Exam 3 lecture 5

Question 1

disease progression of PD

Answer 1

Develops over 5-10 years with an increase in motor symptoms.
Cognitive symptoms may be present after several years of PD
Life expectancy after diagnosis is 15 years

Question 2

clinical presentation of PD (motor)

Answer 2

Tremor
bradykinesia
rigidity
parkinsonian gait (walking style)

Question 3

Clinical presentation of PD (non motor)

Answer 3

Anxiety and depression
constipation
dementia
insomnia
Psychosis

Question 4

non pcol tx of PD

Answer 4

Exercise/physical therapy
nutritional counseling
occupational therapy
psychotherapy
speech therapy

Question 5

Pcol tx of pd

Answer 5

1st line- rule out drug induced PD

Dopamine precursor
dopamine agonist
MAO-B inhibitor

Question 6

Rank drug efficacy with motor symptoms

Answer 6

Levodopa/carbidopa>DA>MAOB-I

Question 7

for most PD pts we initiate

Answer 7

Levodopa

Question 8

When to use dopamine agonist? WHen to avoid dopamine agonist?

Answer 8

Dopamine agonist may be used as initial tx if age<60 yrs and higher risk for dyskinesia

Avoid dopamine agonist as initial tx if
age>70
history of ICD
cognitive impairement
excessive daytime sleepiness
hallucinations

Question 9

What is the dopamine precursor used in PD

Answer 9

CD/LD (carbidopa/levidopa)

Question 10

place in therapy for PD for LD/CD

Answer 10

1st line for initial PD therapy

most effective monotherapy “gold standard”

Question 11

side effects of LD/CD (!)

Answer 11

N/V
LD motor fluctuations/dyskinesia
hallucinations

Question 12

starting dose of LD/CD (!)

Answer 12

25/100 mg CD/LD PO BID-TID with meals

Question 13

What are LD motor fluctuations (!)

Answer 13

wearing off
Freezing
Delayed onset
peak dose dyskinesia

Question 14

Define the LD motor fluctuations (!!)

Answer 14

wearing off- before next dosing interval, signs of motor symptoms
freezing- inability to move due to insufficient or fluctuating DA levels
Delayed onset- Therapeutic benefits delayed
Peak-dose dyskinesias- Involuntary body movement caused by high DA levels

Question 15

What are the types of dopamine agonists used to treat PD

Answer 15

ergots and non ergots

Question 16

Name none ergot dopamine agonists

Answer 16

pramiprexole
ropinirole
rotigotine
apomorphine

Question 17

strating doses for non ergot dopamine agonists

Answer 17

pramipexole IR 0.125 mg PO TID; ER 0.375 mg PO daily

• ropinirole IR 0.25 mg PO TID; ER 2 mg PO daily
• rotigotine 2 mg patch applied to the skin Q24H
• apomorphine 2 mg SC injection prn up to 5 x daily or
  10 mg SL Film up to 5 x daily

Question 18

place in therapy for non ergot DA agonists? What is used more, ergots or non ergots? Why?

Answer 18

1st line for initial PD therapy

non ergots used more because they are less likely to cause LD motor fluctuations.

Question 19

What are MAO-B i drugs? When are they used?

Answer 19

Rasagiline
Selegiline
Safinimide

less effective at controlling motor symotoms

Question 20

place in therapy for MAO-B I drugs

Answer 20

1st line for mild symptoms of PD
2nd line for adjunct

Question 21

starting doses of MAO-B I drugs

Answer 21

Rasagiline- 0.5 mg po
Selegiline- 5 mg PO BID
Safinamide- 50 mg PO QD

Question 22

What drug drug i/a should we be aware of with MAO B i

Answer 22

serotonergic antidepressants
dextromethorphan
serotonergic opioids

Question 23

COMT i MOA

Answer 23

Minimize breakdown of dopamine

Question 24

COMT i drugs and place in therapt

Answer 24

entacapone
opicapone
tolcapone

in combo with levodopa/carbidopa. PRevents wearing offS

Question 25

S/E of COMT i drugs

Answer 25

N/V brown/orange urine discoloration for entacapone (!!!!!)

