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Integrated Drug Structure, Action, and Therapeutics > Dr. Lee's Alzheimer's and Antipsychotic lecture > Flashcards

Dr. Lee's Alzheimer's and Antipsychotic lecture Flashcards

1
Q

What is the term for a drop in cognitive function from a prior level?

A

mild cognitive impairment

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2
Q

What is mild cognitive impairment plus a loss in the ability to care for oneself?

A

Dementia

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3
Q

What is required to make the diagnosis of dementia?

A

A detailed history about prior levels of function.

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4
Q

Is MCI treated with any medication? Dementia?

A

No and yes

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5
Q

What rank in cause of death is Alzheimer’s?

A

6th in the USA

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6
Q

What gene increases the risk of Alzheimer’s?

A

Apolipoprotein E (APOE). Varient E4 increases the risk. A single copy increases risk 3-fold, homozygous e4 increases risk 8-12 fold.

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7
Q

What other family history increases the risk of Alzheimer’s?

A

Cardiovascular disease history in the family

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8
Q

What lifestyles/disease states increase the risk of Alzheimer’s?

A 
Cardiovascular disease in middle age
Smoking
Midlife obesity
Midlife hypertension
midlife hyperlipidemia
diabetes
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9
Q

What increases cognitive reserve to stave off dementia?

A

Education

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10
Q

What maintains cognitive reserve?

A

social engagement

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11
Q

What is the most common form of dementia (60-80%)?

A

Alzheimer’s

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12
Q

In normal aging, neurons are…

A

preserved

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13
Q

In normal aging, brain mass is…

A

preserved

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14
Q

In normal aging, synaptic connections are…

A

lost. this is shown by processing speed decrease and abstract concept linkage decrease.

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15
Q

How are storage of memories affected by normal aging?

A

Takes longer to develop memories

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16
Q

How are retrieval of memories affected by normal aging?

A

Preserved, but retrieval process is slower.

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17
Q

How is thinking and reasoning affected by normal aging?

A

Preserved

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18
Q

What part of the brain is affected early in Alzheimers compared to normal aging?

A

The hippocampus (memory)

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19
Q

What other area of the brain are different in Alzheimer’s compared to normal aging?

A
  • Language is affected
  • The ventricles start to enlarge
  • As more cells die, the sulci get wider
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20
Q

What areas of the brain are rich in cholinergic neurons?

A 
Early:
Memory
Language
Later:
Reasoning and understanding
Disinhibition and behavioral problems
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21
Q

What histology will you see in Alzheimer’s Disease?

A

Amyloid beta peptide insoluble plagues accumulated on the outside of cells.

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22
Q

What protein is formed with B-secretase and y-secretase?

A

Amyloid-beta42.

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23
Q

What protein is formed from alpha-secretase and y-secretase?

A

B-amyloid40.

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24
Q

Is amyloid-beta42 or beta-amyloid40 more plaque-forming?

A

Amyloid-beta 42 is more plaque-forming, while 40 is more soluble.

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25
Q

What is the original protein that is cut to form both amyloid-beta 42 and beta-amyloid 40?

A

APP - amyloid precursor protein

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26
Q

What stabilizes microtubules inside a neuron?

A

Hyperphosphorylated tau protein.

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27
Q

What is the cholinergic hypothesis for Alzheimer’s?

A

That the loss of cholinergic neurons is responsible for AD. This is now considered a downstream event (aka something is killing these neurons, causing AD).

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28
Q

What is the amyloid-beta hypothesis? What is wrong with this hypothesis?

A

A-beta is the initial pathology leading to inflammation and neuronal death. However, almost all adults have A-beta, and A-beta load does not correlate with AD symptoms.

29
Q

What is Tau Hypothesis?

A

Tau-hyperphosphorylation and neurofibrillary tangles is the single common pathway that leads to PD. Tau hypothesis is gaining ground as the predominant hypothesis.

30
Q

What is the inflammation hypothesis?

A

Inflammation is a common event in AD. Nonspecific inflammation damages neurons causing A-beta and NFT (Neurofibrillary tangles). Many believe this is a marker of neuronal damage rather than the cause.

31
Q

What is the novel hypothesis?

A

Impaired glucose transport hypothesis: The brain uses 20% of the body’s energy, but only 2% of the body’s weight. Disruption of energy can lead to:

  • oxidative stress
  • free radical formation
  • Inflammation
  • Neuronal Death
  • Insulin resistance (diabetes)
  • Decreased brain blood flow (vascular disease)
32
Q

What is the consensus about AD?

A

That the disease is multifactorial since there is no single hypothesis. There is no single cause and no single cure. This is common between cancer and AD.

33
Q

What is the usual time between development of amyloid plaques and the development of AD symptoms?

A

10 years or so

34
Q

What does a mini-mental state exam (MMSE) score of 26-30 mean?

A

This is the preclinical stage. No symptoms have occurred, only biomarker changes. (eg only A-beta or tau in the blood or in the cerebrospinal fluid. MRI of the brain).
Controversial since there is no agreed-upon biomarker.

35
Q

What does a MMSE score of 22-26 mean?

A

mild cognitive impairment. cognitive changes have occurred, but no functional changes.

36
Q

What does an MMSE score of less than 22 mean?

A

Dementia due to AD. Mild, moderate, and severe are all categories. Cognitive and functional impairments have occurred.

37
Q

What are characteristics of mild AD?

A
  • problems coming up with the right word
  • trouble remembering names when introduced to new people
  • greater difficulty performing tasks in social or work settings
  • losing or misplacing a valuable object
  • increasing trouble with planning or organizing
38
Q

What are characteristics of moderate AD?

