Alterations of white matter tracts following neurotoxic hippocampal lesions in macaque monkeys: a diffusion tensor imaging study.

Diffusion tensor imaging (DTI) is a valuable tool for assessing presumptive white matter alterations in human disease and animal models. The current study used DTI to examine the effects of selective neurotoxic lesions of the hippocampus on major white matter tracts and anatomically related brain regions in macaque monkeys. Two years postlesion, structural MRI, and DTI sequences were acquired for each subject. Volumetric assessment revealed a substantial reduction in the size of the hippocampus in experimental subjects, averaging 72% relative to controls, without apparent damage to adjacent regions. DTI images were processed to yield measures of fractional anisotropy (FA), apparent diffusion coefficient (ADC), parallel diffusivity (lADC), and perpendicular diffusivity (tADC), as well as directional color maps. To evaluate potential changes in major projection systems, a region of interest (ROI) analysis was conducted including the corpus callosum, fornix, temporal stem, cingulum bundle, ventromedial prefrontal white matter, and optic radiations. Lesion-related abnormalities in the integrity of the fiber tracts examined were limited to known hippocampal circuitry, including the fornix and ventromedial prefrontal white matter. These findings are consistent with the notion that hippocampal damage results in altered interactions with multiple memory-related brain regions, including portions of the prefrontal cortex.

Individual differences in the cognitive and neurobiological consequences of normal aging.

Defining the neural basis of age-related cognitive dysfunction is a major goal of current research on aging. Compelling evidence from laboratory animals and humans indicates that aging does not inevitably lead to cognitive decline. Conducting neurobiological investigations in subjects that have previously undergone behavioral characterization has therefore emerged as a promising strategy for identifying those alterations in brain structure and function that are specifically associated with age-related cognitive impairment.

Why are so many biological systems periodic?

The ubiquity of oscillations in biological systems is well established. Oscillations are observed in all types of organisms from the simplest to the most complex. Periods can range from fractions of a second to months or years. From time to time, it has been suggested that many biological oscillations are the result of the breakdown of effective self-regulation. The opposite view is defended here. It is argued that most periodic behavior is not pathological but rather constitutes the normal operation for these systems. They are present because they confer positive functional advantages for the organism. The advantages fall into five general categories: temporal organization, spatial organization, prediction of repetitive events, efficiency and precision of control.

Formation, separation and characterization of three beta-1,3-glucanases from Sclerotium glucanicum.

The appearance of beta-1,3-glucanases in supernatants of Sclerotium glucanicum cultures was followed by SDS-PAGE and shown to be dependent on cultivation time. Three beta-1,3-glucanases were isolated and purified. Glucanase I and III appeared homogeneous on SDS-PAGE with molecular masses of 85 and 33.5 kDa, respectively. Enzyme I was an endo-splitting beta-1,3-glucanase. In hydrolyzing laminarin it released glucose, laminaritriose and laminaribiose as major endproducts and smaller amounts of higher oligosaccharides. Enzyme III was an exo-beta-1,3-glucanase removing glucose from laminarin and gentiobiose and glucose from scleroglucan. For laminarin as substrate the Km of enzyme I and III was 2.5 and 3.33 mg/ml, respectively. Enzyme II was only partially purified and found to be also an exo-beta-1,3-glucanase, releasing glucose as the only hydrolysis product from laminarin. It did not attack scleroglucan. Its molecular weight was determined to be 78 kDa. Optimum pH and temperature of the three enzymes were determined. The three activities were significantly inhibited by 1 mM Hg2+.

Statistical validation of mutual information calculations: comparison of alternative numerical algorithms.

