PBL 5 Flashcards
what is a cholinesterase inhibitor
stops acetylcholinesterase enzyme from breaking down acetylcholine.
define dementia
it is a chronic progressive neurodegenerative condition that results in impairments in cognition to impair acitivies of daily living
name types of dementia
alzheimers
vascular dementia
frontal temporal
dementia with lewy bodies
what 3 things is there a progressive decline of in dementia
o Memory and Reasoning
o Communication Skills
o Inability to carry out daily activities.
what other conditions does dementia need to be distinguished from
o Normal Ageing: mild, benign memory loss.
o Delirium: acute and reversible disturbance of higher mental function, usually associated with
impaired conscious level and caused by infection, toxic, metabolic substances.
o Pseudodementia: cognitive effect of severe depressive illness.
Difficult to separate from dementia as depression is often secondary to dementia.
o Apathy: loss of motivation that lacks the emotional content of a depressive illness.
what are early clinical features of dementia
Short-term memory loss.
Disorientation in time.
Reduced judgement and planning ability.
what are the modifiable risk factors and the non modifiable risk factors of dementia
non modifiable
- age
- genetic
- family history
- Down syndrome
modifiable
- vascular
- cognitive inactivity
- environment
- depression
what 2 pathological things characterise dementia
Senile/Neuritic Plaques (extracellular deposits of beta-amyloid peptide) particularly in the parietal
lobe/hippocampus.
Intracellular Neurofibrillary Tangles: hyperpolarized tau protein.
what are other structural hallmarks to dementia
Synaptic and neural degeneration
Severe atrophy of cerebral cortex (widening of the sulci).
Enlargement of the ventricular system.
what part of the brain is at risk of degeneration
- medial temporal lobe including the hippocapal complex and entorhinal cortex
what part of the brain is well preserved in the brain
Well preserved areas of the brain: primary sensory/motor
areas, upper regions of prefrontal cortex.
what 3 genes are responsible for early onset dementia
APP chromsome 21
presilin 1 chromsome 14
presilin 2 chromosome 1
what is APP function
Involved in helping neuron growth and repair.
o Over time APP is broken down and recycled.
where is APP expressed
Transmembrane protein expressed in neurons, glial cells, endothelial smooth muscle.
what are the two ways in which APP is recycled
non-amyloidogenic pathway
amyloidgenic pathway - pathological
describe the non amyloidgenic pathway
In normal non-amyloidogenic pathway, alpha and gamma
secretases do not form amyloid-beta peptides but cleave
up the protein into soluble form which is recycled.
describe the amyloidgenic pathway
In diseased amyloidogenic pathway, the transmembrane protein is wrongly cleaved by beta
and gamma secretases which leads to formation of non-soluble amyloid-beta peptides.
These peptides aggregate to form senile plaques
what subunits is gamma secreted made out of
(!) The γ-secretase is made up of subunits. Of
note are PSEN1 and PSEN2 because mutations in
these can cause Alzheimer’s (PSEN1 being the
most common).
what do the plaques do to the nervous system
Can potentially get in-between the neurons which disrupts signalling.
Therefore, impairs various functions like memory. o Start an immune response which causes activation of microglia. o Can also cause amyloid angiopathy when around cerebral vessels
Weakens walls and increases
risk of haemorrhage.
what is the normal function of TAU
Neurons are held together by their cytoskeleton made up of microtubules.
o Ship nutrients and molecules along the cell.
o Located within the neuron.
Tau stabilises microtubules through coordinated binding through kinases/phosphates.
What encodes for Tau
MAPT
what does a mutation in MAPT cause
frontal temporal dementia
what causes Tau to become hyperphosphorylated
Oxidative stress from amyloid plaques cause disregulation of kinase activity o Kinase binds phosphate to the tau protein and causes it to become tangled (hyperphosphorylation) = neurofibrillary tangles.
Tangles stop microtubules form signalling
and can cause apoptosis.
when is early onset dementia
- between the ages of 30-60
- represents less than <5% of patients
what is defined as late onset dementia
over age of 60
what can cause late onset dementia
Strong genetic risk factor is apolipoprotein E (especially ApoE4) on chromosome 19.
Has three alleles
o ApoE2: relatively rare.
o ApoE3: most common and is believed to have a neutral role
o ApoE4: in about 40% of all late onset Alzheimer’s.
what two dementias can you have at the same time
Mixed Dementia: vascular dementia and dementia Lewy bodies.
what are the risk factors for vascular dementia
Risk factors are like those of Alzheimer’s (include diabetes, smoking, hypertension,
hypercholesterolaemia).
describe vascular dementia
Occurs in <20% of dementia cases.
Series of infarcts secondary to cerebrovascular disease lead to neuronal loss.
o CT or MRI shows multiple infarcts.
o Diagnosis relies upon clinical impression/cognitive examining.
Depending on the location of infracts, there is a pattern of cognitive impairments.
