5_Atri

Transcript 5_Atri

Alzheimer’s Dementia: Overview of Evaluation and Care 1 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

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 2  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)

3 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)

Overview

    4 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

5 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

Global impact of AD

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)

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.

Hypothetical model of AD pathophysiological cascade

AD risk factors and the amyloid

Age genetics Cardiovascular risk factors Other age-related brain diseases

cascade hypothesis

• • • • • • • •

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

60 70 80 90 AGE 30 40 50

Amyloid β accumulation

Amyloid deposition Microglial activation

Synaptic dysfunction; glial activation; tangle formation; neuronal death Brain and cognitive reserve ? Environmental factors Cognitive decline

Neurofibrillary tangles Neuronal loss/ neurochemical changes DEMENTIA

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

VaD AD

Spectrum of CVD

Stroke MRI Infarction White Matter Hyperintensities Brain Atrophy

AD Spectrum occurs on a continuum of severity from No



Mild



Marked impairment % of end-stage AD 100 80 60 PRECLINICAL phase 40 20 0 Degree of cognitive impairment 40 50 Onset of MCI* Clinical diagnosis of AD 60 MCI phase 70 DEMENTIA phase 80 Age (years) Estimated start of amyloid deposition

*MCI = mild cognitive impairment

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

The basic dementia work up

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?

The basic dementia work-

information provided by my patients to make

up

• 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: • HTN, mild depression, anxiety and insomnia is admitted

up

along with her outpatient anti-HTN medication regimen  blood pressure falls from 169/88 to 76/43 15 • 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”

The Fallacies & Facts regarding screening - Why & How To Screen?

•

The basic dementia work-

information provided by my patients to make

up

• 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

The basic dementia work-

practice”

up

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 work-

1. Normalize and explain

up

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)

Suggestions for Dementia Screening and Tracking Instruments

19 1.

Global Screen:

AD8 1.

Function - Activities of Daily Living:

FAQ (Functional Assessment Questionnaire scale)

IADLs PSMS Neuropsychiatric/Behavioral (aka. Non-cognitive Behavioral Symptoms, NCBS):

NPI (Neuropsychiatric Inventory)

Cognitive Screen:

MOCA (Montreal Cognitive Assessment) (screen MCI/mild dementia)

Blessed Dementia Scale Information-Memory-Concentration (BDS-IMC scale, aka. “Right side” of the Blessed) (Tracking) 3.

SLUMS (St. Lois Univ. Mental Status exam) Addenbrooke’s Cognitive Exam Revised (ACE-R) Staging, Severity, “Global”:

CDR (Clinical Dementia Rating Scale)

FAST CIBIS-PLUS 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

( )

MMSE

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)

[Number of trials ____ ] Then repeat them (up to 6x) until all three are learned.

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( ) 22 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: (1 point)

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]

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

Global screening instrument: AD8 1.

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

Neuropsychiatric/Behavioral: NPI (Neuropsychiatric Inventory)

Cognitive screen:

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

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

27   

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 28 a. Memory dysfunction: anterograde; deficit in acquisition, storage or retrieval of new information

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

30 c. Visuospatial dysfunction

31 d. Language (communication) dysfunction

32 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)

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)

39 •

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

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)

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

42  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

 Brain Amyloid-beta Biomarkers:   CSF A-beta 42 Amyloid PET neuroimaging  Neurodegeneration Biomarkers:   FDG PET (synaptic) CSF Tau (neuronal injury)  Structural MRI (volume) 43 Jack CR et al. Lancet Neurol. 2010

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” “Moderate Atrophy”

44 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. Feb (2):89-98; and Scheltens, P. Imaging in AD. Dialogues in Clinical Neuroscience 45 (2009)

Lancet Neurology.

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  Microhemorrhages (non-acute) 46 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

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.

52 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

Donepezil Rivastigmine Galantamine Memantine Combination Tx (Memantine added to stable donepezil) Vitamin E 10 mg BID or 28 mg XR QD memantine added to chronic ChEI therapy 1000 IU BID 53

Dosing

5mg or 10mg or 23mg Oral: 3mg-6mg BID Patch: 9.5-13.3 mg/24h 8mg or 12mg BID 10mg BID 28 mg XR QD

Level I Evidence Side Effects Other

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 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 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 Multiple R DB PC trials 6 months. Moderate to severe Two R DB PC moderate to severe trials Few AE’s; occ. mild transient confusion ~weeks3-5 Few AE’s; mild transient confusion ~weeks3-5 4-step titration to max dose, one week apart RTC data in mild AD lacking; observational studies support long-term benefits Two R DB PC trials moderate to severe trial Few AE’s More robust effects on slowing functional than on cognitive decline; “Controversy” re:

