Hematology and serum chemistry values of sooty mangabeys (Cercocebus atys): comparison with rhesus monkeys.

BACKGROUND: The sooty mangabey is a vulnerable West African species that naturally harbors simian immunodeficiency virus (SIV) without pathological symptoms. We present normative hematology and serum chemistry values for this species. METHODS: Hematology analytes from 136 females and 96 males and serum chemistry analytes from 57 females and 26 males were studied. RESULTS: Values of several analytes fell outside published reference ranges in the rhesus monkey, a laboratory standard for Old World primates. Erythrocyte-related parameters were higher in mangabeys than in rhesus monkeys, while platelet counts were lower. Mangabeys also had higher gamma-glutamyltransferase levels and lower urea nitrogen levels. Males had higher erythrocyte-associated values than females. Albumin, globulin, albumin/globulin ratio, calcium, and creatinine changed with age in patterns similar to those reported for the rhesus monkey. CONCLUSIONS: The unique blood profile of the mangabey should be taken into account in clinical and experimental studies of this species.

The genomic response of the ipsilateral and contralateral cortex to stroke in aged rats.

Aged rats recover poorly after unilateral stroke, whereas young rats recover readily possibly with the help from the contralateral, healthy hemisphere. In this study we asked whether anomalous, age-related changes in the transcriptional activity in the brains of aged rats could be one underlying factor contributing to reduced functional recovery. We analysed gene expression in the periinfarct and contralateral areas of 3-month- and 18-month-old Sprague Dawley rats. Our experimental end-points were cDNA arrays containing genes related to hypoxia signalling, DNA damage and apoptosis, cellular response to injury, axonal damage and re-growth, cell lineage differentiation, dendritogenesis and neurogenesis. The major transcriptional events observed were: (i) Early up-regulation of DNA damage and down-regulation of anti-apoptosis-related genes in the periinfarct region of aged rats after stroke; (ii) Impaired neurogenesis in the periinfarct area, especially in aged rats; (iii) Impaired neurogenesis in the contralateral (unlesioned) hemisphere of both young and aged rats at all times after stroke and (iv) Marked up-regulation, in aged rats, of genes associated with inflammation and scar formation. These results were confirmed with quantitative real-time PCR. We conclude that reduced transcriptional activity in the healthy, contralateral hemisphere of aged rats in conjunction with an early up-regulation of DNA damage-related genes and pro-apoptotic genes and down-regulation of axono- and neurogenesis in the periinfarct area are likely to account for poor neurorehabilitation after stroke in old rats.

Age influences the expression of GAP-43 in the rat hippocampus following seizure.

BACKGROUND: Normal aging is associated with impairments in learning and memory and motor function. One viable hypothesis is that these changes reflect an age-related decrease in brain plasticity. OBJECTIVE: The aim of the present study was to identify age-related changes in the time course of expression of the axonal growth associated protein 43 (GAP-43) in a rat model of brain plasticity. METHODS: We examined by Northern blotting, in situ hybridization, and immunohistochemistry the effects of age on the time course of the expression GAP-43 following pentylenetetrazole-induced seizure in the hippocampus of 3-, 18-, and 28-month-old rats. RESULTS: In this model of brain plasticity, young rats displayed a decrease in GAP-43 mRNA levels in CA1, CA3, and polymorphic regions, lasting from 10 h to 3 days after seizure. This was followed by recovery, with peak expression between days 10 and 20. The baseline levels of GAP-43 mRNA decreased with age, especially in the CA3 region. Despite lower baseline levels, middle-aged rats showed the same pattern of upregulation of GAP-43 mRNA expression as the young animals. Old rats showed only minimal upregulation, however, and this occurred only in the polymorphic layer. The level GAP-43 protein itself was higher in old control rats than in the other two control groups, a condition that was transiently reversed by seizure activity. CONCLUSIONS: Middle-aged rats are still capable of a sustained, though diminished, response to seizure activity, while old rats lose this ability. Disruption of the temporal and anatomical coordination of expression of GAP-43 may contribute to the general decline in brain plasticity with age.

