Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

disease in the brain > Alzheimer's (done) > Flashcards

Alzheimer's (done) Flashcards

You may prefer our related Brainscape-certified flashcards:
The Brain flashcards
1
Q

What is dementia?

A

Progressive, irreversible clinical syndrome w a range of cognitive & behavioural symptoms –> including:

  • Memory loss
  • Problems with reasoning & communication
  • Changes in personality
  • Reduction in the person’s ability to carry out daily activities
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What are multiple cognitive deficits?

A
  • Memory dysfunction is major early symptom - especially learning new info
  • Diagnosis req deficits in at least 2 cognitive domains: memory, language, behaviour, visuospatial, or exec function
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are the 2 main criteria req to diagnose dementia?

A
  • Multiple cognitive deficits
  • Cognitive disturbances
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are cognitive disturbances?

A
  • Sufficiently severe to cause impairment of occupations or social functioning (activities of daily living; ADL)
  • Must represent a decline from previous level of functioning
  • Cannot be explained by delirium or other major psychiatric disorder
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

List the 10 causes of cognitive deterioration:

A

1 - Alzheimer Disease (pure ~40% & mixed ~70%)

2 - Vascular disease, Multi-Infarct Dementia

3 - Drugs, Depression, Delirium

4 - Ethanol (5-15%)

5 - Medical/Metabolic systems

6 - Endocrine (thyroid, diabetes), Ears, Eyes Environment

7 - Neurologic (other primary degenerations)

8 - Tumor, Toxin, Trauma

9 - Infection, Idiopathic, Immunologic

10 - Amnesia, Autoimmune, Apnea, Age-Associated Memory Impairment

(Alzheimer’s is main cause)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are the 6 requirements for an AZD diagnosis?

A

A - Multiple cog deficits (1. memory impairment, 2. other cog impairments)

B - Deficits impair social/occupational life

C - Course shows gradual onset & decline

D - Deficits not due to: 1. other drug use, 2. substance-induced conditions

E - Do not occur exclusively during delirium

F - Not due to another psychiatric disorder

(Autopsy needed of +ive diagnosis)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What two diseases have different underlying causes but their outcome is similar?

A

Alzheimer’s disease & vascular dementia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What are the 4 requirements for a Vascular dementia diagnosis?

A

A - Multiple cog deficits (1. memory impairment, 2. other cog impairments)

B - Deficits impair social/occupational life

C - Focal neurological signs & symptoms or lab evidence indicating cerebrovascular disease eitology related to the deficits

D - Not due to delirium

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

When was AZD first described & how was it defined?

A

First described in 1906 by Alois Alzheimer

Progressive deterioration of cognitive function without antecedent cause, such as stroke

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What are the 2 types of onset that can happen in AZD & what are they called?

A

Familial = early onset

Sporadic = late onset

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Why is it important to understand AZD more?

A

Growing problem w an ageing pop –> more than 2% of population are over 65

It costs £20bn/yr in the UK

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is the prevalence of AD?

A

11% in 65 year old –> but rising to 50% of those over 85

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is the life expectancy of AD?

A

5-8 years from diagnosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

How is it determined what stage of AD you are at?

A

An MMSE test must be taken

This is marked out of 30

(Ranked; early diagnosis, mild-moderate 20 or below & severe 5 or below)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is the main diagnostic marker of AD?

A

beta-amyloid plaques

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are beta-amyloid plaques?

A
  • Large neurotoxic aggregates of insoluble protein (42 amino acid peptide termed “beta amyloid”
  • Initially only possible to detect via post-mortem diagnosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Where are beta-amyloid plaques found?

A

Outside the cell:

They are extracellular deposits that form in neural tissue –> causing gliosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What are the two neuropathological elements found in AD?

The two markers seen in the brain

A
  • Beta-amyloid plaques
  • Neurofibrillary tangles
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What are neurofibrillary tangles?

A

Disorganised bundles of filaments in the neuronal cytoplasm

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

How are neurofibrillary tangles formed?

A

Formed by hyperphosphorylated tau proteins, causing aggregation & precipitation of the cytoskeleton

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

How was AD initially certainly diagnosed?

A

A certain diagnosis could only be done via post-mortem histochemistry –> needed to identify beta-amyloid plaques & NFTs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

How can we now diagnose AD?

A

Imaging techniques such as PET & fMRI enable us to see beta-amyloid plaques & NFTs in vivo

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What happens to the brain pathology in early AD?

A

Degeneration of the cells in the hippocampus (links to memory loss)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What happens to the brain pathology in mild to moderate AD?

A

Atrophy of the cerebral cortex, enlarged ventricles

  • Decline in reading judgement & language, emotional outbursts
  • Forget how to do simple tasks (e.g. brushing teeth)
  • Cannot think clearly
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Why do patients with mild to moderate AD begin to experience emotional outbursts?

