1 Alireza Atri, MD, PhD Associate Director, Clinical Programs, Geriatric Research Education &...

Alireza Atri, MD, PhDAssociate 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

Alzheimer’s Dementia: Overview of Evaluation and Care

Disclosure/conflict of interestAlireza 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)

Human beings are members of a whole,In creation of one essence and soul,If one member is afflicted with painOther 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)

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 patient-caregiver dyad basis

Best standard of care treatments combine behavioral and pharmacological treatments, education & care of the patient and caregivers

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

Costs of caring for individuals with Alzheimer’s disease:

Worldwide: $604 billion in 2010 (>1% of world GDP)U.S: 190-220 billion (direct costs)

Global impact of AD

AD is the sixth leading cause of mortality in the U.S. and the only one that is increasing …

Projected numbers of people with AD in the U.S.

AD risk factors and the amyloid cascade hypothesis

Amyloid deposition Microglial

activation Neurofibrillarytangles Neuronal loss/

neurochemical changes

DEMENTIA

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

Age geneticsCardiovascular risk factors

Other age-related brain diseases

Amyloid-βaccumulation

Synaptic dysfunction; glial activation;

tangle formation;neuronal death

Cognitive decline

Brain and cognitive reserve? Environmental factors

Hypothetical model of AD pathophysiological cascade

Concept of co-occurrence of Vascular Disease & AD pathology in Dementia

VaD AD

Spectrum of CVD

MRI Infarction

Stroke

White Matter Hyperintensities

Brain Atrophy

AD Spectrum occurs on a continuum of severity from No Mild Marked impairment

*MCI = mild cognitive impairment

% of end-stage AD100

40 50 7060 80

PRECLINICALphase

MCIphase

DEMENTIAphase

Onsetof MCI*

Clinical diagnosisof AD

Estimated start of amyloid deposition

Age (years)

Degree of cognitiveimpairment

The basic dementia work-up

• 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”

• 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?

• Fallacy 2a: “I can simply rely on the information provided by my patients to make my decisions”

• 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”

• 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 well-controlled but now with escalating # of admissions in the last 2 years due to “out of control diabetes”, “hypoglycemia”, and “exacerbations of CHF”

• Fallacy 2a: “I can simply rely on the information provided by my patients to make decisions”

• Fact 2a: Need to “Trust but verify” – need objective and reliable corroboration to form an informed impression and plan of care

• 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”

• 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

1. Normalize and explain

2. Reliable information

3. Sensitive measures of all domains1. Cognition (e.g. MoCA)

2. Function (ADL measure; e.g. FAQ)

3. Behavior & Neuropsychiatric symptoms (e.g. Neuropsychiatric Inventory)

Why & How To Screen?

Suggestions for Dementia Screening and Tracking Instruments

1. Global Screen:1. AD8

2. Function - Activities of Daily Living:1. FAQ (Functional Assessment Questionnaire scale)2. IADLs3. PSMS

3. Neuropsychiatric/Behavioral (aka. Non-cognitive Behavioral Symptoms, NCBS): 1. NPI (Neuropsychiatric Inventory)

4. 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)

5. Staging, Severity, “Global”:1. CDR (Clinical Dementia Rating Scale)2. FAST3. CIBIS-PLUS4. GDS

ORIENTATION 10 ( )

Spatial: 5 ( ) What is the: (year) (season) (date) (day) (month)

Temporal: 5 ( ) 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 ( ) Ask for the names of the three objects learned above. Give one point for each correct answer.

LANGUAGE 9( )

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: /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

Suggestions for Dementia Screening Instruments

1. Global screening instrument:1. AD8

2. Function - Activities of Daily Living:1. FAQ (Functional Assessment Scale)

3. Neuropsychiatric/Behavioral: 1. NPI (Neuropsychiatric Inventory)

4. Cognitive screen:1. MOCA (Montreal Cognitive Assessment) 2. Blessed Dementia Scale Information-Memory-Concentration

(BDS-IMC scale, aka. “Right side” of the Blessed)3. Addenbrooke’s Cognitive Exam Revised (ACE-R)

Scored out of 30

Cut off for Impairment:

<26* (100% specificity)

*Add 1 point if ≤ 12 yrs education

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 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: 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

b. Frontal systems dysfunction: executive dysfunction or poor judgment & reasoning

c. Visuospatial dysfunction

d. Language (communication) dysfunction

e. Personality changes & Behavioral dysfunction

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)

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)

• 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

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)

