Alzheimer's Disease, Dementia, and Delirium Flashcards
The focus of delirium care is
prevention and reserved for those that will harm themselves or others
*medication in delirium has been known to increase risk of death
Cognitive Impairment
A deficit in cognitive function (memory, ability to reason, planning, attention, language, executive function, visuospatial perception)
Mild cognitive impairment
A drop from a prior level of cognitive function
*Cognitive function declines with age
**If a scientific study does not measure a prior level of function, an MCI cannot be defined
Dementia
Mild cognitive impairment plus the loss in the ability to care for one’s self
This includes activities of daily living: Eating, bathing, grooming, toileting, transferring and cooking
MCI Medication treatment vs Dementia
MCI not treated with any medication
Dementia can be treated with medications
Risk Factors of Dementia
Genetics (Apolipoprotein E variants e2, e3 and e4; single copy of e4 increases risk by 3 fold while homozygous copy of e4 increase by 8-12 fold; family history of CV also increases risk)
Cardiovascular Disease in Middle Age (Smoking, midlife obesity, midlife hypertension, midlife hyperlipidemia, diabetes)
Mild cognitive impairment will increase risk of dementia; Education and social interaction increase cognitive reserve
Most common form of dementia
Alzheimer’s Disease (60-80%)
In normal aging, neurons are ________, brain mass is ________ and synaptic connections are __________.
Preserved, Preserved, Lost
Result is slowed retrieval of memories but no impairment of storing them
Thinking and reasoning are preserved
Early Alzheimer’s
Hippocampus (memory) is affected early
No language affect
Ventricles begin to enlarge and sulci get wider as more cells die
Progression of Alzheiemer’s (general)
Memory first, followed by language and then reasoning/understanding, lastly is dis-inhibition and behavior problems
*the areas affected are rich in cholinergic neurons
Histology of Alzheimer’s
Amyloid beta peptide abnormally fold, causing insoluble plaques that accumulate on the outside of cells
Amyloid beta (A-beta) protein formation
Amyloid Precursor Protein (APP) cleaved by b-secretase then by y-secretase to give Amyloid-beta(42) which is highly plaque forming due to insolubility
When APP is cleaved by a-secretase instead, it gives rise to b-amyloid 40 which is more soluble and less plaque forming
Neuronal cell bright parts (Tau proteins)
Hyperphosphorolated tau proteins represent the bright parts and work to stabilize microtubules
Microtubules transport molecules and nutrients within the cell, axon and dendrites
Cholinergic Hypothesis
Loss of cholinergic neurons is responsible for AD (considered a downstream event)
Amyloid-Beta Hypothesis
A-beta is the initial pathology leading to inflammation and neuronal death
*Almost all adults have A-beta and A-beta load does not correlate with AD symptoms
Tau Hypothesis
Tau-hyperphosphorylation and neurofibillary tangles is the single common pathway that leads to AD
*this hypothesis is gaining ground
Inflammation Hypothesis
Inflammation is common inn AD; Nonspecific inflammation damages neurons causing A-beta and NFT
*many believe this to be a marker of neuronal damage rather than a cause
The novel hypothesis
Impaired glucose transport (brain uses 20% of body’s energy and is only 2% of it’s weight) > Disruption of energy formation can lead to oxidative stress, free radicals, inflammation and neuronal death > insulin resistance (diabetes) and decreased brain blood flow (vascular disease)
AD is multifactorial with _____________
No single cause or cure
*similar to cancer in this regard
There is approximately a _____________ delay between the pathology and symptoms in AD
10 years
Early Onset AD
5% of all AD patient symptoms start before 65 years, but it can start in the 30s
Genetics is a strong influence (familial AD) - APP as well as Presenilin Genes 1 and 2 (PSEN -1, -2)
Diagnosis can be difficult and often misdiagnosed
Will need support and are often still working
No qualification for medicare
Preclinical AD
MMSE of 30-26
No symptoms have occurred, only biomarker changes (e.g. A-beta or tau in the BBB or CSF; MRI of the brain)
This is controversial classification since there is no agreed upon biomarker
Mild Cognitive Impairment Due to Alzheimer’s Disease
MMSE 22-26
Cognitive changes have occurred but no functional changes
Dementia due to Alzheimer’s Disease
MMSE under 22
Functional Impairments have occurred
Mild AD (early-stage) Changes
Problems coming up with the right word or name
Trouble remembering the names when introduced to new people
Having greater difficulty performing tasks in social or work settings
Forgetting material that one has just read
Losing or misplacing a valuable object
Increasing trouble with planning or organizing
Moderate AD (middle-stage) Changes
Forgetfulness of events or about one’s own personal history
Feeling moody or withdrawn, especially in socially or mentally challenging situations
Being unable to recall their own address or telephone number or the high school or college from which they graduated
Confusion about where they are or what day it is
The need for help choosing proper clothing for the season or the occasion
Trouble controlling bladder and bowels in some individuals
Changes in sleep patterns, such as sleeping during the day and becoming restless at night
