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Research paper
White matter imaging helps dissociate tau from TDP-43 in frontotemporal lobar degeneration
  1. Corey T McMillan1,
  2. David J Irwin1,2,
  3. Brian B Avants3,
  4. John Powers1,
  5. Philip A Cook3,
  6. Jon B Toledo2,
  7. Elisabeth McCarty Wood2,
  8. Vivianna M Van Deerlin2,
  9. Virginia M-Y Lee2,
  10. John Q Trojanowski2,
  11. Murray Grossman1
  1. 1Department of Neurology, Perelman School of Medicine, Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  2. 2Department of Pathology & Laboratory Medicine, Perelman School of Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  3. 3Department of Radiology, Penn Imaging and Computing Science Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  1. Correspondence to Dr Corey T McMillan, Department of Neurology, Perelman School of Medicine, Frontotemporal Degeneration Center, University of Pennsylvania, 3400 Spruce Street, 3 West Gates, Philadelphia, PA 19104, USA; mcmillac{at}


Background Frontotemporal lobar degeneration (FTLD) is most commonly associated with TAR-DNA binding protein (TDP-43) or tau pathology at autopsy, but there are no in vivo biomarkers reliably discriminating between sporadic cases. As disease-modifying treatments emerge, it is critical to accurately identify underlying pathology in living patients so that they can be entered into appropriate etiology-directed clinical trials. Patients with tau inclusions (FTLD-TAU) appear to have relatively greater white matter (WM) disease at autopsy than those patients with TDP-43 (FTLD-TDP). In this paper, we investigate the ability of white matter (WM) imaging to help discriminate between FTLD-TAU and FTLD-TDP during life using diffusion tensor imaging (DTI).

Methods Patients with autopsy-confirmed disease or a genetic mutation consistent with FTLD-TDP or FTLD-TAU underwent multimodal T1 volumetric MRI and diffusion weighted imaging scans. We quantified cortical thickness in GM and fractional anisotropy (FA) in WM. We performed Eigenanatomy, a statistically robust dimensionality reduction algorithm, and used leave-one-out cross-validation to predict underlying pathology. Neuropathological assessment of GM and WM disease burden was performed in the autopsy-cases to confirm our findings of an ante-mortem GM and WM dissociation in the neuroimaging cohort.

Results ROC curve analyses evaluated classification accuracy in individual patients and revealed 96% sensitivity and 100% specificity for WM analyses. FTLD-TAU had significantly more WM degeneration and inclusion severity at autopsy relative to FTLD-TDP.

Conclusions These neuroimaging and neuropathological investigations provide converging evidence for greater WM burden associated with FTLD-TAU, and emphasise the role of WM neuroimaging for in vivo discrimination between FTLD-TAU and FTLD-TDP.

  • Dementia
  • Brain Mapping
  • Neuropathology

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