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

Research output: Contribution to journalArticlepeer-review


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 languageEnglish (US)
Article number3452
JournalNature communications
Issue number1
StatePublished - Dec 1 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


Dive into the research topics of 'A molecular pathology, neurobiology, biochemical, genetic and neuroimaging study of progressive apraxia of speech'. Together they form a unique fingerprint.

Cite this