Download Alzheimer`s Disease and Other Dementias

Alzheimer’s and Other Dementias
PSYCH 7955
W Klugh Kennedy, PharmD, BCPP, FASHP, FCCP
Clinical Professor of Pharmacy Practice and Psychiatry
Mercer University, Savannah Georgia
[email protected]
1
Definitions
• Dementia (n): a chronic or persistent disorder of
the mental processes caused by brain disease or
injury and marked by memory disorders,
personality changes, and impaired reasoning.
• Delirium (n): an acutely disturbed state of mind
that occurs in fever, intoxication, and other
disorders and is characterized by restlessness,
illusions, and incoherence of thought and speech.
What is Dementia?
• Dementia is characterized by a loss of, or decline in
memory and other cognitive abilities.
• It is caused by various diseases and conditions that
result in damaged brain cells.
–
–
–
–
Neurodegeneration
Hypoxia
Infection
Other
3
Associated with Dementia
– Parkinson's Disease
– Hydrocephalus
– Multiple Sclerosis
– Vitamin deficiency
– Alcohol
– Medications
– Stroke
– Huntington’s Disease
– Subdural hematoma
– Brain tumor
– Infection
– Inflammation
– Hormonal loss
– Major organ failure
4
Types of Dementia
• Alzheimer’s Disease
• Dementia with Lewy Bodies
• Vascular Dementia
• Creutzfeldt-Jakob Disease
• Reversible causes of
dementia
– B12 deficiency
– Hypothyroidism
– Depression
(pseudodementia)
Alzheimer’s Association http://www.Alz.org
USA National Institutes on Health http://www.NIH.gov
6
Dementia with Lewy Bodies
• Found primarily in individuals with Parkinson’s
Disease
• Lewy Bodies observable in brainstem and cortex
in 25% of patients with dementia
• Lewy Bodies are intracellular cytoplasmic
inclusions
• Composed of neurofilament proteins, ubiquitin,
and α-synuclein
7
Dementia with Lewy Bodies
Symptoms
• Cognitive decline
• Visual Hallucinations
•
Fluctuations in alertness and
attention
• Parkinsonian motor symptoms
Lewy Bodies found in Neurons of Substantia Nigra
8
Vascular Dementias
• Range of cognitive disorders caused by
vascular disease
• Most common is occlusion of cerebral blood
vessels leading to brain injury
• Multiple large or small strokes can lead to
multi-infarct dementia (MID)
9
Creutzfeldt Jacob Disease (CJD)
• Transmissible Spongiform Encephalopathies (TSEs)
– Bovine Spongiform Encephalopathy (Mad Cow Disease)
– Kuru
• Infectious Agent – Prion
• Early and late stage dementia symptoms as well as
– Extrapyramidal Symptoms
– Myclonus
– Dizziness
• No current treatment exists
10
Creutzfeldt Jacob Disease (CJD)
• Neuropathology
– neuronal cell death
– spongiform changes of the
brain
– no inflammatory responses
– amyloid plaques not always
observed
– multiple brain regions are
affected
11
What is Dementia?
• It must include a decline in memory (amnesia) and at least
one of the following:
– Aphasia: Inability to generate coherent speech or understand
spoken or written language
– Agnosia: Inability to recognize or identify objects, assuming
intact sensory function
– Apraxia: Inability to execute motor activities, assuming intact
motor abilities
– Decline in Executive functioning: Decline in ability to think
abstractly, make sound judgments, and plan and carry out
complex tasks
13
Prevalence
• US: 3.5-16.1% of persons aged ≥ 65 yrs suffer from
some sort of dementia
• AD accounts for 50-60% of those dementias
• 5.3 million in US with AD
– Projected 13.2 million by 2050
• Incidence increases with age
– 10% > 65 yrs
• 7% of those 65-74 yrs
• 53% of those 74-85 yrs
14
Prevalence of AD
15
Prevalence of AD
16
Nussbaum RL, Ellis CE. Alzheimer’s disease and Parkinson’s disease. NEJM. 2003; 348:1356–1364.
Human Cost of AD
• Life expectancy after onset of symptoms 3-20
yrs.
