yaakov stern, phd columbia university
TRANSCRIPT
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Cognitive Reserve: An Evolving Concept
Yaakov Stern, PhD
Columbia University
Financial Disclosure
I have financial relationships to disclose:
Employee of: Columbia University
Consultant for: AXOXANT, Lilly, Takeda
Stockholder in: none
Research support from: NIH, AXOXANT, CA Walnut Commission, Piramal
Honoraria from: occasional academic talks
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What is reserve?
Reserve may explain the disjunction between the degree of brain damage and the clinical manifestation of that damage.
Brain Damage Outcome
Reserve
Mechanisms underlying reserve
• Brain reserve:
– More neurons/synapses to lose
– Brain maintenance: Direct effect of lifestyle/ activities on the brain
• Cognitive Reserve:
– Resilience/plasticity of cognitive networks in the face of disruption
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Passive, threshold model of reserve
Lesion
Lesion
Bra
in R
eser
ve C
apac
ity
FunctionalImpairment
Cutoff
Patient 1 Patient 2
Satz, Neuropsychology 1993
Brain reserve: association between head circumference and Alzheimer’s disease
Schofield, et al, 1997
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Brain reserve is not so simpleThe literature suggests that exercise and environmental stimulation can activate brain plasticity mechanisms and remodel neuronal circuitry in the brain.
They can increase:• Vascularization (exercise)• Neurogenesis in the dentate• Brain volume/Cortical thickness• Neuronal survival and resistance to brain insult • Brain‐derived neurotrophic factor (BDNF) ‐‐benefits brain plasticity processes
• Relative lack of brain pathology is the biggest contributor to heterogeneity of cognitive aging
• Various lifestyle factors contribute to resisting the advent of pathology
• Brain maintenance could account for the current level of brain reserve
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PLoS ONE 2008
Lesion
Bra
in R
eser
ve C
apac
ity
FunctionalImpairment
Cutoff
Patient 1 Patient 2
Lesion
Active model of reserve
Stern, JCEN 2002
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Incident dementia in the Washington Heights study
Group NIncidentCases
RelativeRisk 95% CI
Low Education 264 69 2.02 1.3-3.1
High Education 318 37 1
Low Occupation 327 71 2.25 1.3-3.8
High Occupation 201 17 1
.
Stern et al, JAMA 1994
Valenzuela & Sachdev, Psychological Medicine, 2005
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Literacy and memory decline in non‐demented elders
Manly et al, JCEN 2003
VLS WHICAP
N 1023Mean 14.1SD 3.1
N 3443Mean 9.8SD 4.8
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Association of education with cognitive decline in the Washington Heights study
Model‐estimated cognitive trajectories for 76‐year‐old, White, non‐Hispanic Males born 1900‐1909, recruited in 1992, with low (0‐8 years) or high (9‐20 years) education
Zahodne et al, in press
AD Neuropathology
High Reserve (Education)
Low Reserve (Education)
Score at initial visit
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Time
6543210-1
SR
T T
otal
Rec
all
20
15
10
5
Education Group
Low Predicted
High Predicted
Low Actual
High Actual
More rapid memory decline in AD patients with higher educational attainment
Stern et al Neurology 1999;53:1942-1957
Hall, C. B. et al. Neurology 2007;69:1657-1664
Blue indicates less than 7 years education (32 Ss), red indicates 8 to 11 years (64 Ss), and green indicates 12 or more years education (21 Ss).
