CPP2 306 Treatment of Dementia

Alzheimers accounts for ______ of all dementiaz

60-80%

On average, what is the life expectancy following diagnosis of Alzheimer’s disease

Seven years

• Fewer than three percent of individuals live more than fourteen years after diagnsosis

What are the symptoms for Alzheimers disease

Anterograde amnesia

Aphasia - speechlessness

Apraxia - unable to perform learned skilled tasks

Agnosia - inability to recognize common objects

Disturabcne in execution function

Dementia symptoms

Short term memory loss

Impaired memory retrieval

impaired judement and evalutation

Labile and innapropritate emotions

Motor functions is normal till late stages of the disease

Briefly describe the neurpathology of AD

• Neurodegeneration is prominent in many brain areas at autoposy

• High density of plaques and tangles in the frontal and temporal corticles

• Loss of cholinergic neurons in the nucleus basalis of Meynert that project to the frontal cortex

• Loss of locus coeruleus neurons may even precede nBM loss

In AD when does neurodegeneration start?

Neurodegeneration starts many years before appearance of symptoms

Which three enzymes process amyloid precursor protein (APP) in alzheimers disease

• a-secretase

• b-secretase

• y-secretase

What is the role of a-secretase in APP processing?

a-secretase cleaves APP within AB region, preventing amyloid B-formation and producing sAPPa

What is the role of b-secretase in APP processing?

β-secretase initiates the amyloidogenic pathway by cleaving APP at the β site, producing sAPPβ and a membrane-bound C99 fragment that is subsequently cleaved by γ-secretase to generate amyloid-β peptides, including Aβ-40 and the more aggregation-prone Aβ-42.

What is the role of y-secretase in AD

Y secretase cleaves the membran fragment produced by B-secretase to release AB peptides, particularily AB-42, which aggregates into oligomers and plaques and contributes to neural loss (bad!!)

What is sAPPalpha and sAPPbeta

sAPPa = neuro-protective, promotes neurite growth and synaptogenesis, enhances learning and memory

sAPPb = stimulates axonal pruning and neuronal cell death

What is a drug that may delay clinical decline and how?

Aducanumab (& lecanemab)

• A monoclonal antibody that targets soluble and insoluble amyloids

• Promote clearance by Fc receptor-mediated phagocytosis

  • Aducanumab binds to amyloid B plaques or soluble AB

  • the Fc tail of the antibody is now exposed

  • Microglia Fc receptors bind the Fc region to engulf the antibody

What are treatments of Alzheimers disease

Acetylcholine replacement therapy since ACh is lost in AD (important for memory, learning, attention, and executive function)

Using drugs that may delay clinical decline

Why isnt acetylcholine replacement not as successful as replacing Dopamine in Parkinsons disease

Because AD involves progressive neuronal and synaptic degregation, so replacing or increasing acetylcholine cannot compensate for underlying neurodegeneration

How do acetylcholinesterase inhibitors improve symptoms in Alzheimers Diseases?

They prevent the uptake of acetylcholine at the synapse increasing synaptic acetylcholine to modestly enhance cognitive function

What are the acetylcholinesterase inhibitors drugs that are used in treating alzheimers disease

Donepezil

Galantamine

Rivastigmine

Memantine

Nitromemantine

Donepeizil (Aricept); indicated for what type of AD, half life, dosing, bioavailability and plasma protein binding

Reversible ACh-E inhibitor

For mild-moderate AD

Half life of 70 hours

Dosing = weeks to months

100% oral bioavailability and crosses the BBB easily wtih 40% plasma protein binding

Galantamine

• Reversible ACh-E inhibitor & Positive allosteric modulator at nAChRs that enhance Ach release (Dual mechanism)

• For mild-moderate vascualr and AD

• Half life of 7 hours

• Dosing must be titrated over several weeks

• 80-100% oral bioavailability, crosses BBB easily with 18% plasma protein binding

• Sleep aid, memory enhancer

Rivastigmine: ; indicated for what type of AD, half life, dosing, bioavailability and plasma protein binding

butyrylcholinesterase and ACh-E inhibitor

• Mild-moderate alzheimer type AND parkinson related dementia

• hald life of 1.5 hours

• Dosing must be titrated over several weeks

• 40% oral bioavailability and crosses BB easily with 40$ plasma protien binding

• Bypasses cytchrome for reduced drug-drug interactions (reduced adverse effects)

Which Acetylcholinesterase inhibitor used in Alzheimer’s disease has a dual mechanism of action?

Galantamine - inhibits AChE and positively modulates nicotinic ACh receptors

• Makes nicotinic receptors more responsive to ACh

• presynaptic ACh release and downstream signalling

What makes Rivastigmine an important option in Alzheimer’s disease treatment. Who would this be useful to

It bypasses (doesnt rely)on cytochrome P450 pathways and is broken down by esterases instead decreasing interactions with different drugs

• Decreases drug-drug interactions

Useful for elderly people who are already on different drugs

How do donepezil, galantamine, and rivastigmine differ conceptually?

All inhibit AChE, but

• Galantamine = also enhances nicotinic receptor signaling

• Rivastigmine reduces drug-drug interactions by avoiding CYP450 metabolism

What is the action of memantine in alzheimer’s disease?

Memantine is a low affinity, non competitive NMDA receptor anatagonist that partially blocks abnormal glutamate singaling to reduce extitotoxicity

How does memantine not impair learning and memory despite blocking NMDA receptors?

Because memantine preferentially blocks chronically active NMDA receptors while sparing normal, transient synaptic NMDA signaling required for learning and memory

In which stage of alzheimers disease is memantine most effective?

Moderate to severe Alzheimer’s disease particualrily in patients whos intolerant or contraindicated for AChE inhibitors

Why is memantine often combined with acetylcholinesterase inhibitors in AD

Combination improves agitation and behavioural symptoms by targeting both cholinergic deficits and glutamate mediated excitotoxicity

What is nitromemantine

An experimental version of memantine designed to more selectively target chronic or abnormal NMDA receptor activity in AD

What does the added nitroglycerin in nitromemantine do

Enhances targeting/binding to estrasynaptic NMDA receptors reducing toxic signaling while preserving normal synaptim NMDA function

How does nitromemantine reduce excitotoxic NMDA receptor signaling?

By nitrosylating extrasynaptic NMDA receptors, causing desensitization of chronically active NMDA activity

What is valproric acid and why is it mentioned in AD research?

Valproic acid is an antiepileptic and mood stabilizing drug that reduces Beta-amyloid production and plaque formation in mouse models of AD, but has no proven clinical benefit to humans

What is pioglitazone, and why has it been mentioned in AD research

A diabetes drug that reduces inflammation and enhances amyloid clearance in mouse models of AD, but remains experimental for AD

What is the current evidence for antioxidant therapy in AD

Antioxidants block B amyloid neurotoxicity in vitro, but only limited human evidence exists, with modest slowing of disease progression