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Research paper
Longitudinal diffusion imaging across the C9orf72 clinical spectrum
  1. Mary Kay Floeter,
  2. Laura E Danielian,
  3. Laura E Braun,
  4. Tianxia Wu
  1. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
  1. Correspondence to Dr Mary Kay Floeter, National Institute of Neurological Disorders and Stroke National Institutes of Health, Bethesda, MD 20892-1404, USA; floeterm{at}


Introduction Discrepancies between diffusion tensor imaging (DTI) findings and functional rating scales in amyotrophic lateral sclerosis (ALS) may be due to symptom heterogeneity, particularly coexisting cognitive-behavioural dysfunction affecting non-motor regions of the brain. Carriers of expansion mutations in the C9orf72 gene, whose motor and cognitive-behavioural symptoms span a range from ALS to frontotemporal dementia, present an opportunity to evaluate the relationship between symptom heterogeneity and DTI changes.

Methods Twenty-eight C9orf72 mutation carriers with varied cognitive and motor symptoms underwent clinical evaluation and DTI imaging. Twenty returned for two or more follow-up evaluations. Each evaluation included motor, executive and behavioural scales and disease staging using the King’s college staging system.

Results Widespread reduction of white matter integrity occurred in C9orf72 mutation carriers compared with 28 controls. The ALS Functional Rating Scale (ALSFRS-R) and King’s stage correlated with DTI measures of the corticospinal tract and mid-callosum. Cognitive and behavioural scores correlated with diffusion measures of frontal white matter. King’s stage, but not ALSFRS-R, correlated with anterior callosum DTI measures. Over a 6-month follow-up, DTI changes spread from anterior to posterior, and from deep to superficial subcortical white matter. In C9orf72 carriers with ALS or ALS-FTD, changes in corticospinal tractography measures correlated with changes in ALSFRS-R.

Conclusion Discrepancies between DTI findings and clinical measures of disease severity in ALS may partly be accounted for by cognitive-behavioural deficits affecting extramotor white matter tracts. Both ALSFRS-R and King’s stage correlated with corticospinal DTI measures. Group-level DTI changes could be detected over 6 months.

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  • Contributors MKF designed the study, collected clinical data, analysed images and drafted the manuscript. LED acquired and analysed MRI image data, drafted the methods section of the manuscript, created illustrations and provided critical revisions to the manuscript. LEB carried out clinical ratings of patients, organised clinical data and carried out preliminary analyses, and provided critical reading of the manuscript. TW carried out statistical analyses and provided critical insights into longitudinal findings, drafted the statistical section of the manuscript and provided critical revisions.

  • Funding The study was supported by the intramural programme of the National Institutes of Health, National Institute of Neurological Disorders and Stroke Z01 NS003146.

  • Competing interests None declared.

  • Ethics approval NIH Combined Neuroscience IRB.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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