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Nervous System (Semester 5) > 9.2 The ageing brain and Dementia > Flashcards

9.2 The ageing brain and Dementia Flashcards

1
Q

Define dementia

A

A progressive and largely irreversible clinical syndrome that is characterized by global deterioration in intellectual function, behaviour and personality in the presence of normal consciousness and perception.

Dementia is an umbrella term for shared symptoms (affects the higher cognitive functions (initially))

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2
Q

As the disease progresses what symptoms may be experienced and what traits are often preserved?

A

Many patients have preserved positive personality traits and personal attributes. BUT as the disease progresses, patients may experience:

memory loss, language impairment, disorientation, changes in personality, difficulty in carrying out daily activities, self-neglect, psychiatric symptoms (apathy), depression or psychosis, unusual behaviour (aggression), sleep disturbance or disinhibited sexual behaviour

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3
Q

Define Delirium

A

An acutely disturbed state of mind characterized by restlessness, illusions and incoherence caused by an underlying condition or event in vulnerable people

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4
Q

What are the five most common types of dementia?

A
  1. Alzheimer’s disease (most common)
  2. vascular dementia
  3. dementia with Lewy bodies
  4. frontotemporal dementia
  5. Parkinson’s disease
  6. Plus mixed dementia
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5
Q

What are the 5 symptoms of Mild cognitive impairment (MCI)?

A
  1. memory: forgetting recent events or repeating same question
  2. reasoning, planning or problem-solving: struggling with thinking things through
  3. attention - being very easily distracted
  4. language - taking much longer than usual to find the right word for something
  5. visual depth perception: struggling to interpret an object in 3D, judge distances or navigate stairs.
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6
Q

What is Mild cognitive impairment (MCI)?

A

Symptoms of minor problems with cognition that are worse than would normally be expected for a healthy person of their age

The symptoms are not severe enough to interfere significantly with daily life but MCI affects more demanding tasks (e.g. paying bills, managing medication, driving)

An individual with MCI is more likely to develop dementia.

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7
Q

What 2 structures are particularly impaired in Alzheimer’s?

A

Cerebral cortex and Hippocampus

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8
Q

What is the most significant risk factor for development of dementia?

A

The most significant risk factor is age

Increasing age → number of cases doubles every 5 years beyond 65

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9
Q

Give 4 non-modifiable risk factors for development of dementia

A
  1. age
  2. mild cognitive impairment
  3. learning disability e.g Trisomy 21
  4. gender M<f>
    </f><li>genetics – strong family Hx</li><li>ethnicity</li>

</f>

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10
Q

Give 4 modifiable risk factors for development of dementia

A
  1. high alcohol intake
  2. cognitive inactivity and educational attainment
  3. depression
  4. diabetes mellitus
  5. hyperlipidemia
  6. obesity
  7. physical inactivity
  8. smoking
  9. social isolation
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11
Q

What does the rate of dementia progression depend on?

A

Depends upon the underlying cause

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12
Q

Give 3 early features of dementia (acute)

A

1) Loss of memory for recent events
2) Global disruption of personality
3) Gradual development of abnormal behaviour

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13
Q

Give 3 Intermediate features of dementia (subacute)

A

1) Loss of intellect
2) Mood changes blunting of emotions
3) Cognitive impairment with failure to learn

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14
Q

Give 3 late features of dementia (chronic)

A

1) Reduction in self-care
2) Restless wandering
3) Incontinence

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15
Q

What type of demetia is generally young onset?

A

Fronto temporal dementia (FTD)

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16
Q

What is vascular dementia and what is most commonly seen/causal

A

Neurodegeneration secondary to loss of vascular supply to neurons

Multiple mini infarcts blocking blood supply of neurones, is what leads to their loss

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17
Q

Dementia with Lewy bodies (DLB) is considered a ‘hybrid’ of what two dementias and why?

A

Alzheimer’s and Parkinson’s

Lewy bodies composed of the protein Alpha synuclein- seen in parkinsons

Dementia features (symptoms experienced)- seen in Alzheimer’s

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18
Q

What is meant by mixed demetia?

