Alzheimer

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Alzheimers and Other Dementias
PSYCH 7955

• W Klugh Kennedy, PharmD, BCPP, FASHP, FCCP
• Clinical Professor of Pharmacy Practice and
  Psychiatry
• Mercer University, Savannah Georgia
• klughkennedy_at_kennedy-kps.com

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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.

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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

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Associated with Dementia

• Parkinson's Disease
• Hydrocephalus
• Multiple Sclerosis
• Vitamin deficiency
• Alcohol
• Medications
• Stroke

• Huntingtons Disease
• Subdural hematoma
• Brain tumor
• Infection
• Inflammation
• Hormonal loss
• Major organ failure

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Types of Dementia

• Alzheimers Disease
• Dementia with Lewy Bodies
• Vascular Dementia
• Creutzfeldt-Jakob Disease
• Reversible causes of dementia
• B12 deficiency
• Hypothyroidism
• Depression (pseudodementia)

Alzheimers Association http//www.Alz.org USA
National Institutes on Health http//www.NIH.gov
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Dementia with Lewy Bodies

• Found primarily in individuals with Parkinsons
  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 a-synuclein

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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

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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)

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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

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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

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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

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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 gt 65 yrs
• 7 of those 65-74 yrs
• 53 of those 74-85 yrs

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Prevalence of AD
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Prevalence of AD
Nussbaum RL, Ellis CE. Alzheimers disease and
Parkinsons disease. NEJM. 2003 34813561364.
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Human Cost of AD

• Life expectancy after onset of symptoms 3-20 yrs.
• Average 8 yrs
• Life expectancy decreases by 69 after diagnosis
  (lt70 yrs)
• 4th leading cause of death in US

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Financial Cost of AD

• Estimated annual direct cost 48,000
• Estimated annual total cost 174,000
• Estimated annual total US cost 148 billion

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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

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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

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Etiology of AD - Genetics

• Early-Onset Familial Alzheimers Disease (FAD)
• lt 65 yrs
• Faster progression
• lt 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)

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Etiology of AD - Genetics

• Late-Onset Alzheimers Disease
• Apolipoprotein E (ApoE)
• Cholesterol and lipoprotein metabolism
• Chromosome 19
• 3 alleles
• e2 appears to confer protection against AD
• e3 most common
• e4 increased risk of AD
• ApoE4
• Single e4 allele, then 47 risk of AD at 80 yrs
• Both alleles e4, then 91 risk of AD by 80 yrs
• No copies of e4 allele, then 20 risk of AD

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Pathophysiology of Alzheimers Disease

• Two signature pathological findings
• Amyloid Plaques
• Neurofibrillary Tangles (tau proteins)
• Other factors
• Inflammation
• Reduction in Cholinergic Activity
• Excitotoxicity

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Amyloid Cascade Hypothesis

• Brains of AD patients contain Amyloid Plaques
• Amyloid Plaques are aggregates of ß-Amyloid
  protein
• 40-42 amino acid polypeptide
• ß-Amyloid fragments aggregate together
• Eventually form extracellular plaques
• Imbalance between production clearance.
  Aggregates of peptides cause A ß to accumulate

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Amyloid Cascade Hypothesis

• Normal processing of Amyloid Precursor Protein
  (APP) involves cleavage by a-Secretase then
  ?-Secretase

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Amyloid Cascade Hypothesis

• Amyloid Precursor Protein (APP)
• Proteolysis by ß-Secretase then ?-Secretase
• Results in ß-Amyloid polypeptides of length 40-42
  amino acids in length
• Release of ß-Amyloid fragments into extracellular
  space
• ß-Amyloid fragments aggregate to form Amyloid
  Plaques
• 42 length ß-Amyloid fragment believed responsible
  for plaque formation
• Results in toxicity and degeneration of neurons
• Alzheimers Disease

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Amyloid Cascade Hypothesis

• Abnormal processing of Amyloid Precursor Protein
  (APP) involves cleavage by ß-Secretase then
  ?-Secretase

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Amyloid Cascade Hypothesis
? -Secretase complex
?-Secretase Complex
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Neurofibrillary Tangles (NFTs)

• Found inside neurons of AD patients
• Especially in hippocampus cerebral cortex
• Found in Substantia Nigra of Parkinsons 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?

