THE FACES OF ALZHEIMERS DISEASE SELF-PORTRAITS BY WILLIAM UTERMOHLEN

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UNDERSTANDING ALZHEIMERS DISEASE

GOOD WAYS TO HAVE GOOD DAYS

Candice Abrams Flautt, PharmD

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OBJECTIVE UNDERSTAND THE PROCESS AND MANAGEMENT OF ALZHEIMERS DISEASE

Identify

the structural brain abnormalities implicated in the pathophysiology of AD Expand on the resultant cognitive and behavioral changes Discuss in detail the current known treatment options for Alzheimers Disease, and address hypothesized therapies Identify potential tests to predict Alzheimers disease Determine the practioners role in Alzheimers Disease

THE ORIGINS OF ALZHEIMERS DISEASE

Dr.

Alois Alzheimer, a German physician 1901 case study of woman in 50s suffering from mental illness
Symptoms

: memory loss, language problems, and unpredictable behavior Autopsy after death in 1906 revealed dense deposits (neuritic plaques) outside and around nerve cells in brain Inside cells were twisted strands of fiber (neurofibrillary tangles, NFTs)

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POPULATION INFORMATION

Prevalence 1 in 8 persons age >65 Lifetime risk: Women > men

1 in 6 vs 1 in 10

Among top 10 leading causes of death for all ages

6th leading cause of death in U.S. 2009

Risk Factors Age >65 yo

Risk increase 2-fold every 5 years Head trauma, Hearthead connection, lack of mental stimulation APOE e4, PXDH11X ** Familial AD (minor, <5%) vs sporatic AD

Life Exposure Factors

Genetics

PATHOPHYSIOLOGY OF ALZHEIMERS DISEASE

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PROGRESSIVE CEREBRAL WASTING

NEURITIC PLAQUES

Abnormal processing of amyloid-beta proteins (APP) Cleaveage by betasecretase on the amino end & gamma-secretase on the carboxy end Highly amyloidogenic Abeta42 protein which aggregates into diffuse plaques Presence of neuritic plaques begins a secondary cascade of inflammatory events causing additional damage (excitotoxicity, apoptosis)
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AMYLOIDBETA42

The Alzheimer's Disease Cholesterol Protein normally present in blood and cerebrospinal fluid Also found to make up plaques in AD Mayo Clinic in Jacksonville working on a test that correlates high levels with increased risk of AD Steven Younkin, MD, PhD Michael Hutton, PhD

NEUROFIBRILLARY TANGLES (NFTS)

NFTs consist of hyperphosphorylated form of microtubule-associated protein, tau Cleaved tau proteins are critical to NFT formation Murine studies suggest the mutant tau protein primarily initiates neurotoxicity rather than the NFTs NFTs more closely correlate with cognitive decline than neuritic plaques caused by amyloid deposition

LINKING NEURITIC PLAQUES WITH NFTS

Determining

a link between neuritic plaques and

NFTs
Proposed Evidence

link: Cysteine aspartyl proteases (capases), known initiators of apoptosis

suggests A-beta protein accumulation activates capases, and Capases induce the cleavage of tau
It

is this process that is thought to begin early in AD, and initiate the progressive cognitive decline

PLAQUES CAUSING BIG IMPACT

27

Feb 2009 from BBC News Dr. Kishore Kuchibhotla from MassGeneral Institute for Neurodegenerative Disease
Confirms

plaques are known to damage neurons Hypothesizes plaques impact astrocyte cells
Once

thought to be passive support, now discovered to send own chemical signals across long distances
Presence of plaques increases signaling of astrocyte cells Synchronized wave-like fashion to distant areas of the brain

Possibility

for new target for drugs to treat Alzheimers Disease

THE COGNITIVE AND BEHAVIORAL MANIFESTATIONS OF ALZHEIMERS DISEASE

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THE FOUR AS OF ALZHEIMERS DISEASE

Amnesia
Memory

A phasia
Impaired

loss, initially short-term progression to long term

(i.e.: loss of recognition of familiar people, places, and events)

or absent comprehension, or performance of communication

(speech, writing, understanding writing)

Agnosia
Impaired

A praxia
Disorder

ability to recognize familiar objects or correctly interpret various stimuli

(i.e.: comprehending the difference between a toaster and a wristwatch)

of voluntary movement; impairment of purposeful movements requiring skill or dexterity

(i.e.: doorknobs, opening mail, brushing teeth)

STAGES OF ALZHEIMERS DISEASE

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STAGES OF ALZHEIMERS DISEASE

Mild / Early Stage Physical changes
Loss

of hippocampal neuronsloss of short term memory

Presentation Passive

mood, forgetful of familiar places, trouble with recent events, lost understanding of concepts of money/mathematics; denial Daily activities not greatly affected

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STAGES OF ALZHEIMERS DISEASE

