Age-related effects in the neocortical organization of chimpanzees: gray and white matter volume, cortical thickness, and gyrification.

Among primates, humans exhibit the most profound degree of age-related brain volumetric decline in particular regions, such as the hippocampus and the frontal lobe. Recent studies have shown that our closest living relatives, the chimpanzees, experience little to no volumetric decline in gray and white matter over the adult lifespan. However, these previous studies were limited with a small sample of chimpanzees of the most advanced ages. In the present study, we sought to further test for potential age-related decline in cortical organization in chimpanzees by expanding the sample size of aged chimpanzees. We used the BrainVisa software to measure total brain volume, gray and white matter volumes, gray matter thickness, and gyrification index in a cross-sectional sample of 219 captive chimpanzees (8-53 years old), with 38 subjects being 40 or more years of age. Mean depth and cortical fold opening of 11 major sulci of the chimpanzee brains were also measured. We found that chimpanzees showed increased gyrification with age and a cubic relationship between age and white matter volume. For the association between age and sulcus depth and width, the results were mostly non-significant with the exception of one negative correlation between age and the fronto-orbital sulcus. In short, results showed that chimpanzees exhibit few age-related changes in global cortical organization, sulcus folding and sulcus width. These findings support previous studies and the theory that the age-related changes in the human brain is due to an extended lifespan.

Longitudinal cerebral metabolic changes in pig-tailed macaques infected with the neurovirulent virus SIVsmmFGb.

Longitudinal cerebral metabolite changes in pig-tailed macaques inoculated with the simian immunodeficiency virus SIVsmmFGb were evaluated with in vivo proton MRS at 3 T. Blood sample collection, and MRS were carried out before and 2, 4, 8, 12, 16, 20, and 24 weeks after SIV inoculation. Significant reduction of N-acetylaspartate (NAA)/creatine (Cr) and choline (Cho)/Cr ratios in prefrontal gray matter (PGM) and glutamate/glutamine(Glx)/Cr ratio in striatum, and increase of myo-inositol (mI)/Cr in striatum were observed during acute SIV infection. The metabolite alterations during the SIVsmmFGb infection are largely in agreement with previous findings in other non-human primate models and HIV patients. Also, NAA/Cr in PGM and striatum and Glx/Cr in striatum are negatively correlated with the percentage of CD8+ T cells after the SIV infection, suggesting the interaction between brain metabolite and immune dysfunction. The present study complements previous studies by describing the time course of alterations of brain metabolites during SIVsmmFGb infection. The findings further demonstrate the efficacy of the SIVsmmFGb-infected macaque as a model to characterize central nervous system infection using novel neuroimaging approaches and also as a tool for exploration of novel and advanced neuroimaging techniques in HIV/AIDS studies.

Brief communication: Adrenal androgens and aging: Female chimpanzees (Pan troglodytes) compared with women.

Ovarian cycling continues to similar ages in women and chimpanzees yet our nearest living cousins become decrepit during their fertile years and rarely outlive them. Given the importance of estrogen in maintaining physiological systems aside from fertility, similar ovarian aging in humans and chimpanzees combined with somatic aging differences indicates an important role for nonovarian estrogen. Consistent with this framework, researchers have nominated the adrenal androgen dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), which can be peripherally converted to estrogen, as a biomarker of aging in humans and other primates. Faster decline in production of this steroid with age in chimpanzees could help explain somatic aging differences. Here, we report circulating levels of DHEAS in captive female chimpanzees and compare them with published levels in women. Instead of faster, the decline is slower in chimpanzees, but from a much lower peak. Levels reported for other great apes are lower still. These results point away from slowed decline but toward increased DHEAS production as one of the mechanisms underlying the evolution of human longevity.

Cerebral Aß deposition in an Aß-precursor protein-transgenic rhesus monkey.