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Formation of Neurofibrillary Tangles
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Neurofibrillary Tangles(Tau Proteins)
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Apolipoprotein E4 and AD

• Studies suggest ApoE has a role in the clearance
  of ß-Amyloid
• Enhances proteolytic breakdown of Aß
• ApoE incorporated into lipoprotein particle
• ApoE then binds soluble ß-Amyloid in isoform
  dependent manner E2 gt E3 gt E4
• ApoE then endocytosed by various cells in CNS
• ß-Amyloid removed from brain
• APOE4 not as effective as others ? Increased Aß

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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 ß-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

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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

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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

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Excitotoxicity NMDA receptor
So What? Who Cares?
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Vascular Disease and Cholesterol

• Epidemiological link between CVD and AD
• Dysfunctional blood vessels
• May impair delivery of nutrients and reduce
  clearance of ß-Amyloid
• May increase ß-Amyloid toxicity to neurons
• Elevated cholesterol may alter membrane function
  and initiate Amyloid Cascade

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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 ßA in brain
• Increase cerebral blood flow
• However, clinical trials using HRT have thus far
  proven disappointing

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The Big Picture

• Faulty processing of APP leads to ß-Amyloid
• Soluble ßA 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

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The Big Picture
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The Big Picture
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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

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Diagnosis

• Revised diagnostic and research criteria for AD
• Three phases proposed
• Asymptomatic, preclinical AD
• For research purposes
• Symptomatic, pre-dementia (MCI due to AD)
• Dementia due to AD

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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

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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

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Assessment Tests

• Folstein Mini-Mental State Examination?
• Alzheimers Disease Assessment Scale
  Cognitive(ADAS-Cog)
• Alzheimers Disease Cooperative Study
  Activities of Daily Living (ADCS-ADL)
• Others

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Mini Mental State Exam

• Tests on 5 areas of cognition
• Orientation
• Registration
• Attention
• Recall
• Language

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Clinical Presentation of AD

• Cognitive Symptoms

• Noncognitive Symptoms

• Memory Loss
• Aphasia
• Agnosia
• Disorientation
• Impaired Executive Function

• Depression
• Psychosis
• Behavioral Disturbances

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Signs of AD
Alzheimers Association. Symptoms of Alzheimers.
Available at www.alz.org/alzheimers_disease_sympt
oms_of_alzheimers.asp..
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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

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Disease Progression
Sadik K. Wilcock G. The increasing burden of
Alzheimers disease. Alzheimer Dis Assoc Disord.
200317S75S79.
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Stages of Alzheimers Disease
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7 Stages of Alzheimers

• 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_al
zheimers.asp
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7 Stages of Alzheimers

• 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_al
zheimers.asp
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7 Stages of Alzheimers

• 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_al
zheimers.asp
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7 Stages of Alzheimers

• 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_al
zheimers.asp
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7 Stages of Alzheimers

• 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_al
zheimers.asp
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7 Stages of Alzheimers

• 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_al
zheimers.asp
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7 Stages of Alzheimers

• 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_al
zheimers.asp
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Treatment of Dementia

• GOALS
• Prevent or delay disease progression
• Maintain cognitive function
• Reduce behavioral symptoms
• Maintain or improve functional abilities

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Treatment of Dementia

• Nonpharmacotherapy
• Education
• Behavioral Interventions
• Communication
• Planning

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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

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Drug name Brand name Approved For FDA Approved
1. donepezil Aricept 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
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Knowledge Check

• Which of the following are goals of dementia
  treatment?
• Reverse disease progression
• Restore cognitive function
• Eliminate behavioral symptoms
• Maintain or improve functional abilities

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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

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Cholinesterase Inhibitors
Acetylcholinesterase
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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)

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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

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Tacrine (Cognex)

• 1st approved for AD
• Readily crosses BBB
• Modestly improves cognitive symptoms
• Significant side effects
• N V
• Elevations in LFTs
• Dosing
• 10 mg QID to max 160 mg/day
• Not used clinically

• ADME
• Rapidly absorbed after oral administration
• Absorption reduced by food
• 17 Bioavailability
• Metabolized via CYP450
• T ½ 2-4 hours

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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, NV, diarrhea,
  decreased appetite, weight loss
• Dosing
• 5 - 10 mg mild to moderate AD
• 10 - 23 mg moderate to severe AD

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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)

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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

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Donepezil Efficacy
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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, NV

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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 gt 3 days interrupted dosing
• Starting dose (8 mg/day) is NOT therapeutic!

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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

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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

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Galantamine Efficacy
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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, NV, 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

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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
• lt 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

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Rivastigmine (Exelon) Patch

• Indicated for mild to moderate (9.5 13.5 mg)
  and severe (13.5 mg) dementia
• If dose interrupted for gt 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)

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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

85
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

86
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

87
Principles for ChEIs
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NMDA Antagonists

• Memantine (Namenda) only FDA approved NMDA
  antagonist for AD
• Believed to work by blocking action of Glutamate
  at NMDA (N-Methyl-D-Aspartate) receptors
• NMDA receptors involved in memory and learning
• Glutamate excitotoxicity possibly involved in
  pathogenesis of AD
• Memantine shown to modestly improve cognition

89
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
90
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

