title: White matter imaging helps dissociate tau from TDP-43 in frontotemporal lobar degeneration.
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-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.
authors.affiliation: Department of Neurology, Perelman School of Medicine, Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. mcmillac@mail.med.upenn.edu
authors.forename: Corey T
authors.initials: CT
authors.lastname: McMillan
authors.forename: David J
authors.initials: DJ
authors.lastname: Irwin
authors.forename: Brian B
authors.initials: BB
authors.lastname: Avants
authors.forename: John
authors.initials: J
authors.lastname: Powers
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cook
authors.forename: Jon B
authors.initials: JB
authors.lastname: Toledo
authors.forename: Elisabeth
authors.initials: E
authors.lastname: McCarty Wood
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
mesh_terms: D000368:Aged; D016880:Anisotropy; D001344:Autopsy; D001921:Brain / Q000473:pathology*; D015331:Cohort Studies; D003337:Corpus Callosum / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003937:Diagnosis, Differential; D056324:Diffusion Tensor Imaging; D004522:Educational Status; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000175:diagnosis / Q000473:pathology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D009483:Neuropsychological Tests; D012372:ROC Curve; D057177:TDP-43 Proteinopathies / Q000378:metabolism* / Q000473:pathology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D016875:tau Proteins
keywords: Brain Mapping; Dementia; Neuropathology