Bannon: Alzheimer's Disease and Dementia Flashcards
Dementia
Definition:
Prevalence:
Definition: loss of memory and other intellectual abilities serious enough to interfere with daily life
Prevalence: one of the most important age-related medical problems (30-35% of people aged 80-90)
What accounts for 50-70% of all dementias?
Alzheimer’s Disease
Other Types of Dementia
Vascular dementia:
Mixed dementia:
Vascular dementia: post-stroke, multi-infarct (more precipitous course)
Mixed dementia: more common than previously thought
Other Types of Dementia
Others:
Others:
- Parkinson’s Disease
- Frontotemporal dementia
- CJD
- Huntington’s Disease
- Other neurological diseases
Other Types of Dementia
Lewy Body dementia:
Lewy Body dementia: PD plus dementia (Lewy bodies in the midbrain, cortex etc.) Progressive dementia with: o Fluctuating cognition o Many features of PD o REM sleep disturbances o Detailed visual hallucinations o Autonomic instability
Dementia
General Treatment Point:
General Treatment Point: fewer treatments are approved for non-AD dementias; however, AD treatments may be beneficial
Dementia
Mild Cognitive Impairment: (3)
Cognitive decline greater than expected for one’s age and educational level (measured using a cognitive scale)
May not significantly interfere with ADLs
Associated with an increased risk of AD (pre-dementia or transitional state to AD)
Clinical Features and Course of AD
General:
Course:
Cause of Death:
General: progressive and fatal disease with gradual onset of impairment (death in 6-12 years)
Course:
o Short term memory impacted first
o Followed by loss of other cognitive abilities (ability to calculate, use common tools- ideomotor apraxia)
o No effect on distant memories, altertness or motor function until very advanced stage of disease
Cause of Death: most comply due to complications of immobility (ie. pneumonia, pulmonary embolism)
Pathophysiology of AD
Marked atrophy of cerebral cortex:
Marked atrophy of cerebral cortex: uneven loss of cortical and subcortical neurons innervating the cortex (ie. basal forebrain cholinergic cells)
Pathophysiology of AD
Plaques and tangles in hippocampus and associative cortex:
Senile Plaques:
Neurofibrillary Tangles:
Plaques and tangles in hippocampus and associative cortex: the abundance of these generally correlated with cognitive impairment
Pathophysiology of AD
Senile Plaques:
Neurofibrillary Tangles:
Senile Plaques: due to accumulation of beta-amyloid protein; accompanied by degenerating neuronal processes
Neurofibrillary Tangles: microtubule breakdown associated with hyperphosphorylated tau protein
Causes of AD:
Most:
Genetic form:
Most common cause: idiopathic
Genetic Forms (~10% of cases):
o Defect in APP
o Defect in APP processing proteins (presnilins- PS1 and PS2)
o Lipid transporter apolipoprotein E4 is a risk factor
Cholinesterase Inhibitors
Basis:
Basis: loss of ACh in cholinergic neurons of the basal forebrain innervating the cortex in AD; ChE inhibitors prolong half-life of ACh
Cholinesterase Inhibitors
Efficacy:
Efficacy: provide MODEST improvements in cognition and global functions, as well as some transiet stabilization of the disease; do NOT slow ultimate progression of disease (not disease modifiying)
Donepezil
Use: (5)
MOA:
Use:
- Mild, moderate and severe AD
- MCI
- PD with dementia
- Lewy body dementia
- Vascular dementia
MOA: reversible AChE inhibitor
Cholinesterase Inhibitors: (3)
Donepezil
Rivastigmine
Galantamine
Donepezil
Half life:
Metabolism:
Long half-life: once-daily dosing (convenient)
Metabolism: hepatic (CYP2D6/3A4)- watch for potential DDIs
Donepezil
Side Effects: (4)
Side Effects: occur especially during dose escalation; all tend to decrease over time
- GI (N/V/D)
- Muscle cramps
- Bradycardia
- Urinary incontinence
Rivastigmine
Use: (3)
- Mild to moderate AD
- PD with dementia
- Lewy body dementia
Rivastigmine
MOA:
MOA: reversible, non-competitive inhibitor of AChE (also inhibits butyrylcholinesterase)
Rivastigmine
Half-life:
Patch:
Metabolism
Shorter Half-Life: BID dosing
Transdermal patch: also available (good absorption)
