Tonja M. Woods, PharmD, CGP
Wyoming Geriatric Education Center
March 26, 2013

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Dementia General term for cognitive impairment
Characterized by impairment of memory and at least one other cognitive domain
• Aphasia
• Difficulty remembering words → unable to speak, read, or write
• Apraxia
• Unable to do task when asked when willing
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• Agnosia
• Unable to recognize things prior to there being significant
‘memory loss’
Executive function
• Loss of ability to plan, problem solve, memorize things

• Alzheimer ’ s disease (AD) is the most common form
• Other major types:
• Vascular dementia
• Mixed
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Lewy body dementia
• Parkinson ’ s dementia
Frontotemporal dementia
• Reversible dementias

• CNS Disorders
• Adjustment disorder
• Amnestic syndrome
• Delirium
• Depression/mental illness
• Drugs & toxins
• Alcohol
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Antihypertensives
Anxiolytics/sedatives
CNS depressants
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Anticholinergics
Hypoglycemics
• Heavy metals
• Intracranial causes
• Systemic Illness
• Cardiovascular disease
• Deficiency states
• Vitamin B12, folate
• Infection
• Metabolic disorders
• Hypothyroidism
• Hypoglycemia
• Tumors
• Subdural Hematoma

• Cognitive complaints insufficient to warrant a diagnosis of dementia
• Gateway between normal cognition, normal cognitive aging, and dementia
• Includes…
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• cognitive complaint objectively impaired neuropsychological test performance, and… essentially intact ADLs
• Carries a 10-15% chance per year of progressing to AD diagnosis

CBC with sed rate
Serum electrolytes
BUN, SCr
Bilirubin
Thyroid function
Iron, B12, folate
Anemic anoxia, infection, neoplasm
Hyper/hyponatremia, renal function
Renal function
Hepatic dysfunction
Hyper/hypothyroidism
Deficiency states, anemia
Stool occult blood
Syphilis serology
UA
Chest x-ray
ECG
Blood loss, anemia
Neurosyphilis
Infection, proteinuria
Neoplasm, infection, airway disease
Cardiac disease
Brain scan Cerebral tumors, cerebrovascular disease
Depression screen Depression, pseudodementia
Mental status exam General cognitive screen

• “ Amyloid cascade hypothesis ”
• Deposition of amyloidβ peptide in the brain
• Neuritic plaques
• Patches found in the brain; amyloid protein within the center of plaque
• Neurofibrillary tangles
• Twisted pieces of protein called ‘tau’; disrupts normal cell function
• Neurotransmitter abnormalities
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• ↓ Acetylcholine (ACh) synthesis
↑ Glutamate

Cognitive Changes
• Memory loss
• Aphasia
• Apraxia
• Agnosia
• Disorientation
• Impaired executive function
Functional Changes
• Inability to care for self
(ADLs)
Non-cognitive Changes
• Depression, psychotic symptoms
• Behavioral disturbances
• Wandering
• Agitation/aggression
• Motor hyperactivity
• Uncooperativeness
• Combativeness
• Repetitive mannerisms and activities

ADLs
• Bathing
• Dressing
• Transferring from bed or chair
• Walking
• Eating
• Toilet use
• Grooming
Complex ADLs
• Telephone use
• Shopping
• Cleaning
• Using TV/Radio

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Mini-Mental State Examination
(MMSE) and Montreal
Cognitive Assessment (MoCA)
Most common tools used
• Developed for rapid screening to identify cognitive dysfunction
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• Can be performed during office visit
Clinician ’ s Interview-Based
Impression of Change (CIBIC)
Clinician ’ s assessment of a patient based on a comprehensive interview
(may involve caregiver)
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Global Deterioration Scale
(GDS)
Assesses cognitive functional decline in stages

• Stage of Decline
• No cognitive decline
• Features
• Normal cognitive state
• Very mild cognitive decline
• Mild cognitive decline
• Moderate cognitive decline
• Forgetfulness, subjective complaints only; no objective decline
• Objective decline through psych testing; work/social impairment; mild anxiety and denial
• Concentration, complex skills decline; flat affect and withdrawal

• Stage of Decline
• Moderately severe cognitive decline
• Features
• Early dementia; difficulty in interactions; unable to recall or recognize people or places
• Severe cognitive decline
• Very severe cognitive decline
• Requires assistance with bathing, toileting; behavioral symptoms present
(agitation, delusions, aggressive behavior)
• Loss of psychomotor skills and verbal abilities; incontinence; total dependence

…No known cure
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Treat cognitive difficulties
Maintain patient ’ s function as long as possible
Minimize adverse effects of medications
Treat behavioral and psychiatric complications
• appropriately
• Agitation
• Depression
Reduce caregiver burden

• Consider vision, hearing, and other sensory impairments
• Keep requests, demands and tasks simple
• Avoid confrontation
• Redirect activities to divert patient from problematic situations
• Remain calm, firm, and supportive
• Keep environment consistent and safe
• Use lighting to reduce confusion at night

