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PHRM 845 > Exam 3: Alzheimer's and Dementia > Flashcards

Exam 3: Alzheimer's and Dementia Flashcards

1
Q

Ratio female:male for AD

A

2:1

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2
Q

AD symptoms

A

memory loss

impaired ability to learn/reason

impaired ability to carry out daily activities; confusion, untidiness

anxiety, suspicion, hallucinations

motor dysfunction can also occur in late-stage disease

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3
Q

Environmental risk factors AD

A

age

low educational level

reduced mental activity in late life

reduced physical activity in late life

risk for vascular disease

head injury

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4
Q

Amyloid Plaques

A

extracellular

consists of amyloid b peptide

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5
Q

Neurofibrillary Tangles

A

intracellular

consist of hyper-phosphorylated tau

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6
Q

Progression of neuropathology

A

plaques and tangles spreads through the cortex as the disease progresses

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7
Q

Effect of Neuropathology: Entorhinal Cortex

A

memory formation/consolidation

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8
Q

Effect of Neuropathology: hippocampus

A

memory formation/consolidation

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9
Q

Effect of Neuropathology: basal forebrain cholinergic systems

A

learning

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10
Q

Effect of Neuropathology: neocortex

A

memory, learning, cognition

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11
Q

Synapse Loss in AD

A

neurons with neurofibrillary tangles and neurons in the vicinity of amyloid plaques see the destruction of synapse

synapse loss results in reduced levels of neurotransmitters, especially acetylcholine

dysregulated glutamate –> excess excitotoxicity and neurotoxicity

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12
Q

Which is the key pathogenic molecule: AB or tau?

A

AB

mutations in the gene encoding the AB precursor protein (APP) are linked to early onset AD

Trisomy 21 is associated wit hAD like phenotype and the APP gene is located on chromosome 21

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13
Q

Production of AB from APP

A

cleavage of APP by a-secretase in the middle of the AB segment releases a non-amyloidoogenic (non-toxic) fragment

mutations in the APP gene favor cleavage by beta or gamma secretase, resulting in the production of more AB42 relative to AB40

mutations in the gene encoding PSEN1 or 2 alter APP cleavage by gamma secretase, resulting in the production of more AB42 to AB40

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14
Q

Effects of AB aggregation on tau pathology

A

AB aggregation is thought to promote tau hyper-phosphorylation, leading to neurofibrillary tangle formation, cytoskeletal anomalies, and disruption of axonal trafficking

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15
Q

Neurofibrillary Tangle Formation results in cytoskeletal defects

A

in unhealthy areas where tangles have accumulated, the cytoskeletal tracts are disrupted and disorganized, resulting in defects in axonal transport that leads to synaptic dysfunction (tau falls off)

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16
Q

Effects of AB aggregation on microglial activation

A

activated microglia release pro-inflammatory cytokines that cause neuroinflammation

activated microglia also release reactive nitrogen species and reactive oxygen species that cause oxidative stress

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17
Q

Impact of ApoE genetics on AD risk

A

individuals with one or two Apo4 alleles have an increased risk of AD whereas inheritance of hte ApoE2 allele decreases AD risk

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18
Q

Donepezil

A

specific reversible inhibitor of acetylcholinesterase

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19
Q

Rivastigmine

A

inhibits acetylcholinesterase and butyrylcholinesterase (patch or orally)

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20
Q

galantamine

A

selective, reversible inhibitor of acetylcholinesterase AND enhances the action of acetylcholine on nicotinic receptors

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21
Q

Cholinesterase Inhibitor MoA

A

block the degradation of acetylcholine thereby compensating for the loss of acetylcholine that results from the degeneration of cholinergic nerve terminals in AD

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22
Q

Memantine

A

NMDA antagonist that blocks glutamatergic neurotransmission via a noncompetitive mechanism, reduces excitotoxicity

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23
Q

Strategies for Disease Modifying Therapy (AD)

A

AB generation (beta and gamma secretase inhibitors)

AB aggregation (inositol, polyphenols, peptides)

AB clearance (vaccine, AB antibodies (aducanumab, lecanemab, donanemab)

tau kinase inhibitors (lithium, valproate)

glutamate mediated excitotoxcity (induces expression of GLT-1 transporter)

inflammation or oxidative stress (NSAIDS, dietary antioxidants)

24
Q

Florbetapir

A

radiolabeled agent that binds beta-amyloid, visualized by PET scanning

radiolabeled agent specific for tau: 18F-Flortaucipir

25
Q

Vascular Dementia

A

impaired judgment or executive function

occurs as a result of brain injury associated with vascular disease or stroke

26
Q

Dementia with Lewy Bodies

A

combination of cognitive decline and parkinsonian symptoms

visual hallucinations

cortical lewy bodies

27
Q

Frontotemporal Dementia

A

disinhibited behavior

tau accumulations (pick’s bodies)

