Alzheimers Disease

http://a.abcnews.com//images/GMA/alzheimers

Melissa Whitehouse PharmD Candidate 8/1/2013

Learning outcomes
Identify the pathophysiology associated with Alzheimers Disease (AD) Identify the criteria to diagnose a patient as having probable AD Be able to identify symptoms associated with AD and classify by severity Identify medications approved for use in AD Identify mechanisms currently targeted in upcoming medications for use in AD

Background and epidemiology

Dr. Alois Alzheimer in 1906 discovers abnormalities in brain of woman who died of strange mental illness
Clumps: amyloid plaques Bundles of fibers: neurofibrillary tangles

Today: 5.1 million Americans Percentage will continue to increase: number of people >65 years and older is expected to double between 2010 and 2050 increases in the number of cases of Alzheimers Disease Most common cause of dementia Average survival length is 10 years
http://www.nia.nih.gov/alzheimers/topics/alzheimers-basics Jorm AF, Jolley D. The incidence of dementia: a meta-analysis. Neurology. 1998;51(3):728.

Pathophysiology
Amyloid plaques Neurofibrillary tangles Loss of connection between neurons Progressive, irreversible damage resulting in decreased mental function

http://www.nia.nih.gov/alzheimers/topics/alzheimers-basics

Pathophysiology
http://www.nia.nih.gov/alzheimers/alzheimer s-disease-video

http://www.nia.nih.gov/alzheimers/alzheimers-disease-video

Risk factors
Age Women > men Family history Genetic factors Diabetes Hyperlipidemia Smoking
Jorm AF, Jolley D. The incidence of dementia: a meta-analysis. Neurology. 1998;51(3):728.

Symptoms
Cognitive symptoms
Amnesia Anomia Aphasia Agnosia Apraxia

Neuropsychiatric symptoms
Apathy Withdrawal Depression Agitation Aggression Psychosis

http://www.alzfdn.org/AboutAlzheimers/symptoms.html Mendez MF, et. al. Am J Alzheimers Dis Other Demen. 2012 Sep;27(6):413-20.

Stages of AD
Preclinical Mild cognitive impairment (MCI) due to AD
Minor changes in memory and cognition May have minor difficulty with recalling conversations, appointments, and also with allotting time needed for tasks

Dementia due to AD
Mild, moderate or severe
http://www.nia.nih.gov/alzheimers/topics/symptoms

Stages of AD
Mild dementia due to AD
Memory loss
Ex. Repeatedly ask same question

Difficulty problem solving

Ex. Balancing a checkbook

Changes in personality
Withdrawn, depressed, angry, reduced attention

Unable to express themselves Misplacing objects Getting lost Most patients diagnosed in this stage Mini-Mental State Examination (MMSE) 20 to 26
http://www.nia.nih.gov/alzheimers/topics/symptoms

Stages of AD
Moderate dementia due to AD
Poor judgment and confusion Even greater memory loss
Ex. Forget address, phone number, confuse family members

Need help with activities of daily living Significant personality changes

Ex. Extremely suspicious, paranoid, easily agitated, aggressive

MMSE 10 to 20
http://www.nia.nih.gov/alzheimers/topics/symptoms

Stages of AD
Severe dementia due to AD
Lose ability to communicate
Ex. May simply say words or phrases, but not usually a coherent sentence

REQUIRE assistance with ADLs Decline in physical abilities

No longer able to walk, sit up, hold up their head, etc. without assistance. Eventually lose ability to swallow

MMSE < 10
http://www.nia.nih.gov/alzheimers/topics/symptoms

Stages of AD
MMSE
What is the date: (year)(season)(date)(day)(month) - 5 points (one point for each) Where are we: (state)(county)(town)(hospital)(floor) - 5 points Name three objects, pause, ask patient to repeat the objects. Give one point for each correct answer. Then repeat them until he/she learns all three. Count trials and record. The first repetition determines the score, but if the patient cannot learn the words after six trials then recall cannot be meaningfully tested. Maximum score - 3 points. Spell the word WORLD backwards: one point for each letter in correct order. Maximum score 5 points. Ask for the three objects repeated above: one point for each correct. Maximum score - 3 points. Show and ask patient to name a pencil and wrist watch - 2 points. Repeat the following, "No ifs, ands, or buts." Allow only one trial - 1 point. Follow a three stage command, "Take a paper in your right hand, fold it in half, and put it on the floor." Score one point for each task executed. Maximum score - 3 points. On a blank piece of paper write "close your eyes;" ask the patient to read and do what it says 1 point. Give the patient a blank piece of paper and ask him/her to write a sentence. The sentence must contain a noun and verb and be sensible - 1 point. Ask the patient to copy a design (eg, intersecting pentagons). All 10 angles must be present and two must intersect - 1 point.