• Provide frequent reminders and cues
• Predictable routine
• Adjust expectations as patient declines
• Notify healthcare provider in event of changes
• Exercise as a treatment modality
• Been shown to improve physical health, depression, and quality of life in patients with AD
• Traditional interventions require communication abilities that may be compromised in the patient with AD
• Animal studies show decrease in amyloid plaques

• Mental stimulation
• A lot of evidence suggests that exercising the mind reduces the chances of developing AD and other forms of dementia related to old age
• Chess, cards, crossword puzzles, musical instruments, etc.
• Provide NEW mental challenges as well
• May be hard to implement in the elderly

• Ideally would have…
• Resolution of symptomatic effects
• Reverses symptoms by enhancing cognitive function
• Disease-modifying effects
• Halt neurodegenerative-relevant molecular processes
• Minimal adverse effects and drug-drug/drugdisease interactions

• Cholinesterase Inhibitors
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• Donepezil Aricept®
Rivastigmine Exelon®
Galantamine - Razadyne ®
• NMDA Receptor Antagonist
• Memantine Namenda®

• Mild-moderate AD
• Donepezil Aricept®
• Rivastigmine Exelon®
• Galantamine - Razadyne ®
• Moderate-severe AD
• Donepezil Aricept®
• Memantine Namenda®

• Mechanism Of Action (MOA):
• Blocks the breakdown of a chemical in the brain called acetylcholine
• ACh is involved in remembering things and thinking clearly
• 1 in 12 patients improve
• No way to predict beneficial time frame
• Most frequent adverse effects are mild to moderate gastrointestinal symptoms
• Nausea, Vomiting, Diarrhea
• Increase dose slowly

• Dose: 5 – 10 mg daily, 23mg daily
• MOA: blocks breakdown of acetylcholine, therefore, increasing levels of ACh in brain
• Adverse effects:
• N/V, diarrhea, anorexia, dizziness, weight loss
• Drug Interactions:
• Minimal
• 1 st line therapy
• Best tolerated
• *Approved for severe AD dementia

• Dose:
• Oral: 1.5 mg twice daily, ↑ to 3-6 mg twice daily
• Take with food
• Transdermal Patch: 4.6, 9.5, 13.3 mg/day
• MOA: inhibits acetyl- and butyrylcholinesterase
• Adverse Effects:
• N/V, anorexia, fatigue, dizziness
• Drug Interactions: Few
• No adjustments necessary for kidney or liver impairment
• Indicated for Parkinson’s dementia

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• Dose: 4 mg twice daily, ↑ to 12 mg twice daily (ER – once daily)
• Take with food
• MOA: selective, competitive, reversible ACh inhibitor, enhances action of acetylcholine on nicotinic receptors
Adverse Effects:
• N/V, diarrhea, anorexia, weight loss
DI:
• Few
Caution in severe kidney & liver impairment
Formerly named “Reminyl”

• As dose ↑, acetylcholinesterase inhibition ↑
• Increase dose in 4 week intervals as tolerated to minimize gastrointestinal adverse effects
• Switching between agents is not recommended unless patient is not tolerating initial agent
• Avoid interruptions, especially longer than 3 weeks
• 4-point improvement on ADAS-cog considered clinically significant change
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Considered a reversal of progression of disease symptoms by 6 months
Change in MMSE has more clinical usefulness

• Dose: 5 mg/day, ↑ weekly to 20 mg/day in 2 divided doses
• MOA: blocks a brain receptor that is thought to add to the cellular harm associated with AD (glutamate)
• ? neuroprotection
• Adverse Effects: similar to placebo
• GI complaints, confusion, dizziness, headache, hallucinations
• DI:
• Clearance ↓ by 80% when urinary pH >8; caution with carbonic anhydrase inhibitors, sodium bicarbonate
• “improves additional benefit on cognitive/behavioral symptoms” -

• Estrogen
• Not recommended due to possible cardiovascular risk
• Anti-inflammatory agents
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NSAIDs, prednisone
– not recommended, adverse effect potential
COX-2 inhibitors
– not recommended
• Statins
• Lower prevalence associated with pravastatin and lovastatin
• Atorvastatin currently being studied
• Association with cognitive impairment as an adverse effect?
• Simvastatin and lovastatin
• Homotaurine
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• Derived from red algae
Proposed to decrease amyloid plaque in the brain
• Continued studies

• Vitamin E
• Role in treatment only, not proven in prevention
• Do not use doses > 400 IU/day
• Gingko biloba
• 120-240 mg/day of standard leaf extract twice daily may be used early on when decrease in cognitive function is noted
• 2 year study (published Sept 2012 – Lancet), NO decreased risk in progression
• Current practice guidelines do not recommend use in AD
• Huperzine A
• Alkaloid isolated from Chinese club moss
• Similar to gingko, issues arise with long-term use and standardization

• Vitamin D
• Latest studies show that patients with AD had lower levels vs. those without AD
• “Neurosteroid”
• Treatment or Prevention?
• VITAL study (NIH)
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5 years, 20,000 people
Vitamin D & Omega fatty acids – do they affect various aspects of health, including cognition? Standardize testing?

