Morphology and Distribution of TDP-43 Pre-inclusions in Primary Progressive Aphasia

Garam Kim, Kabriya Bolbolan, Ryan Shahidehpour, Pouya Jamshidi, Tamar Devora Gefen, Ivan A. Ayala, Sandra Weintraub, Eileen H Bigio, Marek-Marsel Mesulam, Changiz Geula*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

This work was supported by grants from the National Institute of Neurological Disorders and Stroke (NS085770), National Institute on Deafness and Other Communication Disorders (DC008552), the Louis Family Foundation, Alzheimer's Disease Center Grant from the National Institute on Aging (AG013854), National Institute on Aging (T32 AG20506), and the Florane and Jerome Rosenstone Fellowship.

Diffusely stained phosphorylated 43-kDa TAR DNA-binding protein (TDP-43)-positive “pre-inclusions” have been described. This experiment investigated morphological subtypes of pre-inclusions and their relationship with TDP-43 inclusions in primary progressive aphasia (PPA), a dementia characterized by gradual dissolution of language. Brain sections from 5 PPA participants with postmortem diagnoses of frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) were immunohistochemically stained using an antibody to phosphorylated TDP-43 and quantitatively examined for regional and hemispheric distribution using unbiased stereology. Cortical TDP-43 pre-inclusions included smooth, granular/dot-like, or fibrillar staining with localization to the nucleus, cytoplasm, or both. Mature and pre-inclusions were quantified in a region with high and a region with low mature inclusion density, and contralateral homologs. Regions with lower mature inclusions were characterized by higher densities of pre-inclusions, while increasing burden of inclusions corresponded to lower densities of pre-inclusions (p < 0.05). Mature inclusions showed significant asymmetry that favored the language-dominant hemisphere (p < 0.01), while pre-inclusions displayed the opposite pattern (p < 0.01). Granular-type pre-inclusions were more abundant (p < 0.05) and drove the hemispheric and regional differences (p < 0.02). These results suggest that pre-inclusions are present in greater abundance prior to the formation of mature TDP-43 inclusions, and appear to develop through progressive stages into mature intracytoplasmic, or intranuclear aggregates.

Original languageEnglish (US)
Pages (from-to)229-237
Number of pages9
JournalJournal of neuropathology and experimental neurology
Volume78
Issue number3
DOIs
StatePublished - Mar 1 2019

Fingerprint

National Institute on Aging (U.S.)
Primary Progressive Aphasia
National Institute on Deafness and Other Communication Disorders (U.S.)
Language
National Institute of Neurological Disorders and Stroke
Frontotemporal Lobar Degeneration
Organized Financing
DNA-Binding Proteins
Dementia
Alzheimer Disease
Cytoplasm
Pathology
Staining and Labeling
Antibodies
Brain

Keywords

  • Frontotemporal dementia
  • Frontotemporal lobar degeneration
  • Neurodegeneration
  • Primary progressive aphasia
  • Protei-nopathies
  • TDP-43

ASJC Scopus subject areas

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

Cite this

@article{acce390ef5a74f32abae76e479a3e3ac,
title = "Morphology and Distribution of TDP-43 Pre-inclusions in Primary Progressive Aphasia",
abstract = "This work was supported by grants from the National Institute of Neurological Disorders and Stroke (NS085770), National Institute on Deafness and Other Communication Disorders (DC008552), the Louis Family Foundation, Alzheimer's Disease Center Grant from the National Institute on Aging (AG013854), National Institute on Aging (T32 AG20506), and the Florane and Jerome Rosenstone Fellowship.Diffusely stained phosphorylated 43-kDa TAR DNA-binding protein (TDP-43)-positive “pre-inclusions” have been described. This experiment investigated morphological subtypes of pre-inclusions and their relationship with TDP-43 inclusions in primary progressive aphasia (PPA), a dementia characterized by gradual dissolution of language. Brain sections from 5 PPA participants with postmortem diagnoses of frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) were immunohistochemically stained using an antibody to phosphorylated TDP-43 and quantitatively examined for regional and hemispheric distribution using unbiased stereology. Cortical TDP-43 pre-inclusions included smooth, granular/dot-like, or fibrillar staining with localization to the nucleus, cytoplasm, or both. Mature and pre-inclusions were quantified in a region with high and a region with low mature inclusion density, and contralateral homologs. Regions with lower mature inclusions were characterized by higher densities of pre-inclusions, while increasing burden of inclusions corresponded to lower densities of pre-inclusions (p < 0.05). Mature inclusions showed significant asymmetry that favored the language-dominant hemisphere (p < 0.01), while pre-inclusions displayed the opposite pattern (p < 0.01). Granular-type pre-inclusions were more abundant (p < 0.05) and drove the hemispheric and regional differences (p < 0.02). These results suggest that pre-inclusions are present in greater abundance prior to the formation of mature TDP-43 inclusions, and appear to develop through progressive stages into mature intracytoplasmic, or intranuclear aggregates.",
keywords = "Frontotemporal dementia, Frontotemporal lobar degeneration, Neurodegeneration, Primary progressive aphasia, Protei-nopathies, TDP-43",
author = "Garam Kim and Kabriya Bolbolan and Ryan Shahidehpour and Pouya Jamshidi and Gefen, {Tamar Devora} and Ayala, {Ivan A.} and Sandra Weintraub and Bigio, {Eileen H} and Marek-Marsel Mesulam and Changiz Geula",
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Morphology and Distribution of TDP-43 Pre-inclusions in Primary Progressive Aphasia. / Kim, Garam; Bolbolan, Kabriya; Shahidehpour, Ryan; Jamshidi, Pouya; Gefen, Tamar Devora; Ayala, Ivan A.; Weintraub, Sandra; Bigio, Eileen H; Mesulam, Marek-Marsel; Geula, Changiz.

