A Winding Road: Alzheimer's Disease Increases Circuitous Functional Connectivity Pathways.

John Suckling,Guy Williams,John T O’Brien,Tiago Simas,Shayanti Chattopadhyay,Li Su,Roger Tait,James B Rowe

doi:10.3389/fncom.2015.00140

Abstract

Neuroimaging has been successful in characterizing the pattern of cerebral atrophy that accompanies the progression of Alzheimer’s disease (AD). Examination of functional connectivity, the strength of signal synchronicity between brain regions, has gathered pace as another way of understanding changes to the brain that are associated with AD. It appears to have good sensitivity and detect effects that precede cognitive decline, and thus offers the possibility to understand the neurobiology of the disease in its earliest phases. However, functional connectivity analyzes to date generally consider only the strongest connections, with weaker links ignored. This proof-of-concept study compared patients with mild-to-moderate AD (N = 11) and matched control individuals (N = 12) based on functional connectivities derived from blood-oxygenation level dependent (BOLD) sensitive functional MRI acquired during resting wakefulness. All positive connectivities irrespective of their strength were included. Transitive closures of the resulting connectome were calculated that classified connections as either direct or indirect. Between-group differences in the proportion of indirect paths were observed. In AD, there was broadly increased indirect connectivity across greater spatial distances. Furthermore, the indirect pathways in AD had greater between-subject topological variance than controls. The prevailing characterization of AD as being a disconnection syndrome is refined by the observation that direct links between regions that are impaired are perhaps replaced by an increase in indirect functional pathways that is only detectable through inclusion of connections across the entire range of connection strengths.

Highlights

Within neuroimaging, the integrationist perspective derived from measures of the blood oxygenation-level dependent (BOLD) signal synchronicity between regions has become the primary tool for understanding the functional organization of the brain with fMRI
Using a more lenient statistical threshold of p < 0.001 uncorrected resulted in significant reductions in gray matter volume (GMV) in Alzheimer’s disease (AD) patients in areas including temporal and parietal regions (Supplementary Figure 1)
AD has been described as a disconnection syndrome (Delbeuck et al, 2003), and the available evidence from this study and others deploying functional connectivity would support that notion

Summary

Introduction

The integrationist perspective derived from measures of the blood oxygenation-level dependent (BOLD) signal synchronicity between regions has become the primary tool for understanding the functional organization of the brain with fMRI. That the annual rate of publications on functional integration exceeds that on functional localization (i.e., task-induced activation; Friston, 2011). This approach has been highly successful in providing a new substrate and vocabulary to express both the principles of healthy brain organization, Circuitous Connectivity in Alzheimer’s Disease and the generalised changes to its key elements that are associated with disorder (Lynall et al, 2010). Investigations of functional connectivity in AD are still relatively immature, there is an emerging broad narrative

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Conclusion