White matter imaging helps dissociate tau from TDP-43 in frontotemporal lobar degeneration

Corey T. McMillan, David J. Irwin, Brian B. Avants, John Powers, Philip A. Cook, Jon B. Toledo, Elisabeth Mc Carty Wood, Vivianna M. Van Deerlin, Virginia M.Y. Lee, John Q. Trojanowski, Murray Grossman

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

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-oneout 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. FTLDTAU 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 FTLDTAU, and emphasise the role of WM neuroimaging for in vivo discrimination between FTLD-TAU and FTLD-TDP.

Original languageEnglish (US)
Pages (from-to)949-955
Number of pages7
JournalJournal of Neurology, Neurosurgery and Psychiatry
Volume84
Issue number9
DOIs
StatePublished - Sep 2013

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology
  • Psychiatry and Mental health

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