Moderate / Middle Stage Physical changes
Neuronal

loss spreads to frontal lobeaffects judgment, safety awareness, planning, and other complex thinking

Presentation Difficulty

with routine tasks (brushing teeth), mistaken identity, trouble with language/cognition Daily activities significantly affected

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STAGES OF ALZHEIMERS DISEASE

Severe / Late Stage Physical changes
Neuronal

loss spreads covering larger area of brain affects multiple functions of the brain (i.e. both cognitive and motor)

Presentation Wander,

forgotten identity, speechless, movement disorders, behavior symptoms Very SevereLoss of psychomotor skills (swallowing), choking, incontinence Require complete care from care-giver

THERAPEUTIC GOALS FOR ALZHEIMERS DISEASE

Patient
Slow

Caregiver
Decrease

disease progression
Cognitive

burden, time,

morbidity
~10

Preserve memory and executive functioning

Behavior ADL

Toileting, washing, clothing, cleaning, cooking

million Americans provide unpaid care for a person with AD or another dementia In 2009, AD cost the U.S. 148 billion USD in annual costs

Delay

nursing home placement

TREATMENT GOALS FOR PATIENTS WITH ALZHEIMERS DISEASE

Evaluate Rule

for medication initiation

out delirium of correctable etiology baseline cognitive function

i.e. infection, dehydration, medications, etc. Brain imaging, MMSE, assess ADLs, etc.

Establish

Treatment Nonpharmacological

CBT (cognitive behavioral therapy) Support

Pharmacological

MMSEMINI MENTAL STATE EXAM

Most common exam used to evaluate AD Provides a score about a persons general level of impairment Takes 5 to 10 minutes Assesses 5 areas: Orientation Short-term memory (retention) Attention Short-term memory (recall) Language

Scoring (may differ slightly) Maximum score: 30 2430: normal range 2023: mild cognitive impairmant or possible early-stage/mild AD 1019: middlestage/moderate AD 09: late-stage/severe AD

MMSE

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PHARMACOLOGICAL THERAPEUTIC OPTIONS

Known

treatments

Cholinesterase

inhibitors NMDA (n-methyl-D-aspartate) receptor antagonists

Adjunctive

treatments

Antidepressants,

anxiolytics, antipsychotics, mood stabilizers/seizure medications, vitamin E, sleep medications, alternative treatments

Hypothesized NSAIDS,

treatments

lithium, supplements (ginkgo biloba, etc.)

CHOLINESTERASE INHIBITORS
Alzheimers

disease is a disease of diminishing acetylcholine (ACh)

Acetylcholinesterase

enzyme responsible for breaking

down acetylcholine
Cholinesterase Reduce

inhibitors

breakdown of choline in remaining neurons

Can preserve cognition Cannot protect neurons from degeneration

Useful Aricept

for mild-moderate AD

(donepezil), Exelon (rivastigmine), Razadyne (galantamine), Cognex (tacrine)

CHOLINESTERASE INHIBITORS

Start earlycant regain lost function and memory Duration of treatment 6 months to determine therapeutic failure Total duration unknown (experience shows 4-6 years) Interruptions kept as short as possible (lost ground) Switching drugs Possible additional benefit for cognitive function (no way to predict response) Class AEs: N/V/D are most common Headache, high blood pressure, dizziness, indigestion/heart burn, joint pain, muscle cramping Class drug interactions Anticholinergics (Ditropan)

ORAL CHOLINESTERASE INHIBITORS

Aricept
Class AD Impairment Route Affected by food MOA Time to peak effect T Metabolism Excretion Preserve cognition Dosing frequency ChE-I All stages By mouth No Reversible & non-competitively inhibits central ACHase 3-4h 70h Hepatic (2D6, 3A4) Urine (57%) 6-9mo Bedtime Initial: 5mg/d 10mg/d after 4-6wks Works centrally > peripherally, so less SEs

Exelon
ChE-I Mild-moderate By mouth, transdermal Yes; tolerability increases w/food Reversibly inhibits central ACHase Oral: 1h Patch: 10-16h ( 1st dose) Oral: 1.5h; Patch: 3h Nonhepatic Urine (97%) 6-12mo Oral: twice a day; Patch: once a day Oral: 1.5mg BID, inc 3mg/d q 2wks, max=6mg BID; Patch: 4.6mg/24h, inc to 9.5mg/24h Central activity, low activity peripherally; Less SEs with patch

Razadyne
ChE-I Mild-moderate By mouth Yes Reversible & competitively inhibits central ACHase IR: 1-2.5h ER: 4.5-5h 7h Hepatic (2D6, 3A4) Urine (25%) 9mo IR: twice a day; ER: once a day IR: 4mg BID, 8mg, 12mg x4wks, max 24mg/d ER: 8mg QD, 16mg QD x4wks, max 24mg QD nicotinic receptor agonist to inc ACH from surviving presynaptic nerve terminals