– Average 8 yrs
• Life expectancy decreases by 69% after
diagnosis (<70 yrs)
• 4th leading cause of death in US
17
Financial Cost of AD
• Estimated annual direct
cost: $48,000
• Estimated annual total
cost: $174,000
• Estimated annual total US
cost: $148 billion
18
Family Impact
• 5 million caregivers of AD patients
• 46% ↑ in MD visits by caregivers of dementia
patients
• ↑ distress levels
• ½ caregivers express mild to moderate distress
• 16% have high distress
• ↑ levels of financial strain
• Interference with employment
19
Etiology of AD – Environmental /
Risk Factors
• Increased Age
• Decreased Reserve Capacity of Brain
– Small brain size or head circumference
– Low education level
– Reduced mental or physical activity
• Head injury
– Concussion awareness
• Increased risk for vascular diseases
–
–
–
–
–
–
Hypercholesterolemia
Hypertension
Atherosclerosis
Obesity
Diabetes
Smoking
20
Etiology of AD - Genetics
• Early-Onset Familial Alzheimer’s Disease (FAD)
– < 65 yrs
– Faster progression
– < 5% cases
• Mutations in dominant alleles on 3 chromosomes
– Chromosome 1: PSEN 2: Presenilin 2
– Chromosome 14: PSEN 1: Presenilin 1 (most
aggressive)
– Chromosome 21: APP: Amyloid Precursor Protein
(APP)
21
Etiology of AD - Genetics
• Late-Onset Alzheimer’s Disease
– Apolipoprotein E (ApoE)
• Cholesterol and lipoprotein metabolism
– Chromosome 19
• 3 alleles
– ε2 – appears to confer protection against AD
– ε3 – most common
– ε4 – increased risk of AD
– ApoE4
• Single ε4 allele, then 47% risk of AD at 80 yrs
• Both alleles ε4, then 91% risk of AD by 80 yrs
• No copies of ε4 allele, then 20% risk of AD
22
Pathophysiology of Alzheimer’s
Disease
• Two signature pathological findings
– Amyloid Plaques
– Neurofibrillary Tangles (tau proteins)
• Other factors
– Inflammation
– Reduction in Cholinergic Activity
– Excitotoxicity
23
Amyloid Cascade Hypothesis
• Brains of AD patients contain
Amyloid Plaques
• Amyloid Plaques are aggregates of
β-Amyloid protein
– 40-42 amino acid polypeptide
– β-Amyloid fragments aggregate
together
– Eventually form extracellular
plaques
• Imbalance between production &
clearance. Aggregates of peptides
cause A β to accumulate
24
Amyloid Cascade Hypothesis
• Normal processing of Amyloid Precursor
Protein (APP) involves cleavage by α-Secretase
then γ-Secretase
25
Amyloid Cascade Hypothesis
• Amyloid Precursor Protein (APP)
– Proteolysis by β-Secretase then γ-Secretase
– Results in β-Amyloid polypeptides of length 40-42 amino acids in length
– Release of β-Amyloid fragments into extracellular space
– β-Amyloid fragments aggregate to form Amyloid Plaques
• 42 length β-Amyloid fragment believed responsible for plaque formation
– Results in toxicity and degeneration of neurons
– Alzheimer’s Disease
26
Amyloid Cascade Hypothesis
• Abnormal processing of Amyloid Precursor
Protein (APP) involves cleavage by β-Secretase
then γ-Secretase
27
Amyloid Cascade Hypothesis
γ -Secretase complex
γ-Secretase Complex
28
Neurofibrillary Tangles (NFTs)
• Found inside neurons of AD patients
– Especially in hippocampus & cerebral cortex
– Found in Substantia Nigra of Parkinson’s
Patients
• Tau protein - provides support to
microtubules
• NFTs consist of hyperphosphorylated Tau
protein – these cannot bind to microtubules
so the microtubules collapse
• Hyperphosphorylated Tau aggregates
together to form NFTs which fills cytoplasm
– Do these NFTs cause cell death? Or are NFTs
the consequence of some other process?
29
Formation of Neurofibrillary Tangles
30
Neurofibrillary Tangles
(Tau Proteins)
31
Apolipoprotein E4 and AD
• Studies suggest ApoE has a role in the clearance
of β-Amyloid
• Enhances proteolytic breakdown of Aβ
– ApoE incorporated into lipoprotein particle
– ApoE then binds soluble β-Amyloid in isoform
dependent manner: E2 > E3 > E4
– ApoE then endocytosed by various cells in CNS
– β-Amyloid removed from brain
• APOE4 not as effective as others  Increased Aβ
32
Inflammation
• Evidence:
– Increased levels of pro-inflammatory mediators in AD (e.g.
cytokines)
– Epidemiological studies show NSAIDs may reduce AD risk
• Hypothesis:
– Inflammation occurs due to β-Amyloid accumulation
– Inflammatory mediators (cytokines, NO, complement)
injure neurons
– Results in cell death and neurodegeneration
• Clinical Trials:
– NSAIDs as treatment or prevention have been
disappointing
33
Cholinergic Hypothesis
• Loss in cholinergic neurons reason for decline in
memory and cognition and correlates with AD severity
• However…..
– Cholinergic cell loss a CONSEQUENCE of AD and not a
cause
– Other types of neurons lost in addition to cholinergic
neurons
• Other Neurotransmitter Abnormalities
– Reduction in Serotonergic neurons of Raphe Nuclei
– Reduction in Noradrenergic neurons of Locus Ceruleus
34
Excitotoxicity
• Glutamate is a major excitatory neurotransmitter in
CNS
– Normal levels: aids in memory & learning
– Increased levels: Over-stimulate nerve cells killing them
through Excitotoxicity
• Excitotoxicity is mediated via increased intracellular
Ca2+
• Abnormalities of glutamate pathways found in cortex
and limbic system in AD patients
• Level of involvement in AD, if any, still unclear
35
Excitotoxicity – NMDA receptor
So What? Who Cares?