With the ultimate goal of developing a more representative animal model of Alzheimer's disease (AD), two female amyloid-ß-(Aß) precursor protein-transgenic (APPtg) rhesus monkeys were generated by lentiviral transduction of the APP gene into rhesus oocytes, followed by in vitro fertilization and embryo transfer. The APP-transgene included the AD-associated Swedish K670N/M671L and Indiana V717F mutations (APPSWE/IND) regulated by the human polyubiquitin-C promoter. Overexpression of APP was confirmed in lymphocytes and brain tissue. Upon sacrifice at 10 years of age, one of the monkeys had developed Aß plaques and cerebral Aß-amyloid angiopathy in the occipital, parietal, and caudal temporal neocortices. The induction of Aß deposition more than a decade prior to its usual emergence in the rhesus monkey supports the feasibility of creating a transgenic nonhuman primate model for mechanistic analyses and preclinical testing of treatments for Alzheimer's disease and cerebrovascular amyloidosis.

Longitudinal diffusion tensor imaging and perfusion MRI investigation in a macaque model of neuro-AIDS: a preliminary study.

The Simian immunodeficiency virus (SIV) infected macaque model exhibits neuropathological symptoms similar to those of HIV(+) patients, and is ideal for studying cognitive impairment and neuropathological sequelae of disease in repeated measurements. The aim of this study is to use Diffusion Tensor Imaging (DTI) and perfusion MRI to longitudinally access the disease development in SIV-infected monkeys under controlled conditions and to cross-validate our finding with MRI studies in HIV(+) patients. Three adult male pig-tailed macaques (Macaca nemestrina) were inoculated with the SIVsmmFGb virus. Blood was collected for enumeration of CD4+ and CD8+ T-cells. Serial time-sensitive high-resolution T(2)- weighted structural images, Cerebral Blood Flow (CBF) maps measured with the Continuous Arterial Spin Labeling (CASL) technique, and DTI images were obtained. Animals were sacrificed after 24 weeks. Cognitive behavioral tests were also carried out at each time point. Longitudinal changes in brain volume, CBF, and DTI in selected regions were analyzed statistically. In this study, CD4+ T-cell counts were found declined significantly after SIV infection in all macaques. No significant neurological behavior and brain volume changes were observed following virus inoculation. The CBF was found reduced in the caudate, inferior parietal cortex, and the prefrontal cortex. Fractional Anisotropy (FA) values in the whole brain and several Regions of Interest (ROIs) decreased significantly. These longitudinal changes in CBF and FA are correlated with CD4+ T-cell depletion and/or CD4:CD8 ratio. The MRI findings from this pilot study agree with previous results in HIV(+) patients.

In-vivo diffusion MRI protocol optimization for the chimpanzee brain and examination of aging effects on the primate optic nerve at 3T.

BACKGROUND: Diffusion MRI (dMRI) data acquisition protocols are well-established on modern high-field clinical scanners for human studies. However, these protocols are not suitable for the chimpanzee (or other large-brained mammals) because of its substantial difference in head geometry and brain volume compared with humans. Therefore, an optimal dMRI data acquisition protocol dedicated to chimpanzee neuroimaging is needed. METHODS: A multi-shot (4 segments) double spin-echo echo-planar imaging (MS-EPI) sequence and a single-shot double spin-echo EPI (SS-EPI) sequence were optimized separately for in vivo dMRI data acquisition of chimpanzees using a clinical 3T scanner. Correction for severe susceptibility-induced image distortion and signal drop-off of the chimpanzee brain was performed and evaluated using FSL software. DTI indices in different brain regions and probabilistic tractography were compared. A separate DTI data set from n=34 chimpanzees (13 to 56 years old) was collected using the optimal protocol. Age-related changes in diffusivity indices of optic nerve fibers were evaluated. RESULTS: The SS-EPI sequence acquired dMRI data of the chimpanzee brain with approximately doubled the SNR as the MS-EPI sequence given the same scan time. The quality of white matter fiber tracking from the SS-EPI data was much higher than that from MS-EPI data. However, quantitative analysis of DTI indices showed no difference in most ROIs between the SS-EPI and MS-EPI sequences. The progressive evolution of diffusivity indices of optic nerves indicated mild changes in fiber bundles of chimpanzees aged 40 years and above. CONCLUSION: The single-shot EPI-based acquisition protocol provided better image quality of dMRI for chimpanzee brains and is recommended for in vivo dMRI study or clinical diagnosis of chimpanzees (or other large animals) using a clinical scanner. Also, the tendency of FA decrease or diffusivity increase in the optic nerve of aged chimpanzees was seen but did not show significant age-related changes, suggesting aging may have less impact on optic nerve fiber integrity of chimpanzees, in contrast to previous results for both macaque monkeys and humans.