Dose

Specific Details

TRANSDERMAL ACETYLCHOLINESTERASE INHIBITORS

Exelon Patch

Benefits Once daily application Peripherally metabolized so less side effects Visual confirmation that dose was given Transdermal

No tiny pill No swallowing requirements No food requirements

28-week extension to 24-week safety and tolerability study demonstrated well-tolerated, favorable safety profile
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NMDA RECEPTOR ANTAGONISTS

Glutamate

is thought to be a potential neurotoxin

Glutamate

demonstrates effect after binding at the NMDA receptor

NMDA Can

(n-methyl-D-aspartate) receptor blocker

preserve cognitive, social, and motor impairment for moderately-severe to severe AD

Cannot protect neurons from degeneration Post-Marketing Study of 6-months (N=451) revealed similar results to previous RCT

Evidence

Namenda

(memantine)

NMDA RECEPTOR ANTAGONISTS

1st for moderate-severe AD Used alone or in conjunction with Aricept (AChE-I) Requires titration to maintenance dose Class AEs: Well tolerated Dizziness, confusion, headache, constipation, HTN, cough Class drug interactions: Sodium bicarbonate, amantadine (Symmetrel)

Namenda
Class Impairment Route Affected by food MOA Peak effect T Metabolism Excretion Frequency Dose Specific Details NMDA receptor antagonist Moderate-severe By mouth No Noncompetitive antagonist at n-methyld-aspartate receptor 3-7h 60-80h Nonhepatic Urine (5782% unchanged) Twice a day Initial 5mg/d, inc by 5mg/d x1week; max 20mg/d (10mg BID) Binds to intra-pore Mg-site w/longer dwell time decreases ion channel only during excess stimulation

ADJUNCTIVE TREATMENTS
Antidepressants Low Anxiolytics Anxiety,

mood & irritability Celexa, Prozac, Paxil, Zoloft, Desyrel

Antipsychotics Hallucinations,

restlessness Ativan, Serax

Seizure

medication / mood stabilizer

Tegretol,

hostility, delusions, aggression, agitation Abilify, Clozaril, Haldol, Zyprexa, Seroquel, Risperdal, Geodon
Sleep

Depakote

Vitamin

Antioxidant

proposed to protect nerve cells not a treatment

Medications

Alternative

Treatments

PREVENTATIVE/HYPOTHESIZED STRATEGIES
Management

of cardiovascular risk factors

High

Non-Steroidal

AntiInflammatory Drugs

cholesterol Type 2 diabetes High blood pressure Overweight

Maintain More

Lithium Glycogen

synthase kinase-3 (GSK-3)

Supplementation Ginkgo

mental acuity

years of education cognitive reserve Use it or lose it!

biloba, SAMe, PUFA, Folic Acid, Axona Low fat diet rich in fruits and vegetables

ALZHEIMERS PIPELINE BAPINEUZUMAB

AAB-001,

made by Elan and Wyeth Passive vaccine delivers antibodies against betaamyloid in patients with mild to moderate AD Currently in Phase 3 trials
2.0

mg/kg, 1.0 mg/kg, 0.5mg/kg, placebo APOE e4 carriers, non-carriers Largest clinical program in AD (N~4,000)
Wyeth

report 2 April 2009

Discontinuing

the 2.0 mg/kg dose in two ongoing Phase 3 studies for APOE e4 non-carriers 0.5 mg/kg and 1.0 mg/kg doses will continue as planned

PREDICTIVE TESTS
SPECIFIC GENE THAT CAUSES ALZHEIMERS DISEASE HAS NOT BEEN IDENTIFIED

APOE E4
Scientists

believe 4 to 7 AD risk-factor genes exist and are using a new approach called a genomewide association study (GWAS) One risk factor gene:
Apolipoprotein

E gene found on chromosome 19

Contains instructions necessary to make a protein that is involved in transporting cholesterol in the bloodstream APOE e2, APOE e3, APOE e4
Odds

ratio for two copies: 11.5 Odds ratio for one copy: 4.8 Blood test identifies the APOE alleles a person has
Cannot

predict if a person will develop AD or not

Only indicates risk

SORL1
14

January 2007 online ed. of Nature Genetics, study implicates gene SORL1 in late-onset Alzheimers Disease SORL1Sortilin-related, low-density lipoprotein receptor class A repeat-containing protein
Gene

involved in cellular sorting process for APP

Researchers

found that when SORL1 is present at low levels or in a variant form, beta-amyloid levels increase and may harm neurons Association with AD has been identified and confirmed in three separate studies

