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alzheimer's disease Flashcards

1
Q

what is neurodegeneration?

A

the progressive loss of the structure or function of neurons that leads to neuronal cell death

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2
Q

what are CT and MRI scand used for?

A

-to visualize the brain and check for signs of stoke, brain trauma or bleeding

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3
Q

what is the montreal cognitive assessment test used for?

A

to detect cognitive impairment by evaluating judgement, reasoning, memory, planning and problem solving

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4
Q

what is the montreal cognitive assessement test composed of? how long does it take?

A
  • 30 questions

- 12-14 mins

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5
Q

for the montreal cognitive assessement test, what are patients asked in terms of orientation?

A

patients are asked to state the current date, their address, city, etc.

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6
Q

for the montreal cognitive assessement test, what are patients asked in terms of short term memory?

A
  • patients are given 5 words and asked to repeat them

- they are then asked to preform a separate task before repeating the words again

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7
Q

for the montreal cognitive assessement test, what are patients asked in terms of “clock drawing”?

A
  • patients are asked to draw a clock indicating a given time
  • this task requires auditory comprehension, memory, visuoconstructive skills, etc.
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8
Q

what does a score of 26 or greater on the montreal cognitive assessement test indicate?

A

normal cognitive health

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9
Q

what is the average score on the montreal cognitive assessement test for patients with alzheimer’s disease?

A

16

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10
Q

demenita describes a group of symptoms affecting what?

A
  • memory, thinking, social abilities and those that interfere with daily functioning
  • i.e. it is a broader category used for cognitive impariement
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11
Q

is alzheimers captured under dementia? or vice versa?

A

alzheimers is captured under the umbrella of dementia and is actually the most common cause of it

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12
Q

what are some of the physiological changes associated with dementia?

A

personality changes, depression, anxiety, inappropriate behaviour, agitation, hallucinations and memory loss
-may also see difficulty in reasoning or problem solving/handling hard tasks

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13
Q

what are the common forms of dementia?

A
  • alzheimers (50-75%)
  • vascular (20-30%)
  • lewy body (10-25%)
  • frontotemporal (10-15%)
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14
Q

what is vascular dementia caused by?

A
  • brain damage due to impaired blood flow to the brain

- it can develop after stroke

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15
Q

what factors increase the risk of developing vascular dementia?

A
  • factors that increase the risk of heart disease/stroke:

- smoking, high BP, etc.

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16
Q

the symptoms of vascular dementia vary based on what?

A

the area of the brain with reduced blood flow

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17
Q

how does lewy body dementia occur?

A

protein deposits called lewy bodies that accumulate in neurons

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18
Q

lewy body proteins are also associated with which disease?

A

parkinsons

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19
Q

frontotemporal dementia refers to what?

A

a group of rare disorders that affect and cause atrophy of the frotal and temporal lobes of the brain

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20
Q

what is a common characteristic of frontotemporal dementia?

A

accumulation of Pick bodies in the brain (proteins)

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21
Q

what are the common symptoms of frontotemporal dementia?

A
  • significant issues with behaviour

- aphasia (speech problems)

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22
Q

what age category is most affected by frontotemporal dementia?

A

adults age 40-65 but can also affect young adults

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23
Q

what is the typical life span of alzheimers patients post-diagnosis?

A

4-8 years (can be up to 20)

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24
Q

what is the prevalence of alzheimer’s in canada?

A

7.1%

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25
Q

it’s important to be able to distinguish alzheimers from age-related changes, as both are associated with things like memory loss. Provide an example of the distinction btwn the two.

A
  • alzheimer’s is associated with progressive loss of function while age-related symptoms are usually temporary lapses in function
  • e.g. alzheimers patient forgets how to put their clothes on where age-related patients may temporarily forget a friends phone number
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26
Q

what are some common signs of AD other than memory loss?

A
  • personality changes causing out of character behaviour such as sudden bursts of anger
  • difficulty having a conversation (not making sense)
  • consistent poor judgement such as wearing a heavy jacket during hot weather
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27
Q

what are the risk factors for AD? what is the most important? (7)

A
  • increasing age (most important!!!)
  • lifestyle (smoking, exercise)
  • head trauma
  • head-heart health (heart and brain health are related)
  • genetic abnormalities
  • family history
  • biological sex
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28
Q

why is age the most important risk factor for alzheimers disease?

A
  • at age 65 adults have a 5% chance of developing alzheimers which doubles every 5 years
  • after 85 the risk is ~33%
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29
Q

why is head trauma a risk for alzheimers?

A

there is increasing evidence of a positive correlation btwn head trauma and dementia

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30
Q

what are the genetic abnormalities associated with AD?

