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1.  Cognitively Stimulating Activities: Effects on Cognition across Four Studies with up to 21 Years of Longitudinal Data 
Journal of Aging Research  2012;2012:461592.
Engagement in cognitively stimulating activities has been considered to maintain or strengthen cognitive skills, thereby minimizing age-related cognitive decline. While the idea that there may be a modifiable behavior that could lower risk for cognitive decline is appealing and potentially empowering for older adults, research findings have not consistently supported the beneficial effects of engaging in cognitively stimulating tasks. Using observational studies of naturalistic cognitive activities, we report a series of mixed effects models that include baseline and change in cognitive activity predicting cognitive outcomes over up to 21 years in four longitudinal studies of aging. Consistent evidence was found for cross-sectional relationships between level of cognitive activity and cognitive test performance. Baseline activity at an earlier age did not, however, predict rate of decline later in life, thus not supporting the concept that engaging in cognitive activity at an earlier point in time increases one's ability to mitigate future age-related cognitive decline. In contrast, change in activity was associated with relative change in cognitive performance. Results therefore suggest that change in cognitive activity from one's previous level has at least a transitory association with cognitive performance measured at the same point in time.
PMCID: PMC3449118  PMID: 23024862
2.  Regression-Based Estimates of Observed Functional Status in Centenarians 
The Gerontologist  2010;51(2):179-189.
Purpose of the Study: There is lack of consensus on the best method of functional assessment, and there is a paucity of studies on daily functioning in centenarians. We sought to compare associations between performance-based, self-report, and proxy report of functional status in centenarians. We expected the strongest relationships between proxy reports and observed performance of basic activities of daily living (BADLs) and instrumental activities of daily living (IADLs). We hypothesized that the discrepancy between self-report and observed daily functioning would be modified by cognitive status. We additionally sought to provide clinicians with estimates of centenarians’ observed daily functioning based on their mental status in combination with subjective measures of activities of daily living (ADLs). Design and Methods: Two hundred and forty-four centenarians from the Georgia Centenarian Study were included in this cross-sectional population-based study. Measures included the Direct Assessment of Functional Status, self-report and proxy report of functional status, and the Mini-Mental State Examination (MMSE). Results: Associations between observed and proxy reports were stronger than between observed and self-report across BADL and IADL measures. A significant MMSE by type of report interaction was found, indicating that lower MMSE performance is associated with a greater discrepancy between subjective and objective ADL measures. Implications: Results demonstrate associations between 3 methods of assessing functional status and suggest proxy reports are generally more accurate than self-report measures. Cognitive status accounted for some of the discrepancy between observed and self-reports, and we provide clinicians with tables to estimate centenarians’ performance on observed functional measures based on MMSE and subjective report of functional status.
PMCID: PMC3058129  PMID: 20974657
Daily functioning; Direct Assessment of Functional Status; Self-report; Proxy report; MMSE
3.  Tracking Cognitive Change over 24 Weeks with Longitudinal Functional Magnetic Resonance Imaging in Alzheimer's Disease 
Neuro-Degenerative Diseases  2012;9(4):176-186.
Previous studies have revealed that functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) signal in specific brain regions correlates with cross-sectional performance on standardized clinical trial measures in Alzheimer's disease (AD); however, the relationship between longitudinal change in fMRI-BOLD signal and neuropsychological performance remains unknown. Objective: To identify changes in regional fMRI-BOLD activity that tracks change in neuropsychological performance in mild AD dementia over 6 months.
Twenty-four subjects (mean age 71.6) with mild AD dementia (mean Mini Mental State Examination 21.7, Global Clinical Dementia Rating 1.0) on stable donepezil dosing participated in two task-related fMRI sessions consisting of a face-name paired associative encoding memory paradigm 24 weeks apart during a randomized placebo-controlled pharmaco-fMRI drug study. Regression analysis was used to identify regions where the change in fMRI activity for Novel > Repeated stimulus contrast was associated with the change scores on postscan memory tests and the Free and Cued Selective Reminding Test (FCSRT).