36
Vascular Disease and Cholesterol
• Epidemiological link between CVD and AD
• Dysfunctional blood vessels:
– May impair delivery of nutrients and reduce
clearance of β-Amyloid
– May increase β-Amyloid toxicity to neurons
• Elevated cholesterol may alter membrane
function and initiate Amyloid Cascade
37
Other theories
• Oxidative stress and formation of free radicals
– Studies suggest Vitamin E and C may help prevent AD
• Mitochondrial dysfunction
– Disruption of energy metabolism in neuron
• Loss of estrogen in postmenopausal women
– Incidence AD higher in women than men
– Estrogen can directly or indirectly affect the brain
•
•
•
•
Neuroprotection
Neurotransmitter effects
Reduce βA in brain
Increase cerebral blood flow
– However, clinical trials using HRT have thus far proven disappointing
38
The Big Picture
• Faulty processing of APP leads to β-Amyloid
– Soluble βA monomers and oligomers lead to neuronal dysfunction
and cell death
• Aggregation of Tau Protein leads to Neurofibrillary Tangles
– Production of NFTs results in inability of cell to hold structure
• Causative factor in neurodegeneration, or consequence of some other
process?
• Possible involvement by inflammatory mediators
• Cholinergic dysfunction: a consequence of neurodegeneration
• Excitotoxicity contributing factor
39
The Big Picture
40
The Big Picture
41
Diagnosis
• Under diagnosed in primary care setting
• Usually brought to the attention of a primary care
physician by family member
• Definitive diagnosis only made at autopsy
• However, criteria have been developed to detect
and diagnose dementia
– DSM-V, AAN guidelines, etc
42
Diagnosis
• Revised diagnostic and research criteria for AD
• Three phases proposed:
1) Asymptomatic, preclinical AD

For research purposes
2) Symptomatic, pre-dementia (MCI due to AD)
3) Dementia due to AD
43
Diagnosis
• Rule out:
– Other neurological conditions that cause cognitive deficits
(e.g. Brain Tumor)
– Other psychiatric conditions that cause cognitive deficits
(e.g. MDD, Schizophrenia, delirium)
– Systemic conditions that cause cognitive deficits (e.g.
Hypothyroidism, anemia) – General Medical Conditions
– Substance Related Disorders
44
Diagnostic Tests
• CT scan – useless
• MRI scan – probably useless
• PET, SPECT, fMRI – Still experimental, maybe useless
• Routine Lab Tests
–
–
–
–
–
–
–
CBC
CMP, BMP
LFTs
Thyroid
Vitamin B12
Syphilis – RPR, VDRL
UA
• Lumbar Puncture and analysis of CSF for tau and B-amyloid proteins. –
probably useless, not with out risks
45
Assessment Tests
• Folstein Mini-Mental State Examination?
• Alzheimer’s Disease Assessment Scale – Cognitive
(ADAS-Cog)
• Alzheimer’s Disease Cooperative Study –
Activities of Daily Living (ADCS-ADL)
• Others
46
Mini Mental State Exam
• Tests on 5 areas of cognition
– Orientation
– Registration
– Attention
– Recall
– Language
47
Clinical Presentation of AD
Cognitive Symptoms
Noncognitive Symptoms
•
•
•
•
•
• Depression
• Psychosis
• Behavioral Disturbances
Memory Loss
Aphasia
Agnosia
Disorientation
Impaired Executive
Function
48
Signs of AD
49
Alzheimer’s Association. Symptoms of Alzheimer’s. Available at: www.alz.org/alzheimers_disease_symptoms_of_alzheimers.asp..
Disease Progression
• Onset of AD generally subtle
• Stages:
– Mild: forgets names of places, word-finding difficulties,
trouble using household appliances, loss of interest in
activities
– Moderate: forget recent events, has trouble handling
money, agitated, starts walking or roaming about
– Severe: has trouble using or understanding words, lack of
self-care functions
50
Disease Progression
51
Sadik K. Wilcock G. The increasing burden of Alzheimer’s disease. Alzheimer Dis Assoc Disord. 2003;17:S75–S79.
Stages of Alzheimer’s Disease
52
7 Stages of Alzheimer’s
• Stage 1: No impairment (normal function)
• Stage 2: Very mild cognitive decline
– May be normal age-related changes or the earliest
signs of AD
– Memory lapses
• Forgetting words, names, location of keys, etc.
