Hippocampal neurochemistry, neuromorphometry, and verbal memory in nondemented older adults.

BACKGROUND: Characterization of the behavioral correlates of neuromorphometry and neurochemistry in older adults has important implications for an improved understanding of the aging process. The objective of this study was to test the hypothesis that a measure of hippocampal neuronal metabolism was associated with verbal memory in nondemented older adults after controlling for hippocampal volume. METHODS: 4-T MRI, proton magnetic resonance spectroscopy ((1)H MRS), and neuropsychological assessment were conducted in 48 older adults (23 women; mean age 81 years). Average hippocampal N-acetyl aspartate/creatine ratios (NAA/Cr) and hippocampal volumes were obtained. Neuropsychological evaluation included tests of verbal memory (Buschke and Grober Free and Cued Selective Reminding Test-Immediate Recall [FCSRT-IR], Wechsler Memory Scale-Revised Logical Memory subtest) and attention and executive function (Trail Making Test Parts A and B). RESULTS: Linear regression analysis indicated that after adjusting for age, hippocampal NAA/Cr was a significant predictor of FCSRT-IR performance (beta = 0.38, p = 0.01, R (2) = 0.21). Hippocampal volume was also a significant predictor of FCSRT-IR performance after adjusting for age and midsagittal area (beta = 0.47, p = 0.01, R (2) = 0.24). In a combined model, hippocampal NAA/Cr (beta = 0.33, p = 0.03) and volume (beta = 0.35, p = 0.03) were independent predictors of FCSRT-IR performance, accounting for 30% of the variance in memory. CONCLUSIONS: These findings indicate that nondemented older adults with smaller hippocampal volumes and lower levels of hippocampal N-acetyl aspartate/creatine ratio metabolites perform more poorly on a test of verbal memory. The integrity of both the structure and metabolism of the hippocampus may underlie verbal memory function in nondemented elderly.

Leisure activities and the risk of amnestic mild cognitive impairment in the elderly.

OBJECTIVE: To study the influence of leisure activity participation on risk of development of amnestic mild cognitive impairment (aMCI). METHODS: The authors examined the relationship between baseline level of participation in leisure activities and risk of aMCI in a prospective cohort of 437 community-residing subjects older than 75 years, initially free of dementia or aMCI, using Cox analysis adjusted for age, sex, education, and chronic illnesses. The authors derived Cognitive and Physical Activity Scales based on frequency of participation in individual activities. RESULTS: Over a median follow-up of 5.6 years, 58 subjects had development of aMCI. A one-point increase on the Cognitive (hazard ratio [HR] 0.95, 95% CI 0.91 to 0.99) but not Physical Activities Scale (HR 0.97, 95% CI 0.93 to 1.01) was associated with lower risk of aMCI. Subjects with Cognitive Activity scores in the highest (HR 0.46, 95% CI 0.24 to 0.91) and middle thirds (HR 0.52, 95% CI 0.29 to 0.96) had a lower risk of aMCI compared with subjects in the lowest third. The association persisted even after excluding subjects who converted to dementia within 2 years of meeting criteria for aMCI. CONCLUSIONS: Cognitive activity participation is associated with lower risk of development of amnestic mild cognitive impairment, even after excluding individuals at early stages of dementia.

Estimation of bivariate measurements having different change points, with application to cognitive ageing.

Longitudinal studies of ageing make repeated observations of multiple measurements on each subject. Change point models are often used to model longitudinal data. We demonstrate the use of Bayesian and profile likelihood methods to simultaneously estimate different change points in the longitudinal course of two different measurements of cognitive function in subjects in the Bronx Aging Study who developed Alzheimer's disease (AD). Analyses show that accelerated memory decline, as measured by Buschke Selective Reminding, begins between seven and eight years before diagnosis of AD, while decline in performance on speeded tasks as measured by WAIS Performance IQ begins slightly more than two years before diagnosis, significantly after the decline in memory.

Cognitive performance in surgically menopausal women on estrogen.

Estrogen replacement therapy (ERT) may help maintain normal cognitive function. Nondemented surgically menopausal women on ERT (n = 10) enrolled in a longitudinal aging study performed better than age- and education-matched control subjects (n = 25) on selected tests of verbal memory and constructional ability. These results suggest that ERT initiated soon after surgical menopause can have long-term neuroprotective effects in cognitively intact women.