AChEI & Memantine Combination Therapy RATIONALE & BIOLOGICAL EFFECT

Memantine + donepezil combination therapy – potential synergistic mode of action

D M M D Hippocampus Cortex D M M NBM Cholinergic neuron Glutamate Acetylcholine AChE Acetylcholinesterase Acetylcholine receptor NMDA receptor D M Donepezil Memantine D D AChr M Glutamatergic neuron 55

Memantine + donepezil synergistically affect ACh release in experimental rat model

Hippocampal levels of acetylcholine in rats

800 600 400 200 56 0 Donepezil 0.5 mg/kg (n=11) Sum Memantine 5 mg/kg (n=11) Memantine + 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 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 57  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 Study

Tariot et al., 2004 (MD-02) Grossberg et al.

2013 (MD-50)

Type of memantine therapy (20 mg/day)

10 mg BID Added to stable donepezil therapy (5 –10 mg/day for ≥3 months) 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)

Duration (weeks)

MMSE inclusio n criteria

5 –14, inclusive 24 3-14, inclusive

Number of patients MMSE <20 + receiving donepezil

403 (202 memantine + donepezil; 201 placebo + donepezil) 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) 58 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) 4 2 0 -2

Combination therapy (DPZL+MEM) Donepezil monotherapy

-4 Baseline 4 8 12 18 Study week 24 Endpoint (LOCF)

*p<0.05; **p<0.01; ***p<0.001 versus donepezil monotherapy

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):

   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) 60 Schmitt et al. Alzheimer Dis Assoc Disord 2006; 20 (4): 255 –262; Saxton et al. 60 th Annual Meeting of the American Academy of Neurology, 2008; Chicago, IL, USA

Combination therapy benefits function

Activities of Daily Living inventory (ADCS-ADL 19 ) 1 0 -1 -2

-3

Combination therapy (DPZL+MEM) Donepezil monotherapy

-4 Baseline 4 8 12 18 Study week *p<0.05 versus donepezil monotherapy 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-ADL 19 ):

 Grooming (p<0.01)   Watching TV (p<0.01) Finding belongings (p<0.01) 

Functional subscales (ADCS-ADL 19 ):

 Connectedness/autonomy (p<0.05)  Higher level functions (p<0.05)  Statistically significant less decline in the

total ADCS-ADL 19 score

Feldman et al. Alzheimer Dis Assoc Disord 2006; 20 (4): 263 –268

Combination therapy benefits behavior

Neuropsychiatric Inventory (NPI) 4 2 0 -2

-4 0

Combination therapy (DPZL+MEM) Donepezil monotherapy

12 Study week **p<0.01; ***p<0.001 versus donepezil monotherapy 24 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):

     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 64 

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* (%)**

Combination (n=202) Total patients with AEs Discontinuations due to AEs 78 7.4

Agitation Confusion Fall Influenza-like symptoms Dizziness Headache Urinary tract infection Urinary incontinence Accidental injury Upper respiratory tract infection Peripheral edema Diarrhea Fecal incontinence 9.4

7.9

5.9

5.4

5.0

4.5

2.0

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

Donepezil monotherapy (n=201) 72 12.4

11.9

2.0

7.0

6.5

8.0

2.5

5.0

3.0

8.0

6.5

4.0

8.5

5.0

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

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

Tariot et al., 2004 (MD-02) Grossberg et al.

2013 (MD-50)

Type of memantine therapy (20 mg/day)

Duration (weeks)

MMSE inclusio n criteria

5 –14, inclusive 24 3-14, inclusive

Number of patients MMSE <20 + receiving donepezil

403 (202 memantine + donepezil; 201 placebo + donepezil) 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) 66 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

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

as: = (difference between means)/(standard deviation) Suggested as a guide that: 68 16 yr. old 15 yr. old

Small d = 0.2

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)

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

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 Continue donepezil Start placebo n=73 Receiving drug at end of study n=34 (47%) Randomised N=295 Continue donepezil Start memantine n=73 Receiving drug at end of study n=38 (52%) Discontinue donepezil for placebo Start placebo n=73 Receiving drug at end of study n=20 (27%) Discontinue donepezil for placebo Start memantine n=76 Receiving drug at end of study n=27 (36%) 74 SMMSE=Standardised Mini Mental State Examination Howard et al. N Engl J Med 2012; 366: 893 –903