Executive function is less sensitive to estradiol than spatial memory: performance on an analog of the card sorting test in ovariectomized aged rhesus monkeys.

Functions supported by the frontal lobes are particularly sensitive to the detrimental effects of aging. Recent studies on postmenopausal women find that estrogen replacement therapy benefits performance on tasks dependent on the frontal lobes. To determine whether estrogen has a similar influence in a rhesus monkey model of menopause, we tested five aged, long-term ovariectomized rhesus monkeys in a modified version of the Wisconsin Card Sort test which had been adapted to the nonhuman primate. In this test, monkeys had to select 3-D objects based either on color (blue, red, yellow) or shape (block, tube, cup) and had to be able to switch their response as a function of reinforcement contingencies. The monkeys were treated with placebo and ethinyl estradiol (EE2, 450 ng/kg/day) in alternation with each successive test. Contrary to our hypothesis, estradiol treatment did not affect performance. Because previous studies in the same monkeys [Neurobiol. Aging 23 (2002) 589] had shown that EE2 improves performance on a spatial memory task dependent on the hippocampus, but not on another task dependent upon the frontal lobes (the delayed response), we conclude that executive processes may be less sensitive to the effects of estradiol than hippocampal-dependent tasks.

Estradiol selectively affects processing of conspecifics' faces in female rhesus monkeys.

Estrogen deficiency following ovariectomy or menopause increases the risk of developing diseases such as osteoporosis and may also lead to memory impairment. Although estrogen replacement therapy (ERT) alleviates many symptoms associated with estrogen loss, it is not clear whether it also benefits cognitive function. The effect of estrogens upon cognition can best be studied in an animal model of human menopause, in which estrogen levels can be experimentally manipulated. Six young ovariectomized female rhesus monkeys (6-9 years old) were tested on a battery of touchscreen-based cognitive tasks, including the Matching-to-Sample (MTS) task with mixed delays and the spatial, object, and face conditions of the Delayed Recognition Span Test (DRST). Monkeys were tested 5 days a week, one task per week, for a total of 8 months, while undergoing treatments with placebo and ethinyl estradiol (EE2) in alternating 28-days blocks. Blood samples were collected to verify EE2 levels. We also observed the monkeys by video monitor during test sessions and recorded locomotor activity and response topology. Performance on the face-DRST, a task that involved selecting the new face in an increasing array of rhesus monkey faces, was impaired by EE2 treatment, as compared to placebo. Other tasks were unaffected by EE2. There was no clear evidence of EE2 effects upon motor activity or anxiety. In order to test the reliability of our findings, we conducted an additional experiment in which the monkeys were again given the face-DRST with different categories of face stimuli for 4 months, while receiving placebo and EE2 in alternating 7-days blocks. They performed each task 4-5 days/week for 4 weeks with (1) the same rhesus monkey faces as in the first experiment, (2) human faces, (3) chimpanzee faces, and (4) novel rhesus monkey faces. Face-DRST performance did not vary as a function of treatment when human or chimpanzee faces were used as stimuli. In contrast, periods of EE2 treatment were associated with a lower performance for both sets of rhesus monkey faces. These findings suggest that EE2 treatment has a detrimental effect on processing faces of conspecifics by female rhesus monkeys. We speculate that estrogens may produce this effect by enhancing emotional reactivity to socially relevant stimuli.

Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine.

Heterologous prime/boost regimens have the potential for raising high levels of immune responses. Here we report that DNA priming followed by a recombinant modified vaccinia Ankara (rMVA) booster controlled a highly pathogenic immunodeficiency virus challenge in a rhesus macaque model. Both the DNA and rMVA components of the vaccine expressed multiple immunodeficiency virus proteins. Two DNA inoculations at 0 and 8 weeks and a single rMVA booster at 24 weeks effectively controlled an intrarectal challenge administered 7 months after the booster. These findings provide hope that a relatively simple multiprotein DNA/MVA vaccine can help to control the acquired immune deficiency syndrome epidemic.