A

Combination of various types Eg. AD&VD or AD&DLB

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19
Q

Give 6 causes of dementia (there is heaps!!)

A
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20
Q

Describe the onset of Alzheimer’s disease

A

Insidious onset – slow and steady over several years

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21
Q

What characterises Alzheimer’s disease?

A

Characterised by deterioration in thinking, conceiving, reasoning

AND

Non-cognitive symptoms such as agitation, behavioural, depression, delusions and hallucinations

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22
Q

Give the main early, middle and late stages of Alzheimer’s disease

A

Early = memory disturbance: Impairment of recent memory function and attention

Middle = global cognitive decline: failure of language, visual-special orientation, abstract thinking and judgement

Late = severe global decline: failure of self care, incontinence and total dependence

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23
Q

Early onset AD has a strong genetic link, what are the 3 mutations?

Give the inheritance and average age of onset of AD

A

Mutation: Genes on chromosomes 1, 14 and 21

  • x1: PSEN2 - presenilin 2
  • x14: PSEN1 - presenilin 1
  • x21: APP – amyloid precursor protein

Inherritance: autosomal dominant

Onset: 30-60 yrs

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24
Q

How can we distinguish familial vs sporadic dementia?

A

almost indistinguishable…

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25
Q

Late onset AD is sporadic

What is the most common mutation and average age of onset?

A

Mutation: most common on chromosome 19: APOE gene which helps break down amyloid plaques (several alleles of this gene exist)

  • ε2 rare and maybe protective (later onset)
  • ε3 common and disease neutral
  • ε4 increases risk of AD

Onset: mid 60s +

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26
Q

What can be said about the APOE ε4 allele and development of AD

A

Not everyone with Alzheimer disease have the APOE ε4 allele, and not all people who have this allele will develop the disease

RISK INCREASES based on copies of allele ➞ 2 x ε4 alleles > 1 x ε4 allele > no ε4 alleles

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27
Q

Describe the pathology of Alzheimer’s including changes/losses seen

A

1) Cerebral atrophy starting in the temporal lobes
2) Loss of synaptic connections
3) Neurofibrillary tangles: collections of intraneuronal cytoskeletal filaments esp phosphorylated tau
4) Senile plaques: extracellular deposits of abnormal protein and consist of amyloid-β-protein
5) Inflammation: abnormal proliferation of astrocytes and microglia

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28
Q

Why may a patient with early-mid Alzheimer’s disease remember childhood memories but not recent events

How does this change with disease progression?

A

In early-middle Alzheimers disease the hippocampus is effected, hence short term memory is affected. Whereas long term memory (eg. childhood) is stored in the cortex which is less/ unaffected

As disease progresses, atrophy of the cortex will result in loss of long-term memories

29
Q

Explain the Amyloid hypothesis of Alzheimer’s disease

A

APP (amyloid precursor protein) mutations causes aggregation of amyloid-β which initiates the disease causing processes:

  • inflammation
  • tau-tangle formation
  • synapse dysfunction
  • cell death

Ultimately leading to dementia

30
Q

What is the normal amino acid length of APP peptides in a healthy brain?

What is the proportion of Aβ produced?

A

36–43 amino acids of the APP

Aβ40 and Aβ42 are most common and are produced in a ‘normal’ brain in a proportion of Aβ40 > Aβ42 (more short chains)

31
Q

Explain how Aβ forms from APP

A

Aβ results from cleavage of APP by 2 peptidases

  • β-secretase
  • γ-secretase
32
Q

Mutations in APP are associated with which type of Alzheimer’s?

A

Early-onset Alzheimer’s

33
Q

Explain how a mutation in the APP affects Aβ and therefore leads to Alzheimer’s

A

Mutations in APP increase the relative production of Aβ42 (longer chains)

Aβ42 is more fibrillogenic and therfore are more likely to aggregate and form senile plaques

Fibril formation ➞ soluble oligomers of Aβ also form which are more toxic than plaques and impair functionality of synapses

34
Q

In AD what would be seen in terms of total Aβ and ratio of Aβ40 to Aβ42

A

Total Aβ is usually raised in AD with raised Aβ42 in plaques (Aβ40 < Aβ42)

35
Q

What are PSEN1 and PSEN2 mutations?