75 “Whoa!!! That CAN’T be right!” •

A priori

specified initial target: N target1 =800 • Revised target: N target2 =430 • Enrollment achieved: N actual =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 0.8

0.7

0.6

0.5

Memantine + donepezil Placebo + donepezil Memantine + discontinue donepezil Placebo + discontinue donepezil 0.4

0.3

0.2

0.1

n=72 n=74 n=73 n=72

0.0

0 42 126 210 Days since randomisation

n=20 n=27 n=34 n=38

364 76 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

10 9 8 7 6 5 4 3 2 1 0

0 6 18 30 Visit week 52 Placebo + discontinue donepezil Memantine + discontinue donepezil 78 Multilevel modelling repeated-measures regression; SMMSE=Standardised Mini Mental State Examination; BADLS=Bristol Activities of Daily Living Scale 42 40 38 36

*indeterminate (underpowered) by week 52

34 32 30 28 26 0 6 18 30 Visit week Placebo + donepezil Memantine + donepezil 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: 79  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

Clinical effectiveness studies – Rationale for longitudinal naturalistic observational clinical cohort studies in AD

 Inclusion of ‘real’ patients    Significant comorbidities Concurrent medications Imperfect treatment adherence 80   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 Level Combination (ChEI with add-on memantine) Long-Term Observational Controlled Effectiveness Studies

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

5 10 15 20 25 30 0 Memantine combination therapy ChEI monotherapy No medication 1 2 Years # 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) 82 >16 errors (severe impairment/dementia)

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

3 4

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 d BDS ChEI vs NO-RX 1 0.47*** COMBO vs NO-RX 2 0.39** Years 3 0.32** 4 0.28* 0.56*** 0.73*** 0.76*** 0.77*** COMBO vs ChEI 0.10

0.34** 0.44*** 0.49***

0 1 10 20

COMBO ChEI group No treatment *p<0.05, **p<0.01, ***p<0.001

30 Cohen defined effect sizes as: “small, d = 0.2” “medium, d = 0.5” “large, d = 0.8” 4 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)

•

Are there differences long term?

•

Are there benefits or detriments long term?

No treatment n=144 Atri et al., 2008 382 patients at Mass General Memory Disorders Unit (1990 –2006) ChEI alone n=122 Memantine + ChEI (COMBO) n=116 Average enrolment year Average time in study Outcome measures 1993 2 years 2000 2.2 years Cognition: Blessed Dementia Scale (BDS) Function: Weintraub Activities of Daily Living (ADL) 2002 3.3 years

BSC=best standard care 84

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

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

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

20 30 40 50 60 87 70 80 0 100% dependency Memantine combination therapy ChEI monotherapy No medication 1 Scored from 0% (normal) to 2 Years 3 4

*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 d ADL ChEI vs No treatment COMBO vs No-treatment COMBO vs ChEI 1 0.08

2 0.02

Years 3 -0.03

4 -0.06

0.32* 0.48*** 0.60*** 0.67*** 0.23

0.46*** 0.62*** 0.73***

20 1 30 40 50 60 70 80

COMBO ChEI group No treatment

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

4 Cohen defined effect sizes as: “small, d = 0.2” “medium, d = 0.5” “large, d = 0.8” 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 89

Methods

  Analysis 1 No dementia treatment: n=416 ChEI alone: n=387 ChEI + memantine: n=140 A cohort of 429 patients with:   Probable AD (mean MMSE=18.7, SD=5.1) 1+ years of treatment Analysis 2 ChEI alone: n=387 ChEI + memantine: n=140 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

Combination therapy delays time to nursing home placement in AD; does not prolong life 1.00

0.75

0.50

Memantine + ChEI ChEI monotherapy No dementia medication

Lopez et al., 2009

1.00

0.75

0.50

0.25

0.25

0.00

0.0

2.5

5.0

7.5

10.0

12.5

15.0

Follow-up time (years) 17.5

20.0

0.00

0 Memantine combination therapy ChEI monotherapy 1 2 3 4 Follow-up time (years) 5 • 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 Analysis 1 Analysis 2 ChEI alone: n=387 ChEI + memantine: n=140 6 No dementia treatment: n=416 ChEI alone: n=387 ChEI + memantine: n=140 7 Lopez et al. J Neurol Neurosurg Psychiatry 2009; 80 (6): 600 –607

Vitamin E

94 Dysken JAMA 2014

Antipsychotic use in AD

“YOUR REFLEXES SEEM FINE MR. HART”

Risperidone Efficacy: Meta-Analysis (BEHAVE-AD) Risperidone 1 mg Target symptom Mean difference from placebo

Psychosis -0.79

P-value

=0.03

95% CI

-1.31, -0.27

Risperidone 1 mg Risperidone 2 mg

Aggression Aggression -0.84

-1.50

P P

=0.0002

<0.0001

-1.28, -0.40

-2.05, -0.95

98 Ballard & Howard.

Nat Rev Neurosci .