28
Q

NCD: complex attention

A

sustained/divided attention, processing speed

29
Q

NCD: learning and memory

A

immediate/recent memory, very long term memory

30
Q

NCD: perceptual/motor

A

visual perception/praxis

31
Q

NCD: executive function

A

planning, decision making, working memory, flexibility

32
Q

NCD: language

A

expressive and receptive language (naming and word finding)

33
Q

NCD: social cognition

A

recognition of emotions, range of behavior

34
Q

Mild NCDs

A

modest cognitive decline from a previous level of performance in one or more cognitive domains

does not interfere with independence

not attributed to a delirium epsidoe

35
Q

Major NCDs

A

evidence of significant decline from a previous level of performance in one or more domains

cognitive deficits interfere with independence

not attributed to a delirium episodes

36
Q

Differential diagnosis

A

CV disease/vascular dementia
lewy body dementia
PD
normal pressure hydrocephalus
mixed dementia
pick’s disease
huntington’s disease
reversible causes

37
Q

reversible cognitive decline

A

B12 or folate deficiency
hypothyroidism
CBC
liver function tests
infection (UTI)
depression
RPR/VDRL (syphilis) f

38
Q

Drug Induced NCDs

A

skeletal muscle relaxants
tricyclic antidipreseants
bladder antispasmodics
antihistamines (anti-emetics, allergy/cough cold)

39
Q

Treatment goals

A

slow the symptoms of cognitive decline and preserve functioning for as long as possible

40
Q

Cholinesterase Inhibitors place in therapy

A

first line with no preference as to agent

donepezil fda approved for severe demential and is chosen first due to ease of dose titration and once-daily dosing

donepezil, rivastigmine, galantamine

41
Q

NMDA receptor antagonist place in therapy

A

FDA approved in moderate to severe dementia only

not useful in mild cognitive impairments

marginal benefit usually realized in alzheimers

does not slow or prevent neurodegeneration

memantine, donepezil/memantine

42
Q

Donepezil Dosing

A

initiate 5 mg once daily at bedtime, increase to 10 mg once daily at bedtime for 4-6 weeks

43
Q

Donepezil AEs

A

GI bleeding (caution if used with NSAIDs)

N/V/D

Bradycardia

syncope

insomnia

weight loss

P450 2D6 and 3A4 substrate

44
Q

Galantamine Dosing

A

4 mg twice daily for 4 weeks with breakfast and dinner

doses > 16 mg/day are not recommended for moderate renal/hepatic impairment

45
Q

Galantamine AEs

A

GI bleeding (caution if used with NSAIDs)

N/V/D

Bradycardia

syncope

insomnia

weight loss

P450 2D6 and 3A4 substrate

46
Q

Rivastigmine

A

initiate 1.5 BID for at least 2 weeks and titrate by 1.5 mg BID every 2 weeks

max dose: 6 mg

take with meals to minimize GI effects

47
Q

Rivastigmine AEs

A

toxicity due to not removing previous patch every day

NVD

esophageal rupture in one case (restart lower dose if therapy interrupted

no P450 interactiosn

48
Q

Memantine Dosing

A

dose adjustment required in severe renal impairment

CrCl: 5-29 mL/min, initiate 5 mg once daily x 1 week if tolerated, target dose 5 mg bid

49
Q

Memantine AEs

A

use with caution in patients with seizure disorder

hallucinations

insomnia

confusion

Caution with CA inhibitors and Sodium bicarb

no P450 interactiosn

50
Q

Memantine/Donepezil dosing

A

On donepezil 10 mg only: start Namzaric 7/10 daily and increase by 7 mg increments as tolerated t o28/10 mg target dosing once daily

if on memantine 10 mg bid or ER 28 mg once daily, switch to namzaric 28/10 with evening meal once daily

51
Q

Memantine/Donepezil AEs

A

warning for vagotonic effects like bradycardia and heart block

increased risk of GI ulceration, diarrhea, NV, bladder outflow obstruction

52
Q

Combo Treatment

A

Cholinesterase+NMDA

initial treatment is usually cholinesterase

if declien noted despite treatment at maximum tolerated dose, consider use of NMDA receptor antagonist in combo if pt is in moderate to severe stage

53
Q

Key Concept of Oral Agents

A

sudden start/stop of therapies should be avoided

54
Q

Memantine only works if initiated early on

A

false! can see benefit later on

55
Q

Aducanumab Side Effects

A

ARIA: reiques MRI of brain within one year of starting treatment, then before 7th and 12th dose

56
Q

Lecanemab Side Effects

A

ARIA: up to 30% requires MRI of brain within one year of starting treatment, then before 5th, 7th, and 14th doses

57
Q

Pharmacotherapy of Dementia: mABs

A

requires presence of amyloid beta pathology prior to initiating treatment

PHRM 845 (14 decks)

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