Age effects on atrophy rates of entorhinal cortex and hippocampus
Introduction
The entorhinal cortex (ERC) and hippocampus are thought to be important structures in differentiating Alzheimer's disease (AD) from normal aging. Cross-sectional MRI studies have shown that AD patients have significantly greater ERC and hippocampal atrophy than cognitively normal (CN) subjects [9], [21], [26], [48], [57]. Longitudinal MRI studies have suggested that the rates of ERC and hippocampal atrophy may be useful in predicting AD before the onset of clinical symptoms and in assessing the potential usefulness of pharmacological interventions in treatment trials [10], [22], [24], [27], [43]. However, CN subjects often display ERC and hippocampal atrophy rates that are significantly greater than zero, although substantially less than that seen in AD patients [10], [22]. Moreover, hippocampal atrophy rates tend to increase with age in CN subjects [41], [42], [44]. Raz and co-workers reported that normal aging has a greater effect on hippocampal than ERC atrophy rates and that ERC atrophy rate is not related to age [41], [42]. Together these results suggest that hippocampal atrophy may be more closely associated with normal aging while ERC atrophy may be more closely associated with incipient AD pathologic processes. On the other hand, ERC and hippocampus are both strongly associated with memory function [51]. Since memory impairment typically increases with age [2], [31], it is unclear why normal aging would differentially affect atrophy rates of ERC and hippocampus. Therefore, the first goal of this study was to examine the relationship between age and atrophy rates of the ERC and hippocampus. In an attempt to replicate the results of Raz and co-workers [41], [42], we also examined whether the relationship between age and atrophy rates is different for ERC and hippocampus.
Another risk factor for cognitive impairment, in addition to advanced age, is subcortical cerebral vascular disease, manifested as subcortical infarcts/lacunes and white matter hyperintensities (WMH) on MRI images [8], [13], [37], [46], [50], [58]. A recent clinical study demonstrated that elderly individuals with silent brain infarcts were at greater risk for dementia and cognitive decline than elderly individuals without such lesions [53]. In addition to the subcortical cerebral vascular lesions visible on MRI, microinfarctions, which are usually not visible on MRI, may also be present, especially in subjects with hypertension [28]. Hypertension has been shown as a risk factor for late-life cognitive impairment [12], [32]. Because cognitive decline is related to cerebral atrophy [15], [36], cerebral vascular disease and hypertension may accelerate cerebral atrophy in CN subjects. Therefore, the second goal of this study was to determine if subcortical vascular disease and hypertension, independent of age, contribute to greater ERC and hippocampal atrophy rates.
The apolipoprotein E (APOE) ɛ4 allele is a genetic risk factor for AD and vascular dementia [7], [18]. APOE ɛ4 lowers the age of AD onset [1], and healthy older women with APOE ɛ4 have greater hippocampal atrophy rates than those without APOE ɛ4 [6]. However, it is not known if APOE ɛ4 is also associated with greater ERC atrophy rate in normal aging. Therefore, the third goal of this study was to examine if APOE ɛ4 contributes to greater ERC and hippocampal atrophy rates in CN subjects.
Section snippets
Subjects
All subjects were recruited from the community by flyers and advertisements in local newspapers as control subjects for a dementia study and had undergone two MRI and two neuropsychological evaluations approximately 3.5 ± 0.8 years apart. The subjects received standard neurological examinations [35] at the Memory and Aging Clinic at the University of California at San Francisco and the Alzheimer Center at the University of California at Davis. Global cognitive function assessed with the
Effect of normal aging on atrophy rates of ERC and hippocampus
Fig. 2 shows ERC and hippocampal atrophy rates as a function of age in 27 CN subjects without lacunes and hypertension. ERC atrophy rate significantly increased with age by 0.04 ± 0.02% per year (r = 0.38, p < 0.05). After accounting for baseline WMH volume and APOE ɛ4 status, the relationship between atrophy rate of ERC and age reduced to a trend (p = 0.06); however, both baseline WMH volume and APOE ɛ4 status did not significantly contribute (F-tests, both p > 0.1) to increased atrophy rate of ERC.
Discussion
The main findings of this study were: (1) age was associated with increased ERC and hippocampal atrophy rates; (2) atrophy rate of hippocampus, but not atrophy rate of ERC increased with presence of lacunes; (3) WMH, APOE ɛ4 and hypertension had no effect on atrophy rates of ERC and hippocampus.
The first finding was that ERC and hippocampal atrophy rates increased with increasing age in normal controls. Memory impairment is a prominent symptom of AD. Moreover, the ERC and hippocampus are both
Acknowledgements
This work was supported in part by VA Research Service (MIRECC), VA REAP, NIH/NIA RO1 AG10897, and NIH/NIA PO1 AG12435. We thank Ms. Diana Sacrey and Ms. Meera Krishnan.
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