Diagnosis
Up to 90% accuracy Diagnosis is not confirmed until autopsy Dementia Probable AD Possible AD Probable or possible AD with evidence of AD physiological process See handout- extensive list

Diagnosis
Rule out:
Stroke Dementia with Lewy bodies Frontotemporal dementia Vitamin deficiencies Thyroid disorders

Treatment options
Cognitive Symptoms Cholinesterase Inhibitors
Tacrine Donepezil Rivastigmine Galantamine

Neuropsychiatric Symptoms Atypical antipsychotics

Clozapine Olanzapine Risperidone Quetiapine

Citalopram Sertraline Trazodone

SSRIs

NMDA receptor antagonist

Memantine

Cholinesterase inhibitors
Tacrine (Cognex)
Mild to moderate AD First medication approved Dose: 10 mg four times daily. May increase to 40 mg four times daily in 10 mg increments every 4 weeks. ADR: Elevated ALT/AST (monitor regularly), nausea, vomiting, diarrhea, anorexia, dyspepsia, myalgia, ataxia. Drug interactions: smoking, CYP1A2 No statistical benefit, hepatotoxicity limits use
Lexi-Comp Online [Internet]. Lexi-Drugs [cited 2013 Jul 25].

Cholinesterase inhibitors
Donepezil (Aricept)
Mild to moderate and moderate to severe AD Dose: 5 mg once daily, may increase to 10 mg once daily after 4 to 6 weeks ADRs: Insomnia, nausea, diarrhea, accident, infection, headache Drug interactions: CYP2D6 and CYP3A4, beta-blockers, corticosteroids, neuromuscular blocking agents

www.everydayhealth.com

Lexi-Comp Online [Internet]. Lexi-Drugs [cited 2013 Jul 25].

Cholinesterase inhibitors
Rivastigmine (Exelon)
Mild to moderate AD Dose: 1.5 mg daily, may increase by 1.5 mg/dose every 2 weeks based on tolerability to max dose of 6 mg twice daily ADRs: Dizziness, headache, nausea, vomiting, diarrhea, anorexia, abdominal pain, syncope, hypertension, fatigue, insomnia Drug interactions: may enhance extrapyramidal effects of antipsychotics, beta blockers, corticosteroids, neuromuscularblocking agents, smoking, ginkgo biloba

www.everydayhealth.com

www.everydayhealth.com

Lexi-Comp Online [Internet]. Lexi-Drugs [cited 2013 Jul 25].

Cholinesterase inhibitors
Galantamine (Razadyne)
Mild to moderate AD Dose: 4 mg twice a day for 4 weeks. If tolerated, increase in 4 mg increments up to max dose of 12 mg twice daily. (Also available as ER formulation) ADRs: Nausea, vomiting, diarrhea, bradycardia, hypertension, syncope, dizziness, headache, depression, somnolence, anorexia Drug interactions: may enhance extrapyramidal effects of antipsychotics, beta blockers, corticosteroids, neuromuscular-blocking agents, smoking, ginkgo biloba, ANY QT prolonging drugs

www.everydayhealth.com

Lexi-Comp Online [Internet]. Lexi-Drugs [cited 2013 Jul 25]. http://www.planetdrugsdirect.com/images/products/Razadyne-ER-101391

NMDA receptor antagonist

Memantine (Namenda)
Mild to moderate and moderate to severe AD Dose: 5 mg daily; may titrate by 5 mg daily up to 10 mg twice daily. ADRs: hypertension, heart failure, CVA, syncope, TIA, dizziness, confusion, headache, hallucinations, pain, somnolence, fatigue Drug interactions: carbonic anhydrase inhibitors, sodium bicarbonate, trimethoprim

www.everydayhealth.com

Lexi-Comp Online [Internet]. Lexi-Drugs [cited 2013 Jul 25].

