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
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. "
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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ABSTRACT: In Alzheimer's disease (AD), the hippocampus is an early site of tau pathology and neurodegeneration. Histological studies have shown that lesions are not uniformly distributed within the hippocampus. Moreover, alterations of different hippocampal layers may reflect distinct pathological processes. 7 T MRI dramatically improves the visualization of hippocampal subregions and layers. In this study, we aimed to assess whether 7 T MRI can detect volumetric changes in hippocampal layers in vivo in patients with AD. We studied four AD patients and seven control subjects. MR images were acquired using a whole-body 7 T scanner with an eight channel transmit-receive coil. Hippocampal subregions were manually segmented from coronal T2*-weighted gradient echo images with 0.3 × 0.3 × 1.2 mm(3) resolution using a protocol that distinguishes between layers richer or poorer in neuronal bodies. Five subregions were segmented in the region of the hippocampal body: alveus, strata radiatum, lacunosum and moleculare (SRLM) of the cornu Ammonis (CA), hilum, stratum pyramidale of CA and stratum pyramidale of the subiculum. We found strong bilateral reductions in the SRLM of the cornu Ammonis and in the stratum pyramidale of the subiculum (p < 0.05), with average cross-sectional area reductions ranging from -29% to -49%. These results show that it is possible to detect volume loss in distinct hippocampal layers using segmentation of 7 T MRI. 7 T MRI-based segmentation is a promising tool for AD research.
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ABSTRACT: The hippocampus is one of the most age-sensitive brain regions, yet the mechanisms of hippocampal shrinkage remain unclear. Recent studies suggest that hippocampal subfields are differentially vulnerable to aging and differentially sensitive to vascular risk. Promoters of inflammation are frequently proposed as major contributors to brain aging and vascular disease but their effects on hippocampal subfields are unknown. We examined the associations of hippocampal subfield volumes with age, a vascular risk factor (hypertension), and genetic polymorphisms associated with variation in pro-inflammatory cytokines levels (IL-1β C-511T and IL-6 C-174G) and risk for Alzheimer's disease (APOEε4) in healthy adult volunteers (N = 80; age = 22-82 years). Volumes of three hippocampal subfields, cornu ammonis (CA) 1-2, CA3-dentate gyrus, and the subiculum were manually measured on high-resolution magnetic resonance images. Advanced age was differentially associated with smaller volume of CA1-2, whereas carriers of the T allele of IL-1β C-511T polymorphism had smaller volume of all hippocampal subfields than CC homozygotes did. Neither of the other genetic variants, nor diagnosis of hypertension, was associated with any of the measured volumes. The results support the notion that volumes of age-sensitive brain regions may be affected by pro-inflammatory factors that may be targeted by therapeutic interventions.
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