Alzheimer's Disease, Dementia, and Delirium

Question 1

The focus of delirium care is

Answer 1

prevention and reserved for those that will harm themselves or others

*medication in delirium has been known to increase risk of death

Question 2

Cognitive Impairment

Answer 2

A deficit in cognitive function (memory, ability to reason, planning, attention, language, executive function, visuospatial perception)

Question 3

Mild cognitive impairment

Answer 3

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

Question 4

Dementia

Answer 4

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

Question 5

MCI Medication treatment vs Dementia

Answer 5

MCI not treated with any medication

Dementia can be treated with medications

Question 6

Risk Factors of Dementia

Answer 6

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

Question 7

Most common form of dementia

Answer 7

Alzheimer’s Disease (60-80%)

Question 8

In normal aging, neurons are ________, brain mass is ________ and synaptic connections are __________.

Answer 8

Preserved, Preserved, Lost

Result is slowed retrieval of memories but no impairment of storing them

Thinking and reasoning are preserved

Question 9

Early Alzheimer’s

Answer 9

Hippocampus (memory) is affected early

No language affect

Ventricles begin to enlarge and sulci get wider as more cells die

Question 10

Progression of Alzheiemer’s (general)

Answer 10

Memory first, followed by language and then reasoning/understanding, lastly is dis-inhibition and behavior problems

*the areas affected are rich in cholinergic neurons

Question 11

Histology of Alzheimer’s

Answer 11

Amyloid beta peptide abnormally fold, causing insoluble plaques that accumulate on the outside of cells

Question 12

Amyloid beta (A-beta) protein formation

Answer 12

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

Question 13

Neuronal cell bright parts (Tau proteins)

Answer 13

Hyperphosphorolated tau proteins represent the bright parts and work to stabilize microtubules

Microtubules transport molecules and nutrients within the cell, axon and dendrites

Question 14

Cholinergic Hypothesis

Answer 14

Loss of cholinergic neurons is responsible for AD (considered a downstream event)

Question 15

Amyloid-Beta Hypothesis

Answer 15

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

Question 16

Tau Hypothesis

Answer 16

Tau-hyperphosphorylation and neurofibillary tangles is the single common pathway that leads to AD

*this hypothesis is gaining ground

Question 17

Inflammation Hypothesis

Answer 17

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

Question 18

The novel hypothesis

Answer 18

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)

Question 19

AD is multifactorial with _____________

Answer 19

No single cause or cure

*similar to cancer in this regard

Question 20

There is approximately a _____________ delay between the pathology and symptoms in AD

Answer 20

10 years

Question 21

Early Onset AD

Answer 21

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

Question 22

Preclinical AD

Answer 22

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

Question 23

Mild Cognitive Impairment Due to Alzheimer’s Disease

Answer 23

MMSE 22-26

Cognitive changes have occurred but no functional changes

Question 24

Dementia due to Alzheimer’s Disease

Answer 24

MMSE under 22

Functional Impairments have occurred

Question 25

Mild AD (early-stage) Changes

Answer 25

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

Question 26

Moderate AD (middle-stage) Changes

Answer 26

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

Question 27

Severe AD (late-stage) Changes

Answer 27

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

Question 28

AD vs Vascular Dementia

Answer 28

AD is steady decline in cognitive function, VD is not

Question 29

Vascular Dementia

Answer 29

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)

Question 30

PD and ______________ share the same pathology

Answer 30

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

Question 31

Frontotemporal Dementia

Answer 31

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

Question 32

Treatment options

Answer 32

*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

Question 33

ChEIs

Answer 33

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)

Question 34

Cholinesterase Inhibitors Adverse Effects

Answer 34

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%)

Question 35

Donepezil (dosage form, strength, etc.)

Answer 35

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

Question 36

Rivastigmine Patch (dosage form, strength, etc.)

Answer 36

Patch 4. 6 mg/24 hours starting 9. 5 mg/24 hours starting dose, increased after 4 weeks Can cause rash so rotate sites; fewer side effects than tablet

Question 37

Rivastigmine Oral

Answer 37

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

Question 38

Galantamine (dosage form, strength, etc.)

Answer 38

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

Question 39

Memantine

Answer 39

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

Question 40

Memantine AEs and Considerations

Answer 40

Efficacy similar to ChE inhibitors AE are very mild in comparison

Question 41

Treatment Summary

Answer 41

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 )

Question 42

Targets for Research (B-A)

Answer 42

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

Question 43

Targets for Research (Tau)

Answer 43

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

Question 44

Targets for Research (Insulin)

Answer 44

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

Question 45

Targets for Research (Inflammation)

Answer 45

Statins, NSAQIDs, unsuccessful and probably too far down AD pathway