• Not apparent to others or evident during medical
examination
http://www.alz.org/alzheimers_disease_stages_of_alzheimers.asp
7 Stages of Alzheimer’s
• Stage 3: Mild Cognitive Decline
– Early AD can be dx in some patients
– Friends / family begin to notice deficits
– Problems with word or name-finding
– Performance issues at work noticeable
– Decline in ability to plan / organize
– Lose / misplace valuable object
http://www.alz.org/alzheimers_disease_stages_of_alzheimers.asp
7 Stages of Alzheimer’s
• Stage 4: Moderate Cognitive Decline (Mild AD)
– Medical exam detects clear-cut deficiencies:
• Decreased knowledge in current / recent events
• Impaired ability to perform mental arithmetic (serial 7s)
• Decreased capacity to perform complex tasks (pay bills,
manage finances)
• Reduced memory of personal history
– May seem withdrawn
http://www.alz.org/alzheimers_disease_stages_of_alzheimers.asp
7 Stages of Alzheimer’s
• Stage 5: Moderately Severe Cognitive Decline
(Moderate AD)
– Major gaps in memory and deficits in cognitive
function are very evident
– May be unable to recall address, telephone #, name of
HS or college
– Difficulty with simple mental arithmetic (ex. counting
down by 2s)
– Need help in selecting appropriate clothing for season
– Usually know own name & name of spouse/kids
– No assistance needed with eating or toileting
http://www.alz.org/alzheimers_disease_stages_of_alzheimers.asp
7 Stages of Alzheimer’s
• Stage 6: Severe Cognitive Decline (Moderately
severe AD)
– Significant personality changes emerge
– Need assistance with ADLs
– Lose awareness of recent experiences / events
– May be unable to recall name of spouse / kids but
can distinguish familiar faces
– Need help getting dressed (errors such as putting
shoes on wrong feet, putting PJs over regular
clothes)
http://www.alz.org/alzheimers_disease_stages_of_alzheimers.asp
7 Stages of Alzheimer’s
• Stage 6 (Cont.)
– Major changes in sleep patterns
– Need assistance with toileting (wiping, flushing)
– Increased episodes of urinary or fecal
incontinence
– Significant personality changes / behaviors
• Paranoia or other delusions
• Hallucinations
• Repetitive behaviors (hand-wringing, vocalizations)
– Wandering
http://www.alz.org/alzheimers_disease_stages_of_alzheimers.asp
7 Stages of Alzheimer’s
• Stage 7: Very Severe Cognitive Decline (Severe
or End-Stage AD)
– Final stage
– Lose the ability to respond to their environment,
ability to speak, ability to control movement
– Lose the ability to walk without assistance, site
without support, hold head up, smile.
– Reflexes abnormal, muscles grow rigid
– Impaired swallowing
http://www.alz.org/alzheimers_disease_stages_of_alzheimers.asp
Treatment of Dementia
GOALS:
•
•
•
•
Prevent or delay disease progression
Maintain cognitive function
Reduce behavioral symptoms
Maintain or improve functional abilities
60
Treatment of Dementia
• Nonpharmacotherapy
– Education
– Behavioral Interventions
– Communication
– Planning
61
Treatment of Dementia
• Pharmacotherapy of Cognitive Symptoms
– Cholinesterase Inhibitors
• tacarine, donepezil, rivastagmine, galantamine
– NMDA Antagonists
• Memantine (namenda)
– Potential or alternative treatments:
•
•
•
•
Estrogens
NSAIDs
Lipid Lowering Agents
Vitamin E
62
Drug name
Brand name
1. donepezil
Aricept
Approved For
FDA Approved
All stages
1996
2. galantamine
Razadyne
Mild to moderate
2001
3. memantine
Namenda
Moderate to severe
2003
4. rivastigmine
Exelon
All stages
2000
5. donepezil and
memantine
Namzaric
Moderate to severe
2014
Knowledge Check
Which of the following are goals of dementia
treatment?
A. Reverse disease progression
B. Restore cognitive function
C. Eliminate behavioral symptoms
D. Maintain or improve functional abilities
Cholinesterase Inhibitors
• Neurodegeneration leads to reduction in cholinergic activation in
AD
• Cholinergic neurons activated through nicotinic and muscarinic
receptors in CNS
• Acetylcholine release from vesicles in presynaptic neuron
• Activate receptors on postsynaptic neuron
• Some ACh hydrolyzed via Acetylcholinesterase
• Cholinesterase Inhibitors block Acetylcholinesterase thus increasing
ACh concentration in synaptic cleft
• Results in increased cholinergic activation
65
Cholinesterase Inhibitors
Acetylcholinesterase
66
Cholinesterase Inhibitors
• Cholinesterase inhibitors bind REVERSIBLY to AchE
resulting in accumulation of ACh.