Correlations between changes in postscan memory accuracy and changes in fMRI activity were observed in regions including the angular gyrus, parahippocampal gyrus, inferior frontal gyrus and cerebellum. Correlations between changes in FCSRT-free recall and changes in fMRI were observed in regions including the inferior parietal lobule, precuneus, hippocampus and parahippocampal gyrus.
Changes in encoding-related fMRI activity in regions implicated in mnemonic networks correlated with changes in psychometric measures of episodic memory retrieval performed outside the scanner. These exploratory results support the potential of fMRI activity to track cognitive change and detect signals of short-term pharmacologic effect in early-phase AD studies.
PMCID: PMC3369254  PMID: 22456451
Functional MRI; Clinical trial; Episodic memory; Biomarker; Dementia
4.  Norms from the Georgia Centenarian Study: Measures of verbal abstract reasoning, fluency, memory, and motor function 
We previously presented normative data from a relatively large, population-based sample (n = 244) of centenarians and a reference group of octogenarians (n = 80) for several brief, global neurocognitive tasks adapted for use for older adults with physical and sensory limitations (Miller et al., 2010). Here, we present additional normative data on several domain-specific tasks from these samples from Phase III of the Georgia Centenarian Study, including measures of verbal abstract reasoning, fluency, memory, and motor function. Expected age differences were demonstrated across all cognitive measures, and, consistent with our previous findings, centenarians showed a stronger association between age and performance. Normative tables are presented unweighted as well as population-weighted, and stratified by age and education level. These findings offer a unique contribution to the literature on cognitive aging, as normative performance in this age group is understudied and largely unavailable to clinicians and researchers.
PMCID: PMC4281023  PMID: 23379531
5.  Cortical Signatures of Cognition and their Relationship to Alzheimer’s Disease 
Brain imaging and behavior  2012;6(4):584-598.
Recent changes in diagnostic criteria for Alzheimer’s disease (AD) state that biomarkers can enhance certainty in a diagnosis of AD. In the present study, we combined cognitive function and brain morphology, a potential imaging biomarker, to predict conversion from mild cognitive impairment to AD. We identified four biomarkers, or cortical signatures of cognition (CSC), from regressions of cortical thickness on neuropsychological factors representing memory, executive function/processing speed, language, and visuospatial function among participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Neuropsychological factor scores were created from a previously validated multidimensional factor structure of the neuropsychological battery in ADNI. Mean thickness of each CSC at the baseline study visit was used to evaluate risk of conversion to clinical AD among participants with mild cognitive impairment (MCI) and rate of decline on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score. Of 307 MCI participants, 119 converted to AD. For all domain-specific CSC, a one standard deviation thinner cortical thickness was associated with an approximately 50% higher hazard of conversion and an increase of approximately 0.30 points annually on the CDR-SB. In combined models with a domain-specific CSC and neuropsychological factor score, both CSC and factor scores predicted conversion to AD and increasing clinical severity. As structural magnetic resonance imaging becomes more clinically routine and time-effective than neuropsychological testing, these signatures can be used as biomarkers of conversion to AD andincreasing clinical severity.