Given two time series X and Y , their mutual information, I (X,Y) = I (Y,X) , is the average number of bits of X that can be predicted by measuring Y and vice versa. In the analysis of observational data, calculation of mutual information occurs in three contexts: identification of nonlinear correlation, determination of an optimal sampling interval, particularly when embedding data, and in the investigation of causal relationships with directed mutual information. In this contribution a minimum description length argument is used to determine the optimal number of elements to use when characterizing the distributions of X and Y . However, even when using partitions of the X and Y axis indicated by minimum description length, mutual information calculations performed with a uniform partition of the XY plane can give misleading results. This motivated the construction of an algorithm for calculating mutual information that uses an adaptive partition. This algorithm also incorporates an explicit test of the statistical independence of X and Y in a calculation that returns an assessment of the corresponding null hypothesis. The previously published Fraser-Swinney algorithm for calculating mutual information includes a sophisticated procedure for local adaptive control of the partitioning process. When the Fraser and Swinney algorithm and the algorithm constructed here are compared, they give very similar numerical results (less than 4% difference in a typical application). Detailed comparisons are possible when X and Y are correlated jointly Gaussian distributed because an analytic expression for I (X,Y) can be derived for that case. Based on these tests, three conclusions can be drawn. First, the algorithm constructed here has an advantage over the Fraser-Swinney algorithm in providing an explicit calculation of the probability of the null hypothesis that X and Y are independent. Second, the Fraser-Swinney algorithm is marginally the more accurate of the two algorithms when large data sets are used. With smaller data sets, however, the Fraser-Swinney algorithm reports structures that disappear when more data are available. Third, the algorithm constructed here requires about 0.5% of the computation time required by the Fraser-Swinney algorithm.

Toward a nonhuman primate model of age-dependent cognitive dysfunction.

Neuropsychological studies of memory function in young subjects have provided a valuable strategy for developing a nonhuman primate model of age-dependent cognitive dysfunction. This approach suggests specific directions for future research and underscores the importance of appropriate behavioral analyses in efforts to identify the neural basis of age-related cognitive decline.

Recognition memory deficits in a subpopulation of aged monkeys resemble the effects of medial temporal lobe damage.

The present study examined individual differences in recognition memory function in a group of Old World monkeys (Macaca mulatta). Four young (9-11 years) and 10 aged (22-33 years) monkeys were tested in the same delayed-nonmatching-to-sample (DNMS) recognition memory procedure that has been widely used to study the effects of experimental hippocampal lesions in young subjects. Animals were first trained to a 90% correct learning criterion in the DNMS task using a 10-second delay between the sample and recognition phase of each trial. The memory demands of the task were then increased by gradually extending the retention interval from 15 seconds to 10 minutes. Three of the aged monkeys performed as accurately as young subjects at all delays. The remaining aged monkeys performed well at the shortest delays (15 and 30 seconds), but progressively greater impairments emerged across delays of 60 seconds, 2 minutes, and 10 minutes. These results suggest that recognition memory is only compromised in a subpopulation of aged monkeys. Moreover, aged monkeys that are impaired in the DNMS task exhibit the same delay-dependent pattern of deficits that is the hallmark of memory dysfunction resulting from medial temporal lobe damage.

Cerebral glucose metabolism and memory in aged rhesus macaques.

Positron emission tomography and the glucose metabolic tracer [18F]fluorodeoxyglucose were used to evaluate the relationship between regional cerebral metabolic rates for glucose (rCMRglc), age, and performance on a delayed response (DR) test of memory in the aged monkey. Eleven aged animals, 21-26-years old, were included in the analysis. Regional CMRglc, normalized to values for the entire brain, were determined for the dorsal prefrontal cortex, orbitofrontal cortex, hippocampus, and temporal cortex. The aged animals exhibited significant DR deficits relative to a cohort of normal young monkeys. Variability in DR performance among the aged subjects was significantly correlated with relative hippocampal rCMRglc, and chronological age was a reliable predictor of orbitofrontal rCMRglc ratios. This pattern of results suggests that DR impairments in the aged monkey may partly reflect age-related dysfunction distributed among multiple limbic system structures that participate in normal learning and memory. Overall, the findings support the use of positron emission tomography in efforts to define the relationship between cognitive performance, age, and brain physiology in nonhuman primates.

Morphometric studies of the aged hippocampus: I. Volumetric analysis in behaviorally characterized rats.

