Neurocognitive Disorders

Question 1

TYPES OF NEUROCOGNITIVE DISORDER

Answer 1

Major neurocognitive disorder (MND aka dementia): a syndrome of progressive
loss of cognitive functions such as memory, speech, reasoning, intellectual function

Neurodegenerative disorders are characterized by progressive, irreversible loss of neurons

• involve death of specific populations of neurons, which produces specific functional deficits
• problems with mental function (neurocognitive disorders), movement (hyper or hypokinesias), or both

1. Primary neurodegenerative (cannot be reversed; cognitive symptoms may be treated)
2. Secondary: treated to relieve cognitive symptoms

Question 2

A hallmark of neurodegenerative diseases is…

Answer 2

misfolding, aggregation and accumulation of proteins, which appear to contribute to neuron dysfunction and death

Question 3

ALZHEIMER’S DISEASE

Answer 3

Alzheimer’s is common: over age 65, the #7 cause of death in the US

Progressive and (currently) incurable: symptoms progress from mild to severe

• Death of cholinergic* neuron populations, which project to regions with major roles in memory (e.g., hippocampus)
• Reduced ACh synthesis* in remaining cells

Question 4

Neurofibrillary tangles (Alzheimer’s Disease)

Answer 4

tau proteins that become hyperphosphorylated tend to aggregate into tangles inside microtubules

Question 5

Amyloid plaques (Alzheimer’s Disease)

Answer 5

β and γ secretase enzymes cleave amyloid precursor protein into fragments that aggregate into clumps (plaques) outside neurons

Question 6

CHOLINESTERASE INHIBITORS

Answer 6

MOA: Cholinesterase inhibitors reversibly inactivate AChE → prolongs ACh signal in remaining cells

USE: Mild-severe AD (any new AD diagnosis)

EFFICACY:

• modestly slower decline in functional measures of disease trajectory,
• no convincing evidence for improvement
• Variable response – 30-50% do not respond

Acetylcholinesterase (AChE) enzymes degrade ACh after release into the synapse to terminate signaling

Contraindictions: Bradycardia or cardiac conduction disease

Caution: Severe kidney (galantamine) or liver dysfunction (galantamine, rivastigmine)

Adverse Effects:
GI: nausea, diarrhea, anorexia → dose at night or with food to minimize nausea
CNS: dizziness, insomnia, nightmares → dose in daytime to minimize sleep problems
CV: bradycardia (incidence doubled) → discontinue treatment

Ex. Donepezil (Aricept ®), Rivastigmine (Razadyne ®), Galantamine

Question 7

NMDA RECEPTOR BLOCKERS

Answer 7

MOA: glutamate NMDA receptor antagonist

Memantine is thought to be neuroprotective (reducing glutamate excitotoxity)

USE: vascular dementia, moderate/severe AD

EFFICACY: slightly slower loss of cognitive function

Adverse Effects:

• Excitotoxicity
• NMDA receptor overactivation
• Common: dizziness, confusion
• Serious: worsens delusions / hallucinations

Example: Memantine

Question 8

MONOCLONAL ANTIBODIES

Answer 8

MOA: Antibodies bind to plaques, stimulate immune system to attack and degrade them; aβ fragments are removed from brain out into blood

USE: Alzheimer’s

Effects: AD scores decline ~30% less in treated vs. control over 18m

Adverse Effects:
• Confusion, vomiting, difficulty walking
• Brain edema due to micro-hemorrhages, likely due to aβ fragments damaging BBB (40% of high-dose subjects)

Example: Aducanumab

Question 9

POTENTIAL NEW TARGETS

Answer 9

Tau-Based Targets: preventing tau from aggregating / increasing tangle clearance

Amyloid-Based Targets: clearing away plaques

Secretase inhibitors: preventing initial formation of amyloid β peptides

Question 10

ISSUES IN ALZHEIMER’S DRUG THERAPY

Answer 10

Lack of effective medications:
• Lack of biomarkers / early detection
• Blood-brain barrier hinders drug delivery

PK considerations in elderly:
• Clearance declines with age
• Polypharmacy –increases risk of drug interactions

Other issues:
• Patient ability to communicate
• Patient ability to give consent for treatment
• Adherence to medications