Cross-sectional and longitudinal relationships among age, cognition, and processing speed.

Cross-sectional and longitudinal age effects on cognitive function were examined in 302 older adults followed longitudinally. Processing speed was related to cognitive performance at cross-section, and change in speed predicted within-person longitudinal cognitive decline. Statistical control of processing speed greatly reduced cross-sectional age effects but did not attenuate longitudinal aging effects. This difference in processing speed's ability to account for cross-sectional and longitudinal age effects is discussed in the context of theories of cognitive aging and methodological and statistical issues pertaining to the cross-sectional and longitudinal study of cognitive aging.

Screening for dementia with the memory impairment screen.

OBJECTIVES: To validate a sensitive and specific screening test for AD and other dementias, assess its reliability and discriminative validity, and present normative data for its use in various applied settings. BACKGROUND: To improve discrimination in screening for AD and dementia, we developed the Memory Impairment Screen (MIS), a 4-minute, four-item, delayed free- and cued-recall test of memory impairment. The MIS uses controlled learning to ensure attention, induce specific semantic processing, and optimize encoding specificity to improve detection of dementia. METHODS: Equivalent forms of the MIS were given at the beginning and end of the testing session to assess alternate forms reliability. Discriminative validity was assessed in a criterion sample of 483 aged individuals, 50 of whom had dementia according to Diagnostic and Statistical Manual of Mental Disorders (3rd ed., revised) criteria. RESULTS: The MIS had good alternate forms reliability, high construct validity for memory impairment, and good discriminative validity in terms of sensitivity, specificity, and positive predictive value. We present normative data for use in settings with different base rates (prevalences) of AD and dementia. CONCLUSION: The MIS provides efficient, reliable, and valid screening for AD and other dementias.

Memory and mental status correlates of modified Braak staging.

We assessed the relationships of performance on memory and mental status tests and neuropathologic stage of Alzheimer's disease as defined by Braak and Braak in 29 patients from a prospective clinicopathologic series. We predicted that memory changes would occur at an earlier Braak stage than mental status changes. Staging was accomplished by matching the topographic distribution of neurofibrillary lesions detected with tau immunocytochemistry to the best fitting diagram published by Braak and Braak. Higher Braak stages were associated with decrements in performance on both memory and mental status tests. As predicted, memory performance declined from stages II to III and mental status did not decline until stages III to IV. The association between memory and Braak stage was unchanged after adjusting for neocortical senile plaques, whereas adjustments for Braak stage eliminated the association between cognitive functioning and amyloid burden. We conclude that Braak staging provides a useful summary of Alzheimer's disease neuropathology, which is associated with both memory and mental status performance.

Processing speed and memory in aging and dementia.

We examined the role of processing speed (PS) as a mediator of age-related and dementia-related differences in cued recall and text memory. Consistent with previous research, statistical control of PS significantly attenuated or eliminated age differences on each of the memory measures. However, age-related decline in the ability to benefit from conditions of increased encoding specificity was not mediated by PS. In contrast to the results for age effects, statistical control of PS did not significantly attenuate dementia-related memory differences, suggesting that processing speed is not an important dementia-related memory impairment. The implications of these findings for interpreting residual age effects and the possible influence of preclinical dementia on studies of normal aging are discussed.

The effect of dementia risk factors on comparative and diagnostic selective reminding norms.

Robust comparative and diagnostic norms for the elderly are provided for the Selective Reminding Test (Buschke, 1973). Correcting for factors such as age and education level are appropriate for comparative norms, which are intended for ranking individuals with respect to their age and education matched peers. However, because age and education are both risk factors for dementia, correcting for these factors decreases test sensitivity for detecting dementia. Age- and education-corrected Selective Reminding scores have a sensitivity for detecting dementia that is 28% lower than uncorrected scores. Using information about age in combination with memory scores provided optimal discrimination of dementia. It is concluded that statistically removing the contribution of dementia risk factors from memory test scores can severely decrease discriminative validity for detecting dementia in the elderly.