A

Presenilin 1 and 2 are components of the γ-secretase enzyme

Mutations in PSEN1 and PSEN2 favour longer Aβ formation, thus increasing amyloid plaque formation

36
Q

List 3 mutations linked to Amyloid β plaque formation

A

APP, PSEN1 and PSEN2

All favour longer Aβ formation, leading to increased aggregation and plaque formation

37
Q

Give 4 issues with the amyloid hypothesis

A

1) Aged brains often contain amyloid plaques with no cognitive impairment
2) Amyloid plaque burden poorly correlates with severity
3) Neurofibrillary tangles (NFTs) of tau correlate with cognitive impairment more closely
4) NFTs can exist without amyloid plaques
5) Tau is required for AD in experimental cell models
6) Mutations to tau do not cause aggregation of Aβ
7) Drugs targeting Aβ eg immunotherapies and secretase inhibitors have not been successful

38
Q

What does Tau do and what is contained within its structure?

A

Tau regulates the stability of tubulin assemblies and contains multiple phosphorylation sites

39
Q

What does the Tau hypothesis state and explain this

A

States the principle causative substance of AD is tau

Theorises that in AD tau is hyperphosphorylated and misfolds resulting in inability to regulate microtubules.

This results in cellular damage to:

  • the cytoskeleton,
  • mitochondrial integrity
  • cell transport systems

Also states that misfolded tau may spread between neurons

40
Q

Why can we not conclude problems with Tau only cause AD

A

because although AD is most common, other diseases have been linked with problems with tau

41
Q

Explain how inflammation is thought to cause Aβ plaques and hyperphosphorylation of tau (thus leading to prgression of late onset AD)

A

AD causes a sustained immune response in the brain resulting in Microgliosis and astrogliosis. Both these release ApoE which is linked to late-onset AD

Also, chronically activated microglia release proinflammatory and toxic products, such as ROS, NO, and cytokines which results in:

  1. Increased APP expression + increases Aβ load.
  2. Stimulation of CDK5 activation (kinase that hyperphosphorylates tau)

Overall theorises that persistant neuroinflammation results in progression of the neuropathological changes of AD

42
Q

What are microglia and how are they activated in terms of AD?

A

Microglia are immune cells of CNS, when activated they:

  • change their morphology
  • act like macrophages

Aβ activates microglia to migrate to the plaques and phagocytose Aβ

43
Q

What causes astrogliosis?

A

Microgliosis results in astrogliosis (abnormal increase in the number of astrocytes) due to destruction of neurons

44
Q

What body response is associated with cognitive deficits (particularly MCI and AD)?

A

Correlation between peripheral inflammation and cognitive deficits, particularly with MCI and AD

45
Q

What other common disease is associated a risk of AD and why?

A

Type 2 diabetes, associated with x2 risk of AD

Decreased cerebral glucose metabolism is characteristic in AD

  • Proinflammatory TNFα induces insulin resistance
46
Q

How do we clinically diagnose Dementia

A

1) History (presence of spouse, partner or close family member helpful)
2) Investigations (CV factors, exclude others)
3) Assessment of cognition
4) Referral to memory clinic (consultant psychiatrist, clinical psychologist or dementia nurse)

47
Q

List 2 ways to assess cognition and what each is?

