PHAR 308: Flashcards 11 - Pharmacotherapy for Dementia & Alzheimers

What is Dementia?

A chronic or persistent disorder of mental processes due to organic brain disease

What are five symptoms of dementia?

1. Memory Disorders

2. Personality Change

3. Deterioration of Personal Care

4. Impairment of Reasoning

5. Disorientation 

What is Mild Cognitive Impairment (MCI)

Cognitive decline greater than expected for the age/education level of the individual

What is MCI Important?

More than 50% of MCI patients will progress to Dementia within 5 years of diagnosis

What is Alzheimers disease?

A form of dementia identifiable by accumulation of amyloid Beta plaques and Tau proteins in neural tissue

What is the early stage of alzheimers?

there is no observable change in behaviour but proteins accumulate in the tissue — this stage precedes AD diagnosis by 20-40 years 

What is the middle stage of Alzheimers?

Mild cognitive impairment (10-20 years preceding diagnosis of AD)

What is the final stage of alzheimers?

Impairment to memory, judgement and personal care (has a major impact on life)

What is the distribution of AD cases based on the genetics of the individuals?

10% of AD cases are genetically linked

90% of AD cases are sporadic but of those cases 60% of them have a predisposing genetic mutation

What are the two most common predisposing mutations?

1. APO-E4 which impacts cholesterol transport

2. COX2 which increases inflammation

How does APP mutation lead to AD

APP removal from the cell membrane will follow the alpha seperatas route when not mutated. In the mutated state the APP will be cleaved by beta seperatse and then gamma seperatase which is what leads to the build up of plaque 

How does PSEN1&2 mutation lead to AD?

presenilin proteins will increase beta amyloid plaques by making gamma seperatase more active

What are some of the risk factors for sporadic cases of AD?

1. Prions

2. Slow viruses

3. heavy metals (mercury)

4. Acquired ACh deficiency

5. Acquired autoimmunity against brain tissue

What are some clinical manifestations of AD?

1. Cognitive impairment 

2. Memory Loss

3. Dementia

What are some histopathological menifestations of AD

1. Amyloid Containing Neuritic plaques

2. Intraneuronal neurofibrillary tangles

3. Granulo-Vacuolar degeneration of hippocampal pyramidal cells

How does the Amyloid beta plaques impact brain function?

• Amyloid core in the brain with activated glial cells

• prevent neuronal signalling and increase rate of neuronal degregdation

up to 40% of the extracellular space can be filled with plaques

What are the Neurofibrillary tangles?

tau proteins which form tangles in the cell nucleus and axons. Bundles of tau will reduce cell signalling and lead to death 

What is Granulo-Vacuolar degradation of pyramidal cells?

Pyramindal cells in areas for reason and memory will become bloated at the vacuole in these cells inflates and prevents proper signalling

How does AD change brain morphology/

Less brain matter is present

• reduction to the cortex

• reduction of the hippocampus

• Ventricles becomes larger, filled with more CSF

identified with CAT scans 

What is the pathogenesis of AD

1. Accumulation. of Tau protein and Beta amyloid Plaques

2. Activation of inflammation response which increases oxidative stress and excitotoxicity

3. Neuronal dysfunction due to decreased cholinergic activity and increase glutamergic activity

What are three pharmacotherapies for AD

1. Reversible AChE inhibitors

2. NMDA receptor antagonists

3. Amyloid Immunotherapy

Often combined with Antidepressants to help mitigate mood changes

How are AChE inhibitors used to treat AD?

increase the amount of ACh which is present at the cell synapse

Do not give ACh globally 

Reduce the metabolism of ACh to upregulate ACh signalling 

How are NMDA receptor antagonists used to treat AD

Mematine is an uncompetetive low affinity NMDA receptor antagonist which will inhibit calcium ion flux into the cell for the realease of NMDA

this prevents tonically active cells but permits the NMDA channel to open

What is the point of Amyloid Immunotherapy?

to prevent the progression of the disease by using antibodies (aducanumad) to decrease build up of the Beta amyloid plaques

What stage is the aducannumad used in/

mild dementia because we want to preserve neurons so do not want to be progressed far in the disease 

What is the administration schedule of aducanumab?

Monthly IV administration

What are the three proposed mechanisms of action for aducanumab?

1. Antibody in blood tsream will pull amyloid beta proteins out of brain and attack

2. Direct antibody activity will cross BBB and attack the amyloid beta plaques

3. Activate microglia to remove the amyloid beta plaques