Current Issues in the Diagnosis and Treatment of Alzheimer's

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

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  • Purpose:
    The treatment goals are to maintain quality of life and maximize function and cognition in these
    individuals.
     
    Key Points:
    Evaluation and treatment of mood and behavior disorders play an important role in the treatment of patients with AD.  
    Similarly, we don’t want to forget the importance of the caregiver. Look for stress and/or depression among caregivers.
    It’s important not just to make a diagnosis and reevaluate in 6 or 12 months, but to provide periodic surveillance if medication or therapy is employed for the disease.
    Telephone contact is helpful for many AD patients and their families.
  • Speaker Highlights
    Key point:
    Currently, there are four commonly used pharmacologic agents approved for the treatment of dementia of the Alzheimer’s type: Aricept® (donepezil HCl), EXELON® (rivastigmine tartrate) and EXELON®PATCH (rivastigmine transdermal system), Razadyne® (galantamine HBr), and Namenda® (memantine HCl).
    Supplemental notes:
    The cholinesterase inhibitors Aricept, EXELON, and Razadyne are thought to exert their therapeutic effect by enhancing cholinergic function by inhibition of cholinesterase enzymes.1-3
    Namenda is thought to exert its therapeutic effect by inhibiting the effects of the excitatory amino acid glutamate at N-methyl-D-aspartate (NMDA) receptors in the CNS.4
    References
    Aricept Tablets and Orally Disintegrating Tablets prescribing information. Eisai Incorporated, Teaneck, NJ, 2006.
    Exelon Capsules and Oral Solution prescribing information. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2007.
    Exelon Patch prescribing information. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2007.
    Razadyne Tablets, Oral Solution, and Extended-Release Capsules prescribing information. Ortho-McNeil Neurologics Incorporated, Titusville, NJ, 2006.
    Namenda Tablets and Oral Solution prescribing information. Forest Pharmaceuticals Incorporated, St. Louis, MO, 2007.
  • Key Points
    In the first 1-year, multinational, double-blind study of a cholinesterase inhibitor (ChEI) in AD, Aricept was effective as persistent treatment.19
    Cognition, as measured by the MMSE, remained at or near baseline beyond 6 months (mean baseline MMSE, 19.3).
    Significant differences for Aricept compared with placebo were demonstrated at Weeks 24, 36, and 52 (P<.02).
    See Appendix for study description and safety information (Nordic).
  • Key Points
    This was the first double-blind study of a ChEI in more advanced AD.20
    In this study, Aricept improved cognition, with standardized MMSE scores remaining above baseline for 6 months (mean baseline MMSE, 11.7).
    Significant differences for Aricept compared with placebo were demonstrated at Weeks 12 and 24 (P.0019).
    The MMSE is less sensitive to changes in cognition as the disease progresses to more advanced stages (exhibits a floor effect).
    See Appendix for study description and safety information (Moderate to Severe AD [MSAD]).
  • Key Points
    Behavior was evaluated in the 24-week, multicenter, randomized, double-blind, placebo-controlled MSAD study.20
    NPI scores of Aricept-treated patients were improved from baseline throughout the study and significantly different from placebo at Weeks 4 and 24.
    NPI scores of placebo-treated patients were relatively unchanged, remaining near baseline.
    See Appendix for study description and safety information (MSAD).
  • Key Points
    The effects of Aricept treatment on functional decline in patients with mild to moderate AD were determined in a 1-year, double-blind, placebo-controlled study.15
    Time to reach clinically evident functional decline was measured using the ADFACS.
    Patients exited the study when they experienced a 20% decline in instrumental ADLs, a decline in the ability to perform 1 or more basic ADLs, or a 1-point increase in the Clinical Dementia Rating (CDR) scale.
    Aricept significantly extended the median time to clinically evident functional decline by 5 months versus placebo in this 1-year study. Aricept-treated patients maintained function 72% longer than placebo-treated patients (median of 357 vs 208 days) (P<.002).
    See Appendix for study description and safety information (Preservation of Function).
  • Speaker Highlights
    Key points:
    Treatment is started with EXELON Patch 4.6 mg/24h. After a minimum of 4 weeks of treatment, and if well tolerated, the dosage should be increased to 9.5 mg/24h, which is the recommended effective dosage.
    Patients treated with EXELON capsules or oral solution can be switched to EXELON Patch as follows:
    If on a total daily oral dose of <6 mg, can switch to EXELON Patch 4.6 mg/24h
    If on a total daily oral dose of 6–12 mg, can switch to EXELON Patch 9.5 mg/24h
    Supplemental note:
    The first Patch should be applied on the day following the last oral dose.
    Reference
    Exelon Patch prescribing information. Novartis Pharmaceuticals Corporation, East Hanover, NJ,
    2007.
  • Speaker Highlights
    Key point:
    The observed rates of nausea and vomiting associated with EXELON Patch 9.5 mg/24h treatment approached those observed in the placebo group and are reduced compared with EXELON capsule.
    Supplemental note:
    Gastrointestinal adverse effects, including nausea and vomiting, can be significant and at times severe at higher-than-recommended doses. The dose should be titrated as prescribed and reinitiated at the lowest dose if interrupted for more than a few days.
    Reference
    Exelon Patch prescribing information. Novartis Pharmaceuticals Corporation,
    East Hanover, NJ, 2007.
  • Purpose:
    To highlight the difference between the mechanism of action (MOA) of memantine and
    the MOA associated with the ChEIs as a class.
    Key Points:
    Memantine1
    Memantine may block sustained activation of NMDA receptors by abnormal glutamate activity.
    It is thought that by blocking NMDA receptor calcium channels, memantine inhibits the sustained, low-level influx of excitatory calcium (Ca2+) ions into postsynaptic glutamatergic neurons, thereby preventing the harmful consequences that have been attributed to the persistent activation of such neurons.
    Memantine may restore normal glutamate function, which is important for learning and memory.
    ChEIs2,3
    It is believed that the symptoms of AD are caused, in part, by pathologic deficits in cholinergic neurotransmission. These deficits have been ascribed to the progressive loss of acetylcholine-producing neurons in patients with AD.
  • Purpose:
    To summarize cognitive outcomes in the Reisberg trial.
    Key Points:
    Orientation to slide:
    —Points on the y-axis represent mean change in Severe Impairment Battery (SIB) score from baseline while points on the x-axis represent time.
    — As higher scores indicate better performance than placebo on cognitive tasks, positive mean
    changes above baseline indicate clinical improvement.
    There was a significant difference on the SIB outcome measure favoring memantine treatment at end point
    Over the 6-month period, memantine patients decreased by 3.9 points at end point, while placebo patients decreased by 9.8 points. Therefore, memantine patients had significantly less cognitive decline on the SIB total score compared with placebo.
    Additional Information:
    The SIB evaluates cognitive performance in moderate to severe AD. It includes a 40-item scale, which measures such skills as attention, language, praxis, visuospatial ability, construction, memory, and social interaction. The test is scored from 0 (greatest impairment) to 100.
    SIB baseline scores were 68.3 for placebo and 65.9 for memantine.
    Alzheimer’s Disease Cooperative Study (ADCS) reports that for patients with untreated AD whose MMSE scores are 5-9, the average deterioration rate on the SIB is roughly 3.19 points per month; and for patients with untreated AD whose MMSE scores are 10-15, the rate of change is 2.08 points per month. Over the
    6-month period, this resulted in a 12- to 18-point drop.
  • Purpose:
    To summarize functional outcomes.
    Key Points:
    Orientation to slide:
    Points on the y-axis represent mean changes in Alzheimer’s Disease Cooperative Study–
    Activities of Daily Living (19 item) (ADCS-ADL19) scores from baseline while points
    on the x-axis show when measurements were taken.
    As with the SIB scale, higher scores indicate better functioning than placebo; hence, positive changes above baseline represent an improvement in functional ability.
    Patients in the memantine group demonstrated significantly less deterioration in functional performance as measured by ADCS-ADL19 than patients in the placebo group over the course of the study.
    At end point, memantine patients declined by approximately 3 points while placebo patients declined by approximately 5 points.
    Additional Information:
    The ADCS-ADL19 inventory is a comprehensive battery of ADL/instrumental ADCS questions aimed at measuring the functional ability of patients with moderate to severe AD. It includes a subset of 19 items selected to best assess moderate to severe patients. The ADCS-ADL19 determines a patient’s ability to perform ADL ranging from total independence to total disability. Some of the 19 items evaluated included eating, walking, toileting, bathing, grooming and dressing, attending to conversation, doing household activities, and traveling beyond home.
  • Current Issues in the Diagnosis and Treatment of Alzheimer's