Metabolism: ChE hydrolysis (no drug-drug interactions)
Rivastigmine
Side Effects/Efficacy
Side Effects/Efficacy: similar to donezepil
- GI (N/V/D)
- Muscle cramps
- Bradycardia
- Urinary incontinence
Galantamine
Use: (2)
Mild to moderate AD
Vascular dementia
Galantamine
MOA:
MOA: reversible competitive inhibitor of AChE; also binds allosterically to nACh receptors
Galantamine
Shorter Half-Life:
Metabolism:
Excretion:
Shorter Half-Life: BID dosing; now also an extended release form
Metabolism: liver (CYP2D6/3A4)- some DDIs
Excretion: some also excreted unchanged
Galantamine
Side Effects/Efficacy:
Side Effects/Efficacy: similar to donezepil and rivastigmine
- GI (N/V/D)
- Muscle cramps
- Bradycardia
- Urinary incontinence
NMDA Receptor Antagonist (Memantine)
Use: (3)
o Moderate to severe AD
o Vascular dementia
o May also help manage aggression/agitation
NMDA Receptor Antagonist (Memantine)
MOA:
MOA: uncompetitive antagonist at NMDA receptors
Only binds to R when it has already bound glutamate
Therefore, use-dependent blockade of overly active NMDA that pass Ca++ and may lead to excitotoxicity (ie. more activate neurons more likely to be targeted)
NMDA Receptor Antagonist (Memantine)
Dosing:
Excretion:
o Dosing: BID
o Excretion: unchanged in the urine (no metabolism)
NMDA Receptor Antagonist (Memantine)
Efficacy:
Side Effects:
Efficacy: similar to ChE inhibitors
Side Effects: generally safe and well-tolerated
o Headaches, dizziness, confusion
Treatment of Behavioral and Psychotic Symptoms
Remember to look for:
Remember to look for drug interactions and medical problems (ie. discomfort): if outbursts, emotional distress, restlessness, hallucinations, delusions etc.
Off-Label Use of Drugs: must use caution
Antidepressants:
Anxiolytics:
Antidepressants: mood/irritability
Anxiolytics: anxiety/restlessness
Off-Label Use of Drugs: must use caution
Antipsychotics:
Antipsychotics: formerly used for agitation, but now a black box warning of an increased risk of death due to heart attack, pneumonia or other infection from use
- If these must be used, use the lowest dose possible for a trial period and ONLY after behavioral measures have been tried
Special Case of Lewy Body Dementia
Difficult to manage
- Very high risk of adverse responses to APDs (sedation, parkinsonism, neuroleptic malignant syndrome)- use clozapine if needed
- PD drugs also an issue (ChEI may help)
Hospital Delirium
Population:
Description:
Population: elderly hospital patients (not previously demented)
Description: sudden state of confusion accompanied by hallucinations and agitation
Hospital Delirium
Cause:
- Cause: unclear; many apparent triggers o Infection (ie. pneumonia) o Surgery o Catheter insertion o Some mediations o Sleep interruption for tests o Lack of eyeglasses or dentures
Hospital Delirium
Results: (3)
o Hinders recovery and extends hospitalization
o Leads to placement in nursing home or rehab
o Increases likelihood of death or subsequent dementia
Hospital Delirium
Prevention: (4)
o Adjust schedules to allow patients more sleep
o ensure the patient has eyeglasses, dentures and hearing aids
o Remove catheter and IV when feasible
o Increase physical and cognitive exercise
AD Neuroimaging Initiative
Collaborative Effort:
Collaborative Effort: recruited MCI and AD patients and controls and looked for biomarkers
o Combination of memory tests, PET scans and CSF amyloid predicts very early stage AD
AD Neuroimaging Initiative
Florbetapir F-18 PET Imaging:
Florbetapir F-18 PET Imaging: detects plaques and predicts beta-amyloid deposits seen at autopsy; now FDA approved as a diagnostic test for AD
New Therapeutics (Disease Modification): (2)
Anti-Amyloid Therapies
Anti-Tau/Tangles Therapy
Anti-Amyloid Therapies: (3)
Increasing Aβ Clearance (Immunotherapy)
Decreasing Aβ Generation
Disruption of Amyloid Aggregation
Anti-Amyloid Therapies
Increasing Aβ Clearance (Immunotherapy)
Active Vaccination:
Active Vaccination: worked well in mouse models but still in human trials
- Postmortem tissue of 2 patients in the trial show no amyloid plaques but still died of severe end-stage dementia (amyloid hypothesis?)
