Lifespan brain activity, β-amyloid, and Alzheimer's disease - PubMed (original) (raw)

Lifespan brain activity, β-amyloid, and Alzheimer's disease

William J Jagust et al. Trends Cogn Sci. 2011 Nov.

Abstract

Alzheimer's disease (AD) is the most common cause of progressive cognitive decline and dementia in adults. While the amyloid cascade hypothesis of AD posits an initiating role for the β-amyloid (Aβ) protein, there is limited understanding of why Aβ is deposited. A growing body of evidence based on in vitro, animal studies and human imaging work suggests that synaptic activity increases Aβ, which is deposited preferentially in multimodal brain regions that show continuous levels of heightened activation and plasticity across the lifespan. Imaging studies of people with genetic predispositions to AD are consistent with these findings, suggesting a mechanism whereby neural efficiency or cognitive reserve may diminish Aβ deposition. The aggregated findings unify observations from cellular and molecular studies with human cognitive neuroscience to reveal potential mechanisms of AD development.

Copyright © 2011 Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1. Spatial convergence between Aβ, DMN, heteromodal cortex and cortical hubs

Examination across these panels reveals a high degree of convergence between amyloid distribution, multimodal cortex, cortical hubs and regions utilizing aerobic glycolysis, which is more consistent than the overlap between PIB uptake and the DMN. (a) PIB. Patterns of amyloid deposition in normal elderly controls with slightly elevated PIB values (N=15) are contrasted to low PIB elderly control subjects (N=49; thresholded using clusters at z>1.64 with a cluster significance threshold of p=0.05, corrected; statistical maps were binarized and displayed in Caret v5.6). These slightly elevated subjects have PIB levels below AD but higher than presumably Aβ-free young subjects (N=11; age 20–30), and likely represent the earliest signs of Aβ accumulation (see [44]). (b) DMN. 1 sample t-test of functional connectivity maps of the DMN (using a seed in the posterior cingulate at MNI coordinates 0, −54, 26; N=51; thresholded using clusters at z>3.09 with a cluster significance threshold of p=0.05, corrected; statistical maps were binarized and displayed in Caret v5.6). (c) Heteromodal Cortex. Cortical labeling of heteromodal cortex, adapted from [73]. (d) Hubs. Distribution of cortical hubs. Warmer colors reflect a greater degree of connectivity with other voxels (assessed by counting the number of voxels with a correlation coefficient greater than 0.25 with that specific voxel). Reproduced, with permission, from[16]. (e) Aerobic Glycolysis. Distribution of aerobic glycolysis. Red/yellow colors reflect greater aerobic glycolysis whereas green/blue colors reflect less aerobic glycolysis. Reproduced, with permission, from [18].

Figure 2

Figure 2. Amyloid and brain activity across the lifespan

Hypothetical trajectories of brain activation across the life span as a function of cognitive reserve (CR) and APOE4. In this model, reserve is associated with increased neuronal efficiency (i.e., lower activation). Consequently, variability in lifelong patterns of brain activation results in different starting points for amyloid accumulation (red line). The blue line represents a ‘secondary’ compensatory response that may be induced by the additional burden imposed by amyloid accumulation, which eventually also fails during a period of decline. This alternative end is possible in all 3 scenarios, but for simplicity is shown only for the low reserve trajectory. These trajectories also describe proposed patterns across different brain regions that vary in their propensity for Aβ deposition. For instance, the high CR trajectory, which displays low levels of activation across the lifespan, is indicative of unimodal regions, whereas the low CR trajectory, which displays high levels of activation across the lifespan, is indicative of multimodal regions.

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