Fluctuations in spatial recognition memory across the menstrual cycle in female rhesus monkeys.

Findings are inconsistent regarding whether women's cognitive performance fluctuates across phases of the menstrual cycle, but differences in methodology and the use of reported cycle phase rather than precise hormonal measures may underlie these disparities. Studies in monkeys may help resolve these discrepant findings, since hormonal status can be reliably determined. We tested four young (5-7 years old) female rhesus monkeys daily during one entire menstrual cycle on three cognitive tasks displayed on a computerized touch-screen system: a Matching to Sample task with a 30 s delay (MTS-30s), a Matching to Sample task without delay (MTS-no delay) and the spatial condition of the Delayed Recognition Span Test (spatial-DRST). Blood samples were collected at specific time intervals throughout the cycle and assayed for estradiol and progesterone in order to identify hormonal status. There was a nonsignificant trend for the MTS-30s scores to be better during the follicular and luteal phases, when estradiol levels were low, than during the peri-ovulatory phase, when estradiol levels were at their highest. MTS-no delay performance did not vary as a function of hormonal status. Spatial-DRST scores were significantly better during the follicular and luteal phases than during the peri-ovulatory phase of the cycle. These data in the female rhesus monkey support the hypothesis that spatial memory performance is sensitive to estradiol variations across the menstrual cycle, with better performance associated with low estradiol levels.

Hematologic and blood biochemical variables of captive chimpanzees: cross-sectional and longitudinal analyses.

Hematologic and blood biochemical variables are of great importance in medical and veterinary practice. In addition, these analytes may have significance as potential biomarkers of aging. Previous reports on normative values of these variables in the chimpanzees are based on cross-sectional studies that did not include individuals of advanced age. To address this omission, we performed cross-sectional and longitudinal analyses of hematologic and blood biochemical data collected from chimpanzees over a 9-year period. One-hundred forty-six females and 106 males of ages representing the entire life span of the species were studied. We derived normative cross-sectional values of 14 commonly measured hematologic and 20 blood biochemical variables, which should provide a useful reference for clinical blood studies in chimpanzees. In addition, we found in a cross-sectional regression analysis of our data that most analytes varied significantly between males and females, and that they varied markedly with age. Most variables had year-to-year consistency within the same individuals, as indicated by statistically significant intra-year correlation coefficients. Finally, we performed a longitudinal analysis of the analytes in chimpanzees by calculating the slopes and intercepts of the best-fitting trend line for each individual. The resulting slopes were analyzed by sex and by decade of age of subjects to determine whether trends were consistent. Consistent trends detected in the longitudinal analysis were usually restricted to the first decade of life, and thus represented maturational processes. The overall lack of within-animal trends covering all or most of the period from early adulthood through old age in this 9-year study suggests that a longer period of follow-up than used here may be required to document senescence-related changes.

Progressive infection in a subset of HIV-1-positive chimpanzees.

Chimpanzees are susceptible to infection with human immunodeficiency virus (HIV)-1; however, infected animals usually maintain normal numbers of CD4(+) T lymphocytes and do not develop immunodeficiency. We have examined 10 chronically infected HIV-1-positive chimpanzees for evidence of progressive infection. In addition to 1 animal that developed AIDS, 3 chimpanzees exhibit evidence of progressive HIV infection. All progressors have low CD4(+) T cell counts (<200 cells/microL), severe CD4:CD8 inversion, and marked reduction in interleukin-2 receptor expression by CD4(+) T cells. In comparison with HIV-positive nonprogressor chimpanzees, progressors have higher plasma and lymphoid virus loads, greater CD38 expression in CD8(+)/HLA-DR(+) T cells, and greater serum concentrations of soluble tumor necrosis factor type II receptors and beta2-microglobulin, all markers of HIV progression in humans. These observations show that progressive HIV-1 infection can occur in chimpanzees and suggest that the pathogenesis of progressive infection in this species resembles that in humans.

