Elsevier

Brain Research

Volume 1495, 7 February 2013, Pages 18-29
Brain Research

Research Report
Hippocampus–precuneus functional connectivity as an early sign of Alzheimer's disease: A preliminary study using structural and functional magnetic resonance imaging data

https://doi.org/10.1016/j.brainres.2012.12.011Get rights and content

Abstract

Alzheimer's disease (AD) is characterized by structural atrophies in the hippocampus (HP) and aberrant patterns of functional connectivities (FC) between the hippocampus and the rest of the brain. However, the relationship between cortical atrophy levels and corresponding degrees of aberrant FC patterns has not been systematically examined. In this study, we investigated whether there was an explicit link between structural abnormalities and corresponding functional aberrances associated with AD using structural and functional magnetic resonance imaging (fMRI) data. To this end, brain regions with cortical atrophies that are associated with AD were identified in the HP in the left (L) and right (R) hemispheres using structural MRI data from volume analyses (p<0.03 for L-HP; p<0.04 for R-HP) and voxel-based morphometry analyses (p<4×10−4 for L-HP; p<2×10−3 for R-HP). Aberrantly reduced FC levels between the HP (with atrophy) and precuneus were also consistently observed in fMRI data from AD than HC brains that were analyzed by the Pearson's correlation coefficients (p<3×10−4 for L-HP; and p<8×10−5 for R-HP). In addition, the substantial negative FC levels from the HC brains between the precuneus and post central gyrus (PoCG) without structural atrophy were also significantly diminished from the AD brains (p<5×10−5 for L-PoCG; and p<6×10−5 for R-PoCG). The effect sizes of these aberrant FC levels associated with AD were greater than that of cortical atrophy levels when comparing using normalized Z score and Cohen's d measures, which indicates that an aberrant FC level may precede cortical atrophy.

Highlights

► Structural atrophy (SA) with Alzheimer's disease (AD) was in the hippocampus (HP). ► Functional connectivity (FC) between the HP and precuneus was reduced from AD. ► FC between the post central gyrus and precuneus was significantly lower from AD. ► Effect size of FC levels was significantly greater than effect size of SA levels. ► Aberrant FC than SA seems to be a valuable biomarker for early detection of AD.

Introduction

Structural abnormalities of the human brain, as measured via non-invasive magnetic resonance imaging (MRI), have been implicated in various neurodegenerative illnesses, including Alzheimer's disease (AD) (Frisoni et al., 2010, Dickerson and Sperling, 2008). The characteristic traits estimated from the structural MRI (sMRI) data include atrophies of regional volumes and reduced gray matter (GM) intensities, especially in the medial temporal lobe (MTL) (Frisoni et al., 2010, Risacher et al., 2009). Frisoni et al. (2010) conducted a volume analysis (VA) using sMRI data and then used the results as a clinical assessment tool for suspected AD patients. In this study, the authors suggested that the atrophies within the MTL area, including the hippocampus (HP), were a valid biomarker to represent AD status for the assessment of individual patients. Furthermore, abnormally altered functional connectivity (FC) patterns, as measured by blood oxygenation level-dependent (BOLD) functional MRI (fMRI), have also been reported to be a potential biomarker for the diagnosis of AD (Greicius et al., 2004, Bai et al., 2009, Wang et al., 2007).

A growing body of evidence suggests that both structural atrophy and functional alterations are implicated in the early stages of AD (Gili et al., 2011, Sorg et al., 2007). For example, Gili et al. (2011) estimated GM intensities using sMRI data with a voxel-based morphometry (VBM) method and estimated FC patterns using resting-state fMRI data of mild cognitive impairment (MCI) and AD groups with a group independent component analysis (ICA) method. The greater degree of aberrant FC patterns observed in both the MCI and AD groups were in the posterior cingulate cortex (PCC) and medial prefrontal cortex relative to the rest of the brain regions (Gili et al., 2011). On the other hand, the observed structural atrophies in the MCI group were significantly limited, with only marginal changes observed in the PCC and precuneus relative to the AD group (Gili et al., 2011). Thus, it is possible that aberrant FC patterns may appear earlier than GM atrophies during the progression of AD pathology. However, there have been limited attempts to explicitly identify potentially crucial information about structural atrophies and levels of aberrant FC patterns in the early stage of AD using non-invasive MRI.

The aim of the present study was to provide preliminary evidence on the link between the degree of structural atrophy and the level of aberrant FC patterns that are associated with an early stage of AD. More specifically, we hypothesized that the functional aberrance estimated with FC levels would precede the structural abnormality estimated with structural atrophy. Furthermore, the spatial patterns (SPs) with aberrant FC levels can be identified from the seed brain regions with structural atrophy and possibly even from brain regions without structural atrophy as evaluated with an effect size. As a result, we will suggest a brain region that would represent the potentially early sign of AD status, so that the FC level in this region can be adopted as a potential biomarker to assist a diagnosis of the AD status. To this end, brain regions were automatically parcellated from sMRI data using the VA method, and cortical atrophies were identified at the voxel level using the VBM method. Then, the average BOLD time series (TS) were calculated from the seed regions-of-interest (ROIs) within brain regions that either displayed atrophies or did not display atrophies. These BOLD TS were then used as references for the subsequent FC analyses. Next, FC patterns were calculated with voxel-wise partial correlation coefficients (CCs) using the reference BOLD TS selected from the two seed ROIs in each hemisphere and the BOLD TS from the voxels in the remaining brain areas. For the group-level statistical analyses, potentially significant changes in the FC patterns between healthy control (HC) and AD groups were compared using two-sample t-tests. Finally, an effect size of severity associated with AD was compared between observed structural abnormalities and aberrant FC levels.

Section snippets

Results

Fig. 1 shows the marginal levels of structural atrophies in terms of volume sizes observed in the left HP (p<0.03) and right HP (p<0.04) in the AD group relative to the HC group. The normalized regional volumes of the bilateral PCC and precuneus as well as the PoCG were not significantly different between the two groups (p>0.05). The intra-cranial volume (ICV) values between the two groups were also not significantly different (AD: 1.27×103 cm3±0.18×103 cm3; HC: 1.27×103±0.19×103 cm3; p=0.96).

Summary

In this study, we presented preliminary evidence that there is a close link between abnormal structural atrophies and corresponding aberrant FC patterns that are both associated with AD status. The structural atrophies were observed in the bilateral HP, especially in the rostral portion of the left HP, as revealed with the VBM method. Compared to the marginal levels of structural atrophies that have been implicated in AD, the FC levels between the HP and rest of the brain were substantially

Overview

Fig. 6 illustrates an overall flow diagram of the procedures used in the present study. First, the seed regions with and without atrophy were identified by determining regional volume segmentations with VA and voxel-based identifications of GM intensities with VBM. Second, after the brain regions with and without atrophy were identified as seed regions, FC analyses were performed between the seed regions and the remaining whole brain areas. Third, the characteristic traits of GM intensities and

Funding sources

This work was supported by the WCU (World Class University) program through the National Research Foundation (NRF) of Korea and was funded by the Ministry of Education, Science and Technology (R31-10008) and the Basic Science Research Program, NRF grant of Korea (2012–0002342).

Acknowledgments

The authors would like to thank Dr. Seung-Schik Yoo and Mr. Dong-Youl Kim for their valuable discussions and logistic support in preparation of this manuscript.

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