Combined pathologies in FTLD-TDP types A and C

Tamar Devora Gefen*, Saman S. Ahmadian, Qinwen Mao, Garam Kim, Mustafa Seckin, Borna Bonakdarpour, Eliana Marisa Ramos, Giovanni Coppola, Rosa Rademakers, Emily Rogalski, Alfred W Rademaker, Sandra Weintraub, Marek-Marsel Mesulam, Changiz Geula, Eileen H Bigio

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

This study investigated the presence of combined pathologies in a large cohort of autopsies that show a primary pathologic diagnosis of phosphorylated 43-kDa TAR DNA-binding protein (FTLD-TDP), the majority of which portrayed clinical phenotypes consistent with primary progressive aphasia or behavioral variant frontotemporal dementia (bvFTD). Thirty-eight cases with FTLD-TDP (30 type-A and 8 type-C) were identified to determine characteristic differences between cases with and without combined pathologies. Findings indicated that combined pathologies co-occur with FTLD-TDP type-A at a high frequency (50%)-greater than when compared to FTLDTDP type-C cases (12.5%). Those with FTLD-TDP type-A and combined pathologies showed significantly longer lifespans (p < 0.05), and longer disease durations (p < 0.05), than those with only FTLDTDP type-A. Cases with FTLD-TDP type-A and known genetic mutations tended not to show combined pathology. Those with the GRN mutation and FTLD-TDP type-A showed a significantly younger age of onset (p < 0.05) and younger age at death (p < 0.01) compared to noncarriers. In 1 bvFTD case, we highlight the rare presence of "triple" FTLD-TDP type-A, FTLD-tau, and Alzheimer pathology. The ante- and post-mortem features associated with combined pathologies in FTLD-related disorders are of useful consideration in the stratification of patients to drug trials, and in the development of therapeutic targets for FTLD.

Original languageEnglish (US)
Pages (from-to)405-412
Number of pages8
JournalJournal of neuropathology and experimental neurology
Volume77
Issue number5
DOIs
StatePublished - May 1 2018

Fingerprint

Frontotemporal Dementia
Pathology
Frontotemporal Lobar Degeneration
Primary Progressive Aphasia
Mutation
DNA-Binding Proteins
Age of Onset
Autopsy
Phenotype

Keywords

  • Frontotemporal dementia
  • Frontotemporal lobar degeneration
  • Neuropathology
  • Primary progressive aphasia
  • TDP-43

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

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title = "Combined pathologies in FTLD-TDP types A and C",
abstract = "This study investigated the presence of combined pathologies in a large cohort of autopsies that show a primary pathologic diagnosis of phosphorylated 43-kDa TAR DNA-binding protein (FTLD-TDP), the majority of which portrayed clinical phenotypes consistent with primary progressive aphasia or behavioral variant frontotemporal dementia (bvFTD). Thirty-eight cases with FTLD-TDP (30 type-A and 8 type-C) were identified to determine characteristic differences between cases with and without combined pathologies. Findings indicated that combined pathologies co-occur with FTLD-TDP type-A at a high frequency (50{\%})-greater than when compared to FTLDTDP type-C cases (12.5{\%}). Those with FTLD-TDP type-A and combined pathologies showed significantly longer lifespans (p < 0.05), and longer disease durations (p < 0.05), than those with only FTLDTDP type-A. Cases with FTLD-TDP type-A and known genetic mutations tended not to show combined pathology. Those with the GRN mutation and FTLD-TDP type-A showed a significantly younger age of onset (p < 0.05) and younger age at death (p < 0.01) compared to noncarriers. In 1 bvFTD case, we highlight the rare presence of {"}triple{"} FTLD-TDP type-A, FTLD-tau, and Alzheimer pathology. The ante- and post-mortem features associated with combined pathologies in FTLD-related disorders are of useful consideration in the stratification of patients to drug trials, and in the development of therapeutic targets for FTLD.",
keywords = "Frontotemporal dementia, Frontotemporal lobar degeneration, Neuropathology, Primary progressive aphasia, TDP-43",
author = "Gefen, {Tamar Devora} and Ahmadian, {Saman S.} and Qinwen Mao and Garam Kim and Mustafa Seckin and Borna Bonakdarpour and Ramos, {Eliana Marisa} and Giovanni Coppola and Rosa Rademakers and Emily Rogalski and Rademaker, {Alfred W} and Sandra Weintraub and Marek-Marsel Mesulam and Changiz Geula and Bigio, {Eileen H}",
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Combined pathologies in FTLD-TDP types A and C. / Gefen, Tamar Devora; Ahmadian, Saman S.; Mao, Qinwen; Kim, Garam; Seckin, Mustafa; Bonakdarpour, Borna; Ramos, Eliana Marisa; Coppola, Giovanni; Rademakers, Rosa; Rogalski, Emily; Rademaker, Alfred W; Weintraub, Sandra; Mesulam, Marek-Marsel; Geula, Changiz; Bigio, Eileen H.

