Shared Vulnerability of Two Synaptically-Connected Medial Temporal Lobe Areas to Age and Cognitive Decline: A Seven Tesla Magnetic Resonance Imaging Study

Stanford Center for Memory Disorders, Department of Neurology and Neurological Sciences and Department of Radiology, Stanford University School of Medicine, Stanford, California 94110.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 10/2013; 33(42):16666-72. DOI: 10.1523/JNEUROSCI.1915-13.2013
Source: PubMed


The medial temporal lobe (MTL) is the first brain area to succumb to neurofibrillary tau pathology in Alzheimer's disease (AD). Postmortem human tissue evaluation suggests that this pathology propagates in an ordered manner, with the entorhinal cortex (ERC) and then CA1 stratum radiatum and stratum lacunosum-moleculare (CA1-SRLM)-two monosynaptically connected structures-exhibiting selective damage. Here, we hypothesized that, if ERC and CA1-SRLM share an early vulnerability to AD pathology, then atrophy should occur in a proportional manner between the two structures. We tested this hypothesis in living humans, using ultra-high field 7.0 T MRI to make fine measurements of MTL microstructure. Among a pool of age-matched healthy controls and patients with amnestic mild cognitive impairment and mild AD, we found a significant correlation between ERC and CA1-SRLM size that could not be explained by global atrophy affecting the MTL. Of the various structures that contribute axons or dendrites into the CA1-SRLM neuropil, only ERC emerged as a significant predictor of CA1-SRLM size in a linear regression analysis. In contrast, other synaptically connected elements of the MTL did not exhibit size correlations. CA1-SRLM and ERC structural covariance was significant for older controls and not patients, whereas the opposite pattern emerged for a correlation between CA1-SRLM and episodic memory performance. Interestingly, CA1-SRLM and ERC were the only MTL structures to atrophy in older controls relative to a younger comparison group. Together, these findings suggest that ERC and CA1-SRLM share vulnerability to both age and AD-associated atrophy.

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    • "Another group found linear atrophy in the CA1/2 area (Shing et al., 2011; Raz et al., 2014). Kerchner et al. (2013) described a diminution of the entorhinal cortex and CA1-SRLM width in older adults compared to their younger counterparts. In other studies, the manual delineation covered almost the whole hippocampus. "
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    ABSTRACT: Hippocampal atrophy, as evidenced using magnetic resonance imaging (MRI), is one of the most validated, easily accessible and widely used biomarkers of Alzheimer's disease (AD). However, its imperfect sensitivity and specificity have highlighted the need to improve the analysis of MRI data. Based on neuropathological data showing a differential vulnerability of hippocampal subfields to AD processes, neuroimaging researchers have tried to capture corresponding morphological changes within the hippocampus. The present review provides an overview of the methodological developments that allow the assessment of hippocampal subfield morphology in vivo, and summarizes the results of studies looking at the effects of AD and normal aging on these structures. Most studies highlighted a focal atrophy of the CA1 subfield in the early (predementia or even preclinical) stages of AD, before atrophy becomes more widespread at the dementia stage, consistent with the pathological literature. Preliminary studies have indicated that looking at this focal atrophy pattern rather than standard whole hippocampus volumetry improves diagnostic accuracy at the Mild Cognitive Impairment (MCI) stage. However, controversies remain regarding changes in hippocampal subfield structure in normal aging and regarding correlations between specific subfield volume and memory abilities, very likely because of the strong methodological variability between studies. Overall, hippocampal subfield analysis has proven to be a promising technique in the study of AD. However, harmonization of segmentation protocols and studies on larger samples are needed to enable accurate comparisons between studies and to confirm the clinical utility of these techniques. Copyright © 2015. Published by Elsevier Ltd.
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