Hippocampal Subregions Differentially Associate with Standardized Memory Tests

Recent studies suggest that individual hippocampal subregions perform distinct cognitive operations and are differentially targeted by aging and disease. Although originally developed to assess global hippocampal function, whether performance on standard memory tests used in neuropsychological batteries is associated with individual hippocampal subregions remains unknown. Here we addressed this issue by imaging 210 neuropsychologically characterized subjects using a high-resolution variant of functional magnetic resonance imaging that generates maps reflective of basal hippocampal metabolism. Regression analysis revealed memory tests that differentially associate with two hippocampal subregions, the entorhinal cortex (EC) and the dentate gyrus (DG). Whereas performance on the delayed retention component of the Selective Reminding Test was associated with the EC, performance on the recognition component of the Benton Visual Retention Test (BVRT) was associated with the DG. Furthermore, elevation in blood glucose, previously shown to target the DG, was found to correlate selectively with the recognition component of the BVRT. These findings provide further evidence that the hippocampal subregions perform distinct roles, and, interpreted in the context of previous neuropsychological and imaging studies, confirm that aging and Alzheimer's disease target different hippocampal subregions

Structural MRI Covariance Patterns Associated with Normal Aging and Neuropsychological Functioning

Structural magnetic resonance imaging (MRI) studies have shown dramatic age-associated changes in grey and white matter volume, but typically use univariate analyses that do not explicitly test the interrelationship among brain regions. The current study used a multivariate approach to identify covariance patterns of grey and white matter tissue density to distinguish older from younger adults. A second aim was to examine whether the expression of the age-associated covariance topographies is related to performance on cognitive tests affected by normal aging. Eighty-four young (mean age=24.0) and 29 older (mean age=73.1) participants were scanned with a 1.5T MRI machine and assessed with a cognitive battery. Images were spatially normalized and segmented to produce grey and white matter density maps. A multivariate technique, based on the subprofile scaling model, was used to capture sources of between- and within-group variation to produce a linear combination of principal components that represented a "pattern" or "network" that best discriminated between the two age groups. Univariate analyses were also conducted with statistical parametric maps. Grey and white matter covariance patterns were identified that reliably discriminated between the groups with greater than 0.90 sensitivity and specificity. The identified patterns were similar for the univariate and multivariate techniques, and involved widespread regions of the cortex and subcortex. Age and the expression of both patterns were significantly associated with performance on tests of attention, language, memory, and executive functioning. The results suggest that identifiable networks of grey and white matter regions systematically decline with age and that pattern expression is linked to age-related cognitive decline

Cerebral Blood Flow and Gray Matter Volume Covariance Patterns of Cognition in Aging

Advancing age results in altered cognitive and neuroimaging-derived markers of neural integrity. Whether cognitive changes are the result of variations in brain measures remains unclear and relating the two across the lifespan poses a unique set of problems. It must be determined whether statistical associations between cognitive and brain measures truly exist and are not epiphenomenal due solely to their shared relationships with age. The purpose of this study was to determine whether cerebral blood flow (CBF) and gray matter volume (GMV) measures make unique and better predictions of cognition than age alone. Multivariate analyses identified brain-wide covariance patterns from 35 healthy young and 23 healthy older adults using MRI-derived measures of CBF and GMV related to three cognitive composite scores (i.e., memory, fluid ability, and speed/attention). These brain-cognitive relationships were consistent across the age range, and not the result of epiphenomenal associations with age and each imaging modality provided its own unique information. The CBF and GMV patterns each accounted for unique aspects of cognition and accounted for nearly all the age-related variance in the cognitive composite scores. The findings suggest that measures derived from multiple imaging modalities explain larger amounts of variance in cognition providing a more complete understanding of the aging brain

The Impact of Age-Related Changes on Working Memory Functional Activity

This work investigated associations of age-related brain atrophy and functional neural networks identified using multivariate analyses of BOLD fMRI data in young and elder participants (young, N=37; mean age=25; elders, N=15; mean age=74). Two networks were involved in retaining increasing loads of verbal information in working memory. Network utilizations were used to test associations between function and indices of grey matter volume changes using voxel based morphometry. Global changes in brain volume were not associated with the secondary network. Lower regional grey matter volume in the left pre-central gyrus within the primary network was associated with increased secondary network utilization independent of age group. Decreased regional grey matter volume was associated with increased age only in the elders. Increased secondary network expression was associated with increased slope of reaction times across memory load, in the elders. These results support the theory of neural compensation, that elder participants recruit additional neural resources to maintain task performance in the face of age-related decreases in regional grey matter volume

