Current Issues in the Diagnosis and Treatment of Alzheimer's

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Information about Current Issues in the Diagnosis and Treatment of Alzheimer's
Health & Medicine

Published on February 17, 2014

Author: WIWomensHealth

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Malgorzata Franczak, MD. Associate Professor of Neurology, Medical College of Wisconsin

Current Issues In The Diagnosis and Treatment of Alzheimer’s Malgorzata Franczak, MD Associate Professor of Neurology Medical College of Wisconsin Director of the Normal Pressure Hydrocephalus Program Director of the Community Engagement

Diagnosis of Alzheimer’s Disease 15

In 2011 The National Institute on Aging and The Alzheimer’s Association proposed new criteria and guidelines for diagnosing Alzheimer’s Disease 15

Three stages of Alzheimer’s Disease A. Preclinical AD B. Mild Cognitive Impairment due to AD C. Dementia due to AD Biomarkers tests A. Biomarkers showing levels of beta-amyloid accumulation in the brain B. Biomarkers showing that neurons in the brain are injured or actually destroyed 15

Preclinical Alzheimer’s Disease 1. Individuals have no symptoms 2. Measurable changes in the brain, CSF and/or blood that indicate the earliest signs of disease are found 15

Cognitive Continuum Normal Mild Cognitive Impairment Dementia CP926864- 9

Mild Cognitive Impairment (MCI) 1. Memory complaint, preferably corroborated by an informant 2. Memory impairment documented according to appropriate reference values 3. Essentially normal performance in non memory cognitive domains 4. Generally preserved activities of daily living 5. Not demented 15

0 100 0 12 88 12 24 76 24 Months 36 64 36 48 52 48 Alzheimer's disease MCI

Hypothetical temporal ordering of neuropathological processes in the course of Alzheimer disease and corresponding imaging and biomarker measures Petersen, R. C. et al. Arch Neurol 2009;66:1447-1455. Copyright restrictions may apply.

Behavioral drug management Cognitive drug management Medical management Psychosocial Management

Treatment Goals  Maintain quality of life  Maximize function  Enhance cognition  Treat mood and behavior problems  Educate and counsel caregiver to alleviate stress  Regular office visits  Frequent telephone contact with family members  Coordination of multidisciplinary team

 FDA-approved drugs commonly used for the treatment of AD  Aricept® (donepezil hydrochloride)  Indicated for mild, moderate, or severe dementia of the Alzheimer’s type  Exelon® (rivastigmine tartrate) and EXELON®PATCH (rivastigmine transdermal system)  Indicated for mild to moderate dementia of the Alzheimer’s type  Indicated for mild to moderate Parkinson’s disease dementia (PDD)  Razadyne® (galantamine hydrobromide)  Indicated for mild moderate and advanced dementia of the Alzheimer’s type  Namenda® (memantine hydrochloride) is an NMDA receptor antagonist  Indicated for moderate to severe dementia of the Alzheimer’s type Aricept® is a registered trademark of Eisai Incorporated; Razadyne ® is a registered trademark of Ortho-McNeil Neurologics Incorporated; Namenda® is a registered trademark of Forest Pharmaceuticals Incorporated.

P<.001 MMSE change from baseline 1.0 Clinical improvement P=.019 0.5 P=.001 P<.001 0.0 -0.5 -1.0 -1.5 -2.0 Aricept (n=142) Placebo (n=144) -2.5 -3.0 0 12 24 36 52 Endpoint Study week Adapted with permission from Winblad et al. Neurology. 2001;57:489-495. See Appendix for study description and safety information (Nordic). Clinical decline

MMSE change from baseline Clinical improvement 3 P=.0004 P<.0001 P=.0019 2 1 0 -1 Aricept (n=144) Placebo (n=146) Clinical decline -2 0 12 24 Endpoint Study week Adapted with permission from Feldman et al. Neurology. 2001;57:613-620. See Appendix for study description and safety information (Moderate to Severe AD [MSAD]).

Tpmx82250816Alzheimer’s.v2 - 19 6/27/02 13:47 Mean Change From Baseline ± SE in ADAS-cog/11 GAL-USA-9: Change From Baseline in ADAS-cog/11 Scores -6 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 Baseline 3 12-month Placebo 1 Estimation of decline–Stern Equa tion2 Galantamine 24-32/24 mg 3 6 9 12 18 Time (months) 24 30 36 1. Torfs K et al Poster presented at the Sixth International Stockholm/Springfield Symposium on Advances in Alzheimer Therapy, April 2000. 2. Ster n RG et al. Am J Psychiatry. 1994;151:3. 3. Data on file. Janssen Pharmaceutica.

Donepezil-treated group 95% confidence interval Historical control Mean change (± SE) from baseline in ADAS-cog scores -10 0 10 20 30 40 50 60 14 26 38 50 62 74 86 98 110 124 136 146 158 170 182 194 206 213 230 242 254 Weeks Reprinted with permission from Rogers SL et al. Eur Neuropsychopharmacol. 2000;10:195-203.

