CONFIDENTIAL © 2014 PAREXEL INTERNATIONAL CORP.
WORKING GROUP:
BEHAVIORAL AND
PSYCHIATRIC SYMPTOMS
IN DEMENTIA
2/21/17, Washington DC
Co-chairs
Larry Ereshefsky
David Miller
Luca Pani
2
BPSD WORKING GROUP PROPOSAL ABSTRACT
• Objectives: This working group is being convened to focus on the methodological challenges
facing the development of treatments for the Behavioral and Psychiatric Symptoms of Dementia
(BPSD). This group was in part stimulated by the EMA Alzheimer’s Disease Workshop.
• Convey critical importance of treating BPSD, i.e., Apathy as a means to improve patient QOL,
extend patient’s stay in their home environment; improve overall
• Review of lessons learned from ongoing and prior clinical trials for BPSD.
• Proposing innovative trials designs and regulatory acceptance;
• Managing intrinsic variability of symptoms;
– Evolving AD diagnostic and biomarker approaches
– Staging of illness and impact on symptoms, response, study design;
• Regulatory perspectives
• Workshop Deliverables and Action items/Steps to move the field forward
– Extend collaboration with ISTAART PIA; review activities of PIA and FRS for AAIC;
– Finalize program for 2017 Autumn meeting in Paris
– Consider establishing WG team to:
» look at challenges and lessons learned from past/current clin trials to treat BPSD; create
review article, road map, and/or report for presentation at ISCTM or other meetings
3
AGENDA FOR WORKING GROUP ON BPSD
Introductions/Dinner
1. Collaboration between ISTAART, NPS PIA and ISCTM BPSD WG
Co-Chairs – Krista Lanctôt, Joanne Bell PIA
2. Discussion with drug sponsors providing insights Part I:
Agitation/Psychosis/BPSD
3. Discussion with drug sponsors providing insights Part II: Apathy
4. To assess the feasibility/desirability for ISCTM to support a consensus
group.
Identify opportunities and pathways for collaboration with the Biomarkers Consortium even
though the FNIH Endpoints Working Group was not funded
5. Neurocircuitry/Biomarker strategies
6. Action Items/Deliverables:
4
RX OF EXISTING SYMPTOMS OR DELAYS/PREVENTION OF LIKELY TO OCCUR SYMPTOMS OF NPS
5
AGENDA
• Collaboration between ISTAART, NPS PIA and ISCTM
BPSD WG
• Co-Chairs – Krista Lanctôt, Joanne Bell PIA
• Report on joint NPS PIA and BPSD ISCTM activities including featured
research symposium submitted February 1st to AAIC
• Other activities related to ongoing collaborations, including ISCTM
involvement in the PIA Day and ISTAART involvement in Paris ISCTM
meeting
6
AAIC FRS SUBMITTED, LONDON, JULY 16-20, 2017
ADDRESSING THE CHALLENGES IN TREATING APATHY
ASSOCIATED WITH ALZHEIMER'S DISEASE
• Larry Ereshefsky and Krista
Lanctot, co-chairs
• Drug Development and Treatment
of Apathy, David Miller
• Apathy Neurocircuitry, Brain
Imaging Findings and
Implications, David Sultzer
• Examining the Neurocircuitry of
Apathy and Markers of
Neurodegeneration in Early
Alzheimer’s Disease, Gad Marshall
• Pathways Forward in Treating
Apathy: Regulatory Perspectives,
Karl Broich
7
• Session 4: Addressing challenges in the drug development of
behavioral and psychological symptoms in dementia
• The constellation of symptoms/syndromes comprising BPSD (NPS) present
a challenge at all levels of health care, from unmet patient and caregiver
needs, to drug discovery, to clinical trials, as well as to regulatory pathways.
A review of the ‘lessons learned’ from recent efforts to develop drug
treatments for Agitation or Psychosis in neurodegenerative disorders will be
applied to enable methodological discussions on the development of
treatments for Apathy in Alzheimer’s Disease (AD). We will explore how
Apathy symptoms and potential biomarkers ‘evolve’ across the spectrum
from Mild Brain Impairment (MBI) to Mild Cognitive Impairment (MCI) to AD.