Basic Dementia Workup

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

Dynamic Biomarkers of the Alzheimer’s Spectrum Pathological Cascade

Jack CR et al. Lancet Neurol. 2010

Structural Imaging: MRI vs CTMRI>>CT (if no contraindication) and can significantly change your management

MRI is better at detecting: Atrophy (e.g. hippocampal atrophy, ventricular enlargement

““Normal”Normal” ““Moderate Atrophy”Moderate Atrophy”

Scheltens, P. Imaging in AD. Dialogues in Clinical Neuroscience (2009)

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 (2009)

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

microangiopathic changes) and micro/lacunar infarcts Microhemorrhages (non-acute) Hydrocephalus

Selective Use of Additional Tests Under Special Circumstances

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

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. 83-87%)

Hansson et al. Lancet Neuro, 2006; Li et al. Neurology, 2007

FDG and PIB PET in early AD (82 yo MMSE 27)

K. Johnson MGH

MULTIFACTORIAL Treatment of Alzheimer’s disease

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

Antidepressants Antipsychotics** (**risperidone approved by EMA for short-term treatment of

refractory severe agitation & psychosis in AD dementia) Vitamin E, C

Other pharmacological agents taken Gingko biloba, cerebrovascular agents, antioxidants, statins, anti-inflammatories,

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 BIDPatch: 9.5-13.3 mg/24h

Multiple R DB PC trials 6 months. 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 BID28 mg XR QD

Multiple R DB PC trials 6 months. Moderate to severe

Few AE’s; occ. mild transient confusion ~weeks3-5

4-step titration to max dose, one 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 moderate to severe trials

Few AE’s; mild transient confusion ~weeks3-5

RTC data in mild AD lacking; observational studies support long-term benefits

Vitamin E 1000 IU BID Two R DB PC trials moderate to severe trial

Few AE’s More robust effects on slowing functional than on cognitive decline; “Controversy” re:Survival data

AChEI & Memantine Combination Therapy

RATIONALE & BIOLOGICAL EFFECT

Memantine + donepezil combination therapy – potential synergistic mode of action

Cholinergic neuron

MemantineGlutamatergic

neuron

Donepezil

Cortex

Hippocampus

Acetylcholine

Glutamate

AcetylcholinesteraseAChE

Acetylcholine receptor

NMDA receptor

Memantine + donepezil synergistically affect ACh release in experimental rat model

Hippocampal levels of acetylcholine in rats

Memantine5 mg/kg (n=11)

Memantine + donepezil (n=11)

Donepezil0.5 mg/kg (n=11)

Ihalainen et al. Neuropharmacology 2011; 61 (5-6): 891–899

Experiment conducted in the presence of 5 M neostigmine*p<0.05 (t-test; t=2.6) versus sumSum=sum of increases elicited by each drug individually

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

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

Tariot PN, et al. JAMA 2004; Grossberg et al. CNS drugs 2013; Porsteinsson AP, et al. Curr Alzheimer Res 2008

Study 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)

202(105 memantine + donepezil;97 donepezil monotherapy)

Combination therapy benefits cognition

Severe Impairment Battery (SIB)

*p<0.05; **p<0.01; ***p<0.001 versus donepezil monotherapy Tariot et al. JAMA 2004; 291 (3): 317–324

rsenin

Baseline 4 8 12 18 24

Study week

Endpoint (LOCF)

Donepezil monotherapy

Combination therapy (DPZL+MEM)

Post hoc analyses of cognitive effects

Cognitive subscales (SIB): Memory (p<0.05) Language (p<0.05) Praxis (p<0.05)

Post hoc-derived functional communication and language subscales: 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

Benefits for memantine combination therapy (versus donepezil monotherapy) on:

Combination therapy benefits function

Activities of Daily Living inventory (ADCS-ADL19)

*p<0.05 versus donepezil monotherapy Tariot et al. JAMA 2004; 291 (3): 317–324

Baseline 4 8 12 18 24

Study week

rsenin

-4Endpoint (LOCF)

Combination therapy (DPZL+MEM)Donepezil monotherapy

Post hoc analyses of functional effects

Functional single items (ADCS-ADL19): Grooming (p<0.01) Watching TV (p<0.01) Finding belongings (p<0.01)

Functional subscales (ADCS-ADL19): 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

Benefits for memantine combination therapy(versus donepezil monotherapy) on:

Donepezil monotherapy

Combination therapy benefits behavior

Neuropsychiatric Inventory (NPI)

