Clinicopathological correlations in behavioural variant frontotemporal dementia

David C. Perry, Jesse A. Brown, Katherine L. Possin, Samir Datta, Andrew Trujillo, Anneliese Radke, Anna Karydas, John Kornak, Ana C. Sias, Gil D. Rabinovici, Maria Luisa Gorno-Tempini, Adam L. Boxer, Mary De May, Katherine P. Rankin, Virginia E. Sturm, Suzee E. Lee, Brandy R. Matthews, Aimee W. Kao, Keith A. Vossel, Maria Carmela TartagliaZachary A. Miller, Sang Won Seo, Manu Sidhu, Stephanie E. Gaus, Alissa L. Nana, Jose Norberto S. Vargas, Ji Hye L. Hwang, Rik Ossenkoppele, Alainna B. Brown, Eric J. Huang, Giovanni Coppola, Howard J. Rosen, Daniel Geschwind, John Q. Trojanowski, Lea T. Grinberg, Joel H. Kramer, Bruce L. Miller, William W. Seeley

Research output: Contribution to journalArticlepeer-review

217 Scopus citations


Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer's disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least 'possible' bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual patients share atrophy in anterior cingulate, frontoinsula, striatum, and amygdala, indicating that degeneration of these regions is intimately linked to the behavioural syndrome produced by these diverse aetiologies. In addition to these unifying features, symptom profiles also differed among pathological subtypes, suggesting distinct anatomical vulnerabilities and informing a clinician's prediction of pathological diagnosis. Data-driven classification into one of the 10 most common pathological diagnoses was most accurate (up to 60.2%) when using a combination of known predictive factors (genetic mutations, motor features, or striking atrophy patterns) and the results of a discriminant function analysis that incorporated clinical, neuroimaging, and neuropsychological data.

Original languageEnglish (US)
Pages (from-to)3329-3345
Number of pages17
Issue number12
StatePublished - Dec 1 2017

Bibliographical note

Funding Information:
This study was supported by grants P01AG019724 (B.L.M.), P50AG023501 (B.L.M.), P30AG10124 (J.Q.T.), P01AG17856 (V.M.-Y.L.) and K23AG045289 (D.C.P.), U54NS092089 (A.L.B.), R01AG038791 (A.L.B.) from the NIH National Institutes of Health, as well as the Tau Consortium, the Consortium for Frontotemporal Dementia Research, the Marie Curie FP7 International Outgoing Fellowship [628812] (R.O.) and the donors of Alzheimer’s Disease Research, a program of BrightFocus Foundation (R.O.).

Publisher Copyright:
© 2017 The Author. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.


  • Alzheimer's disease
  • Pick's disease
  • corticobasal degeneration
  • frontotemporal dementia
  • frontotemporal lobar degeneration


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