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Towards a Network Biomarker for Alzheimer's Disease

Meta-analysis of functional network alterations in Alzheimer's disease: towards a network biomarker

Heidi I.L. Jacobs, Joaquim Radua, Helen C. Lückmann and Alexander T. Sack

The increasing prevalence of Alzheimer's disease (AD) emphasizes the need for sensitive biomarkers. Memory, a core deficit in AD, involves the interaction of distributed brain networks. In this meta-analysis we proposed that biomarkers should be sought at the level of disease-specific disturbances in large-scale neural networks instead of alterations in a single brain region. To that end, we performed the first voxel-level quantitative meta-analysis of default mode connectivity and task-related activation in 1196 patients and 1255 controls to detect robust changes in components of large-scale neural networks. The results from the multi-modal meta-analyses showed that with disease progression, specific components of networks are widespread altered, and that the nature and extent of these alterations also varies with disease progression of AD. Two main neural hubs were identified: the medial parietal regions (see Figure) and the subcortical areas. Both components showed robust but different changes in rest and task-related modalities depending on the disease stage. Specific compensatory mechanisms are only seen in the earliest stages in subparts of these components, before clinical symptoms are eviden. Therefore, these large-scale network alterations could become a functional network biomarker or a target for interventions. These results underline the need to further fine-grain these networks spatially and temporally across disease stages. To conclude, these results show that AD should indeed be considered as a syndrome involving neural network disruption before cognitive deficits are detectable. Large-scale and longitudinal epidemiological studies are necessary to investigate the diagnostic accuracy of the suggested network biomarker.


Figure: Multimodal meta-analysis of default mode network connectivity and task-related activation in mild cognitive impairment patients

Note:The upper panel depicts coronal and sagital section of the brain, while the lower panel shows a transversal section of the brain. The green area (precuneus) shows where MCI patients have less DMN connectivity with conjoining less task-related activation than controls.


Jacobs HI, Radua J, Lückmann HC, Sack AT. (2013). Meta-analysis of functional network alterations in Alzheimer's disease: Toward a network biomarker. Neurosci Biobehav Rev. 2013 Mar 21;37(5):753-765. doi: 10.1016/j.neubiorev.2013.03.009. [Epub ahead of print]