Question 26

treatment initiation and flow for PD

Answer 26

Non pharm always first DOPAMINE PRECURSOR (most) (2nd line- DA, MAO-B, COMT) MAO-B (contingent) (2nd line- DA, dopamine precursor) DA (contingent) (2nd line MAO-B and COMT)

Question 27

Pros, cons and who of dopamine agonists

Answer 27

pros- once daily dosing formulations better tolerated by younger patients limited by motor fluctuations cons- expensive less symptomatic benefits than CD/LD many adverse effects who- age <60 at higher risk of dyskinesia

Question 28

Avoid dopamine agonists if

Answer 28

age>70 hallucinations ICD cognitive impairement excessive daytime sleepiness

Question 29

pros, cons, who of CD/LD

Answer 29

pros- gold standard due to symptomatic benefit cheap variety of dosage forms cons- motor fluctuations dosing frequency (can be >3x per day) who- most

Question 30

pros, cons, who of MAO-B

Answer 30

pros- generally well tolerated delays onset of motor fluctuation cons- least effective agent against motor symptoms dietary restriction (risk serotonin syndrome) who- high risk of motor fluctuations minor sx

Question 31

Develop a therapeutic plan to manage levodopa-induced motor fluctuations (!!!) wearing off

Answer 31

wearing off- increase CD/LD doe or frequency add DA agonist, MAOI or COMTI XR CD/LD

Question 32

Develop a therapeutic plan to manage levodopa-induced motor fluctuations (!!!) freezing

Answer 32

increase CD/LD dose or frequency add DA agonist Add ODT CD/LD

Question 33

Develop a therapeutic plan to manage levodopa-induced motor fluctuations (!!!) delayed onset

Answer 33

Take CD/LD on empty stomach ODT CD/LD void CR/XR CD/LD

Question 34

Develop a therapeutic plan to manage levodopa-induced motor fluctuations (!!!) peak dose dyskineses

Answer 34

Add amantidine lower dose of DA or CD/LD

Question 35

Recommend management of non-motor symptoms for a patient with PD (!!!)

Answer 35

constipation- evaluate for meds causing constipation increase fluid intake, physical actvity stool softener/ axatives or probiotics Insomnia- melatonin AVoid benzodiazepines (diazepam, lorazepam, oxazepam) orthostatic HTN- Non- pcol counseling midrodrine, droxidopa Medical equipment to stabilize it Anxiety/depression- Avoid benzodiazepines, CBT (cognitive behavioral therapy) SSRI/SNRI dementia- cholinesterase inhibitor (donepezil, rivastigamine) avoid anticholinergics, benzodiazepines, antihistamines, sedatives) Psychosis/delirium- Avoid- haloperidol, olanzepine, plaiperidone, risperidone

Question 36

What are the cardinal signs of AD? Seen more in men or women?

Answer 36

brain shrinkage, senile plaques, neurofibrillary tangles seen more in females

Question 37

AD symptoms

Answer 37

memory loss (especially recent) impaired ability to learn and reason impaired ability to carry out daily activities, confusion and untidiness anxiety, suspicion, hallucinations motor dysfunction in later stages

Question 38

environmental risk factors for AD

Answer 38

low educational level reduced mental activity in late life reduced physical activity in late life head injury neuropathology (loss of brain volume)

Question 39

difference between amyloid plaques and neurofibrillary tangles

Answer 39

amyloid plaques- extracellular neurofibrillary tangles- intracellular amyloid plaques consist of amyloid B peptide (AB) neurofibrillary tangles consist of hyper phosphorylated tau

Question 40

Neuropathology primarily affect areas of higher cognitive areas of higher cognitive function, what areas are these and what is affected? (AD)

Answer 40

entorhinal cortex- memory formation/consolidation) Hippocampus- memory formation/consolidation Basal forebrain- learning neocortex- memory, learning cognition

Question 41

T/F pathology is causing synaptic degeneration (AD)

Answer 41

true

Question 42

What is synapse loss in AD mainly due to?

Answer 42

reduced levels of neurotransmitters, especially ach, but also serotonin, norepinephrine, dopamine

Question 43

What happens to neurons in areas close to neurofibrillary tangles and amyloid plaques

Answer 43

destruction of synaose

Question 44

Genetic evidence suggests which pathogenic molecule is key for AD (AB or TAU)

Answer 44

AB- amyloid plaques TAU- neurofibrillary tangles genetic evidence suggests AB mutations in AB precursors are linked to early onset AD

Question 45

APP gene is located in which chromosome? What can this lead to

Answer 45

located in chromosome 21 (same one linked to downs syndrome) can lead to AD like symptoms in 4th decade of life in trisomy 21 pts

Question 46

Aβ peptide is released from the transmembrane amyloid precursor protein (APP) by the activity of

Answer 46

β-secretase (BACE1) and γ-secretase.

