MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer’s disease☆
Introduction
Quantitative, high resolution magnetic resonance imaging (MRI) techniques provide a unique tool for examining alterations in brain anatomy in vivo during healthy aging and in age-related degenerative diseases. Such techniques are especially useful in identifying the anatomical origins of Alzheimer’s disease (AD).
The entorhinal cortex (EC) and the hippocampal formation (HF) are part of the mesial temporal lobe memory system [42], [50]; the EC connects the neocortex with the HF via the perforant path, thereby providing the latter with multimodal sensory information. These brain regions have received special attention in investigations on the pathophysiology of AD, since memory dysfunction is one of its earliest hallmarks.
Post mortem pathological studies have implicated the EC and the transentorhinal region as early sites of involvement in AD and in individuals with mild cognitive impairment [4], [5], [6], [18], [21], [35], [46]. However, the EC has received less attention in in vivo investigations, partly due to the fact that MRI-derived quantitative protocols for this structure were only recently developed [2], [22].
Atrophy of the HF, a region important for the acquisition of certain types of new information (i.e., declarative knowledge), has been well documented in AD using quantitative volumetric MRI analyses [7], [12], [13], [14], [23], [24], [29], [30], [31], [32], [38], [40], [48], [49]. More recently, atrophy of the EC was demonstrated in AD with MRI-based quantitation of its volume [27], [49]. Yet, while in vivo anatomical investigations using structural MRI are rapidly proliferating, relatively few volumetric studies have focused strictly on patients in the earliest stages of AD or on those with mild cognitive impairment (see, for example, [31], [49]).
Two studies that measured the entire parahippocampal gyrus failed to detect significant atrophy in this structure in patients with a clinical diagnosis of very mild AD [14], [24]. In these mild cases, however, there was significant hippocampal atrophy. These results were initially somewhat surprising, given the early pathological involvement of the entorhinal and transentorhinal cortices in the disease process. In the two studies cited above, parahippocampal gyrus volume included both white and gray matter and, in the case of the report from our laboratory [14], measurements continued beyond the anatomical boundaries of the entorhinal and perirhinal cortices. As a result, any changes in the EC itself may have been masked. It was, therefore, important to use newly developed protocols for the quantitation of the EC in order to re-examine its involvement in patients with very mild or incipient AD.
In addition to patients with very mild AD, individuals at high risk for AD are now being studied in order to identify anatomical changes that precede a clinical diagnosis and to develop sensitive in vivo markers that might be predictive of conversion to AD. One such group consists of those patients who have cognitive complaints, cognitive impairment, or both, but who do not meet diagnostic criteria for dementia after a thorough evaluation. Such groups are of special interest, since they provide information on the transitional state between normal aging and AD, although definitions and designations of this subgroup have varied [8], [15], [25], [36], [37]. A number of investigations have suggested that when followed longitudinally, these individuals are at increased risk for developing AD [1], [3], [9], [15], [31], [36], [43]. Furthermore, there is increased risk for incident dementia among elderly people with subjective (or informant corroborated) memory complaints, even if their baseline cognitive assessment is normal [17], [26], [39], [44], [45].
Of the few MRI studies that have examined the volumes of mesial temporal lobe structures in elderly patients with mild cognitive impairment or age-associated memory impairment, some have found hippocampal atrophy [7], [10], [25], [49], while others have not [32], [41]. Two recent investigations that assessed MRI-based entorhinal volume in such patients found significant EC atrophy compared to controls [31], [49].
The present research was undertaken to compare the extent of MRI-derived hippocampal and entorhinal atrophy in very mild and incipient AD in an attempt to determine the earliest sites of pathological involvement in the disease process and to develop in vivo anatomical markers.
Section snippets
Subjects
Data reported here were obtained from the following three groups of participants: 1) 34 healthy elderly normal control subjects (NC), 2) 28 patients who were evaluated for cognitive complaints, but who did not meet clinical criteria for dementia; they are referred to here as non-demented patients or ND, and 3) 16 patients with very mild probable AD. The major difference between the ND patients and the elderly controls is that the patients were recruited from a clinic where they were being
Results
As indicated above, all patients in the ND group sought formal evaluations due to complaints of cognitive decline. Because there were no significant differences in EC or HF volumes based on the presence or absence of cognitive deficits on formal testing (data not shown), the group of ND patients was considered as a whole in all subsequent analyses.
Demographic and MMSE data are presented in Table 1. Separate one-way ANOVAs showed that the three groups did not differ in age or level of
Discussion
A major strength of our study is the inclusion of extremely mild cases of AD and a comparison of the anatomical changes detected in vivo in these mild cases with those observed in patients who do not meet diagnostic criteria, but are at risk for AD.
Individuals at risk for AD are of interest since they provide valuable information on the transitional state between normal aging and AD. Different investigators have used different definitions to characterize this population, although recently
Acknowledgments
We thank Dr. Jeffrey Kordower for his cogent and critical comments on the manuscript.
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This research was supported by grants P01 AG09466 and P30 AG10161 from the National Institute on Aging, National Institutes of Health.