• Alexander G Thompson, Bernd Taschler, Stephen M Smith, and Martin R Turner.
• Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK alexander.thompson@ndcn.ox.ac.uk martin.turner@ndcn.ox.ac.uk.
• J. Neurol. Neurosurg. Psychiatr. 2024 Mar 13; 95 (4): 360365360-365.

BackgroundAmyotrophic lateral sclerosis (ALS) is a disease of the motor network associated with brain structure and functional connectivity alterations that are implicated in disease progression. Whether such changes have a causal role in ALS, fitting with a postulated influence of premorbid cerebral architecture on the phenotypes associated with neurodegenerative disorders is not known.MethodsThis study considered causal effects and shared genetic risk of 2240 structural and functional MRI brain scan imaging-derived phenotypes (IDPs) on ALS using two sample Mendelian randomisation, with putative associations further examined with extensive sensitivity analysis. Shared genetic predisposition between IDPs and ALS was explored using genetic correlation analysis.ResultsIncreased white matter volume in the cerebral hemispheres was causally associated with ALS. Weaker causal associations were observed for brain stem grey matter volume, parieto-occipital white matter surface and volume of the left thalamic ventral anterior nucleus. Genetic correlation was observed between ALS and intracellular volume fraction and isotropic free water volume fraction within the posterior limb of the internal capsule.ConclusionsThis study provides evidence that premorbid brain structure, in particular white matter volume, contributes to the risk of ALS.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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