Elsevier

Neurobiology of Aging

Volume 33, Issue 4, April 2012, Pages 670-680
Neurobiology of Aging

Regular paper
Homocysteine, neural atrophy, and the effect of caloric restriction in rhesus monkeys

https://doi.org/10.1016/j.neurobiolaging.2010.06.003Get rights and content

Abstract

Higher serum homocysteine (Hcy) levels in humans are associated with vascular pathology and greater risk for dementia, as well as lower global and regional volumes in frontal lobe and hippocampus. Calorie restriction (CR) in rhesus monkeys (Macaca mulatta) may confer neural protection against age- or Hcy-related vascular pathology. Hcy was collected proximal to a magnetic resonance imaging (MRI) acquisition in aged rhesus monkeys and regressed against volumetric and diffusion tensor imaging indexes using voxel-wise analyses. Higher Hcy was associated with lower white matter volume in pons and corpus callosum. Hcy was correlated with lower gray matter volume and density in prefrontal cortices and striatum. CR did not influence Hcy levels. However, control monkeys exhibited a strong negative correlation between Hcy and global gray matter, whereas no relationship was evident for the CR monkeys. Similar group differences were also seen across modalities in the splenium of the corpus callosum, prefrontal cortices, hippocampus, and somatosensory areas. The data suggest that CR may ameliorate the influence of Hcy on several important age-related parameters of parenchymal health.

Introduction

Homocysteine (Hcy), biosynthesized from the essential amino acid methionine, is associated with pathological aging and is a candidate biomarker of cardiovascular and dementia risk (Blasko et al., 2008, McCully, 2001, Zylberstein et al., 2009). Circulating levels of Hcy in humans tend to increase with age and contribute to cerebrovascular pathology in part through endothelial thrombosis, fibrous arteriosclerotic plaques, and degradation of the epithelial cells in the blood vessel wall (Marlatt et al., 2008). Higher circulating Hcy has been associated with smaller total brain volume (Seshadri et al., 2008), lower regional volumes including hippocampus (den Heijer et al., 2003, Wilhelm et al., 2008), and perhaps by extension cognitive decline (Nurk et al., 2005).

In rats, infusion of Hcy via microdialysis into the striatum resulted in hypersecretion of excitatory amino acids and more brain damage following experimentally induced strokes (Ganguly et al., 2008). In addition, serum Hcy has been correlated with hippocampal degeneration related to alcohol dependence (Wilhelm et al., 2008), as well as with lower temporal and frontal lobar volumes (Seshadri et al., 2008). Hcy also may sensitize dopaminergic neurons to environmental toxins and adversely hamper DNA repair (Mangas et al., 2004). Higher levels of Hcy are also detected in the cerebellum across a wide variety of species relative to whole brain (Broch and Ueland, 1984). Oligodendrocytes appear to be especially sensitive to Hcy-related damage, as Hcy is highly associated with axonal demyelination as well as periventricular and subcortical white matter hyperintensities (Vermeer et al., 2002, Wong et al., 2006). However, Hcy does not appear to adversely impact all brain structures such as the amygdala (den Heijer et al., 2003), and others have found no relationship between Hcy levels and central white and gray matter volumes (Longstreth et al., 2004, Morra et al., 2009).

We sought to extend and clarify these findings in an established nonhuman primate model of aging, the rhesus monkey, which shows many similar physiological and neural changes to humans during aging (Roth et al., 2004). Although Hcy levels do not appear to rise as markedly with age in nonhuman primates (Preston et al., 2002), dietary manipulations that result in transient hyperhomocysteinemia do impact vasculature physiology in the expected atherogenic manner (Harker et al., 1976, Lentz et al., 1996, Lentz et al., 2001).

Our cohort of monkeys was derived from a longitudinal study on the benefits of consuming a calorie restriction diet (CR; Colman et al., 2009). In addition to a salubrious change in glucoregulation, CR confers protective effects on the vasculature in this specific sample and rhesus monkeys in general — despite the fact that cardiovascular disease rarely occurs in this species unless experimentally placed on a high fat diet (Edwards et al., 1998, Ungvari et al., 2008). By extension, CR may still reduce Hcy concentrations and/or protect against Hcy-associated changes in the aging brain. Rhesus monkeys do not show an overall decrease in brain weight in old age (Herndon et al., 1998), but do evince reductions in gray matter and white matter in many regions (Wisco et al., 2008).

Because aging is related to lower regional volume in diffuse areas (Sowell et al., 2003), a previously validated voxel-wise approach (McLaren et al., 2009) was used to gauge the association of Hcy with both global and regional white matter and gray matter volumes. In addition, the microstructural tissue density of myelin and axons was determined via diffusion tensor imaging and estimated by fractional anisotropy, followed by axial diffusivity (λ1) and radial diffusivity ([λ2 + λ3]/2), in order to examine whether fractional anisotropy changes were related primarily to alterations in axons or myelin (Song et al., 2002). Tissue density of gray matter and white matter was also jointly determined using mean diffusivity. Finally, we investigated if monkeys on the CR diet showed less Hcy-related atrophy relative to control animals per unit increase in Hcy (μmol/L). These analyses were conducted using cross-sectional magnetic resonance imaging (MRI) and physiological data.

Section snippets

Study population

Forty-five rhesus monkeys (Macaca mulatta) between 19 and 31 years of age were used from a larger longitudinal CR project at the Wisconsin National Primate Research Center. Eighteen animals were fed a semi-purified diet (mean age ± SD, 23.84 ± 2.79; 12 females, 6 males), while 27 CR subjects (mean age ± SD, 24.32 ± 2.77; 15 females, 12 males) had been on a moderately restricted diet (30% reduction of intake) for approximately 12 to 17 years starting in 1989. Details of the CR manipulation have

Hcy and demographics

The dietary groups did not differ significantly by age or gender. Hcy values for the monkeys were within the standard reference curve of the assay kit, comparable to human values, and conformed to a Gaussian distribution without significant skewness. One CR animal had an Hcy value (25 μmol/L) more than 3 standard deviations above the sample mean and was excluded from analyses. The presence or absence of this animal's data did not affect the physiological or neural results beyond a loss of

Discussion

Serum Hcy was detected at levels within the range of reference human values in 45 aged rhesus monkeys, and was related to altered volumetric and microstructural tissue density indexes in prefrontal, parietal, temporal, and subcortical areas previously found to be sensitive to presumed cerebrovascular changes. Hcy was nonsignificantly higher in our CR animals. A similar CR manipulation lasting 3 months also found a nonsignificant 6.43% increase in Hcy (Chen et al., 2009).

Despite statistically

Disclosure statement

The authors have no actual or perceived conflicts of interest regarding the content of this manuscript.

The study was approved by the Institutional Animal Care and Use Committee.

Acknowledgements

This study was supported in part by the National Institutes of Health RR000167, AG11915, AG000213, and GM007507. AAW was supported by the Ford Foundation, National Science Foundation, and a fellowship established by the Marian S. Schwartz fund. The study was also supported with resources and use of facilities at the William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.

The assistance of Brent W. Thiel, Michele E. Fitzgerald, Ron Fisher, Scott T. Baum, Josh Smith, and the Waisman

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