NIH Public Access Author Manuscript Arch Neurol. Author manuscript; available in PMC 2009 November 1.

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1 NIH Public Access Author Manuscript Published in final edited form as: Arch Neurol November ; 65(11): doi: /archneur Alzheimer s and Cognitive Reserve: Education Effect Varies with [ 11 C]PIB Uptake Catherine M. Roe, PhD 1,2, Mark A. Mintun, MD 1,3, Gina D Angelo, PhD 1,4, Chengjie Xiong, PhD 1,4, Elizabeth A. Grant, PhD 1,4, and John C. Morris, MD 1,2,5,6 1 Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, USA 2 Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA 3 Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA 4 Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA 5 Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA 6 Physical Therapy, Washington University School of Medicine, St. Louis, Missouri, USA Abstract Objective To evaluate the cognitive reserve hypothesis by examining whether individuals of greater educational attainment have better cognitive function than individuals with less education in the presence of elevated fibrillar brain amyloid. Design, Setting, and Participants Uptake of N-methyl-[ 11 C]2-(4 -methylaminophenyl)-6- hydroybenzothiazole, or [ 11 C]PIB for Pittsburgh Compound-B, was measured for participants assessed between August 15, 2003 and January 8, 2008 at the Washington University Alzheimer s Disease Research Center and diagnosed either as nondemented (N=161) or with dementia of the Alzheimer type (N=37). Multiple regression was used to determine whether [ 11 C]PIB uptake interacted with level of educational attainment to predict cognitive function. Main Outcome Measures Scores on the Clinical Dementia Rating - Sum of Boxes (CDR-SB), Mini-Mental State Exam (MMSE), and Short Blessed Test (SBT), and individual measures from a psychometric battery. Results [ 11 C]PIB uptake interacted with years of education in predicting scores on the CDR-SB (p=.003), the MMSE (p<.001), the SBT (p=.03) and a measure of verbal abstract reasoning and conceptualization (p=.02), such that performance on these measures increased with increasing education for participants with elevated PIB uptake. Education was unrelated to global cognitive functioning scores among those with lower PIB uptake. Conclusions These results support the hypothesis that cognitive reserve influences the association between Alzheimer disease pathology and cognition. Corresponding author: Catherine M. Roe, PhD; Washington University School of Medicine; 660 S. Euclid Avenue; Campus Box 8111; St. Louis, Missouri 63110; Phone: (314) , cathyr@wustl.edu. Dr. Catherine Roe had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Author contributions: Study concept and design: Roe, Morris. Acquisition of data: Mintun, Grant, Morris. Analysis and interpretation of data: Roe, Mintun, D Angelo, Xiong, Grant, Morris. Drafting of the manuscript: Roe. Critical revision of the manuscript for important intellectual content: Roe, Mintun, D Angelo, Xiong, Grant, Morris. Statistical analysis: Roe, D Angelo, Xiong. Obtained funding: Mintun, Morris. Administrative, technical, or material support: D Angelo, Xiong, Grant. Study supervision: Morris.