Cognitive function in aged ovariectomized female rhesus monkeys.

To determine whether ovariectomy exacerbates age-related cognitive decline, the performance of 6 aged monkeys that had been ovariectomized early in life (OVX-Aged) was compared to that of 8 age-matched controls with intact ovaries (INT-Aged) and that of 5 young controls with intact ovaries (INT-Young) in tasks of visual recognition memory, object and spatial memory, and executive function. The OVX-Aged monkeys were marginally more impaired than the INT-Aged monkeys on the delayed nonmatching-to-sample with a 600-s delay. In contrast, they performed significantly better than the INT-Aged controls on the spatial condition of the delayed recognition span test. The hypothesis that prolonged estrogenic deprivation may exaggerate the age-related decline in visual recognition memory will require additional support. However, the findings suggest that long-term ovariectomy may protect against the development with aging of spatial memory deficits.

Spatial cognition in rhesus monkeys: male superiority declines with age.

Twelve young (4-7 years of age) and 14 old (20-27 years of age) male and female rhesus monkeys were tested on seven cognitive tasks. Males and females performed similarly on tasks of object memory and executive function, but young males outperformed young females on a spatial memory task (Delayed Recognition Span Test) that requires the identification of a new stimulus among an increasing array of serially presented stimuli. This superior level of spatial ability in young males declined sharply with age, so that old males did not perform significantly better than old females. These findings in the nonhuman primate suggest that biological rather than sociocultural factors underlie the sex differences in cognition and their diminution with age.

Brain weight throughout the life span of the chimpanzee.

Studies on human postmortem material report lower brain weights in older than in younger cohorts, whereas there is no apparent change with age in the rhesus monkey. In view of these contrasting results, we examined the pattern of brain weight across the life span in the chimpanzee, one of the closest biological relatives of humans. To place the study in context of the empirical life expectancy of the chimpanzee, we first performed a survival analysis on data from 275 chimpanzees that were maintained in the colony of the Yerkes Primate Center. The survival analysis revealed the maximum life spans of female and male chimpanzees to be about 59 and 45 years, respectively. We examined fresh brain weights from 76 chimpanzees ranging in age from birth to 59.4 years of age. The brains were taken from 9 infants (birth to 1 year of age), 25 juveniles (1-7 years), 13 adolescents (7-15 years), 21 young adults (15-30 years), and 8 old adults (over 30 years). Adult brain weight was achieved by the age of 7 years. The adolescent and young adult chimpanzees had the largest brain weights; in these two age groups combined, the mean brain weight (+/- standard deviation) was 368.1 g (+/-37.3) for females (n = 17) and 405.6 g (+/-39.4) for males (n = 17). This sex difference was statistically significant (P < 0.01). Simple linear regression performed on the combined material from females and males aged 7 years and older revealed a decline in brain weight with advancing age of 1.1 g/year (P < 0.05). When the effect of sex on brain weight was statistically controlled for, the loss of brain weight with age was 0.9 g/year (P = 0.07). These results suggest that brain weight declines moderately with age in the chimpanzee as it does in humans.

Neutralizing antibody-independent containment of immunodeficiency virus challenges by DNA priming and recombinant pox virus booster immunizations.

Eight different protocols were compared for their ability to raise protection against immunodeficiency virus challenges in rhesus macaques. The most promising containment of challenge infections was achieved by intradermal DNA priming followed by recombinant fowl pox virus booster immunizations. This containment did not require neutralizing antibody and was active for a series of challenges ending with a highly virulent virus with a primary isolate envelope heterologous to the immunizing strain.

Age-related decline in DHEAS is not related to cognitive impairment in aged monkeys.