**p<0.01; ***p<0.001 versus donepezil monotherapy Cummings et al. Neurology 2006; 67 (1): 57–63

rsenin

Study week

Endpoint (LOCF)

0 12 24

Combination therapy (DPZL+MEM)

Post hoc analyses of behavioral effects

Behavioral domains (NPI): 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

Significantly less caregiver distress, due to the patient’s: 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

Benefits for memantine combination therapy (versus donepezil monotherapy)

*Occurring in ≥5% of patients in either treatment group

Most frequent adverse events* (%)

Combination (n=202)

Donepezil monotherapy (n=201)

Total patients with AEs

Discontinuations due to AEs

Agitation

Confusion

Influenza-like symptoms

Dizziness

Headache

Urinary tract infection

Urinary incontinence

Accidental injury

Upper respiratory tract infection

Peripheral edema

Diarrhea

Fecal incontinence

Tariot et al. JAMA 2004; 291 (3): 317–324

Confusion was more common in patients receiving combination therapy, but this did not lead to more discontinuations

Gastrointestinal AEs possibly ameliorated by combination therapy

Fewer patients receiving combination therapy discontinued due to AEs

Agitation possibly ameliorated with combination therapy

Combination Therapy (ChEI + memantine) in AD – Phase III, EFFICACY placebo‑controlled 24-week studies

Tariot PN, et al. JAMA 2004; Grossberg et al. CNS drugs 2013; Porsteinsson AP, et al. Curr Alzheimer Res 2008

Study 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)

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)

202(105 memantine + donepezil;97 donepezil monotherapy)

Evidence LevelCombination (ChEI with add-on memantine)

Efficacy RCTs

Measuring Magnitude of Clinical Effects (clinical significance) - Effect Sizes

Source: Cohen J. (1988). Statistical power analysis for the behavioral sciences (2nd ed.).Hillsdale, NJ: Lawrence Earlbaum Associates.

• 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:

Small d = 0.2

16 yr. old 15 yr. old

Medium d = 0.5

Large d = 0.8

Atri & Molinuevo, et al. Alzheimer Res Ther. 2013 Jan 21;5(1):6

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)

Combination Treatment has good safety profile (meta-analysis; MMSE<20)

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, double-blind, 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

Howard et al. N Engl J Med 2012; 366: 893–903SMMSE=Standardised Mini Mental State Examination

Start memantinen=73

Receiving drug at end of study

n=38 (52%)

Continue donepezil

Start placebon=73

n=34 (47%)

Continue donepezil

Start memantinen=76

n=27 (36%)

Discontinue donepezil for placebo

Start placebon=73

n=20 (27%)

Discontinue donepezil for placebo

Randomised N=295

“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

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

Howard et al. N Engl J Med 2012; 366: 893–903Kaplan–Meier actuarial plot of the cumulative probability of withdrawal from the assigned study drug

Days since randomisation3640 42 126 210

Continue donepezil vs. discontinue donepezil

Hazard ratio: 0.5195% CI: 0.36 to 0.72

p<0.001

Start memantine vs. start placeboHazard ratio: 0.66

95% CI: 0.47 to 0.93p=0.02

Memantine + donepezil

Placebo + donepezil

Memantine + discontinue donepezil

Placebo + discontinue donepezil

Memantine + donepezil

Visit week

6 18 30 520

provement

Placebo + discontinue donepezil

Memantine + discontinue donepezil

Multilevel modelling repeated-measures regression; SMMSE=Standardised Mini Mental State Examination; BADLS=Bristol Activities of Daily Living Scale Howard et al. N Engl J Med 2012; 366: 893–903

Visit week

6 18 30 520

) Improvem

Placebo + donepezil

*indeterminate (underpowered) by week 52

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

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: 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 LevelCombination (ChEI with add-on memantine) Long-Term

Observational Controlled Effectiveness Studies

Combination therapy slows long-term decline in cognition (BDS)

Years1 2 3 40

Worsening

*p<0.05, **p<0.01, ***p<0.001 versus no medication; #p<0.01, ###p<0.001 versus ChEI monotherapy

# 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)

No medication

ChEI monotherapy

Memantine combination therapy

Atri et al. Alzheimer Dis Assoc Disord 2008; 22: 209–221

Predictive cognitive scores and effect sizes

Cohen’s dBDS Years

1 2 3 4

Cohen defined effect sizes as:“small, d = 0.2”“medium, d = 0.5”“large, d = 0.8”

Worsening

1 2 3 4

No treatmentChEI groupCOMBO

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

No treatmentn=144

Average enrolment year

Average time in study

Cognition: Blessed Dementia Scale (BDS)

Function: Weintraub Activities of Daily Living (ADL)

Mixed effects and GEE modeling analysis of 4-year trajectory of progression

•Are there differences long term?

