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August 25, 2020; 95 (8) Article

A prospective harmonized multicenter DTI study of cerebral white matter degeneration in ALS

Sanjay Kalra, Hans-Peter Müller, Abdullah Ishaque, Lorne Zinman, Lawrence Korngut, Angela Genge, Christian Beaulieu, View ORCID ProfileRichard Frayne, Simon J. Graham, Jan Kassubek
First published July 9, 2020, DOI: https://doi.org/10.1212/WNL.0000000000010235
Sanjay Kalra
From the Division of Neurology (S.K.), Department of Medicine, Neuroscience and Mental Health Institute (S.K., A.I.), and Department of Biomedical Engineering (C.B.), University of Alberta, Edmonton, Canada; Department of Neurology (H.-P.M., J.K.), University of Ulm, Germany; Sunnybrook Health Sciences Centre (L.Z., S.J.G.), University of Toronto, Ontario; Departments of Clinical Neurosciences (L.K., R.F.) and Radiology (R.F.), Hotchkiss Brain Institute, University of Calgary, Alberta; Montreal Neurological Institute and Hospital (A.G.), McGill University, Quebec; and Seaman Family MR Research Centre (R.F.), Foothills Medical Centre, Calgary, Alberta, Canada.
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Hans-Peter Müller
From the Division of Neurology (S.K.), Department of Medicine, Neuroscience and Mental Health Institute (S.K., A.I.), and Department of Biomedical Engineering (C.B.), University of Alberta, Edmonton, Canada; Department of Neurology (H.-P.M., J.K.), University of Ulm, Germany; Sunnybrook Health Sciences Centre (L.Z., S.J.G.), University of Toronto, Ontario; Departments of Clinical Neurosciences (L.K., R.F.) and Radiology (R.F.), Hotchkiss Brain Institute, University of Calgary, Alberta; Montreal Neurological Institute and Hospital (A.G.), McGill University, Quebec; and Seaman Family MR Research Centre (R.F.), Foothills Medical Centre, Calgary, Alberta, Canada.
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Abdullah Ishaque
From the Division of Neurology (S.K.), Department of Medicine, Neuroscience and Mental Health Institute (S.K., A.I.), and Department of Biomedical Engineering (C.B.), University of Alberta, Edmonton, Canada; Department of Neurology (H.-P.M., J.K.), University of Ulm, Germany; Sunnybrook Health Sciences Centre (L.Z., S.J.G.), University of Toronto, Ontario; Departments of Clinical Neurosciences (L.K., R.F.) and Radiology (R.F.), Hotchkiss Brain Institute, University of Calgary, Alberta; Montreal Neurological Institute and Hospital (A.G.), McGill University, Quebec; and Seaman Family MR Research Centre (R.F.), Foothills Medical Centre, Calgary, Alberta, Canada.
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Lorne Zinman
From the Division of Neurology (S.K.), Department of Medicine, Neuroscience and Mental Health Institute (S.K., A.I.), and Department of Biomedical Engineering (C.B.), University of Alberta, Edmonton, Canada; Department of Neurology (H.-P.M., J.K.), University of Ulm, Germany; Sunnybrook Health Sciences Centre (L.Z., S.J.G.), University of Toronto, Ontario; Departments of Clinical Neurosciences (L.K., R.F.) and Radiology (R.F.), Hotchkiss Brain Institute, University of Calgary, Alberta; Montreal Neurological Institute and Hospital (A.G.), McGill University, Quebec; and Seaman Family MR Research Centre (R.F.), Foothills Medical Centre, Calgary, Alberta, Canada.
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Lawrence Korngut
From the Division of Neurology (S.K.), Department of Medicine, Neuroscience and Mental Health Institute (S.K., A.I.), and Department of Biomedical Engineering (C.B.), University of Alberta, Edmonton, Canada; Department of Neurology (H.-P.M., J.K.), University of Ulm, Germany; Sunnybrook Health Sciences Centre (L.Z., S.J.G.), University of Toronto, Ontario; Departments of Clinical Neurosciences (L.K., R.F.) and Radiology (R.F.), Hotchkiss Brain Institute, University of Calgary, Alberta; Montreal Neurological Institute and Hospital (A.G.), McGill University, Quebec; and Seaman Family MR Research Centre (R.F.), Foothills Medical Centre, Calgary, Alberta, Canada.
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Angela Genge
From the Division of Neurology (S.K.), Department of Medicine, Neuroscience and Mental Health Institute (S.K., A.I.), and Department of Biomedical Engineering (C.B.), University of Alberta, Edmonton, Canada; Department of Neurology (H.-P.M., J.K.), University of Ulm, Germany; Sunnybrook Health Sciences Centre (L.Z., S.J.G.), University of Toronto, Ontario; Departments of Clinical Neurosciences (L.K., R.F.) and Radiology (R.F.), Hotchkiss Brain Institute, University of Calgary, Alberta; Montreal Neurological Institute and Hospital (A.G.), McGill University, Quebec; and Seaman Family MR Research Centre (R.F.), Foothills Medical Centre, Calgary, Alberta, Canada.
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Christian Beaulieu
From the Division of Neurology (S.K.), Department of Medicine, Neuroscience and Mental Health Institute (S.K., A.I.), and Department of Biomedical Engineering (C.B.), University of Alberta, Edmonton, Canada; Department of Neurology (H.-P.M., J.K.), University of Ulm, Germany; Sunnybrook Health Sciences Centre (L.Z., S.J.G.), University of Toronto, Ontario; Departments of Clinical Neurosciences (L.K., R.F.) and Radiology (R.F.), Hotchkiss Brain Institute, University of Calgary, Alberta; Montreal Neurological Institute and Hospital (A.G.), McGill University, Quebec; and Seaman Family MR Research Centre (R.F.), Foothills Medical Centre, Calgary, Alberta, Canada.
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Richard Frayne
From the Division of Neurology (S.K.), Department of Medicine, Neuroscience and Mental Health Institute (S.K., A.I.), and Department of Biomedical Engineering (C.B.), University of Alberta, Edmonton, Canada; Department of Neurology (H.-P.M., J.K.), University of Ulm, Germany; Sunnybrook Health Sciences Centre (L.Z., S.J.G.), University of Toronto, Ontario; Departments of Clinical Neurosciences (L.K., R.F.) and Radiology (R.F.), Hotchkiss Brain Institute, University of Calgary, Alberta; Montreal Neurological Institute and Hospital (A.G.), McGill University, Quebec; and Seaman Family MR Research Centre (R.F.), Foothills Medical Centre, Calgary, Alberta, Canada.
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  • ORCID record for Richard Frayne
Simon J. Graham
From the Division of Neurology (S.K.), Department of Medicine, Neuroscience and Mental Health Institute (S.K., A.I.), and Department of Biomedical Engineering (C.B.), University of Alberta, Edmonton, Canada; Department of Neurology (H.-P.M., J.K.), University of Ulm, Germany; Sunnybrook Health Sciences Centre (L.Z., S.J.G.), University of Toronto, Ontario; Departments of Clinical Neurosciences (L.K., R.F.) and Radiology (R.F.), Hotchkiss Brain Institute, University of Calgary, Alberta; Montreal Neurological Institute and Hospital (A.G.), McGill University, Quebec; and Seaman Family MR Research Centre (R.F.), Foothills Medical Centre, Calgary, Alberta, Canada.
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Jan Kassubek
From the Division of Neurology (S.K.), Department of Medicine, Neuroscience and Mental Health Institute (S.K., A.I.), and Department of Biomedical Engineering (C.B.), University of Alberta, Edmonton, Canada; Department of Neurology (H.-P.M., J.K.), University of Ulm, Germany; Sunnybrook Health Sciences Centre (L.Z., S.J.G.), University of Toronto, Ontario; Departments of Clinical Neurosciences (L.K., R.F.) and Radiology (R.F.), Hotchkiss Brain Institute, University of Calgary, Alberta; Montreal Neurological Institute and Hospital (A.G.), McGill University, Quebec; and Seaman Family MR Research Centre (R.F.), Foothills Medical Centre, Calgary, Alberta, Canada.
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Citation
A prospective harmonized multicenter DTI study of cerebral white matter degeneration in ALS
Sanjay Kalra, Hans-Peter Müller, Abdullah Ishaque, Lorne Zinman, Lawrence Korngut, Angela Genge, Christian Beaulieu, Richard Frayne, Simon J. Graham, Jan Kassubek
Neurology Aug 2020, 95 (8) e943-e952; DOI: 10.1212/WNL.0000000000010235

