Patrick R. Hof

Morphological alterations in neurons forming corticocortical projections in the neocortex of aged Patas monkeys

Recent studies indicate that the cognitive processes mediated by the prefrontal cortex, such as working memory, are impaired during normal aging. These disturbances in cortical function may be a consequence of abnormalities in neocortical circuits, even though the numbers of cortical neurons are preserved in normal aging. We performed retrograde tract-tracing of cortical projections connecting the temporal cortex to the prefrontal cortex in combination with dye-filling and three-dimensional neuronal reconstructions in aged patas monkeys. Age-related changes affected the apparent complexity of the apical dendrites of projection neurons and caused a significant loss of dendritic spines at all levels of their dendritic trees. These results indicate that normal aging is accompanied by neuronal changes that are quite subtle, and possibly involves discrete cellular components of certain cortical neurons selectively rather than inducing major alterations such as cell death.

Aging of the cerebral cortex differs between humans and chimpanzees

Several biological changes characterize normal brain aging in humans. Although some of these age-associated neural alterations are also found in other species, overt volumetric decline of particular brain structures, such as the hippocampus and frontal lobe, has only been observed in humans. However, comparable data on the effects of aging on regional brain volumes have not previously been available from our closest living relatives, the chimpanzees. In this study, we used MRI to measure the volume of the whole brain, total neocortical gray matter, total neocortical white matter, frontal lobe gray matter, frontal lobe white matter, and the hippocampus in a cross-sectional sample of 99 chimpanzee brains encompassing the adult lifespan from 10 to 51 y of age. We compared these data to brain structure volumes measured in 87 adult humans from 22 to 88 y of age. In contrast to humans, who showed a decrease in the volume of all brain structures over the lifespan, chimpanzees did not display significant age-related changes. Using an iterative age-range reduction procedure, we found that the significant aging effects in humans were because of the leverage of individuals that were older than the maximum longevity of chimpanzees. Thus, we conclude that the increased magnitude of brain structure shrinkage in human aging is evolutionarily novel and the result of an extended lifespan.

Inhibitory interneurons of the human prefrontal cortex display conserved evolution of the phenotype and related genes.

Inhibitory interneurons participate in local processing circuits, playing a central role in executive cognitive functions of the prefrontal cortex. Although humans differ from other primates in a number of cognitive domains, it is not currently known whether the interneuron system has changed in the course of primate evolution leading to our species. In this study, we examined the distribution of different interneuron subtypes in the prefrontal cortex of anthropoid primates as revealed by immunohistochemistry against the calcium-binding proteins calbindin, calretinin and parvalbumin. In addition, we tested whether genes involved in the specification, differentiation and migration of interneurons show evidence of positive selection in the evolution of humans. Our findings demonstrate that cellular distributions of interneuron subtypes in human prefrontal cortex are similar to other anthropoid primates and can be explained by general scaling rules. Furthermore, genes underlying interneuron development are highly conserved at the amino acid level in primate evolution. Taken together, these results suggest that the prefrontal cortex in humans retains a similar inhibitory circuitry to that in closely related primates, even though it performs functional operations that are unique to our species. Thus, it is likely that other significant modifications to the connectivity and molecular biology of the prefrontal cortex were overlaid on this conserved interneuron architecture in the course of human evolution.

Comparative Neuropathology of Brain Aging in Primates

aKastor Neurobiology of Aging Laboratories and Fishberg Research Center for Neurobiology, Departments of bGeriatrics and Adult Development, cRadiology, dOtolaryngology and ePathology, Mount Sinai School of Medicine, fDepartment of Anthropology, Columbia University, gNew York Consortium in Evolutionary Primatology, New York, N.Y., hDivision of Neurobiology, Behavior, and Genetics, Bioqual Inc., Rockville, Md., and iFoundation for Comparative and Conservation Biology, Rockville, Md., USA; jDepartment of Anatomical Sciences, University of the Witwatersrand, Parktown, South Africa

Age-Related Morphologic Alterations in the Brain of Old World and New World Anthropoid Monkeys

Anthropoid monkeys are subdivided into two large groups, the New World platyrrhine monkeys (callithricids and cebids) and the Old World catarrhine monkeys (macaques, baboons, guenons, and leaf-eating monkeys). Most taxa are poorly known from a neurobiological point of view, but many species are used for laboratory studies (in particular, some macaques and baboons [Macaca and Papio], the Patas monkey [Erythrocebus], and the Central and South American marmoset [Callthrix], owl [Aotus], squirrel [Saimiri], and capuchin [Cebus] monkeys). Aging is particularly well documented among these taxa from the long-tailed and rhesus macaques and from the squirrel monkey. The neurobiological basis of declining cortical function in primate aging remains to be defined. One possibility is that the structural integrity of the neocortex is compromised by frank neuronal degeneration, synaptic loss, or other morphologic alterations. The consensus emerging from recent studies, however, is that many cortical areas, including subdivisions of the hippocampal, prefrontal, motor, and sensory cortices known to participate critically in sensory integration and memory-related processes, are relatively resistant to cell death during normal aging in monkeys. In contrast, subcortical structures are more consistently affected in a manner that correlates with the severity of cognitive deficits. Importantly, recent ultrastructural and cellular analyses have demonstrated that subtle alterations involving the neuropil as well as restricted domains of the dendritic trees are likely to contribute massively, together with molecular changes in specific neurotransmitter receptor proteins, to the cognitive and memory deficits observed in aged anthropoid monkeys.

