Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease

Daniel T. Ohm; Angela J. Fought; Alfred Rademaker; Garam Kim; Jaiashre Sridhar; Christina Coventry; Tamar Gefen; Sandra Weintraub; Eileen Bigio; Marek Marsel Mesulam; Emily Rogalski; Changiz Geula

doi:10.1111/bpa.12783

Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease

Daniel T. Ohm^*, Angela J. Fought, Alfred Rademaker, Garam Kim, Jaiashre Sridhar, Christina Coventry, Tamar Gefen, Sandra Weintraub, Eileen Bigio, Marek Marsel Mesulam, Emily Rogalski, Changiz Geula

^*Corresponding author for this work

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

13 Scopus citations

Abstract

The neuropathologic basis of in vivo cortical atrophy in clinical dementia syndromes remains poorly understood. This includes primary progressive aphasia (PPA), a language-based dementia syndrome characterized by asymmetric cortical atrophy. The neurofibrillary tangles (NFTs) and amyloid-ß plaques (APs) of Alzheimer's disease (AD) can cause PPA, but a quantitative investigation of the relationships between NFTs, APs and in vivo cortical atrophy in PPA-AD is lacking. The present study measured cortical atrophy from corresponding bilateral regions in five PPA-AD participants with in vivo magnetic resonance imaging scans 7–30 months before death and acquired stereologic estimates of NFTs and dense-core APs visualized with the Thioflavin-S stain. Linear mixed models accounting for repeated measures and stratified by hemisphere and region (language vs. non-language) were used to determine the relationships between cortical atrophy and AD neuropathology and their regional selectivity. Consistent with the aphasic profile of PPA, left language regions displayed more cortical atrophy (P = 0.01) and NFT densities (P = 0.02) compared to right language homologues. Left language regions also showed more cortical atrophy (P < 0.01) and NFT densities (P = 0.02) than left non-language regions. A subset of data was analyzed to determine the predilection of AD neuropathology for neocortical regions compared to entorhinal cortex in the left hemisphere, which showed that the three most atrophied language regions had greater NFT (P = 0.04) and AP densities (P < 0.01) than the entorhinal cortex. These results provide quantitative evidence that NFT accumulation in PPA selectively targets the language network and may not follow the Braak staging of neurofibrillary degeneration characteristic of amnestic AD. Only NFT densities, not AP densities, were positively associated with cortical atrophy within left language regions (P < 0.01) and right language homologues (P < 0.01). Given previous findings from amnestic AD, the current study of PPA-AD provides converging evidence that NFTs are the principal determinants of atrophy and clinical phenotypes associated with AD.

Original language	English (US)
Pages (from-to)	332-344
Number of pages	13
Journal	Brain Pathology
Volume	30
Issue number	2
DOIs	https://doi.org/10.1111/bpa.12783
State	Published - Mar 1 2020

Funding

We would like to thank the participants and their families for making this study possible. We are also grateful for the technical assistance provided by Adam Martersteck, Aneesha Nilakantan, PhD, Allison Rainford, Farzan Rahmani and Derin Cobia, PhD, as well as the assistance with data collection provided by Benjamin Rader, MS, and Mallory Ward, MS. This work was supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) (NS095652), NINDS (NS085770), NINDS (NS075075), National Institute on Aging (NIA) (T32 AG20506), NIA (AG056258), Northwestern Alzheimer's Disease Center (NIA, AG13854), National Institute on Deafness and Other Communication Disorders (NIDCD) (DC008552) and the Florane and Jerome Rosenstone Fellowship.