To determine whether endogenous DHEAS level is related to cognitive performance in the rhesus monkey, we tested 9 young and 14 old monkeys on the acquisition and the 120 s delay condition of the delayed non-matching to sample and on the spatial delayed recognition span test. A single summary measure of cognitive ability, the cognitive performance index (CPI), was derived from these three tests. As expected, the mean level of DHEAS as well as the CPI declined with age. DHEAS level, however, was not significantly correlated with CPI, after controlling for the relationship of age to these two variables. Further, impaired and unimpaired aged monkeys did not differ in DHEAS level. These findings suggest that DHEAS is not independently associated with age-related cognitive decline in the rhesus monkey.

Differential rearing affects corpus callosum size and cognitive function of rhesus monkeys.

This study investigated the effects of different rearing conditions on neural and cognitive development of male rhesus monkeys (Macaca mulatta). Infants raised individually in a nursery from 2 to 12 months of age (NURSERY, n=9) were compared to age-matched infants raised in a semi-naturalistic, social environment (CONTROL, n=11). Various brain regions were measured by MRI. Although overall brain volumes did not differ between NURSERY and CONTROL animals, corpus callosum (CC) size, measured in mid-sagittal sections, was significantly decreased in the NURSERY group. Group differences were most evident in the posterior aspects of the corpus callosum and appeared to result from changes in the number of cross-hemispheric projections rather than from a decrease in cortical gray matter volume. The decrease in corpus callosum size in the NURSERY animals persisted after 6 months of social housing in a peer-group. Rearing group differences were not found in other structures analyzed, including the hippocampus, cerebellum and anterior commissure. In cognitive testing, NURSERY animals had more difficulty acquiring the delayed non-matching to sample (DNMS) task, but showed no deficits in subsequent memory performance when a 2 or 10 min delay was imposed. The NURSERY infant monkeys were also impaired in object, but not in spatial, reversal learning, although there were no differences in a simple object discrimination task. The cognitive deficits exhibited by the NURSERY animals were significantly correlated with the alterations found in the CC. In summary, rearing environment was associated with sustained differences in cross-hemispheric projections, white matter volume and cognitive performance.

Brain weight does not decrease with age in adult rhesus monkeys.

Cross-sectional studies on adult human autopsy material have shown that younger cohorts have heavier brains than older groups. We sought to determine whether a similar pattern is present in the rhesus monkey, a species that serves as a useful model of human brain and cognitive aging. Data were obtained from necropsies of 399 rhesus monkeys (180 females; 219 males), of ages covering the entire adult lifespan of this species. In addition to fresh brain weight, variables considered were age, sex, body weight, heart weight, identity of the prosector, and circumstance of death. Initial bivariate analyses revealed a significant sex difference in brain weight (mean for males: 96.1 g; for females: 86.1 g; p < 0.001), as well as significant correlations of brain weight with body weight (r = 0.20, p < 0.01 for females; r = 0.27, p < 0.001 for males), and heart weight (r = 0.27, p < 0.001 for females; r = 0.38, p < 0.001 for males). Identity of prosector, circumstance of death, and age were not significantly related to brain weight in bivariate analyses. Multiple linear regression, controlling for possible confounding effects of body weight and sex, also suggested that brain weight is stable throughout adulthood in the rhesus monkey.

Age-related brain changes in rhesus monkeys: a magnetic resonance spectroscopic study.

Brain metabolites were measured by proton magnetic resonance spectroscopy in five young (4-10 years of age) and six old (24-30 years of age) adult rhesus monkeys. The two age groups had similar levels of N-acetylaspartate and of choline relative to creatine, but the ratio of myo-inositol/creatine was higher in each old monkey than in any of the young animals. There was no significant relationship between the metabolite ratios and cognitive performance. The findings indicate that a consistent pattern of non-invasively detectable biochemical changes occurs in the brain with ageing. Whether these changes have functional significance in age-related pathologies, or are simply markers of brain ageing will be the subject of future studies.