•Are there benefits or detriments long term?

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)

Outcomemeasures

BSC=best standard care

2 years

ChEI alonen=122

2.2 years

Memantine + ChEI (COMBO) n=116

3.3 years

Atri et al., 2008

382 patients at Mass General Memory Disorders Unit (1990–2006)

Combination therapy slows long-term decline in function (ADL)

Worsening

1 2 3 40

*p<0.05 versus no medication; ***p<0.001 versus no medication;

###p<0.001 versus ChEI monotherapyScored from 0% (normal) to 100% dependency

No medication

ChEI monotherapy

Cohen’s dADL Years

1 2 3 4

Predictive functional dependence and effect sizes

Significantly different from 0; *p<0.05; ***p<0.001

Worsening

1 2 3 4Years

ChEI vs No-treatment

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***

Cohen defined effect sizes as:“small, d = 0.2”“medium, d = 0.5”“large, d = 0.8”

No treatmentChEI groupCOMBO

Long-term study of time to institutionalisation – methods

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:

Probable AD (mean MMSE=18.7, SD=5.1) 1+ years of treatment

Subjects received: 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

Lopez et al., 2009

Analysis 1No dementia treatment: n=416ChEI alone: n=387ChEI + memantine: n=140

ChEI alone: n=387ChEI + memantine: n=140

Analysis 2

• 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

Combination therapy delays time to nursing home placement in AD; does not prolong life

Follow-up time (years)

70 1 2 3 4 5 6

ChEI monotherapy

Analysis 1No dementia treatment: n=416ChEI alone: n=387ChEI + memantine: n=140

ChEI alone: n=387ChEI + memantine: n=140

Analysis 2

Lopez et al. J Neurol Neurosurg Psychiatry 2009; 80 (6): 600–607

Follow-up time (years)

20.00.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5

Memantine + ChEI

ChEI monotherapyNo dementiamedication

Lopez et al., 2009

Vitamin E

94 Dysken JAMA 2014

Antipsychotic use in AD

“YOUR REFLEXES SEEM FINEMR. HART”

Risperidone Efficacy: Meta-Analysis (BEHAVE-AD)

Targetsymptom

Meandifference

from placeboP-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.

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

Somnolence1 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

Peripheral edema

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

Ballard & Howard. Nat Rev Neurosci. 2006;7(6):492–500.

Adverse Events with Risperidone

Meta-Analysis: Negative Impact of Antipsychotic Treatment on Cognition (MMSE)

Schneider et al. Am J Geriatr Psychiatry. 2006;14(3): 191–210.

WMD: 0.73 [0.38, 1.09]

101Ballard et al. Cochrane Database of Systematic Reviews. 2006, Issue 1. Art. No.: CD003476. DOI: 10.1002/14651858.CD003476.pub2.

Meta-analysis: Risperidone Increases Risk of Cerebrovascular Events in AD

Number of cerebrovascular adverse events before end of treatment at 8–13 weeks

Mortality and Antipsychotics in People with Dementia

Wang et al. NEJM 2005:

mortality risk even higher with typical antipsychotics

Trial Information Summary of the Results

FDAMeta-analysis of 17 placebo-

controlled trials of atypical neuroleptics in AD

Significant 1.7-fold increase in mortality with neuroleptics

Schneider et al. JAMA 2005

Meta-analysis of 15 placebo-controlled trials of atypical

neuroleptics in AD

Significant 1.54-fold increased mortality risk, with

absolute increase of 1%

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.

DART-AD differential survival: antipsychotics are associated with increased mortality risk

Ballard et al. Lancet Neurol 2009; 8 (2): 151–157

Number of months

Survival rate on placebo 71% 59% 53%

Survival rate on a antipsychotic 46% 30% 26%

24 36 42

Relative risk= 1.8Log rank p=0.02

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

105 Porsteinsson JAMA 2014

107 Atri A. Am J Manag Care. 2011.

Necessary • Early detection,

assessment & staging

• Sustained targeting& tailoring to patient, caregivers & environment

Practical Multifactorial Management of AD

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”

• Behavioral approaches – both general and targeted to the patient-caregiver 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”

• 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

Pharmacological• Eliminate inappropriate

medications

• Stage-appropriate combination therapy

• Cautious and judicious use of other medications when necessary

Elimination of redundant and inappropriate medicationssee Beers Criteria

Medications to avoid in older cognitively impaired individuals; adapted from Beers Criteria (AGS, 2012)

Elimination of redundant and inappropriate medicationssee Beers Criteria

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

• “Early”: start AChEIs (cholinesterase-inhibitors)*, stablize

• How early?

