Alzheimer’s Dementia:
Overview of Evaluation and Care
Alireza Atri, MD, PhD
Associate Director, Clinical Programs,
Geriatric Research Education & Clinical Center (GRECC)
ENRM VA Bedford Medical Center
Memory Disorders Unit & MA Alzheimer’s Disease Research Center
Dept. of Neurology, Massachusetts General Hospital
Harvard Medical School
1
Disclosure/conflict of interest
Alireza Atri – past 3 years
 I am not/have not been part of any speakers bureau
 Support: NIH, Veterans Administration (VA)
 Institutional Research Grant: Forest Research Institute
 Scientific Advisory Board, Consultation and/or
lectures/CME programs: Alzheimer’s Association
(MA/NH), Daiichi-Sankyo, Forest Research Institute,
Harvard Medical School Continuing Education (HMS
CE), Lundbeck, Merck, Merz, Veterans Health
Administration Office of Research (ORD RRD)
2
Human beings are members of a whole,
In creation of one essence and soul,
If one member is afflicted with pain
Other members uneasy will remain.
If you have no sympathy for human pain,
The name of human you cannot retain.
Saadi Shirazi (Persian/Iranian Poet, 1184–1283)
3
Overview
 Early detection of cognitive impairment and dementia is
crucial: it allows for early education, and care and planning
to minimize harm, establish practical and healthy habits, and
to shore up existing functions before they are lost
 Good evidence level for benefits of AD treatments
(pharmacological and non-pharmacological)
 Must balance risks and benefits on an individual patientcaregiver dyad basis
 Best standard of care treatments combine behavioral and
pharmacological treatments, education & care of the patient
and caregivers
4
 reduce long-term clinical decline and delay time to full-time disability
 reduce caregiver burden
 Provide cumulative and meaningful benefits
No man is an island, entire of itself...
Any man’s death diminishes me, because I am
involved in mankind; and therefore never send
to know for whom the bell tolls; it tolls for thee
John Donne
5
Global impact of AD
Costs of caring for individuals with Alzheimer’s disease:
6
Worldwide: $604 billion in 2010 (>1% of world GDP)
U.S: 190-220 billion (direct costs)
AD is the sixth leading cause of mortality in the
U.S. and the only one that is increasing …
7
Projected numbers of people with AD in the U.S.
8
Hypothetical model of AD pathophysiological cascade
AD risk factors and the amyloid
cascade hypothesis
Age genetics
Risk factors:
• Aging and
gender (F>M)
• Family history
• Severe head
injury
• Altered cerebral
perfusion
• ApoE 4 (CLU,
CR1, PICALM,
SORL1, TOMM
40) genotype
• Environmental
stressors
• Gene mutations
• Cerebral
amyloidosis
9
Amyloid-β
accumulation
Amyloid
deposition
AGE
30
40
50
60
70
80
90
Cardiovascular risk factors
Other age-related brain diseases
Synaptic dysfunction;
glial activation;
tangle formation;
neuronal death
Cognitive
decline
Brain and cognitive reserve
? Environmental factors
Microglial
activation
Neurofibrillary
tangles Neuronal loss/
neurochemical
changes
DEMENTIA
Concept of co-occurrence of Vascular
Disease & AD pathology in Dementia
VaD
10
AD
Spectrum of CVD
Stroke
MRI Infarction
White Matter Hyperintensities
Brain Atrophy
11
AD Spectrum occurs on a continuum of
severity from No  Mild  Marked impairment
Onset Clinical diagnosis
of MCI*
of AD
% of end-stage AD
100
80
PRECLINICAL
phase
60
MCI
phase
DEMENTIA
phase
40
20
Degree of cognitive
impairment
0
40
50
60
70
Estimated start of amyloid deposition
12
*MCI = mild cognitive impairment
80 Age (years)
The Fallacies & Facts regarding
screening - Why & How To Screen?
•
Fallacy 1: “I can tell if there’s something
wrong with them, and besides, if I start
asking them these kinds of questions they’d
be offended”
The basic dementia workup
•
•
13
Fact 1a: “Physician heal thyself” – we must
disabuse ourselves of such false and
damaging notions
Fact 1b: normalize and explain rationale and
benefits of screening  you’d be delivering
good care that is appreciated
The Fallacies & Facts regarding
screening - Why & How To Screen?
•
•
14
Fallacy 2a: “I can simply rely on the
information provided by my patients to make
my decisions”
The basic dementia workup
Fallacy 2b: “Screening doesn’t make a
difference – dementia declares itself, and
catching it early makes no difference to my
patient’s health or my practice”
The Fallacies & Facts regarding
screening - Why & How To Screen?
•
Consider two typical cases:
•
Case 1: Mrs. Smith 78 y.o. woman with difficult to control
HTN, mild depression, anxiety and insomnia is admitted
to the hospital for pneumonia, is started on antibiotics
along with her outpatient anti-HTN medication regimen 
blood pressure falls from 169/88 to 76/43
•
Case 2: Mr. Jones 74 y.o. recent widower with IDDM x20
yrs, HTN, CAD, s/p MI and h/o CHF, all previously wellcontrolled but now with escalating # of admissions in the
last 2 years due to “out of control diabetes”,
“hypoglycemia”, and “exacerbations of CHF”
15
The basic dementia workup
The Fallacies & Facts regarding
screening - Why & How To Screen?
16
•
Fallacy
2a: “I candementia
simply rely on theworkThe
basic
information provided by my patients to make
up
decisions”
•
Fact 2a: Need to “Trust but verify” – need
objective and reliable corroboration to form
an informed impression and plan of care
The Fallacies & Facts regarding
screening - Why & How To Screen?
•
Fallacy 2b: “Screening doesn’t make a difference
– dementia declares itself, and catching it early
makes no difference to my patient’s health or my
practice”
The basic dementia workup
•
17
Fact 2b: Unrecognized cognitive impairments
affect patient health and safety, and clinicians
often contribute to poor patient medical and safety
outcomes by violating “primumum non-nocere”
when we form wrong impressions and plans and
ask too much of patients who have unrecognized
diminished capacity
Why & How To Screen?
The
basic
dementia
work1. Normalize and explain
up
2. Reliable information
3. Sensitive measures of all domains
1. Cognition (e.g. MoCA)
2. Function (ADL measure; e.g. FAQ)
3. Behavior & Neuropsychiatric symptoms (e.g.
Neuropsychiatric Inventory)
18
Suggestions for Dementia Screening and Tracking
Instruments
1.
2.
3.
4.
5.
19
Global Screen:
1.
AD8
Function - Activities of Daily Living:
1.
FAQ (Functional Assessment Questionnaire scale)
2.
IADLs
3.
PSMS
Neuropsychiatric/Behavioral (aka. Non-cognitive Behavioral Symptoms, NCBS):
1.
NPI (Neuropsychiatric Inventory)
Cognitive Screen:
1.
MOCA (Montreal Cognitive Assessment) (screen MCI/mild dementia)
2.
Blessed Dementia Scale Information-Memory-Concentration (BDS-IMC
scale, aka. “Right side” of the Blessed) (Tracking)
3.
SLUMS (St. Lois Univ. Mental Status exam)
4.
Addenbrooke’s Cognitive Exam Revised (ACE-R)
Staging, Severity, “Global”:
1.
CDR (Clinical Dementia Rating Scale)
2.
FAST
3.
CIBIS-PLUS
4.
GDS
20
21
ORIENTATION 10 (
Spatial: 5 (
)
) What is the: (year) (season) (date) (day) (month)
Temporal: 5 (
MMSE
) Where are we: (state) (county) (town) (facility) (floor)
REGISTRATION
3(
)
Name three objects and have person repeat them back. Give one point for each correct answer on the first trial.
1. _______ 2. _______ 3. _______
(e.g. Apple, Penny, Table)
Then repeat them (up to 6x) until all three are learned.
[Number of trials ____ ]
ATTENTION AND CALCULATION 5 (
)
Serial 7's. Count backwards from 100 by serial 7's. One point for each correct answer. Stop after 5 answers. [
93 86 79 72 65 ]
Alternatively spell "world" backwards. [ D - L - R - O - W ]
RECALL 3 (
LANGUAGE 9(
) Ask for the names of the three objects learned above. Give one point for each correct answer.
)
Name: a pen (1 point) and a watch (1 point)
Repeat the following: "No ifs, ands, or buts" (1 point)
Follow a three-stage command: "Take this paper in your [non-dominant] hand, fold it in half and put it on the floor". (3
points)
[1 point for each part correctly performed]
Read to self and then do: CLOSE YOUR EYES (1 point)
Write a sentence [subject, verb and makes sense] (1 point)
Copy design [ 5 sided geometric figure; 2 points must intersect]
(1 point)
Score:
22
/30
Cognitive Screening in Primary Care
 Why is MMSE not sensitive to early cognitive
changes or dementia in many populations?
 not enough memory load


