Structural and functional connectome alterations across King’s stages in amyotrophic lateral sclerosis
Edoardo Spinelli1, Alma Ghirelli4, Silvia Basaia2, Camilla Cividini2, Nilo Riva3, Tommaso Russo5, Elisa Canu2, Veronica Castelnovo2, Massimo Filippi6, Federica Agosta7
1Neuroimaging Research Unit, Division of Neuroscience and Neurology Unit, 2Neuroimaging Research Unit, Division of Neuroscience, 3Neurorehabilitation Unit and Experimental Neuropathology Unit, IRCCS San Raffaele Scientific Institute, 4Neuroimaging Research Unit, Division of Neuroscience and Neurology Unit, 5Experimental Neuropathology Unit and Neurology Unit, 6Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, Neurorehabilitation Unit and Neurophysiology Service, 7Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University
Objective:
To explore the rearrangements of structural and functional connectivity within and among brain networks underlying the clinical spreading of amyotrophic lateral sclerosis (ALS), as described by the King’s staging system, in order to suggest objective, continuous measures mirroring disease progression.
Background:
The identification of quantitative and reproducible markers of disease progression in ALS is of paramount importance for study design and inclusion of homogenous patient cohorts into clinical trials, as there is currently no validated disease-stage biomarker for ALS.
Design/Methods:
104 patients with ALS and 61 age- and sex-matched healthy controls underwent clinical and brain magnetic resonance imaging (MRI) on a 3T scanner. Patients were stratified into four groups, according to the King’s staging system. No patient had comorbid frontotemporal dementia. Structural and functional connectivity values within and between different anatomical brain regions were obtained using diffusion tensor and resting-state functional MRI data, respectively. Comparisons between groups were performed using age- and sex-adjusted ANOVA models. Correlations were tested using Pearson’s coefficient.
Results:
Compared with controls, a significant, progressive reduction of structural connectivity within brain nodes of the sensorimotor network was observed in ALS patients across King’s stages 2, 3 and 4 (p<0.006). Patients in stages 3 and 4 also showed significant loss of structural connectivity between frontal and sensorimotor regions (p=0.001). A significant disruption of functional connectivity within frontotemporal regions was found only in stage 4 (p=0.025). Sensorimotor structural connectivity showed a strong correlation with ALSFRS-r scores (r=0.31, p=0.001).
Conclusions:
Brain MRI allows to demonstrate and quantify increasing disruption of structural connectivity involving the sensorimotor and frontal networks in ALS, mirroring disease progression. Frontotemporal functional disconnection seems to characterize only advanced disease stages. Our findings demonstrate the utility of MRI connectomics to stratify patients and stage brain pathology in ALS in a reproducible way, which mirrors clinical progression.