• Need to have an informed discussion with patient

When to Start?

FDA label indication: 1. ChEI’s:Donepezil: mild, moderate and severe ADGalantamine & Rivastigmine: mild to moderate AD2. Memantine (NMDA antagonist): moderate to severe AD

RCTs of ChEIs in MCI:RCTs of ChEIs in MCI:Failure to meet Failure to meet a priori a priori specified primary end points; a big caveat specified primary end points; a big caveat

for donepezil on other outcome measuresfor donepezil on other outcome measures

DonepezilDonepezil RivastigmineRivastigmine GalantamineGalantamine

Long-term Long-term ‘‘conversionconversion’’ trials trials

ADCSADCS

(3 years)(3 years)InDDEx InDDEx

(3-4 years) (3-4 years) Gal 11 and Gal 18 Gal 11 and Gal 18

(2 years)(2 years)

‘‘SSymptomaticymptomatic’’ trialstrials

401 (24 weeks)401 (24 weeks)

412 (52 weeks)412 (52 weeks)-- --

Primary outcomesPrimary outcomes NegativeNegative NegativeNegative NegativeNegative

Other outcomesOther outcomes

ADCSADCS: Significant delay : Significant delay in conversion all groups in conversion all groups for first 24 months (RR for first 24 months (RR reduction of 58% at 12 reduction of 58% at 12 months; 36% at 24 months; 36% at 24 months), and months), and throughout entire 36 throughout entire 36 month trial for APOE-e4 month trial for APOE-e4 carrierscarriers

401 & 402401 & 402: Positive : Positive outcomes on modified outcomes on modified ADAS-cogADAS-cog

Salloway S, et al. Neurology. 2004;63:651–657 Petersen RC, et al. N Engl J Med. 2005;352:2379-88Feldman HH, et al. Lancet Neurol. 2007;6:501-12; Winblad etal Neurology 2008;70:202402035

Doody R, et al.Neurology 2009;72:1555-61

• 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

When to Start?

FDA label indication: 1. ChEI’s:Donepezil: mild, moderate and severe ADGalantamine & Rivastigmine: mild to moderate AD2. 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

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 BENZODIAZIPINESAtri, 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

Current Trends in Effective Multifactorial Management of AD

Atri A. Am J Manag Care. 2011.

Pharmacological• Eliminate inappropriate

medications

• Stage-appropriate combination therapy

• Cautious and judicious use of other medications when necessary

Caregivers are the glue• Sustained therapeutic alliance

• Tailored to patient & support environment

• Safety first

• Pragmatic: simplification of care routine where possible, consider preferences

When to Stop?

• End/Terminal-Stage Dementia/AD: non-verbal, no meaningful interaction or personhood, non-ambulatory

• No indication for ANY medications (except for comfort)

Multiple ways to define treatment benefits

Stabilisation

Assessing benefitsPlacebo Active

Less thanexpected decline

Improvement

Mean changes in symptom domains

Cognition

ADLsBehaviour

Inter-relationship between symptom domains

ADLsBehaviour

Cognition

128 Geldmacher et al. J Nutr Health Aging 2006; 10: 417–429

Severe

Untreated

Successful treatment

Treatment expectations versus expected decline

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

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 Depends on who is paying Delaying late-stage dementia makes economic sense

Effective Multifactorial Management of AD

Early detection, education,

communication,care coordination

& support

Non-Pharmacological:

behavioral strategies; ongoing

monitoring of health & safety and providing support

to patient & caregivers

Pharmacological: reduce potentialfor harm; slow clinical decline

using approved anti-AD medications;

judicial use of other Rx as needed

Provide meaningful benefits to patients, families &

caregivers

Atri A. Am J Manag Care. 2011.

Summary

Early diagnosis and management of AD is ethically, medically, scientifically and economically supported

Multifactorial AD care involves a combination of non-pharmacological and pharmacological approaches; it can: 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 sometimesTo help oftenTo console always

1 Alireza Atri, MD, PhD Associate Director, Clinical Programs, Geriatric Research Education &...

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