Frequently arises out of subcortical ischaemic disease and then presents more insidiously.
what is frontal temporal dementia /picks disease characterised by
Characterised by argyrophilic inclusion bodies (accumulate in frontal/temporal lobes).
describe frontatemporal /picks disease
Occurs in <20% of dementia cases.
Used to describe several different conditions including:
o Frontotemporal dementia-behavioural variant: frontal lobe distribution of disease initially.
o Frontotemporal dementia-language variant: includes primary progressive aphasia/semantic
dementia, temporal distribution initially.
describe dementia with levy bodies
Characterized by:
o Marked fluctuation in symptoms.
o Vivid visual hallucinations.
o Extrapyramidal (parkinsonian) symptoms.
Dementia symptoms will arise first before Parkinsonian symptoms.
Supporting features:
o Greater number of impairments in attention and visuospatial orientation
o Postural instability with frequent falls.
o Positive DaTScan.
what is dementia with Lewy bodies characterised by
o Marked fluctuation in symptoms.
o Vivid visual hallucinations.
o Extrapyramidal (parkinsonian) symptoms.
dementia may also be a result of…
cerebral trauma
what conditions can dementia occur in
- cerebral tumours
- parkinsons disease
- Huntington’s disease
- motor neurone disease
- multiple sclerosis
how do you diagnose dementia
History Taking.
Cognitive and Mental State Examination.
o Examination of attention, concentration, orientation, short and long-term memory etc…
Physical Examination.
Review of medication.
what scans are done to rule out other causes of memory loss
CT scan: rules out hydrocephalus/tumour
o Confirms cerebral trophy/vascular lesions.
MRI: shows cerebral infarcts more clearly.
HMPAO-SPECT: shows frontotemporal dementia.
how does the mini mental examination work
Minimal Mental State Examination (MMSE): no longer free to use but works as follows (note: these
scores must be interpreted considering activities of daily living (AD).
o Maximum score is 30 points
o 20-24 suggest mild dementia.
o 13-20 suggest moderate dementia.
o Less than 12 suggest severe dementia.
- in alzhiemers disease the score decreases by 2-4 each year
what is the Montreal cognitive assessment score out of
30
why is the Montreal congtivie assessment better than the mini mental state examination
Better than MMSE because of it tests a greater variety of cognitive domains, is free and
discriminations more accurately between ageing and mild cognitive impairment.
describe basic dementia screening tests that should be done
Routine haematology.
Biochemistry tests (electrolytes, calcium, glucose, renal/liver function).
Thyroid function tests.
Serum vitamin B12/folate levels.
describe how learning and memory happens and what effect dementia has on this
Learning and memory are associated with changes in various brain regions:
o Corticolimbic circuits
o Long-term potentiation/depression (LTP/LTD): changes in synaptic connections/efficiency.
Potentiation = increase in synaptic strength
Depression = decrease in synaptic strength.
o Reduced Excitatory Synaptic Transmission: due to elevated alpha beta amyloid peptides.
Reduce the AMPA (AMPARs) and NMDA glutamate receptors (NMDARs).
Shift activation of these pathways to pathways involved in induction of LTD/synaptic
loss (impairs LTP and enhances LTD).
name some acetylcholinesterase inhibitors ( used in mild to moderate)
Donepezil
Galantamine
Rivastigmine
what is the mechanism of action of acetylcholinervse inhibitors
Cholinergic forebrain pathways innervating limbic/cortical structures degenerate in AD. Especially:
Basal forebrain cholinergic system.
Nucleus Basalis of Meynert.
Horizontal/vertical diagonal bands of Broca.
Medial Septal Nucleus.
o Inhibiting acetylcholinesterase stops breakdown of acetylcholine.
o Acetylcholine which promotes healthy cognition (alertness, level of interest etc…).
These drugs are also effective in DwLB.
what are the moderate/severe stages drugs used for dementia
NMDA receptor antagonists
name NMDA receptor antagonists
Memantine
what is the mechanism of action of NDMA receptor antagonists
AD may be associated with a slow form of excitoxicity and increased glutamate.
o Blocking release of glutamate help easing distressing/challenging behaviours/delusion.
what non pharmacological therapies should be used for alzheiemrs
Cognititive Stimulation Theraphy
Should be offered to all newly diagnosed patients.
Delivered in a seven-week course.
Learning about impairments and how to manage them.
Reminiscence Theraphy
Discussion of past activities, events and experiences.
describe the prognosis of the patient
John is expected to decline over several years.
o Average duration is 8-10 years but this varies largely between individuals.
He will become completely dependent and may require medium/long-term nursing care.
describe help places for patients with dementia
Admiral Nurses
Mental Health nurses specialised in dementia.
o Provide tools/skills to help family with condition.
o Invaluable source of contact/support for families.
Alzheimer’s Society Dementia Advisors:
Non-clinical professionals who assist in similar ways to the admiral nurses.
Advance Care Planning
Allows him to make choices and decisions about his future care.
