Differential effects of aging and Alzheimer's disease on medial temporal lobe cortical thickness and surface area
Introduction
The cortex of the medial temporal lobe subserves fundamental mnemonic functions, providing critical input from heteromodal association cortices to the hippocampal formation and receiving reciprocal afferents from the hippocampal formation (Van Hoesen and Pandya, 1975a, Van Hoesen and Pandya, 1975b, Van Hoesen et al., 1975). Medial temporal cortex can be subdivided into entorhinal, perirhinal, and posterior parahippocampal regions, based on distinct cytoarchitectural features (Insausti et al., 1995, Van Hoesen, 1997). These features have been linked with macroscopic landmarks, such that the identification of landmarks in high-resolution MRI data can be used to define MTL regional boundaries (Insausti et al., 1998, Bobinski et al., 1999, Goncharova et al., 2001). Although boundaries defined by macroscopic anatomical features do not correspond perfectly to microscopic histologic subdivisions (Amunts et al., 2005), this approach has been useful in the in vivo measurement of entorhinal atrophy in early clinical and incipient phases of Alzheimer's disease (AD) (Killiany et al., 2000, Xu et al., 2000, de Leon et al., 2001, Dickerson et al., 2001, Du et al., 2001).
The entorhinal and perirhinal cortices are devastated by neurofibrillary pathology and cell loss very early in the course of AD (Hyman et al., 1984, Braak and Braak, 1991, Price et al., 1991, Gomez-Isla et al., 1996, Van Hoesen et al., 2000, Kordower et al., 2001). The posterior parahippocampal cortex caudal to these regions appears to be less affected, and demonstrates pathologic change in somewhat more advanced stages of the disease. It is less clear whether and how medial temporal cortical regions are affected by the normal aging process: although neurofibrillary pathology is more common in these regions in normal older adults, there appears to be no age-related neuronal loss (Price et al., 2001, von Gunten et al., 2005).
Over nearly the past decade, MRI techniques to measure entorhinal cortical volume have been developed (Insausti et al., 1998, Bobinski et al., 1999, Goncharova et al., 2001) and have revealed – in living individuals – reduced volume in early AD and mild cognitive impairment (Killiany et al., 2000, Xu et al., 2000, de Leon et al., 2001, Dickerson et al., 2001, Du et al., 2001). In addition, age-related loss of entorhinal volume has been reported (Du et al., 2006). Yet, as with the entire cortical mantle, the volume of specific bounded regions is related directly to both the thickness of the cortical region and its surface area, but neither of these elements of medial temporal cortical anatomy has yet been studied in aging or AD. Thus, it is not clear whether age-related and AD-related entorhinal volume loss result from similar changes in thickness and surface area, or whether distinct processes might be revealed within these component measures. Furthermore, little investigation of the perirhinal and posterior parahippocampal cortical regions has been reported (Insausti et al., 1998, Pruessner et al., 2002).
We undertook this study to determine whether AD is associated with morphometric alterations within the medial temporal cortex that are distinct from normal aging. We developed a novel method, described in a companion article (Feczko et al., 2009), for measuring the thickness, surface area, and volume of entorhinal, perirhinal, and posterior parahippocampal cortex using a semi-automated computational morphometric procedure. Since previous histologic literature employing stereologic methods indicates that AD is associated with reduced cortical thickness (Gomez-Isla et al., 1996, Regeur, 2000), we hypothesized that entorhinal and perirhinal cortical thinning would be observed in AD, while normal aging would not be associated with such thinning but would be related to loss of surface area due to non-specific global grey and white matter loss (Fotenos et al., 2005). Although previous studies have been performed of the effects of aging and AD on cortical thickness, they have been exploratory in nature, surveying the entire hemispheric thickness, without rigorous measurement protocols for defining the boundaries of MTL cortical regions (Salat et al., 2004, Lerch et al., 2005). As discussed in the accompanying article, individual variability in the morphology of the collateral sulcus makes it difficult, even with surface-based coordinate systems (Fischl et al., 1999a, Fischl et al., 1999b), to co-register individuals well enough to reliably identify these regions without the intervention of a manual operator, which was employed in the present methodology.
Section snippets
Participants
A total of 105 adults (age 18–97) participated in this study, all of whom were paid for their participation. Data from subsets of the participants have been published in previous studies (Buckner et al., 2004, Buckner et al., 2005, Salat et al., 2004, Fotenos et al., 2005).
Younger adults were recruited from the Washington University community. Nondemented and demented older adults were recruited exclusively from the ongoing longitudinal sample of the Washington University AD Research Center
Subject characteristics
The Normal Younger group consisted of right-handed volunteers (n = 29, age range 18–31, mean age = 23.6 ± 3.7; 20 females (f)/9 males (m)) with normal cognition. The Normal Older group (n = 47, age range 66-90, mean age = 76.2 ± 6.8; 30f/17m) demonstrated normal cognition, with overall CDR Ratings of 0 and MMSE scores of 25–30. The Mild AD group (n = 29, age range 56–90; mean age = 74.3 ± 10.2; 18f/11m) included individuals with very mild (CDR = 0.5) to mild (CDR = 1) levels of impairment, with MMSE scores ranging
Discussion
We developed and applied a new protocol for measuring the volume, thickness, and surface area of the ERC, PRC, and PPHC to investigate these morphometric properties in mild AD in comparison to normal older and younger groups. Both AD and aging are associated with smaller volumes of all three MTL cortical regions, although volume loss is greater in AD than in aging. However, aging and AD appear to have differential effects on the fundamental component morphometric properties that make up
Conflict of interest
There are no actual or potential conflicts of interest.
Acknowledgements
This study was supported by grants from the NIA (K23-AG22509, P50-AG05681, P01-AG03991), the NCRR (P41-RR14075 R01 RR16594-01A1, the NCRR BIRN Morphometric Project BIRN002, U24 RR021382 & U24-RR021382), and the Mental Illness and Neuroscience Discovery (MIND) Institute. Additional support was provided by the National Institute for Biomedical Imaging and Bioengineering (R01 EB001550), the National Institute for Neurological Disorders and Stroke (R01 NS052585-01) and the National Alliance for
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2022, NeuroImageCitation Excerpt :In this study we consider five MRI metrics. From T1-weighted structural MRI we derive measurements of cortical thickness (CT) and surface area (SA), which have been routinely used to track age-related alterations of brain structure (Dickerson et al., 2009; Fjell, Westlye, et al., 2014; Frangou et al., 2022; Habeck et al., 2020; Lemaitre et al., 2012; Lerch et al., 2017; Querbes et al., 2009; Raz & Rodrigue, 2006; Salat et al., 2004; Storsve et al., 2014; Tamnes et al., 2013). We also incorporated diffusion tensor imaging (DTI) indices of mean and radial diffusivity (MD, RD) and fractional anisotropy (FA).