Keywords

Alzheimer's disease
amyloid-ß plaques
cortical atrophy
neurofibrillary tangles
primary progressive aphasia

ASJC Scopus subject areas

Clinical Neurology
General Neuroscience
Pathology and Forensic Medicine

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10.1111/bpa.12783

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title = "Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease",

abstract = "The neuropathologic basis of in vivo cortical atrophy in clinical dementia syndromes remains poorly understood. This includes primary progressive aphasia (PPA), a language-based dementia syndrome characterized by asymmetric cortical atrophy. The neurofibrillary tangles (NFTs) and amyloid-{\ss} plaques (APs) of Alzheimer's disease (AD) can cause PPA, but a quantitative investigation of the relationships between NFTs, APs and in vivo cortical atrophy in PPA-AD is lacking. The present study measured cortical atrophy from corresponding bilateral regions in five PPA-AD participants with in vivo magnetic resonance imaging scans 7–30 months before death and acquired stereologic estimates of NFTs and dense-core APs visualized with the Thioflavin-S stain. Linear mixed models accounting for repeated measures and stratified by hemisphere and region (language vs. non-language) were used to determine the relationships between cortical atrophy and AD neuropathology and their regional selectivity. Consistent with the aphasic profile of PPA, left language regions displayed more cortical atrophy (P = 0.01) and NFT densities (P = 0.02) compared to right language homologues. Left language regions also showed more cortical atrophy (P < 0.01) and NFT densities (P = 0.02) than left non-language regions. A subset of data was analyzed to determine the predilection of AD neuropathology for neocortical regions compared to entorhinal cortex in the left hemisphere, which showed that the three most atrophied language regions had greater NFT (P = 0.04) and AP densities (P < 0.01) than the entorhinal cortex. These results provide quantitative evidence that NFT accumulation in PPA selectively targets the language network and may not follow the Braak staging of neurofibrillary degeneration characteristic of amnestic AD. Only NFT densities, not AP densities, were positively associated with cortical atrophy within left language regions (P < 0.01) and right language homologues (P < 0.01). Given previous findings from amnestic AD, the current study of PPA-AD provides converging evidence that NFTs are the principal determinants of atrophy and clinical phenotypes associated with AD.",

keywords = "Alzheimer's disease, amyloid-{\ss} plaques, cortical atrophy, neurofibrillary tangles, primary progressive aphasia",

author = "Ohm, {Daniel T.} and Fought, {Angela J.} and Alfred Rademaker and Garam Kim and Jaiashre Sridhar and Christina Coventry and Tamar Gefen and Sandra Weintraub and Eileen Bigio and Mesulam, {Marek Marsel} and Emily Rogalski and Changiz Geula",

note = "Funding Information: We would like to thank the participants and their families for making this study possible. We are also grateful for the technical assistance provided by Adam Martersteck, Aneesha Nilakantan, PhD, Allison Rainford, Farzan Rahmani and Derin Cobia, PhD, as well as the assistance with data collection provided by Benjamin Rader, MS, and Mallory Ward, MS. This work was supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) (NS095652), NINDS (NS085770), NINDS (NS075075), National Institute on Aging (NIA) (T32 AG20506), NIA (AG056258), Northwestern Alzheimer's Disease Center (NIA, AG13854), National Institute on Deafness and Other Communication Disorders (NIDCD) (DC008552) and the Florane and Jerome Rosenstone Fellowship. Publisher Copyright: {\textcopyright} 2019 International Society of Neuropathology",

year = "2020",

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doi = "10.1111/bpa.12783",

language = "English (US)",

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T1 - Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease

AU - Ohm, Daniel T.

AU - Fought, Angela J.

AU - Rademaker, Alfred

AU - Kim, Garam

AU - Sridhar, Jaiashre

AU - Coventry, Christina

AU - Gefen, Tamar

AU - Weintraub, Sandra

AU - Bigio, Eileen

AU - Mesulam, Marek Marsel

AU - Rogalski, Emily

AU - Geula, Changiz

N1 - Funding Information: We would like to thank the participants and their families for making this study possible. We are also grateful for the technical assistance provided by Adam Martersteck, Aneesha Nilakantan, PhD, Allison Rainford, Farzan Rahmani and Derin Cobia, PhD, as well as the assistance with data collection provided by Benjamin Rader, MS, and Mallory Ward, MS. This work was supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) (NS095652), NINDS (NS085770), NINDS (NS075075), National Institute on Aging (NIA) (T32 AG20506), NIA (AG056258), Northwestern Alzheimer's Disease Center (NIA, AG13854), National Institute on Deafness and Other Communication Disorders (NIDCD) (DC008552) and the Florane and Jerome Rosenstone Fellowship. Publisher Copyright: © 2019 International Society of Neuropathology

