Bidirectional Relationship between Functional Connectivity and Amyloid-beta Deposition in Mouse Brain

Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 03/2012; 32(13):4334-40. DOI: 10.1523/JNEUROSCI.5845-11.2012
Source: PubMed

ABSTRACT Brain region-specific deposition of extracellular amyloid plaques principally composed of aggregated amyloid-β (Aβ) peptide is a pathological signature of Alzheimer's disease (AD). Recent human neuroimaging data suggest that resting-state functional connectivity strength is reduced in patients with AD, cognitively normal elderly harboring elevated amyloid burden, and in advanced aging. Interestingly, there exists a striking spatial correlation between functional connectivity strength in cognitively normal adults and the location of Aβ plaque deposition in AD. However, technical limitations have heretofore precluded examination of the relationship between functional connectivity, Aβ deposition, and normal aging in mouse models. Using a novel functional connectivity optical intrinsic signal (fcOIS) imaging technique, we demonstrate that Aβ deposition is associated with significantly reduced bilateral functional connectivity in multiple brain regions of older APP/PS1 transgenic mice. The amount of Aβ deposition in each brain region was associated with the degree of local, age-related bilateral functional connectivity decline. Normal aging was associated with reduced bilateral functional connectivity specifically in retrosplenial cortex. Furthermore, we found that the magnitude of regional bilateral functional correlation in young APP/PS1 mice before Aβ plaque formation was proportional to the amount of region-specific plaque deposition seen later in older APP/PS1 mice. Together, these findings suggest that Aβ deposition and normal aging are associated with region-specific disruption of functional connectivity and that the magnitude of local bilateral functional connectivity predicts regional vulnerability to subsequent Aβ deposition in mouse brain.

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Available from: David M Holtzman, Jan 20, 2014
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    • "In mouse brains, the amount of Aβ in the interstitial fluid and the development of amyloid plaques are associated with synaptic activity (Selkoe 2006; Bero et al. 2011, 2012). These findings suggest that the brain hubs tend to have amyloid plaque deposition that leads to functional disconnections among regions. "
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    ABSTRACT: Alzheimer's disease (AD) is associated not only with regional gray matter damages, but also with abnormalities in functional integration between brain regions. Here, we employed resting-state functional magnetic resonance imaging data and voxel-based graph-theory analysis to systematically investigate intrinsic functional connectivity patterns of whole-brain networks in 32 AD patients and 38 healthy controls (HCs). We found that AD selectively targeted highly connected hub regions (in terms of nodal functional connectivity strength) of brain networks, involving the medial and lateral prefrontal and parietal cortices, insula, and thalamus. This impairment was connectivity distance-dependent (Euclidean), with the most prominent disruptions appearing in the long-range connections (e.g., 100-130 mm). Moreover, AD also disrupted functional connections within the default-mode, salience and executive-control modules, and connections between the salience and executive-control modules. These disruptions of hub connectivity and modular integrity significantly correlated with the patients' cognitive performance. Finally, the nodal connectivity strength in the posteromedial cortex exhibited a highly discriminative power in distinguishing individuals with AD from HCs. Taken together, our results emphasize AD-related degeneration of specific brain hubs, thus providing novel insights into the pathophysiological mechanisms of connectivity dysfunction in AD and suggesting the potential of using network hub connectivity as a diagnostic biomarker.
    Cerebral Cortex 10/2014; DOI:10.1093/cercor/bhu246 · 8.67 Impact Factor
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    • "To investigate the strength of network connections, 10 seed locations were positioned at coordinates expected to correspond to the left and right olfactory, motor, somatosensory, retrosplenial, and visual cortices using a histological atlas (Franklin and Paxinos, 2008) as described previously (Bero et al., 2012; White et al., 2011). Seed timetraces were calculated by averaging the time traces within 0.25 mm of a seed locus (containing approximately 30 pixels). "
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    ABSTRACT: Recent human neuroimaging studies indicate that spontaneous fluctuations in neural activity, as measured by functional connectivity magnetic resonance imaging (fcMRI), are significantly affected following stroke. Disrupted functional connectivity is associated with behavioral deficits and has been linked to long-term recovery potential. FcMRI studies of stroke in rats have generally produced similar findings, although subacute cortical reorganization following focal ischemia appears to be more rapid than in humans. Similar studies in mice have not been published, most likely because fMRI in the small mouse brain is technically challenging. Extending functional connectivity methods to mouse models of stroke could provide a valuable tool for understanding the link between molecular mechanisms of stroke repair and human fcMRI findings at the systems level. We applied functional connectivity optical intrinsic signal imaging (fcOIS) to mice before and 72hours after transient middle cerebral artery occlusion (tMCAO) to examine how graded ischemic injury affects the relationship between functional connectivity and infarct volume, stimulus-induced response, and behavior. Regional changes in functional connectivity within the MCA territory were largely proportional to infarct volume. However, subcortical damage affected functional connectivity in somatosensory cortex as much as larger infarcts of cortex and subcortex. The extent of injury correlated with cortical activations following electrical stimulation of the affected forelimb and with functional connectivity in somatosensory cortex. Regional homotopic functional connectivity in motor cortex correlated with behavioral deficits measured using an adhesive patch removal test. Spontaneous hemodynamic activity within the infarct exhibited altered temporal and spectral features in comparison to intact tissue; failing to account for these regional differences significantly affected apparent post-stroke functional connectivity measures. Thus, several results were strongly dependent on how the resting-state data were processed. Specifically, global signal regression alone resulted in apparently distorted functional connectivity measures in the intact hemisphere. These distortions were corrected by regressing out multiple sources of variance, as performed in human fcMRI. We conclude that fcOIS provides a sensitive imaging modality in the murine stroke model; however, it is necessary to properly account for altered hemodynamics in injured brain to obtain accurate measures of functional connectivity.
    NeuroImage 05/2014; 99. DOI:10.1016/j.neuroimage.2014.05.051 · 6.36 Impact Factor
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    • "Dysfunction begins in the DMN, a set of regions that partially overlaps with amyloid deposition. It is likely that the amyloid deposition plays a causative role in DMN dysfunction (Bero et al., 2011, 2012). The timing of this dysfunction is still debated, but it certainly begins during the preclinical period . "
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    ABSTRACT: Much effort in recent years has focused on understanding the effects of Alzheimer's disease (AD) on neural function. This effort has resulted in an enormous number of papers describing different facets of the functional derangement seen in AD. A particularly important tool for these investigations has been resting-state functional connectivity. Attempts to comprehensively synthesize resting-state functional connectivity results have focused on the potential utility of functional connectivity as a biomarker for disease risk, disease staging, or prognosis. While these are all appropriate uses of this technique, the purpose of this review is to examine how functional connectivity disruptions inform our understanding of AD pathophysiology. Herein we examine the rationale and methodological considerations behind functional connectivity studies and then provide a critical review of the existing literature. In closing, we propose a hypothesis regarding the development and spread of functional connectivity deficits seen in AD.
    05/2014; 4(5). DOI:10.1089/brain.2014.0236
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