Aricept 10 mg 357 days (n=214 at baseline) P<.002 Placebo 208 days (n=217 at baseline) 0 50 100 150 200 250 Median time to functional decline (days) Mohs et al. Neurology. 2001;57:481-488. See Appendix for study description and safety information (Preservation of Function). 300 350

Aricept 23 mg Screened 2186 Randomized 1467 Donepezil 23 mg 963 Donepezil 10 mg 471 Completed 399 Withdrawn 72 Reason for withdrawal AE 8.1% Lack of efficiency 0.1 Other 7 Completed 687 Withdrawn 278 Reason for withdrawal AE 18.6% Lack of efficiency 0 Other 9.1

Aricept 23 mg GI Adverse events 10 mg Diarrhea Nausea Vomiting Anorexia 8.3 11.8 2.5 1.7 23 mg 5.3 3.4 9.2 5.3

4 SIB Change from Baseline LS mean (±SE) Aricept 23 mg Aricept 10 mg 2 1 0 1 2 0 6 12 18 Weeks of Drug Treatment 24

EXELON Patch is applied once daily Maintenance Rx Initial Rx 4 WEEKS** EXELON Patch 4.6 mg/24h Daily Rivastigmine Oral Dosage EXELON Patch 9.5 mg/24h Daily EXELON Patch Dosage <6 mg 4.6 mg/24 h 6 to 12 mg 9.5 mg/24 h *Dose should be increased after a minimum of 4 weeks only if initial dose is well tolerated. When switching from oral rivastigmine, apply the first patch on the day following the last oral dose. Exelon Patch prescribing information. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2007.

Patients reporting adverse events, % 35 30 25 23% 20 17% 15 10 7% 5 0 5% EXELON EXELON Placebo (n=302) Capsule Patch 12 mg/d 9.5 mg/24h (n=294) (n=291) Nausea 6% 3% EXELON EXELON Placebo (n=302) Capsule Patch 12 mg/d 9.5 mg/24h (n=294) (n=291) Vomiting Safety population. Exelon Patch prescribing information. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2007.

Severe Impairment Battery ADCS-ADL

      Developers: Merz,Lunbeck,Forest Non competitive low affinity NMDA receptor (like amandatine) Trials in AD VaD MCI in the EU Available since January 2004 One month titration to10mg bid Indication for advanced AD MMSE < 14

Memantine in Moderate to Severe AD Study The Memantine Group Exhibited Significantly Superior Cognitive Function Compared With the Placebo Group P<.001 0 -2 *P=.002 -4 † P<.001 Deterioration Mean Change From Baseline in SIB Score Improvement P=.068 2 -6 -8 Memantine -10 Placebo -12 0 n= n= *. 4 12 126 126 119 117 107 106 Week 28 End Point 96 83 124 123

Memantine in Moderate to Severe AD Study P=.145 1 P=.106 0 *P=.003 -1 -2 † P=.02 Deterioration Mean Change From Baseline in ADCS-ADL19 Score Improvement Memantine-Treated Patients Demonstrated Significantly Less Functional Deterioration vs Placebo -3 -4 -5 Memantine -6 Placebo -7 0 n= n= 4 12 126 126 119 117 107 106 Week 28 End Point 97 84 124 123 *OC analysis. †LOCF analysis Adapted with permission 2004 from: Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ. N Engl J Med. 2003;348:1333-1341. Copyright © 2003 Massachusetts Medical Society. All rights reserved. Data on file, Forest Laboratories, Inc.

Namenda XR 28 mg Time course of the change from baseline in SIB score for patients completing 24 weeks of treatment. 4 3 Namenda XR 28 mg 2 1 AChEI 0 -1 4 8 12 16 weeks 20 24

Time course of the CIBIC-Plus score for patients completing 24 weeks of treatment. 3.6 3.8 Namenda XR 28 mg Mean (± SEM) CIBC-Plus Score 4 AChEI 4.2 4.4 4 8 12 16 weeks 20 24

Adverse reactions observed with a frequency of ≥ 2% and occurring with a rate greater than placebo Adverse reaction Placebo (n = 335) % NAMENDA XR 28mg (n = 341) % Gastrointestinal Disorders Diarrhea 4 Constipation 1 Abdominal pain 1 Vomiting 1 Infections and infestations Influenza 3 Investigations Weight, increased 1 Musculoskeletal and connective tissue disorders Back pain 1 5 3 2 2 4 3 3

     Fish oils Coconut oil B complex vitamins Ginko Biloba Prevagen

Figure 2. Dynamic biomarkers of the Alzheimer's pathological cascade Aβ is identified by CSF Aβ42 or PET amyloid imaging. Tau-mediated neuronal injury and dysfunction is identified by CSF tau or fluorodeoxyglucose-PET. Brain structure is measured by use of structural MRI. Aβ=β-amyloid. MCI=mild cognitive impairment.

 Prevent build up of plaque (anti-amyloid) o o slow aggregation into plaques o dissolve plaques o  slow or prevent amyloid production by inhibiting clipping enzymes or by vaccine therapy increase clearance Prevent build up of paired helical filaments (tau focused) o o  slow or prevent tau aggregation and dysfunction dissolve paired helical filaments Prevent brain cell dysfunction and death o slow or prevent oxidative stress, inflammation, reduced blood flow o increase levels of protective molecules in brain o maintain viable connections between cells

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