A

The thinning of the gyrus occurs here - emotional effects begin when the amygdala is affected

The amygdala controls emotions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What is the brain pathology like in advanced to final AD?

A
  • Death of more nerve cells
  • Agitation, wandering
  • Inability to recognise faces & communicate
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

What are the transmitter systems that are involved in AD pathogenesis?

A
  • Loss of specific NT pathways to cortex & hippocampus (*later flashcard details what these are)
  • Reduction in glutamate levels (precedes Abeta plaques)
  • Loss of GABAergic cortical interneurons
28
Q

What are the specific NT pathways from cortex & hippocampus that are lost during AD? *

A
  • Cholinergic ACh (correlated w dementia)
  • Noradrenaline (NA)
  • Serotonin (5-HT)
29
Q

What is one of the first NTs we see loss of in AD?

A

ACH (forebrain ACh)

30
Q

How does decreased forebrain ACh in AD occur?

A

Reduced ChAT (responsible for the synthesis of ACh) = red ACH synthesis

  • Selective loss of nicotinic receptor subtypes in hippocampus & cortex (nAChRa7)
31
Q

What is the main symptomatic treatment used with decreased ACh levels in AD?

A

Blocking ACh degradation by inhibiting acetylcholine esterase (AChE) = major symptomatic treatment

32
Q

How does blocking ACh degradation by inhibiting (AChE) help symptoms?

A
  • Inc ACh at synapses (different drugs not he market)
  • May improve, maintain or slow the decline of cognitive, behavioural & functional performance in patients w mild-moderate AD

Needs early intervention to work

33
Q

How do AChE blockers impact the patient?

A

Shows an improvement in function, behaviour & cognition

Treatment delays nursing home placement (20 weeks)

34
Q

What are some example of AChE blockers used to treat AD & how effective are they?

A
  • Donepezil = 38 weeks
  • Rivastigmine = 38-42 weeks
  • Galantamine = 52 weeks (24-30% better)

(Weeks show how long they significantly improve over placebo)

Essentially these do work but not very well

35
Q

What are major events of neurotoxicity in AD?

A

Major events are:

  • Loss of Ca2+ homeostasis
  • Excitotoxicity
36
Q

How does neurotoxicity in AD occur?

A

A multi-stage process involving multiple cell types (astrocytes, microglia & neutrons)

Major pathogenic theory is the “amyloid cascade hypothesis”

37
Q

What are the 5 stages of the “amyloid cascade hypothesis”?

A

1 - Mis-metabolism of Amyloid Precursor Protein (APP)

2 - Oxidative stress

3 - Neurotoxic insult

4 - Excessive excitatory receptor activation (glutamate)

5 - Apoptosis (cell death)

38
Q

What are the 2 major pathwaysof APP metabolism (stage1)?

A
  • Non-amyloidogenic (good news)
  • Amyloidogenic (bad news)
39
Q

What is amyloid precursor protein (APP)?

A

A single transmembrane domain protein

  • Expressed everywhere (req for neural growth & repair)
  • Has a short half-life & rapidly metabolised
40
Q

APP can be cleaved at 3 sites by sectretase enzymes:

1 - What are these called?

A

a- , b- and y-secretase

41
Q

APP can be cleaved at 3 sites by sectretase enzymes:

2 - Where do each of the 3 enzymes act?

A

y-secretase found in both non-amyloidogenic & amyloidogenic pathways –> on the intracellular side

a-secretase found in non-amyloidogenic (good)

b-secretase found in amyloidogenic (BAD)

42
Q

Why is amyloidogenic processing of APP bad?

A

In amyloidogenic processing, APP is cleaved by b-secretase

b-secretase cuts slightly higher up protein than a-secretase

From this we get the Ab aggregates (the 42 ones are most aggressive)

43
Q

Which of these two is neurotoxic & what is the other?

Secreted form of APPb & AB peptide

A

Secreted form of APPb = Neuroprotective

AB peptide = neurotoxic

44
Q

What does Secreted form of APPb do? (7points)

A
  • Regulates proteases
  • Involved in cell adhesion
  • Promotes neuronal survival
  • Protects against neurotoxic or ischaemic insult
  • Modulates glutamate responses
  • Regulates intracellular Ca2+
  • Regulated cytokine release = anti-inflammatory
45
Q

What does AB peptide do? (4 points)

A
  • Renders neurons vulnerable to excitotoxicity
  • Disrupts neuronal Ca2+ homeostasis
  • Aggregation of b-amyloid increases toxicity
  • Promotes cytokine release = inflammatory
46
Q

How does dominantly inherited AD start the amyloid cascade hypothesis?

A

1 - Missense mutations in the APP or PS1 or PS2 genes

2 - Increased Ab42 production throughout life

3 - Rest of amyloid cascade hypothesis

47
Q

How does non-dominantly inherited AD start the amyloid cascade hypothesis?