91
Memantine (Namenda)

• Dosing IR tabs
• 5 mg Q Day x gt 1 week, then
• 5 mg BID x gt 1 week, then
• 5 mg Q AM and 10 mg Q PM x gt 1 week, then
• 10 mg BID
• Dosing ER caps
• 7 mg Q Day x gt 1 week, then
• 14 mg Q Day x gt 1 week, then
• 21 mg Q Day x gt 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

92
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

93
Principles for memantine
94
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

95
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

96
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

97
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
  ß-Amyloid plaques in patients with mild AD
• No positive clinical studies linking improvement
  in cognition with statins

98
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

99
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

100
Potential Treatments in Research

• ?-Secretase Inhibitors
• e.g. Semagecestat
• Phase III IDENTITY Study showed negative
  outcome
• Anti ß -Amyloid Agents
• e.g. Solanezumab
• Currently Phase III EXPEDITION Study

101
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 -

102
Treatment of Behavioral psychotic symptoms of
dementia (BPSD)
103
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

104
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

105
Non-Pharmacologic Interventions

• Music
• Aromatherapy
• Bright lights
• Massage / touch
• Validation
• Reminiscence
• Establish routine for meals, bedtime, etc.

106
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

107
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 _at_ toilet and shower
• Nightlights

108
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109
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)

110
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

111
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

112
Wandering

• Identify triggers (boredom, hunger, thirst, etc.)
• Whats 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

113
Wandering

• Cover / disguise doors and exits
• Locks on doors
• Alzheimers Association MedicAlert Safe Return
• GPS tracker / band

114
Physical and/or Verbal Agitation

• Cohen-Mansfield Four categories of agitation
• 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

115
Sleep Disturbances

• Prevalent in dementia patients
• Can include hypersomnia, insomnia, sleep-wake
  cycle reversal, fragmented sleep, daytime
  napping, night-time awakenings

116
Sleep Disturbances

• Assessment
• Depression
• Fear
• Pain
• Meds that ? insomnia / incontinence
• Interventions
• Adult day care
• Warm milk / high carb snack
• Melatonin

117
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

118
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

119
Psychotic Symptoms

• Hallucinations vs. Perceptual Differences
• Visual / auditory / tactile hallucinations
• Hallucinations more common with Lewy Body
• Rule out other causes
• Hearing aids
• MRPs
• Infections

120
AD vs. Vascular Dementia

• Alzheimers Dementia
• Similar rates of psychotic sx
• Slow, steady decline

• Vascular Dementia
• Higher prevalence / severity of depression
• Less aberrant motor behaviors
• Executive functioning more impaired
• Patient aware of deficits
• Gait disorders

121
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

122
Fronto-Temporal Lobe Dementia

• AKA Picks 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)

123
Pharmacologic interventions for bpsd
124
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

125
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

126
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

127
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

128
Antidepressants

• SNRIs
• Avoid if s/e are problematic with patient hx
• Mirtazapine
• Promotes sleep _at_ lower doses
• Can improve appetite, weight gain
• Trazodone
• Useful _at_ HS ? sedation or in daytime if agitation

129
Sedative / Hypnotics

• Zaleplon (Sonata) / zolpidem (Ambien) ramalteon (
  Rozerem)
• Can be used safely in elderly
• Monitor for daytime sedation, dizziness, falls

130
Diphenhydramine

• Avoid use for anxiety, sleep, etc.
• Beers Criteria
• Drug-drug interaction (with ChEIs)
• Drug-disease interaction (w AD)

131
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)

132
Guideline for Alzheimers Disease Management. CA
workgroup on Guidelines for Alzheimers Disease
Management
133
From Efficacy and Comparative Effectiveness of
Atypical Antipsychotic Medications for Off-Label
Uses in Adults  A Systematic Review and
Meta-analysis
JAMA. 2011306(12)1359-1369. doi10.1001/jama.201
1.1360
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.
134
From Efficacy and Comparative Effectiveness of
Atypical Antipsychotic Medications for Off-Label
Uses in Adults  A Systematic Review and
Meta-analysis
JAMA. 2011306(12)1359-1369. doi10.1001/jama.201
1.1360
135
From Efficacy and Comparative Effectiveness of
Atypical Antipsychotic Medications for Off-Label
Uses in Adults  A Systematic Review and
Meta-analysis
JAMA. 2011306(12)1359-1369. doi10.1001/jama.201
1.1360
136
Typical APs

• Avoid 2 cardiac / EPS / TD
• TD seen in 50 of elderly after 2 years use

Guideline for Alzheimers Disease Management. CA
workgroup on Guidelines for Alzheimers Disease
Management
137
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

138
Guideline for Alzheimers Disease Management. CA
workgroup on Guidelines for Alzheimers Disease
Management
139
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

140
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

141
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