Brain activation during encoding and recognition of verbal and figural information in older adults.

Positron emission tomography (PET) patterns of cerebral blood flow associated with verbal and figural memory are described in relation to their value as functional probes for studying longitudinal changes that occur in the aging brain. Relative to a matching control task, verbal and figural encoding increase blood flow in prefrontal cortex (PFC), anterior cingulate, insular, lateral and medial temporal, occipital cortex and the cerebellum. Additionally, medial temporal regions exhibited greater activity during figural encoding relative to verbal encoding. During recognition, blood flow increases in prefrontal, cingulate, insular, and lateral temporal and Broca's areas. Analysis of hemispheric asymmetry reveals that the prefrontal cortex exhibits regionally dependent results. Prefrontal region BA 10 demonstrates more bilateral activation during encoding and retrieval, whereas BA 46 shows right greater than left activation during both encoding and retrieval. Overall, the two tasks activate diverse regions within the frontal, temporal and occipital lobes of the brain, including areas that show age-related structural changes, proving their usefulness in the longitudinal assessment of brain function in the elderly.

One-year age changes in MRI brain volumes in older adults.

Longitudinal studies indicate that declines in cognition and memory accelerate after age 70 years. The neuroanatomic and neurophysiologic underpinnings of cognitive change are unclear, as there is little information on longitudinal brain changes. We are conducting a longitudinal neuroimaging study of nondemented older participants in the Baltimore Longitudinal Study of Aging. This report focuses on age and sex differences in brain structure measured by magnetic resonance imaging during the first two annual evaluations. Cross-sectional results from 116 participants aged 59-85 years reveal significantly larger ventricular volumes and smaller gray and white matter volumes in older compared with younger participants and in men compared with women. Regional brain volumes show that the effects of age and sex are not uniform across brain regions. Age differences are greatest for the parietal region. Sex differences tend to be larger for frontal and temporal than parietal and occipital regions. Longitudinal analysis demonstrates an increase of 1526 mm(3) in ventricular volume over 1 year, but no detectable change in total or regional brain volumes. Definition of the pattern and rate of longitudinal brain changes will facilitate the detection of pathological brain changes, which may be predictors of dementia.

Effects of estrogen replacement therapy on PET cerebral blood flow and neuropsychological performance.

Reports that estrogen may protect against age-associated memory decline and Alzheimer's Disease have kindled interest in the effects of estrogen replacement therapy (ERT) on cognition and brain function. As part of a 9-year study in the Baltimore Longitudinal Study of Aging, we are performing annual magnetic resonance imaging, positron emission tomography (PET), and neuropsychological assessments to examine brain structure and function in individuals aged 55 and older. PET measurements of regional cerebral blood flow (rCBF) are obtained under 3 conditions: rest and verbal and figural delayed recognition memory tasks. Fifteen women receiving ERT (with or without the addition of progesterone) were compared with a matched sample of 17 untreated women. There were no significant differences between groups in regional brain volumes or ventricular size. However, ERT users and nonusers showed significant differences in PET-rCBF relative activation patterns during the memory tasks. During verbal memory processing, there were significant interactions in rCBF activations for the right parahippocampal gyrus, right precuneus, right frontal regions, and left hypothalamus. During figural memory processing, significant interactions were observed for right parahippocampal and inferior parietal regions and for left visual association and anterior thalamic regions. ERT users also showed better performance on neuropsychological tests of figural and verbal memory and on some aspects of the PET activation tests, although the two groups did not differ in education, overall verbal ability, or performance on other neuropsychological tests. These findings confirm our previous observation of the beneficial effects of ERT on figural memory. Moreover, differences in rCBF activation patterns between ERT users and nonusers suggest an area for future research to examine mechanisms through which ERT may influence memory and other cognitive abilities.

Verbal and figural recognition memory: task development and age associations.