Diagnosis of early dementia by the Double Memory Test: encoding specificity improves diagnostic sensitivity and specificity.

OBJECTIVE: To compare the Double Memory Test (DMT) with standard memory tests in the diagnosis of early dementia. BACKGROUND: Diagnosis of dementia requires memory impairment, but few memory tests coordinate acquisition and retrieval to optimize encoding specificity for high sensitivity and specificity. The DMT was developed to improve early diagnosis. DESIGN: We compared the discriminative validity of the DMT, Paired Associates (PA), and Logical Memory (LM) memory tests in a nested case-control study of 30 cases of early dementia and 90 controls matched for age, education, and sex. METHODS: The DMT includes memory tests with (CCR) and without (ICR) encoding specificity. Both tests use category cues to elicit retrieval, but CCR optimizes encoding specificity because the same cues are used for acquisition and retrieval. ICR does not because category cues are used only for retrieval. We used conditional logistic regression to estimate diagnostic sensitivity and specificity. RESULTS: The median BIMC of dementia cases was 10, indicating mild dementia. CCR had much higher sensitivity (93%) and specificity (99%) than ICR (53%, 94%), PA (68%, 91%), and LM (48%, 92%). CCR had the greatest advantage in the mildest cases. CONCLUSIONS: CCR has substantially higher sensitivity and specificity for diagnosis of early dementia than memory tests that do not coordinate acquisition and retrieval. Superior discrimination by CCR is due to an encoding specificity deficit in dementia that increases the difference in recall by cases and controls. CCR is an efficient test with excellent discriminative validity that should facilitate diagnosis of early dementia.

The effects of preclinical dementia on estimates of normal cognitive functioning in aging.

Individuals with preclinical dementia have begun to decline cognitively, but still perform within normal limits on cognitive testing. As a group, subjects with preclinical dementia have lower scores on neuropsychological tests than their dementia-free counterparts. This study examines the effects of preclinical dementia on estimates of normal cognitive function in the aged using data from a longitudinal study. Individuals with preclinical dementia at baseline were retrospectively identified based on subsequent development of dementia. Age-adjusted norms were computed using baseline data for the Selective Reminding Test and the WAIS verbal and performance scores, both including (conventional norms) and then excluding (robust norms) preclinical cases. The results indicate that by failing to exclude preclinical dementia, conventional normative studies underestimate the mean, overestimate the variance, and overestimate the effect of age on cognitive measures. Methods are discussed for selecting robust elderly samples that are relatively free of contamination by preclinical dementia.

Aging, encoding specificity, and memory change in the Double Memory Test.

Aged and young adults were tested by category cued recall after learning with category cues (CCR) or with item cues (ICR). CCR was about twice ICR for both aged and young adults. The aged recalled less than the young and did not benefit as much from greater encoding specificity and deeper processing in CCR. ICR and CCR were correlated, so that expected CCR can be predicted from ICR. The regression of CCR on ICR was linear for young adults, but was piecewise linear for the aged, showing that the relationship between ICR and CCR was not uniform for the aged adults. Lower than expected CCR by a subset of aged without clinical dementia may be a sign of preclinical dementia.

Proportional slowing and addition speed in old and young adults.

An addition and copying task was used to compare processing speed in young and old adults. Consistent with previous studies, no age differences in the problem-size effect were observed (Geary & Wiley, 1991). However, the old adults were slower overall, and an analysis of the distributions of old and young individuals indicated that the form of this slowing was proportional. These analyses also demonstrated that proportional slowing was uniform in the old adults, such that the fastest and slowest old individuals were slowed by the same factor. Because the regression of old-young mean response times can be insensitive to differential age effects, comparisons of old and young distributions are recommended to support claims regarding proportional slowing and uniformity of age effects across individuals. Finally, the results suggest that requiring Ss to initiate a new operation produced a larger age effect than requiring Ss to repeat an operation.

Implicit and explicit memory in young, old, and demented adults.