only 3 items
highly concrete and high frequency objects/words
 delay period not long enough
23
Suggestions for Dementia Screening
Instruments
1.
Global screening instrument:
1.
2.
Function - Activities of Daily Living:
1.
3.
NPI (Neuropsychiatric Inventory)
Cognitive screen:
1.
2.
3.
24
FAQ (Functional Assessment Scale)
Neuropsychiatric/Behavioral:
1.
4.
AD8
MOCA (Montreal Cognitive Assessment)
Blessed Dementia Scale Information-Memory-Concentration
(BDS-IMC scale, aka. “Right side” of the Blessed)
Addenbrooke’s Cognitive Exam Revised (ACE-R)
MOCA
Scored out of 30
Cut off for Impairment:
<26* (100% specificity)
*Add 1 point if ≤ 12 yrs education
25
Neuropsychological Testing
 When initial evaluation is borderline or in pts
with unusual clinical profiles
 To establish a baseline and track longitudinal
change
 To clarify patterns of cognitive impairment
 To consider percentile performance in each
test and domain

26
Especially useful in pts with superior premorbid ability
Neuropsychological Testing
 To help distinguish between
depression/mood disorders & dementia
 To help determine competency
 To assist in the evaluation and counseling of
dementia in the early stages:




27
Determination of disability
Determine specific weaknesses
Determine specific strengths
Recommend strategies for safety and more
efficient functioning
Minimum of TWO cognitive OR behavioral domains impaired
a. Memory dysfunction: anterograde; deficit in acquisition, storage
or retrieval of new information
28
b. Frontal systems dysfunction: executive dysfunction or poor
judgment & reasoning
29
c. Visuospatial dysfunction
30
d. Language (communication) dysfunction
31
e. Personality changes & Behavioral dysfunction
32
33
AD DEMENTIA CLASSIFICATION
1. Probable AD dementia (clinical classification)
2. Possible AD dementia (clinical classification)
3. Probable or Possible AD dementia with
evidence of the AD pathophysiological
process (research classification)
34
AD DEMENTIA CLASSIFICATION
1. Probable AD (PrAD) dementia with
increased level of certainty
i. PrAD with documented decline
ii. PrAD in carrier of causative AD
genetic mutation (APP, PSEN1,
PSEN2) (but NOT ApoEe4)
35
36
37
38
• strokes that are temporally related to onset or worsening of
cognitive impairment
• multiple or extensive infarcts or severe white matter
hyperintensity burden
• core features of Diffuse Lewy Body Dementia (DLB) other
than dementia itself
• prominent features of Primary Progressive Aphasia(PPA)
• evidence of another concurrent, active neurological disease, or
non-neurological medical comorbidity or use of medication that
could have a substantial effect on cognition
39
AD DEMENTIA CLASSIFICATION
2. Possible AD dementia
1. Atypical course (sudden onset or
insufficient historical detail or objective
cognitive documentation of progressive
decline)
2. Mixed Presentation (VaID, DLB
features, medications or other illness)
40
Basic Dementia Workup

-
41
Laboratory tests:
CBC w/ diff
Chem 20 w/ glucose & Liver function tests
Vitamin B12
TSH – thyroid function
ESR and hsCRP – screen for occult general (systemic)
infectious, inflammatory or neoplastic (cancer) process
Homocysteine
Lipid panel – cholesterol
Atrophy of AD Brain
 Atrophy of hippocampus & temporal lobe > frontal &
parietal lobe >> occipital lobe & motor cortex
 Pattern is characteristic, but not specific for AD
42
Dynamic Biomarkers of the Alzheimer’s
Spectrum Pathological Cascade
 Brain Amyloid-beta
Biomarkers:


CSF A-beta42
Amyloid PET neuroimaging
Jack CR et al.
Lancet Neurol.
2010
43
 Neurodegeneration
Biomarkers:



FDG PET (synaptic)
CSF Tau (neuronal injury)
Structural MRI (volume)
Structural Imaging: MRI vs CT
MRI>>CT (if no contraindication) and can significantly
change your management
 MRI is better at detecting:

Atrophy (e.g. hippocampal atrophy, ventricular enlargement
“Normal”
44
“Moderate Atrophy”
Scheltens, P. Imaging in AD. Dialogues in Clinical Neuroscience (2009)
Structural Imaging: MRI vs CT
MRI>>CT (if no contraindication) and can significantly
change your management
 MRI is better at detecting:


Atrophy (e.g. hippocampal atrophy, ventricular enlargement
Cerebrovascular disease burden: Leukoaraiosis (white matter
microangiopathic changes) and micro/lacunar infarcts
From: O’Brien, JT, et al. 2003. Vascular Cognitive Impairment. Lancet Neurology.
Feb (2):89-98; and Scheltens, P. Imaging in AD. Dialogues in Clinical Neuroscience
45
(2009)
Structural Imaging: MRI vs CT
MRI>>CT (if no contraindication) and can significantly
change your management
 MRI is better at detecting:



46
Atrophy (e.g. hippocampal atrophy, ventricular enlargement
Cerebrovascular disease burden: Leukoaraiosis (white matter
microangiopathic changes) and micro/lacunar infarcts
Microhemorrhages (non-acute)
Atri et al. Prevalence and effects of lobar microhemorrhages in early-stage dementia. Neurodeg Dis 2005
Structural Imaging: MRI vs CT
MRI>>CT (if no contraindication) and can significantly
change your management
 MRI is better at detecting:




47
Atrophy (e.g. hippocampal atrophy, ventricular enlargement
Cerebrovascular disease burden: Leukoaraiosis (white matter
microangiopathic changes) and micro/lacunar infarcts
Microhemorrhages (non-acute)
Hydrocephalus
Selective Use of Additional Tests
Under Special Circumstances




48
CSF: Abeta/tau/phospho-tau profile
Cerebral Metabolism or blood flow: FDG-PET >> SPECT
Amyloid-PET
Other tests for rare dementing conditions/mimics
CSF Biomarkers for AD (and other
neurodegenerative dementias);
Abeta-42 and Tau Levels






49
Low Abeta-42
High Tau
High Phospho-Tau
Low ATI (A-beta to Tau+Phos-Tau index; <1.0)
Sensitivity (88-95%) > specificity (83-87%)
Predictive potential: longitudinal studies
 “Conversion” from “normal control” (Latent AD) to
“MCI” (Prodromal AD) (Tau/A-beta ratio > 2.4)
 “Conversion” from MCI to AD (sens. 95%, spec. 8387%)
Hansson et al. Lancet Neuro, 2006; Li et al. Neurology, 2007
FDG and PIB PET in early AD
(82 yo MMSE 27)
50
K. Johnson MGH
MULTIFACTORIAL Treatment of
Alzheimer’s disease
51
Symptomatic treatment of AD
– current status
FDA-approved indication/labels for AD:
 Disease specific
 Cholinesterase inhibitors (ChEIs): donepezil*, rivastigmine, galantamine*
 NMDA antagonist: memantine
* Generic forms available in the U.S.
No FDA-Approval indication/label for AD:

Non-specific




Other pharmacological agents taken

52
Antidepressants
Antipsychotics** (**risperidone approved by EMA for short-term treatment of
refractory severe agitation & psychosis in AD dementia)
Vitamin E, C

Gingko biloba, cerebrovascular agents, antioxidants, statins, antiinflammatories, vitamins (B/C), antiepileptic agents, fish oil/omega-3 fatty acids,
hormones, “nootropics”
None have proven efficacy in AD dementia RCTs
Summary of Level I Evidence from pivotal studies in AD Dementia
Treatment
Dosing
Level I Evidence
Side Effects
Other
Donepezil
5mg or 10mg or
23mg
Multiple R DB PC
trials 3-12 months.
Mild, mod, severe
Low incidence GI
esp diarrhea and
nausea
ODT and Generic
available for 5 and
10 mg doses
Rivastigmine
Oral: 3mg-6mg BID Multiple R DB PC
Patch: 9.5-13.3
trials 6 months.
mg/24h
Mild to moderate
Low-moderate GI
incl anorexia,
diarrhea & vomiting
w/ oral; rash w/ TP
Start doses not
effective. 13.3
mg/24h patch
better when pt
declines
Galantamine
8mg or 12mg BID
Multiple R DB PC
trials 6 months.
Mild to moderate
Low incidence GI
esp diarrhea and
nausea
ER available for
QD. Start dose not
effective. Generic
available
Memantine
10mg BID
28 mg XR QD
Multiple R DB PC
Few AE’s; occ. mild 4-step titration to
trials 6 months.
transient confusion max dose, one
Moderate to severe ~weeks3-5
week apart
Combination Tx
(Memantine added
to stable
donepezil)
10 mg BID or 28
mg XR QD
memantine added
to chronic ChEI
therapy
Two R DB PC
Few AE’s; mild
moderate to severe transient confusion
trials
~weeks3-5
RTC data in mild
AD lacking;
observational
studies support
long-term benefits
Vitamin E
1000 IU BID
Two R DB PC trials Few AE’s
moderate to severe
trial
More robust effects
on slowing
functional than on
cognitive decline;
53
AChEI & Memantine
Combination Therapy
RATIONALE & BIOLOGICAL
EFFECT
54
Memantine + donepezil combination therapy
– potential synergistic mode of action
D M
D
AChr
M
D
NBM
M
Cholinergic
neuron
M
D
M
D
Hippocampus
Cortex
Glutamate
Acetylcholine
AChE
Acetylcholinesterase
Acetylcholine receptor
NMDA receptor
55
D
M
Donepezil
Memantine
Glutamatergic
neuron
Memantine + donepezil synergistically
affect ACh release in experimental rat
model
Percentage increase in ACh (SE)
Hippocampal levels of acetylcholine in rats
800
600
400
200
0
Donepezil
Sum Memantine
Memantine +
0.5 mg/kg (n=11)
5 mg/kg (n=11) donepezil (n=11)
Experiment conducted in the presence of 5 M neostigmine
*p<0.05 (t-test; t=2.6) versus sum
Sum=sum of increases elicited by each drug individually
56
Ihalainen et al. Neuropharmacology 2011; 61 (5-6): 891–899
Memantine + donepezil has a
potential synergistic effect
 Memantine and donepezil, applied individually, each
produce an increase in extracellular ACh in the
hippocampus of anaesthetised rats – driven by different
mechanisms
 Combined treatment with both drugs produces an
enhancement in ACh levels – greater than the sum of
the parts
 The action of memantine and donepezil together
suggests a potential synergistic interaction on synaptic
ACh release
57
Ihalainen et al. Neuropharmacology 2011; 61 (5-6): 891–899;
Giovannini et al. J Neurosci 1994; 14: 1358–1365
Combination Therapy (ChEI + memantine) in AD – Phase
III, EFFICACY placebo-controlled 24-week studies
Study
58
Type of memantine
therapy (20 mg/day)
Duration
(weeks)
MMSE
inclusio
n criteria
Number of patients
MMSE <20 + receiving donepezil
Tariot et al.,
2004
(MD-02)
10 mg BID Added to
stable donepezil therapy
(5–10 mg/day for ≥3
months)
24
5–14,
inclusive
403
(202 memantine + donepezil;
201 placebo + donepezil)
Grossberg et al.
2013
(MD-50)
28 mg XR to any
approved ChEI therapy (5
or 10 mg/day donepezil: 6,
9 or 12 mg/day
rivastigmine; 16 or 24
mg/day galantamine for
≥3 months)
24
3-14,
inclusive
661
(333 memantine XR + ChEI;
328 placebo + ChEI)
Porsteinsson
et al., 2008
(MD-12)
Added to any approved
ChEI therapy (5 or 10
mg/day donepezil: 6, 9 or
12 mg/day rivastigmine;
16 or 24 mg/day
galantamine for ≥3
months)
24
10–22,
inclusive
202
(105 memantine + donepezil;
97 donepezil monotherapy)
Tariot PN, et al. JAMA 2004; Grossberg et al. CNS drugs 2013; Porsteinsson AP, et al. Curr Alzheimer Res 2008
Combination therapy benefits cognition
Severe Impairment Battery (SIB)
Improvement
2
0
Worsening
Mean change from baseline
4
-2
Combination therapy (DPZL+MEM)
Donepezil monotherapy
-4
Baseline
4
8
12
18
Study week
59
*p<0.05; **p<0.01; ***p<0.001 versus donepezil monotherapy
24
Endpoint
(LOCF)
Tariot et al. JAMA 2004; 291 (3): 317–324
Post hoc analyses of cognitive effects
Benefits for memantine combination therapy
(versus donepezil monotherapy) on:

Cognitive subscales (SIB):




Post hoc-derived functional communication and language
subscales:


60
Memory (p<0.05)
Language (p<0.05)
Praxis (p<0.05)
Naming capabilities (p<0.01)
Functional communication (according to caregivers) (p<0.01)
Schmitt et al. Alzheimer Dis Assoc Disord 2006; 20 (4): 255–262;
Saxton et al. 60th Annual Meeting of the American Academy of Neurology, 2008; Chicago, IL, USA
Combination therapy benefits function
Activities of Daily Living inventory (ADCS-ADL19)
0
-1
Worsening
Mean change from baseline
Improvement
1
-2
-3
Combination therapy (DPZL+MEM)
Donepezil monotherapy
-4
Baseline
4
8
12
Study week
61
*p<0.05 versus donepezil monotherapy
18
24
Endpoint
(LOCF)
Tariot et al. JAMA 2004; 291 (3): 317–324
Post hoc analyses of functional effects
Benefits for memantine combination therapy
(versus donepezil monotherapy) on:

Functional single items (ADCS-ADL19):




Functional subscales (ADCS-ADL19):



62
Grooming (p<0.01)
Watching TV (p<0.01)
Finding belongings (p<0.01)
Connectedness/autonomy (p<0.05)
Higher level functions (p<0.05)
Statistically significant less decline in the total ADCS-ADL19 score
Feldman et al. Alzheimer Dis Assoc Disord 2006; 20 (4): 263–268
Combination therapy benefits behavior
Neuropsychiatric Inventory (NPI)
2
0
-2
Combination therapy (DPZL+MEM)
-4
Donepezil monotherapy
0
12
24
Study week
63
Worsening
Mean change from baseline
Improvement
4
**p<0.01; ***p<0.001 versus donepezil monotherapy
Endpoint
(LOCF)
Cummings et al. Neurology 2006; 67 (1): 57–63
Post hoc analyses of behavioral effects
Benefits for memantine combination therapy (versus donepezil monotherapy)

Behavioral domains (NPI):






Significantly less caregiver distress, due to the patient’s:




64
Agitation (p<0.01)
Irritability (p<0.01)
Appetite/eating changes (p<0.05)
Most other domains showed non-significant improvement
This behavioral response was stable over time
Agitation/aggression
Night-time behaviour
Eating changes
Prevention of emergence of agitation, irritability, and night-time
behavior (all p<0.05)
Cummings et al. Neurology 2006; 67 (1): 57–63
Most frequent adverse events* (%)
Total patients with AEs
Discontinuations due to AEs
Combination
(n=202)
Donepezil monotherapy
(n=201)
78
7.4
72
12.4
Agitation
9.4
11.9
Confusion
7.9
2.0
Fall
7.4ameliorated
7.0in
Agitation possibly
with
Confusion
was more
common
Fewer
receiving combination
Influenza-like symptoms combination patients
7.4 patients
6.5 therapy,
therapy
receiving combination
therapy discontinued due to8.0
AEs
Dizziness
but 6.9
this did not lead to more
Headache
6.4
2.5
discontinuations
Urinary tract infection
5.9
5.0
Urinary incontinence
5.4
3.0
Gastrointestinal
AEs possibly8.0
Accidental injury
5.0
ameliorated
by combination therapy
Upper respiratory tract infection
5.0
6.5
Peripheral edema
5.0
4.0
Diarrhea
4.5
8.5
Fecal incontinence
2.0
5.0
*Occurring in ≥5% of patients in either treatment group
65
Tariot et al. JAMA 2004; 291 (3): 317–324
Combination Therapy (ChEI + memantine) in AD – Phase
III, EFFICACY placebo-controlled 24-week studies
Study
66
Type of memantine
therapy (20 mg/day)
Duration
(weeks)
MMSE
inclusio
n criteria
Number of patients
MMSE <20 + receiving donepezil
Tariot et al.,
2004
(MD-02)
10 mg BID Added to
stable donepezil therapy
(5–10 mg/day for ≥3
months)
24
5–14,
inclusive
403
(202 memantine + donepezil;
201 placebo + donepezil)
Grossberg et al.
2013
(MD-50)
28 mg XR to any
approved ChEI therapy (5
or 10 mg/day donepezil: 6,
9 or 12 mg/day
rivastigmine; 16 or 24
mg/day galantamine for
≥3 months)
24
3-14,
inclusive
661
(333 memantine XR + ChEI;
328 placebo + ChEI)
Porsteinsson
et al., 2008
(MD-12)
Added to any approved
ChEI therapy (5 or 10
mg/day donepezil: 6, 9 or
12 mg/day rivastigmine;
16 or 24 mg/day
galantamine for ≥3
months)
24
10–22,
inclusive
202
(105 memantine + donepezil;
97 donepezil monotherapy)
Tariot PN, et al. JAMA 2004; Grossberg et al. CNS drugs 2013; Porsteinsson AP, et al. Curr Alzheimer Res 2008
Evidence Level
Combination (ChEI with add-on memantine)
Efficacy RCTs
67
Measuring Magnitude of Clinical Effects
(clinical significance) - Effect Sizes
• Effect size is a name given to a family of indices that measure the
magnitude of a treatment effect
• Cohen defined the effect size d as:
= (difference between means)/(standard deviation)
Suggested as a guide that:
16 yr. old
15 yr. old
Small d = 0.2
68
18 yr. old
15 yr. old
Medium d = 0.5
Source: Cohen J. (1988). Statistical power analysis for the behavioral sciences (2nd ed.).
Hillsdale, NJ: Lawrence Earlbaum Associates.
18 yr. old
13 yr. old
Large d = 0.8
Combination therapy (memantine + donepezil) is
superior to placebo added to donepezil monotherapy
in all three key domains of meta-analysis (MMSE < 20)
MMSE <20 (5-19)
69
Atri & Molinuevo, et al. Alzheimer
Res Ther. 2013 Jan 21;5(1):6
Combination Treatment has good safety
profile (meta-analysis; MMSE<20)
70
Atri & Molinuevo, et al.
Alzheimer Res Ther.
2013 Jan 21;5(1):6
*
71
*indeterminate (underpowered)
DOMINO 52-week study: donepezil and
memantine in moderate to severe AD
 52-week, multicentre, doubleblind, placebo-controlled, clinical
trial in outpatients:
 With probable or possible AD
(SMMSE score 5–13)
 Stable on 10 mg/day donepezil
 Whose clinician was considering a
change in drug treatment
 Participants were randomly
assigned to one of:
 Continue donepezil
 Discontinue donepezil
 Continue donepezil and start
memantine
 Discontinue donepezil and start
memantine
Randomised N=295
Continue
donepezil
Continue
donepezil
Discontinue
donepezil
for placebo
Discontinue
donepezil
for placebo
Start placebo
n=73
Start memantine
n=73
Start placebo
n=73
Start memantine
n=76
Receiving drug
at end of study
n=34 (47%)
Receiving drug
at end of study
n=38 (52%)
Receiving drug
at end of study
n=20 (27%)
Receiving drug
at end of study
n=27 (36%)
SMMSE=Standardised Mini Mental State Examination
74
Howard et al. N Engl J Med 2012; 366: 893–903
“Whoa!!! That
CAN’T be right!”
• A priori specified initial target: Ntarget1=800
• Revised target: Ntarget2=430
• Enrollment achieved: Nactual=295
(37% of initial target; 68% of revised target)
• Had high (72%) and disproportionate
withdrawal rate over one year
Atri et al. Neurodeg Dis 2012; 10 (1–4): 170–174
Howard et al. N Engl J Med 2012; 366: 893–903
75
Neurology Today; April 19, 2012: 12-13
DOMINO cumulative probability of study drug
withdrawal: 28% of the adjusted target (n=430) completed
52 weeks, spread over 4 treatment arms
Memantine + donepezil
0.7
Placebo + donepezil
0.6
Memantine + discontinue donepezil
Placebo + discontinue donepezil
0.5
n=27
0.4
n=34
n=72
0.3
n=38
n=74
0.2
n=73
n=72
0.1
0.0
0
76
n=20
42
WORSE DROP-OUT
Probability of withdrawal from
study drug
0.8
Continue donepezil
Start memantine
vs. discontinue
vs. startdonepezil
placebo
Hazard
Hazard
ratio: ratio:
0.51 0.66
95% CI:
0.36
0.72
95%
CI:to
0.47
to 0.93
p<0.001
p=0.02 364
210
126
Days since randomisation
Kaplan–Meier actuarial plot of the cumulative probability of
withdrawal from the assigned study drug
Howard et al. N Engl J Med 2012; 366: 893–903
8
7
38
*
6
5
4
3
2
1
0
36
34
*
32
30
28
26
0
6
18
30
52
Visit week
78
BADLS (±SE)
40
SMMSE (±SE)
9
Improvement
42
Improvement
10
*indeterminate
(underpowered) by week 52
0
6
18
30
Visit week
Placebo + discontinue donepezil
Placebo + donepezil
Memantine + discontinue donepezil
Memantine + donepezil
Multilevel modelling repeated-measures regression;
SMMSE=Standardised Mini Mental State Examination;
BADLS=Bristol Activities of Daily Living Scale
52
Howard et al. N Engl J Med 2012; 366: 893–903
DOMINO-AD 52-week study: summary
Supports and extends the preponderance of clinical
evidence and clinical wisdom that these anti-AD medications
produce real benefits in slowing clinical decline, that:
 Donepezil and memantine monotherapy are both superior to placebo
for at least one year
 Stopping treatment was harmful
 Memantine resulted in much less behavioural worsening of NPI scores
(p=0.002), with a benefit that was equivalent to 83% of the 12-month
deterioration compared to placebo
 Graphical data suggest that combination therapy trajectory is superior
to monotherapy in cognition, function and behavior for initial 30 weeks
Howard et al. N Engl J Med 2012; 366: 893–903
Neurology Today; April 19, 2012: 12-13
79
Clinical effectiveness studies –
Rationale for longitudinal naturalistic observational clinical
cohort studies in AD
 Inclusion of ‘real’ patients



