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					Cognitive Reserve

     Yaakov Stern
  Columbia University
 Qu’est-ce que la réserve?

  Altérations                   Manifestations
  cérébrales                    cliniques
                    Réserve



La réserve peut expliquer la disjonction entre
le degré d’altération cérébrale et les
manifestations cliniques de ces lésions.
  Active vs. Passive Models

One convenient, although not entirely
accurate, subdivision of reserve models is
whether they envision reserve as a passive
process, or see the brain as actively
attempting to cope with or compensate for
pathology.
        Passive Models

• Brain Reserve
• Neuronal Reserve
• Threshold
 Threshold Summarized by Satz (1993)
• Hypothetical construct: “Brain Reserve
  Capacity” (BRC)
• Concrete examples of BRC: brain size,
  neuronal count
• There is individual variation in BRC
• Education is one index of BRC
• There is a critical threshold of BRC. Once
  depleted past this critical point, specific
  clinical or functional deficits emerge.
Passive, Threshold Model
Brain Reserve Capacity
                          Lesion


                                     Lesion


                                                  Functional
                                                 Impairment
                                                    Cutoff




                         Patient 1   Patient 2
  Threshold: a passive model of
             reserve
• Assumes that there is some fixed cutoff or
  threshold at which functional impairment
  will occur.
• Quantitative vs. Qualitative
  – Assumes that a specific type of brain damage
    will have the same effect in each person.
  – Does not recognize individual differences in
    processing cognitive or functional tasks in the
    face of by brain damage.
        Active Model of
            Reserve
• Relies on the quality of the response -- not
  the amount of BRC.
• Relies more on the “software” than the
  “hardware”
• Reserve can vary when BRC is held
  constant
                            Active Model


                                      Lesion
Brain Reserve Capacity



                          Lesion

                                                  Functional
                                                 Impairment




                         Patient 1   Patient 2
          Cognitive Reserve
• Resilience/plasticity of cognitive networks
  in the face of disruption
  – Neural Reserve: efficiency/capacity of existing
    brain networks
  – Neural Compensation: ability to adapt alternate
    networks or brain areas
       Research Approach
Brain Damage             Outcome
               Reserve


Attempt to hold one or more components
constant and allow the others to vary
Brain Reserve: Association Between Head
 Circumference and Alzheimer’s Disease




                             Schofield, et al, 1997
Brain Reserve is Not So Simple
Exercise and environmental stimulation can
activate brain plasticity mechanisms and remodel
neuronal circuitry in the brain.
They can increase vascularization, neuronal
survival and resistance to brain insult, BDNF,
serotonin, dopamine, IGF-1, neurogenesis in the
dentate.
Isn’t more flexible thinking mediated by neurons
and synapses anyway?
   Advancing AD Pathology




Initiation   Promoting              Diagnosis   Death
Factors      Factors


                         Clinical
                         Symptoms
                         Appear
Incident Dementia in The Washington
           Heights Study

                        Incident      Relative
    Group         N      Cases         Risk       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
                 Father’s
                occupation
0.11                           0.25
                     0.38

                 Cognition
                 at 8 years
       0.20           0.45
                Education
                by 26 years

                      0.36

              Own occupation
0.24            at 43 years
                               0.50


                     0.13


               NART at 53
                                      Richards, JCEN 2003
                       High Reserve

Low Reserve




 Age-related Neural Changes
Literacy and memory decline
   in non-demented elders




                 Manly et al, JCEN 2003
                                  High Reserve (Education)

        Low Reserve (Education)




Score at initial visit




              AD Neuropathology

                                  Stern et al Neurology 1999
More rapid memory decline in AD patients
   with higher educational attainment
     SRT Total Recall   20




                        15




                                                                   Education Group
                        10
                                                                     Low Predicted

                                                                     High Predicted

                                                                     Low Actual

                        5                                            High Actual
                         -1   0   1   2          3   4   5     6

                                          Time

                                                             Stern et al Neurology 1999
Progression of composite cognitive score
    before and after incidence of AD




                            Scarmeas et al, JNNP, 2005
                      Bronx Aging Study




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).
                                                                 Hall, C. B. et al. Neurology 2007;69:1657-1664
                    Reserve, AD Pathology, and
Clinical Severity
                        Clinical Diagnosis

                                                       Low reserve



                                                       High reserve
                      mild AD
                      MCI




                                                      Diagnostic Threshold
                      normal




                                Mild            Moderate

                                       AD Pathology
                                                                      Stern, JINS 2002
     Education and rCBF
                               Controlling for clinical
                               disease severity, there is an
                               inverse relationship
                               between education and a
                               functional imaging proxy
                               for AD pathology

                               Similar findings have been
                               noted for occupational
                               attainment and leisure
                               activities

Stern et al, Ann Neurol 1992
Education Occupation and rCBF
            Stepwise multiple regression

Education:
Predictors of P3 detector flow:         R squared
 mMMS, BDRS, age, age at onset, duration .190
 + education                              .304

Occupation:
Predictors of P3 detector flow:        R squared
  age, mMMS, BDRS, duration, education     .293
 + interpersonal skills                   .437
 + physical demands                       .515

                         Stern et al: Ann Neurol 1992; Neurology 1995
Interaction of AD Pathology and Education
                                   Education * AD path = 0.088, p<.01
Global Cognitive Function