A

1 - Failure of Ab clearance mechanisms (e.g. Inheritance of ApoE4, faulty Ab degradation, etc)

2 - Gradually rising Ab42 levels in brain

3 - Rest of amyloid cascade hypothesis

48
Q

What is the rest of the amyloid cascade hypothesis?

A

3 - Accumulations & oligomerization of Ab42 in limbic & association cortices

4 - Subtle effects of Ab oligomers on synaptic efficacy

5 - Gradual deposition of Ab42 oligomers as diffuse plaques

6 - Microglial & astrocytic activation & attendant inflammatory responses

7 - Altered neuronal ionic homeostasis; oxidative injury

8 - Alerted kinase/phosphatase activities lead to tangles

9 - Widespread neuronal/synaptic dysfunction & selective neuronal loss w attendant NT deficits

= Dementia

49
Q

What % of AD is familial (inherited)?

A

Only 5-10% –> usually early onset

Most cases not directly genetic/familial!

50
Q

What are the 3 important genetic loci involved in familial AD?

A

1 = APP –> chromosome 21

2 = Presenilin 1 (PS1) –> chromosome 14

3 = Presenilin 2 (PS2) –> chromsome 1

51
Q

What genes increase the risk of sporadic AD?

A

1 - Inc risk w E4 allele of apolipoprotein (ApoE4) –> Involved in ~25% of AD cases

2 - Inc risk w some immune-related genes (e.g. TREM2 - doubles risk)

52
Q

What do the genetic loci that cause inherited & sporadic AD do?

A

Familial = all 3 genetic loci alter APP PROCESSING –> favouring Ab42 (more aggregative)

Sporadic = alter CLEARANCE of Ab42 aggregates

53
Q

What are the genetic risk factors for AD?

A

Familial = APP mutations, presenilins 1&2 (inc Ab production)

Sporadic = ApoE4 & other genes (dec Ab clearance)

54
Q

What are the biochemical factors of AD?

A
  • Inflammation
  • Free radicals
  • Nerve growth factor
55
Q

What are the 3 risk factors for AD?

A
  • Genetic factors
  • Biochemical factors
  • Other risk factors
56
Q

What are the other risk factors for AD?

A
  • Age
  • Gender - 2x more freq in women
  • Head size - larger head = more risk
  • Educational level - more time in education = lower risk
  • Stress
57
Q

What is the overall neuropathology of AD?

A
  • b-amyloid plaques
  • Neurofibrillary tangles
  • Neuronal loss
  • Synaptic loss
58
Q

What is the neurochemical pathology of AD?

A
  • ACh deficit
  • NA deficit
  • 5-HT deficit
59
Q

What are the 3 current therapeutic strategies for treating AD?

A

1 - Boost cholinergic transmission

2 - Alter glutamatergic function

3 - Anti-amyloid immunisation

60
Q

What are the 2 methods of boosting cholinergic transmission treat AD?

A

AChE inhibitors –> several drugs approved (donazepil, galantamine, tacrine & rivastigmine)

Muscarinic agonists (arecoline, pilocarpine)

61
Q

How good are AChE inhibitors when used to treat AD? (Boost cholinergic transmission)

A
  • Slows progress & boost cognition
  • Need to be administered early on
  • Produces modest, temporary improvements in 2/3 of patients (12-18 moths)
62
Q

How good are muscarinic agonists when used to treat AD? (Boost cholinergic transmission)

A

Only tested in animal models –> some efficacy but side effects unknown

63
Q

What are the 2 methods used to alter glutamatergic function to treat AD?

A
  • Nootropic agents (e.g. paracetamol) –> enhance cog function, but mechanism is controversial (bc boosts glutamatergic function)
  • NMDA antagonists (e.g. memantine)
64
Q

How was anti-amyloid immunisation used to treat AD?

A

Monoclonal antibody against Ab (approved in 2021) –> targets amyloid plaques

Highly effective at reducing amyloid load in animal models –> some +ive results in clinical trials in humans

65
Q

Why was anti-amyloid immunisation discontinued in 2024 as a treatment for AD?

A

Other mAbs targeting different stages of amyloid deposition have been developed

This is promising - effect sizes are moderate –> does this call into questions amyloid hypothesis?

66
Q

What are the 5 future therapeutic strategies being developed?

A
  • b & y-secretase inhibitors/a-secretase stimulators
  • Anti amyloid immunisation
  • Anti-inflammatory drugs
  • Tau kinase inhibitors
  • Tau aggregation inhibitors (immunisation)

Please refer to slide 6.2 as each of these drugs relate to a stage in the amyloid cascade hypothesis

67
Q

Review the summary slide

A

Well done x

disease in the brain (22 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions