Zooming in on the hippocampus in aging and age-related diseases

Abstract

The hippocampal formation is a brain structure important for memory and emotion regulation. The hippocampal formation is susceptible to aging and age-related diseases, which is manifested as volume loss, visible on MRI scans. The hippocampal formation consists of several subfields with different cellular and molecular characteristics. These subfields are thought to be differentially associated to aging and age-related diseases. However, no clear picture emerges from previous MRI studies regarding the relation of aging and age-related diseases with hippocampal subfield volumes. Most of these studies were performed at conventional MRI with relatively low resolution images, which may have hindered the precise assessment of hippocampal subfields. With the new high resolution 7 tesla MRI scanner hippocampal subfields can be visualized in great detail. In part I of this thesis we aimed to quantify hippocampal subfield volumes and hippocampal T2 hyperintensities, focal signal abnormalities at 7 tesla MRI. In part II of this thesis we aimed to investigate the association of aging and age-related diseases with hippocampal subfield volumes. In part I, we presented a new protocol for the assessment of hippocampal subfields at 7 tesla MRI. Our high resolution data enabled the assessment of the major hippocampal subfields covering most of the longitudinal axis of the hippocampal formation. We also established that this protocol had good-to-excellent intra-rater reliability. Besides hippocampal subfield volumes, we used 7 tesla MRI to investigate focal signal abnormalities, so-called hippocampal T2 hyperintensities. We found that T2 hyperintensities were present in 97% of participants aged between 40 and 80 years, they were not related to age or memory and there appeared to be two types. Both types were also found in a small post-mortem substudy; one type appeared to be a cavity filled with cerebrospinal fluid and the other appeared to be a microinfarct. In part II of this thesis we used this protocol to investigate the association of aging and age-related disease with hippocampal subfield volumes. The first disease that we studied was Alzheimer disease. We found that all hippocampal subfields were smaller in patients with Alzheimer disease. Thus, in early Alzheimer disease no specific vulnerability of hippocampal subfields was observed. In relation to aging and depression, specific patterns of subfield atrophy were established. To further understand subfield atrophy in aging and age-related diseases, future studies should entangle the mechanisms underlying and the risk factors involved in hippocampal subfield atrophy. Furthermore, to understand the etiology in Alzheimer disease, future studies should focus on an earlier stage of disease, for example on patients with Mild Cognitive Impairment who have a high likelihood of developing Alzheimer disease. We also investigated brain and hippocampus atrophy in type 2 diabetes mellitus, since the hippocampus is suggested to be especially vulnerable to type 2 diabetes. In a pooled analysis of three studies, we found that brain atrophy, but not hippocampal atrophy, was associated with type 2 diabetes.