Patterns of cognitive decline in aged rhesus monkeys.

Although cognitive decline has been well established as a consequence of aging in non-human primate models, the prevalence or frequency of impairment for specific age ranges has not been described. The first aim of this study was to estimate prevalence of cognitive impairment on each of the six tests of cognitive performance by comparing the performance of early-aged (19-23 years old), advanced-aged (24-28 years old), and oldest-aged (29+ years old) monkeys to that of young adults (< 15 years old). The second aim was to derive a single overall measure of cognitive performance to help classify behavioral function in our aged monkeys. Accordingly, we obtained performance measures for these age groups on six behavioral measures: (1) acquisition of the delayed non-matching-to-sample task (DNMS); (2) performance of the DNMS with a delay of 120 sec; (3) the spatial condition of the delayed recognition span test (DRST); (4) the color condition of the DRST; (5) spatial reversal learning; and (6) object reversal learning. Early-aged monkeys displayed prevalence rates of impairment significantly greater than zero on all tasks except the DRST-color. The highest prevalence of impairment was observed in this age group in a task measuring spatial memory (DRST). Significant trends toward progressively higher impairment rates in advanced-aged and oldest-aged monkeys were observed for DNMS-acquisition, DRST-color and spatial reversal learning tasks. A linear transformation of standardized scores on the six cognitive tests was derived by means of principal components analysis (PCA). The first PCA (PCA1) included data from 30 monkeys with available data on all six measures, and yielded a composite measure which declined linearly with increasing age (r = -0.74). A second PCA (PCA2) was performed on data from 53 monkeys for which three test scores (DNMS-acquisition, DNMS-120s delay, and DRST-spatial condition) were available. The composite score derived from this analysis was highly correlated (r = 0.93) with the composite score from PCA1, suggesting that a score based on only three tests may provide an adequate classification of global cognitive ability.

Chronic medical conditions and risk of fall injury events at home in older adults.

OBJECTIVE: To evaluate the association between selected chronic medical conditions (CMCs) and fall injury events at home among community-dwelling older persons. DESIGN: Population-based case-control study. SETTING: The general community. PARTICIPANTS: Persons aged 65 and older living at home, excluding those using a wheelchair; 467 cases and 691 control subjects were studied. MEASUREMENTS: The main independent variables were self-reported histories of 10 CMCs: diabetes, high blood pressure, anemia, heart attack, Parkinson's disease, stroke, emphysema, cancer (other than skin), cataracts, and glaucoma. RESULTS: The final multivariate model included variables for age, sex, body mass, dependency in activities of daily living, current exercise (three or more times per week), mental status scores, and three CMCs. Persons with a history of stroke or anemia had an increased risk of a fall injury event: for stroke the adjusted odds ratio (aOR) equalled 1.7 (95% confidence interval (CI), 1.0-3.0); for anemia the aOR equalled 1.5 (95% CI, 1.0-2.2). Those with a history of high blood pressure had decreased risk (aOR = .7, 95% CI 0.5-0.9). CONCLUSIONS: Persons 65 and older with a self-reported history of anemia or stroke are at increased risk of a fall injury event in the home, whereas those with a self-reported history of high blood pressure are at decreased risk.

Recognition memory span in rhesus monkeys of advanced age.

Assessment of recognition memory was performed on eight rhesus monkeys of advanced age (25 to 27 years of age) using the delayed recognition span test (DRST). Their performance was compared to that of five young adult animals (5 to 7 years of age) on two stimulus conditions of the DRST: spatial position and color. Both trial unique and repeating series were used for each of the two conditions. As a group, aged monkeys were impaired on both the spatial and color conditions of the DRST, achieving about two-thirds of the span of the young adult group in each condition. Error analyses revealed that monkeys in the aged group also produced more perseverative responses (i.e., displacing the previously correct disk) than did young adults. Together the findings suggest that monkeys of advanced age are impaired on tasks with memory loading demand characteristics.