PCDH11X

11 January 2009 online ed. of Nature Genetics, report of 2stage genome-wide association study Steven Younkin, MD, PhD, consultant-researcher George M. Eisenberg, Professor of Neuroscience in the College of Medicine at Mayo Clinic in Jacksonville, FL Scanned entire genome of 844 Alzheimers patients, 1255 control subjects Findings: women who inherited 2 copies of variant in PCDH11X gene, on chromosome x, are at greater risk of developing Alzheimers Disease Odds ratio for women with two copies: 1.75 Odds ratio for women with one copy: 1.26 Odds ratio for men with one copy: 1.18

PRACTITIONERS ROLE IN ALZHEIMERS DISEASE

Identification Treatment must be started earlyidentify those needing evaluation Inform that dementia is not a normal part of aging Let patients known that medications are available Intermediary We are the most readily available health care provider Serve as a liaison between patients and doctors (efficacy, side effects, dosage forms, etc.) Ensure patients go to appointments, get refills on time Support We can help with medication administration (spreadsheet, calendar, pill boxes, reminders/alarms) Unique opportunity to develop close contact with patients and gain their confidence

PRINCIPLES FOR A DIGNIFIED DIAGNOSIS

Written by persons with dementia

Talk to me directly, the person with dementia Tell the truth Test early Take my concerns seriously, regardless of my age Deliver the news in plain, but sensitive language Coordinate with other care providers Explain the purpose of different tests and what you hope to learn Give me tools for living with this disease Work with me on a plan for healthy living Recognize that I am an individual, and the way I experience this disease is unique Alzheimers is a journey, not a destination

REFERENCES

2007: The Year in Alzheimer Science. Alzheimers Association. 2009. 2009 Alzheimers Disease Facts and Figures. Alzheimers Association. Alzheimers & Dementia, Volume 5, Issue 3. Alzheimers Disease Genetics Fact Sheet. Alzheimers Disease Education & Referral (ADEAR) Center, A Service of the National Institute on Aging National Institutes of Health U.S. Department of Health and Human Services. NIH Publication No. 08-6424. November 2008. www.nia.nih.gov/Alzheimers Alzheimers plaques big impact. BBC News. Published 27 Feb 2009. news.bbc.co.uk/go/pr/fr/-/2/hi/health/7910513.stm Clerici F, Vanacore N, Elia A, et al. Memantine in moderately-severe-to-severe Alzheimers disease: a postmarketing surveillance study. Drugs Aging. 2009;26(4):32132. DeKosky S, Williamson J, Fitzpatrick A, et al. Ginkgo biloba for Prevention of Dementia: A Randomized Controlled Trial. JAMA. 2008;300(19):2253-2262. Guideline for Alzheimers Disease Management. California Workgroup for Alzheimers Disease Management. Final Report 2008. California Version. April 2008. Grossberg G, Sadowski C, Frostl H, et al. Satety and tolerability of the rivastigmine patch: results of a 28-week open-label extension. Alzheimer Dis Asooc Disord. Apr-Jun 2009;23(2):158-64.

REFERENCES

Hampel H, Ewers M, Burger K, et al. Lithium trial in Alzheimers disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry. Jun 2009; 70(6):922-31. Holt J, Stiltner L, Wallace R. Clinical inquiries. Do patients at high risk of Alzheimers disease benefit from early treatment? J Fam Pract. Jun 2009;58(6):320-2. Mayo Clinic Researches Find that Variants in a Gene on the X Chromosome are Associated with Increased Susceptibility to Alzheimers Disease. Mayo Foundation for Medical Education and Research. Accessed 14 January 2009. www.mayoclinic.org Panza F, Frisardi V, Capurso C, et al. Polyunsaturated fatty acid and Sadenosylmethionine supplementation in predementia and Alzheimers disease: a review. Scientific World Journal. May 2009;9:373-89. Shadien M-F, Larson E. Dementia Syndromes. UpToDate. Updated 7 January 2008. What is the Mini Mental State Exam? How the Mini Mental State Exam is Used in the Diagnosis of Alzheimers Disease. Alzheimers Disease. Hill, Carrie PhD. Updated 29 July 2008. alzheimers.about.com

ALZHEIMERS DISEASE MYTHS

Memory

loss is a natural part of aging Alzheimers Disease is not fatal Only older people get Alzheimers Disease Drinking from aluminum cans or using aluminum pots can cause Alzheimers Disease Aspartame causes memory loss Flu shots increase the risk of developing Alzheimers Disease Silver dental fillings increase the risk of developing Alzheimers Disease Treatments are available to stop the progression of Alzheimers Disease

MORE ALZHEIMERS DISEASE INFORMATION

World

Alzheimers Day is 21 September, originally launched in 1994 Alzheimers Disease International

Organization

of 71 Alzheimers Disease Associations around the world, in conjunction with the WHO www.alz.co.uk
2007:

The Year in Alzheimers Disease Science