Alzheimer's

Question 1

AD symptoms

Answer 1

1. memory loss (especially recent memories)
2. impaired ability to learn, reason
3. impaired ability to carry out daily activities; confusion, untidiness
4. anxiety, suspicion, hallucinations
5. motor dysfunction can also occur in late-stage disease

Question 2

Environmental risk factors of AD

Answer 2

1. Age
2. Low educational level
3. Reduced mental activity in late life
4. Reduced physical activity in late life
5. Risks for vascular disease
6. Hear injury

Question 3

AD neuropathology

Answer 3

1. loss of brain volume
2. amyloid plaques and neurofibrillary tangles
3. synapse loss

Question 4

Amyloid plaques

Answer 4

extracellular; consist of amyloid-beta peptide (Abeta)

Question 5

Neurofibrillary tangles

Answer 5

intracellular; consist of hyperphosphorylated tau

Question 6

Neuropathology primarily affects which areas of high cognitive function?

Answer 6

1. Entorhinal cortex
2. Hippocampus
3. Basal forebrain cholinergic systems
4. Neocortex
5. Nucleus basalis

Question 7

A striking feature of neurons with neurofibrillary tangles and neurons in the vicinity of amyloid plaques is

Answer 7

destruction of synapses

Question 8

Synapse loss results in

Answer 8

1. reduced levels of neurotransmitters - especially acetylcholine, but also serotonin, norepinephrine, and dopamine
2. dysregulated glutamate -> excess excitotoxicity and neurotoxicity

Question 9

Genetic evidence that suggests a key role for Abeta?

Answer 9

1. Mutations in the gene encoding the Abeta precursor protein, APP, are linked to early onset AD
2. Trisomy 21 is associated with an AD-like phenotype, and the APP gene is located on chr 21
3. Mutations in the gene encoding presenilin proteins involved in cleaving Abeta from APP are linked to early onset AD

Question 10

Abeta peptide is released from

Answer 10

the transmembrane amyloid precursor protein (APP) by the activity of beta-secretase (BACE1) and gamma-secretase

Question 11

Cleavage of APP by alpha-secretase in the middle of the Abeta segment releases

Answer 11

a non-amyloidogenic (non-toxic) fragment

Question 12

Mutations in the APP gene favor

Answer 12

cleavage by beta- or gamma-secretase, resulting in the production of more Abeta or more Abeta42

Question 13

What do mutations in the gene encoding presenilin-1 or presenilin-2 (PSEN1 or PSEN2) do?

Answer 13

alter APP cleavage by gamma-secretase, resulting in the production of more Abeta or more Abeta42

Question 14

Abeta aggregation is thought to promote

Answer 14

tau hyperphosphorylation, leading to neurofibrillary tangle formation, cytoskeletal anomalies, and disruption of axonal trafficking

Question 15

What is Entresto?

Answer 15

Valsartan + Sacubitril: new CHF drug

Question 16

What is the concern about Entresto?

Answer 16

It is a Neprilysin inhibitor and there’s concern that inhibitors of Neprilysin could contribute to AD

Question 17

Neurofibrillary tangle formation results in

Answer 17

cytoskeletal defects

Question 18

What happens in unhealthy areas of the brain where tangles have accumulated?

Answer 18

the cytoskeletal tracks are disrupted and disorganized, resulting in trafficking defects and synaptic dysfunction

Question 19

Abeta is thought to induce neurotoxicity indirectly by

Answer 19

triggering microglial activation, a process that is probably aimed at clearing amyloid from the brain

Question 20

Activated microglia release

Answer 20

1. pro-inflammatory cytokines (PGs, interleukins, TNF-alpha) that cause neuroinflammation
2. reactive nitrogen species and reactive oxygen species that cause oxidative stress

Question 21

CV risk factors in AD

Answer 21

1. elevated LDL and decreased HDL increase AD risk
2. vascular disease may accelerate AD pathogenesis (decreased nutrient delivery to the brain, decreased Abeta clearance, increased Abeta accumulation)

Question 22

How does diabetes increase the risk of AD?

