To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
This study hypothesizes that the brain shows hyper connectedness as amyotrophic lateral sclerosis (ALS) progresses. 54 patients (classified as “early stage” or “advanced stage”) and 25 controls underwent magnetoencephalography and MRI recordings. The activity of the brain areas was reconstructed, and the synchronization between them was estimated in the classical frequency bands using the phase lag index. Brain topological metrics such as the leaf fraction (number of nodes with degree of 1), the degree divergence (a measure of the scale-freeness) and the degree correlation (a measure of disassortativity) were estimated. Betweenness centrality was used to estimate the centrality of the brain areas.In all frequency bands, it was evident that, the more advanced the disease, the more connected, scale-free and disassortative the brain networks. No differences were evident in specific brain areas. Such modified brain topology is sub-optimal as compared to controls. Within this framework, our study shows that brain networks become more connected according to disease staging in ALS patients.
Objective.To investigate structural and functional neural organization in amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS) and progressive muscular atrophy (PMA) patients.Methods.173 ALS, 38 PLS, 28 PMA sporadic patients and 79 healthy controls were recruited from three Italian centers. Subjects underwent clinical, neuropsychological and brain MRI evaluations. Using graph analysis and connectomics, global and lobar topological network properties and regional structural and functional brain connectivity were assessed. The association between structural and functional network organization and clinical/cognitive data was investigated.Results.Compared to healthy controls, ALS and PLS patients showed altered structural global network properties, as well as local topological alterations and decreased structural connectivity in sensorimotor, basal ganglia, frontal and parietal areas. PMA patients showed preserved global structure. Patient groups did not show significant alterations of functional network topological properties relative to controls. Increased local functional connectivity was observed in ALS patients in the precentral, middle and superior frontal areas, and in PLS patients in the sensorimotor, basal ganglia and temporal networks. In both ALS and PLS patients, structural connectivity alterations correlated with motor impairment, while functional connectivity disruption was closely related to executive dysfunctions and behavioral disturbances.Conclusions.This multicenter study showed widespread motor/extra-motor network degeneration in ALS and PLS, suggesting that graph analysis and connectomics might represent a powerful approach to detect upper motor neuron degeneration, extra-motor brain changes and network reorganization associated with the disease. Network-based advanced MRI provides an objective in vivo assessment of motor neuron diseases, delivering potential prognostic markers.
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