Elsevier

NeuroImage

Volume 47, Issue 4, 1 October 2009, Pages 1678-1690
NeuroImage

Resting-state BOLD networks versus task-associated functional MRI for distinguishing Alzheimer's disease risk groups

https://doi.org/10.1016/j.neuroimage.2009.06.021Get rights and content

Abstract

To assess the ability of resting-state functional magnetic resonance imaging to distinguish known risk factors for AD, we evaluated 17 cognitively normal individuals with a family history of AD and at least one copy of the apolipoprotein e4 allele compared to 12 individuals who were not carriers of the APOE4 gene and did not have a family history of AD. Blood oxygen level dependent fMRI was performed evaluating encoding-associated signal and resting-state default mode network signal differences between the two risk groups. Neurocognitive testing revealed that the high risk group performed worse on category fluency testing, but the groups were equivalent on all other cognitive measures. During encoding of novel face–name pairs, there were no regions of encoding-associated BOLD activations that were different in the high risk group. Encoding-associated deactivations were greater in magnitude in the low risk group in the medial and right lateral parietal cortex, similar to findings in AD studies. The resting-state DMN analysis demonstrated nine regions in the prefrontal, orbital frontal, temporal and parietal lobes that distinguished the two risk groups. Resting-state DMN analysis could distinguish risk groups with an effect size of 3.35, compared to an effect size of 1.39 using encoding-associated fMRI techniques. Imaging of the resting state avoids performance related variability seen in activation fMRI, is less complicated to acquire and standardize, does not require radio-isotopes, and may be more effective at identifying functional pathology associated with AD risk compared to non-resting fMRI techniques.

Introduction

Functional imaging has been demonstrated to be able to distinguish people at risk for Alzheimer's disease (AD) prior to any clinical manifestations of neurodegeneration in young and middle aged individuals (Bookheimer et al., 2000, Fleisher et al., 2005Fleisher et al., 2008, Reiman et al., 1996, 2004). These studies and others provide evidence that there may be identifiable changes in brain physiology prior to potential clinical manifestations of dementia. Over the past two decades functional magnetic resonance imaging (fMRI) has become a prominent tool for studying blood oxygenation levels associated with various cognitive activities. Most studies have focused on the use of cognitive tasks to explore fMRI blood oxygenation level dependent (BOLD) signal activity, to define functional brain maps relating to anatomical structures, and to define related networks of brain activity. Although this has proven useful for understanding functional brain pathways, it is not clear that these activation techniques will be practical for use as biomarkers to identify individuals predisposed to developing dementia or useful as outcome measures in preventative drug studies. fMRI activation studies unfortunately suffer from intra and inter-subject variability, scanner variability, are dependent on task performance, and often involve lengthy scan times with complex study designs that are hard to standardize, and are difficult to perform in cognitively impaired individuals. fMRI evaluation of the resting state of the brain may be a sufficient and relevant target for studies of pre-clinical dementia.

The amplitude of the hemodynamic response to an external stimulus is dependent on the basal state of the brain (Ances et al., 2008, Brown et al., 2003, Buxton et al., 2004, Davis et al., 1998). Exposure to the same sensory stimulus will generate different fMRI responses depending on whether the basal state is high or low. For example, in individuals with a copy of the apolipoprotien E epsilon 4 allele (APOE4) and a family history of dementia, compared to individuals without these risk factors, differences reported in medial temporal lobe activations during encoding may simply reflect differences in the basal neuro-physiologic state (Fleisher et al., 2008). In fact, when alterations in the resting state are accounted for, the activation states may no longer reveal significant absolute differences. This implies that the resting state may often drive differences reported in activation state fMRI studies of AD and AD risk (Fleisher et al., 2008). One advantage to resting-state fMRI is that it is not dependent on differential task performance such as memory encoding, which is of particular concern when studying neurodegenerative processes and evaluating disease modifying therapies for prevention and treatment of dementia. Due to these issues, in part, there is an increasing interest in development of resting-state fMRI as a potential biomarker for preventative drug development in AD.

Echo planar imaging of the default mode network (DMN) explores resting-state neuronal network dysfunction in AD and has potential to be a sensitive marker for preclinical AD patho-physiology. The DMN represents a network of coordinated low frequency fluctuation (LFF) in specific functional neuronal networks. It is manifested as key brain regions that are elevated in states of relative rest, which are responsible for attention to environmental stimuli, reviewing of past knowledge, and planning of future behaviors (Binder et al., 1999, Raichle et al., 2001). These regions predominantly consist of midline and lateral frontal regions, and medial and lateral parietal regions extending into posterior cingulate/retrosplenial (pC/rsp) cortex (Buckner and Vincent, 2007). These same regions that are activated at rest appear to be suppressed during various cognitive activities, including encoding of new memories (Pihlajamaki et al., 2008, Rombouts et al., 2005, Sorg et al., 2007). For this reason, two methods have been developed utilizing the DMN to identify diseases of cognition and risk for dementia in the BOLD fMRI literature. One method explores task-related deactivations and the other focuses on differences in resting-state BOLD networks. These default networks may be particularly affected by the neurodegenerative process of AD (Buckner et al., 2008). With this, several groups have reported both reduced resting-state connectivity (Buckner et al., 2005) and alterations in fMRI task-induced deactivation responses in aging (Andrews-Hanna et al., 2007, Lustig et al., 2003) mild cognitive impairment (MCI) (Rombouts et al., 2005) and AD patients (Buckner and Vincent, 2007, Lustig et al., 2003, Persson et al., 2008, Rombouts et al., 2005, Sorg et al., 2007, Wang et al., 2006, 2007) compared to healthy controls.