A

~20 genes associated with the risk of developing AD

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31
Q

how many AD cases actually result from inheriting a familial form?

A

5%

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32
Q

which biological sex is more at risk for AD? why? (2)

A
  • females have a higher risk for developing AD than men
  • current theories suggest that this is bc females generally live longer or that it has to do with hormonal changes during menopause
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33
Q

what are the two most commonly used methods of classifying AD?

A

(1) age of onset

(2) etiology

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34
Q

when can AD be considered early onset?

A

when an individual develops AD before the age of 65

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35
Q

when can AD be considered late onset?

A

when an individual develops AD after the age of 65

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36
Q

are the vast majority of AD cases early onset or late onset?

A

late

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37
Q

is the etiology of AD multifactorial? is it related to age?

A

yes & yes

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38
Q

what is sporadic AD?

A

AD due to the combination of genetic and environmental factors

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39
Q

what percentage of late onset cases are sporadic?

A

70%

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40
Q

what is familial AD?

A

AD that can be inherited and that may have known genetic etiologies

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41
Q

what percentage of early onset cases are familial?

A

> 50%

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42
Q

is there a specific test for AD? if so what is it?
if not what how do we confirm AD?
what does this mean for the length of the diagnostic period?

A
  • no - can only confirm in autopsy

- typically takes a long time to diagnose

43
Q

how is AD typically diagnosed?

A
  • based on the process of elimination of other possible causes such as:
  • Vit. B12/thiamine deficiencies
  • drug/alcohol intoxication
  • CNS infection
  • clinical depression
44
Q

are late onset patient usually asymptomatic? if so until when? if not why?

A

yes - usually asymptomatic until around age 65 - when loved ones start to notice issues

45
Q

when an individual is suspected to have AD, what diagnostic process do they typically undergo?

A

three phase differential diagnostic process

distinguish disease from others with common symptoms

46
Q

what is phase 1 of the three phase differential diagnostic process?

A

visit a family doctor about symptoms

47
Q

what is phase 2 of the three phase differential diagnostic process?

A

receive a refferal to a specialist (such as a neurologist, geriatrician or psychiatrist)

48
Q

what is phase 3 of the three phase differential diagnostic process?

A

actively monitor symptoms as the disease progresses

49
Q

are there advantages to establishing an early diagnosis? what are they? do these advantages outweigh ethical concerns of diagnosis, considering there is no cure for alzheimers?

A
  • yes
  • social and clinical (more treatments options available, quality of life decisions and advocay related to their condition)
  • yes
50
Q

what process results in the formation of the 2 neuropathological hallmarks of AD? what are they?

A

protein aggregation results in:

(1) amyloid beta plaques
(2) tau tangles

51
Q

where are amyloid beta plaques found in the brain?

A

the space btwn nerve cells in the brain

52
Q

how do Aβ plaques interfere with normal neuronal cell function?

A

they tangle with the knotted threads of the tau proteins interfering with microtube trafficking and cell signalling

53
Q

what type of proteins are tau proteins? what is their function in a healthy individual?

A
  • microtubule-associated proteins

- help transport nutrients through the brain

54
Q

how do tau tangles arise in AD patients? what is the result of these tangles?

A
  • tau proteins twist, forming threads/tangles which keep nutrients from reaching brain cells
  • ultimately causes neuronal cell death
55
Q

where can tau tangles occur?

A

intracellular, cytoplasmic, nuclear or extracellular spaces

56
Q

the presence/absenece and the location of tau tangles can indicate what about AD?

A

the presence, stage and sometimes the disease risk

57
Q

how are Aβ proteins made?

A

made from the amyloid precursor protein (APP) through proteolytic cleavage of APP by specific enzymes

58
Q

what sort of protein is APP?

A

single-pass transmembrane protien that spans the membrane

59
Q

is APP expressed at high levels in the brain? its rapidly metabolized by what?

A
  • yes

- proteases

60
Q

why is it that Aβ proteins accumulate in the brain?

A

not clear - hypothesized that it is due to changes in APP metabolism of Aβ elimination

61
Q

what are the two processes by which enzyme complexes cleave APP? are both processes healthy? why do these processes occur?