What are accepted diagnostic criteria for Apathy in AD and will disease
progression affect treatment targets and assessment tools? How should
pseudo-specificity be addressed in identifying and assessing apathy?
Differentiation from depression and relationship with changes in cognition
will be discussed. What are the challenges of conducting translational and
proof of concept work in patients with Apathy in MBI/MCI? The application of
neurocircuitry strategies and other biomarker approaches in early drug
development could de-risk POC. Regulatory considerations of approaches
and methodologies to improve the likelihood of meaningful signal detection
and acceptable registration trials will be discussed.
8
BEHAVIORAL
AND
PSYCHIATRIC
SYMPTOMS IN
DEMENTIA
(BPSD): A
WAY
FORWARD?
ISCTM
AUTUMN
MEETING, LE
MERIDIEN,
PARIS,
SEPTEMBER
2ND 2017
0830 Background, brief overview of session’s purpose Larry Ereshefsky
Luca Pani
0840 Current drug development for the treatment of Agitation
Address Strengths/weaknesses and trial design considerations of current studies
-- add influence of non drug interventions??
Clive Ballard, King’s College
9:10 Lessons Learned Part II Agitation: Paul Rosenberg,
Johns Hopkins
0940 Discussant, Panel-Audience Discussion: Jill Rasmussen/
Joanne Bell,
1000 Break
1015 Why focus on apathy? David Miller, Bracket
1045 Neuro-circuitry and implications for drug development ; study designs for treatment of
Apathy
Krista Lanctot,
Sunnybrook Health
Sciences Centre,
Toronto
1115 Similarities/differences in the symptoms of apathy in Psychiatry (schizophrenia and
depresson), and in neurodegenerative disorders (Alzheimer’s and Parkinson’s Disease)
Pharma discussant on neurocircuitry strategies: Update on FNIH thinking to address
Apathy/Reward across various diagnostic categories (i.e., assessment tools,
differences in symptom presentation, biological/biomarker implications)
Larry Ereshefsky,
Follow the Molecule
Stephane Pollentier,
Boehringer Ingelheim
(tent)
1200 Regulatory View point(s) EMA confirmed…US view point (necessary?)
Identify a regulatory consultant to provide
Valentina Mantua
and Karl Broich,
EMA
Invite Alzheimer’s
Association, Maria
Carrillo, to comment,
lack funding to
support; would she
be attending ECNP
(to be asked by PIA)
1230-
1 PM
Discussant, Panel-Audience discussionAdjourn
Larry Ereshefsky/
Luca Pani plus
presenters
9
STRATEGIES FOR FDA ENGAGEMENT AND
COMMENTARY IN PARIS SYMPOSIUM
• SC/EC suggested a few strategies:
– Pre-recorded comments from a key FDA Regulator on the path forward for Apathy
– Question/Answer interview, also pre-recorded with symposium leader, incorporating
content from the presentations (will require advance input from presenters)
– Less likely, more complex, ‘live’ videoconferencing. Session on Saturday, runs
afternoon to evening EST
– Available by phone to provide comments or Q/A
• Would also ask Valentina, Luca, and/or Karl to highlight in their comments that describe
areas of communication and engagement between EMA and FDA
Drug development for Behavioral
Symptoms of Dementia:
Methodological Challenges and
Potential Solutions
CEDRIC O’GORMAN MD
THE BPSD WORKING GROUP
WASHINGTON D.C.
21 FEBRUARY 2017
Background: The Need for BPSD
medicines
No approved treatments for BPSD
Lack of required studies to support efficacy of antipsychotics for BPSD or psychosis of dementia
Many negative and some positive registrational studies – what can we learn?
Non-approved use of existing antipsychotics (20-50%1) and other sedative medications have serious safety concerns (increased mortality, CVAs, drowsiness, falls, increased morbidity)
Class labelling for atypical antipsychotics (weight, type 2 diabetes, metabolic syndrome and hyperlipidemia)
BPSD are highly prevalent and a leading cause of institutionalization
Clinicians and regulators recognize the need for newer safer and effective treatments for BPSD
1. Feng, Z. et al. (2009) Use of physical restraints and antipsychotic
medications in nursing homes. Int J Geriatr Psychiatry 24: 1110–1118.
