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Front. Aging Neurosci. | doi: 10.3389/fnagi.2018.00047

Longitudinal diffusion tensor imaging resembles patterns of pathology progression in behavioral variant frontotemporal dementia (bvFTD)

 Jan Kassubek1*,  Hans-Peter Müller1, Kelly del Tredici1,  Michael Hornberger2,  Matthias L. Schroeter3, Karsten Müller3, Sarah Anderl-Straub1, Ingo Uttner1,  Murray Grossman4, Heiko Braak1,  John Hodges5, Olivier Piguet6,  Markus Otto1 and Albert C. Ludolph1
  • 1Dept. of Neurology, University of Ulm, Germany
  • 2Department of Clinical Neurosciences, University of Cambridge, United Kingdom
  • 3Universitätsklinikum Leipzig, Germany
  • 4Department of Neurology, University of Pennsylvania School of Medicine, United States
  • 5University of New South Wales, Australia
  • 6Centre of Excellence in Cognition and its Disorders (ARC), Australia

Objective: Recently, the characteristic longitudinal distribution pattern of the underlying phosphorylated TDP-43 (pTDP-43) pathology in the behavioral variant of frontotemporal dementia (bvFTD) excluding Pick’s disease (PiD) across specific brain regions was described. The aim of the present study was to investigate whether in vivo investigations of bvFTD patients by use of diffusion tensor imaging (DTI) were consistent with these proposed patterns of progression.
Methods: Sixty-two bvFTD patients and 47 controls underwent DTI in a multicenter study design. Of these, 49 bvFTD patients and 34 controls had a follow-up scan after approximately 12 months. Cross-sectional and longitudinal alterations were assessed by a two-fold analysis, i.e., voxelwise comparison of fractional anisotropy (FA) maps and a tract of interest-based (TOI) approach, which identifies tract structures that could be assigned to brain regions associated with disease progression.
Results: Whole brain-based spatial statistics showed white matter alterations predominantly in the frontal lobes cross-sectionally and longitudinally. The TOIs of bvFTD neuroimaging stages 1 and 2 (uncinate fascicle – bvFTD pattern I; corticostriatal pathway – bvFTD pattern II) showed highly significant differences between bvFTD patients and controls. The corticospinal tract-associated TOI (bvFTD pattern III) did not differ between groups, whereas the differences in the optic radiation (bvFTD pattern IV) reached significance. The findings in the corticospinal tract were due to a ‘dichotomous’ behavior of FA changes there.
Conclusion: Longitudinal TOI analysis demonstrated a pattern of white matter pathways alterations consistent with patterns of pTDP-43 pathology.

Keywords: Frontotemporal Lobar Degeneration, Diffusion Tensor Imaging, fractional anisotropy, Neuropathology, staging.

Received: 12 Aug 2017; Accepted: 12 Feb 2018.

Edited by:

Changiz Geula, Northwestern University, United States

Reviewed by:

Arun Bokde, Trinity College, Dublin, Ireland
Ashish Raj, Weill Cornell Medical College, Cornell University, United States  

Copyright: © 2018 Kassubek, Müller, del Tredici, Hornberger, Schroeter, Müller, Anderl-Straub, Uttner, Grossman, Braak, Hodges, Piguet, Otto and Ludolph. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Jan Kassubek, University of Ulm, Dept. of Neurology, RKU, Oberer Eselsberg 45, Ulm, D-89081, Germany,