The grandmother effect: implications for studies on aging and cognition.

BACKGROUND: Women experience more years of vigorous life after ovulation has ceased than do females of other primate species. Is this an epiphenomenon of the greater life expectancy humans have enjoyed in the past century or so, or is long post-menopausal survival the result of an evolutionary selection process? Recent research implies the latter: Long post-menopausal survival came about through natural selection. One prominent line of thought explaining this selection process is the grandmother hypothesis. OBJECTIVE: To evaluate the implications of the hypothesis for non-human primate studies of aging and cognition. METHOD: The author presents a synopsis of the hypothesis, evaluates the uniqueness of the 'grandmother effect' to humans, and discusses its implications for non-human primate models of cognitive aging. RESULTS: The hypothesis contends that, in past epochs, women who remained vigorous beyond their fertile years may have enhanced their reproductive success by providing care for their grandchildren. This care would have enabled their daughters to resume reproduction sooner, endowing them with greater lifetime fertility. Genes of grandmothers possessing such old-age vigor would be more likely to persist in subsequent generations. Is midlife menopause a uniquely human phenomenon, or does the chimpanzee, our closest primate relative, also display this trait? If so, we might expect a grandmother effect in this species as well. However, female chimpanzees continue to cycle until near the end of their maximum life span of about 60 years. CONCLUSION: Long survival beyond fertility and a long life expectancy are distinctive human adaptations. The robustness of ancestral human grandmothers necessarily included resistance to cognitive decline through preservation of functions present in many primates but also development of processes of social cognition unique to our species. Cognitive traits such as language and social cognitive functions may function in our species in particular as mechanisms to compensate for age-related decline. This has significant implications for research in which non-human primates are considered as models of human cognitive aging; it also means that some processes can be studied only in humans.

The grandmother effect and the uniqueness of the human aging phenotype.

This issue of Gerontology includes a response by van Bodegom et al. to Herndon's recent article on the implications of the grandmother hypothesis for studies of aging and cognition. Although this hypothesis will doubtlessly continue to stimulate discussion, we focus here on our contention that human and non-human primate life histories have evolved essential differences and that these should be addressed in studies comparing aging in humans and chimpanzees.

Age-related decline in executive function as a hallmark of cognitive ageing in primates: an overview of cognitive and neurobiological studies.

Executive function (EF) is a complex construct that reflects multiple higher-order cognitive processes such as planning, updating, inhibiting and set-shifting. Decline in these functions is a hallmark of cognitive ageing in humans, and age differences and changes in EF correlate with age-related differences and changes in association cortices, particularly the prefrontal areas. Here, we review evidence for age-related decline in EF and associated neurobiological changes in prosimians, New World and Old World monkeys, apes and humans. While EF declines with age in all primate species studied, the relationship of this decline with age-related alterations in the prefrontal cortex remains unclear, owing to the scarcity of neurobiological studies focusing on the ageing brain in most primate species. In addition, the influence of sex, vascular and metabolic risk, and hormonal status has rarely been considered. We outline several methodological limitations and challenges with the goal of producing a comprehensive integration of cognitive and neurobiological data across species and elucidating how ageing shapes neurocognitive trajectories in primates with different life histories, lifespans and brain architectures. Such comparative investigations are critical for fostering translational research and understanding healthy and pathological ageing in our own species. This article is part of the theme issue 'Evolution of the primate ageing process'.

Ovarian aging in squirrel monkeys (Saimiri sciureus).

In female squirrel monkeys (Saimiri sciureus), the reproductive period normally extends from approximately 2.5 years to the mid-teens. In the present study, we examined the age-associated cytological changes in the ovaries of 24 squirrel monkeys ranging in age from newborn to approximately 20 years. We found a significant, age-related decline in the number of primordial follicles, with the most pronounced loss occurring between birth and 5 years. After approximately 8 years of age, relatively few primordial follicles were evident in the ovarian sections examined. An unusual feature of the aging squirrel monkey ovary is the emergence of highly differentiated, encapsulated clusters of granulosa cells that increase in size and number, particularly after the age of 8 years. Many of these cells express anti-Müllerian hormone, and, histologically, the clusters resemble granulosa cell tumors in humans. However, granulosa cell clusters (GCCs) are present in both ovaries of all older squirrel monkeys, and they display no obvious signs of malignancy, suggesting that they are a normal feature of ovarian aging in this species. Our findings indicate that reproductive senescence in female squirrel monkeys, as in other primates, involves the inexorable depletion of ovarian follicles. In addition, the consistent appearance of abundant, well-differentiated clusters of granulosa cells in older squirrel monkeys, prior to the cessation of reproduction, suggests that these structures may influence the later stages of reproductive potential in this species. Analysis of GCCs in older squirrel monkeys also could yield insights into the pathophysiology of granulosa cell tumors in humans.

