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.