ALS imprints on the brain linked to the connectome

In order to study the topology of functional networks, functional connectome maps are often thresholded after which only the strongest functional connections remain for analysis. The experiments described in chapter 2 show that graph metrics computed on proportionally thresholded functional connectomes, effectively filtered to keep a fixed number of strongest connections, are heavily influenced by the overall level of functional connectivity of a subject. In patient-control investigations, a difference in overall functional connectivity between groups is shown to interfere with topological effects. In chapter 4 functional connections were included for analysis if the corresponding region pair was also anatomically directly connected in the structural connectome. The integrated structural and functional connectome analyses of chapter 4 revealed overlapping structural and functional connectivity impairment among direct connections of the motor cortex. Connections more distant from the motor cortex showed structural effects but were functionally mostly spared, possibly indicative of functional effects to be secondary to primary structural connectivity disease effects. Chapter 3 touches upon structure-function relationships of brain networks taking a theoretical approach, simulating functional connectivity as synchrony between regions structurally connected according to the white matter connectome. Anatomical hub regions are shown to have a leading role in establishing synchrony between regions of different functional modules. Introducing structural connectivity impairments to these regions resulted in widespread functional effects hindering global integration in the brain network. These simulation findings, although based on a theoretical model, hugely simplifying neural communication, may help us understand how functional effects could arise from (disease-related) structural connectivity impairments. In a unique cohort of a family of asymptomatic C9orf72 mutation carriers and noncarriers, chapter 5 shows that before any clinical signs of ALS, mutation carriers did reveal reduced cortical thickness as compared with the noncarriers. Strikingly, no white matter involvement was detected in the carriers and cortical thinning was observed not in the anticipated motor cortex, but in temporal and parietal regions. These findings may represent developmental effects that predispose carriers to the neurodegenerative processes underlying ALS later in life. Furthermore, these results are in support of the ALS neuroimaging signature to develop close to the onset of disease as suggested in other studies. In chapter 6 it is argued that the healthy connectome governs patterns of spread across the brain of pathogenic protein aggregates in ALS, showing stages of neuropathology can be predicted from connectome topology. A similar relationship between the wiring of the healthy connectome and stages of neuropathology in bvFTD, Alzheimer and Parkinson was observed (chapter 7). With ALS and all three aforementioned neurodegenerative disorders belonging to the so-called ‘proteinopathies’, a class of protein misfolding diseases, the white matter connectome may be a crucial infrastructure in proteinopathies facilitating disease propagation across the brain. Taken together, the findings presented in this thesis relate to a range of ALS imprints on the brain including structural and functional connectivity impairment, cortical thinning in the asymptomatic phase of C9orf72 repeat expansion carriers and spread patterns of misfolded protein aggregation following the network organization of the white matter connectome