PBL 5

Question 1

what is a cholinesterase inhibitor

Answer 1

stops acetylcholinesterase enzyme from breaking down acetylcholine.

Question 2

define dementia

Answer 2

it is a chronic progressive neurodegenerative condition that results in impairments in cognition to impair acitivies of daily living

Question 3

name types of dementia

Answer 3

alzheimers
vascular dementia
frontal temporal
dementia with lewy bodies

Question 4

what 3 things is there a progressive decline of in dementia

Answer 4

o Memory and Reasoning
o Communication Skills
o Inability to carry out daily activities.

Question 5

what other conditions does dementia need to be distinguished from

Answer 5

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.

Question 6

what are early clinical features of dementia

Answer 6

 Short-term memory loss.
 Disorientation in time.
 Reduced judgement and planning ability.

Question 7

what are the modifiable risk factors and the non modifiable risk factors of dementia

Answer 7

non modifiable

• age
• genetic
• family history
• Down syndrome

modifiable

• vascular
• cognitive inactivity
• environment
• depression

Question 8

what 2 pathological things characterise dementia

Answer 8

 Senile/Neuritic Plaques (extracellular deposits of beta-amyloid peptide) particularly in the parietal
lobe/hippocampus.

 Intracellular Neurofibrillary Tangles: hyperpolarized tau protein.

Question 9

what are other structural hallmarks to dementia

Answer 9

 Synaptic and neural degeneration
 Severe atrophy of cerebral cortex (widening of the sulci).
 Enlargement of the ventricular system.

Question 10

what part of the brain is at risk of degeneration

Answer 10

• medial temporal lobe including the hippocapal complex and entorhinal cortex

Question 11

what part of the brain is well preserved in the brain

Answer 11

Well preserved areas of the brain: primary sensory/motor

areas, upper regions of prefrontal cortex.

Question 12

what 3 genes are responsible for early onset dementia

Answer 12

APP chromsome 21
presilin 1 chromsome 14
presilin 2 chromosome 1

Question 13

what is APP function

Answer 13

 Involved in helping neuron growth and repair.

o Over time APP is broken down and recycled.

Question 14

where is APP expressed

Answer 14

Transmembrane protein expressed in neurons, glial cells, endothelial smooth muscle.

Question 15

what are the two ways in which APP is recycled

Answer 15

non-amyloidogenic pathway

amyloidgenic pathway - pathological

Question 16

describe the non amyloidgenic pathway

Answer 16

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.

Question 17

describe the amyloidgenic pathway

Answer 17

 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

Question 18

what subunits is gamma secreted made out of

Answer 18

(!) 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).

Question 19

what do the plaques do to the nervous system

Answer 19

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.

Question 20

what is the normal function of TAU

Answer 20

 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.

Question 21

What encodes for Tau

Answer 21

MAPT

Question 22

what does a mutation in MAPT cause

Answer 22

frontal temporal dementia

Question 23

what causes Tau to become hyperphosphorylated

Answer 23

 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.

Question 24

when is early onset dementia

Answer 24

• between the ages of 30-60

- represents less than <5% of patients

Question 25

what is defined as late onset dementia

Answer 25

over age of 60

Question 26

what can cause late onset dementia

Answer 26

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.

Question 27

what two dementias can you have at the same time

Answer 27

Mixed Dementia: vascular dementia and dementia Lewy bodies.

Question 28

what are the risk factors for vascular dementia

Answer 28

Risk factors are like those of Alzheimer’s (include diabetes, smoking, hypertension, hypercholesterolaemia).

Question 29

describe vascular dementia

Answer 29

 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.

Question 30

what is frontal temporal dementia /picks disease characterised by

Answer 30

Characterised by argyrophilic inclusion bodies (accumulate in frontal/temporal lobes).

Question 31

describe frontatemporal /picks disease

Answer 31

 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.

Question 32

describe dementia with levy bodies

Answer 32

 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.

Question 33

what is dementia with Lewy bodies characterised by

Answer 33

o Marked fluctuation in symptoms. o Vivid visual hallucinations. o Extrapyramidal (parkinsonian) symptoms.

Question 34

dementia may also be a result of...

Answer 34

cerebral trauma

Question 35

what conditions can dementia occur in

Answer 35

- cerebral tumours - parkinsons disease - Huntington's disease - motor neurone disease - multiple sclerosis

Question 36

how do you diagnose dementia

Answer 36

 History Taking.  Cognitive and Mental State Examination. o Examination of attention, concentration, orientation, short and long-term memory etc…  Physical Examination.  Review of medication.

Question 37

what scans are done to rule out other causes of memory loss

Answer 37

 CT scan: rules out hydrocephalus/tumour o Confirms cerebral trophy/vascular lesions.  MRI: shows cerebral infarcts more clearly.  HMPAO-SPECT: shows frontotemporal dementia.

Question 38

how does the mini mental examination work

Answer 38

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

Question 39

what is the Montreal cognitive assessment score out of

Answer 39

30

Question 40

why is the Montreal congtivie assessment better than the mini mental state examination

Answer 40

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.

Question 41

describe basic dementia screening tests that should be done

Answer 41

 Routine haematology.  Biochemistry tests (electrolytes, calcium, glucose, renal/liver function).  Thyroid function tests.  Serum vitamin B12/folate levels.

Question 42

describe how learning and memory happens and what effect dementia has on this

Answer 42

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).

Question 43

name some acetylcholinesterase inhibitors ( used in mild to moderate)

Answer 43

 Donepezil  Galantamine  Rivastigmine

Question 44

what is the mechanism of action of acetylcholinervse inhibitors

Answer 44

 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.

Question 45

what are the moderate/severe stages drugs used for dementia

Answer 45

NMDA receptor antagonists

Question 46

name NMDA receptor antagonists

Answer 46

Memantine

Question 47

what is the mechanism of action of NDMA receptor antagonists

Answer 47

 AD may be associated with a slow form of excitoxicity and increased glutamate. o Blocking release of glutamate help easing distressing/challenging behaviours/delusion.

Question 48

what non pharmacological therapies should be used for alzheiemrs

Answer 48

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.

Question 49

describe the prognosis of the patient

Answer 49

 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.

Question 50

describe help places for patients with dementia

Answer 50

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.