Emerging Therapies

Emerging therapies
AZD3293 and also MK-8931: a beta-secretase inhibitor
Phase I clinical trial and phase II/III clinical trial Start date: 3/2013 and 11/2012 End date: 7/2014 and 4/2017 Status: recruiting

http://www.nia.nih.gov/alzheimers/alzheimers-disease-video

Emerging therapies
BAN2401: a monoclonal antibody that selectively binds beta amyloid aggregates
Phase II clinical trial Start date: 12/2012 End date: 4/2016 Status: recruiting

http://www.nia.nih.gov/alzheimers/alzheimers-disease-video

Emerging therapies
TRx0237 (LMTX): reduces levels of aggregated misfolded tau proteins
Phase III clinical trial Start date: 11/2012 End date: 8/2014 Status: recruiting

http://www.nia.nih.gov/alzheimers/alzheimers-disease-video

Emerging therapies
Exendin-4 (Exenatide)
Specifically, GLP-1 stimulates the growth of neurites (developing neurons) in cell culture, and both GLP-1 and exendin-4 protect mature neurons against cell death. In fact, research increasingly suggests that there may be a link between some neurodegenerative disorders and metabolic dysfunction. http://www.nia.nih.gov/newsroom/features/exendin-4-lizard-laboratory-andbeyond#sthash.AjvXL0kn.dpuf

Phase II clinical trial Start date: 11/2010 End date: 12/ 2015 Status: recruiting

Emerging therapies
Nicotine transdermal patch
Preliminary trial showed a benefit in cognitive function
Newhouse P, et. al. Neurology. 2012 Jan 10;78(2):91-101.

More studies need to be done

Summary
AD is a progressive, irreversible disease associated with amyloid plaques and neurofibrillary tangles resulting in decreased cognitive function AD can be classified into stages: preclinical, mild cognitive impairment, and dementia due to AD. Dementia due to AD can further be classified as mild, moderate or severe Current treatments only help with symptoms of cognitive impairment Drugs currently in clinical trials are promising options for the symptoms and progression of AD

Questions?

References

National Institute on Aging. [Internet]. About Alzheimer's Disease: Alzheimers Basics. [cited 2013 Jul 25]. Available from: http://www.nia.nih.gov/alzheimers/topics/alzheimers-basics Mendez MF, Lee AS, Joshi A, Shapira JS. Nonamnestic presentations of early-onset Alzheimer's disease. Am J Alzheimers Dis Other Demen. 2012 Sep;27(6):413-20. Jorm AF, Jolley D. The incidence of dementia: a meta-analysis. Neurology. 1998;51(3):728. Van Duijn CM, et. al. Familial aggregation of Alzheimer's disease and related disorders: a collaborative re-analysis of case-control studies. Int J Epidemiol. 1991;20 Suppl 2:S13-20. Luchsinger JA, et. al. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology. 2005;65(4):545. National Institute on Aging. [Internet]. About Alzheimer's Disease: Symptoms. [cited 2013 Jul 25]. Available from: http://www.nia.nih.gov/alzheimers/topics/symptoms Folstein MF, Folstein SE, McHugh PR."Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189.

References
McKhann GM, et. al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on AgingAlzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):263-9. doi: 10.1016/j.jalz.2011.03.005. Epub 2011 Apr 21. Trinh NH, Hoblyn J, Mohanty S, Yaffe K. Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a meta-analysis. JAMA. 2003 Jan 8;289(2):210-6. Lexi-Comp Online [Internet]. Hudson (OH): Lexi-Comp Inc. 1978. Lexi-Drugs [cited 2013 Jul 25]. Available from: http://www.lexi.com Registration and login required. National Institute on Aging. [Internet]. Clinical Trials. [cited 2013 Jul 27]. Available from: http://www.nia.nih.gov/search/site/alzheimer%27s?f[0]=bundle%3Aclintrials. Newhouse P, et. al. Nicotine treatment of mild cognitive impairment: a 6-month double-blind pilot clinical trial. Neurology. 2012 Jan 10;78(2):91-101.