• FDA approved Cholinesterase Inhibitors
– Tacrine (Cognex®)
– Donepezil (Aricept®)
– Galantamine (Razadyne®)
– Rivastigmine (Exelon®)
67
Cholinesterase Inhibitors (Warnings)
• Neurological effects
– Exacerbate or induce extrapyramidal symptoms; worsening of PD
tremor
– May potentiate seizures
• Peptic ulcers / GI bleeding due increased acid secretion
• Anesthesia with succinylcholine type muscle relaxation
– DC short-term if surgery planned
• Cardiac conduction effects
– Caution if h/o bradycardia / syncope
• Urinary obstruction
• Asthma / obstructive pulmonary disease
68
Tacrine (Cognex®)
• 1st approved for AD
• Readily crosses BBB
• Modestly improves
cognitive symptoms
• Significant side effects
– N&V
– Elevations in LFTs
• Dosing
• ADME
– Rapidly absorbed after oral
administration
– Absorption reduced by food
– 17% Bioavailability
– Metabolized via CYP450
– T ½ : 2-4 hours
– 10 mg QID to max 160
mg/day
• Not used clinically
69
Donepezil (Aricept®)
•
•
•
•
•
Approved for mild, moderate, & severe AD
Readily crosses BBB
Little effect in periphery
Modestly improves cognitive symptoms
AE profile
• 5-10% GI upset, insomnia, N&V, diarrhea,
decreased appetite, weight loss
• Dosing
• 5 - 10 mg mild to moderate AD
• 10 - 23 mg moderate to severe AD
70
Donepezil (Aricept®)
• ADME
•
•
•
•
•
•
Well absorbed after oral administration
100% Bioavailability
Metabolized via CYP450 2D6 (minor)
T ½ : 70 hours
Time to peak: 3-4 hours
Excreted via kidneys (57%) and intestine (15%)
71
Donepezil (Aricept®)
• Initiate at 5 mg QHS and increase to 10 mg after 4 – 6
weeks
– May take with or without food
• Increase to 23 mg after minimum of 3 months on 10 mg
• Special Populations
– Low body weight; decreased clearance = increased AEs
• Incidence of weight loss increased at dose of 23 mg
• Aricept ODT is bioequivalent to regular tabs
72
Donepezil Efficacy
73
Galantamine (Razadyne®)
•
•
•
•
Indicated for mild & moderate AD
Readily crosses BBB with little effect in periphery
Similar cognitive improvement as Aricept
AE profile
– 6-24% GI upset, insomnia, N&V
74
Galantamine (Razadyne®)
• Razadyne (BID); Razadyne ER (Q Day)
– Switch from IR tablet to ER capsule; use same daily
dose
• Dosing
–
–
–
–
Initial 8 mg/day x 4 weeks
Increase to 16mg/day x 4 weeks
May increase to 24 mg/day
Re-titrate after > 3 days interrupted dosing
• Starting dose (8 mg/day) is NOT therapeutic!
75
Galantamine (Razadyne®)
• ADME
–
–
–
–
–
–
–
Rapidly absorbed
Food decreases Cmax but not AUC
90% Bioavailability
Metabolized via CYP450 (2D6, 3A4)
T ½ : 7 hours
Time to peak: 1 hour (I.R.), 4 hours (E.R.)
25% excreted via kidneys
76
Galantamine (Razadyne®)
• Special Populations
– Moderate renal or hepatic impairment max dose = 16
mg/day
– Severe renal or hepatic impairment; use not
recommended
• Recommended to take with food and plenty of
fluids
• Name confusion Razadyne® vs. Rozerum®
77
Galantamine Efficacy
78
Rivastigmine (Exelon®)
• Indicated for mild, moderate, and severe AD and
PD dementia
• Available as oral or patch
• Similar efficacy to other cholinesterase inhibitors
• AE profile
– 7-47% GI upset, N&V, diarrhea
– CNS - dizziness, headache, tremor
• Dosing
– 1.5mg BID to max. 6mg BID
– 4.6 mg, 9.5 mg, or 13.3 mg per 24hr patch
79
Rivastigmine (Exelon®)
• Dosing
– PO:
•
•
•
•
1.5mg BID x 4 weeks then
3 mg BID x 4 weeks then
4.5 mg BID x 4 weeks then
6 mg BID (max dose)
– Patch:
• 4.6 mg, 9.5 mg, or 13.3 mg per 24hr patch
• Increase dose after 1 month
– Converting from PO to Patch
• < 6 mg/day  4.6 mg/24h
• 6-12 mg/day  9.5 mg/24h
• Apply patch on the day following the last PO dose
80
Rivastigmine (Exelon®) Patch
• Indicated for mild to moderate (9.5 & 13.5 mg) and severe
(13.5 mg) dementia
– If dose interrupted for > 3 days then re-titrate from 4.6 mg
• Special populations
– Mild to moderate hepatic impairment & Low body weight
• consider 4.6 mg for both initial and maintenance dose
• Apply to clean, dry, hairless skin on upper or lower back every
24 hrs (rotate sites)
• Application site reactions (erythema / pruritis) are common
(6-12%)
81
Rivastigmine (Exelon®)
• ADME
– Rapidly absorbed
– 90% Bioavailability
– Metabolized via hydrolysis by acetylcholinesterase
– Time to peak: 1 hour (oral), ~8 hours (patch)
– 97% excreted via kidneys
84
Take Home Message on
Cholinesterase Inhibitors
• No real difference in efficacy between drugs
• Drug use determined on tolerability, price, etc
• Tacrine not on the market any longer
• Improvements in cognition modest