PMCID: PMC3553578  PMID: 22718430
MRI; Freesurfer; cortical thickness; ADNI; cognition; brain mapping
6.  Neuropsychological Test Performance and Cognitive Reserve in Healthy Aging and the Alzheimer’s Disease Spectrum: A Theoretically-Driven Factor Analysis 
Accurate measurement of cognitive function is critical for understanding the disease course of Alzheimer’s disease (AD). Detecting cognitive change over time can be confounded by level of premorbid intellectual function or cognitive reserve and lead to under or over diagnosis of cognitive impairment and AD. Statistical models of cognitive performance that include cognitive reserve can improve sensitivity to change and clinical efficacy. We used confirmatory factor analysis to test a four-factor model comprised of memory/language, processing speed/executive function, attention, and cognitive reserve factors in a group of cognitively healthy older adults and a group of participants along the spectrum of amnestic mild cognitive impairment to AD (aMCI-AD). The model showed excellent fit for the control group (χ2 = 100, df = 78, CFI = .962, RMSEA = .049) and adequate fit for the aMCI-AD group (χ2 = 1750, df = 78, CFI = .932, RMSEA = .085). Though strict invariance criteria were not met, invariance testing to determine if factor structures are similar across groups yielded acceptable absolute model fits and provide evidence in support of configural, metric, and scalar invariance. These results provide further support for the construct validity of cognitive reserve in healthy and memory impaired older adults.
PMCID: PMC3600814  PMID: 23039909
mild cognitive impairment; brain reserve; executive function; memory function; dementia; cognition
7.  Dynamic Associations of Change in Physical Activity and Change in Cognitive Function: Coordinated Analyses of Four Longitudinal Studies 
Journal of Aging Research  2012;2012:493598.
The present study used a coordinated analyses approach to examine the association of physical activity and cognitive change in four longitudinal studies. A series of multilevel growth models with physical activity included both as a fixed (between-person) and time-varying (within-person) predictor of four domains of cognitive function (reasoning, memory, fluency, and semantic knowledge) was used. Baseline physical activity predicted fluency, reasoning and memory in two studies. However, there was a consistent pattern of positive relationships between time-specific changes in physical activity and time-specific changes in cognition, controlling for expected linear trajectories over time, across all four studies. This pattern was most evident for the domains of reasoning and fluency.
PMCID: PMC3457643  PMID: 23029615
8.  Social Activity and Cognitive Functioning Over Time: A Coordinated Analysis of Four Longitudinal Studies 
Journal of Aging Research  2012;2012:287438.
Social activity is typically viewed as part of an engaged lifestyle that may help mitigate the deleterious effects of advanced age on cognitive function. As such, social activity has been examined in relation to cognitive abilities later in life. However, longitudinal evidence for this hypothesis thus far remains inconclusive. The current study sought to clarify the relationship between social activity and cognitive function over time using a coordinated data analysis approach across four longitudinal studies. A series of multilevel growth models with social activity included as a covariate is presented. Four domains of cognitive function were assessed: reasoning, memory, fluency, and semantic knowledge. Results suggest that baseline social activity is related to some, but not all, cognitive functions. Baseline social activity levels failed to predict rate of decline in most cognitive abilities. Changes in social activity were not consistently associated with cognitive functioning. Our findings do not provide consistent evidence that changes in social activity correspond to immediate benefits in cognitive functioning, except perhaps for verbal fluency.
PMCID: PMC3444000  PMID: 22991665
9.  A web-based normative calculator for the uniform data set (UDS) neuropsychological test battery 
With the recent publication of new criteria for the diagnosis of preclinical Alzheimer's disease (AD), there is a need for neuropsychological tools that take premorbid functioning into account in order to detect subtle cognitive decline. Using demographic adjustments is one method for increasing the sensitivity of commonly used measures. We sought to provide a useful online z-score calculator that yields estimates of percentile ranges and adjusts individual performance based on sex, age and/or education for each of the neuropsychological tests of the National Alzheimer's Coordinating Center Uniform Data Set (NACC, UDS). In addition, we aimed to provide an easily accessible method of creating norms for other clinical researchers for their own, unique data sets.
Data from 3,268 clinically cognitively-normal older UDS subjects from a cohort reported by Weintraub and colleagues (2009) were included. For all neuropsychological tests, z-scores were estimated by subtracting the raw score from the predicted mean and then dividing this difference score by the root mean squared error term (RMSE) for a given linear regression model.
