The document discusses current issues in diagnosing and treating Alzheimer's disease. It outlines the three stages of Alzheimer's (preclinical, mild cognitive impairment, dementia) and biomarkers used for diagnosis. It also discusses FDA-approved drugs for treatment including donepezil, rivastigmine, galantamine, and memantine. Clinical trials show these drugs can improve cognition and function compared to placebo. Non-drug approaches like lifestyle changes and supplements are also mentioned.
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Current Issues in Alzheimer's Diagnosis and Treatment
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
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. 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. 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
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
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.
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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.
13. 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.
14. 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
15. 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]).
16. 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.
17. 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.
18. 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
19. 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
22. 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.
27. 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
33. 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.
34.
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
Notes de l'éditeur
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.