Challenges in the development of
medicines for BPSD
Clinical Trial Design Considerations
Patient Population – Who? What? Where? (At home vs. In assisted-living; nursing homes etc)
Diagnosis
Symptom Eligibility: Duration, Severity and Frequency
Duration of treatment
Patient-reported outcomes
Role of the caregiver
Rating, Raters & Rater Training
Understanding how placebo response may differ in this setting
Trial design (traditional, adaptive, placebo-lead in, SPCD, Enrichment, Learn & Confirm, Arm-dropping)
Clinical Trial Collaborators (adjudication and monitoring)
Trajectory of response versus endpoint analysis
Role of non-pharmacologic intervention
Allowance of concomitant meds?
Challenges in the development of
medicines for BPSD
Choosing an appropriate outcome measures: Primary & Secondary
A number of reliable and valid measures of agitation/aggression
Sensitivity of outcome measures to change over time
Qualitative versus Quantitative
Pseudo-specificity
Clinical Meaningfulness
Harm vs. Benefit – Composite Endpoint of Safety and Efficacy
The Role of Cognition, Functioning and Quality of Life
Regulatory Path
With no approved medicines for BPSD, the regulatory path is unclear
Special Considerations in an Elderly Population
Reduced burden of assessments on the patient
Concomitant Medications
Safety
Death
Potential strategies to address
methodological challenges
Despite lack of approved therapies, much clinical data has been generated
How can we best utilize these existing data to inform future clinical design?
Great variability in criteria across studies
Industry Partner Collaboration
Both drug developers and regulators are keen to see drugs approved for BPSD
How can developers and regulators partner in the development of a consensus
statement/guidance document for BPSD clinical development?
Plans for White Paper and Consensus Statement
Participants from Industry, Regulatory authorities, Clinicians, Researchers,
Organizations
15
2016 WG PRIOR COMMENTS: HOW DOES STAGE OF ILLNESS INTERACT WITH DRUG DEVELOPMENT STRATEGY AND APPROVAL?• NPSD has fluctuating course over illness• Symptom clusters, are these fixed and useful aggregations?
• i. Study duration• ii . Risk factors and selection of study population• iii. Challenges
• Measurement: Appropriate rating instruments for registration and approval• Influence of patient care environment, culture, and stage of illness on rating
scales validity/reliability• i. Sensitivity of scales
• ii. Use of broad and/or specific scales as primary outcome» Raised as an issue today at EC/SC
» Cohen-Mansfield Agitation acceptable to PMDA? » NPI» BEHAVE- AD
• iii. Assessments and Scales to assess WORSENING of cognition or function, i.e, MMSE, ADCS-ADL mentioned by PMDA; adequate?
• Regulatory questions• Future directions• i. Use of a neurocircuitry based approach modeled on valences and RDOC
16
DISCUSSION POINTS: HOW TO MOVE FORWARD?• Does Pharma have interest, assets and resources to pursue novel
Rx’s of Apathy?– What is the state of the field?