Examining the Multifactorial Nature of Cognitive Aging with Covariance Analysis of Positron Emission Tomography Data

Research has indicated that there may be age-related and Alzheimer's disease (AD) -related reductions in regional cerebral blood flow (rCBF) in the brain. This study explored differences in age- and AD-related rCBF patterns in the context of cognitive aging using a multivariate approach to the analysis of H215O PET data. First, an rCBF covariance pattern that distinguishes between a group of younger and older adults was identified. Individual subject's expression of the identified age-related pattern was significantly correlated with their performance on tests of memory, even after controlling for the effect of age. This finding suggests that subject expression of the covariance pattern explained additional variation in performance on the memory tasks. The age-related covariance pattern was then compared to an AD-related covariance pattern. There was little evidence that the two covariance patterns were similar, and the age-related pattern did a poor job of differentiating between cognitively-healthy older adults and those with probable AD. The findings from this study are consistent with the multifactorial nature of cognitive aging

A Forward Application of Age Associated Gray and White Matter Networks

To capture patterns of normal age-associated atrophy, we previously used a multivariate statistical approach applied to voxel based morphometry that identified age-associated gray and white matter covariance networks (Brickman et al. [2007]: Neurobiol Aging 28:284-295). The current study sought to examine the stability of these patterns by forward applying the identified networks to an independent sample of neurologically healthy younger and older adults. Forty-two younger and 35 older adults were imaged with standard high-resolution structural magnetic resonance imaging. Individual images were spatially normalized and segmented into gray and white matter. Covariance patterns that were previously identified with scaled subprofile model analyses were prospectively applied to the current sample to identify to what degree the age-associated patterns were manifested. Older individuals were also assessed with a modified version of the Mini Mental State Examination (mMMSE). Gray matter covariance pattern expression discriminated between younger and older participants with high optimal sensitivity (100%) and specificity (90.5%). While the two groups differed in the degree of white matter pattern expression (t (75) = 5.26, P < 0.001), classification based on white matter expression was relatively low (sensitivity = 80% and specificity = 61.9%). Among older adults, chronological age was significantly associated with increased gray matter pattern expression (r (32) = 0.591, P < 0.001) but not with performance on the mMMSE (r (31) = -0.314, P = 0.085). However, gray matter pattern expression was significantly associated with performance on the mMMSE (r (31) = -0.405, P = 0.024). The findings suggest that the previously derived age-associated covariance pattern for gray matter is reliable and may provide information that is more functionally meaningful than chronological age

Telephone-Based Identification of Mild Cognitive Impairment and Dementia in a Multicultural Cohort

Background: Telephone-based interviews can be used for screening and to obtain key study outcomes when participants in longitudinal studies die or cannot be seen in person, but must be validated among ethnically and educationally diverse people. Objective: To determine the accuracy of a telephone interview in classifying (1) demented from nondemented participants, (2) cognitively impaired participants from cognitively normal participants, and (3) participants with mild cognitive impairment (MCI) from those with normal cognition or (4) MCI from dementia among an ethnically and educationally diverse community-based sample. Method: The sample consisted of 377 (30.5% non-Hispanic white, 34.7% non-Hispanic black, and 33.7% Caribbean Hispanic) older adults. The validation standard was diagnosis of dementia and MCI based on in-person evaluation. The Telephone Interview for Cognitive Status (TICS) and the Dementia Questionnaire (DQ) were administered within the same assessment wave. Results: The sample included 256 people (67.9%) with normal cognition, 68 (18.0%) with MCI, and 53 (14.1%) with dementia. Validity of the TICS was comparable among non-Hispanic whites, non-Hispanic blacks, and Hispanics. Among non-Hispanic whites, the DQ had better discrimination of those with dementia from those without dementia and from those with MCI than among other racial/ethnic groups. Telephone measures discriminated best when used to differentiate demented from nondemented participants (88% sensitivity and 87% specificity for the TICS; 66% sensitivity and 89% specificity for DQ) and when used to differentiate cognitively normal participants from those with cognitive impairment (ie, MCI and dementia combined; 73% sensitivity and 77% specificity for the TICS; 49% sensitivity and 82% specificity for DQ). When demographics and prior memory test performance were used to calculate pretest probability, consideration of the telephone measures significantly improved diagnostic validity. Conclusions: The TICS has high diagnostic validity for identification of dementia among ethnically diverse older adults, especially when supported by the DQ and prior visit data. However, telephone interview data were unable to reliably distinguish MCI from normal cognition

