A molecular pathology, neurobiology, biochemical, genetic and neuroimaging study of progressive apraxia of speech

Keith A. Josephs; Joseph R. Duffy; Heather M. Clark; Rene L. Utianski; Edythe A. Strand; Mary M. Machulda; Hugo Botha; Peter R. Martin; Nha Trang Thu Pham; Julie Stierwalt; Farwa Ali; Marina Buciuc; Matthew Baker; Cristhoper H. Fernandez De Castro; Anthony J. Spychalla; Christopher G. Schwarz; Robert I. Reid; Matthew L. Senjem; Clifford R. Jack; Val J. Lowe; Eileen H. Bigio; Ross R. Reichard; Eric J. Polley; Nilufer Ertekin-Taner; Rosa Rademakers; Michael A. DeTure; Owen A. Ross; Dennis W. Dickson; Jennifer L. Whitwell

doi:10.1038/s41467-021-23687-8

A molecular pathology, neurobiology, biochemical, genetic and neuroimaging study of progressive apraxia of speech

Keith A. Josephs^*, Joseph R. Duffy, Heather M. Clark, Rene L. Utianski, Edythe A. Strand, Mary M. Machulda, Hugo Botha, Peter R. Martin, Nha Trang Thu Pham, Julie Stierwalt, Farwa Ali, Marina Buciuc, Matthew Baker, Cristhoper H. Fernandez De Castro, Anthony J. Spychalla, Christopher G. Schwarz, Robert I. Reid, Matthew L. Senjem, Clifford R. Jack, Val J. LoweEileen H. Bigio, Ross R. Reichard, Eric J. Polley, Nilufer Ertekin-Taner, Rosa Rademakers, Michael A. DeTure, Owen A. Ross, Dennis W. Dickson, Jennifer L. Whitwell

^*Corresponding author for this work

Pathology

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42 Scopus citations

Abstract

Progressive apraxia of speech is a neurodegenerative syndrome affecting spoken communication. Molecular pathology, biochemistry, genetics, and longitudinal imaging were investigated in 32 autopsy-confirmed patients with progressive apraxia of speech who were followed over 10 years. Corticobasal degeneration and progressive supranuclear palsy (4R-tauopathies) were the most common underlying pathologies. Perceptually distinct speech characteristics, combined with age-at-onset, predicted specific 4R-tauopathy; phonetic subtype and younger age predicted corticobasal degeneration, and prosodic subtype and older age predicted progressive supranuclear palsy. Phonetic and prosodic subtypes showed differing relationships within the cortico-striato-pallido-nigro-luysial network. Biochemical analysis revealed no distinct differences in aggregated 4R-tau while tau H1 haplotype frequency (69%) was lower compared to 1000+ autopsy-confirmed 4R-tauopathies. Corticobasal degeneration patients had faster rates of decline, greater cortical degeneration, and shorter illness duration than progressive supranuclear palsy. These findings help define the pathobiology of progressive apraxia of speech and may have consequences for development of 4R-tau targeting treatment.

Original language	English (US)
Article number	3452
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23687-8
State	Published - Dec 1 2021

Funding

C.R.J. serves on an independent data monitoring board for Roche, has consulted for and served as a speaker for Eisai, and consulted for Biogen, but he receives no personal compensation from any commercial entity. V.J.L. is a consultant for AVID Radiopharmaceuticals, Eisai Co. Inc., Bayer Schering Pharma, GE Healthcare, and Merck Research, and receives research support from GE Healthcare, Siemens Molecular Imaging, and AVID Radiopharmaceuticals. M.L.S. owns stocks in Align Technology, Inc., Inovio Pharmaceuticals Inc., LHC Group, Inc., Mesa Laboratories, Inc., Natus Medical Inc., and Varex Imaging Corporation. All other authors declare no competing interests. We wish to thank Kris Johnson, Linda Rousseau, Virginia Phillips, and Monica Casey-Castanedes for pathological support. This study was funded by the National Institutes of Health, grants R01-DC12519, R01-DC010367, R01-DC14942, R01-NS89757, and UL1TR002377.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Josephs, K. A., Duffy, J. R., Clark, H. M., Utianski, R. L., Strand, E. A., Machulda, M. M., Botha, H., Martin, P. R., Pham, N. T. T., Stierwalt, J., Ali, F., Buciuc, M., Baker, M., Fernandez De Castro, C. H., Spychalla, A. J., Schwarz, C. G., Reid, R. I., Senjem, M. L., Jack, C. R., ... Whitwell, J. L. (2021). A molecular pathology, neurobiology, biochemical, genetic and neuroimaging study of progressive apraxia of speech. Nature communications, 12(1), Article 3452. https://doi.org/10.1038/s41467-021-23687-8