– Lack of current ‘pharma’ sponsored studies for Rx of Apathy highlights the challenges facing us
– We believe there are substantial health care and patient outcome gains in Rx Apathy; yet this is a ’negative’ symptom as compared to agitation and psychosis that are ‘positive’ more ‘evident’ symptoms
• Rx of existing symptoms or delays/prevention of likely to occur symptoms
• Methodologies to address ‘pseudospecificity’ concerns
• Rating and evaluations assessment tools limitations
• Publications will be considered as an interim work product and will evolve to mesh with the publication plans of the PIA
• Develop position paper/roadmap that could lead to broadly supported Consensus Conference to meaningfully move drug development in this field further along
17
Unknown † Evaluation of the Efficacy of Rasagiline in Apathy in Drug-
naïve Patients With Parkinson's Disease by a Multi-center
Study
Drug-naïve Patients With Parkinson's Disease; Apathy
Drug: AZILECT®; Drug: Placebo
Completed Bupropion for the Treatment of Apathy in Alzheimer's
Dementia
Apathy in Dementia
Drug: Elontril; Drug: placebo
Completed Rasagiline and Apathy in Parkinson's Disease
Parkinson's Disease Apathy
Drug: Rasagiline
Completed Apathy Associated With Alzheimer's Disease
Dementia; Alzheimer Disease, Apathy
Drug: Dextroamphetamine; Drug: Methylphenidate
Completed
Has ResultsTreatment of Apathy in Alzheimer's Disease With Modafinil
Apathy; Alzheimer's Disease,
Drug: Modafinil; Drug: Placebo
Active, not recruiting Transcranial Magnetic Stimulation for Apathy in Mild
Cognitive Impairment:Pilot Study
Apathy; Mild Cognitive Impairment
Device: Neurostar repetitive transcranial magnetic stimulator
Recruiting Repetitive Transcranial Magnetic Stimulation for Apathy in
Alzheimer's Dementia
Apathy; Alzheimer's Dementia
Device: Neurostar repetitive transcranial magnetic stimulator
Completed
Has ResultsMethylphenidate for Apathy in Alzheimer's Dementia: A
Controlled Study
Alzheimer's Disease; Apathy; Dementia
Drug: Methylphenidate; Other: Placebo
Recruiting Non Motors Aspects in De Novo Parkinson's Disease
Parkinson Disease; Apathy
Drug: Rotigotine; Drug: Placebo
Has ResultsTrial to Evaluate The Efficacy Of Rotigotine on Parkinson's
Disease-Associated Motor Symptoms And Apathy
Idiopathic Parkinson's Disease, Apathy
Drug: Rotigotine; Other: Placebo
18
Completed Study of Rivastigmine to Treat Parkinsonian Apathy Without
Dementia
Parkinson's Disease; Apathy; no Dementia
Drug: rivastigmine; Drug: placebo
Terminated
Has Results
Exploring the Use of Transdermal Methylphenidate to Reduce
Fall Risk in Patients With Dementia.
Dementia; Accidental Falls; Apathy
Drug: Transdermal Methylphenidate
Recruiting Apathy in Dementia Methylphenidate Trial 2
Apathy; Alzheimer's Disease
Drug: Methylphenidate; Drug: Placebo
Unknown † Improving Function, Quality of Life, Glycemia in Diabetics With
Dementia
Diabetes Mellitus; Alzheimer's Disease; Apathy; Dementia
Drug: Methylphenidate; Drug: Placebo
Recruiting Efficacy of RIVAstigmine on Motor, Cognitive and Behavioural
Impairment in Progressive Supranuclear Palsy
Progressive Supranuclear Palsy (PSP), behavioral impair
Drug: Rivastigmine; Drug: Placebo
Unknown † Efficacy of Continuous Apomorphine Infusion on Cognitive and
Neuropsychological Functions in Parkinson's Disease
Parkinsons's Disease NPS
Drug: Continuous Apomorphine infusion; Drug: Usual dopaminergic
per os treatment
Completed Long-Term Effects of Amantadine in Parkinsonian (AMANDYSK)
Parkinson's Disease
Drug: mantadix
Completed D-serine Adjuvant Treatment for Parkinson's Disease
Parkinson's Disease
Drug: D-serine (~2g/day)
19
Completed Serotonergic Function and Behavioural and Psychological
Symptoms of Frontotemporal Dementia
Frontotemporal Dementia, NPS
Drug: Citalopram
Completed
Has Results
"Pilot Study of Armodafinil in Patients With Dementia With Lewy
Bodies"
Dementia With Lewy Bodies, Attention deficits