    1. 1. 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
    2. 2. Diagnosis of Alzheimer’s Disease 15
    3. 3. In 2011 The National Institute on Aging and The Alzheimer’s Association proposed new criteria and guidelines for diagnosing Alzheimer’s Disease 15
    4. 4. 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
    5. 5. 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
    6. 6. Cognitive Continuum Normal Mild Cognitive Impairment Dementia CP926864- 9
    7. 7. 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
    8. 8. 0 100 0 12 88 12 24 76 24 Months 36 64 36 48 52 48 Alzheimer's disease MCI
    9. 9. 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.
    10. 10. Behavioral drug management Cognitive drug management Medical management Psychosocial Management
    11. 11. 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
    12. 12.  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.
    13. 13. 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
    14. 14. 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]).
    15. 15. 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.
    16. 16. 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.
    17. 17. 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
    18. 18. 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
    19. 19. 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
    20. 20. 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
    21. 21. 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.
    22. 22. 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.
    23. 23. Severe Impairment Battery ADCS-ADL
    24. 24.       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
    25. 25. 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
    26. 26. 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.
    27. 27. 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
    28. 28. 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
    29. 29. 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
    30. 30.      Fish oils Coconut oil B complex vitamins Ginko Biloba Prevagen
    31. 31. 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.
    32. 32.  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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