Age-related changes in the mesial temporal lobe: the parahippocampal white matter region

Abstract

The perforant pathway originates from cells in the entorhinal cortex and relays sensory information from the neocortex to the hippocampus, a region critical for memory function. Imaging studies have demonstrated structural alterations in the parahippocampal white matter in the region of the perforant pathway in people at risk for developing Alzheimer's disease. It is not clear, however, if changes noted in this region are indicative of pathological aging or are a function of the normal aging process. We compared magnetic resonance imaging (MRI)-derived mesial temporal lobe volumes in 51 healthy older individuals and 40 young participants, with an emphasis on the parahippocampal white matter. Yearly clinical evaluations showed that 9 of the older cohort declined in cognitive function. Parahippocampal white matter, hippocampal, and entorhinal cortex volumes were significantly reduced in healthy older people who remained stable over time compared with young participants. These findings suggest that volume differences in mesial temporal lobe gray and white matter structures may take place as a result of the normative aging process.

Introduction

The entorhinal cortex and hippocampus are part of the mesial temporal lobe memory system (Squire and Zola-Morgan, 1991, Young et al., 1997). Neurons of the entorhinal cortex receive multimodal sensory information from primary sensory and association cortices (Amaral et al., 1987, Van Hoesen and Pandya, 1975a, Van Hoesen et al., 1975) and relay this information to the hippocampus via the axons that make up the perforant pathway (Hyman et al., 1984, Van Hoesen and Pandya, 1975b).

Quantitative structural magnetic resonance imaging (MRI) techniques provide a tool for examining alterations in brain anatomy in vivo during healthy and pathological aging. Such changes in anatomy can be used as a proxy measure of the underlying pathology in neurodegenerative diseases. For example, using such techniques, a number of studies have now reported that atrophy of the entorhinal cortex and hippocampus, structures known to be pathologically involved very early in Alzheimer's disease (AD, Braak and Braak, 1991, Braak and Braak, 1995, Braak et al., 1998), can provide sensitive markers of risk for AD among older people with mild cognitive impairment (MCI) or subjective cognitive complaints (Cardenas et al., 2002, Chao et al., 2010, deToledo-Morrell et al., 2004, Devanand et al., 2007, Dickerson et al., 2001, Jack et al., 1999, Jessen et al., 2006, Killiany et al., 2000, Killiany et al., 2002, Saykin et al., 2006, Stoub et al., 2005, Tapiola et al., 2008). These results are not surprising, because memory dysfunction is one of the earliest hallmarks of AD.

In addition to gray matter regions, there has recently been increased interest in assessing structural changes in white matter regions in those at risk for AD, as well as in healthy older adults (Allen et al., 2005, Bartzokis et al., 2001, Bartzokis et al., 2003, Bartzokis et al., 2004, Good et al., 2001, Guttmann et al., 1998, Jernigan et al., 2001, Raz et al., 2005, Resnick et al., 2003, Rogalski et al., 2009, Salat et al., 2009, Smith et al., 2007, Stoub et al., 2006). The studies that investigated the effects of aging on cerebral white matter found mostly diffuse decreases in white matter volume associated with aging (Allen et al., 2005, Guttmann et al., 1998, Jernigan et al., 2001, Raz et al., 2005, Resnick et al., 2003, Salat et al., 2009). However, age-related atrophy in the parahippocampal white matter has not received much attention.

Recent work from our laboratory has demonstrated decreased parahippocampal white matter volume in the region of the perforant pathway in people with amnestic mild cognitive impairment (aMCI), who are at risk for developing AD, compared with healthy older controls (Rogalski et al., 2009, Stoub et al., 2006). Such alterations in parahippocampal white matter could degrade information flow from the entorhinal cortex to the hippocampus and contribute to the memory deficit observed in amnestic MCI and very mild AD. It is unclear, however, if volume changes in this region take place as a function of the aging process per se or are due to age-related pathological processes.

Investigations in animal models of aging have demonstrated that cell numbers remain the same in Layer II of the entorhinal cortex, as well as in hippocampal CA3 and dentate gyrus regions (Rasmussen et al., 1996). However, there is a decrease in synaptophysin markers in CA3 (Smith et al., 2000) and a reduction in actual synapse numbers in the middle molecular layer of the hippocampal dentate gyrus (Geinisman et al., 1986, Geinisman et al., 1992). Additionally, electrophysiological experiments have shown a decrease in the presynaptic fiber potential in old, memory impaired rats (Barnes, 1979, Barnes and McNaughton, 1980), suggesting a pruning of axon collaterals from the perforant pathway to the dentate gyrus. If there is a cross-species correspondence in the types of brain changes that occur during aging, then the rodent data predict that humans should also show changes in the region of the perforant pathway as a function of age.

The present in vivo structural imaging study was undertaken to examine if healthy older individuals show volume changes, compared with younger adults, in the parahippocampal white matter region that includes the perforant pathway. In addition, we investigated the volumes of surrounding structures including the hippocampus and entorhinal cortex, regions important for episodic memory function, such as memory for events and things.