Elsevier

Neurobiology of Aging

Volume 27, Issue 10, October 2006, Pages 1405-1415
Neurobiology of Aging

Hippocampal volume is preserved and fails to predict recognition memory impairment in aged rhesus monkeys (Macaca mulatta)

https://doi.org/10.1016/j.neurobiolaging.2005.07.019Get rights and content

Abstract

Aged monkeys exhibit deficits in memory mediated by the medial temporal lobe system, similar to the effects of normal aging in humans. The contribution of structural deterioration to age-associated memory loss was explored using magnetic resonance imaging techniques. We quantified hippocampal, cerebral and ventricular volumes in young (n = 6, 9–12 years) and aged (n = 6, 24–29 years) rhesus monkeys. Eleven subjects were tested on a recognition memory task, delayed non-matching-to-sample (DNMS). Compared to young animals, aged monkeys exhibited robust learning deficits and significant memory impairments when challenged with longer retention intervals. Hippocampal volume was statistically equivalent across age groups, differing by less than 6%, and there was no correlation between this measure and DNMS performance. Variability in cerebral volume was greater in the aged compared to young monkeys and this parameter was marginally correlated with DNMS performance with a 10-min delay. These findings confirm and extend the conclusion of recent post-mortem histological analyses demonstrating that normal cognitive aging occurs independently of gross structural deterioration in the primate hippocampus.

Introduction

Research in non-human primates has established a valuable model for identifying the neurobiological changes responsible for age-related memory decline [2], [9], [12], [40], [58]. Although relevant morphometric data have come primarily from analyses of post-mortem brain tissue [7], [17], [22], [30], [36], [38], recent advances in in vivo imaging techniques, including structural MRI, offer several advantages. With this approach, brain alterations during aging can be measured in close temporal correspondence with behavioral assessment, when significant relationships between brain structure and function are likely to be most apparent. In addition, the use of MRI technology provides a window on the aged brain unconfounded by histological processing variables, such as perfusion-related shrinkage, that can be influenced in an age-dependent manner and cloud the interpretation of quantitative morphometric results. Finally, regional brain volume measured from MRI images has the potential to detect subtle age-related alterations distributed across multiple neuronal and non-neuronal tissue constituents. To the degree that cognitive decline results from a constellation of changes (e.g. neuronal atrophy, dendritic shrinkage and fiber abnormalities), techniques sensitive to multiple measures of structural integrity may be essential for revealing the basis of the functional impairment.

Memory that is dependent on the hippocampal formation and related medial temporal lobe structures is vulnerable to normal aging [9], [12], [20], [40], [42], [58], [60]. Unfortunately, partly due to the contribution of prodromal, undiagnosed dementia, the prevalence and severity of decline attributable to normal aging has proved difficult to determine in humans [51], [57]. Whereas some studies have demonstrated a loss of hippocampal volume with age [35], [47], [56], others have not [25], [52], [54] and suggest that hippocampal atrophy may be an indication of underlying Alzheimer's disease [8], [14], [21], [25]. By comparison, rhesus macaques and other Old World monkeys display reliable age-associated memory impairments but do not develop certain neuropathological hallmarks of Alzheimer's disease [23]. Therefore, non-human primates provide a powerful model for defining the neurobiological and functional deficits specifically attributable to normal aging.

Previous studies have demonstrated reliable impairments in aged monkeys across a variety of cognitive testing procedures [19], including tests of recognition memory [32], [39], [42], that are known to require the hippocampus and associated perirhinal and parahippocampal cortices [4], [53], [59]. Although a variety of morphometric analyses have been conducted in non-human primates [7], [17], [22], in vivo hippocampal volume has not been previously assessed in behaviorally characterized aged monkeys. The current study was designed to test the possibility that age-related memory decline in the monkey is coupled with gross structural alterations affecting total hippocampal volume. Ventricular and cerebral hemisphere volumes were also quantified to determine whether diffusely distributed atrophy, rather than change discretely localized to the hippocampus, predicts the cognitive outcome of aging.

Section snippets

Subjects

Six young adult (9–12 years) and six aged (24–29 years) rhesus monkeys (Macaca mulatta) served as subjects. Age groups were balanced for sex with three male and three female monkeys in each. Average longevity in captive rhesus monkeys is less than 25 years and human age equivalence has been estimated at 1:3 [55]. Accordingly, the age range of the young group corresponds to humans roughly 27–36 years old and 70–90 years old for the aged group. All young females exhibited regular menstrual

Results

DNMS scores and the volumetric estimates for the individual young and aged monkeys are listed in Table 1.

Discussion

The in vivo imaging results presented here add to a growing body of evidence concerning the neurobiological consequences of normal aging. The findings do not support the view that pronounced structural degeneration in the primate hippocampus is an obligatory correlate of age-related cognitive decline. Detailed quantification revealed a non-significant, numerical reduction of less than 6% in the total volume of the aged monkey hippocampus relative to adult control values, and no evidence of a

Acknowledgements

We would like to thank: Dr. Patrick Hof, Dr. Jeffrey Roberts, Mary Roberts, Sania Fong, Carmel Stanko, Michelle Permenter, Dr. Cindy Schumann, Julia Hamstra, Kevin Kelliher and Dr. Cynthia Erickson. This work supported by NIH Grants: AG003376, AG10606, AG09973, NS16980 and the California National Primate Research Center Base Grant, RR-00016.

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