Significant comorbidities
Concurrent medications
Imperfect treatment adherence
 Strengths:

High validity; higher power (larger sample sizes and
durations), collect data over several stages of AD; better
capacity to assess questions of practical importance; ethically
& practically favorable
 Limitations:


80
Drug therapy is often not assigned randomly,
Selection factors associated with long-term drug exposure
cannot be ruled out as alternative explanations for findings
Evidence Level
Combination (ChEI with add-on memantine) Long-Term
Observational Controlled Effectiveness Studies
81
Combination therapy slows long-term
decline in cognition (BDS)
10
Worsening
Predicted mean BDS score (errors)
5
15
20
Memantine combination therapy
25
ChEI monotherapy
No medication
30
0
1
# of mistakes: 0–37 errors
0–3 errors (normal, MCI or very mild impairment)
4–10 errors (mild impairment/dementia)
11–16 errors (moderate impairment/dementia)
>16 errors (severe impairment/dementia)
82
2
Years
3
4
*p<0.05, **p<0.01, ***p<0.001 versus no medication;
#p<0.01, ###p<0.001 versus ChEI monotherapy
Atri et al. Alzheimer Dis Assoc Disord 2008; 22: 209–221
Predictive cognitive scores and
effect sizes
Years
Cohen’s dBDS
1
Years
3
4
ChEI vs NO-RX
0.47***
0.39**
0.32**
0.28*
COMBO vs
NO-RX
0.56***
0.73***
0.76***
0.77***
COMBO vs
ChEI
0.10
0.34**
0.44***
0.49***
*p<0.05, **p<0.01, ***p<0.001
4
0
Model predicted mean
errors (± 95% CI)
2
3
Worsening
1
2
10
20
30
COMBO
ChEI group
No treatment
Cohen defined effect sizes as:
“small, d = 0.2”
“medium, d = 0.5”
“large, d = 0.8”
83
Atri et al. Alzheimer Dis Assoc Disord 2008; 22: 209–221
Study Aim: To compare long-term clinical trajectory of
cognition and function between 3 treatment groups of
AD patients (No-Tx=BSC, ChEI only, COMBO)
Atri et al., 2008
• Are there differences
long term?
• Are there benefits or
detriments long term?
382 patients at Mass General Memory Disorders Unit (1990–2006)
No treatment
n=144
ChEI alone
n=122
Memantine + ChEI (COMBO)
n=116
Average enrolment year
1993
2000
2002
Average time in study
2 years
2.2 years
3.3 years
Cognition: Blessed Dementia Scale (BDS)
Outcome
measures
Function: Weintraub Activities of Daily Living (ADL)
Mixed effects and GEE modeling analysis
of 4-year trajectory of progression
BSC=best
standard care
84
Atri et al. Alzheimer Dis Assoc Disord 2008; 22: 209–221
Combination therapy slows long-term
decline in function (ADL)
20
40
Worsening
Predicted mean level of
dependence (%)
30
50
60
Memantine combination therapy
70
ChEI monotherapy
No medication
80
0
1
2
3
4
Years
Scored from 0% (normal) to
100% dependency
87
*p<0.05 versus no medication;
***p<0.001 versus no medication;
###p<0.001 versus ChEI monotherapy
Atri et al. Alzheimer Dis Assoc Disord 2008; 22: 209–221
Predictive functional dependence
and effect sizes
Years
Cohen’s dADL
1
2
3
4
0.08
0.02
-0.03
-0.06
COMBO vs
No-treatment
0.32*
0.48***
0.60***
0.67***
COMBO vs
ChEI
0.23
0.46***
0.62***
0.73***
3
4
20
Model predicted mean
% dependent (± 95% CI)
1
2
30
Worsening
ChEI vs Notreatment
Years
40
50
60
70
80
COMBO
ChEI group
No treatment
Significantly different from 0; *p<0.05; ***p<0.001
Cohen defined effect sizes as:
“small, d = 0.2”
“medium, d = 0.5”
“large, d = 0.8”
88
Atri et al. Alzheimer Dis Assoc Disord 2008; 22: 209–221
Long-term study of time to institutionalisation
– methods
Lopez et al., 2009
Objectives
 To examine the effect of combination therapy on time to nursing
home admission and time to death
Methods
 A cohort of 429 patients with:



Subjects received:



89
Probable AD (mean MMSE=18.7, SD=5.1)
1+ years of treatment
Analysis 1
No dementia treatment: n=416
ChEI alone: n=387
ChEI + memantine: n=140
Analysis 2
ChEI alone: n=387
ChEI + memantine: n=140
Annual physical/neuropsychological assessments in the clinic
Biannual telephone interviews
Survival analysis was conducted with multivariable Cox
proportional hazard models
Lopez et al. J Neurol Neurosurg Psychiatry 2009; 80 (6): 600–607
Combination therapy delays time to nursing
home placement in AD; does not prolong life
1.00
Memantine + ChEI
0.75
ChEI monotherapy
No dementia
medication
Estimated proportion not
admitted to nursing home
Estimated proportion not
admitted to nursing home
Lopez et al., 2009
0.50
0.25
0.00
1.00
0.75
0.50
0.25
0.00
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
0
1
2
3
4
5
6
7
Follow-up time (years)
Follow-up time (years)
• Patients taking combination therapy were 3–7
times less likely to be placed in a nursing
home than patients receiving ChEI
monotherapy
• No association was found with medication use
and time to death
90
Memantine combination therapy
ChEI monotherapy
Analysis 1
No dementia treatment: n=416
ChEI alone: n=387
ChEI + memantine: n=140
Analysis 2
ChEI alone: n=387
ChEI + memantine: n=140
Lopez et al. J Neurol Neurosurg Psychiatry 2009; 80 (6): 600–607
Vitamin E
91
92
93
94
Dysken JAMA 2014
Antipsychotic use in AD
“YOUR REFLEXES SEEM FINE
MR. HART”
97
Risperidone Efficacy: Meta-Analysis (BEHAVE-AD)
Target
symptom
Mean
difference
from placebo
P-value
95% CI
Risperidone 1 mg
Psychosis
-0.79
P=0.03
-1.31, -0.27
Risperidone 1 mg
Aggression
-0.84
P=0.0002
-1.28, -0.40
Risperidone 2 mg
Aggression
-1.50
P<0.0001
-2.05, -0.95
Ballard & Howard. Nat Rev Neurosci . 2006; 7(6):492–500.
98
Adverse Events with Risperidone
Adverse Events
Dose/Day
Risperidone
Placebo
Odds Ratio
95% CI
P-value
Extrapyramidal
symptoms
1 mg
32/500
20/571
1.78
1.00, 3.17
P<0.05
2 mg
35/165
12/163
3.39
1.69, 6.80
P=0.0006
Gait
1 mg
21/402
1/408
7.47
2.21, 25.28
P=0.001
1 mg
138/665
72/685
2.36
1.71, 3.24
P<0.00001
2 mg
46 /165
13/163
2.36
2.30, 8.64
P<0.00001
Respiratory tract
infection
1 mg
15/149
6/163
2.93
1.11, 7.76
P=0.03
Fever
2 mg
24/165
12/163
2.14
1.03, 4.44
P=0.04
0.5 mg
24/149
9/163
3.29
1.47, 7.32
P=0.004
1 mg
32/315
15/333
2.43
1.29, 4.59
P=0.006
2 mg
30/165
9/163
3.80
1.74, 8.29
P=0.0008
Somnolence
Peripheral edema
Ballard & Howard. Nat Rev Neurosci. 2006;7(6):492–500.
99
Meta-Analysis: Negative Impact of Antipsychotic Treatment
on Cognition (MMSE)
WMD: 0.73 [0.38, 1.09]
100
Schneider et al. Am J Geriatr Psychiatry. 2006;14(3): 191–210.
Meta-analysis: Risperidone Increases Risk of
Cerebrovascular Events in AD
Number of cerebrovascular adverse events before end of treatment at 8–13 weeks
101
Ballard et al. Cochrane Database of Systematic Reviews. 2006, Issue 1. Art. No.: CD003476. DOI: 10.1002/14651858.CD003476.pub2.
Mortality and Antipsychotics in People with Dementia
Trial Information
Summary of the Results
FDA
Meta-analysis of 17 placebocontrolled trials of atypical
neuroleptics in AD
Significant 1.7-fold increase
in mortality with neuroleptics
Schneider et al.
JAMA 2005
Meta-analysis of 15 placebocontrolled trials of atypical
neuroleptics in AD
Significant 1.54-fold
increased mortality risk, with
absolute increase of 1%
 Wang et al. NEJM 2005:
mortality risk even higher with typical antipsychotics
FDA Alert [6/16/2008]; Schneider et al. JAMA. 2005;294(15):1934–1943; Wang et al. N Engl J Med. 2005;353(22):2335–2341.
102
DART-AD differential survival: antipsychotics
are associated with increased mortality risk
80
Relative risk= 1.8
Log rank p=0.02
70
Survival rate (%)
60
50
40
30
20
10
0
24
36
42
Number of months
103
Survival rate on placebo
71%
59%
53%
Survival rate on a antipsychotic
46%
30%
26%
Ballard et al. Lancet Neurol 2009; 8 (2): 151–157
Antipsychotic treatment
 Over short-term treatment periods atypical
antipsychotics, particularly risperidone, shown
to have modest efficacy (effect size, d~0.2)
 Modest efficacy has to be balanced against
potential risks/detrimental effects in estimating
individualized risk-benefit calculus
 With longer-term treatment, benefits are less
clear-cut and the risks of severe adverse
outcomes increase
104
105
Porsteinsson JAMA 2014
Practical Multifactorial Management of AD
Necessary
• Early detection,
assessment & staging
• Sustained targeting
& tailoring to patient,
caregivers &
environment
107
Atri A. Am J Manag Care. 2011.
Practical Multifactorial Management of AD
Necessary
• Early detection,
assessment & staging
• Sustained targeting
& tailoring to patient,
caregivers &
environment
108
Atri A. Am J Manag Care. 2011.
Non-Pharmacological
Interventions
• Psycho-education
• Behavioral interventions
• Fostering support
networks
• Monitoring health,
safety & environment
• Caring for Caregivers
Non-pharmacological Interventions
& Behavioral Approaches:
• Psycho-education including:
• AD dementia in general and effects on cognition,
function and behaviors
• Dementia care expectations
• The “progression and regression model of aging and
dementia”
109
Non-pharmacological Interventions
& Behavioral Approaches:
• Behavioral approaches – both general and targeted to the patientcaregiver dyad; these include:
• Simplification of environment
• Establishing routines
• Providing a safe, calm, and consistent care environment
• Utilizing strategies such as
• interacting calmly
• redirection to pleasurable activities and environment
• reassurance
• providing only necessary information in a manner that the
patient can appreciate (i.e., in simple language and small
chunks) and at the appropriate time
• “benign therapeutic fibbing”
• “Never saying No” to “allow the moment to pass”
110
Non-pharmacological Interventions
& Behavioral Approaches:
• Establishing and fostering support networks for the patient and
caregivers
• Identifying and monitoring health and safety risks for patient and
others needs
• stove
• weapon
• driving safety
• falling prey to fraud
• poor work or financial decision making
• Advance planning for medical, legal and financial decision-making
• Caring for Caregivers, including caregiver support and respite care
111
Practical Multifactorial Management of AD
Necessary
• Early detection,
assessment & staging
• Sustained targeting
& tailoring to patient,
caregivers &
environment
112
Atri A. Am J Manag Care. 2011.
Non-Pharmacological
Interventions
• Psycho-education
• Behavioral interventions
• Fostering support
networks
• Monitoring health,
safety & environment
• Caring for Caregivers
Pharmacological
• Eliminate inappropriate
medications
• Stage-appropriate
combination therapy
• Cautious and judicious
use of other
medications when
necessary
Elimination of redundant and inappropriate medications
see Beers Criteria
113
Medications to avoid in older cognitively impaired individuals; adapted from
Beers Criteria (AGS, 2012)
Elimination of redundant and inappropriate medications
see Beers Criteria
114
Medications to avoid in older cognitively impaired individuals; adapted from
Beers Criteria (AGS, 2012)
Treating Underlying Conditions that
Exacerbate Dementia Symptoms
• “Treating” underlying medical and psychiatric conditions that can
exacerbate dementia symptoms, including:
• dehydration
• sleep problems/dysregulation
• obstructive sleep apnea
• pain
• constipation
• infections
• electrolyte and metabolic derangements
• anxiety
• depression
• psychosis
• fear
115
When to Start?
• “Early”: start AChEIs (cholinesterase-inhibitors)*,
stablize
• How early?
• Need to have an informed discussion with patient
116
FDA label indication:
1. ChEI’s:
Donepezil: mild, moderate and severe AD
Galantamine & Rivastigmine: mild to moderate AD
2. Memantine (NMDA antagonist): moderate to severe AD
RCTs of ChEIs in MCI:
Failure to meet a priori specified primary end points; a big caveat
for donepezil on other outcome measures
Long-term
‘conversion’ trials
‘Symptomatic’ trials
Primary outcomes
Other outcomes
Donepezil
Rivastigmine
Galantamine
ADCS
InDDEx
(3-4 years)
Gal 11 and Gal 18
(2 years)
-
-
Negative
Negative
-
-
(3 years)
401 (24 weeks)
412 (52 weeks)
Negative
ADCS: Significant delay in
conversion all groups for
first 24 months (RR
reduction of 58% at 12
months; 36% at 24
months), and throughout
entire 36 month trial for
APOE-e4 carriers
401 & 402: Positive
outcomes on modified
ADAS-cog
117
Salloway S, et al. Neurology. 2004;63:651–657 Petersen RC, et al. N Engl J Med. 2005;352:2379-88
Feldman HH, et al. Lancet Neurol. 2007;6:501-12; Winblad etal Neurology 2008;70:202402035
Doody R, et al.Neurology 2009;72:1555-61
118
119
When to Start?
• Early: start AChEIs (cholinesterase-inhibitors)*,
stablize
* Unless severe/active/unstable GI bleed/PUD,
arrhythmia/cardiac dz, seizure disorder, syncope
add memantine** (or vice-versa)
** unless poor kidney function (GFR<30 then cut dose in ½)
• Sustain multi-modal care and pharmacological Tx
120
FDA label indication:
1. ChEI’s:
Donepezil: mild, moderate and severe AD
Galantamine & Rivastigmine: mild to moderate AD
2. Memantine (NMDA antagonist): moderate to severe AD
General Considerations
 Remove deleterious medications; slowly start and maintain combination
treatment with ChEI and memantine-add-on; treat exacerbating and
comorbid conditions; promote quality sleep, life and health
121