A

(1) non-amyloidogenic pathway (normal process that produces soluble products that are recycled)
(2) amyloidogenic pathway (detremental process that produces neurotixic Aβ peptides)
- occur bc APP proteins get old and need to be broken down

62
Q

describe the non-amyloidogenic pathway

A

-APP is cleaved by alpha-secretase to generate 2 fragments:
1 = C-83 (83 amino acid c-term fragment)
-remains in the membrane
2 = N-term soluble APP-alpha
-released into extracellular space
-cleavage for this pathway results in the A-β domain, prohibiting Aβ peptide formation

63
Q

describe the amyloidogenic pathway

A
  • APP is cleaved by beta-secretase
  • releases a large N-term fragment (known as soluble APP beta) into the extracellular space
  • Gamma-secretase then cleaves the remaining fragement releasing an Aβ peptide
  • these peptides may then aggregate, contributing to AD
64
Q

what are example proteins with secretase activity?

A

PSEN1 / PSEN2

65
Q

the development of A-beta aggregates occurs in stages, what are they?

A

(1) lag phase
(2) elongation phase
(3) stationary phase

66
Q

describe the lag phase of Aβ aggregate development

A
  • soluble, pre-fibril oligomers (aka nuclei) are formed

- i.e. native protein –> misfolded protein

67
Q

describe the elongation phase of Aβ aggregate development

A
  • oligomeric species act as templates to sequester other aggregate prone intermediates, leading to rapid fibril growth
  • i.e. midfolded protein –> rapid fibril growth
68
Q

describe the stationary phase of Aβ aggregate development

A
  • the insoluble mature amyloid fibrils formed have reached max fibril growth
  • i.e. fibrils are just chillen
69
Q

what happens after the stationary phase?

A

fibrils cluster together to form plaques - which disrupt cell functioning in the brain

70
Q

why is the deposition of Aβ aggregates thought to be a critical component of the cognitive dysfunction characteristic of AD?

A

the deposition of Aβ proteins preceeds the onset of the clinical phenotype in this disease

71
Q

what is the relationship btwn brain atrophy and alzheimers disease?

A
  • as Aβ plaques continue to accumulate, neurons continue to degenerate and die, causing the brain to shrink
  • gyri get narrower, sulci get wider and ventricles get wider
  • normal brain must be held by two hands, alzheimers brain can be held with one
72
Q

how many genes are thought to increase the risk of AD? of these genes, how many are confirmed familial forms?

A
  • 20 total known
  • 3 confirmed familial forms (thought to make up 50% of inherited/familial cases)
  • i.e. 17 = risk factors
73
Q

what are some examples of known genetic mutations that increase the risk of AD?

A
  • APP
  • PSEN1
  • PSEN2
  • APOE
74
Q

Describe how mutations in the APP gene can lead to AD.

What is the inheritance pattern for this gene?

What age of onset is this gene mutation correlated with?

Is this mutation related to familial AD or just a known risk factor?

A
  • responsible for amyloid beta A4 protein - increases beta-secretase activity
  • inheritance = autosomal dominant
  • correlated to the 40-60 age of onset
  • thought to contribute to ~5% of familial cases
75
Q

Describe how mutations in the PSEN1 gene can lead to AD.

What is the inheritance pattern for this gene?

What age of onset is this gene mutation correlated with?

Is this mutation related to familial AD or just a known risk factor?

A
  • presenilin-1 - thought to increase gamma-secretase activity
  • autosomal dominant
  • age 30-58
  • thought to contribute to 50-75% of inherited cases
76
Q

Describe how mutations in the PSEN2 gene can lead to AD.

What is the inheritance pattern for this gene?

What age of onset is this gene mutation correlated with?

Is this mutation related to familial AD or just a known risk factor?

A
  • presenilin-2 - thought to increase gamma secretase activity
  • autosomal dominant
  • age 45-88
  • thought to contribute to less than 1% of inherited cases
77
Q

wat protein is the APOE gene responsible for?

what age of onset is this gene mutation correlated with?

is this mutation related to familial AD or just a known risk factor?

A
  • responsible for apolipoprotein E4
  • age 40-90
  • 1/17 risk factors for AD
78
Q

do different familial mutation variants that affect APP cleavage location exist? if so what does this effect? if not why?

A
  • yes

- can alter clinical phenotype (geneotype informs phenotype)

79
Q

what is a notable property of gamma-secretase that contributes to familial mutation variants? can all variants from aggregates?

A
  • it can cleave APP at different sites, resulting in Aβ proteins that range in size from 39-43 aa
  • yes, all can form aggregates
80
Q

what is cerebral amyloid angiopathy?