Previous study of scopolamine and memory (Grober et al., 1989) showed that young adults given moderate or high doses of scopolamine maintained maximum cued recall in spite of a dose-dependent decrement in free recall when memory was assessed by cued selective reminding (CSR), a procedure which circumvents inattention and induces semantic processing. Intact recall by CSR indicates either that scopolamine impairs memory indirectly through effects on attention and information processing or that it impairs explicit memory but not implicit memory. In the present study which was done to determine if CSR reflects explicit or implicit memory, a free association test was used to estimate implicit memory after CSR was administered; explicit memory was estimated with a final trial of cued recall. Data from young, nondemented, and demented adults indicate that CSR reflects explicit memory supporting the interpretation of the previous study that scopolamine does not produce direct impairment of explicit memory.

Does scopolamine directly impair memory?

Enhanced cued recall, a procedure which circumvents inattention and induces semantic processing, was used to determine if scopolamine produces direct impairment of specific memory mechanisms or indirect impairment of memory secondary to impairment of other cognitive processes. In two studies, cognitively normal young adults given moderate or high doses of scopolamine maintained maximum cued recall in spite of a dose-dependent decrement in free recall. This finding suggests that cholinergic blockade may impair memory indirectly through effects on other cognitive processes.

Screening for dementia by memory testing.

Enhanced cued recall provides a simple and clinically useful memory test for identifying dementia in the elderly. Because this test induces semantic processing and coordinates encoding and retrieval for maximum recall, genuine memory deficits due to impairment of specific memory processes can be distinguished from apparent memory deficits due to use of inefficient strategies or impairment of other cognitive processes. Since genuine memory deficits in the elderly are usually associated with dementia, their identification is highly predictive of clinical dementia. The present study validates the use of enhanced cued recall as a screening test for dementia in 70 aged subjects. All but one person with a pure amnesia were correctly classified. Enhanced cued recall correctly classified 97% of the 120 subjects in this and the previous study. Enhanced cued recall shows learning not revealed by free recall, providing more accurate measurement of memory, and distinguishes demented from nondemented elderly more accurately than either free recall or recognition.

Impaired ranking of semantic attributes in dementia.

The present work explored the loss of semantic attributes that is said to occur in dementia. In the first two experiments, subjects had to select attributes that went with concepts like airplane and church. The finding that demented subjects maintained high levels of accuracy when selecting attributes suggested that the semantic content of their concepts was relatively well preserved. The organization of the content was explored in a third experiment by having subjects order attributes according to their relative importance in defining concepts. While demented subjects performed better than chance, they did not rank attributes as well as healthy aged subjects, suggesting a disruption in organization whereby the importance of central attributes is reduced. The hypothesized disruption in organization is viewed in relation to the learning and memory deficit that is the hallmark of the dementias.

Cued recall in amnesia.

Use of a search procedure to control processing during learning results in apparently normal cued recall by some amnesic patients with impaired free-recall learning. This suggests that their ability to encode and retrieve may be relatively intact when they are induced to carry out effective processing during learning. When processing is controlled during learning, cued recall should be useful for neuropsychological evaluation of residual learning and memory capacity.

Speed of recall in aging.

This experiment investigated age differences in the speed of verbal recall under experimentally controlled processing conditions. Twelve normal aged and 12 young adults learned a set of items by a procedure that required them to search a list to identify instances of common conceptual categories. This search procedure was used to control for age differences in initial processing. Memory for the target items was tested by free recall and cued recall in which each item was cued by its category label. There were no age differences in either rate of free recall or speed of cued recall under these conditions. This result appears to be inconsistent with the Birren hypothesis, which predicts age differences in the speed of verbal recall. This experiment illustrates the importance of experimentally controlled processing conditions for evaluating of age-related changes in cognitive speed.

Age differences in cognitive effort in recall.

A secondary task methodology was used to investigate age differences in the amount of cognitive effort demanded by free recall. Aged and young adults performed a reaction time task while simultaneously retrieving a list of items in multitrial free-recall learning. RTs were slower in aged than young adults on each trial, suggesting that free recall is more demanding for older persons. In addition, the secondary task did not interfere with recall by older adults, suggesting that this technique is feasible in older persons. These results are consistent with the cognitive-effort hypotheses which postulate age differences in the demands of memory processing to be one factor underlying age-related deficits. An additional finding suggested that age differences in retrieval effort may also be related to differences in list organization.