Drug: Armodafinil
Completed Study of Methylphenidate to Treat Gait Disorders And Attention
Deficit In Parkinson's Disease (PARKGAIT-II)
Parkinson's Disease; Attention deficits, Gait Disorders; Dementia
Drug: methylphenidate; Drug: placebo
Terminated Multicenter Placebo Controlled Study to Assess the Effect of
Rasagiline on Sleep-wake Disturbances in Patients With Parkinson's
Disease
Parkinson's Disease Sleep disturbance
Drug: Rasagiline
Completed Rasagiline in Cognitive-impairment Related Depression: AzileCt in
COgnitive-impairment Related DepressiOn
Depressive Symptoms; Parkinson's Disease
Drug: Rasagiline; Drug: Placebo
Terminated Amantadine for the Treatment of Behavioral Disturbance in
Frontotemporal Dementia (FTD)
Dementia NPS
Drug: amantadine
Completed Efficacy Assessment of Three Non Pharmacological Therapies in
Alzheimer's Disease
Alzheimer's Disease
Behavioral: Standard intervention protocol; Behavioral: Standard
intervention protocol + Cognitive training therapy; Behavioral: Standard
intervention protocol + Reminiscence therapy; Behavioral: Standard
intervention protocol + "Made-to-measure" program
20
Completed
Has Results
Aripiprazole in the Treatment of Patients With Psychosis Associated
With Dementia of Alzheimer's Type
Dementia, Alzheimer Type, psychosis
Drug: Aripiprazole (BMS-337039); Drug: Placebo
Completed
Has Results
Rotigotine Versus Placebo to Evaluate the Efficacy on Depressive
Symptoms in Idiopathic Parkinson's Disease Patients
Idiopathic Parkinson's Disease
Drug: Rotigotine; Drug: Placebo
Completed Study of Memantine for Gait Disorders And Attention Deficit In
Parkinson's Disease
Parkinson's Disease; Gait Disorders, Neurologic
Drug: memantine; Drug: placebo
Recruiting INfusion VErsus STimulation in Parkinson's Disease
Parkinson's Disease
Drug: Continuous intrajejunal infusion of levodopa-
carbidopa; Device: deep brain stimulation
Completed
Has Results
Tango for Treatment of Motor and Non-motor Manifestations in
Parkinson's Disease.
Parkinson's Disease
Other: Argentinean Tango classes; Other: Simple pamphlet about the exerci
se in PD
Recruiting Transcranial Direct Current Stimulation for Depression in
Alzheimer's Disease Patient - Preliminary Research
Alzheimer Disease; Depression
Device: Transcranial Direct Current Stimulation; Other: Sham Stimulation
Completed
Has Results
Rasagiline for the Symptomatic Treatment of Fatigue in Parkinson's
Disease
Parkinson's Disease, Fatigue
Drug: Rasagiline; Drug: Placebo
21
AGENDA
5. Neurocircuitry/Biomarker strategies
• How do reward and hedonic pathways relate to apathy studies in AD?
• Discussion on role of MBI (mild behavioral impairment) in apathy,
neurocircuitry/biomarker studies, differentiation with depression?
22
SUMMARY OF BRAIN FUNCTION AND BEHAVIOUR: ARE THESE
QUANTIFIABLE BY NEUROCIRCUITRY APPROACHES ACROSS
DEMENTIAS?
Ref: Rivard And Puxty BPSD Handbook for Family Physicians 2009
Behavioral and Psychiatric Symptoms in Dementia WG ISCTM Feb 2017
S. Pollentier*
* = Full time employee of Boehringer Ingelheim
This presentation represents my individual opinion
• Topics to be covered
– Clinical Endpoints Working group proposal for the
Biomarkers Consortium/FNIH
– ECNP Experimental Medicines Working Group
meeting March 15 Leiden/Netherlands
– IMI-initiative PRISM
Co-chairs: Jenni Pacheco, PhD, NIMH;
Stephane Pollentier, MD, Boehringer Ingelheim
Clinical Endpoints Working Group: To identify a clinical
outcome measure for “anhedonia, amotivation“ appropriate for
use in late stage drug development (i.e. regulatory acceptable)
• Literature review 2015
• Workshop on behavioral measures around the positive
valence system – February 2016
• Project Concept Proposal November 1, 2016
• Scale development is cumbersome
• Reluctant industry support
• Concerns of contruct validity
• Acceptance issues across CNS disorders
• Why repeat attempts which have failed?
