Automatic classification of AD pathology in FTD phenotypes using natural speech.

INTRODUCTION: Screening for Alzheimer's disease neuropathologic change (ADNC) in individuals with atypical presentations is challenging but essential for clinical management. We trained automatic speech-based classifiers to distinguish frontotemporal dementia (FTD) patients with ADNC from those with frontotemporal lobar degeneration (FTLD). METHODS: We trained automatic classifiers with 99 speech features from 1 minute speech samples of 179 participants (ADNC = 36, FTLD = 60, healthy controls [HC] = 89). Patients' pathology was assigned based on autopsy or cerebrospinal fluid analytes. Structural network-based magnetic resonance imaging analyses identified anatomical correlates of distinct speech features. RESULTS: Our classifier showed 0.88 ± $ \pm $ 0.03 area under the curve (AUC) for ADNC versus FTLD and 0.93 ± $ \pm $ 0.04 AUC for patients versus HC. Noun frequency and pause rate correlated with gray matter volume loss in the limbic and salience networks, respectively. DISCUSSION: Brief naturalistic speech samples can be used for screening FTD patients for underlying ADNC in vivo. This work supports the future development of digital assessment tools for FTD. HIGHLIGHTS: We trained machine learning classifiers for frontotemporal dementia patients using natural speech. We grouped participants by neuropathological diagnosis (autopsy) or cerebrospinal fluid biomarkers. Classifiers well distinguished underlying pathology (Alzheimer's disease vs. frontotemporal lobar degeneration) in patients. We identified important features through an explainable artificial intelligence approach. This work lays the groundwork for a speech-based neuropathology screening tool.

Automated Measures of Syntactic Complexity in Natural Speech Production: Older and Younger Adults as a Case Study.

PURPOSE: Multiple methods have been suggested for quantifying syntactic complexity in speech. We compared eight automated syntactic complexity metrics to determine which best captured verified syntactic differences between old and young adults. METHOD: We used natural speech samples produced in a picture description task by younger (n = 76, ages 18-22 years) and older (n = 36, ages 53-89 years) healthy participants, manually transcribed and segmented into sentences. We manually verified that older participants produced fewer complex structures. We developed a metric of syntactic complexity using automatically extracted syntactic structures as features in a multidimensional metric. We compared our metric to seven other metrics: Yngve score, Frazier score, Frazier-Roark score, developmental level, syntactic frequency, mean dependency distance, and sentence length. We examined the success of each metric in identifying the age group using logistic regression models. We repeated the analysis with automatic transcription and segmentation using an automatic speech recognition (ASR) system. RESULTS: Our multidimensional metric was successful in predicting age group (area under the curve [AUC] = 0.87), and it performed better than the other metrics. High AUCs were also achieved by the Yngve score (0.84) and sentence length (0.84). However, in a fully automated pipeline with ASR, the performance of these two metrics dropped (to 0.73 and 0.46, respectively), while the performance of the multidimensional metric remained relatively high (0.81). CONCLUSIONS: Syntactic complexity in spontaneous speech can be quantified by directly assessing syntactic structures and considering them in a multivariable manner. It can be derived automatically, saving considerable time and effort compared to manually analyzing large-scale corpora, while maintaining high face validity and robustness. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24964179.

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, p = 0.04); word frequency (mean difference 0.07, 95% CI 0.008-0.14, p = 0.03); word ambiguity (mean difference 0.02, 95% CI 0.0008-0.05, p = 0.04); and interjection count per 100 words (mean difference 0.33, 95% CI 0.07-0.59, p = 0.01). Three speech measures deteriorated over time in carriers only: particle count per 100 words per month (ß = -0.02, 95% CI -0.03 to -0.004, p = 0.009); total narrative production time in seconds per month (ß = -0.24, 95% CI -0.37 to -0.12, p < 0.001); and total number of words per month (ß = -0.48, 95% CI -0.78 to -0.19, p = 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.

Digital markers of motor speech impairments in spontaneous speech of patients with ALS-FTD spectrum disorders.