2 Roe et al. Page 2 Introduction Methods Clinical assessment The cognitive reserve hypothesis states that persons with greater cognitive reserve are able to withstand more Alzheimer s disease (AD) pathology without becoming demented by using cognitive processing approaches or compensatory brain networks. 1,2 Education is a commonly-used proxy of cognitive reserve. Adjusting for level of AD pathology determined at autopsy, greater education has been associated with better cognitive function during life. 3, 4 Education interacts with AD pathology such that a greater pathological burden is required to show an effect on cognition among persons with more education. 3,4 A recent advance in AD research is the development of positron emission tomography (PET) radiotracers to image fibrillar amyloid-beta (Aβ) pathology in vivo. In individuals diagnosed with mild dementia of the Alzheimer type (DAT), those with 15 or more years of education (N=12) were found to have higher uptake of N-methyl-[ 11 C]2-(4 -methylaminophenyl)-6- hydroybenzothiazole, or [ 11 C]PIB for Pittsburgh Compound-B, in the frontal cortex compared with [ 11 C]PIB levels in 13 individuals with 6 years of education. 5 These results suggest that more Aβ pathology was required among highly educated individuals than less educated individuals to manifest mild DAT, supporting the cognitive reserve hypothesis. 5 We used [ 11 C]PIB imaging to further explore the cognitive reserve hypothesis by testing whether education and level of fibrillar brain Aβ interactively affect cognitive functioning in nondemented participants and those with DAT. Data were obtained from participants in longitudinal studies conducted by the Washington University Alzheimer s Disease Research Center. Participants completing clinical and cognitive assessments and determined to be either nondemented or to have DAT who also completed a PET scan to determine [ 11 C]PIB uptake were included. Details regarding recruitment, enrollment, and clinical assessment in these studies were published previously. 6 Briefly, experienced clinicians conduct a semistructured interview of the participant and a knowledgeable collateral source and a general physical and neurologic examination of the participant. The Mini-Mental State Examination 7 (MMSE) and the Short Blessed Test 8 (SBT), two objective measures commonly used to globally assess and rate dementia severity, can be derived from the clinical assessment,although the scores are not available to the clinicians. Without reference to cognitive test scores, clinicians assign a Clinical Dementia Rating 9 (CDR) based on the participant s cognitive ability to function in each of six individually-scored domains (or boxes): memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Absence of dementia is indicated by a CDR score of 0. A CDR of 0.5 or higher indicates that the clinician believes that the participant s cognitive abilities have declined relative to his or her previous levels of performance (i.e., the participant serves as his or her own control). Very mild, mild, moderate, and severe dementia is represented by CDR scores of 0.5, 1, 2, and 3, respectively. The Sum of Boxes (CDR-SB) is obtained by summing the scores from the individual domains. 10 For this study, CDR-SB, MMSE, and SBT are considered measures of global cognitive function. For participants with CDR 0.5 or greater, a clinical diagnosis was assigned in accordance with standard criteria. 11 Our clinical diagnostic criteria for DAT have been validated 12 with 93% accuracy for histopathological AD, 6 including individuals diagnosed with DAT at the CDR 0.5 level who elsewhere may be considered to represent mild cognitive impairment (MCI). 13