Bronx Aging Study
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Father’s occupation
Cognitionat 8 years
Education by 26 years
Own occupationat 43 years
NART at 53
0.380.25
0.50
0.11
0.13
0.36
0.45
0.24
0.20
Richards, JCEN 2003
• Different aspects of life experience contribute independently to CR
• CR is a formative latent variable, not reflective– Important consideration
for summary measures of reserve
• This observation also provides hope that even experiences later in life might contribute to CR
Low reserve
High reserve
mild
AD
no
rma
lM
CI Diagnostic Threshold
ModerateMild
AD Pathology
Clin
ical
Sev
erity
Reserve, AD pathology, and clinical diagnosis
Stern, JINS 2002
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Stern et al, Ann Neurol 1992
Controlling for clinical disease severity, there is an inverse relationship between education and a functional imaging proxy for AD pathology
Education and rCBF
22 years
15 years
18 years
Education * AD path = 0.088, p<.01
Bennett DA et al, Neurology 2003
Interaction of AD pathology and education
Summary Measure of AD Pathology
Glo
bal C
ogni
tive
Fun
ctio
n
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Current study of the neural implementation of cognitive reserve
Task or NP performance,
Clinical Outcome
VolumeCortical ThicknessWMH BurdenWM Tract integrityResting CBFResting connectivityAmyloid burden
Activation Task PerformanceCognitive DomainsFunction / ADLCognitive decline over time/Incident MCI/AD
Measured IQEducation/LiteracyLeisure ActivityCR Network
Age-or AD-related
pathology
Task-relatednetwork
expression
Measured CR orCR-specific
network
BrainMaintenance
CognitiveReserve
The role of education and verbal abilities in altering the effect of age‐related gray matter differences on cognition
Age Group
Volume
GF
Life experience
Steffener et al, PLoS ONE 2014
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Areas with significant mediated moderation
Age Group
Volume
GF
LE
Steffener et al, PLoS ONE 2014
Mediated moderation sample result
Steffener et al, PLoS ONE 2014
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Using Functional Imaging to Study CR• Goal: To understand how cognitive reserve may be neurally implemented. – Emphasis on networks mediating CR, not task performance
• Working hypothesis: CR operates through individual differences in how tasks are processed in the brain.
• Basic approach: Challenge participants with a demanding task and investigate differences in task‐related activation between individuals with high and low CR.
• Assumption: Because CR modulates most aspects of cognitive performance in the presence of pathology, this approach should work with most demanding tasks.
Modified Sternberg Task
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1 3 6
set size
RT
(m
s)
Y
E
”Load-related” activation: the change in activation as set size increasesWe focus on load-related activation because CR might be more related to the coping with increases in task demand than to task-specific features.
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Load‐dependent Activation During Retention: Neural Reserve and Neural Compensation
• Two patterns were expressed during retention
• The primary network was expressed by both groups, but more efficient in the young
• The second network was expressed only by the elders– Higher expression was
associated with poorer performance
– Elders with greater volume loss in the primary network were more likely express it
– Thus this is a compensatory pattern
Zarahn et al., Neurobiol Aging 2007Steffener at al., Brain Imaging and Behavior 2009
Elder Young
Compensatory Network
Gre
ater
Net
wor
k E
xpre
ssio
n
Less Efficient Processing (RT slope)
Primary Network
Steffener and Stern, Biochimica et Biophysica Acta 2012
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A generalized “task‐invariant” neural representation of CR • CR allows people to better maintain function in
multiple activities and cognitive domains in the face of brain pathology.
• If a particular brain network subserves CR, it should be active across tasks with varying processing demands.
• Goal: Can we identify a pattern of CR‐related brain activity :– that is common to 12 different tasks– whose expression in other tasks correlates a CR proxy– whose expression moderates the relationship between
cortical thickness and task performance
Deriving a task‐invariant CR network• 255 subjects from RANN study, age 20‐80, with complete neuroimaging
for 12 different tasks
• Randomly divide data into training sample of 200 observations and test sample of 41 observations
• In derivation sample, use scaled Subprofile modeling (SSM) to derive best‐fit NART patterns
• Project derived pattern into test sample and estimate NART in all 12 tasks
• Repeat steps 500 times, each time storing the derived patterns and the test prediction quality
• Compute weighted Z‐map of pattern loadings for the 500 patterns
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-1200 -1000 -800 -600 -400 -200 0 200 40090
95
100
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135
Pattern expression in ECF task
NA
RT
IQ
Single
Dual
Expression of the task‐invariant CR network in a different fMRI activation task (in different people) correlates with NART
-2 -1.5 -1 -0.5 0 0.50.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Subject scores of structural pattern
VO
CA
B a
ccur
acy
p<0.01
High NARTIQ-pattern
Low NARTIQ-pattern
Expression of the task‐invariant CR network moderates between cortical thickness and task performance
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Clinical Implications: Cognitive reserve, aging and AD
• Two individuals who appear the same clinically, whether demented of non‐demented, can have widely divergent levels of underlying age‐related neural changes or AD pathology.
