Connectome-based propagation model in amyotrophic lateral sclerosis

Jil M Meier, Hannelore K van der Burgh, Peter Bede, Siemon C de Lange, Orla Hardiman, Leonard H van den Berg, Martijn P van den Heuvel

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

OBJECTIVE: Clinical trials in amyotrophic lateral sclerosis (ALS) continue to rely on survival or functional scales as endpoints, despite the emergence of quantitative biomarkers. Neuroimaging-based biomarkers in ALS have been shown to detect ALS-associated pathology in vivo, although anatomical patterns of disease spread are poorly characterized. The objective of this study is to simulate disease propagation using network analyses of cerebral MRI data to predict disease progression.

METHODS: Using brain networks of ALS patients (n=208) and matched controls across longitudinal time points, network-based statistics unraveled progressive network degeneration originating from the motor cortex and expanding in a spatiotemporal manner. We applied a computational model to the MRI scan of patients to simulate this progressive network degeneration. Simulated aggregation levels at the group- and individual level were validated with empirical impairment observed at later time points of white matter and clinical decline using both internal and external datasets.

RESULTS: We observe that computer simulated aggregation levels mimic true disease patterns in ALS patients. Simulated patterns of involvement across cortical areas show significant overlap with the patterns of empirically impaired brain regions on later scans, both at the group and individual levels. These findings are validated using an external longitudinal dataset of 30 patients.

INTERPRETATION: Our results are in accordance with established pathological staging systems and may have implications for patient stratification in future clinical trials. Our results demonstrate the utility of computational models in ALS to predict disease progression and underscore the potential as a prognostic biomarker. This article is protected by copyright. All rights reserved.

Original languageEnglish
Pages (from-to)725-738
JournalAnnals of Neurology
Volume87
Issue number5
DOIs
Publication statusE-pub ahead of print - 18 Feb 2020

Bibliographical note

This article is protected by copyright. All rights reserved.

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