Abnormalities of the DMN seen with fMRI may signify underlying physiologic defects associated with AD. For instance, there is evidence of a relationship between medial temporal lobe memory networks, frontoparietal attentional networks and the DMN, which appears to be required for successful memory formation (Buckner et al., 2005, Miller et al., 2008, Pihlajamaki et al., 2008). Also, decreased connectivity between the hippocampus, entorhinal cortex and the posterior cingulate cortex in AD has been proposed to represent early changes in functional brain networks in AD (Greicius et al., 2004). Evidence that supports this includes findings that the cortical regions that make up the DMN are similar to areas of early brain atrophy, hypometabolism, decreased perfusion, and fibrillar amyloid deposition in early AD and mild cognitive impairment (MCI) (Buckner et al., 2005, Edison et al., 2007, Forsberg et al., 2008, Jack et al., 2008, Johnson et al., 1998, Klunk et al., 2004, Minoshima et al., 1997). In particular, the posterior cingulate and precuneus cortex are regions that have the most prominent deactivations during cognitive tasks and are increased during the resting state (Buckner et al., 2005, Greicius et al., 2004). Very recently data was presented demonstrating that decrease in the DMN in cognitively normal APOE4 carriers is associated with increase in cortical fibrillar amyloid (Buckner et al., 2009, Hedden et al., 2009). And, differences in DMN signal have been noted in APOE4 carriers as young as 20–35 years old (Filippini et al., 2009). In addition, suppression of encoding-associated fMRI deactivation in the posterior cortical default network is associated with increased amyloid plaque burden in the precuneus/posterior cingulate cortex measured by Pittsburg compound B positron emission tomography (PiB-PET) imaging (Sperling et al., 2008). Further, failure of deactivation of medial posterior DMN during encoding is associated with worse memory performance (Miller et al., 2008) Overall, these findings suggest that “suspending” the default network during working memory is necessary for successful encoding, is impaired in AD, and potentially is associated with underlying amyloid pathology, even prior to clinical dementia in association with the APOE4 allele.

In an effort to further develop tools for early identification of Alzheimer's disease pathology and risk, we studied individuals with high and low risk for developing AD using BOLD fMRI. We compared the ability to distinguish AD risk groups using activation and deactivation fMRI during an encoding task versus resting-state BOLD DMN correlation analysis. Resting-state data was extracted from the encoding scans which included periods of relative rest. The overall aim of this study was to comparatively evaluate the utility of DMN BOLD fMRI in distinguishing risk for Alzheimer's disease pathology, and as a potential biomarker for preventative treatment trial.

Section snippets

Study population

Twenty-nine healthy right-handed volunteers, fifty to sixty-five years of age, were evaluated. Seventeen had a significant family history of dementia in a first degree relative and at least one copy of the APOE4 gene. Twelve participants had neither a family history of dementia nor a copy of the APOE4 gene. Participants were drawn from normal control participants in the University of San Diego (UCSD) Alzheimer's Disease Research Center, from the UCSD student, staff, and faculty population, as

Demographics and cognitive testing

Participants in the high risk group (n = 17) all had a significant family history of dementia in a first degree relative and at least one copy of the APOE4 gene (e3,e4 = 13; e4,e4 = 4). The low risk group (n = 12) had no family history of dementia and no copies of the APOE4 gene (e3,e3 = 11; e2,e3 = 1). Ages ranged from 51 years to 65 years (high risk = 58.6 ± 4.1; low risk = 57.6 ± 4.5). These groups did not significantly differ by age, gender or education (Table 1). There were no differences in brain volume

Discussion

This study supports recent reports that that resting-state BOLD fMRI can identify differences based on risk for AD. In comparison with encoding-associated BOLD activations and deactivations, evaluation of network connectivity of low frequency fluctuations more readily detected variability associated with AD risk and provided superior effect sizes for distinguishing risk groups. Medial and dorsolateral prefrontal cortex and temporal lobe structures showed increased DMN connectivity, with

Acknowledgment

This research was supported by grant k23 AG24062 from the National Institute on Aging, National Institutes of Health.

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