• Do not alter course of disease
85
Counseling points on Cholinesterase Inhibitors
• Use as directed
• Adverse Events
– Inform patients/caregivers of potential for nausea, vomiting, &
diarrhea with potential for dehydration
• Especially upon initiation and dose increase
– Skin reactions with Exelon patch
• Do not use with other cholinergic drugs (e.g., other AChEIs)
• Variable efficacy, but does not cure AD
• Anticholinergics recommended to be avoided
86
Principles for ChEIs
NMDA Antagonists
• Memantine (Namenda®) – only FDA approved NMDA antagonist for
AD
• Believed to work by blocking action of Glutamate at NMDA (NMethyl-D-Aspartate) receptors
• NMDA receptors involved in memory and learning
• Glutamate excitotoxicity possibly involved in pathogenesis of AD
• Memantine shown to modestly improve cognition
88
Memantine (Namenda®)
– Glutamate excitatory
neurotransmitter
– Over activation of NMDA
receptor results in
excitotoxicity
– Memantine binds to Mg2+ site
in ion channel – it is an
uncompetitive inhibitor
– Causes ion channel pore to be
closed to Ca2+ influx
NMDA Receptor
89
Memantine (Namenda®)
• Approved for moderate to severe AD
• Shown to modestly slow cognitive decline in AD
patients
• Used as monotherapy or with ChE Inhibitor
• Well tolerated – no significant AEs
– H/A, dizziness, sedation, agitation, constipation
90
Memantine (Namenda®)
Dosing IR tabs:
• 5 mg Q Day x > 1 week, then
• 5 mg BID x > 1 week, then
• 5 mg Q AM and 10 mg Q PM x > 1 week, then
• 10 mg BID
Dosing ER caps:
• 7 mg Q Day x > 1 week, then
• 14 mg Q Day x > 1 week, then
• 21 mg Q Day x > 1 week, then
• 28 mg Q Day
Switching from IR to ER:
• Begin ER product day after last dose of IR
• If on 10 mg BID  28mg Q Day
91
Memantine (Namenda®)
• ADME
– T1/2: 60-80 hours
– Time to peak: 3-7 hours
– 82% excreted via kidneys
• Place in Therapy:
– Improvements (small) in cognition
– Improvements in ADLs
– Improvements in behaviors
92
Principles for memantine
Other approaches - MAOIs
• Theoretical based on MOA
– Norepinephrine decreased in AD patients
– Inhibition of MAO results in increase norepinephrine
centrally
• Selegiline
– Some trials showed positive outcomes using selegiline
• Improvements in memory and attention
– Other studies showed no significant improvements
94
Other approaches – Anti-inflammatory
Agents
• Theoretically could help due to involvement of
inflammatory mediators
• Studies suggest protective effect
• Clinical studies less positive
– Prednisone, Diclofenac, Indomethacin all negative
• Prednisone associated with decline in cognitive
symptoms and behavior
• NSAIDs associated with risks but no benefits
95
Other approaches - Estrogens
• Increases cerebral blood flow
• Neuroprotective
• Epidemiological studies suggest lowers risk
• Clinical trials negative
– WHIMS – Estrogen increased dementia
• Estrogen risks e.g., stroke
96
Other approaches – Lipid Lowering
Agents
• Link between AD risk and cholesterol
• Epidemiological studies suggest lower AD in those
taking statin
– Only for lovastatin and pravastatin
• In one study simvastatin showed decrease in βAmyloid plaques in patients with mild AD
• No positive clinical studies linking improvement in
cognition with statins
97
Other approaches - Vitamin E
• Oxidative Stress and Free Radical possibly involved in AD
• Vitamin E is an antioxidant
• Single prospective clinical study showed a positive outcome
for Vitamin E
• Conflicting data from epidemiological studies
• Vitamin E also associated with risks (although minimal)
• Fatigue, GI upset
• Increased risk of bleeding if taken with NSAID/ASA
• Doses above 400units/day should be avoided if possible
98
Other approaches – Ginko Biloba
• A number of studies show mild improvement in cognitive function
in demented patients
– One study showed Ginko 160mg QD comparable to donepezil 5mg QD
• Has been shown to improve cognition in patients suffering MCI and
in young to middle aged individuals
• Possible MOA:
– Increases cerebral blood flow
– Acts as antioxidant – neuroprotective
– Anti-inflammatory properties
• Adverse effects rare – GI upset
• Use cautiously in patients taking NSAIDS/ASA
99
Potential Treatments in Research
• γ-Secretase Inhibitors
– e.g. Semagecestat
– Phase III – IDENTITY Study showed negative
outcome
• Anti β -Amyloid Agents
– e.g. Solanezumab
– Currently Phase III – EXPEDITION Study
100
Potential Treatments in Research
• Sleep?
– Melatonin, Ramelteon (Rozerem)
• Females more vulnerable?