For each neuropsychological test, an estimated z-score was calculated for any raw score based on five different models that adjust for the demographic predictors of SEX, AGE and EDUCATION, either concurrently, individually or without covariates. The interactive online calculator allows the entry of a raw score and provides five corresponding estimated z-scores based on predictions from each corresponding linear regression model. The calculator produces percentile ranks and graphical output.
An interactive, regression-based, normative score online calculator was created to serve as an additional resource for UDS clinical researchers, especially in guiding interpretation of individual performances that appear to fall in borderline realms and may be of particular utility for operationalizing subtle cognitive impairment present according to the newly proposed criteria for Stage 3 preclinical Alzheimer's disease.
PMCID: PMC3308021  PMID: 22078663
Alzheimer's disease; cognitive aging; MCI; memory; norms
10.  Cognitive Performance in Centenarians and the Oldest Old: Norms from the Georgia Centenarian Study 
We present normative data from a large population-based sample of centenarians for several brief, global neurocognitive tasks amenable for frail elders. Comparative data from octogenarians are included. A total of 244 centenarians and 80 octogenarians from Phase III of the Georgia Centenarian Study were administered the Mini-Mental Status Examination, Severe Impairment Battery, and Behavioral Dyscontrol Scale. Centenarians (age 98–107) were stratified into three age cohorts (98–99, 100–101, 102–107), octogenarians into two 5-year cohorts (80–84, 85–89). Highly significant differences were observed between groups on all measures, with greater variation and dispersion in performance among centenarians, as well as stronger associations between age and performance. Descriptive statistics and normative ranges (unweighted and population-weighted) are provided by age cohort. Additional statistics are provided by education level. While most previous centenarian studies have used convenience samples, ours is population-based and likely more valid for comparison in applied settings. Results suggest centenarians look different than do even the oldest age range of most normative aging datasets (e.g., 85–90). Results support using global measures of neurocognition to describe cognitive status in the oldest old, and we provide normative comparisons to do so.
PMCID: PMC2974270  PMID: 20521181
Normative; Centenarians; Cognition; MMSE; SIB; BDS; Population-based
11.  Anti-RAGE and Aβ Immunoglobulin Levels Are Related to Dementia Level and Cognitive Performance 
Blood-based immunoglobulins (IgGs) may mark the presence of amyloid plaques characterizing the progression of Alzheimer's disease (AD). Previous studies suggest that anti-RAGE and anti-Aβ IgGs increase proportionately with accumulation of amyloid-beta (Aβ) peptides at receptor sites for advanced glycation end products (RAGE), within cortical areas of brain tissue. We assessed the relationship between these potential markers and an AD-type cognitive profile. We hypothesized that these specific IgG levels would be positively correlated with Clinical Dementia Rating (CDR) scores as well as index scores on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in domains associated with cortical function.
Participants were 118 older adults (mean age = 74, standard deviation = 10.5) drawn from the community and local physician referrals. Participants were reassigned into five groups based on CDR. Blood IgG levels were determined through an affinity purification process.
Analysis of covariance analyses revealed that CDR scores were significantly related to anti-RAGE, F(4,106) = 12.93, p < .001, and anti-Aβ, F(4,106) = 17.08, p < .001, after controlling for age and total IgG levels. Regression analyses indicated significant variance accounted for by anti-RAGE and anti-Aβ above and beyond total IgG effects. Additional regression identified specific RBANS domains accounting for significant variance in anti-RAGE levels including language (t = −3.74, p < .001) and delayed memory (t = −2.31, p < .05), whereas language accounted for a significant amount of variance in anti-Aβ levels (t = −3.96, p < .001).
Anti-RAGE and anti-Aβ IgGs correlate strongly with global scores of dementia. Furthermore, they are associated with a profile of deficiency in domains associated with specific cortical function. Results suggest potential for anti-Aβ and anti-RAGE IgGs as blood biomarkers for AD.
PMCID: PMC2655015  PMID: 19196906
Dementia; Alzheimer's disease; Biomarker; RAGE; Aβ; Immunoglobulin; Cognition

Results 1-11 (11)