Changes in Digital Speech Measures in Asymptomatic Carriers of Pathogenic Variants Associated With Frontotemporal Degeneration.

Background And Objectives: Clinical trials developing therapeutics for frontotemporal degeneration (FTD) focus on pathogenic variant carriers at preclinical stages. Objective, quantitative clinical assessment tools are needed to track stability and delayed disease onset. Natural speech can serve as an accessible, cost-effective assessment tool. We aimed to identify early changes in the natural speech of FTD pathogenic variant carriers before they become symptomatic.

Methods: In this cohort study, speech samples of picture descriptions were collected longitudinally from healthy participants in observational studies at the University of Pennsylvania and Columbia University between 2007 and 2020. Participants were asymptomatic but at risk for familial FTD. Status as "carrier" or "noncarrier" was based on screening for known pathogenic variants in the participant's family. Thirty previously validated digital speech measures derived from automatic speech processing pipelines were selected a priori based on previous studies in patients with FTD and compared between asymptomatic carriers and noncarriers cross-sectionally and longitudinally.

Results: A total of 105 participants, all asymptomatic, included 41 carriers: 12 men [30%], mean age 43 ± 13 years; education, 16 ± 2 years; MMSE 29 ± 1; and 64 noncarriers: 27 men [42%]; mean age, 48 ± 14 years; education, 15 ± 3 years; MMSE 29 ± 1. We identified 4 speech measures that differed between carriers and noncarriers at baseline: mean speech segment duration (mean difference -0.28 seconds, 95% CI -0.55 to -0.02, = 0.04); word frequency (mean difference 0.07, 95% CI 0.008-0.14, = 0.03); word ambiguity (mean difference 0.02, 95% CI 0.0008-0.05, = 0.04); and interjection count per 100 words (mean difference 0.33, 95% CI 0.07-0.59, = 0.01). Three speech measures deteriorated over time in carriers only: particle count per 100 words per month (β = -0.02, 95% CI -0.03 to -0.004, = 0.009); total narrative production time in seconds per month (β = -0.24, 95% CI -0.37 to -0.12, < 0.001); and total number of words per month (β = -0.48, 95% CI -0.78 to -0.19, = 0.002) including in 3 carriers who later converted to symptomatic disease.

Discussion: Using automatic processing pipelines, we identified early changes in the natural speech of FTD pathogenic variant carriers in the presymptomatic stage. These findings highlight the potential utility of natural speech as a digital clinical outcome assessment tool in FTD, where objective and quantifiable measures for abnormal behavior and language are lacking.