A

1) GPCOG (general practitioner assessment of cognition
2) Addenbrookes cognitive examination – III (ACE-III)
* Attention, Memory, Fluency, Language, Visuospatial

48
Q

How do we manage dementia? (3)

A

1) cholinesterase inhibitors: donepezil, rivastigmine & galantamine
2) N-methyl-D-aspartate receptor antagonist: memantine

These slow/arrest cognitive decline for approx. 9months, NOT curative

3) multidisciplinary approach (exercise programmes, GP, social and community support)

49
Q

What is multi-infarct dementia

A

A specific type of vascular dementia (neurodegeneration secondary to loss of vascular supply to neurons)

It is multiple strokes which result in extensive cerebral damage. Tends to be multifocal small artery occlusion resulting in a progressive loss of function cortex

50
Q

Give 3 clinical features of multi-infarct dementia

A

1) Stepwise rather than gradual
2) Usually cardiovascular disease, hypercholesterolaemia,
3) Better preservation of personality, insight and social responsivenes

51
Q

How do we diagnose multi-infarct dementia?

A

History and MRI (typically showing bilateral multifocal small areas of deep cortical infarcts)

52
Q

How do we manage multi-infarct dementia?

A

1) address risk factors e.g HTN, cholesterol, diabetes, smoking etc…
2) anticoagulation

53
Q

What would be seen in multi infarct dementia on a CT

A

Global atrophy, diffuse white matter lesions, lacunes and infarcts

54
Q

What are the characteristic features of Lewy body dementia?

A

1) parkinsonism
2) cognitive impairment fluctuates day to day ‘pseudo delerium’
3) complex visual hallucinations
4) sensitivity to neuroleptic meds (antipsychotics exacerbate symptoms)

55
Q

What is Lewy body dementia?

A

Progressive dementia caused by defects in Ach and dopamine signalling

Midpoint between AD and PD

56
Q

What 2 things are seen in Lewy body dementia?

A

Lewy bodies and amyloid plaques

57
Q

What are Lewy bodies and in which region of the brain are they located (in Lewy body dementia)?

A

Lewy bodies are eosinophilic cytoplasmic inclusions that contain protein alpha-synuclein

Located in frontotemporal region

58
Q

How do we manage Lewy body dementia compared to AD

A

Similar to AD but respond better to cholinesterase inhibitors than AD

Do not respond well to anti-PD medications

59
Q

How does frontotemporal dementia compare to other demesias discussed?

A

Less common form of dementia but more familial

60
Q

What parts of the brain are affected in frontotemporal dementia and therefore give 3 clinical features

A

Parts of brain that deal with behaviour, problem solving, planning and emotions

Clinical features

  • personality changes, behavioural changes and language difficulties
  • difficulty planning, decisions, sympathy, empathy
  • memory typically minimally affected
61
Q

How do we diagnosis frontotemporal dementia and what are we looking for exactly?

A

1) Clinical and MRI (looking for ‘knife blade atrophy’)
2) Abnormal tau protein clumps: Pick bodies

62
Q

How do we manage frontotemporal dementia

A

supportive

63
Q

How do we assess Delirium?

A

ICD-10

64
Q

What are the 3 types of Delirium and which can be more difficult to recognise?

A

1) Hyperactive delirium: a subtype of delirium characterised by people who have heightened arousal and can be restless, agitated or aggressive
2) Hypoactive delirium: a subtype of delirium characterised by people who become withdrawn, quiet and sleepy
3) Mixed

** Hypoactive and mixed delirium can be more difficult to recognise

65
Q

What is the onset of Delirium and give 4 risk factors

A

Onset: comes on within hours to weeks

Risk factors: old age, dementia, major surgery, hospital admission

66
Q

Give 4 causes of delirum?

A

UTI (most common), chest infection, constipation, disorientation, dehydration, drugs

67
Q

How do you diagnosis and manage delirium?

A

Diagnosis: clinical

Management: medications ➞ short term haloperidol or olanzapine

68
Q

List 4 strategies to prevent delirium?

A

Clock and calendar, re-orientation, regularity, prevent dehydration and constipation, good sleep, address sensory impairments

69
Q

What is the relationship between delirium and dementia

list 2 other things delirium

A

Those who suffer an episode of delirium are more likely to have dementia

Other consequences of delirum: longer hospital stays, die, or acquire complications

Nervous System (Semester 5) (21 decks)

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