3 Roe et al. Page 3 PET imaging Within a few weeks of the clinical assessment, psychometricians administer to all participants a 1.5-hour psychometric battery 13 without knowledge of the CDR or clinical diagnosis. The battery includes tests measuring specific types of cognitive processes: Animal Naming, 14 Trailmaking A and B, 15 Free and Cued Selective Reminding Test 16 (SRT), and the Similarities subtest of the Wechsler Adult Intelligence Scale III (WAIS III Similarities). 17 Detailed information on the imaging procedures is available. 18 In brief, PET imaging is conducted using a Siemens 961 HR ECAT PET scanner (CTI, Knoxville, KY) or a Siemens 962 HR+ ECAT PET scanner (CTI) with [ 11 C]PIB synthesized in accordance with standard protocol. 19 After a transmission scan to measure attenuation, [ 11 C]PIB (4.5 to 20.1 mci, mean=12.2 mci) is administered intravenously with initiation of a 60-minute dynamic PET scan in three dimensional mode (septa retracted; 24 5 seconds frames; 9 20 seconds frames; 10 1 minute frames). The measured attenuation factors and a ramp filter are used to reconstruct the dynamic PET images. A fully three-dimensional single scatter simulation algorithm is used to correct scatter. 20 In addition to PET imaging, all participants have anatomic magnetic resonance imaging (MRI) using medium resolution (1mm 1mm 1.25 mm) MPRAGE T1- weighted volume acquisitions. A high-resolution, low noise anatomic image data set for regionof-interest (ROI) determination is created for each participant by aligning and averaging 3 MPRAGE sequences. 18,21 Mean cortical binding potential Statistical analysis Each participant s structural MRI is registered to a standard atlas target 22 that minimizes bias due to atrophy. 21 Alignment of PET-MRI within a participant is accomplished via use of an in-house cross-modal registration algorithm and ANALYZE (Mayo Clinic, Rochester MN) is used to create three-dimensional ROIs for each participant based on his or her individual MRI. 18 The ROIs are applied to unblurred images of the PET dynamic data, yielding high-resolution regional time-activity curves. Each time-activity curve is analyzed for PIB specific binding using the Logan graphical analysis, 23 taking the cerebellum ROI data as a reference tissue input function. 24 The cerebellum was chosen as the reference region because there is little specific binding of PIB in postmortem samples of cerebellar cortex even among individuals with AD at autopsy. 19 The slope produced by Logan graphical analysis is equal to the tracer distribution volume (DV) in the tissue of interest when compared to the input function. A binding potential 25 (BP) for each ROI is calculated using the equation BP=DV-1 to express the regional binding values in a manner proportional to the number of binding sites. Mean BP values from the prefrontal cortex, gyrus rectus, lateral temporal cortex, and precuneus ROIs are used to calculate a mean cortical binding potential (MCBP) value based on brain regions known to have high PIB uptake among participants with DAT. 18 A MCPB of 0.18 serves as a borderline value, as nearly all DAT individuals have MCPBs above that value and all young healthy individuals have MCBPs below that value. 18 Participants were dichotomized into PIB negative (PIB-, MCBP<0.18) or positive (PIB+, MCBP>.18) groups. Multiple linear regression analysis using PROC REG (SAS Institute Inc, Cary, North Carolina) was used to test for a significant interaction between education and PIB group (PIB+ vs. PIB-) in predicting test scores. Better performance is indicated by lower scores for the CDR-SB, the SBT, Trailmaking A and Trailmaking B; and by higher scores on the MMSE, Animal Naming, SRT, and WAIS III Similarities. Education in years, PIB group, and a term representing their interaction were included in all models. The stepwise selection procedure identified variables that improved the model fit, using the default SAS criteria for model entry (0.10) and exit (0.15). Candidate variables for

4 Roe et al. Page 4 Results Comment stepwise entry included sex, age group, the presence of at least one apolipoprotein E (APOE) ε4 (APOE4+ vs. APOE4-) allele, and time between clinical assessment and PIB scan. Age (median=67.7 years) and time between clinical assessment and PIB scan (median=0.42 years) were dichotomized using median splits. Preliminary examination of the data suggested a potential interaction between age group and APOE ε4 status for the global tests, such that older participants without an APOE ε4 allele did better on the cognitive tests than older participants with an APOEε4 allele, but test scores were similar for the APOE ε4 groups among younger participants. Therefore, a term representing that interaction was also a candidate for stepwise entry. Because regression diagnostics indicated that the residuals were skewed, CDR-SB values were log-transformed after adding 0.5 to each value. For tests showing a significant education X PIB interaction, least square mean scores and 95% confidence intervals for PIB+ and PIB- participants within three education categories were calculated in order to illustrate the form of the interaction. For cognitive tests where the interaction term was not significant, the regression analysis was repeated including the main effects of PIB and education, but not their interaction. To determine whether the results were specific to the cutoff used to divide participants into groups with high and low amyloid uptake, the final regression models were repeated treating PIB uptake as a continuous variable, by substituting MCBP for PIB group. Fishers Exact Test was used to determine whether the PIB groups differed with regard to a clinical history of vascular risk factors (heart disease, hypertension, diabetes, and stroke). One-hundred ninety-eight participants, 161 nondemented and 37 DAT (CDR 0.5, N=26; CDR 1, N=9; CDR 2, N=2) individuals met inclusion criteria (Tables 1 and 2). No significant differences between the PIB+ and PIB- groups were found for history of heart disease (p=.31), hypertension (p=.15), diabetes (p=.31), or stroke (p=.06). PIB+/- status interacted significantly with years of education in predicting scores on the global tests and the WAIS III Similarities subtest (Table 3). As illustrated in Figure 1, no significant differences between the education groups were found for CDR-SB, MMSE, and SBT among participants who were PIB-, but better global functioning scores were associated with more education among those with elevated PIB uptake. On the WAIS III Similarities subtest, scores increased with increasing education for participants with and without PIB elevation, but significant differences between the PIB groups were found only for participants in the two lower education groups. PIB status and education did not interact to predict scores on Animal Naming (p=.45), the SRT (Free Recall, p=.50; Total, p=.35), or either Trailmaking test (A, p=.71, B, p=.19). After repeating the analyses without the interaction term, better cognitive functioning on all tests was significantly associated with PIB-status, and was associated with more years of education for Animal Naming, SRT Free Recall, and Trailmaking B (Table 3). Similar results were found when PIB uptake was treated as a continuous variable, with significant interactions between education and MCBP found for the global tests (CDR-SB: p=.004; MMSE: p<.001; SBT: p=. 01) and the WAIS III Similarities subtest (p=.04). These results provide support for the cognitive reserve hypothesis. On each of three measures of global cognitive functioning, education interacted with PIB status to predict cognitive function, such that persons with greater education maintain better global cognitive functioning in the presence of Aβ pathology. In both nondemented and DAT individuals, the interaction