Reduce stress

Reduce excessive EtOH intake

Promote restorative sleep (diagnose and treat sleep apnea)

Promote general physical, social & mental activity and health (and
good diet and exercise)

Treat anxiety and depression that is not responsive to behavioral
interventions and combination treatment with ChEI+memantine

Consider ECASA 81, Vitamin E* (*unless severe cardiovascular disease,
on blood thinners, bleeding history/diathesis), Vitamin C, Vit B6/B12/folate

RESIST antipsychotics, NO BENZODIAZIPINES
Atri, A. Effective Pharmacological Management of Alzheimer’s Disease. Am J Managed Care, 2011.
What else to screen for (cont.)
Screening for:
Home Safety
Public Safety - DRIVING
Medico-legal and legal issues
Stress, depression and support services for
caregiver - CARE FOR THE CAREGIVER
122
123
124
Current Trends in Effective
Multifactorial Management of AD
Necessary
• Early detection,
assessment & staging
• Sustained targeting
& tailoring to patient,
caregivers &
environment
Non-Pharmacological
Interventions
• Psycho-education
• Behavioral interventions
• Fostering support
networks
• Monitoring health,
safety & environment
• Caring for Caregivers
Caregivers are the glue
• Sustained therapeutic alliance
• Tailored to patient & support
environment
• Safety first
• Pragmatic: simplification of care routine
where possible, consider preferences
125
Atri A. Am J Manag Care. 2011.
Pharmacological
• Eliminate inappropriate
medications
• Stage-appropriate
combination therapy
• Cautious and judicious
use of other
medications when
necessary
When to Stop?
• End/Terminal-Stage Dementia/AD: non-verbal, no
meaningful interaction or personhood, nonambulatory
• No indication for ANY medications (except for
comfort)
126
Multiple ways to define treatment
benefits
Assessing benefits
Mean changes in
symptom domains
Placebo
Active
Stabilisation
Improvement
+
+
Cognition
Cognition
0
Behaviour
0
Behaviour
ADLs
-
-
Less than
expected decline
+
0
127
Inter-relationship between
symptom domains
ADLs
Treatment expectations versus
expected decline
Global symptom
severity
Mild
Successful
treatment
Untreated
Severe
Time
128
Geldmacher et al. J Nutr Health Aging 2006; 10: 417–429
Why Diagnose and Treat as Early as
Possible?
Ethically:
 Primum non nocere (“Above all, do no harm”)
 Nonmaleficence: proven safety
 Beneficence:


proven efficacy (decrease progression and delay emergence
and severity of symptoms)
prevent harm from exploitation, promote safety
 Autonomy: patients and families should be masters of
their fate
 Justice: care should be available to all
129
Why Diagnose and Treat as Early as Possible?
Medically:






Greater opportunity to care for patient and families
Pathways are potentially most viable and function at its highest
(cognition, daily living functions, behavior, quality of life)
Proven clinically significant benefits in populations of patients
Allow patients to make own life decisions (medical, legal, financial,
social, psychological) and to make beneficial lifestyle changes
Possibility of entering clinical trials for experimental medications
Minimizes the potential of being exploited or abused
Economically: overall advantageous


130
Depends on who is paying
Delaying late-stage dementia makes economic sense
Effective Multifactorial Management of AD
Early detection,
education,
communication,
care coordination
& support
Pharmacological:
reduce potential
for harm; slow
clinical decline
using approved antiAD medications;
judicial use of other
Rx as needed
Provide meaningful benefits
to patients, families &
caregivers
131
Atri A. Am J Manag Care. 2011.
NonPharmacological:
behavioral
strategies; ongoing
monitoring of
health & safety and
providing support
to patient &
caregivers
Summary
 Early diagnosis and management of AD is ethically,
medically, scientifically and economically supported
 Multifactorial AD care involves a combination of nonpharmacological and pharmacological approaches; it can:
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ameliorate current symptoms
delay and reduce emerging problem behaviors
reduce the pace of overall clinical decline
delay nursing home placement
lower the impact of illness on patients and caregiver
provide palliation
Provide cumulative and meaningful benefits over the
course of illness
To cure sometimes
To help often
To console always
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