The present investigation examined the structural integrity of the aged hippocampus by using computer-aided morphometry to quantify the volume of principal hippocampal circuits in young, mature adult, and aged Long-Evans rats. A key feature of the experimental design was that the status of hippocampal-dependent learning and memory was documented prior to histologic evaluation. The following regions, which were visualized by using Timm staining, were included in the analysis: 1) outer portions of the dentate gyrus molecular layer (OML) innervated by the lateral entorhinal cortex, 2) middle portions of the molecular layer (MML) that receive input from the medial entorhinal cortex, 3) the commissural/associational zone (IML) immediately adjacent to the granule cell layer, and 4) the hilus and mossy fiber projection to the CA3 pyramidal cell field (MF). To identify morphometric changes that emerge during the same segment of the life span as age-related learning impairment, analysis of the volumetric results focused on comparisons between the mature adult group and the aged group. Among the individual regions that were analyzed, age-related decreases in total volume were restricted to the MML. This effect, however, occurred against a background of other, subtle changes that, together, reflected substantial reorganization in the normal balance of hippocampal circuitry. Age-related decreases in the proportion of the molecular layer (ML) that comprises the MML were accompanied by a corresponding increase in relative IML volume. The ratio between the volumes of the MML and the MF also displayed significant age-related decline. Overall, aging affected septal levels of the hippocampus disproportionately, and, with the exception of MML/MF volume ratio, the temporal hippocampus was spared. Finally, the status of spatial learning among the aged animals correlated selectively with decreases in the MML/ML and MML/MF ratios. These results demonstrate that the effects of aging are regionally selective and circuit specific, and they suggest that connectional reorganization may contribute to age-related decline in the computational functions of the hippocampus.

Hippocampal dependent learning ability correlates with N-methyl-D-aspartate (NMDA) receptor levels in CA3 neurons of young and aged rats.

Hippocampal N-methyl-D-Aspartate (NMDA) receptors mediate mechanisms of cellular plasticity critical for spatial learning in rats. The present study examined the relationship between spatial learning and NMDA receptor expression in discrete neuronal populations, as well as the degree to which putative age-related changes in NMDA receptors are coupled to the effects of normal aging on spatial learning. Young and aged Long-Evans rats were tested in a Morris water maze task that depends on the integrity of the hippocampus. Levels of NR1, the obligatory subunit for a functional NMDA receptor, were subsequently quantified both biochemically by Western blot in whole homogenized hippocampus, and immunocytochemically by using a high-resolution confocal laser scanning microscopy method. The latter approach allowed comprehensive, regional analysis of discrete elements of excitatory hippocampal circuitry. Neither method revealed global changes, nor were there region-specific differences in hippocampal NR1 levels between young and aged animals. However, across all subjects, individual differences in spatial learning ability correlated with NR1 immunofluorescence levels selectively in CA3 neurons of the hippocampus. Parallel confocal microscopic analysis of the GluR2 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor failed to reveal reliable differences as a function of age or spatial learning ability. This analysis linking age, performance, and NR1 levels demonstrates that although dendritic NR1 is generally preserved in the aged rat hippocampus, levels of this receptor subunit in selective elements of hippocampal circuitry are linked to spatial learning. These findings suggest that NMDA receptor abundance in CA3 bears a critical relationship to learning mediated by the hippocampus throughout the life span.

Visual discrimination and reversal learning in the aged monkey (Macaca mulatta).

Visual discrimination and reversal learning were assessed in young adult (10-12 years old, n = 4) and aged (23-27 years old, n = 5) female rhesus monkeys. Performance was comparable across age groups in many tasks, suggesting that the acquisition of stimulus-reward associations remains largely intact in the aged monkey. Most older subjects, however, required more training than any young animal to learn an initial pattern discrimination. In combination with previous findings from the same groups of monkeys, these data suggest that deficits in attending to the relevant stimulus features in novel testing procedures may contribute to poor performance in aged subjects across a variety of learning and memory tasks. In addition, preliminary findings from a discrimination probe procedure raise the possibility that aged subjects may adopt alternate testing strategies that compensate for some aspects of age-dependent cognitive dysfunction.

An evaluation of spatial information processing in aged rats.

