Resting-state BOLD networks versus task-associated functional MRI for distinguishing Alzheimer's disease risk groups
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.
References (101)
- et al.
Regional differences in the coupling of cerebral blood flow and oxygen metabolism changes in response to activation: implications for BOLD-fMRI
NeuroImage
(2008) - et al.
Disruption of large-scale brain systems in advanced aging
Neuron
(2007) - et al.
Frequency of stages of Alzheimer-related lesions in different age categories
Neurobiol. Aging
(1997) - et al.
A parametric study of prefrontal cortex involvement in human working memory
NeuroImage
(1997) - et al.
Unrest at rest: default activity and spontaneous network correlations
NeuroImage
(2007) - et al.
Modeling the hemodynamic response to brain activation
NeuroImage
(2004) AFNI: software for analysis and visualization of functional magnetic resonance neuroimages
Comput. Biomed. Res.
(1996)- et al.
A method for using blocked and event-related fMRI data to study “resting state” functional connectivity
NeuroImage
(2007) - et al.
Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain
Neuron
(2002) - et al.
"Mini-mental state". A practical method for grading the cognitive state of patients for the clinician
J. Psychiatr. Res.
(1975)
PET imaging of amyloid deposition in patients with mild cognitive impairment
Neurobiol. Aging
Appearance modeling of 11C PiB PET images: characterizing amyloid deposition in Alzheimer's disease, mild cognitive impairment and healthy aging
NeuroImage
Revision of the apolipoprotein E compensatory mechanism recruitment hypothesis
Alzheimers Dement.
Verbal fluency performance in dementia of the Alzheimer's type: a meta-analysis
Neuropsychologia
Alzheimer A beta neurotoxicity: promotion by antichymotrypsin, ApoE4; inhibition by A beta-related peptides
Neurobiol. Aging
On the tip of the tongue: an event-related fMRI study of semantic retrieval failure and cognitive conflict
Neuron
Does the brain have a baseline? Why we should be resisting a rest
NeuroImage
Altered deactivation in individuals with genetic risk for Alzheimer's disease
Neuropsychologia
Impaired medial temporal repetition suppression is related to failure of parietal deactivation in Alzheimer disease
Am. J. Geriatr. Psychiatry
Physiological noise reduction for arterial spin labeling functional MRI
Neuroimage
Putting names to faces: successful encoding of associative memories activates the anterior hippocampal formation
NeuroImage
Association of apolipoprotein E polymorphism with outcome after head injury
Lancet
Changes in hippocampal connectivity in the early stages of Alzheimer's disease: evidence from resting state fMRI
NeuroImage
Nonlinear spatial normalization using basis functions
Hum. Brain Mapp.
Letter and category fluency in patients with frontal lobe lesions
Neuropsychology
Conceptual processing during the conscious resting state. A functional MRI study
J. Cogn. Neurosci.
Neuropsychological function and apolipoprotein E genotype in the preclinical detection of Alzheimer's disease
Psychol. Aging
Differential BOLD brain response to verbal paired-associate learning by APOE genotype in nondemented older adults: a functional MRI study
Neurobiol. Aging
FMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer's disease
Neurology
Patterns of brain activation in people at risk for Alzheimer's disease
N. Engl. J. Med.
Neuropathological stageing of Alzheimer-related changes
Acta Neuropathol. (Berl)
BOLD and perfusion response to finger-thumb apposition after acetazolamide administration: differential relationship to global perfusion
J. Cereb. Blood Flow Metab.
Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory
J. Neurosci.
The brain's default network: anatomy, function, and relevance to disease
Ann. N.Y. Acad. Sci.
Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer's disease
J. Neurosci.
Control of goal-directed and stimulus-driven attention in the brain
Nat. Rev., Neurosci.
The neural basis of the central executive system of working memory
Nature
Calibrated functional MRI: mapping the dynamics of oxidative metabolism
Proc. Natl. Acad. Sci. U. S. A.
Cognitive change and the APOE epsilon 4 allele
Nature
Integrating clinical assessment with cognitive neuroscience: construct validation of the California Verbal Learning Test
J. Consult. Clin. Psychol.
Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD
Neurology
Amyloid, hypometabolism, and cognition in Alzheimer disease: an [11C]PIB and [18F]FDG PET study
Neurology
Distinct patterns of brain activity in young carriers of the APOE-{varepsilon}4 allele
Proc. Natl. Acad. Sci. U. S. A.
Identification of Alzheimer disease risk by functional magnetic resonance imaging
Arch. Neurol.
Cerebral perfusion and oxygenation differences in Alzheimer's disease risk
Neurobiol. Aging
Apolipoprotein-E modulates the cytotoxic effect of beta-amyloid on rat brain endothelium in an isoform-dependent specific manner
Int. J. Mol. Med.
Executive frontal functions
Exp. Brain Res.
Image-based method for retrospective correction of physiological motion effects in fMRI: RETROICOR
Magn. Reson. Med.
Effect of task difficulty on cerebral blood flow during perceptual matching of faces
Hum. Brain Mapp.
Evidence from functional neuroimaging of a compensatory prefrontal network in Alzheimer's disease
J. Neurosci.
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