Do Neuropsychological Tests Have the Same Meaning in Spanish Speakers as They Do in English Speakers?

OBJECTIVE: The purpose of this study was to examine whether neuropsychological tests translated into Spanish measure the same cognitive constructs as the original English versions. METHOD: Older adult participants (N = 2,664), who did not exhibit dementia from the Washington Heights Inwood Columbia Aging Project (WHICAP), a community-based cohort from northern Manhattan, were evaluated with a comprehensive neuropsychological battery. The study cohort includes both English (n = 1,800) and Spanish speakers (n = 864) evaluated in their language of preference. Invariance analyses were conducted across language groups on a structural equation model comprising four neuropsychological factors (memory, language, visual-spatial ability, and processing speed). RESULTS: The results of the analyses indicated that the four-factor model exhibited partial measurement invariance, demonstrated by invariant factor structure and factor loadings but nonequivalent observed score intercepts. CONCLUSION: The finding of invariant factor structure and factor loadings provides empirical evidence to support the implicit assumption that scores on neuropsychological tests are measuring equivalent psychological traits across these two language groups. At the structural level, the model exhibited invariant factor variances and covariances

Physical Activity, Diet, and Risk of Alzheimer Disease

CONTEXT: Both higher adherence to a Mediterranean-type diet and more physical activity have been independently associated with lower Alzheimer disease (AD) risk but their combined association has not been investigated. OBJECTIVE: To investigate the combined association of diet and physical activity with AD risk. DESIGN, SETTING, AND PATIENTS: Prospective cohort study of 2 cohorts comprising 1880 community-dwelling elders without dementia living in New York, New York, with both diet and physical activity information available. Standardized neurological and neuropsychological measures were administered approximately every 1.5 years from 1992 through 2006. Adherence to a Mediterranean-type diet (scale of 0-9; trichotomized into low, middle, or high; and dichotomized into low or high) and physical activity (sum of weekly participation in various physical activities, weighted by the type of physical activity [light, moderate, vigorous]; trichotomized into no physical activity, some, or much; and dichotomized into low or high), separately and combined, were the main predictors in Cox models. Models were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, body mass index, smoking status, depression, leisure activities, a comorbidity index, and baseline Clinical Dementia Rating score. MAIN OUTCOME MEASURE: Time to incident AD. RESULTS: A total of 282 incident AD cases occurred during a mean (SD) of 5.4 (3.3) years of follow-up. When considered simultaneously, both Mediterranean-type diet adherence (compared with low diet score, hazard ratio [HR] for middle diet score was 0.98 [95% confidence interval {CI}, 0.72-1.33]; the HR for high diet score was 0.60 [95% CI, 0.42-0.87]; P = .008 for trend) and physical activity (compared with no physical activity, the HR for some physical activity was 0.75 [95% CI, 0.54-1.04]; the HR for much physical activity was 0.67 [95% CI, 0.47-0.95]; P = .03 for trend) were associated with lower AD risk. Compared with individuals neither adhering to the diet nor participating in physical activity (low diet score and no physical activity; absolute AD risk of 19%), those both adhering to the diet and participating in physical activity (high diet score and high physical activity) had a lower risk of AD (absolute risk, 12%; HR, 0.65 [95% CI, 0.44-0.96]; P = .03 for trend). CONCLUSION: In this study, both higher Mediterranean-type diet adherence and higher physical activity were independently associated with reduced risk for AD