Participants

We examined 153 native English speakers with PSPS (n = 41), CBS (n = 46), and naPPA (n = 25), and healthy controls (HC, n = 41). Patients were examined at the Hospital of the University of Pennsylvania by experienced neurologists (MG, DJI) and the clinical phenotype was reviewed in a multidisciplinary consensus conference according to published clinical research criteria [1, 3, 15, 36]. All patients were assessed between January 2000 and June 2019. Thirty-one of these cases had a neuropathological diagnosis of a tauopathy (PSP, CBD, or Pick’s disease). Some of the naPPA patients have been reported previously, but not in comparison to PSPS-CBS [12–14, 17, 18, 37]. We excluded cases with other neurological (e.g., vascular disease, hydrocephalus, head trauma), medical (e.g., infectious, inflammatory, metabolic), or primary psychiatric (e.g., psychosis, major depression, bipolar) conditions that could confound our observations. We excluded 4 patients with PSPS-CBS diagnosis because it was not clear whether the primary diagnosis was PSPS or CBS. Demographic and clinical characteristics of the patient groups are summarized in Table 1. We combined patients with PSPS and CBS who did not have concomitant naPPA (PSPS-CBS, n = 87) since these groups were matched for sex, age, education, and disease duration, and their speech characteristics were similar (Supplementary Table 1). Mini-Mental State Exam (MMSE) was used to measure overall disease severity and was obtained within 6 months of the speech sample. However, since MMSE scores differed in PSPS and CBS patients (t = 2.71, p = 0.009, 95% confidence interval (CI) 0.74 to 4.88), we also compared PSPS and CBS groups separately for speech and language impairments (see Supplementary Table 1). The PSPS-CBS and the naPPA groups were matched for education, sex, age, disease duration, and MMSE scores. The HC group matched both patient groups in age, sex, and education.

Demographic and clinical characteristics of patient groups and healthy controls

PSPS, progressive supranuclear palsy syndrome; CBS, corticobasal syndrome; naPPA, non-fluent/agrammatic primary progressive aphasia; y, year; MMSE, Mini-Mental State Examination; M, males.

In the course of preparing for this study, we discovered a small group of patients with PSPS-CBS and concomitant naPPA (PSPS-CBS + naPPA, n = 8). We did not include these patients in the PSPS-CBS and naPPA patient groups studied below, but we analyzed them separately. We excluded one patient with CBS, naPPA, and concomitant behavioral variant frontotemporal degeneration to constrain this secondary analysis to PSPS-CBS with a concomitant well-defined naPPA diagnosis. This subgroup of patients with both naPPA and PSPS-CBS is summarized in Supplementary Table 2 and Supplementary Figures 1 and 2.

To determine the frequency of clinical AoS features in our cohort, we reviewed all available clinical charts (n = 82) between 2009 and 2019 (earlier charts were not available). We found a total of five patients with features clinically judged to be consistent with AoS. This included two patients from the PSPS-CBS group, one patient from the naPPA group, and one from the PSPS-CBS + naPPA group. One patient from the PSPS-CBS + naPPA group presented with PPAoS. Patients with PPAoS have features of AoS, but these features are isolated from other disorders, such as aphasia [21]. Due to these small sample sizes, we were unable to pursue a statistical analysis of AoS in this study.

This study complies with guidelines on human experimentation. All participants were enrolled in study protocols and participated in an informed consent procedure in accordance with the Declaration of Helsinki approved by the Institutional Review Board of the University of Pennsylvania.