Question 47

What happens if APP is cleaved by alpha secretase in middle of AB segment instead of β-secretase (BACE1) and γ-secretase.

Answer 47

Cleavage of APP by α-secretase in the middle of the Aβ segment releases a non-amyloidogenic (non-toxic) fragment

Question 48

difference between Aβ42 and Aβ40

Answer 48

Aβ42 forms amyloid fibrils more readily than Aβ40.

Question 49

How is Aβ42 formed more that Aβ40 and what are the effects of this

Answer 49

Mutations in the APP gene favor cleavage by β- or γ-secretase, resulting in the production of more Aβ42 relative to Aβ40. - Mutations in the gene encoding presenilin-1 or presenilin-2 (PSEN1 or PSEN2), which are components of the γ-secretase complex, alter APP cleavage by γ-secretase, resulting in the production of more Aβ42 compared to Aβ

Question 50

What does AB aggregation lead to? (!!)

Answer 50

AB aggregation is thought to promote tau hyperphosphorylation leading to neurofibrillary tangle formation, cytoskeleton and disruption of axonal trafficking

Question 51

why do anomalies with tau lead to disruption in cytoskeleton (!!)

Answer 51

Tau normal function is to be bound to microtubules and stabilize them. Anomalies affect this In unhealthy areas where tangles have accumulated, the cytoskeletal tracks are disrupted and disorganized, resulting in defects in axonal transport that lead to synaptic dysfunction

Question 52

effect of AB aggregation on microglial activation

Answer 52

AB induces neurotoxicity indirectly by triggering microglial activation.

Question 53

what happens when microglia is activated by AB

Answer 53

Activated microglia release pro-inflammatory cytokines (e.g. prostaglandins, interleukins, tumor necrosis factor-α) that cause neuroinflammation. - Activated microglia also release reactive nitrogen species (e.g. nitric oxide, peroxynitrite) and reactive oxygen species (superoxide, hydrogen peroxide) that cause oxidative stress

Question 54

Understand how ApoE genetics status modulates AD risk

Answer 54

There are three ApoE isoforms as a result of polymorphisms in the ApoE gene: ApoE2, ApoE3, and ApoE4. → Individuals with one or two ApoE4 alleles have an increased risk of AD, whereas inheritance of the ApoE2 allele decreases AD risk

Question 55

Cholinesterase inhibitor use and drugs

Answer 55

Used to treat AD Donepezil (aricept) Rivastigimine Galantamine

Question 56

MOA of donepezil, rivastigamine, galantamine

Answer 56

Donepezil- Specific reversible inhibitor of ach rivastigamine- inhibits acetylcholinesterase and butyrylcholinesterase galantamine- selective reversible inhibitor of achetylcholinesterase and enhances action of acetylcholine.

Question 57

Use antiglutaminergic agents and drugs?

Answer 57

Use- AD therapy Memantine- NMDA antagonist that blocks glutamatergic neurotransmission via a noncompetitive mechanism, reduces excitotoxicity

Question 58

what is glutamate

Answer 58

an excitatory neurotransmitter that is required for learning and memory

Question 59

Describe pathogenic mechanisms being targeted in the development of new AD therapies.

Answer 59

1) AB targetting 2) non amyloid therapy

Question 60

AB therapy targets

Answer 60

AB- generation(b and gamma secretase inhibitors) AB-aggregation- (inositol, polyphenols) AB clearence- (AB antibody)

Question 61

non amyloid targets

Answer 61

Tau-kinase inhibitors glutamate mediated excitotoxicity inflammation of oxidative stress

Question 62

Understand how florbetapir (18F) and other imaging agents can be used to monitor amyloid formation in living individuals (what is florbetapir and how does it work)

Answer 62

18F is a radiolabled agent that binds B amyloid visualized by PET scanning

Question 63

Know similarities and differences between AD and other dementias (DLB, FTDP) name and describe non AD dementias

Answer 63

Non-AD dementias Vascular dementia- impaired judgement or executive function is a more common initial symptom than the memory loss characteristic of AD. Occurs as a result of brain injury associated with stroke. Dementia with lewy bodies (DLB)- Combination of cognitive and parkinsonian symptoms. Visual hallucinations are core diagnostic features. Front temporal dementia (FTD)- disinhibited behavior, poor impulse control, antisocial behavior. Neuropathology is characterized by presence of tau accumulations.