– Decrease in function 2x as fast as males
•
•
•
•
•
•
Beta-amyloids- vaccines
Tau proteins - vaccines
Inflammation – NSAIDs failed
Insulin Resistance
Brain Imaging and Biomarkers - *
Genetics - *
101
TREATMENT OF BEHAVIORAL &
PSYCHOTIC SYMPTOMS OF DEMENTIA
(BPSD)
Behavioral Symptoms
• Affects up to 90%
– Not included in defining criteria of dementia in
current classifying systems
• Cause disability, patient distress, caregiver
burden, institutionalization
• Can be annoying / disruptive  threatening /
dangerous
Behavioral Symptoms
• Spectrum of behaviors
–
–
–
–
–
Apathy
Wandering
Agitation
Verbal and/or physical aggression
Psychotic symptoms
• Evaluate any change in behavior
– Meds
– Pain
– Infection
• Evaluate triggers contributing to behaviors
– Hunger, cold, pain
• Non-pharmacological interventions 1st line
Non-Pharmacologic Interventions
•
•
•
•
•
•
•
Music
Aromatherapy
Bright lights
Massage / touch
Validation
Reminiscence
Establish routine for meals, bedtime, etc.
Non-Pharmacologic Interventions
• Modify environment (reduce stimulation)
– Loud or violent TV, clutter
• Exercise
– Maintains ambulation & improves mood
• Intervene early
• Remain calm / voice tone / eye contact
• Use visual cues or barriers to discourage wandering
Non-Pharmacologic Interventions
•
•
•
•
•
•
•
Break tasks into simple steps
Distractions
Give choices in clothing
Calendars & clocks to orient to time
Gates / locks on doors
Grab bars @ toilet and shower
Nightlights
Depression
• Affects up to 50% of patients
• Symptoms masked by dementia
• Manifests differently in AD patients
– Irritability / anxiety / functional decline
• Somatic concerns, fear, worry
– Dysphoria at earlier stages
– Agitation / apathy / motor function decline at later stages
• Non Pharm Tx:
– Exercise
– Increase pleasurable activities (art, writing, music,
gardening)
Agitation
• Complex issue r/t assessment and
intervention
– Ex. Agitation vs. anxiety
• Vague term
• “Inappropriate verbal, vocal, or motor activity
that is not judged by an outside observer to
result directly from the needs or confusion of
the agitated individual.” - Cohen-Mansfield,
2010
Agitation
• Can include aberrant motor behavior
– Wandering
– Repetitive, purposeless behaviors
– Socially inappropriate activities (ex. sexual
behaviors)
• Must rule out: Hunger / cold / hot /
discomfort / pain, etc.
• Modify environment
• Pharm Tx: PRN medications
Wandering
• Identify triggers (boredom, hunger, thirst, etc.)
– What’s the goal of wandering for patient?
– Searching for something?
•
•
•
•
Non-Pharm Tx: Music therapy, PT
Exercise / redirection
Not likely to respond to meds unless 2’ anxiety
Burn calories  will need increased intake
Wandering
• Cover / disguise doors and exits
• Locks on doors
• Alzheimer’s Association MedicAlert + Safe
Return
• GPS tracker / band
Physical and/or Verbal Agitation
• Cohen-Mansfield: Four categories of agitation:
1.
2.
3.
4.
Physically non-aggressive behavior
Verbally non-aggressive behavior
Physically aggressive behavior
Verbally aggressive behavior
• Many times aimed towards caregiver
• Threshold:
–
–
–
–
Harmful to self or others
Interferes with functioning
Cause disability
Impede care
Sleep Disturbances
• Prevalent in dementia patients
• Can include: hypersomnia, insomnia, sleepwake cycle reversal, fragmented sleep,
daytime napping, night-time awakenings
Sleep Disturbances
• Assessment:
– Depression
– Fear
– Pain
– Meds that  insomnia / incontinence
• Interventions:
– Adult day care
– Warm milk / high carb snack
– Melatonin
Sleep Disturbances
• Sleep Hygiene:
– Bedroom free of distractions
– Limit naps
– Exercise in am or early pm
– Limit caffeine / nicotine / extra fluids in pm
– Dressed in daytime clothing
– Night light for safety
Psychotic Symptoms
• Delusions (fixed false beliefs)
• Less complex than in non-demented patients
• Typically involves suspiciousness,
abandonment, misidentification
– People breaking in
– Family poisoning patient
– Conspiracy to take $$ / abandon pt
Psychotic Symptoms
•
•
•
•
Hallucinations vs. Perceptual Differences
Visual / auditory / tactile hallucinations
Hallucinations more common with Lewy Body
Rule out other causes
– Hearing aids
– MRPs
– Infections
AD vs. Vascular Dementia
Alzheimer’s Dementia
Vascular Dementia
• Similar rates of
• Higher prevalence / severity
psychotic sx
of depression
• Slow, steady decline
• Less aberrant motor
behaviors
• Executive functioning more
impaired
• Patient aware of deficits
• Gait disorders
Dementia w/Lewy Bodies
• 15-25% of dementias
– DA and ACH deficits
• DA loss  EPS / Parkinsonian symptoms
– More delusions
– Fluctuating cognition
– Hallucinations (detailed visual hallucinations)
• Occur early in disease
Fronto-Temporal Lobe Dementia
• AKA: Pick’s Disease
• See changes in behavior/personality rather than
in cognitive function
• Dramatic change in personal/social behavior
• Neglect of personal hygiene
• Loss of basic emotions
• Hyperorality (gluttony, excessive smoking, altered
food preferences – ex. sweets)
• Pacing
• Reduced speech (some patients become mute)
PHARMACOLOGIC INTERVENTIONS
FOR BPSD
Alzheimer's Drugs
• ChEI
– Modest effect on neuropsychiatric symptoms
– Apathy, depression, aberrant motor behaviors
most likely to improve
• Memantine
– Agitation & irritability most likely to improve
General Principles
• Treating symptom of a disease / will not
modify disease
• Monitor for adverse effects
• Use lowest dose possible
• Select meds with “clean” S/E profile OR use
S/E profile to benefit
Benzodiazepines
• Targeted Behaviors: Anxiety / Insomnia /
Acute Agitation
• Avoid using, if possible.
