EXAM #3: NEURODEGENERATIVE DISORDERS Flashcards
What are the main characteristics of Neurodegnerative Disorders?
1) Loss of neurons
2) Due to BOTH genetic and environmental factors
3) Pathology= aggregation of misfolded proteins
What specific region is associated with neuronal loss in AD?
Hippocampus
What specific region is associated with neuronal loss in PD?
Basal Ganglia
What specific region is associated with neuronal loss in ALS
Cortical and spinal motor neurons
What protein accumulates in AD?
1) Beta-amyloid plaques
2) Neurofibrillary tangles
(Intracellular)
What protein accumulates in PD?
Alpha-synuclein
What protein accumulates in Huntington’s Disease?
Huntington Protein
What protein accumulates in Prion Disease?
Extracellular prion amyloid plaques
Who first diagnosed Alzheimer’s Disease?
Alois Alzheimer
Who was the first patient diagnosed with AD?
Frau August Deter
What is the most prevalent form of gradually progressive dementia?
AD
What are the cognitive symptoms of AD?
1) Loss of short-term memory
2) Aphasia
3) Apraxia
4) Agnosia
5) Disorientation
What is apraxia?
Inability to carry out motor activity despite intact motor system
What is agnosia?
Inability to recognize objects, persons, sounds, shapes, or smells
What are the noncognitive symptoms of AD?
1) Depression
2) Psychotic symptoms
What typically causes death in AD?
Complications of immobility i.e. pneumonia or PE
What is the Cholinergic Hypothesis of AD?
Memory deficits are due to a degeneration of subcortical cholinergic neurons
Describe the pathology of AD.
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
What is the connection between Beta-Amyloid, AD, and Down’s Syndrome?
APP gene (which is cleaved to Beta-Amyloid) is located on chromosome 21
What genes are mutated in early onset AD?
1) APP
2) Presenilin 1 and 2
What is the function of Presenilin?
Cleavage of APP
What genetic variation is late onset AD associated with?
Epsiolon 4 allele of ApoE
What is the role of ApoE in AD?
ApoE clears Beta-Amyloid
What is the function of Episolon 4 ApoE in AD?
This form of ApoE does not clear Beta-Amyloid as well as other isoforms and increases the development of AD
What is the Tau Hypothesis of AD?
- Tau normally supports microtubules and the neuronal cytoskeleton
- HYPERphosphorylation of Tau causes aggregates i.e. neurofibrillary tangles to form
What are the outcomes of neuofibrillary tangles in AD?
1) Microtubular disintegration and instability
2) Collapse of neuronal transport
3) Altered NT release and synaptic function
4) Cell death
What class of drug is the first line treatment for cognitive symptoms of AD?
Cholinesterase inhibitors
What is the mechanism of action of the Cholinesterase Inhibitors?
Block AChE and Butyrylcholinesterase mediated breakdown of ACh to choline and acetate
List the drugs that are used as Cholinesterase Inhibitors in the first line treatment of AD.
1) Tacrine
2) Donepezil
3) Rivastigmine
4) Galantamine
Why is Tacrine no longer used today for the treatment of AD?`
Hepatotoxicity
Note that is also had a very short half-life and needed to be taken 4x per day*
What is the mechanism of action of Donepezil?
AChE inhibition
What is unique about Donepezil compared to the other AChEs used to treat AD?
Long half life (70 hrs) that allows for ONCE A DAY dosing
Which of the first line agents for AD blocks BOTH AChE and Butyrylcholinesterase?
Rivastigmine
How often does Rivastigmine need to be dosed?
Twice per day
What AChE can be given as a transdermal patch? What are the clinical implcations?
Rivastigmine–less GI adverse effects
What are the typical side effects of AChEs used to treated AD?
1) Nausea
2) Vomiting
3) Diarrhea
What are the side effects of AChE overdose?
SLUDGE
- Salivation
- Lacrimation
- Urination
- Defecation
- GI cramps
- Emesis
What is the MOA of Memantine?
Non-competitive NMDA antagonist
What is the role of Memantine in AD?
Neuroprotection by reducing glutamate excitotoxicity
What class of drugs are primarily used to treat the psychotic symptoms of AD?
Atypical antipsychotics
What drugs should be used to treat depression in AD?
SSRIs
What drugs should NOT be used to treat depression in AD?
TCAs–alpha-1 effects cause orthostatic hypotension (fall risk)
