The Residual Approach to Measuring Cognitive Reserve in Aging and Dementia

The Residual Approach toMeasuring Cognitive Reserve in Aging and Dementia Bruce Reed & Dan Mungas University of California, Davis UC Davis Alzheimer’s Disease Center

Acknowledgements • Funded in part by Grant R13AG030995-01A1 from the National Institute on Aging • The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government. UC Davis Alzheimer’s Disease Center

“What a waste it is to lose one’s mind, or not to have a mind as being truly wasteful. How true that is.” --Dan Quayle UC Davis Alzheimer’s Disease Center

The prevalence of AD is strongly linked to age UC Davis Alzheimer’s Disease Center From: Nessbaum & Ellis (2003). NEJM, 348: 1356.

Incident first infarcts: cases per 100, 000 Rates of cerebrovascular disease strongly linked to age Leary, et al., 2003 Bryan, et al., 1997 UC Davis Alzheimer’s Disease Center

Trajectories of cognitive function in later life • Are heterogeneous • Become more negative, on average, with advancing age Average slopes for 5 year age blocks Distribution of slopes of change Individual 5 year change trajectories data: Wilson, et al. Psych & Aging 2002 UC Davis Alzheimer’s Disease Center

Brain Pathology Cognitive Baseline Cognitive Decline A simple model to explain decline Reserve is a construct that attempts to explain variability in the amount or rate of cognitive change following brain insult. UC Davis Alzheimer’s Disease Center

Reserve can be thought of as the difference between a person’s actual level of cognitive performance and the average level of performance that would be expected given the amount of brain pathology present • Is it useful to operationally define reserve in this way? UC Davis Alzheimer’s Disease Center

Reserve Cognitive baseline Brain Pathology Cognitive Decline Modeling Reserve UC Davis Alzheimer’s Disease Center

Reserve Cognitive baseline Brain Pathology Cognitive Decline Using a residual to measure reserve • Potential advantages • explicitly defined • wide range of measurement; likely to be nicely distributed • a direct estimate; makes no assumptions about what contributes to reserve • determinants of reserve can be tested • a dynamic (time-specific) measure; will change as disease progresses • hypotheses about how reserve might change can be tested • measures of reserve can be domain-specific • Not a perfect or pure measure • Captures unmeasured systematic variance and sources of random error. • Whether or not it is a useful measure of reserve can be empirically tested UC Davis Alzheimer’s Disease Center

Initial Approach • Used regression to define a residual term. Used the residual values for each person as variables in subsequent analyses. • Initial conceptual model: • Episodic memory = brain pathology + R • Episodic Memory measure = composite score derived from list learning data • MRI used to estimate brain pathology • Atrophy (total brain volume) • R = reserve UC Davis Alzheimer’s Disease Center

Hypothesis: Reserve inversely related to cognitive status(Normal > MCI > demented) UC Davis Alzheimer’s Disease Center

Hypothesis: Reserve inversely related to cognitive status(Normal > MCI > demented) Memory Residuals by Syndrome UC Davis Alzheimer’s Disease Center

Hypothesis: Reserve protects against cognitive decline:Decline is slower in persons with high reserve UC Davis Alzheimer’s Disease Center

Hypothesis: Reserve protects against cognitive decline:Decline is slower in persons with high reserve Rate of Change in Executive Function by Memory Residual UC Davis Alzheimer’s Disease Center

Hypothesis: Reserve influences the likelihood of conversion from MCI to dementia UC Davis Alzheimer’s Disease Center

Hypothesis: Reserve influences the likelihood of conversion from MCI to dementia Rate of Conversion from CDR = 0.5 to CDR ≥ 1.0 by Memory Residual Group UC Davis Alzheimer’s Disease Center

limitations • Because the regression does not incorporate education, the residual (error) term contains the variance associated with education. As education is the most commonly used proxy for reserve this makes it unclear what additional information the residual provides • There are additional MRI measures of brain pathology, not in the model; these effects, too, are in the residual • The regression approach, because it uses results of one model in a second separate model (as if the data were independent) is not optimal UC Davis Alzheimer’s Disease Center

Revised approach • New conceptual model: Mem = demographics + MRI pathology + R • Demographics = sex, education, ethnicity) • MRI = total brain matter, hippocampal volume, WMH • residual variance • Two stage analytic approach. • 1) LVM to create uncorrelated component scores; Mem-D, Mem-B, Mem-R • 2) hypothesis testing using these LVs. UC Davis Alzheimer’s Disease Center

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Data • 288 subjects. 158 normal, 92 MCI, 38 demented • 96 African Americans, 74 Hispanics (32 tested in English, 42 tested in Spanish), and 118 Caucasians. • Education M = 12.7 yrs (range 0-25) • Age M = 74.7 yrs (range 60-93) • Mean evaluations = 3.5; 74% had 3 or more evaluations. N of evaluations truncated at 5. UC Davis Alzheimer’s Disease Center

Mem-D ~ 20% of episodic memory variance • Mem-B ditto • Mem-R ~ 50% of episodic memory variance UC Davis Alzheimer’s Disease Center

H1: Reserve is associated with global cognitive function: lower reserve -> lower cognitive status. UC Davis Alzheimer’s Disease Center

H1: Reserve is associated with global cognitive function:reserve correlates with CDR sum of boxes UC Davis Alzheimer’s Disease Center

H2: Mem-R is positively associated with another possible index of reserve, specifically reading ability UC Davis Alzheimer’s Disease Center

H3: Reserve modifies the risk of conversion to a worse cognitive syndrome UC Davis Alzheimer’s Disease Center

H4: Higher Reserve is associated with slower decline in executive function UC Davis Alzheimer’s Disease Center

H5: Reserve modifies the effect of brain atrophy on rates of decline in executive function UC Davis Alzheimer’s Disease Center

SummaryConsistent with the reserve hypothesis, a residual-based estimate of reserve: • Correlates with an education-related index of reserve: higher reading scores -> higher reserve • Correlates with contemporaneous, global, cognitive status; lower reserve -> worse dx and worse global cognition • Is associated with rates of decline in executive function: higher reserve is associated with slower decline • Reduces the risk of conversion from baseline dx to worsened cognitive status • Modifies the impact of brain atrophy on cognitive function: brain pathology has a greater effect on cognitive function in low reserve cases than in high reserve cases. UC Davis Alzheimer’s Disease Center

Mem-R is model- dependent • Other measures of pathology could be used • Add’l structural measures • fMRI • Molecular imagining • Other biomarkers, e.g. CSF abeta and tau • These would “purify” and presumably strengthen Mem-R as a measure of reserve • Other demographic variables could be added • We used education in order to provide proof of principle • Additional demographic variables might not improve Mem-R UC Davis Alzheimer’s Disease Center

What is Mem-D? • Education (as captured in Mem-D) did not affect change independently of MRI variables • Are there factors that affect baseline cognitive performance but which do not modify rates of change? UC Davis Alzheimer’s Disease Center

future Goal: to study reserve by • Measuring brain pathology with PIB PET and MRI • In an exceptionally diverse sample (education range 0 - 20) • Modeling reserve as a residual term • And testing an alternative hypotheses on the mechanism of education effects UC Davis Alzheimer’s Disease Center

The Residual Approach to Measuring Cognitive Reserve in Aging and Dementia