Sub-Regional Hippocampal Injury is Associated with Fornix Degeneration in Alzheimer’s Disease

Imaging of Dementia and Aging Laboratory, Department of Neurology, Center for Neuroscience, University of California at Davis Davis, CA, USA.
Frontiers in Aging Neuroscience (Impact Factor: 4). 04/2012; 4:1. DOI: 10.3389/fnagi.2012.00001
Source: PubMed


We examined in vivo evidence of axonal degeneration in association with neuronal pathology in Alzheimer's disease (AD) through analysis of fornix microstructural integrity and measures of hippocampal subfield atrophy. Based on known anatomical topography, we hypothesized that the local thickness of subiculum and CA1 hippocampus fields would be associated with fornix integrity, reflecting an association between AD-related injury to hippocampal neurons and degeneration of associated axon fibers. To test this hypothesis, multi-modal imaging, combining measures of local hippocampal radii with diffusion tensor imaging (DTI), was applied to 44 individuals clinically diagnosed with AD, 44 individuals clinically diagnosed with mild cognitive impairment (MCI), and 96 cognitively normal individuals. Fornix microstructural degradation, as measured by reduced DTI-based fractional anisotropy (FA), was prominent in both MCI and AD, and was associated with reduced hippocampal volumes. Further, reduced fornix FA was associated with reduced anterior CA1 and antero-medial subiculum thickness. Finally, while both lesser fornix FA and lesser hippocampal volume were associated with lesser episodic memory, only the hippocampal measures were significant predictors of episodic memory in models including both hippocampal and fornix predictors. The region-specific association between fornix integrity and hippocampal neuronal death may provide in vivo evidence for degenerative white matter injury in AD: axonal pathology that is closely linked to neuronal injury.

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Available from: Owen Thomas Carmichael, May 19, 2014
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    • "A number of previous studies have found that the fornix is affected in aMCI, with changes such as lower FA and increased RD reported (Lee et al., 2012; Metzler-Baddeley et al., 2012a; Oishi et al., 2012; Zhuang et al., 2013). We had predicted that the aMCI group would show similar changes in fornix WM indices consistent with compromised WM, however we found no evidence of this in the current study, with no differences in fornix WM microstructural indices between the groups. "
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    ABSTRACT: In this study, we wished to examine the relationship between the structural connectivity of the fornix, a white matter (WM) tract in the limbic system, which is affected in amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease, and the resting-state functional connectivity (FC) of two key related subcortical structures, the thalamus, and hippocampus.Twenty-two older healthy controls (HC) and 18 older adults with aMCI underwent multi-modal MRI scanning.The fornix was reconstructed using constrained-spherical deconvolution-based tractography. The FC between the thalamus and hippocampus was calculated using a region-of-interest approach from which the mean time series were exacted and correlated. Diffusion tensor imaging measures of the WM microstructure of the fornix were correlated against the Fisher Z correlation values from the FC analysis.There was no difference between the groups in the fornix WM measures, nor in the resting-state FC of the thalamus and hippocampus. We did however find that the relationship between functional and structural connectivity differed significantly between the groups. In the HCs, there was a significant positive association between linear diffusion (CL) in the fornix and the FC of the thalamus and hippocampus, however, there was no relationship between these measures in the aMCI group. These preliminary findings suggest that in aMCI, the relationship between the functional and structural connectivity of regions of the limbic system may be significantly altered compared to healthy ageing.The combined use of diffusion weighted imaging and functional MRI may advance our understanding of neural network changes in aMCI, and elucidate subtle changes in the relationship between structural and functional brain networks.
    Frontiers in Aging Neuroscience 02/2015; 7(10). DOI:10.3389/fnagi.2015.00010 · 4.00 Impact Factor
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    • "Once the first ROIs have been determined, it would be possible to focus on these regions exclusively and separately in order to enclose and analyze in detail the pertinent anatomical regions (Ahmed et al., 2013). For instance, some research suggests that distinct regions of the hippocampus are affected differently in AD (Burger, 2010; Lee et al., 2012). Therefore, a rigorous study using SVM-RFE might be recommended for exhaustive anatomical inspections and analyzing particular cases. "
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    ABSTRACT: Accurate identification of the most relevant brain regions linked to Alzheimer's disease (AD) is crucial in order to improve diagnosis techniques and to better understand this neurodegenerative process. For this purpose, statistical classification is suitable. In this work, a novel method based on support vector machine recursive feature elimination (SVM-RFE) is proposed to be applied on segmented brain MRI for detecting the most discriminant AD regions of interest (ROIs). The analyses are performed both on gray and white matter tissues, achieving up to 100% accuracy after classification and outperforming the results obtained by the standard t-test feature selection. The present method, applied on different subject sets, permits automatically determining high-resolution areas surrounding the hippocampal area without needing to divide the brain images according to any common template.
    Frontiers in Aging Neuroscience 02/2014; 6:20. DOI:10.3389/fnagi.2014.00020 · 4.00 Impact Factor
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    • "A recent investigation demonstrated that a part of structural changes observed in the parahippocampal cingulum were independent of hippocampal atrophy (Salat et al., 2010). Studies examining the relationship between hippocampal atrophy and disruption of its efferent pathway (i.e., the fornix bundle) in both Mild Cognitive Impaired (MCI) and AD subjects have been more consistent (Pievani et al., 2010; Firbank et al., 2011; Lee et al., 2012; Mielke et al., 2012; Zhuang et al., 2012). In these studies, fornix microstructural alteration was significantly associated with reduced hippocampal volume in both MCI and AD subjects, leading the authors to hypothesize that concomitant alterations of these structures may reflect neurodegenerative processes occurring during AD as well as constituting a specific hallmark of the disease. "
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    ABSTRACT: While hippocampal atrophy has been described during healthy aging, few studies have examined its relationship with the integrity of White Matter (WM) connecting tracts of the limbic system. This investigation examined WM structural damage specifically related to hippocampal atrophy in healthy aging subjects (n = 129), using morphological MRI to assess hippocampal volume and Diffusion Tensor Imaging (DTI) to assess WM integrity. Subjects with Mild Cognitive Impairment (MCI) or dementia were excluded from the analysis. In our sample, increasing age was significantly associated with reduced hippocampal volume and reduced Fractional Anisotropy (FA) at the level of the fornix and the cingulum bundle. The findings also demonstrate that hippocampal atrophy was specifically associated with reduced FA of the fornix bundle, but it was not related to alteration of the cingulum bundle. Our results indicate that the relationship between hippocampal atrophy and fornix FA values is not due to an independent effect of age on both structures. A recursive regression procedure was applied to evaluate sequential relationships between the alterations of these two brain structures. When both hippocampal atrophy and fornix FA values were included in the same model to predict age, fornix FA values remained significant whereas hippocampal atrophy was no longer significantly associated with age. According to this latter finding, hippocampal atrophy in healthy aging could be mediated by a loss of fornix connections. Structural alterations of this part of the limbic system, which have been associated with neurodegeneration in Alzheimer's disease, result at least in part from the aging process.
    Frontiers in Aging Neuroscience 12/2013; 5:84. DOI:10.3389/fnagi.2013.00084 · 4.00 Impact Factor
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