Anti-Amyloid Therapies
Increasing Aβ Clearance (Immunotherapy)
Passive Immunization:
Passive Immunization: with humanized monoclonal Ab against Aβ (bapineuzumab)
- Worked in animal model and now in phase 3 clinical trials
Anti-Amyloid Therapies
Decreasing Aβ Generation: (2)
Inhibition of BACE1
Inhibition of γ-Secretase
Anti-Amyloid Therapies
Decreasing Aβ Generation
Inhibition of γ-Secretase Agents: (2)
Semagecestat
Novel Targeting via γ-Secretase Activating Protein (GSAP)
Anti-Amyloid Therapies
Decreasing Aβ Generation
Inhibition of γ-Secretase
Semagecestat:
Semagecestat: passed phase I and II trials but halted in phase III
o Did not slow progression of AD but rather caused dose-dependent decrease in cognitive function and ADLs compared to placebo
o Also caused an increased risk for skin cancer
o One problem with this approach is this enzyme affects production of ~20 proteins (some of which have critical brain functions- Notch, cadherins)
Anti-Amyloid Therapies
Decreasing Aβ Generation
Inhibition of γ-Secretase
Novel Targeting via γ-Secretase Activating Protein (GSAP):
o GSAP is a targeting protein that determines that enzymes substrates
o If inhibited or genetically inactivated, AD model mice we normal with no plaques
o Renews hope for γ-secretase related therapeutics
Anti-Amyloid Therapies
Disruption of Amyloid Aggregation: (2)
Arenflurbril and Tramiprosate
PTB2 (Modulator of Copper and Zinc)
Anti-Amyloid Therapies
Disruption of Amyloid Aggregation
Arenflurbril and Tramiprosate:
Arenflurbril and Tramiprosate: amyloid-targeting drugs that showed some activity at reducing amyloid levels, but not clinical effect in phase 3 trials
Anti-Amyloid Therapies
Disruption of Amyloid Aggregation
PTB2 (Modulator of Copper and Zinc):
PTB2 (Modulator of Copper and Zinc): showed clinical benefit and decreased CSF amyloid in phase 2
Anti-Tau/Tangles Therapy
Tau Protein:
Targeting:
Tau Protein: stabilizes neuronal microtubules in axons; hyperphosphorylation leads to formation of paired helical filaments that disrupt axons
Targeting: targeting of tau has been the scientific minority in terms of drug development
Anti-Tau/Tangles Therapy
AL-108 (NAP):
- Derived from neuroprotective protein
- In phase 2 trials, intranasal administration dose-dependently improved short-term recall and working memory in MCI
- Reduces tangles and plaques in animal models
Anti-Tau/Tangles Therapy Methylthioninium Chloride (Methylene Blue):
In phase 2 trials, showed cognitive benefit over 4 year period (major issues with trial have been raise)
Postulated to work clinically by disrupting tau-mediated tangle formation (disrupts tau-tau binding)
Anti-Tau/Tangles Therapy
Lithium and Valproic Acid:
- Both inhibit glycogen synthase kinase 3 (may be involved in tau hyperphosphorylation)
- Clinical trials of both are currently underway
Risk and Protective Factors and Related Interventions
Non-Modifiable Risk Factors:
o Age
o Genetics
o Head injury
.
Risk and Protective Factors and Related Interventions
Modifiable Risk Factors: (5)
o Obesity o Diabetes o HTN o Hypercholesterolemia o Alcohol intake and smoking
Risk and Protective Factors and Related Interventions
Protective Factors:: (2)
o Cognitive reserve (education, occupation, mental activities)
o Physical activity
Risk and Protective Factors and Related Interventions
Related Interventions:
Despite the above information, RCTs have not shown a benefit of the following on the development of Alzheimer’s Disease:
- Antihypertensives, statins, B vitamins, omega-3, ginkgo biloba, antioxidants, cognitive interventions
Current View of Management of AD Patients
Early Diagnosis:
Early Diagnosis: of MCI and identification of subtype should now allow earlier intervention in AD
o Amnesic MCI: conversion rate to AD is 50% over 2.5 years
Current View of Management of AD Patients
Lifestyle Issues and Nonpharmacological Interventions: (4)
o Brighter lights
o Modify physical layout of space
o Use of activities and food with positive emotional content (persists even with memory impairment)
o Stress management and support for caregiver
Current View of Management of AD Patients
Optimization of Pharmacotherapy
% that discontinue:
What decreases GI effects?
~50% of patients on new AD medications with discontinue in 4 months due to side effects of perceived/real lack of efficacy
Slower titration of ChEIs to decrease GI effects
Current View of Management of AD Patients
Optimization of Pharmacotherapy
Switch to another ChEI after:
Combination therapy of ChEI and memantine may:
Switch to another ChEI after 1 week washout period (50% of those who fail to respond to one will respond to another)
Combination therapy of ChEI and memantine may help therapeutic and adverse effects
o If behavioral disturbances occur (as they often do in advanced AD), try lifestyle changes and ChEI/memantine combinations BEFORE APDs