• Thus, the clinical diagnosis of normal aging, MCI or AD may be accompanied by very minimal pathology or more than enough to meet pathological criteria for AD.
• Measuring CR therefore becomes an important component of diagnosing and characterizing aging and dementia.
Clinical implications: Cognitive reserve, aging and AD
• Optimal clinical evaluation of age‐related cognitive change or AD should include:– A measure of pathology
• age‐related atrophy, amyloid imaging
– A measure of an individual’s CR, that is, the ability the ability to cope with this pathology:
• Proxies for CR such as education or IQ• fMRI measured expression of “CR networks”
• This type of evaluation is important for – early diagnosis and characterization– prognosis– measuring progression over time– assessing of the effect of interventions
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How would reserve‐based interventions work?
Aging/AD Pathology Clinical Disease
BrainReserve
CognitiveReserve
?
Eight out of 11 studies reported that aerobic exercise interventions resulted in … improvements in cognitive capacity.
The largest effects on cognitive function were found on motor function and auditory attention (effect sizes of 1.17 and 0.50 respectively).
Moderate effects were observed for cognitive speed (effect size 0.26) and visual attention (effect size 0.26).
Cochrane Review: Physical activity and enhanced fitness to improve cognitive function in older people without known
cognitive impairment
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Scarmeas et al. JAMA 2009
Physical Activity, Diet and Risk of Alzheimer’s Disease
Problems with cognitive interventions in aging
• Small effect size
• Poor generalization to other cognitive domains (far vs near transfer)
• Poor generalization day‐to‐day functions or IADLs
• Questionable sustainability of effects
• Relation to rate of aging or dementia onset not established
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Space fortress intervention study• Emphasis Change Training:
– Subjects perform the whole task during training, but are required to systematically change their emphasis on major sub‐components of the task.
– Encourages subjects to explore the response alternative space
– Promotes executive control
– Is associated with improved transfer of training
• Our study had 3 groups: 12 weeks of game play with and without emphasis change training, and a no gameplay control groupThe Space Fortress
Game
.0
.3
.5
.8
1.0
1.3
1.5
1.8
2.0
Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week10
Week11
Week12
EC
AC
Fortress Destruction
Space Fortress: Fortress Destruction
Blumen at al, Frontiers in Aging Neuroscience,2010
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8
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Baseline Post
EC AC
PC
Time of Test
Space Fortress: Cognitive Outcome
Stern et al, Aging, Neuropsychology and Cognition, 2012
Scr
een
ing
1st
Bas
elin
e vi
sít
2nd
Bas
elin
e vi
sit
RA
ND
OM
IZA
TIO
N
INTENSIVE INTERVENTION
REGULAR HEALTH ADVICE
INT
ER
VE
NT
ION
KIC
K-O
FF
MINI-INTERVENTION
3 6 9 12 15 18 21 24
NUTRITION:7 group sessions,
3 individual sessions
COGNITIVE TRAINING:9 group sessions
Independent training
EXERCISE:1-2x/wk muscle2-4x/wk aerobic
EXERCISE:2x/wk muscle
4-5x/vk aerobic
EXERCISE:2x/wk muscle strength training
5-6x/wk aerobic training
MONITORING AND MANAGEMENT OF METABOLIC AND VASCULAR RISK FACTORS
Nurse: Visit every 3 months, Physician: 3 additional visits
months
INTERVENTION SCHEDULE
COGNITIVE TRAINING:2 group sessios
Independent training
Kivipelto et al., Alzheimer & Dementia 2013
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What will the large‐scale project to enhance CR look like?
• Healthy elderly population
• Intensive, extensive, combined interventions
• Long‐term follow‐up
• Outcomes:
– Rapidity of cognitive/functional decline
– Incident dementia
Conclusions
• Epidemiologic and imaging evidence support the concept of reserve
• Reserve is malleable: it is influenced by aspects of experience in every stage of life
• Two forms of reserve:– Brain reserve: passive, supported by brain maintenance– Cognitive reserve: active
• The concept of cognitive reserve is applicable to a wide range of conditions that impact on brain function at all ages
• Imaging studies can help clarify the neural implementation of reserve
• Influencing reserve may delay or reverse the effects of aging or brain pathology