Assessing neuronal networks: Understanding Alzheimer's disease

Abstract

Findings derived from neuroimaging of the structural and functional organization of the human brain have led to the widely supported hypothesis that neuronal networks of temporally coordinated brain activity across different regional brain structures underpin cognitive function. Failure of integration within a network leads to cognitive dysfunction. The current discussion on Alzheimer's disease (AD) argues that it presents in part a disconnection syndrome. Studies using functional magnetic resonance imaging, positron emission tomography and electroencephalography demonstrate that synchronicity of brain activity is altered in AD and correlates with cognitive deficits. Moreover, recent advances in diffusion tensor imaging have made it possible to track axonal projections across the brain, revealing substantial regional impairment in fiber-tract integrity in AD. Accumulating evidence points towards a network breakdown reflecting disconnection at both the structural and functional system level. The exact relationship among these multiple mechanistic variables and their contribution to cognitive alterations and ultimately decline is yet unknown.Focused research efforts aimed at the integration of both function and structure hold great promise not only in improving our understanding of cognition but also of its characteristic progressive metamorphosis in complex chronic neurodegenerative disorders such as AD. Page 3 of 50A c c e p t e d M a n u s c r i p t 3 IntroductionFunctional neuroimaging studies in humans and animals suggest that particular brain regions are necessary for specific cognitive functions. The activations of different brain regions, however, do not appear to occur independently from each other but may occur in a sequential spatio-temporally ordered fashion Murphy et al., 1993). The involved regions integrate into a large-scale network which forms the basis of cognition and closely relates to its complex underlying systemic structural architecture (Horwitz et al., 2005;Lee et al., 2006;Luria, 1973;McIntosh, 2004;Rogers et al., 2007). For example, successful associative learning has been shown to correlate with a change in the effective connectivity, i.e., the influence of activation of one brain region onto another, within a specific neuronal network (Buchel et al., 1999). From the neuroanatomical perspective, connectivity of brain activity is predicted to be confined towards pathways of neuroanatomical connections between specific brain regions (Greicius et al., 2008;Toosy et al., 2004). These neuroanatomical constraints allow generating useful predictive models, specific working hypotheses concerning the effect of localized lesions on specific network functions in complex chronically progressive neurodegenerative system disorders such as Alzheimer's disease (AD).Thus a failure of the regions of a network to interact at a high level of coordination may underpin the cognitive disorders which are present in AD. The failure of network function may be due to interaction failure among the region...

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