinesterase inhibitors than AD for cognitive and non-cognitive symptoms (Rivastigmine mainly used, unlicensed)
Movement disorders treated in similar way to PD
Great care with anti-psychotic drugs- neuroleptic sensitivity reactions could worsen motor symptoms, only used as a last resort
Frontotemporal dementia (FTD)
Also called pick’s disease or frontal lobe dementia
Least common type, younger onset (45-65)
Frontal lobes crucial for social behaviour and personality
Behavioural and language variants
Recent memory typically preserved initially
Differences between variants less clear as disease progresses
Frontotemporal dementia treatment
No benefit of cholinesterase inhibitors, can make symptoms worse and increase aggression
Non-pharmacological help with symptoms
SSRIs help with apathy and some behavioural symptoms
Atypical anti-psychotics- consider risks vs benefits
