Longitudinal diffusion imaging across the C9orf72 clinical spectrum
Open accessAbstract
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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DTI studies concluded sensitive detection of white matter changes in an early phase of bvFTD over varying follow-up time (0.5 to 2.5 years).
“A relatively large amount of studies on diffusion tensor imaging (DTI), visualizing the microstructure of white matter (WM) tracts, concluded sensitive detection of WM changes in an early phase of the disease, over varying follow-up time (0.5 to 2.5 years)”
From The pursuit for markers of disease progression in behavioral variant frontotemporal dementia: a scoping review to optimize outcome measures for clinical trials (2024) · cites this paper as Floeter et al., 2018
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- Authors
- Floeter, M. K., Danielian, L. E., Braun, L. E., & Wu, T.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Floeter, Mary Kay
- ORCID
- Wu, Tianxia
- Venue
- Journal of Neurology, Neurosurgery & Psychiatry
- Publisher
- BMJ
- Published
- 2017-10-20
- Volume
- 89
- Issue
- 1
- Pages
- 53-60
- ISSN
- 0022-3050 (ISSN-L)
- 1468-330X
- PMC
- PMC6454927
- OpenAlex
- W2766580430
- Cited by
- 51
- References
- 40
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 5 · 2022: 3 · 2021: 9 · 2020: 14 · 2019: 8 · 2018: 2 · 2017: 1
- FWCI
- 4.76
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Neurology Neurosurgery & Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health, National Institute of Neurological Disorders and Stroke
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- amyotrophic lateral sclerosis, frontotemporal dementia, white matter integrity, corticospinal tract, executive dysfunction, behavioural symptoms, symptom heterogeneity, disease staging, ALSFRS-R
- MeSH terms
- C9orf72 Protein, Adult, Amyotrophic Lateral Sclerosis, Brain, Female, Humans, Longitudinal Studies, Male, Middle Aged, Neuropsychological Tests, Prospective Studies, Pyramidal Tracts, Disease Progression, Diffusion Tensor Imaging, Frontotemporal Dementia, White Matter
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