Combined pathologies in FTLD-TDP types A and C

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

doi:10.1093/jnen/nly018

Combined pathologies in FTLD-TDP types A and C

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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 language	English (US)
Pages (from-to)	405-412
Number of pages	8
Journal	Journal of neuropathology and experimental neurology
Volume	77
Issue number	5
DOIs	https://doi.org/10.1093/jnen/nly018
State	Published - May 1 2018

Funding

This work was supported by grants from the National Institute of Neurological Disorders and Stroke (NS085770; NS097261), National Institute on Aging (AG045571; T32 AG20506), the John Douglas French Alzheimer's Foundation, the Northwestern University Alzheimer's Disease Center (AG13854), The Davee Foundation, and the Florane and Jerome Rosenstone Fellowship Send correspondence to: Tamar Gefen, PhD, Northwestern University, Cog-nitive Neurology and Alzheimer’s Disease Center (CNADC), 320 E. Su-perior Street, Searle Building 11th Floor, Chicago, IL 60611; E-mail: [email protected] This work was supported by grants from the National Institute of Neurologi-cal Disorders and Stroke (NS085770; NS097261), National Institute on Aging (AG045571; T32 AG20506), the John Douglas French Alzheim-er’s Foundation, the Northwestern University Alzheimer’s Disease Cen-ter (AG13854), The Davee Foundation, and the Florane and Jerome Rosenstone Fellowship The authors have no duality or conflicts of interest to declare.

Keywords

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

ASJC Scopus subject areas

General Medicine

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10.1093/jnen/nly018

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.",

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author = "Tamar Gefen 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 Alfred Rademaker and Sandra Weintraub and Mesulam, {M. Marsel} and Changiz Geula and Bigio, {Eileen H.}",

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doi = "10.1093/jnen/nly018",

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

AU - Gefen, Tamar

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

AU - Weintraub, Sandra

AU - Mesulam, M. 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.

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KW - Frontotemporal lobar degeneration

KW - Neuropathology

KW - Primary progressive aphasia

KW - TDP-43

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ER -

Combined pathologies in FTLD-TDP types A and C

Abstract

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Keywords

ASJC Scopus subject areas

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