EXAM #3: NEURODEGENERATIVE DISORDERS

Question 1

What are the main characteristics of Neurodegnerative Disorders?

Answer 1

1) Loss of neurons
2) Due to BOTH genetic and environmental factors
3) Pathology= aggregation of misfolded proteins

Question 2

What specific region is associated with neuronal loss in AD?

Answer 2

Hippocampus

Question 3

What specific region is associated with neuronal loss in PD?

Answer 3

Basal Ganglia

Question 4

What specific region is associated with neuronal loss in ALS

Answer 4

Cortical and spinal motor neurons

Question 5

What protein accumulates in AD?

Answer 5

1) Beta-amyloid plaques
2) Neurofibrillary tangles

(Intracellular)

Question 6

What protein accumulates in PD?

Answer 6

Alpha-synuclein

Question 7

What protein accumulates in Huntington’s Disease?

Answer 7

Huntington Protein

Question 8

What protein accumulates in Prion Disease?

Answer 8

Extracellular prion amyloid plaques

Question 9

Who first diagnosed Alzheimer’s Disease?

Answer 9

Alois Alzheimer

Question 10

Who was the first patient diagnosed with AD?

Answer 10

Frau August Deter

Question 11

What is the most prevalent form of gradually progressive dementia?

Answer 11

AD

Question 12

What are the cognitive symptoms of AD?

Answer 12

1) Loss of short-term memory
2) Aphasia
3) Apraxia
4) Agnosia
5) Disorientation

Question 13

What is apraxia?

Answer 13

Inability to carry out motor activity despite intact motor system

Question 14

What is agnosia?

Answer 14

Inability to recognize objects, persons, sounds, shapes, or smells

Question 15

What are the noncognitive symptoms of AD?

Answer 15

1) Depression

2) Psychotic symptoms

Question 16

What typically causes death in AD?

Answer 16

Complications of immobility i.e. pneumonia or PE

Question 17

What is the Cholinergic Hypothesis of AD?

Answer 17

Memory deficits are due to a degeneration of subcortical cholinergic neurons

Question 18

Describe the pathology of AD.

Answer 18

1) Amyloid Precursor Protein is cleaved to Beta-Amyloid
2) There is an imbalance between Beta-Amyloid production and clearance
3) Beta-Amyloid is toxic to neurons

Question 19

What is the connection between Beta-Amyloid, AD, and Down’s Syndrome?

Answer 19

APP gene (which is cleaved to Beta-Amyloid) is located on chromosome 21

Question 20

What genes are mutated in early onset AD?

Answer 20

1) APP

2) Presenilin 1 and 2

Question 21

What is the function of Presenilin?

Answer 21

Cleavage of APP

Question 22

What genetic variation is late onset AD associated with?

Answer 22

Epsiolon 4 allele of ApoE

Question 23

What is the role of ApoE in AD?

Answer 23

ApoE clears Beta-Amyloid

Question 24

What is the function of Episolon 4 ApoE in AD?

Answer 24

This form of ApoE does not clear Beta-Amyloid as well as other isoforms and increases the development of AD

Question 25

What is the Tau Hypothesis of AD?

Answer 25

- Tau normally supports microtubules and the neuronal cytoskeleton - HYPERphosphorylation of Tau causes aggregates i.e. neurofibrillary tangles to form

Question 26

What are the outcomes of neuofibrillary tangles in AD?

Answer 26

1) Microtubular disintegration and instability 2) Collapse of neuronal transport 3) Altered NT release and synaptic function 4) Cell death

Question 27

What class of drug is the first line treatment for cognitive symptoms of AD?

Answer 27

Cholinesterase inhibitors

Question 28

What is the mechanism of action of the Cholinesterase Inhibitors?

Answer 28

Block AChE and Butyrylcholinesterase mediated breakdown of ACh to choline and acetate

Question 29

List the drugs that are used as Cholinesterase Inhibitors in the first line treatment of AD.

Answer 29

1) Tacrine 2) Donepezil 3) Rivastigmine 4) Galantamine

Question 30

Why is Tacrine no longer used today for the treatment of AD?`

Answer 30

Hepatotoxicity ****Note that is also had a very short half-life and needed to be taken 4x per day*****

Question 31

What is the mechanism of action of Donepezil?

Answer 31

AChE inhibition

Question 32

What is unique about Donepezil compared to the other AChEs used to treat AD?

Answer 32

Long half life (70 hrs) that allows for ONCE A DAY dosing

Question 33

Which of the first line agents for AD blocks BOTH AChE and Butyrylcholinesterase?

Answer 33

Rivastigmine

Question 34

How often does Rivastigmine need to be dosed?

Answer 34

Twice per day

Question 35

What AChE can be given as a transdermal patch? What are the clinical implcations?

Answer 35

Rivastigmine--less GI adverse effects

Question 36

What are the typical side effects of AChEs used to treated AD?

Answer 36

1) Nausea 2) Vomiting 3) Diarrhea

Question 37

What are the side effects of AChE overdose?

Answer 37

SLUDGE - Salivation - Lacrimation - Urination - Defecation - GI cramps - Emesis

Question 38

What is the MOA of Memantine?

Answer 38

Non-competitive NMDA antagonist

Question 39

What is the role of Memantine in AD?

Answer 39

Neuroprotection by reducing glutamate excitotoxicity

Question 40

What class of drugs are primarily used to treat the psychotic symptoms of AD?

Answer 40

Atypical antipsychotics

Question 41

What drugs should be used to treat depression in AD?

Answer 41

SSRIs

Question 42

What drugs should NOT be used to treat depression in AD?

Answer 42

TCAs--alpha-1 effects cause orthostatic hypotension (fall risk)