The spatial learning abilities of young, middle-age, and senescent rats were investigated in two experiments using several versions of the Morris water maze task. In Experiment 1, Long-Evans hooded rats were trained to find a submerged escape platform hidden within the water maze. During this phase of testing, aged rats exhibited acquisition deficits compared with either young or middle-age subjects. With continued training, however, all age groups eventually achieved comparable asymptotic levels of performance. Subsequent testing in Experiment 1 revealed that following original training, aged rats were not impaired in learning a novel escape location or in their ability to locate a visible, cued escape platform. In an attempt to identify the basis of the age-related impairments observed in Experiment 1, naive young and aged rats in Experiment 2 were initially tested for their ability to locate a cued escape platform in the water maze. During this phase of testing, the escape latencies of both young and aged rats rapidly decreased to equivalent asymptotic levels. Subsequent analyses revealed that following cue training, young subjects exhibit a significant spatial bias for the region of the testing apparatus where the platform was positioned during training. In contrast, aged rats showed no spatial bias. Training was continued in Experiment 2 using a novel submerged platform location for each subject. During these place training trials, the escape latencies of senescent rats were longer than those of young subjects. These impairments were also accompanied by a lack of spatial bias among aged rats relative to young control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Learning and memory for hierarchical relationships in the monkey: effects of aging.

Young and aged rhesus monkeys were tested on 2 versions of a transitive inference task measuring learning and memory for hierarchical relationships. Animals initially acquired 4 object discrimination problems arranged such that the relationship between the stimuli followed the hierarchy A > B > C > D > E. The second version of the task was similar but involved a series of 7 objects. Learning and memory for the hierarchical relationships were evaluated during probe trials in which novel pairs of nonadjacent items (e.g., B and D) were presented for a response. Standard task accuracy measures failed to distinguish young and aged subjects at any point in training. In contrast, response latency effects that are indicative of relational information processing in young monkeys were entirely absent in aged subjects. The findings highlight the value of a relational memory framework for establishing a detailed neuropsychological account of cognitive aging in the monkey.

Impaired spatial information processing in aged monkeys with preserved recognition memory.

Spatial information processing was examined in a non-human primate model of cognitive aging, using procedures formally similar to tasks designed for rats. The test apparatus was a large open field containing eight reward locations. Monkeys rapidly learned to visit each location once per trial, and probe manipulations confirmed that young animals navigated according to the distribution of cues surrounding the maze. In contrast, aged monkeys solved the task using a response sequencing strategy, independent of extramaze spatial information. Object recognition memory was normal in the aged group. The results reveal substantial correspondence in the cognitive effects of aging across rat and primate models, and they establish appropriate procedures for testing the long-standing proposal that the role of the hippocampus in normal spatial learning is similarly conserved.

Reproductive senescence predicts cognitive decline in aged female monkeys.

The present investigation provide evidences from a non-human primate model that naturally occurring menopause predicts a prominent signature of age-related cognitive decline. Young and aged rhesus monkeys were tested on a delayed response (DR) task known to the sensitive to aging, and reproductive status was evaluated according to menstrual cyclicity and urinary hormone profiles. Peri-/postmenopausal monkeys exhibited significant DR impairments relative to either age-matched premenopausal females, or young control subjects. In addition, markers of endocrine decline in the aged animals were selectively correlated with behavioral performance measures that distinguished premenopausal and peri-/postmenopausal monkeys. These results document that menopause is coupled to cognitive decline in the monkey, and they establish a valuable primate model for defining the effects of endocrine aging on brain and behavioral function.

The time of origin of somatostatin-immunoreactive neurons in the rat hippocampal formation.

Experiments utilizing a combination of [3H]thymidine autoradiography and immunohistochemistry were conducted to determine the time of origin of somatostatin-immunoreactive (SSIR) neurons in the hippocampal formation of the rat. A quantitative and topographic description of neurogenesis in this peptide-containing neuronal system was generated using a computer-aided system to plot the position of labeled cells. Dissected and 'flattened' hippocampal preparations were used to facilitate the analysis of spatial gradients of SSIR cell development. The results indicate that most SSIR hippocampal cells are generated during a short embryonic period which extends from the 12th through the 15th day of gestation (E12-E15). Within this period of development, the distribution of SSIR cells follows a spatial gradient along the transverse or subiculo-dentate axis of the hippocampus. The earliest formed SSIR neurons, generated on E12 and E13, are preferentially distributed to the subiculum, those generated on E14 are most commonly observed throughout the CA1-CA3 fields of the hippocampus and SSIR neurons which become postmitotic on E15 are more heavily represented in the hilar region of the dentate gyrus than cells born at other stages of development. There was no clear-cut neurogenic gradient along the septotemporal axis of the hippocampus. These results indicate that somatostatin cells in the rat hippocampal formation are generated during the same prenatal period when glutamic acid decarboxylase (GAD)-positive neurons become postmitotic. These studies also suggest that quantitative developmental analyses of chemically specific cell types can reveal prominent features of cortical ontogeny that are not readily apparent in standard [3H]thymidine preparations.