A

where Aβ proteins build up on the walls of arteries in the brain, increasing the risk for stroke caused by bleeding and dementia

81
Q

describe the flemsih A692G mutation in the APP gene

A
  • cerebral amyloid angiopathy present
  • amyloid plaques present
  • tau tangles present
  • presents as recurrent cerebral hemorrhage, dementia or both
82
Q

describe the dutch E693Q mutation in the APP gene

A
  • cerebral amyloid angiopathy present
  • amyloid plaques absent
  • tau tangles absent
  • presents as severe recurrent cerebral hemorrhage, followed by dementia
83
Q

describe the arctic E693G mutation in the APP gene

A
  • cerebral amyloid angiopathy present
  • amyloid plaques present WITH characteristic ring-like structures
  • tau tangles present
  • presents as dementia only
84
Q

describe the iowa D694N mutation in the APP gene

A
  • cerebral amyloid angiopathy present
  • amyloid plaques present WITH extensive Aβ deposition
  • tau tangles present
  • presents as dementia only
85
Q

what is a common method by which physicians scan for known mutations relating to AD?

A

qRT-PCR

86
Q

as AD is currently incurable, the treatment of AD focuses on what?

A

slowing the progression of symptoms

87
Q

There are currently how many drugs approved in canada for slowing the progression of AD? what are they?

A

4:

  • 3 of them = cholinesterase inhibitors
  • other 1 = N-methyl-D-asparate (NMDA) receptor antagonist
88
Q

the type of drug prescribed to treat AD depends on?

A

stage of the disease

89
Q

generally describe the mechanism of action for cholinesterase ihibitors and why they are used to treat AD

A
  • ach is a NT essential for learning and memory
  • with AD, there is a progressive loss of ach containing neurons in particular, making cholinesterasei a good choice for treatment
  • these drugs function by inhibiting the breakdown and reuptake of ach
90
Q

what are the three cholinesterase inhibitors approved for use in canada?

A

brand name (generic name)

  • aricept (donepezil)
  • reminyl (galantamine)
  • excelon (rivastigmine)
91
Q

what is the approved use for each of the 3 cholinesterase inhibitors?

A
  • aricept - all stages of AD
  • reminyl - mild to moderate (early) stages
  • excelon - mild to moderate (early) stages
92
Q

what are some of the complications associated with cholinesterase inhibitors?

A

nausea, vomitting, loss of appetite, increased frequency of bowel movements, slowed HR, headaces

93
Q

generally describe the mechanism of action for NMDA receptor antagonists and why they are used to treat AD

A

-normally, at rest NMDA receptors are bound to MG
-they then bind glutamate, releasing MG, connecting neurons, facilitating the uptake of Ca, propogating the electirical/chemical signals important for learning and memory
-with AD, excess glutamate release and Aβ proteins (can bind NMDA receptors too) cause excess Ca uptake, = neuronal toxicity
(neurons cant differentiate btwn learning and resting state = death)
-these drugs block (stabilize) NMDA receptors to reduce inappropriate glutamate binding, improving mental function

94
Q

what is the only approved NMDA receptor antagonist in canada?

A 
brand name (generic name)
-memantine (Ebixa)
95
Q

what is the approved use for memantine?

A

moderate to severe (late) stage AD

96
Q

what are some of the complications associated with memantine?

A

headache, dizziness, sedation, fatigue, insomnia, muscle cramps

97
Q

memantine can be used in combination with what? for what purpose? is it ever used alone?

A
  • often alone
  • can be used with aricept
  • to further reduce severe symptoms
98
Q

what is a promising advancement in AD in terms of diagnostic testing? what would this allow for?

A
  • working on a diagnostic blood test which would identify phosphorylated tau proteins in the plasma for patients with familial AD
  • would allow for earlier treatment
99
Q

what are two promising treatment advancements for AD?

A
  • PRI-002 (drug) small molecule that disrupts the ability of Aβ molecules to form oligomers
  • if successful will reduce the number of Aβ oligomers (slowing disease progression)
  • Aducanumab (drug) monoclonal antibody targeting Aβ proteins
  • if sucessful will block oligomer formation and the interference that these oligomers cause
100
Q

what is the hypothesized function of APP proteins?

A

helps the neuron grow and repair

101
Q

the collection of beta amyloid plaques in the brain can directly disrupt neuronal cell function, can these plaques also indirectly affect neuronal cell function?

A
  • yes
  • can trigger an immune response that causes inflammation
  • cerebral amyloid angiopathy is another example
102
Q

how do amyloid plaques influence tau tangles?

A
  • tau proteins support microtubules which transport nutrients through the cell
  • its thought that amyloid plaque buildup outside a neuron triggers kinase proteins inside the neuron
  • these protiens add a phosphate group to tau proteins, causing them to leave microtubules and aggregate inside the neuron
  • this disrupts microtuble function, and may lead to apoptosis
103
Q

is down syndrome a risk for AD? why or why not?

A
  • yes

- extra chromosome 21 - where APP gene is located

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