Alzheimer's and Parkinson's Flashcards
Name two characteristics of Alzheimer’s and five areas it causes problems with.
- Dementia and not related to a distinct cause
2. Causes problems with memory, language, judgment/thinking, personality and perception
Who gets Alzheimer’s Disease? When?
In early onset symptoms appear before age 60 and are related to genetic factors
In late onset symptoms appear after age 60
Prevalence 5% at 65
Over 90% at 95 years of age.
What two general characteristics are attributed to Alzheimers?
Brain shrinkage and localized loss of neurons.
What are the three hallmarks of Alzheimers?
- Decrease in cholinergic transmission (decreased ACh in hippocampus (memory and learning)/frontal cortex (executive function)
- Amyloid plaques (beta or alphabeta)
- Neurofibrillary tangles (hyperphosphorylated tau protein)
What two treatments are there for Alzheimers? Do they cure it?
Cholinesterase Inhibitors and NMDA Receptor antagonist.
Neither serve as a cure, the disease progresses these just alleviate symptoms for a period of time
Which type of treatment for Alzheimers prevents the breakdown of acetylcholine in the synapse? What does this do? When are they indicated? What kind of imporvement?
Cholinesterase inhibitors.
WE are trying to make up for the deficit in cholinergic transmission.
Indicated for mild to moderate AD
Slight improvement in cognitive function.
Name three examples of cholinesterase inhibitors. How are they administered? What are some side effects?
Donepezil (Aricept)
Rivastigmine (Exelon)
Galantamine (Razadyne)
Oral administration one or two times per day
Side effects: Bronchoconstriction, diarrhea, dizziness, headache and nausea.
Name an NMDA Receptor Antagonist. When is it indicated? What kind of benefits? Side effects (9)?
Memantine (Namenda) Indicated in moderate to severe Modest benefits Laundry list of side effects: Anemia Diarrhea Dizziness Fatigue Hypertension Rash Sedation Urinary Frequency Weight Gain
Memantine is proposed to work by two different mechanisms. Name them.
- Blocks leaky channels to help reduce calcium induced excitement
- Blocks leaky channels to help reduce background noise making signals relatively stronger
amyloid beta plaques result from the processing of what protein?
APP: Amyloid precursor protein.
In the non-amyloidogenic pathway APP gets cleaved by what? Do we for amyloid beta?
APP protein gets cleaved by alpha-secretase which cuts the alphabeta in half so NO amyloid beta is formed.
In the amyloidogenic pathway APP is cleaved by what? Do we form amyloid beta?
APP gets cleaved by beta-secretase.
amyloidbeta is produces aggregates and forms clots.
Why do we care about amyloid beta plaques?
To be honest I don’t care about them.
Just saying.
But if I did…
The effects of the amyloid beta plaques are unclear. Cognitive effects are more likely to be a result of the soluble amyloid beta derivatives from the plaques rather than the plaques themselves.
Is there a genetic involvement in amyloid beta plaques?
Early onset AD is heavily due to genetic factors. Many mutations associated with AD increase the amount of amyloid beta
What is the ApoE genotype responsible for?
Encodes for a protein that facilitates the clearance of amyloid beta plaques.
Why is the ApoE genotype a significant risk factor for AD?
Variations of the gene affect clearance of the amyloid beta plaques.
ApoE2: lower than normal risk for AD
ApoE3: normal risk for AD
ApoE4: Increased risk for AD
One copy of ApoE4 = 3 fold increase
Two copies of ApoE4= 12-15 fold increased risk (substantial early onset)
Tau Proteins are hyper-phosphorylated in AD. What is the normal tau protein responsible for? What happens when it is hyper-phosphorylated?
Tau protein in microtubules in normal neurons maintains shape. In AD with hyper-phosphorylation, the protein can no longer support microtubules and they fall apart. Proteins become tangled and form those Neurofibrillary tangles which correlate with neuronal death.
Where are the three potential drug targets for amyloid beta plaques?
Block synthesis
Promote clearance
Block plaque formation
Where is the one potential target for tau proteins?
Block aggregation
What is Parkinsons Disease? What characterizes it?
A movement disorder occurring mostly in the elderly caused mainly by environmental factors but there are some genetic risk factors
Characterized by:
Cognitive impairment/depression (later stages)
Difficulty starting and stopping movement
Dyskinesias
Muscle rigidity
Tremor at rest
What is the main area of concern in PD? Why?
The basal ganglia (striatum, globus pallidus, subthalamic nuclei, substantia nigra)
The basal ganglia is responsible for staring purposeful movement and suppressing unwanted movement
What results in controlled movement? What happens in PD?
The balance of Dopamine and ACh.
In PD there is reduced Dopamine in the striatum resulting in an imbalance.
Pharmacologically how do we treat PD?
Increase the dopamine with dopaminergic agents or prevent cholinergic inhibition of dopamine release with anticholinergic agents.
How do dopaminergic Agents work?
Increase the amounts of dopamine in striatum. Increased delivery or decreased degradation. Mimic the effects of dopamine (agonists).
What is the first line therapy for PD?
What is the problem with it?
Levodopa. 80% of patients show improvement. 20% regain near normal motor function.
Wears off over 2-3 years (probably due to advanced neurodegeneration)
Compared to Dopamine what is Levodopa?
Levodopa is a dopamine pre-cursor which is degraded to dopamine providing dopamine in the striatum. This happens in the periphery and brain. Dopamine does not cross the BBB.
What degrades Levodopa to Dopamine?
Decarboxylases and catecholamine O-methyl transferase (COMT)
Why do we have to give large doses when levodopa is given alone?
Only a small portion will reach the brain because DA does not cross the BBB. Large amounts of DA cause problems for the periphery.
What has been the solution to the levodopa dosing issue?
Give it with carbidopa (which inhibits peripheral decarboxylase) and entacapone (COMT inhibitor) so its not peripherally degraded.
Normally just carbidopa is added and then entacapone is added when the effectiveness wanes.
What side effects are associated with Levodopa?
Acute: anorexia, hypotension, nausea and psychosis
Involuntary movements
on and off effect fluctuates between hypokinesia and improvements.
What adverse drug reaction are we concerned with Levodopa?
non selective MAOIs.
Overload of dopamine and norepi can occur = hypertension.
Name two Dopamine agonists that mimic dopamine in the striatum. What are they selective for? How effective? Side effects?
Pramipexole & Ropinirole
D2/D3 receptors
Highly effective
Fewer than ones targetting D1/D2 just N/V BUTTT may cause hallucinations and compulsive behaviors.
What two drugs increase DA in the synapse?
Selegiline and Amantadine
Which PD drug is a MAO-B inhibitor, decreases DA degradation and does not have the unwanted effects of non-selective MAOIs?
Selegiline
Which drug for PD enhances dopamine release into the synapse?
Amantadine
Anticholinergic drugs are antagonists at what receptor? Where are these receptors present? A blockade of these receptor causes?
muscarinic
receptors are present in striatum
Relieves the inhibition of dopaminergic neurons resulting in more dopamine release.
What is one example of an anticholinergic? Side effects?
Benztropine Constipation Dry mouth Impaired vision Urinary retention
Do the therapies for PD cure or stop the progression of the disease?
No.
Describe the pathology behind PD?
Lewy bodies: may be harmful or beneficial
Protein aggregates composed of alpha-synuclein protein. The function of alpha synuclein is unclear. May function at synapses or ER-Golgi trafficking.