Answer 22

defects in insulin signaling may lead to accumulation of toxic glucose metabolites in the brain, decreased Abeta clearance

Question 23

ApoE responsible for

Answer 23

transporting cholesterol in brain (LDL); defects in cholesterol metabolism may alter membrane structure and function, which in turn affects Abeta deposition

Question 24

Three ApoE isoforms

Answer 24

ApoE2, ApoE3, and ApoE4

Question 25

Significance of individuals with one or two ApoE4 alleles?

Answer 25

One or two ApoE4 alleles increase the risk of AD

Question 26

Significance of individuals with an ApoE2 allele

Answer 26

decreases the risk of AD

Question 27

Cholinesterase inhibitors block

Answer 27

The conversion of acetylcholine to acetic acid and choline; thereby compensating for the loss of acetylcholine that results from the degenration of cholinergic nerve terminals in AD

Question 28

Cholinesterase inhibitors

Answer 28

1. Donepezil (Aricept) 2. Rivastigmine 3. Galantamine

Question 29

Donepezil (Aricept)

Answer 29

specific, reversible inhibitor of acetylcholinesterase

Question 30

Rivastigmine

Answer 30

inhibits acetylcholinesterase and butyrylcholinesterase

Question 31

Galantamine

Answer 31

selective, reversible inhibitor of acetylcholinesterase and enhances the action of acetylcholine on nicotinic receptors (increases acetylcholine release from cholinergic neurons)

Question 32

Memantine

Answer 32

NMDA antagonist that blocks glutamatergic neurotransmission via a noncompetitive mechanism

Question 33

Glutamate is an

Answer 33

excitatory neurotransmitter that is involved in long-term potentiation, a neuronal mechanism required for learning and memory

Question 34

Excess glutamate signaling leads to

Answer 34

excitotoxicity, a mechanism that can result in neuronal death

Question 35

Candidate agents that target Abeta generation

Answer 35

beta and gamma-secretase inhibitors

Question 36

Molecules that modulate Abeta generation or aggregation, including cholesterol or ApoE

Answer 36

statins and bexarotene

Question 37

Candidate agents that target Abeta aggregation

Answer 37

inositol, polyphenols [resveratrol], peptides

Question 38

Candidate agents that target Abeta clearance

Answer 38

vaccines, Abeta antibodies

Question 39

Candidate tau kinase inhibitors

Answer 39

lithium, valproate

Question 40

Candidate agents that reduce inflammation or oxidative stress

Answer 40

NSAIDs, dietary antioxidants [Vitamin E, polyphenols]

Question 41

Florbetapir

Answer 41

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

Question 42

Limitation of florbetapir/PET scan

Answer 42

does not establish AD diagnosis (amyloid in other diseases could also be detected)

Question 43

Non-AD dementias

Answer 43

1. Vascular dementia 2. Dementia with Lewy bodies (DLB) 3. Frontotemporal demena - Pick's disease

Question 44

Common initial presentation of vascular dementia

Answer 44

impaired judgment or executive function

Question 45

Vascular dementia occurs as a result of

Answer 45

brain injury, associated with vascular disease or stroke

Question 46

The nature of deficit in thinking or physical function in vascular dementia is determined by

Answer 46

location of the brain injury

Question 47

Dementia with Lewy bodies

Answer 47

combination of cognitive decline and parkinsonian symptoms; cognitive decline more prevalent at disease onset than for PD

Question 48

Core diagnositic feature of dementia with Lewy bodies

Answer 48

visual hallucinations

Question 49

Neuropathology of dementia with Lewy bodies is characterized by

Answer 49

the presence of cortical Lewy bodies

Question 50

Frontotemporal dementia (Pick's disease)

Answer 50

disinhibited behavior, poor impulse control, antisocial behavior, disturbances in executive functioning

Question 51

Neuropathology of Pick's disease is characterized by

Answer 51

presence of tau accumulations (Pick's bodies)