OBJECTIVE: To evaluate automated digital speech measures, derived from spontaneous speech (picture descriptions), in assessing bulbar motor impairments in patients with ALS-FTD spectrum disorders (ALS-FTSD). METHODS: Automated vowel algorithms were employed to extract two vowel acoustic measures: vowel space area (VSA), and mean second formant slope (F2 slope). Vowel measures were compared between ALS with and without clinical bulbar symptoms (ALS + bulbar (n = 49, ALSFRS-r bulbar subscore: x¯ = 9.8 (SD = 1.7)) vs. ALS-nonbulbar (n = 23), behavioral variant frontotemporal dementia (bvFTD, n = 25) without a motor syndrome, and healthy controls (HC, n = 32). Correlations with bulbar motor clinical scales, perceived listener effort, and MRI cortical thickness of the orobuccal primary motor cortex (oral PMC) were examined. We compared vowel measures to speaking rate, a conventional metric for assessing bulbar dysfunction. RESULTS: ALS + bulbar had significantly reduced VSA and F2 slope than ALS-nonbulbar (|d|=0.94 and |d|=1.04, respectively), bvFTD (|d|=0.89 and |d|=1.47), and HC (|d|=0.73 and |d|=0.99). These reductions correlated with worse bulbar clinical scores (VSA: R = 0.33, p = 0.043; F2 slope: R = 0.38, p = 0.011), greater listener effort (VSA: R=-0.43, p = 0.041; F2 slope: p > 0.05), and cortical thinning in oral PMC (F2 slope: ß = 0.0026, p = 0.017). Vowel measures demonstrated greater sensitivity and specificity for bulbar impairment than speaking rate, while showing independence from cognitive and respiratory impairments. CONCLUSION: Automatic vowel measures are easily derived from a brief spontaneous speech sample, are sensitive to mild-moderate stage of bulbar disease in ALS-FTSD, and may present better sensitivity to bulbar impairment compared to traditional assessments such as speaking rate.

Apraxia of Speech in the Spontaneous Speech of Nonfluent/Agrammatic Primary Progressive Aphasia.

Background: Apraxia of speech (AOS) is a core feature of nonfluent/agrammatic primary progressive aphasia (naPPA), but its precise characteristics and the prevalence of AOS features in spontaneous speech are debated. Objective: To assess the frequency of features of AOS in the spontaneous, connected speech of individuals with naPPA and to evaluate whether these features are associated with an underlying motor disorder such as corticobasal syndrome or progressive supranuclear palsy. Methods: We examined features of AOS in 30 patients with naPPA using a picture description task. We compared these patients to 22 individuals with behavioral variant frontotemporal dementia and 30 healthy controls. Each speech sample was evaluated perceptually for lengthened speech segments and quantitatively for speech sound distortions, pauses between and within words, and articulatory groping. We compared subgroups of naPPA with and without at least two features of AOS to assess the possible contribution of a motor impairment to speech production deficits. Results: naPPA patients produced both speech sound distortions and other speech sound errors. Speech segmentation was found in 27/30 (90%) of individuals. Distortions were identified in 8/30 (27%) of individuals, and other speech sound errors occurred in 18/30 (60%) of individuals. Frequent articulatory groping was observed in 6/30 (20%) of individuals. Lengthened segments were observed rarely. There were no differences in the frequencies of AOS features among naPPA subgroups as a function of extrapyramidal disease. Conclusion: Features of AOS occur with varying frequency in the spontaneous speech of individuals with naPPA, independently of an underlying motor disorder.

Digital markers of motor speech impairments in natural speech of patients with ALS-FTD spectrum disorders.

Background and objectives: Patients with ALS-FTD spectrum disorders (ALS-FTSD) have mixed motor and cognitive impairments and require valid and quantitative assessment tools to support diagnosis and tracking of bulbar motor disease. This study aimed to validate a novel automated digital speech tool that analyzes vowel acoustics from natural, connected speech as a marker for impaired articulation due to bulbar motor disease in ALS-FTSD. Methods: We used an automatic algorithm called Forced Alignment Vowel Extraction (FAVE) to detect spoken vowels and extract vowel acoustics from 1 minute audio-recorded picture descriptions. Using automated acoustic analysis scripts, we derived two articulatory-acoustic measures: vowel space area (VSA, in Bark 2 ) which represents tongue range-of-motion (size), and average second formant slope of vowel trajectories (F2 slope) which represents tongue movement speed. We compared vowel measures between ALS with and without clinically-evident bulbar motor disease (ALS+bulbar vs. ALS-bulbar), behavioral variant frontotemporal dementia (bvFTD) without a motor syndrome, and healthy controls (HC). We correlated impaired vowel measures with bulbar disease severity, estimated by clinical bulbar scores and perceived listener effort, and with MRI cortical thickness of the orobuccal part of the primary motor cortex innervating the tongue (oralPMC). We also tested correlations with respiratory capacity and cognitive impairment. Results: Participants were 45 ALS+bulbar (30 males, mean age=61±11), 22 ALS-nonbulbar (11 males, age=62±10), 22 bvFTD (13 males, age=63±7), and 34 HC (14 males, age=69±8). ALS+bulbar had smaller VSA and shallower average F2 slopes than ALS-bulbar (VSA: | d |=0.86, p =0.0088; F2 slope: | d |=0.98, p =0.0054), bvFTD (VSA: | d |=0.67, p =0.043; F2 slope: | d |=1.4, p <0.001), and HC (VSA: | d |=0.73, p =0.024; F2 slope: | d |=1.0, p <0.001). Vowel measures declined with worsening bulbar clinical scores (VSA: R=0.33, p =0.033; F2 slope: R=0.25, p =0.048), and smaller VSA was associated with greater listener effort (R=-0.43, p =0.041). Shallower F2 slopes were related to cortical thinning in oralPMC (R=0.50, p =0.03). Neither vowel measure was associated with respiratory nor cognitive test scores. Conclusions: Vowel measures extracted with automatic processing from natural speech are sensitive to bulbar motor disease in ALS-FTD and are robust to cognitive impairment.