Opiate antagonist facilitation of time-dependent memory processes: dependence upon intact norepinephrine function.

Post-training administration of opiate antagonists improves retention of recent learning in laboratory animals tested on a variety of tasks. We examined the possibility that this effect of opiate antagonist treatment might be due to release of brain norepinephrine (NE) function from opioid peptide inhibition. The behavioral testing procedure in the experiments consisted of one-trial passive avoidance conditioning. Rats received post-training treatments immediately after the training trial and retention was tested 24 h later. Lesions of the dorsal noradrenergic bundle (DNB) that were induced by 6-hydroxydopamine (6-OHDA) were found to prevent the memory enhancing effect of post-training naloxone administration. The memory enhancing effect of naloxone was restored when NE neurons were protected from 6-OHDA by pretreatment with a NE uptake inhibitor. Earlier research indicated that the amygdala complex is one brain site that is sensitive to the effects of opiate manipulations on memory processes. In this study, lesions of the DNB were also found to prevent the memory enhancing effect of intracranial opiate antagonist administration into the amygdala complex.

Alterations in [3H]desmethylimipramine binding in the aged rat brain: an in vitro autoradiographic demonstration.

Using in vitro autoradiographic receptor binding, the present report provides a descriptive analysis of [3H]desmethylimipramine ([3H]DMI) binding in the aged rat brain. Small circular patches of intense [3H]DMI binding were present within the caudate nucleus in every aged brain examined. Occasionally, similar patches of label were present in restricted cortical regions of aged brains. Comparable patches of [3H]DMI binding were never observed in young brains used in these investigations. Additional evidence suggests that these age-dependent changes in [3H]DMI binding are anatomically restricted to the loci indicated above.

Developing an effective adult nutrition screening tool for a community hospital.

OBJECTIVE: To develop a sensitive and specific nutrition screening tool that conforms to the requirements of the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) and is effective in any given hospital population. DESIGN: A two-step prospective evaluation was performed in two unrelated community hospitals to determine the effectiveness of a current nutrition screening tool, and to develop a new, more sensitive tool that permits efficient use of available personnel. STATISTICAL ANALYSES: Standard calculations for sensitivity, specificity, positive predictive value, and negative predictive value were used to compare the results of various screening methods with those of full nutrition assessments. Stepwise discriminant analysis was used to determine specific parameters that contributed to the diagnosis of malnutrition and to derive a predictive equation based on these parameters. METHODS: In part 1, 100 patients admitted consecutively were evaluated using a subjective screening tool; the results were compared with those from full nutrition assessment of the same patients. Stepwise discriminant analysis identified three parameters most closely related to malnutrition, and a multivariant equation relative to nutrition risk was derived. In part 2, 151 randomly selected adult medical and surgical patients were evaluated at admission with the same screening tool used in part 1. Additionally, prealbumin level was determined on admission. The results of the screening, the discriminant analysis equation from part 1, and both methods incorporating the prealbumin level were compared with the results of a full nutrition assessment. RESULTS: In part 1, discriminant analysis identified total lymphocyte count, percentage weight loss, and serum albumin level as the three best indicators of malnutrition. A multivariant equation incorporating these objective parameters was derived. In part 2, the equation yielded better sensitivity and specificity results than other screening methods. Inclusion of prealbumin level did not improve screening methods. CONCLUSIONS: The revised screening tool described can be used as the basis of an effective screening program that meets the proposed JCAHO nutrition care standards.