5 Roe et al. Page 5 Acknowledgments References between education and Aβ pathology takes the form of a floor effect such that differences between individuals with and without Aβ pathology increase with increasing years of education. 3 Based on autopsy data, there may be a ceiling effect when extensive Aβ pathology is present as in late-stage DAT. 4 Presumably, as the AD pathological burden increases, a greater proportion of highly-educated participants reach the threshold for dementia and the initial advantage provided by cognitive reserve decreases. Longitudinal imaging of Aβ pathology in vivo will soon allow us to determine whether these inferences from cross-sectional studies are accurate. Correlations between educational attainment and scores on global cognitive functioning tests such as the MMSE may indicate test bias. We found no difference in global test scores between the education groups among participants who were PIB-, only those who were PIB+, suggesting that some education-based differences in scores on global cognitive tests may reflect cognitive reserve differences that mitigate the presence of Aβ pathology. Education interacted with amyloid uptake to predict scores on the WAIS III Similarities subtest, a measure of verbal abstract reasoning and conceptualization, but not tests assessing category fluency, controlled word list learning and verbal/visual memory, and attention, visual searching, and mental processing speed. Abstract reasoning may be one of the first types of cognitive processes to be affected in early DAT. Among multiple neuropsychological tests, performance on tests of abstract reasoning, along with memory, were found to best differentiate individuals with mild DAT from those with normal cognition. 26 Performance on the abstract reasoning task used here has also been found to be strongly related to education. 27 Cognitive reserve, as reflected in education, may have a stronger, or earlier, effect on specific cognitive processes compared with others. However, greater Aβ deposition was related to worse performance on all tests examined here, either as part of an interaction effect or by itself. This study had several strengths including a large sample comprised of both demented and nondemented individuals and multiple measures of cognitive function. There also are limitations, including the high mean educational level of the sample. We also conducted multiple statistical tests, so some statistically significant differences reported here may be due to chance. Nonetheless, the findings extend the examination of the cognitive reserve hypothesis by indicating that persons who are PIB positive and have the highest education are clinically rated as less impaired and perform better on cognitive tests than PIB positive individuals with less education. Dr. Catherine Roe had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Supported by grants P50-AG05681, P01-AG03991, and P01-AG26276 from the National Institute on Aging and P30-NS from the National Institute of Neurological Disorders and Stroke, of the National Institutes of Health, Bethesda, MD; and the Charles and Joanne Knight Alzheimer Research Initiative of Washington University s Alzheimer s Disease Research Center. The authors thank Washington University colleagues Dr. Martha Storandt for providing data, Denise Maue-Dreyfus and Dr. Monique Williams for helpful comments, and the Genetics Core of the Washington University Alzheimer s Disease Research Center for APOE genotyping. 1. Stern Y. Cognitive reserve and Alzheimer disease. Alzheimer Dis Assoc Disord 2006;20(2): [PubMed: ] 2. Mortimer JA, Borenstein AR, Gosche KM, Snowdon DA. Very early detection of Alzheimer neuropathology and the role of brain reserve in modifying its clinical expression. J Geriatr Psychiatry Neurol 2005;18(4): [PubMed: ]