                                                                      22 years

                                                           18 years


                                                15 years




                            Summary Measure of AD Pathology
                                                  Bennett DA et al, Neurology 2003
         Influence of CR in the association
       between WMH severity and cognition
                                                          The direct relation between
                                                          cognitive reserve and WMH in
                                                          women was -0.04 (ns).
                                                          By including the executive/speed
                                                          or the language cognitive variable
                                                          in the model, the path coefficient
                                                          between cognitive reserve and
                                                          WMH volume changed from
                                                          negative to significantly positive
                                                          (0.23 and 0.46). When cognitive
                                                          function is statistically controlled,
                                                          women with higher measures of
                                                          cognitive reserve had more severe
Presented path coefficients:                              WMH pathology.
visual-spatial ability/memory/executive-speed/language.
*p < .05. **p<.01. ***p< .001
                                                                          Brickman et al, submitted
 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.
 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
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.
Brain Damage                             Outcome

                        Reserve

                         Task-related
                           network
                          expression




                                             Task or NP
   Age- or AD-related                      performance,
       pathology                          Clinical Outcome




                        Measured CR or
                          CR-specific
                           Network
   Scheme for evaluating task-related network
         expression in young and old


Neural Reserve                              Neural Compensation




                           Stern, Cognitive Reserve, Neuorpsychologia, 2009
       Modified Sternberg Task
                                            1700

                                            1600

                                            1500

                                            1400




                                  RT (ms)
                                            1300

                                            1200
                                                                      Y
                                            1100                      E
                                            1000

                                             900

                                             800
                                                   1      3       6

                                                       set size


”Load-related” activation: the change in activation as set size
increases
We focus on load-related activation because CR might be more
related to the coping with increases in task demand than to task-
specific features.
           Load-dependent Activation During Retention:
            Neural Reserve and Neural Compensation
                                   Primary Network


                                                                    • 2 spatial patterns were expressed
                                                                    • The primary network was
                                                                      expressed by both young and old
                             Compensatory Network                   • Higher expression of the primary
                                                                      network was associated with
                                                                      poorer performance,  Neural
Greater Network Expression




                                                                      Reserve
                                                                    • The 2nd, “compensatory”
                                                                      network was expressed primarily
                                                                      by the elders; higher expression
                                                                      was associated with poorer
                                Elder
                                Young                                 performance

                             Less Efficient Processing (RT slope)
                                                                           Zarahn et al., Neurobiol Aging 2007
                                                         +
                                        Network 1               Network 2
                                         smaller is better (more efficiency)


                       -                                                               +

      -         Local                           -
Age            Density                                                                         Slope RT
      larger is better (less atrophy)                                -                       smaller is better
                                                                                             (faster speed of
                                                                                             processing)
                                        Cognitive
                                         Reserve




                                                             Steffener at al., Brain Imaging and Behavior 2009
        A Generalized 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.
• In other words: CR-related activation may
  not be task specific
• Goal: Are there patterns of CR-related brain
  activity common to two different tasks?
   Generalized Representation Of CR
Strategy
2 activation tasks with
different demands:
- Letter task: Stimuli are
1, 3, or 6 letters
- Shape Task: Stimuli are
1, 2 or 3 shapes
Goal
Can we find common CR-
related activation?
Generalized Representation Of CR
               • In younger subjects, a brain
                 network was identified during the
                 encoding phase of two different
                 tasks whose load-related increase
                 in expression correlated with CR
               • Older subjects expressed the
                 network only in the letter task
               • In the context of these tasks, this
                 network represents a neural
                 instantiation of CR

               • Areas in this CR-related network
                 have been associated with
                 executive and control processes


                                 Stern et al., Cerebral Cortex, 2007
                                  u1
                                              Picture Vocab




                                  u2
                                                Education




                                  u3
                                                 WRAT




                                                                  Reserve
                                                                 Cognitive




                                  u4
                                               Occupation




                                  u5
                                                  BNT




                                  u6
                                                VLT-Total
                                                                             .44*




                                              VLT- Delayed




                                  u7
                                                                   Memory
                                                                                    .-.34*




                                            VLT- Recognition




                                  u8
                                                                                             .84*




                                            Pegboard, dominant
                                  u9
                                                                   Speed




                                            Pegboard, non-dom
                                  u10




                                            Odd-man-out Total
                                  u11
                                                                                                     Executive Function




                                             Category Fluency
                                                                                                    Cognitive Reserve and




                                  u12 u13




                                              Letter Fluency
                                                                 Function
                                                                 Executive




                                             Trails difference
                                  u14




                                              Letter Number
                                  u15



Siedlecki et al, JINS, in press
Using interventions studies to test
       theories of reserve

  Aging/AD Pathology   Clinical Disease

                   ?

          Brain        Cognitive
         Reserve        Reserve
               Conclusions
• Epidemiologic and imaging evidence support the
  concept of cognitive reserve
• Reserve is malleable: it is influenced by aspects of
  experience in every stage of life
• Cognitive reserve may be mediated by
  efficiency/capacity of existing brain networks,
  ability to enlist new, compensatory networks, or
  “pure” CR-related networks
• The concept of cognitive reserve is applicable to a
  wide range of conditions that impact on brain
  function at all ages
• Influencing cognitive reserve may delay or reverse
  the effects of aging or brain pathology.

				
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