Measurement of hippocampal subfields and age-related changes with high resolution MRI at 4 T
Introduction
Aging can be associated with alterations of cognitive functions even in people spared from brain diseases commonly associated with older age and known to affect cognition, e.g., cerebrovascular disease or Alzheimer's disease (AD) [23]. One of the most prominently affected cognitive domains is memory [2]. This suggests that the hippocampal formation, which is crucial for storage and retrieval of information, might be particularly vulnerable to the aging process. The reasons for the age-associated impairment of the hippocampus are not completely understood and are most probably complex, as a variety of biochemical and electrophysiological changes compromising neuronal excitability and plasticity in old age have been described [7], [25]. Whether these functional changes are also associated with neuronal cell loss is a matter of debate. Some histological studies reported significant hippocampal neuronal cell loss with increasing age [22], [38] while others found no significant cell loss despite the presence of corresponding behavioral changes [21], [28], [31]. Neuroimaging findings, i.e., MRI based hippocampal volumetry, are similarly ambiguous. Some studies have shown significant hippocampal volume loss with increasing age [18], [29], [34] and others found no hippocampal volume differences between aged and young subjects [12], [40], [41]. However, an accurate characterization of the typical age-related hippocampal changes in vivo is very important because AD in the early stages is also associated with hippocampal volume loss [15], [16] and mild cognitive impairment, making the differentiation from normal aging difficult.
The hippocampus is not a homogeneous structure but divided into several subfields with distinctive histological characteristics: the subiculum (with the subdivisions pre-subiculum, para-subiculum and subiculum proper), the four cornu ammonis sectors (CA1–4) and the dentate gyrus. These subfields are functionally interconnected in two main intrahippocampal pathways: (1) The polysynaptic intrahippocampal pathway, which is composed of the entorhinal cortex, the dentate gyrus, CA3, 4 and CA1 and the subiculum. (2) The direct pathway, which is composed of the entorhinal cortex, CA1 and the subiculum [5]. Despite the tight functional interconnection, there is evidence of a functional specialization of the subfields, e.g., CA1 seems to be involved in temporal pattern association and intermediate term memory while CA3 is responsible for spatial pattern association, detection of novelty and short-term memory [20]. Furthermore, there is also evidence that different disease processes affect subfields differently and several histopathological studies suggest that this is also the case for aging and AD [9], [32], [47]. Therefore, measuring volume loss in hippocampal subfields might yield a better distinction between normal aging and early AD than measuring global hippocampal volume loss. However, this requires that the inner structure of the hippocampal formation can be depicted on MRI. On a clinical 1.5 T magnet the sensitivity of the MR signal is usually too low to obtain sufficient resolution to identify individual subfields without the application of sophisticated, often lengthy imaging protocols. Nonetheless, there have been several attempts to visualize age and AD related structural and perfusion changes in hippocampal subfields [1], [39]. Recent advancements with high field MRI (3–4 T), achieving increased gray/white matter contrast due to the increased signal sensitivity at high fields, additional magnetization transfer effects and T1 weighting, have resulted in superb anatomical images of the brain at sub-millimeter resolution, that can be acquired within a few minutes [4], [43]. Therefore, using a 4 T MRI system, the aims of this study were the following: (1) To test if hippocampal subfields, particularly, entorhinal cortex, subiculum, CA1, CA2 and CA3 and CA4, can be reliably identified and marked using anatomical landmarks on high resolution MR images. (2) To test if age-specific volume changes of subfields can be detected. Based on the findings of histological studies, we expected to find age-related changes in the subiculum [47], [48] and CA1 [38] and the latter to be more pronounced in Alzheimer's disease [47].
Section snippets
Subject population
Forty-two subjects were recruited from the community as controls for a dementia study by flyers and advertisements in local newspapers (cf. Table 1). Exclusion criteria included any poorly controlled medical illness (untreated diabetes, hypertension, thyroid disease) and/or use of medication or recreational drugs that could affect brain function, a history of brain trauma, brain surgery or evidence for ischemic events (lacunes, stroke) and skull defects on the MRI. Normal cognitive functioning
Reliability
Table 2 displays the ICC for the two raters indicating generally high consistency within and between raters (ICC > 0.75). However, the markings of the right subiculum were unreliable (ICC < 0.5). This was mostly likely due to artifacts from the posterior cerebral artery causing geometrical distortions in the region of the subiculum which made its consistent marking difficult.
Age effect
Regression analysis showed a strong negative effect of age (p = 0.0001) and ICV (p = 0.001) but not of gender on total
Discussion
There were two major findings of this study: (1) It is possible to reliably depict details of the internal structure of the hippocampal formation on high resolution T2 weighted MRIs at 4 T. These internal structures can be used to measure several hippocampal subfields in vivo. (2) Using this method, we found an age related volume loss in CA1 which was most pronounced in the seventh decade of life. This suggests that the age related loss of total hippocampal volume is mainly driven by a volume
Acknowledgments
The authors wish to thank Ms. Crystal Paul and Ms. Sabrina Fox for expert technical assistance, Ms. Jennifer Hlavin and Jessica Black for subject recruitment and Dr. John Kornak for statistical advice. The study was supported by grant RO1 AG010897 to Dr. M.W. Weiner. The study was approved by the committee of human research at the University of California, San Francisco (UCSF), and written informed consent was obtained from all participating subjects or their legal representatives according to
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