Parsing Anhedonia - Reward Processing(Der-Avakian, Trends in Neurosci, 2012)
Reward Deficits Animals Humans Circuits
ConsummatorySucrose intake/
preference
CPAS/CSAS
SHAPS
FCPCS
• NAc, ventral pallidum, OFC
AnticipatoryPositive/negative
contrastTEPS
• ACC, OFC, mPFC, basal
ganglia, thalamus,
hypothalamus
Motivational
Effort-based tasks (e.g.,
progressive ratio,
concurrent choice, ICSS)
EEfRT
• VTA to NAc
• Amygdala
• vmPFC to NAc
• ACC
• Lateral hypothalamus
Learning
Response Bias
Probabilistic Reward
Task
• Dorsal basal ganglia
(caudate)
• ACC
RDoC - Positive Valence domainConstructs & Sub-constructs & Tasks
1. Reward Responsiveness
1.1. Initial Response to Reward Simple Guessing Task
1.2. Reward Anticipation Monetary Incentive Delay Task
1.3. Reward Satiation Fixed-ratio Satiation Schedule
2. Reward Learning
2.1. Habit Devaluation Task ; Habit Task
Habit Learning Task
2.2. Probabilistic & Reinforcement
Learning
Probabilistic Reward Task
Pavlovian Conditioning
Drifting double bandit
Probabilistic Stimulus Selection Task
2.3. Reward Prediction Error Rutledge Passive Lottery Task
Drifting double bandit
3. Reward Valuation
3.1. Reward (probability) Probability Choice Task
Willingness To Pay Task
3.2. Delay Delayed Discounting Task
3.3. Effort Effort Expenditure for Reward TaskNational Advisory Mental Health Council Workgroup on Tasks and Measures for RDoC , April 5-6, 2016
Immediate wins of a pilot study proposal
• Establish standardization of manuals and methodology (task
parameters)
• Evaluate performance in multi-site setting
• Confirm use of measures across spectrum of CNS disorders
• Generate traction for inclusion in industry sponsored drug
development studies
• Lay foundation for further qualification process steps and
additional tools – and a next project aimed at validation
Concept Proposal for a Pilot Study
• Indications / Target populations:
• indications that have an anhedonia component as a deficiency such as stable schizophrenia; early Parkinson‘s disease ; abstinent cocaine users ; …)
• N= 80 to 100 subjects
• Pragmatic selection of tests :
– Response Bias Probabilistic Reward Task
– Effort Expenditure for Rewards Task
• Multi-site setting: > 3 sites
• Estimated Budget= 0.5 Million tbc
Decision: proposal not considered in line with BC objectives (too close to „clinical endpoint“)
ECNP Experimental Medicine Network Validation of Reward Processing tasks15th March 2017
Location: Leiden University Medical School.LUMC Building 2 (Research building), Einthovenweg 20NL-2333 ZC LEIDEN
(Approx 20 mins direct train journey from Schiphol, Amsterdam).
Information if interested: [email protected] Dawson ([email protected])
10.30 1. Introduction and welcome
a. Overview of objectives for the meeting Gerry
Dawson
10.45 2. Review of reward processing
a. Overview of available tasks
b. Clinical experience with the PRT
c. An academic perspective on task validation
Diego
Pizzagalli
11.45 3. Why do we need validated reward processing task
for drug discovery
a. The need to validating tasks for use in clinical trials
b. Potential routes to validation?