The goal of the present study was to develop and validate parallel tests of verbal and figural delayed-recognition memory with similar task demands and difficulty levels. Such tasks would allow examination of age differences and longitudinal age changes in visual recognition memory for two types of stimuli, activate divergent neural systems, and allow us to use the same procedures within the confines of functional neuroimaging as those we use in standard neuropsychological administration. The tasks introduced here include a delay between target presentation and test phase, are matched in difficulty, and yield moderate levels of performance. Individual and group differences in task performance were examined in 80 cognitively normal men and women in two older age groups: 60 to 69 and 70 to 85. Accuracy averaged 74% in both tasks, with lower performance in the oldest age group. Although accuracy was equivalent between tasks, subjects had a more liberal response bias in the figural than verbal task. Performance on the new recognition-memory tests was significantly related to Benton Visual Retention Test (BVRT; Benton [1963]. New York: The Psychological Corporation) and California Verbal Learning Test (CVLT; Delis, Kramer, Kaplan, & Ober [1987]. New York: The Psychological Corporation) performance measures. The absence of floor or ceiling effects, wide range of individual variability, and demonstrated concurrent validity of the present tasks suggest their potential utility in functional neuroimaging studies and in the early detection of cognitive decline.

Protein kinase C in the hippocampus is altered by spatial but not cued discriminations: a component task analysis.

The exact role of the mammalian hippocampus in memory formation remains essentially as an unanswered question for cognitive neuroscience. Experiments with humans and with animals indicate that some types of mnemonic associative processes involve hippocampal function while others do not. Support for the spatial processing hypothesis of hippocampal function has stemmed from the impaired performance of rats with hippocampal lesions in tasks that require spatial discriminations, but not cued discriminations. Previous procedures, however, have confounded the interpretation of spatial versus cued discrimination learning with the number and kinds of irrelevant stimuli present in the discrimination. An empirical set of data describing a role of protein kinase C (PKC) in different mnemonic processes is similarly being developed. Recent work has implicated the activation of this serine-threonine kinase in a variety of learning paradigms, as well as long-term potentiation (LTP), a model system for synaptic plasticity which may subserve some types of learning. The present study employs the principles of component task analysis to examine the role of membrane-associated PKC (mPKC) in hippocampal-dependent memory when all factors other than the type of learning were equivalent. The results indicate that hippocampal mPKC is altered by performance in hippocampally-dependent spatial discriminations, but not hippocampally-independent cued discriminations and provide a general experimental procedure to relate neural changes to specific behavioral changes.

D-cycloserine, a novel cognitive enhancer, improves spatial memory in aged rats.

D-cycloserine, a partial agonist of the NMDA receptor-associated glycine site, can enhance cognition. The present experiment examines the behavioral effects of D-cycloserine on cognitive deficits in male Fischer-344 rats, 24 months old. Rats 24 months old (n = 42) received either vehicle or one of 3 doses of D-cycloserine prior to testing. Young rats, 4 months old (n = 13), received vehicle prior to testing. Place discrimination and repeated acquisition were tested in the water maze and a variety of sensorimotor tasks were given. Aging impaired performance in all tasks. D-cycloserine improved performance in place discrimination and repeated acquisition. No doses affected sensorimotor function. These results support the hypothesis that D-cycloserine has cognition enhancing properties and that it may be useful in treating disorders involving cognitive impairment.

Comparative cognition and assessment of cognitive processes in animals.

Comparative cognition is an approach that seeks to describe cognitive processes in general computational terms so that the appropriate behavioral testing procedures can be established for any animal, including humans. Some examples of this approach are discussed in the context of memory and attention, emphasizing the ways in which historically disparate research traditions can be integrated together to provide new approaches for behavioral testing in animals. This comparative approach helps to integrate animal models using different species, and to develop tasks that have more direct connection to the assessment of cognitive processes in people.

Discrimination learning alters the distribution of protein kinase C in the hippocampus of rats.

Protein kinase C (PKC), an enzyme that plays an essential role in eukaryotic cell regulation (Nishizuka, 1988; Huang et al., 1989), is critical to memory storage processes both in the marine snail Hermissenda crassicornis and in the rabbit (Alkon et al., 1988; Bank et al., 1988; Olds et al., 1989). Specifically, activation of PKC mimics neurobiological correlates of classical conditioning in both Hermissenda and the rabbit, and the distribution of the enzyme within the rabbit hippocampus changes after Pavlovian conditioning. Here, we report that the amount of PKC, as assayed by specific binding of 3H-phorbol-12,13-dibutyrate (3H-PDBU), decreased significantly within the hippocampal CA3 cell region in rats trained to solve a water maze task either by cognitive mapping or by visual discrimination strategies, but not in control rats. Furthermore, hippocampal lesions interfered with acquisition of both of these tasks. We interpret these findings to support the conclusion that distributional changes of PKC within the mammalian hippocampus play a crucial role in memory storage processes.