No effect of different estrogen receptor ligands on cognition in adult female monkeys.

Many studies in women and animal models suggest that estrogens affect cognitive function. Yet, the mechanisms by which estrogens may impact cognition remain unclear. The goal of the present study was to assess the effects of different estrogen receptor (ER) ligands on cognitive function in adult ovariectomized female rhesus monkeys. The monkeys were tested for 6 weeks on a battery of memory and attentional tasks administered on a touchscreen: the object, face, and spatial versions of the Delayed Recognition Span Test (DRST) and a Visual Search task. Following a 2-week baseline period with oil vehicle treatment, monkeys were randomly assigned to one of 3 treatment groups: estradiol benzoate (EB), selective ERbeta agonist (diarylpropionitrile DPN) or selective ER modulator tamoxifen (TAM). In each treatment group, monkeys received oil vehicle for 2 weeks and the drug for 2 weeks, in a cross-over design. After a 4-week washout, a subset of monkeys was re-tested on the battery when treated with a selective ERalpha agonist (propyl-pyrazole-triol, PPT) or oil vehicle. Overall, drug treatments had no or negligible effects on cognitive performance. These results support the contention that exogenous estrogens and selective estrogen receptor modulators (SERMS) do not significantly affect cognition in young adult female macaques. Additional studies are needed to determine whether the cognitive effects of estrogens in monkeys of more advanced age are mediated by ERbeta, ERalpha or complex interactions between the two receptors.

Effect of menstrual cycle on resting brain metabolism in female rhesus monkeys.

Little is known about the effects of the menstrual cycle on brain activity in primates. Here, we use 18F-fluorodeoxyglucose positron emission tomography to monitor changes in resting brain glucose metabolism across the menstrual cycle in female rhesus monkeys. Results showed greater activity in right lateral orbitofrontal cortex, a region involved in processing negatively valenced emotional stimuli, in the follicular compared with luteal phase. Estradiol levels were negatively correlated with activity in cortical and brainstem regions involved in emotional processing, and positively correlated with activity in areas involved in cognitive control and emotion regulation. In summary, the data suggest that in primates, fluctuations of ovarian hormones across the menstrual cycle influence activity in brain areas involved in emotion and its regulation.

Cellular and molecular events underlying the dysregulated response of the aged brain to stroke: a mini-review.

BACKGROUND: Age-related brain injuries, including stroke, are a major cause of physical and mental disabilities. OBJECTIVE: Therefore, studying the basic mechanism underlying functional recovery after brain stroke in aged subjects is of considerable clinical interest. METHODS: This review summarizes the effects of age on recovery after stroke in an animal model, with emphasis on the underlying cellular mechanisms. RESULTS: Data from our laboratory and elsewhere indicate that, behaviorally, aged rats were more severely impaired by stroke than young rats, and they also showed diminished functional recovery. Infarct volume did not differ significantly between young and aged animals, but critical differences were apparent in the cytological response to stroke, most notably an age-related acceleration in the development of the glial scar. Early infarct in older rats is associated with premature accumulation of BrdU-positive microglia and astrocytes, persistence of activated oligodendrocytes, a high incidence of neuronal degeneration and accelerated apoptosis. In aged rats, neuroepithelial-positive cells were rapidly incorporated into the glial scar, but these neuroepithelial-like cells did not make a significant contribution to neurogenesis in the infarcted cortex in young or aged animals. The response of plasticity-associated proteins like MAP1B, was delayed in aged rats. Tissue recovery was further delayed by an age-related increase in the amount of the neurotoxic C-terminal fragment of the beta-amyloid precursor protein (A-beta) at 2 weeks poststroke. CONCLUSION: The available evidence indicates that the aged brain has the capability to mount a cytoproliferative response to injury, but the timing of the cellular and genetic response to cerebral insult is dysregulated in aged animals, thereby further compromising functional recovery. Elucidating the molecular basis for this phenomenon in the aging brain could yield novel approaches to neurorestoration in the elderly.