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title = "A molecular pathology, neurobiology, biochemical, genetic and neuroimaging study of progressive apraxia of speech",

abstract = "Progressive apraxia of speech is a neurodegenerative syndrome affecting spoken communication. Molecular pathology, biochemistry, genetics, and longitudinal imaging were investigated in 32 autopsy-confirmed patients with progressive apraxia of speech who were followed over 10 years. Corticobasal degeneration and progressive supranuclear palsy (4R-tauopathies) were the most common underlying pathologies. Perceptually distinct speech characteristics, combined with age-at-onset, predicted specific 4R-tauopathy; phonetic subtype and younger age predicted corticobasal degeneration, and prosodic subtype and older age predicted progressive supranuclear palsy. Phonetic and prosodic subtypes showed differing relationships within the cortico-striato-pallido-nigro-luysial network. Biochemical analysis revealed no distinct differences in aggregated 4R-tau while tau H1 haplotype frequency (69%) was lower compared to 1000+ autopsy-confirmed 4R-tauopathies. Corticobasal degeneration patients had faster rates of decline, greater cortical degeneration, and shorter illness duration than progressive supranuclear palsy. These findings help define the pathobiology of progressive apraxia of speech and may have consequences for development of 4R-tau targeting treatment.",

author = "Josephs, {Keith A.} and Duffy, {Joseph R.} and Clark, {Heather M.} and Utianski, {Rene L.} and Strand, {Edythe A.} and Machulda, {Mary M.} and Hugo Botha and Martin, {Peter R.} and Pham, {Nha Trang Thu} and Julie Stierwalt and Farwa Ali and Marina Buciuc and Matthew Baker and {Fernandez De Castro}, {Cristhoper H.} and Spychalla, {Anthony J.} and Schwarz, {Christopher G.} and Reid, {Robert I.} and Senjem, {Matthew L.} and Jack, {Clifford R.} and Lowe, {Val J.} and Bigio, {Eileen H.} and Reichard, {Ross R.} and Polley, {Eric J.} and Nilufer Ertekin-Taner and Rosa Rademakers and DeTure, {Michael A.} and Ross, {Owen A.} and Dickson, {Dennis W.} and Whitwell, {Jennifer L.}",

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Josephs, KA, Duffy, JR, Clark, HM, Utianski, RL, Strand, EA, Machulda, MM, Botha, H, Martin, PR, Pham, NTT, Stierwalt, J, Ali, F, Buciuc, M, Baker, M, Fernandez De Castro, CH, Spychalla, AJ, Schwarz, CG, Reid, RI, Senjem, ML, Jack, CR, Lowe, VJ, Bigio, EH, Reichard, RR, Polley, EJ, Ertekin-Taner, N, Rademakers, R, DeTure, MA, Ross, OA, Dickson, DW & Whitwell, JL 2021, 'A molecular pathology, neurobiology, biochemical, genetic and neuroimaging study of progressive apraxia of speech', Nature communications, vol. 12, no. 1, 3452. https://doi.org/10.1038/s41467-021-23687-8

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AU - Josephs, Keith A.

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AU - Clark, Heather M.

AU - Utianski, Rene L.

AU - Strand, Edythe A.

AU - Machulda, Mary M.

AU - Botha, Hugo

AU - Martin, Peter R.

AU - Pham, Nha Trang Thu

AU - Stierwalt, Julie

AU - Ali, Farwa

AU - Buciuc, Marina

AU - Baker, Matthew

AU - Fernandez De Castro, Cristhoper H.

AU - Spychalla, Anthony J.

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AU - Reid, Robert I.

AU - Senjem, Matthew L.

AU - Jack, Clifford R.

AU - Lowe, Val J.

AU - Bigio, Eileen H.

AU - Reichard, Ross R.

AU - Polley, Eric J.

AU - Ertekin-Taner, Nilufer

AU - Rademakers, Rosa

AU - DeTure, Michael A.

AU - Ross, Owen A.

AU - Dickson, Dennis W.

AU - Whitwell, Jennifer L.

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N2 - Progressive apraxia of speech is a neurodegenerative syndrome affecting spoken communication. Molecular pathology, biochemistry, genetics, and longitudinal imaging were investigated in 32 autopsy-confirmed patients with progressive apraxia of speech who were followed over 10 years. Corticobasal degeneration and progressive supranuclear palsy (4R-tauopathies) were the most common underlying pathologies. Perceptually distinct speech characteristics, combined with age-at-onset, predicted specific 4R-tauopathy; phonetic subtype and younger age predicted corticobasal degeneration, and prosodic subtype and older age predicted progressive supranuclear palsy. Phonetic and prosodic subtypes showed differing relationships within the cortico-striato-pallido-nigro-luysial network. Biochemical analysis revealed no distinct differences in aggregated 4R-tau while tau H1 haplotype frequency (69%) was lower compared to 1000+ autopsy-confirmed 4R-tauopathies. Corticobasal degeneration patients had faster rates of decline, greater cortical degeneration, and shorter illness duration than progressive supranuclear palsy. These findings help define the pathobiology of progressive apraxia of speech and may have consequences for development of 4R-tau targeting treatment.

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A molecular pathology, neurobiology, biochemical, genetic and neuroimaging study of progressive apraxia of speech

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