In: Journal of neuropathology and experimental neurology, Vol. 78, No. 3, 01.03.2019, p. 229-237.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Morphology and Distribution of TDP-43 Pre-inclusions in Primary Progressive Aphasia

AU - Kim, Garam

AU - Bolbolan, Kabriya

AU - Shahidehpour, Ryan

AU - Jamshidi, Pouya

AU - Gefen, Tamar Devora

AU - Ayala, Ivan A.

AU - Weintraub, Sandra

AU - Bigio, Eileen H

AU - Mesulam, Marek-Marsel

AU - Geula, Changiz

PY - 2019/3/1

Y1 - 2019/3/1

N2 - This work was supported by grants from the National Institute of Neurological Disorders and Stroke (NS085770), National Institute on Deafness and Other Communication Disorders (DC008552), the Louis Family Foundation, Alzheimer's Disease Center Grant from the National Institute on Aging (AG013854), National Institute on Aging (T32 AG20506), and the Florane and Jerome Rosenstone Fellowship.Diffusely stained phosphorylated 43-kDa TAR DNA-binding protein (TDP-43)-positive “pre-inclusions” have been described. This experiment investigated morphological subtypes of pre-inclusions and their relationship with TDP-43 inclusions in primary progressive aphasia (PPA), a dementia characterized by gradual dissolution of language. Brain sections from 5 PPA participants with postmortem diagnoses of frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) were immunohistochemically stained using an antibody to phosphorylated TDP-43 and quantitatively examined for regional and hemispheric distribution using unbiased stereology. Cortical TDP-43 pre-inclusions included smooth, granular/dot-like, or fibrillar staining with localization to the nucleus, cytoplasm, or both. Mature and pre-inclusions were quantified in a region with high and a region with low mature inclusion density, and contralateral homologs. Regions with lower mature inclusions were characterized by higher densities of pre-inclusions, while increasing burden of inclusions corresponded to lower densities of pre-inclusions (p < 0.05). Mature inclusions showed significant asymmetry that favored the language-dominant hemisphere (p < 0.01), while pre-inclusions displayed the opposite pattern (p < 0.01). Granular-type pre-inclusions were more abundant (p < 0.05) and drove the hemispheric and regional differences (p < 0.02). These results suggest that pre-inclusions are present in greater abundance prior to the formation of mature TDP-43 inclusions, and appear to develop through progressive stages into mature intracytoplasmic, or intranuclear aggregates.

AB - This work was supported by grants from the National Institute of Neurological Disorders and Stroke (NS085770), National Institute on Deafness and Other Communication Disorders (DC008552), the Louis Family Foundation, Alzheimer's Disease Center Grant from the National Institute on Aging (AG013854), National Institute on Aging (T32 AG20506), and the Florane and Jerome Rosenstone Fellowship.Diffusely stained phosphorylated 43-kDa TAR DNA-binding protein (TDP-43)-positive “pre-inclusions” have been described. This experiment investigated morphological subtypes of pre-inclusions and their relationship with TDP-43 inclusions in primary progressive aphasia (PPA), a dementia characterized by gradual dissolution of language. Brain sections from 5 PPA participants with postmortem diagnoses of frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) were immunohistochemically stained using an antibody to phosphorylated TDP-43 and quantitatively examined for regional and hemispheric distribution using unbiased stereology. Cortical TDP-43 pre-inclusions included smooth, granular/dot-like, or fibrillar staining with localization to the nucleus, cytoplasm, or both. Mature and pre-inclusions were quantified in a region with high and a region with low mature inclusion density, and contralateral homologs. Regions with lower mature inclusions were characterized by higher densities of pre-inclusions, while increasing burden of inclusions corresponded to lower densities of pre-inclusions (p < 0.05). Mature inclusions showed significant asymmetry that favored the language-dominant hemisphere (p < 0.01), while pre-inclusions displayed the opposite pattern (p < 0.01). Granular-type pre-inclusions were more abundant (p < 0.05) and drove the hemispheric and regional differences (p < 0.02). These results suggest that pre-inclusions are present in greater abundance prior to the formation of mature TDP-43 inclusions, and appear to develop through progressive stages into mature intracytoplasmic, or intranuclear aggregates.

KW - Frontotemporal dementia

KW - Frontotemporal lobar degeneration

KW - Neurodegeneration

KW - Primary progressive aphasia

KW - Protei-nopathies

KW - TDP-43

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