A
  • forgetfulness of events or personal history
  • moody or withdrawn in social or mentally challenging situations
  • unable to recall address, phone number, or high school that was graduated from
  • confusion about what day it is
  • need help choosing clothes for season/occasion
  • changes in sleep habits/patterns: increased sleeping during the day
  • increased risk of wandering and becoming lost
  • personality or behavior changes, including suspicions, repetitive behavior
39
Q

What are some characteristics of severe AD (late stage)?

A
  • full-time care required
  • lose awareness of recent experiences/surroundings
  • high level of assistance required for daily living
  • physical abilities changes, such as walking, sitting, and swallowing (eventually)
  • increased difficulty communicating
  • vulnerability to infections, especially pneumonia
40
Q

What is the difference as far as slope between AD and vascular dementia?

A

AD has a steady decline in cognitive function (2 pts of MMSE every year) vs vascular dementia has a stepwise decrease in slope in accordance with a new infarction or narrowing of an artery

41
Q

What % of dementia is vascular dementia?

A

10-20%

42
Q

When is memory affected in vascular dementia?

A

Memory is generally preserved until later, depending on where the infarcts are. Motor symptoms can occur.

43
Q

Does dementia usually occur on its own, or in conjunction with other disease states?

A

Usually co-occurs with other dementias. Share same risk factors. Modifies slope to be in the middle between the two.

44
Q

What disease state shares pathology with Lewy body dementia? What is this caused by?

A

PD. Abnormal folding of the alpha-synuclein protein.

45
Q

What symptoms are present with Lewy-body dementia?

A

Inattention
Executive dysfunction
Visuospatial impairment
Visual hallucinations are more common
Memory loss less prominent (physical symptoms more seen)
Lewy bodies are seen in later PD often development into lewy-body dementia
Physical symptoms of PD and the dementia of Lewy body

46
Q

What is another name for Frontotemporal dementia? Why is it called this? What %age of dementias are this one?

A

Pick’s disease. There are no active areas in the frontotemporal region. 2%.

47
Q

What is one of the most common early-onset dementias?

A

Pick’s disease

48
Q

What symptoms go along with Pick’s disease?

A
  • disinhibition, apathy, loss of empathy
  • aphasia: word-finding difficulty, halted speech
  • often confused with depression
  • does well on cognitive testing, memory and executive function preserved
49
Q

What areas of the brain are inactive for AD?

A

The hippocampus and temporal lobe. (Hippocampus for short-term memories, and temporal lobe for long-term memory, visual and auditory input, language recognition).

50
Q

What are the two approved treatments for AD?

A

Cholinesterase inhibitors

NMDA antagonist

51
Q

What drugs are cholinesterase inhibitors?

A 
Donepezil
Galatamine
Rivastigmine
Tacrine - still approved, no longer marketed due to hepatotoxicity
(mild to severe)
52
Q

What drug is an NMDA antagonist?

A

Memantine (moderate to severe)

53
Q

How do cholinesterase inhibitors act?

A

They increase the ACh at the synaptic cleft by stopping breakdown of ACh at postsynaptic neurons.

54
Q

Cholinesterase inhibitors;

  • Function?
  • If removed?
  • How do you choose?
A
  • Efficacy is limited, does not increase function. Delays symptoms for 6 months. Not disease modifying.
  • If removed, pt would return to their lower level of functioning as if they were never on the Cholinesterase inhibitor
  • choice is based upon tolerability
55
Q

What are the adverse effects of cholinesterase inhibitors?

A

Gi: nausea, vomiting, diarrhea (up to 50% for rivastigmine)
Anorexia, weight loss, pain (up to 25%)
Bradycardia, dizziness, syncope (up to 25%)
muscle tremor, weakness (23%), urinary incontinence (3%)
Insomnia, vivid dreams (up to 15%)

56
Q

How often should you increase cholinesterase inhibitors?

A

every 4-6 weeks. Goal is highest tolerable dose.

57
Q

What is the mechanism of an NMDA antagonist?

A

Binds once channel is open, prevents overstimulation by glutamate. Blocks the channel. Could be disease modifying, but no evidence.

58
Q

How do you use memantine?

A

In mono therapy (if cholinesterase is not tolerated) or in combo with cholinesterase inhibitor if dementia is severe.

59
Q

What is the efficacy of one type of therapy for AD over another?

A

If mono therapy, very similar efficacy. Dual therapy slightly better than either of the mono therapies.

60
Q

What are the side effects of memantine in comparison to ChE inhibitors?

A

Very mild SEs.

61
Q

What are currently first line?

A

ChE inhibitors, probably because generic was available. Yes are worse.

62
Q

What is second-line?

A

Memantine, but now generic is available. SEs are better, med is better tolerated. Efficacy is similar.

63
Q

What are four targets for research?

A

1) B-A Cascade, predominate target, with little progress
- phase I studies have shown to decrease B-A and inflammatory biomarkers. However, need to start earlier and hard to find candidates without doing a population-wide study. Posiphen keeps APP from forming :clears B-A from brain: AB42 is not formed
2) Tau: TRx0237 is a prodrug for methylthionium chloride
3) Insulin (SR-Exenatide, nasal insulin, Kaiser study)
4) Inflammation (statins, NSAIDS… not successful)

64
Q

Which medications have dose-limiting side effects?

A

ChE inhibitors

65
Q

What will future treatments most likely target?

A

Tau, inflammation, and insulin resistance. Maybe multiple targets at once on a population-wide scale necessary to prevent.

66
Q

What is the incidence of delirium in hospitalized older adults?

A

30%

67
Q

What is the incidence of delirium in older adults hospitalized for his fractures or injurious falls?

A

50%

68
Q

What percent of delirium is missed in hospitalized older adults?

A

70%

Integrated Drug Structure, Action, and Therapeutics (20 decks)

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