Age-related decline in cognitive flexibility in female chimpanzees.

Data on cognitive aging in chimpanzees are extremely sparse, yet can provide an invaluable phylogenetic perspective, especially because Alzheimer disease (AD)-like neuropathology has recently been described in the oldest chimpanzee brains. This finding underscores the importance of data on cognitive aging in this fellow hominin, our closest biological relative. We tested 30 female chimpanzees, 12-56 years old, on a computerized analog of the Wisconsin Card Sort test. This test assesses cognitive flexibility, which is severely impaired in normal aging and AD. Subjects selected stimuli according to color or shape; the rewarded dimension (i.e., color or shape) switched without warning and the chimpanzee had to adapt her responses accordingly. We found that increasing age was associated with an increased number of perseverative errors and an increased number of trials to reach criterion in each switching dimension. The number of aborted trials was similar across age groups. These data show that similar to humans, chimpanzees show a clear age-related decline in cognitive flexibility that is already observed at middle age.

Defective IL-2 production by HIV-1-specific CD4 and CD8 T cells in an adolescent/young adult cohort.

Here we investigate the effect of viremia and the influence of HAART on the frequency and quality of HIVspecfic T cells in an adolescent/young adult cohort. Measurements of viral loads and the magnitude and quality of antiviral cellular immune responses were performed on 14 HAART-naive and 8 treated HIV-1-infected adolescents. Cross-sectional correlations between viral load and cellular immune responses were determined and data were analyzed by viral load (<4000, 4000-40,000, and >40,000 copies/ml plasma) and patient treatment status. All 22 patients showed a broad IFN-gamma ELISPOT response that was proportional to viral load (r = 0.53, p = 0.02), recognizing an average of five to eight peptide pools throughout Gag, Pol, Env, Tat, Rev, and Nef. Intracellular cytokine staining was performed with pools of overlapping peptides corresponding to HIV Gag to distinguish CD8 response from CD4 response. Among untreated patients with increased viral load there was a constant IFN-gamma CD8 response but a declining IFN-gamma CD4 response. HIV-specific IL-2 production was consistently low in CD8 cells but inversely related to viral load in CD4 cells (r = -0.52, p = 0.02). In this crosssectional analysis, time on HAART was associated with an increased frequency of antiviral IFN-gamma- and IL-2-coproducing CD4 cells (r = 0.98, p <0.001), but not of antiviral CD8 cells. Our results suggest that T cells coproducing IL-2 and IFN-gamma are a better marker for immunological competence than T cells producing IFN-gamma alone. They also suggest that HAART may be associated with an improved capacity for IL-2 production by antiviral CD4 T cells in a time-dependent manner. Longitudinal studies are clearly necessary to assess the impact of HAART on these parameters.

Relationships among cognitive function, fine motor speed and age in the rhesus monkey.

Declines in fine motor skills and cognitive function are well known features of human aging. Yet, the relationship between age-related impairments in motor and cognitive function remains unclear. Rhesus monkeys, like humans, show marked decline in cognitive and fine motor function with age and are excellent models to investigate potential interactions between age-related declines in cognitive and motor functioning. We investigated the relationships among cognition, motor function and age in 30 male and female rhesus monkeys, 5-28 years of age, tested on a battery of cognitive tasks [acquisition of the delayed non-matching-to-sample (DNMS), DNMS-120s, DNMS-600s, acquisition of delayed recognition span test (DRST), spatial-DRST and object-DRST] and a fine motor task (Lifesaver test). Global cognitive ability, as assessed by the cognitive performance index (CPI), was impaired with age in both sexes, while age-related motor slowing was found only in males. After age was controlled for, half the variance in CPI was predicted by motor speed, with better cognitive ability associated with slower motor skills. Analyses at the level of each cognitive task revealed that motor speed and age predicted the rate of acquisition of the DNMS. This relationship was robust in males and absent in females. Motor speed was not a significant predictor of any other cognitive variable. We conclude that the relationship between cognition and motor function (1) may be limited to non-spatial tasks; (2) exists independently of age; (3) may reflect different contributions of the fronto-striatal system; (4) may be particularly evident in males.

