(3.7) Patho and Pharmacology of Alzheimer's and other Dementias Flashcards
What are the cardinal signs of Alzheimer’s?
Brain shrinkage, senile plaques, neurofibrillary tangles
What is the ratio of females to males that have AD?
2:1 female to male
What are the sxs of AD?
- Memory loss (esp recent mem)
- Impaired ability to learn, reason
- Impaired ability to carry out ADLs
- Confusion, untidiness
- Anxiety, suspicion, hallucinations
- Motor dysfunction in late stage disease
What are environmental risk factors for AD?
- Age
- Low educational level
- Reduced mental activity in late life
- Reduced physical activity in late life
- Risks for vascular disease
- Head injury
What is the neuropathology of AD in simplest terms?
Loss of brain volume
What is present in the brains of AD pts?
Amyloid plaques and neurofibrillary tangles
Where are amyloid plaques?
Extracellular
What do amyloid plaques consist of?
Amyloid-beta peptide (AB)
Where are neurofibrillary tangles?
Intracellular
What do neurofibrillary tangles consist of?
Hyper-phosphorylated tau
What parts of the brain does earlier stage AD start at?
- Entorhinal complex (memory formation/consolidation)
- Basal forebrain cholinergic systems (learning)
To what parts of the brain does AD spread to?
- Hippocampus (memory formation/consolidation)
- Neocortex (memory, learning, cognition)
What is a striking feature of neurons w NFT and/or in vicinity of plaques?
Destruction of synapses
What does synapse loss result in?
Reduced levels of neurotransmitters esp ACh, but also serotonin, NE, DA
What is another consequence of synapse loss?
Dysregulated glutamate which causes excess excitotoxicity and neurotoxicity
Regarding AB, what is linked to early onset AD?
- Mutations in the gene encoding the AB precursor protein (APP)
- Mutations in the gene encoding presenilin proteins involved in cleaving AB from APP
What is the connection between Down’s syndrome and AD?
- Trisomy 21 is associated w an AD-like phenotype in 4th decade of life
- APP gene is located on chromosome 21
What does NFT formations result in?
Cytoskeletal defects
What happens at unhealthy microtubules where tangles have accumulated?
Cytoskeletal tracks are disrupted and disorganized, resulting in defects in axonal transport that lead to synaptic dysfunction
In addition to causing damage to the neurons directly, what else is AB thought to do?
Induce neurotoxicity indirectly by triggering microglial activation
Why does AB induce microglial activation?
Process aimed at clearing the amyloid from the brain
What do activated microglia release that causes damage?
- Proinflammatory cytokines (e.g. prostaglandins, interleukins, tumor necrosis factor alpha) that cause neuroinflammation
- Reactive nitrogen and oxygen species that cause oxidative stress
What is ApoE?
Responsible for transporting cholesterol in brain
What can altered ApoE function do?
Can affect AB aggregation or clearance
Which individuals regarding ApoE genetics have an increased risk of AD?
Individuals w one or two ApoE4 alleles
Which individuals regarding ApoE genetics have a decreased risk of AD?
Individuals w inheritance of ApoE2 allele
What is MOA of cholinesterase inhibitors?
Block the enzymatic rxn of ACh to acetic acid + choline, thereby compensating for loss of ACh that results from degeneration of cholinergic nerve terminals in AD
What drugs are in the cholinesterase inhibitors class?
- Donepezil (Aricept)
- Rivastigmine
- Galantamine
What is Donepezil?
A specific, reversible cholinesterase inhibitor of acetylcholinesterase
What is Rivastigmine?
A cholinesterase inhibitor of acetylcholinesterase and butyrylcholinesterase
What is Galantamine?
A selective, reversible cholinesterase inhibitor of acetylcholinesterase and enhances action of ACh on nicotinic receptors
What drug is in the anti-glutamatergic therapy?
Memantine
What is the MOA of memantine?
NMDA receptor antagonist that blocks glutamatergic neurotransmission via a noncompetitive mechanism
What is the result of memantine’s MOA?
Reduced excitotoxicity
What is Namzaric?
Combination drug of memantine ER + donepezil
How is imaging of AB done?
A radiolabeled agent called Florbetapri (18F) binds to AB and is visualized by PET scan
How is imaging of Tau done?
Using a tau specific radiolabeled agent called 18F-Flortaucipir
What characterizes vascular dementia?
- Impaired judgment or executive fxn
- Less memory loss than AD
How does vascular dementia occur?
Occurs as a result of brain injury associated w vascular disease or stroke
How is the nature of vascular dementia’s sxs determined?
Location of brain injury
What characterizes dementia w lewy bodies (DLB)?
Combination of cognitive decline and parkinsonian sxs
What is a core diagnostic feature of DLB?
Visual hallucinations
What is the neuropathology of DLB?
Presence of cortical lewy bodies
What characterizes frontotemporal dementia (FTD) [e.g. Picks’ disease]?
Disinhibited behavior, poor impulse control, antisocial behavior
What is the neuropathology of FTD?
Presence of tau accumulations (Picks’ bodies in case of Picks’ disease)
What is mixed dementia?
Anomalies linked to more than one dementia can exist simultaneously in the brain