• Aspirin
• October 2012: observational study of 489 women (70-92 yo) showed those on ASA were less likely to show decline on MMSE
• Citicoline
• Supplement marketed to “help memory in patients with vascular mild cognitive impairment and may hinder cognitive deterioration”
• Originally developed in Japan for stroke
• Increases phosphatidylcholine in the brain

• High concentration of medium chain triglycerides
• Alternative source of fuel for the brain
• Marketed for mild to moderate AD
• No clinical testing
• $85/month
• 120cal & 12g sat fat/packet
• Coconut Oil
• Blend of short and medium chain TG
• Caprylic Acid
• Found in Axona

• Solanezumab
• Monoclonal Antibody
• Labproduced molecule that mimics the antibodies in one’s body, designed to produce as if part of one’s normal cellular make-up and can help block amyloid formation
• Phase 3 trial data shows promise in slowing progression of cognitive decline but not functional decline
• Bexarotene - Targretin ®
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• Currently on the market for the treatment of skin cancer
Effective in animal study at removing large amounts of amyloid from the brain
• Further investigation needed in humans
• ~$2500/month if approved

• Angiotensin Receptor Blockers (ARBs)
• 890 patients, reduced amyloid deposition in the brain
• Improve cognitive function
• Study-design needs improvement

• Decision must be individualized – often a family decision
• Assess the following:
• Quality of Life
• Treatment Goals
• Potential Benefit
• Adverse Effect
Potential

PROS
• 1 in 12 benefits
• Sets the ‘cognition clock’ back by ~6 months
• Patient feels empowered
• Family is encouraged / feels “peace of mind”
CONS
• 1 in 12 benefits
• 1 in 12 experiences AE
• Does not slow rate of disease progression
• Not proven to reduce need for nursing home placement
• Cost vs. Benefit

• Quality of life is poor
• Adverse effects are intolerable
• Gastrointestinal side effects
• Cardiac side effects
• Bradycardia
• If improvement is not observed within 3-6 months or with dose titration
• When slowing disease progression is no longer a goal
• i.e. Severe impairment, Rapid decline
• As disease progresses, nonpharmacologic interventions become more important

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• Psychotic symptoms
• Psychosis
• Delusions
• Hallucinations
Depression
• Disruptive behavior
• Agitation
• Aggression
• Hyperactivity
• Hypervocalization
• Disinhibition

• AChI and Namenda® have been shown to have small to modest benefit
• Small beneficial effect on caregiver burden and active time use among caregivers of patients with AD
• Nonpharmacologic modalities should be tried first before using other treatments

• Atypical Antipsychotics
• May be useful for particular neuropsychiatric symptoms, but no indication for management of behavioral symptoms in AD
• Seroquel, Risperdal, Zyprexa, Abilify, Saphris, Geodon,
Fanapt, Invega, Latuda, Clozaril
• Adverse effects can be significant and common
• Somnolence, extrapyramidal symptoms, abnormal gait, worsening cognition, cerebrovascular events, and increased risk of death
• 2-fold higher mortality rate vs. placebo in elderly
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Cardiovascular causes
• Infectious causes

• Others
• Benzodiazepines
• Xanax, Ativan, Valium, Halcion
• Anticonvulsants
• Carbamazepine
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Valproic Acid
Lamotrigine
• Buspirone
• Selegiline

• Occurs in about 50% of patients with AD, but could be more because of difficulty with diagnosis
• SSRIs most commonly recommended
• Prozac, Zoloft, Celexa, Lexapro, Paxil
• SNRIs an alternative
• Effexor, Pristiq, Cymbalta, Savella
• Avoid agents with anticholinergic activity

• Approximately 60% of patients with AD have 3+ comorbidities
• Increased risk for poly-pharmacy and drug-drug interactions
• Prevent Medication Related Problems!!!
• Need for interdisciplinary care team!
• Patient-Centered Medical Home

• Caregiver burden is a huge component of AD management
• 75% of care is provided by family and friends
• Greatest financial cost of AD is institutionalized care
• Understand the resources that are available for your patients…and their caregivers!

• Alzheimer ’ s Association
• www.alz.org
(general information)
• www.alz.org/Care/overview.asp
(for caregivers)
• American Health Assistance Foundation
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• www.ahaf.org/alzdis/about/adcare.htm
Alzheimer ’ s Foundation of America
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• http://www.alzfdn.org/
Mayo Clinic – AD information
• http://www.mayoclinic.com/health/alzheimers/AZ99999
• Clinical Trials about Alzheimers
• http://clinicaltrials.gov/ (Search: Alzheimers)