• Use PRN at 1/3 to 1/2 usual dose
• Use agents with shorter t ½
• S/E: increased cognitive impairment, fall risk,
paradoxical agitation
• Avoid EtOH
Antidepressants
• Targeted Behavior: Depression / Agitation /
Insomnia
• SSRIs:
– Mx CP450 drug interactions
– S/E: Activation / sedation / insomnia / dizziness
• Use S/E to “benefit” (ex. sedation)
• TCAs:
– Avoid 2’ S/E profile
Antidepressants
• SNRIs:
– Avoid if s/e are problematic with patient hx
• Mirtazapine:
– Promotes sleep @ lower doses
– Can improve appetite, weight gain
• Trazodone:
– Useful @ HS  sedation or in daytime if agitation
Sedative / Hypnotics
• Zaleplon (Sonata) / zolpidem (Ambien)
ramalteon ( Rozerem)
• Can be used safely in elderly
• Monitor for daytime sedation, dizziness, falls
Diphenhydramine
•
•
•
•
Avoid use for anxiety, sleep, etc.
Beer’s Criteria
Drug-drug interaction (with ChEIs)
Drug-disease interaction (w AD)
Atypical APs
• Targeted Behavior: Psychotic symptoms,
aggressive / combative behaviors
• NOT FDA approved
• Use when all other options tried / failed
• Black Box Warning: Increased risk of stroke /
death in dementia patients
• S/E: EPS and TD (less than with typicals)
Guideline for Alzheimer’s Disease Management. CA workgroup on Guidelines for Alzheimer’s Disease Management
From: Efficacy and Comparative Effectiveness of Atypical Antipsychotic Medications for Off-Label Uses in
Adults: A Systematic Review and Meta-analysis
JAMA. 2011;306(12):1359-1369. doi:10.1001/jama.2011.1360
Figure Legend:
Total global scores are presented and include the symptoms of delusion, hallucination, dysphoria, anxiety, agitation or aggression,
euphoria, disinhibition, irritability, apathy, aberrant motor activity, and behavioral disturbances. Weights are from a random-effects
analysis. The size of the data markers is proportional to the sample size of the trial. aThe data used for this study were abstracted
from the meta-analysis by Schneider et al.
From: Efficacy and Comparative Effectiveness of Atypical Antipsychotic Medications for Off-Label Uses in
Adults: A Systematic Review and Meta-analysis
JAMA. 2011;306(12):1359-1369. doi:10.1001/jama.2011.1360
From: Efficacy and Comparative Effectiveness of Atypical Antipsychotic Medications for Off-Label Uses in
Adults: A Systematic Review and Meta-analysis
JAMA. 2011;306(12):1359-1369. doi:10.1001/jama.2011.1360
Typical APs
• Avoid 2’ cardiac / EPS / TD
– TD seen in 50% of elderly after 2 years use
Guideline for Alzheimer’s Disease Management. CA workgroup on Guidelines for Alzheimer’s Disease Management
Mood Stabilizers / AEDs
• Targeted Behaviors: Delusions / Hallucinations
/ Psychomotor agitation / Combativeness
• Not FDA approved
• When used with atypical APs, may allow for
dose reductions
• Treat to response of symptoms
• No “therapeutic” level, but monitor if risk of
toxicity
Guideline for Alzheimer’s Disease Management. CA workgroup on Guidelines for Alzheimer’s Disease Management
Behavioral Symptoms
• Affects up to 90%
– Not included in defining criteria of dementia in
current classifying systems
• Cause disability, patient distress, caregiver
burden, institutionalization
• Can be annoying / disruptive  threatening /
dangerous
Behavioral Symptoms
• Spectrum of behaviors
–
–
–
–
–
Apathy
Wandering
Agitation
Verbal and/or physical aggression
Psychotic symptoms
• Evaluate any change in behavior
– Meds
– Pain
– Infection
• Evaluate triggers contributing to behaviors
– Hunger, cold, pain
• Non-pharmacological interventions 1st line