2006; 7(6):492 –500.

Adverse Events with Risperidone

Adverse Events Extrapyramidal symptoms Gait Somnolence Respiratory tract infection Fever Peripheral edema Dose/Day

1 mg 2 mg 1 mg 1 mg 2 mg

Risperidone

32/500 35/165 21/402 138/665 46 /165 1 mg 15/149 2 mg 0.5 mg 1 mg 2 mg 24/165 24/149 32/315 30/165

Placebo

20/571 12/163 1/408 72/685 13/163 6/163 12/163 9/163 15/333 9/163

Odds Ratio

1.78

3.39

7.47

2.36

95% CI

1.00, 3.17

1.69, 6.80

2.21, 25.28

1.71, 3.24

2.30, 8.64

P-value

<0.05

=0.0006

=0.001

<0.00001

2.93

1.11, 7.76

=0.03

2.14

3.29

2.43

3.80

1.03, 4.44

1.47, 7.32

1.29, 4.59

1.74, 8.29

=0.04

=0.004

=0.006

=0.0008

99 Ballard & Howard.

Nat Rev Neurosci.

2006;7(6):492 –500.

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

100 Schneider et al.

Am J Geriatr Psychiatry.

2006;14(3): 191 –210.

WMD: 0.73 [0.38, 1.09]

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 FDA Schneider et al. JAMA 2005

Meta-analysis of 17 placebo controlled trials of atypical neuroleptics in AD Meta-analysis of 15 placebo controlled trials of atypical neuroleptics in AD

Summary of the Results

Significant 1.7-fold increase in mortality with neuroleptics 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.

103

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

Relative risk= 1.8

Log rank p=0.02

80 70 60 50 40 30 20 10 0 Survival rate on placebo Survival rate on a antipsychotic 24 71% 46% 36

Number of months

59% 30% 42 53% 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 104  With longer-term treatment, benefits are less clear-cut and the risks of severe adverse outcomes increase

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

Non-Pharmacological Interventions

• • • Psycho-education Behavioral interventions Fostering support networks • Monitoring health, safety & environment • Caring for Caregivers 108 Atri A.

Am J Manag Care

. 2011.

Non-pharmacological Interventions & Behavioral Approaches:

109 • 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”

110

Non-pharmacological Interventions & Behavioral Approaches:

• 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”

111

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

Practical 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

Pharmacological

• Eliminate inappropriate medications • Stage-appropriate combination therapy • Cautious and judicious use of other medications when necessary 112 Atri A.

Am J Manag Care

. 2011.

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)

115

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

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 117 Long-term ‘ conversion ’ trials ‘S ymptomatic ’ trials Primary outcomes Other outcomes

Donepezil

ADCS (3 years) 401 (24 weeks) 412 (52 weeks) Negative

Rivastigmine

InDDEx (3-4 years) -

Galantamine

Gal 11 and Gal 18 (2 years) Negative 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 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) 120 • Sustain multi-modal care and pharmacological Tx 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

121  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 BENZODIAZIPINES

Atri, A. Effective Pharmacological Management of Alzheimer’s Disease.

Am J Managed Care

, 2011.

122

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

123

124

125

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

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 Atri A.

Am J Manag Care

. 2011.

126

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)

127

Multiple ways to define treatment benefits

Mean changes in symptom domains

Cognition Behaviour ADLs

0 + Assessing benefits Placebo Active

Improvement Stabilisation

+ Inter-relationship between symptom domains

Cognition

Behaviour ADLs

Less than expected decline

+ 0 -

128

Treatment expectations versus expected decline

Mild Successful treatment Untreated Severe Time

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

129

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

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 130

Effective Multifactorial Management of AD

Early detection, education, communication, care coordination & support Pharmacological: reduce potential for harm; slow clinical decline using approved anti AD medications; judicial use of other Rx as needed Non Pharmacological: behavioral strategies; ongoing monitoring of health & safety and providing support to patient & caregivers Provide meaningful benefits to patients, families & caregivers

131 Atri A.

Am J Manag Care

. 2011.

Summary

132   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

133