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Abstract

Objective To evaluate progressive white matter (WM) degeneration in amyotrophic lateral sclerosis (ALS).

Methods Sixty-six patients with ALS and 43 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium (CALSNIC). Participants underwent a harmonized neuroimaging protocol across 4 centers that included diffusion tensor imaging (DTI) for assessment of WM integrity. Three visits were accompanied by clinical assessments of disability (ALS Functional Rating Scale–Revised [ALSFRS-R]) and upper motor neuron (UMN) function. Voxel-wise whole-brain and quantitative tract-wise DTI assessments were done at baseline and longitudinally. Correction for site variance incorporated data from healthy controls and from healthy volunteers who underwent the DTI protocol at each center.

Results Patients with ALS had a mean progressive decline in fractional anisotropy (FA) of the corticospinal tract (CST) and frontal lobes. Tract-wise analysis revealed reduced FA in the CST, corticopontine/corticorubral tract, and corticostriatal tract. CST FA correlated with UMN function, and frontal lobe FA correlated with the ALSFRS-R score. A progressive decline in CST FA correlated with a decline in the ALSFRS-R score and worsening UMN signs. Patients with fast vs slow progression had a greater reduction in FA of the CST and upper frontal lobe.

Conclusions Progressive WM degeneration in ALS is most prominent in the CST and frontal lobes and, to a lesser degree, in the corticopontine/corticorubral tracts and corticostriatal pathways. With the use of a harmonized imaging protocol and incorporation of analytic methods to address site-related variances, this study is an important milestone toward developing DTI biomarkers for cerebral degeneration in ALS.

ClinicalTrials.gov identifier NCT02405182.

Glossary

ALS=
amyotrophic lateral sclerosis;
ALSFRS-R=
ALS Functional Rating Scale–Revised;
CALSNIC=
Canadian ALS Neuroimaging Consortium;
CST=
corticospinal tract;
DTI=
diffusion tensor imaging;
FA=
fractional anisotropy;
FDR=
false discovery rate;
TFAS=
tract-wise FA statistics;
TOI=
tract of interest;
UMN=
upper motor neuron;
WBSS=
whole brain–based spatial statistics;
WM=
white matter

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Editorial, page 327

  • Received December 2, 2019.
  • Accepted in final form February 17, 2020.
  • © 2020 American Academy of Neurology
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