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 Matthews, Aimee W. Kao, Keith A. Vossel, Maria Carmela Tartaglia & 18 others Zachary 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 journalArticle

40 Citations (Scopus)

Abstract

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
JournalBrain
Volume140
Issue number12
DOIs
StatePublished - Dec 1 2017

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Frontotemporal Lobar Degeneration
Frontotemporal Dementia
Motor Neuron Disease
Atrophy
Pick Disease of the Brain
Tauopathies
Progressive Supranuclear Palsy
Chromosomes, Human, Pair 17
Gyrus Cinguli
Amyotrophic Lateral Sclerosis
Discriminant Analysis
Proteasome Endopeptidase Complex
Temporal Lobe
Ubiquitin
Amygdala
Neuroimaging
Neurodegenerative Diseases
Autopsy
Alzheimer Disease

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Perry, D. C., Brown, J. A., Possin, K. L., Datta, S., Trujillo, A., Radke, A., ... Seeley, W. W. (2017). Clinicopathological correlations in behavioural variant frontotemporal dementia. Brain, 140(12), 3329-3345. https://doi.org/10.1093/brain/awx254

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

In: Brain, Vol. 140, No. 12, 01.12.2017, p. 3329-3345.

Research output: Contribution to journalArticle

Perry, DC, Brown, JA, Possin, KL, Datta, S, Trujillo, A, Radke, A, Karydas, A, Kornak, J, Sias, AC, Rabinovici, GD, Gorno-Tempini, ML, Boxer, AL, De May, M, Rankin, KP, Sturm, VE, Lee, SE, Matthews, B, Kao, AW, Vossel, KA, Tartaglia, MC, Miller, ZA, Seo, SW, Sidhu, M, Gaus, SE, Nana, AL, Vargas, JNS, Hwang, JHL, Ossenkoppele, R, Brown, AB, Huang, EJ, Coppola, G, Rosen, HJ, Geschwind, D, Trojanowski, JQ, Grinberg, LT, Kramer, JH, Miller, BL & Seeley, WW 2017, 'Clinicopathological correlations in behavioural variant frontotemporal dementia', Brain, vol. 140, no. 12, pp. 3329-3345. https://doi.org/10.1093/brain/awx254
Perry DC, Brown JA, Possin KL, Datta S, Trujillo A, Radke A et al. Clinicopathological correlations in behavioural variant frontotemporal dementia. Brain. 2017 Dec 1;140(12):3329-3345. https://doi.org/10.1093/brain/awx254
Perry, David C. ; Brown, Jesse A. ; Possin, Katherine L. ; Datta, Samir ; Trujillo, Andrew ; Radke, Anneliese ; Karydas, Anna ; Kornak, John ; Sias, Ana C. ; Rabinovici, Gil D. ; Gorno-Tempini, Maria Luisa ; Boxer, Adam L. ; De May, Mary ; Rankin, Katherine P. ; Sturm, Virginia E. ; Lee, Suzee E. ; Matthews, Brandy ; Kao, Aimee W. ; Vossel, Keith A. ; Tartaglia, Maria Carmela ; Miller, Zachary A. ; Seo, Sang Won ; Sidhu, Manu ; Gaus, Stephanie E. ; Nana, Alissa L. ; Vargas, Jose Norberto S. ; Hwang, Ji Hye L. ; Ossenkoppele, Rik ; Brown, Alainna B. ; Huang, Eric J. ; Coppola, Giovanni ; Rosen, Howard J. ; Geschwind, Daniel ; Trojanowski, John Q. ; Grinberg, Lea T. ; Kramer, Joel H. ; Miller, Bruce L. ; Seeley, William W. / Clinicopathological correlations in behavioural variant frontotemporal dementia. In: Brain. 2017 ; Vol. 140, No. 12. pp. 3329-3345.
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abstract = "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.",
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AU - Brown, Jesse A.

AU - Possin, Katherine L.

AU - Datta, Samir

AU - Trujillo, Andrew

AU - Radke, Anneliese

AU - Karydas, Anna

AU - Kornak, John

AU - Sias, Ana C.

AU - Rabinovici, Gil D.

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AU - Boxer, Adam L.

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AU - Brown, Alainna B.

AU - Huang, Eric J.

AU - Coppola, Giovanni

AU - Rosen, Howard J.

AU - Geschwind, Daniel

AU - Trojanowski, John Q.

AU - Grinberg, Lea T.

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