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

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23687-8

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