Sex differences in age-related motor slowing in the rhesus monkey: behavioral and neuroimaging data.

The nigrostriatal system is critical for fine motor function and its deterioration during aging is thought to underlie the decline in fine manual ability of old persons. Because estrogen has a neuroprotective effect on this system, one might expect women's motor function to be less vulnerable to the detrimental effects of aging than that of men. We examined this hypothesis in the rhesus monkey, which has been established as an excellent model of human age-related motor impairment. We tested 28 young and old rhesus monkeys of both sexes in a task involving the retrieval of a Life Saver candy from rods of different complexity to determine whether fine motor ability (1) is sexually dimorphic, (2) declines with age and (3) declines differently in males and females. In addition, we measured the whole brain volume, the volumes of the caudate, putamen, hippocampal formation and the area of the corpus callosum in a subset of the monkeys (n=15) for which magnetic resonance images of the brain were available. All monkeys performed similarly in the test with the simplest rod. In the test with complex rods; however, age-related slowing of motor function was evident in males, but not in females. Age-related decreases in the normalized caudate and putamen volumes were similar in males and in females. In addition, motor speed was not significantly correlated to any of the neuroanatomical measures under study. Further studies will be necessary to uncover the neurohormonal bases of the differential age-related motor decline between males and females.

Studies in macaques on cross-clade T cell responses elicited by a DNA/MVA AIDS vaccine, better conservation of CD8 than CD4 T cell responses.

One of the unknowns faced by an HIV/AIDS vaccine is the ability of a single clade vaccine to protect against the multiple genetic subtypes and recombinant forms of HIV-1 present in the current pandemic. Here, we use a macaque model to investigate the ability of our clade B vaccine that consists of DNA priming and modified vaccinia Ankara (MVA) virus boosting to elicit T cell responses that recognize an A/G recombinant of HIV-1. To test for cross-reactive T cells, intracellular cytokine staining was conducted using five pools of Gag and six pools of Env peptides representing B or A/G sequences. Studies using the peptide pools revealed essentially complete conservation of the CD8 response but only approximately 50% conservation of the CD4 response. Thus, the ability of an HIV vaccine for one clade to protect against other clades may be more limited by the ability to provide CD4 T cell help than the ability to elicit CD8 effector functions.

Sex, age, and training modulate spatial memory in the rhesus monkey (Macaca mulatta).

The authors tested 90 rhesus monkeys (Macaca mulatta) on a task of spatial memory, the spatial Delayed Recognition Span Test. The results showed that performance declined significantly with age, males had greater scores than females, and the rate of apparent decline with age was greater in males than in females. Both working and reference memory declined with age, but only working memory showed sex differences. The authors compared these data with that of 22 monkeys who were trained on a simpler version of the task before formal testing. Training had no effect on males but dramatically improved working memory in young females. The results confirm a male advantage in spatial working memory at a young age and confirm a greater decline with age in males than in females. It is important to note that prior training completely reverses the deficits of young females.

A non-human primate test of abstraction and set shifting: an automated adaptation of the Wisconsin Card Sorting Test.

Functional assessment of the prefrontal cortices in the non-human primate began with the seminal work of Jacobsen in the 1930s. However, despite nearly 70 years of research, the precise nature of the cognitive function of this region remains unclear. One factor that has limited progress in this endeavor has been the lack of behavioral tasks that parallel most closely those used with humans. In the present study, we describe a test for the non-human primate that was adapted from the Wisconsin Card Sorting Task (WCST), perhaps the most widely used test of prefrontal cognitive function in humans. Our adaptation of this task, the Conceptual Set-Shifting Task (CSST), uses learning criteria and stimuli nearly identical to those of the WCST. The CSST requires the animal to initially form a concept by establishing a pattern of responding to a given stimulus class, maintain responding to that stimulus class, and then shift to a different stimulus class when the reward contingency changes. The data presented here establishes baseline performance on the CSST for young adult rhesus monkeys and demonstrates that components of prefrontal cognitive function can be effectively assessed in the non-human primate in a manner that parallels the clinical assessment of humans.