The Study of Brain Aging in Great Apes

The great apes are the closest biological relatives of humans. The resemblence is close from genetics to brain structure and cognitive function. Endocasts from fossil hominoids and hominids reveal that the brains of Australopithecus were similar in size and shape to those of modern chimpanzees, and that a dramatic increase in brain size occurred as Homo evolved. Studies of extant great apes (bonobos, chimpanzees, gorillas, and orangutans) in the wild and in captivity have provided evidence on patterns of sociality, behavior, communication, cognition, and self–awareness. These data have identified many characteristics that are apparently homologous among apes and humans, suggesting that these were also present in a common ancestor. Cerebral lateral asymmetries recently reported in the great apes suggest that some of the neurological foundations of language have long been present in the ape-human lineage. Neuronal loss with aging is associated with neurodegenerative pathology in humans. Studies of great ape brains using quantitative stereology have not yet found substantial neuronal loss associated with aging in the entorhinal cortex and CA1 field of the hippocampus, regions that are especially vulnerable to age-related cell loss in humans. However, two neuronal types have been recently found in anterior cingulate cortex that are unique to humans and great apes. One of these cell types, a large spindle cell found in a region implicated in self-awareness and regulation of autonomic functions, is diminished by about 60% in human victims of Alzheimers disease. The application to great apes of improved methods of assessing cognitive decline, genetic risk, and gene expression, along with functional imaging and quantitative stereological research, offers prospects of additional insights into normal and pathological brain aging.

Induction of MC-1 immunoreactivity in axons after injection of the Fc fragment of human immunoglobulins in macaque monkeys

Abstract. Although previous studies have suggested an increased activation of humoral immunity in neurodegenerative diseases, it remains unclear whether this phenomenon is secondary to lesion formation or contributes directly to their development. Using stereotaxic injections in macaque monkey cerebral cortex, we studied the effects of human immunoglobulins on the neuronal cytoskeleton. Under these conditions, several MC-1-immunoreactive axons were observed in the vicinity of injection site. No MC-1 or TG-3 staining was detected in neuronal soma. Ultrastructurally, several axons in the same area displayed curly formations and accumulation of twisted tubules but not paired helical filaments. These data suggest that Fc fragment induce conformational changes of tau and subtle structural alterations in axons in this model. Immunocytochemical analyses in human autopsy materials revealed the presence of human Fc fragments as well as Fc receptors only in large pyramidal neurons known to be vulnerable in brain aging and Alzheimers disease, further supporting a possible role of immunoglobulins in neurodegeneration.

Menopause and Reproductive Senescence in Comparative Context

Menopause and reproductive senescence can be more fully understood by examining these phenomena where they occur in nonhuman mammals, as well as humans, and especially by comparisons among primates. In addition to concerns about human health and welfare, successful programs for wildlife management and agriculture, and the propagation and conservation of endangered species depend on detailed understanding of reproduction and fertility throughout the life span. Appropriate care of elderly primates in zoological gardens also requires knowledge of their health, behavior, and reproductive status. Information on female primate fertility, reproductive senescence, and associated health-risks is scattered throughout the scientific literature, and includes emphases ranging from comparative medicine and primate models of human health to zoology and human evolution. This chapter introduces a range of issues and reviews studies of female primate reproductive senescence and menopause. These topics are examined in greater depth in the subsequent chapters of this volume.

Studies of Age-Related Neuronal Pathology in Great Apes

It is clear that there is much to be learned from the investigation of brain aging in the great apes. Given the close genetic relationships of humans and great apes and the apes’ ability, especially in captivity, to survive to ages that begin to approach that of humans, the parallels and opportunities for research are numerous. To date only aspects of the pathology of Alzheimer’s disease have been demonstrated in the brains of great apes of advanced age, but the number of well-studied animals is quite small. If the great apes fail to develop lesions comparable to that of Alzheimer’s disease and Parkinson’s disease, then considering the 2–3% differences in genetic material, this would argue for a search for differences in genetic loci of importance to the etiopathogenesis of these two important human diseases. Furthermore, this then represents an important opportunity for the study of neuronal loss and other aspects of normal brain aging in the absence of superimposed lesions associated with these two age-related human diseases. The study of the aging process in the great ape species will provide data of importance to understanding the aging process in these animals themselves. As increasing numbers of great apes survive to advanced age in protected environments, the problems associated with aging will assume increasing importance. All such studies have been hampered by the lack of significant numbers of well prepared specimens from appropriately aged animals. The availability of the collection of specimens being prepared by the Great Ape Aging Project represents an important contribution to those interested in these problems.