PY - 2020/3/1

Y1 - 2020/3/1

N2 - The neuropathologic basis of in vivo cortical atrophy in clinical dementia syndromes remains poorly understood. This includes primary progressive aphasia (PPA), a language-based dementia syndrome characterized by asymmetric cortical atrophy. The neurofibrillary tangles (NFTs) and amyloid-ß plaques (APs) of Alzheimer's disease (AD) can cause PPA, but a quantitative investigation of the relationships between NFTs, APs and in vivo cortical atrophy in PPA-AD is lacking. The present study measured cortical atrophy from corresponding bilateral regions in five PPA-AD participants with in vivo magnetic resonance imaging scans 7–30 months before death and acquired stereologic estimates of NFTs and dense-core APs visualized with the Thioflavin-S stain. Linear mixed models accounting for repeated measures and stratified by hemisphere and region (language vs. non-language) were used to determine the relationships between cortical atrophy and AD neuropathology and their regional selectivity. Consistent with the aphasic profile of PPA, left language regions displayed more cortical atrophy (P = 0.01) and NFT densities (P = 0.02) compared to right language homologues. Left language regions also showed more cortical atrophy (P < 0.01) and NFT densities (P = 0.02) than left non-language regions. A subset of data was analyzed to determine the predilection of AD neuropathology for neocortical regions compared to entorhinal cortex in the left hemisphere, which showed that the three most atrophied language regions had greater NFT (P = 0.04) and AP densities (P < 0.01) than the entorhinal cortex. These results provide quantitative evidence that NFT accumulation in PPA selectively targets the language network and may not follow the Braak staging of neurofibrillary degeneration characteristic of amnestic AD. Only NFT densities, not AP densities, were positively associated with cortical atrophy within left language regions (P < 0.01) and right language homologues (P < 0.01). Given previous findings from amnestic AD, the current study of PPA-AD provides converging evidence that NFTs are the principal determinants of atrophy and clinical phenotypes associated with AD.

AB - The neuropathologic basis of in vivo cortical atrophy in clinical dementia syndromes remains poorly understood. This includes primary progressive aphasia (PPA), a language-based dementia syndrome characterized by asymmetric cortical atrophy. The neurofibrillary tangles (NFTs) and amyloid-ß plaques (APs) of Alzheimer's disease (AD) can cause PPA, but a quantitative investigation of the relationships between NFTs, APs and in vivo cortical atrophy in PPA-AD is lacking. The present study measured cortical atrophy from corresponding bilateral regions in five PPA-AD participants with in vivo magnetic resonance imaging scans 7–30 months before death and acquired stereologic estimates of NFTs and dense-core APs visualized with the Thioflavin-S stain. Linear mixed models accounting for repeated measures and stratified by hemisphere and region (language vs. non-language) were used to determine the relationships between cortical atrophy and AD neuropathology and their regional selectivity. Consistent with the aphasic profile of PPA, left language regions displayed more cortical atrophy (P = 0.01) and NFT densities (P = 0.02) compared to right language homologues. Left language regions also showed more cortical atrophy (P < 0.01) and NFT densities (P = 0.02) than left non-language regions. A subset of data was analyzed to determine the predilection of AD neuropathology for neocortical regions compared to entorhinal cortex in the left hemisphere, which showed that the three most atrophied language regions had greater NFT (P = 0.04) and AP densities (P < 0.01) than the entorhinal cortex. These results provide quantitative evidence that NFT accumulation in PPA selectively targets the language network and may not follow the Braak staging of neurofibrillary degeneration characteristic of amnestic AD. Only NFT densities, not AP densities, were positively associated with cortical atrophy within left language regions (P < 0.01) and right language homologues (P < 0.01). Given previous findings from amnestic AD, the current study of PPA-AD provides converging evidence that NFTs are the principal determinants of atrophy and clinical phenotypes associated with AD.

KW - Alzheimer's disease

KW - amyloid-ß plaques

KW - cortical atrophy

KW - neurofibrillary tangles

KW - primary progressive aphasia

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Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease

Abstract

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Keywords

ASJC Scopus subject areas

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