6 Roe et al. Page 6 3. Bennett DA, Wilson RS, Schneider JA, et al. Education modifies the relation of AD pathology to level of cognitive function in older persons. Neurology 2003;60(12): [PubMed: ] 4. Roe CM, Xiong C, Miller JP, Cairns NJ, Morris JC. Interaction of neuritic plaques and education predicts dementia. Alzheimer Dis Assoc Disord. In press 5. Kemppainen NM, Aalto S, Karrasch M, et al. Cognitive reserve hypothesis: Pittsburgh Compound B and fluorodeoxyglucose positron emission tomography in relation to education in mild Alzheimer disease. Ann Neurol 2008;63(1): [PubMed: ] 6. Berg L, McKeel DW Jr, Miller JP, et al. Clinicopathologic studies in cognitively healthy aging and Alzheimer s disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch Neurol 1998;55(3): [PubMed: ] 7. Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12(3): [PubMed: ] 8. Katzman R, Brown T, Fuld P, Peck A, Schechter R, Schmimmel H. Validation of a short Orientation- Memory-Concentration Test of cognitive impairment. Am J Psychiatry 1983;140(6): [PubMed: ] 9. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993;43 (11): [PubMed: ] 10. Berg L, Miller JP, Baty J, Rubin EH, Morris JC, Figiel G. Mild senile dementia of the Alzheimer type. Evaluation of intervention. Ann Neurol 1992;31(3): [PubMed: ] 11. Morris JC, Weintraub S, Chui HC, et al. The Uniform Data Set (UDS): clinical and cognitive variables and descriptive data from Alzheimer Disease Centers. Alzheimer Dis Assoc Disord 2006;20(4): [PubMed: ] 12. Morris JC, McKeel DW Jr, Fulling K, Torack RM, Berg L. Validation of clinical diagnostic criteria for Alzheimer s disease. Ann Neurol 1988;24(1): [PubMed: ] 13. Storandt M, Grant EA, Miller JP, Morris JC. Longitudinal course and neuropathologic outcomes in original vs revised MCI and in pre-mci. Neurology 2006;67(3): [PubMed: ] 14. Goodglass, H.; Kaplan, E. J. Animal Naming (Fluency in Controlled Association). Lea & Febiger; Philadelphia: Boston Diagnostic Aphasia Examination Booklet, III, ORAL EXPRESSION. 15. Armitage SG. An analysis of certain psychological tests used for the evaluation of brain injury. Psychological Monographs 1945;60(1): Grober E, Buschke H, Crystal H, Bang S, Dresner R. Screening for dementia by memory testing. Neurology 1988;38(6): [PubMed: ] 17. Wechsler, D. Manual: Wechsler Adult Intelligence Scale-III. Psychological Corporation; New York: Mintun MA, LaRossa GN, Sheline YI, et al. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 2006;67(3): [PubMed: ] 19. Mathis CA, Wang Y, Holt DP, Huang GF, Debnath ML, Klunk WE. Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. J Med Chem 2003;46 (13): [PubMed: ] 20. Accorsi R, Adam LE, Werner ME, Karp JS. Optimization of a fully 3D single scatter simulation algorithm for 3D PET. Phys Med Biol 2004;49(12): [PubMed: ] 21. Buckner RL, Head D, Parker J, et al. A unified approach for morphometric and functional data analysis in young, old, and demented adults using automated atlas-based head size normalization: reliability and validation against manual measurement of total intracranial volume. Neuroimage 2004;23(2): [PubMed: ] 22. Talairach, J.; Tournoux, P. Co-planar sterotaxic atlas of the human brain. Thieme Medical; New York: Logan J, Fowler JS, Volkow ND, et al. Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 1990;10(5): [PubMed: ] 24. Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 1996;16(5): [PubMed: ]