c. Summary of US biomarker consortium discussions
Stephane
Pollentier
ECNP Experimental Medicine Network
Validation of Reward Processing tasks 15th March 2017
ECNP Experimental Medicine Network
Validation of Reward Processing tasks 15th March 2017
1.00 4. Methodologies
a. IoP experience with reward
processing
b. Uni. of Manchester experience with
reward processing
c. Reward Processing and EEG
Mitul Mehta
Bill Deakin
Valerie Bertaina-Anglade
2.30 5. Perspectives from:
Roche
Lundbeck
Janssen
Heptares
TDB
Søren Rahn Christensen
Peter de Boer
Pradeep Nathan
3.30 6. Discussion & Next Steps
IMI-Project PRISM
Measured by Smart Phone App
Effort-Expenditure for Reward Task
Plos One 2009;4(8)
Measure of Reward
Valuation
Choose hard or easy taskProbability of win: 12 – 50 – 88%
Response Bias Probabilistic Reward Task
Measure of Reward Learning
40 of 100 trials inform on RewardBias toward Rich rewarded (30:10)
Discriminate 11.5 vs 13 mm
NEUROCIRCUITRY/ BIOMARKER STRATEGIES
( S L I D E S N OT P R E S E N T E D D U E TO T I M E C O N S T R A I N T S )
Krista L. Lanctôt, PhDSenior Scientist, Sunnybrook Research Institute;Head, Neuropsychopharmacology;Professor of Psychiatry and Pharmacology, University of Toronto
ISCTM Workgroup Meeting, Washington, Feb 2017
NEUROCIRCUITRY/ BIOMARKER STRATEGIES
How do reward and hedonic pathways relate to apathy studies in AD?
QUESTIONS
Are the reward/anhedonia/social/apathy related evaluations discussed in many ways looking to the subdivisions of RDOC domains suitable for apathy in AD (and other neurodegenerative disorders)?
Neurocircuitry/Biomarker strategies
How do reward and hedonic pathways relate to apathy studies in AD?
Discussion on role of MBI (mild behavioural impairment) in apathy, neurocircuitry/biomarker studies, differentiation with depression
APATHY IN AD IS LINKED TO SPECIFIC NEUROBIOLOGICAL FACTORS
Regional Cortical Atrophy
anterior cingulate, orbitofrontal
+/- Dorsolateral PFC, medial frontal, basal ganglia
White Matter Lesions
Frontal or diffuse white matter hyperintensities
Regional Hypometabolism
anterior cingulate, medial OF, (medial thalamus)
Regional Hypoperfusion
Anterior cingulate, mid OF, (DLPFC, Basal ganglia)
Cortical Receptors
Low DA transporter in putamen
Low ACh binding in L frontal cortex
Apathy Workgroup. NPS PIA. Lanctot et al
Alzheimer’s Dement 2017
OPTIMIZING TREATMENT OF APATHY IN ALZHEIMER’S DISEASE
1. Neuroimaging
• SPECT shows patients with
apathy have alterations in
rCBF in crucial areas of the
brain reward system
Lanctôt et al 2007
SPECT—SHOWS NONDEPRESSED AD PATIENTS WITH APATHY HAVE DIFFERENCES IN RCBF IN AREAS CRUCIAL TO DA BRAIN REWARD SYSTEM
0.000.100.200.300.400.500.600.700.800.901.00
rCBF R
atio
Apathetic n=23
Non-Apathetic n=28
Lanctôt et al 2007
OPTIMIZING TREATMENT OF APATHY IN ALZHEIMER’S DISEASE
200
450
Baseline 60 min 120 min 180 min 240 min
AR
CI P
os
itiv
e E
ffe
cts
Co
mp
os
ite
Apathetic (n=13)
Non-Apathetic (n=7)
2. Pharmacologic challenge—
• In AD patients (n=20) apathetic
patients experience fewer
positive effects following D-
AMPH challenge Repeated
Measures ANOVA F1,17
=4.93,
p=0.04
• Suggests differences in the
DAergic systemLanctôt et al 2008
OPTIMIZING TREATMENT OF APATHY IN ALZHEIMER’S DISEASE
3. Clinical trial
• Pilot data show apathy decreases
following methlyphenidate
• D-Amph challenge predicts response
Herrmann et al 2008
-20
-15
-10
-5
0
5
AES Total NPI Total MMSE
Methylphenidate Placebo
APATHY IN DEMENTIA METHYLPHENIDATE TRIAL (ADMET)
Double blind, placebo-controlled, 6-week, 3-centre* RCT in 60 patients with AD
efficacy and safety of methylphenidate (20 mg/d) for clinically significant apathy in AD
Rosenberg, Lanctôt, et al 2013
Supported by the National Institute for Aging R01 AG033032-01
PRIMARY OUTCOMES
0%
5%
10%
15%
20%
25%
methylphenidate placebo
% moderate or marked improvement on CGIC