In: Journal of neuropathology and experimental neurology, Vol. 77, No. 5, 01.05.2018, p. 405-412.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Combined pathologies in FTLD-TDP types A and C

AU - Gefen, Tamar Devora

AU - Ahmadian, Saman S.

AU - Mao, Qinwen

AU - Kim, Garam

AU - Seckin, Mustafa

AU - Bonakdarpour, Borna

AU - Ramos, Eliana Marisa

AU - Coppola, Giovanni

AU - Rademakers, Rosa

AU - Rogalski, Emily

AU - Rademaker, Alfred W

AU - Weintraub, Sandra

AU - Mesulam, Marek-Marsel

AU - Geula, Changiz

AU - Bigio, Eileen H

PY - 2018/5/1

Y1 - 2018/5/1

N2 - This study investigated the presence of combined pathologies in a large cohort of autopsies that show a primary pathologic diagnosis of phosphorylated 43-kDa TAR DNA-binding protein (FTLD-TDP), the majority of which portrayed clinical phenotypes consistent with primary progressive aphasia or behavioral variant frontotemporal dementia (bvFTD). Thirty-eight cases with FTLD-TDP (30 type-A and 8 type-C) were identified to determine characteristic differences between cases with and without combined pathologies. Findings indicated that combined pathologies co-occur with FTLD-TDP type-A at a high frequency (50%)-greater than when compared to FTLDTDP type-C cases (12.5%). Those with FTLD-TDP type-A and combined pathologies showed significantly longer lifespans (p < 0.05), and longer disease durations (p < 0.05), than those with only FTLDTDP type-A. Cases with FTLD-TDP type-A and known genetic mutations tended not to show combined pathology. Those with the GRN mutation and FTLD-TDP type-A showed a significantly younger age of onset (p < 0.05) and younger age at death (p < 0.01) compared to noncarriers. In 1 bvFTD case, we highlight the rare presence of "triple" FTLD-TDP type-A, FTLD-tau, and Alzheimer pathology. The ante- and post-mortem features associated with combined pathologies in FTLD-related disorders are of useful consideration in the stratification of patients to drug trials, and in the development of therapeutic targets for FTLD.

AB - This study investigated the presence of combined pathologies in a large cohort of autopsies that show a primary pathologic diagnosis of phosphorylated 43-kDa TAR DNA-binding protein (FTLD-TDP), the majority of which portrayed clinical phenotypes consistent with primary progressive aphasia or behavioral variant frontotemporal dementia (bvFTD). Thirty-eight cases with FTLD-TDP (30 type-A and 8 type-C) were identified to determine characteristic differences between cases with and without combined pathologies. Findings indicated that combined pathologies co-occur with FTLD-TDP type-A at a high frequency (50%)-greater than when compared to FTLDTDP type-C cases (12.5%). Those with FTLD-TDP type-A and combined pathologies showed significantly longer lifespans (p < 0.05), and longer disease durations (p < 0.05), than those with only FTLDTDP type-A. Cases with FTLD-TDP type-A and known genetic mutations tended not to show combined pathology. Those with the GRN mutation and FTLD-TDP type-A showed a significantly younger age of onset (p < 0.05) and younger age at death (p < 0.01) compared to noncarriers. In 1 bvFTD case, we highlight the rare presence of "triple" FTLD-TDP type-A, FTLD-tau, and Alzheimer pathology. The ante- and post-mortem features associated with combined pathologies in FTLD-related disorders are of useful consideration in the stratification of patients to drug trials, and in the development of therapeutic targets for FTLD.

KW - Frontotemporal dementia

KW - Frontotemporal lobar degeneration

KW - Neuropathology

KW - Primary progressive aphasia

KW - TDP-43

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U2 - 10.1093/jnen/nly018

DO - 10.1093/jnen/nly018

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