7 Roe et al. Page Mintun MA, Raichle ME, Kilbourn MR, Wooten GF, Welch MJ. A quantitative model for the in vivo assessment of drug binding sites with positron emissioin tomography. Ann Neurol 1984;15(3): [PubMed: ] 26. Caccappolo-Van Vliet E, Manley J, Tang M, Marder K, Bell K, Stern Y. The neuropsychological profiles of mild Alzheimer s disease and questionable dementia as compared to age-related cognitive decline. J Int Neuropsychol Soc 2003;9(5): [PubMed: ] 27. Johnson B, Santana V, Schupf N, et al. The heritability of abstract reasoning in Caribbean Latinos with familial Alzheimer s disease. Dement Geriatr Cogn Disord 2007;24(6): [PubMed: ]

8 Roe et al. Page 8 Figure 1. Least square mean scores by education group for PIB+ and PIB- participants. a a Error bars represent 95% confidence intervals. P-values indicate the significance of t-tests between the means. CDR-SB=Clinical Dementia Rating-Sum of Boxes; MMSE=Mini-Mental State Exam; SBT=Short Blessed Test; WAIS=Wechsler Adult Intelligence Scale.

9 Roe et al. Page 9 Demographic characteristics (N=198) Table 1 Mean/N SD/% Age, y Women, % % 1 apolipoprotein E ε4 allele (APOE ε4+), % % Time between clinical assessment and PET, y Education, y Mean cortical binding potential CDR-SB score a MMSE score a SBT score a PET=positron emission tomography a The range from best to worst performance for the Clinical Dementia Rating-Sum Box (CDR-SB), is 0-18, for the Mini Mental State Examination (MMSE) is 30-0, and for the Short Blessed Test (SBT) is 0-28.

10 Roe et al. Page 10 Results of the multiple regression models. a Table 2 Global Tests Tests Assessing Specific Cognitive Processes CDR-SB MMSE SBT Animal Naming SRT Free Recall SRT Total Trailmaking A Trailmaking B WAIS III Similarities (N=198) (N=198) (N=194) (N=190) (N=184) (n=184) (N=190) (N=190) (N=189) PIB+ <.001 <.001 <.001 <.001 <.001 < < Education, y <.001 <.001 PIB+ X Education.003 < Older age < < APOE ε Older age X APOE ε Male gender Longer time between CA and scan CDR-SB=Clinical Dementia Rating-Sum of Boxes; MMSE=Mini-Mental State Exam; SBT=Short Blessed Test; SRT=Selective Reminding Test; WAIS=Wechsler Adult Intelligence Scale; PIB=Pittsburgh Compound-B; CA=clinical assessment; APOE=apolipoprotein E. a Empty cells indicate that the corresponding variable or interaction term did not meet stepwise entry and exit criteria for a particular model.

11 Roe et al. Page 11 Table 3 Number (%) of PIB+ and PIB- participants in each education group PIB- PIB+ (MCBP<0.18) (MCBP>=0.18) High school or below ( 12 years) 22 (15.8) 16 (27.1) Some college or college graduate (13-16 years) 69 (49.6) 29 (49.2) Post-college (>16 years) 48 (34.5) 14 (23.7) Total PIB=Pittsburgh Compound-B; MCBP=Mean Cortical Binding Potential.