o Odds ratio (95% CI) for improvement in CGI-C was 3.7 (1.3, 10.8) (p=0.02)
Rosenberg, Lanctôt et al J Clin Psychiatry 2013
Supported by the National Institute for Aging R01 AG033032-01
Mean (SD) 6-week change in AES scores was -1.9 (1.5) for methylphenidate and 0.6 (1.4) for placebo (p=0.23)
SECONDARY OUTCOMES• NPI Apathy score
improvement 1.8 points (95% CI 0.3, 3.4) greater in methylphenidate vs. placebo (p=0.02)
-10
-5
0
5
10
15
baseline week 6 change
Mean (SE) NPI apathy score
methylphenidate placebo
• MMSE showed trend favouringmethylphenidate: estimated difference of 1.5 (95% C.I. -0.1, 3.1) (p=0.06)
-5
0
5
10
15
20
25
baseline week 6 change
Mean (SE) MMSE score
methylphenidate placebo
Rosenberg, Lanctôt et al J Clin Psychiatry 2013
Supported by the National Institute for Aging R01 AG033032-01
MBI
MBI-MILD BEHAVIOURAL IMPAIRMENT
MBI criteria, proposed by the International Society to Advance Alzheimer's Research and Treatment (ISTAART) (Ismail et al., 2016) changes in behavior or personality observed by the patient, informant, or
clinician starting in later life (age ≥50 years)
persisting at least intermittently for a minimum of 6 months (Ismail et al., 2016).
change from the person’s usual behavior or personality as evidenced by at least one of the following five domains: decreased motivation (i.e. apathy),
affective dysregulation,
impulse control,
social inappropriateness
abnormal perception or thought content
impairments in social, occupational, or interpersonal function must be attributable to NPS, and not to cognitive decline in MBI.
APATHY AND MBI
39.2% of elderly subjects with MBI had apathy from a community based sample (Barcelos-Ferreira et al., 2015).
Taragano et al. demonstrated an apathy prevalence of 29.4% among geriatric outpatients (Taragano et al., 2009).
MCI AND APATHY
neuroimaging studies reveal consistent abnormalities within regions responsible for motivation such as the anterior cingulate and frontal regions (Grambaite et al., 2011)
Apathy in MCI has also been associated with reduced fronto-parietal control network connectivity (Munro et al 2015)
lower inferior temporal cortical thickness (Guercio et al., 2015b)
significantly decreased metabolism in the posterior cingulate cortex (Delrieu et al., 2014)
greater amyloid burden (Marshall et al 2013)
Abnormalities in frontal regions (associated with impairments in planning and decision making) and anterior cingulate (related to emotional blunting and loss of motivation) consistently associated with apathy in AD and MCI. (Stella 2014)
DIAGNOSTIC CRITERIA
core feature of apathy, diminished motivation, present x ≥4 weeks
2/3 dimensions of apathy (reduced goal-directed behaviour, goal-directed cognitive activity, and emotions) present
identifiable functional impairments attributable to apathy
exclusion criteria are specified to exclude symptoms and states that mimic apathy
Inter-rater reliability high (kappa 0.93, p=.0001)
Robert et al 2009, Mulin et al 2011
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AGENDA
6. Workshop Deliverables and Action items/Steps to move the
field forward
– Establish sub-groups that:
» Focus on lessons learned in seeking approval for Rx’s of Agitation and
Psychosis; develop a methodologies paper summarizing challenges and
strategies to address
» Work to develop a road-map (or white paper, publication) that forms the
basis of our efforts to further treatment of Apathy in dementia
– Extend collaboration with ISTAART PIA; review activities of PIA and FRS
for AAIC;
– Finalize program for 2017 Autumn meeting in Paris
– Consider establishing WG team to:
» look at challenges and lessons learned from past/current clin trials to
treat BPSD; create review article, white paper, and/or report for
presentation at ISCTM or other meetings
Luca [email protected]
Italian Medicines Agency
European Medicines Agency
Comments
ISCTM Working GroupFebruary 2017, Washington DC