An increased risk of wandering and becoming lost
Personality and behavioral changes, including suspiciousness and delusions or compulsive, repetitive behavior like hand-wringing or tissue shredding
Severe AD (late-stage) Changes
Require full time, around the clock assistance with daily personal care
Lose awareness of recent experiences as well as of their surroundings
Require high levels of assistance with daily activities and personal care
Experience changes in physical abilities, including the ability to walk, sit, and eventually swallow
Have increasing difficulty communicating
Become vulnerable to infections, especially pneumonia
AD vs Vascular Dementia
AD is steady decline in cognitive function, VD is not
Vascular Dementia
Accounts for around 10-20% of all dementias and is caused by cerebrovascular infarcts or narrowing of the arteries that is progressive
Symptoms are dependent on where infarct is; memory generally preserved until later; motor symptoms can co-occur
Symptom progression is stepwise and associated with a new infarct or narrowing of an artery
Often co-occurs with other dementias (co-prevalence with AD is very common due to sharing of many risk factors)
PD and ______________ share the same pathology
Lewy Body Dementia
Caused by abnormal folding of alpha-synuclein protein
Inattention, executive dysfunction and visuospatial impairment
Visual hallucinations are more common; memory loss is more prominent
Lewy bodies are seen in later PD and often develop into Lewy body dementia
Frontotemporal Dementia
Was called Pick’s disease as described by Arnold Pick
Accounts for 2% of all dementias
One of the most common forms of early-onset dementia, as prevalent as AD in those under 65
Social behavior and personality changes (disinhibition, apathy, loss of empathy)
Aphasia (difficulty finding words, halting speech)
Often confused with depression
Does well on cognitive testing, memory and executive function are preserved
Treatment options
*all approved for AD, but we used them for dementia
Cholinesterase Inhibitors (Donepzil, Galatamine, Rivastigmine, Tacrine - no longer marketed due to hepatotoxicity)
NMDA antagonist (memantine) - FDA approved for moderate to severe AD
ChEIs
Cholinesterase Inhibitors MOA: Increase ACh at synaptic cleft helping with loss of cholinergic neurons
All have same efficacy (does not increase functioning, about 6 months of delayed symptoms)
None are disease modifying (if removed from treatment, patient would return to lower level of functioning as if they were never on drug)
Choice is based on tolerability (Donepezil appears to be more tolerated than oral Rivastigmine, Galantamine is in between)
Cholinesterase Inhibitors Adverse Effects
Cholinergic Side Effects
GI: NVD (up to 50% for Rivastigmine; dose limiting, increase dose every 4-6 weeks)
Anorexia, weight loss, abdominal pain
Bradycardia, dizziness, syncope, falls, accidents
Muscle tremor, weakness, and urinary incontinence (only 3%)
Insomnia, vivid dreams (up to 15%)
Donepezil (dosage form, strength, etc.)
Tablet or ODT
5mg orally, once daily
Target dose 10mg/day, increased every 4-6 weeks, up to 23mg after 3 months of treatment
Generic available
Rivastigmine Patch (dosage form, strength, etc.)
Patch
- 6 mg/24 hours starting
- 5 mg/24 hours starting dose, increased after 4 weeks
Can cause rash so rotate sites; fewer side effects than tablet
Rivastigmine Oral
Tablet or oral solution
Start at 1.5 mg twice daily
Target 6 mg twice daily (increased 2-4 weeks by 1.5 mg twice daily)
Give with meals
Generic avilable
Galantamine (dosage form, strength, etc.)
IR, tab or solution, ER
Start 4 mg bid (8 mg qd for ER)
Target 12 mg bid (or 24 qd) and may be increased by intervals of 4 mg (8mg) monthly
Give with meals
Generic Available
Memantine
NMDA receptor modulator
Overstimulation by glutamate can cause excitotoxicity and neuronal death (memantine only binds once the ion channel is open, blocks the channel and prevents overstimulation)
Hypothetically could be disease modifying
Can be added to ChE inhibitor (only modest improvement and usually reserved for severe dementia)
*efficacy is no greater than ChE inhibitor alone in monotherapy
Memantine AEs and Considerations
Efficacy similar to ChE inhibitors
AE are very mild in comparison
Treatment Summary
ChE inhibitors are first line (generic available, efficacy is same, high rate of AEs with rivastigmine tablet having the most)
Memantine is second-line (first generic now available, some improvement in efficacy in combo, better tolerated than ChE inhibitors )
Targets for Research (B-A)
B-A cascade (AN1792 vaccine against B-A protein ended due to encephalopathy, no improvement in cognition)
IVIG administration showed less brain atrophy and less loss of cognitive function at 1 year, but not 2 years (less progressed to AD)
Posiphen prevents APP formation while vaccines clear B-A from the brain
Targets for Research (Tau)
Aggregation inhibitors (Methylthionium chloride)
Phase 2 trials showed an 81% decrease in progression compared to placebo
TRx0237 is a prodrug for Methylthionium chloride in phase 3 trials
Targets for Research (Insulin)
SR-Exenatide in phase 1
Nasal insulin phase 2/3 studies in MCI and early AD patients, however, currently the study is halted for unknown reasons
Kaiser is studying Metformin in diabetic patients and decreased risk of AD
Targets for Research (Inflammation)
Statins, NSAQIDs, unsuccessful and probably too far down AD pathway