Prosodic characteristics of prepausal words produced by patients with neurodegenerative disease.

Prosody of patients with neurodegenerative disease is often impaired. We investigated changes to two prosodic cues in patients: the pitch contour and the duration of prepausal words. We analyzed recordings of picture descriptions produced by patients with neurodegenerative conditions that included either cognitive (n=223), motor (n=68), or mixed cognitive and motor impairments (n=109), and by healthy controls (n=28; HC). A speech activity detector identified pauses. Words were aligned to the acoustic signal; pitch values were normalized in scale and duration. Analyses of pitch showed that the ending (90th-100th percentile) of prepausal words had a lower pitch in the mixed and motor groups than the cognitive group and HC. The pitch contour from the midpoint of words to the end showed a steep rising slope for HC, but patients showed a gentle rising or flat slope. This suggests that HC signaled the continuation of their description after the pause with rising contour; patients either failed to keep describing the picture due to cognitive impairment or could not raise pitch due to motor impairments. Prepausal words showed longer duration relative to non-prepausal words with no significant differences between the groups. This suggests that prepausal lengthening is preserved in patients.

Lexical and Acoustic Speech Features Relating to Alzheimer Disease Pathology.

BACKGROUND AND OBJECTIVES: We compared digital speech and language features of patients with amnestic Alzheimer's disease (aAD) or logopenic variant primary progressive aphasia (lvPPA) in a biologically confirmed cohort and related these features to neuropsychiatric test scores and CSF analytes. METHODS: We included patients with aAD or lvPPA with cerebrospinal fluid (CSF) (phosphorylated Tau (p-Tau)/Aß≥ 0.09 and total Tau/Aß≥ 0.34) or autopsy confirmation of AD pathology and age-matched healthy controls (HC) recruited at the Frontotemporal Degeneration Center of the University of Pennsylvania for a cross-sectional study. We extracted speech and language variables with automated lexical and acoustic pipelines from participants' oral picture descriptions. We compared the groups and correlated distinct features with clinical ratings and CSF p-Tau levels. RESULTS: We examined patients with aAD (n=44; 62±8 years; 24 females; Mini-Mental State Exam (MMSE)=21.1±4.8) or lvPPA (n=21; 64.1±8.2 years; 11 females; MMSE=23.0±4.2), and healthy controls (HC) (n=28; 65.9±5.9 years, 15 females; MMSE=29±1). Patients with lvPPA produced fewer verbs (10.5±2.3; p=0.001), adjectives (2.7±1.3, p=0.019), and more fillers (7.4±3.9; p=0.022) with lower lexical diversity (0.84±0.1; p=0.05) and higher pause rate (54.2±19.2; p=0.015) than aAD (verbs: 12.5±2; adjectives: 3.8±2; fillers: 4.9±4.5; lexical diversity: 0.87±0.1; pause rate: 45.3±12.8). Both groups showed some shared language impairments compared with HC. Word frequency (MMSE: ß=-1.6, p=0.009, BNT: ß=-4.36, p<0.001), adverbs (MMSE: ß=-1.9, p=0.003, BNT: ß=-2.41, p=0.041), pause rate (MMSE: ß=-1.21, p=0.041, BNT: ß=-2.09, p=0.041), and word length (MMSE: ß=1.75, p=0.001, BNT: ß=2.94, p=0.003) were significantly correlated with both MMSE and BNT, but other measures were not correlated with MMSE and/or BNT. Prepositions (r=-0.36, p=0.019), nouns (r=-0.31, p=0.047), speech segment duration (r=-0.33, p=0.032), word frequency (r=0.33, p=0.036), and pause rate (r=0.34, p=0.026) were correlated with patients' CSF p-Tau levels. DISCUSSION: Our measures captured language and speech differences between the two phenotypes that traditional language-based clinical assessments failed to identify. This work demonstrates the potential of natural speech in reflecting underlying variants with AD pathology.

Digital Speech Analysis in Progressive Supranuclear Palsy and Corticobasal Syndromes.

BACKGROUND: Progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS) as well as non-fluent/agrammatic primary progressive aphasia (naPPA) are often associated with misfolded 4-repeat tau pathology, but the diversity of the associated speech features is poorly understood. OBJECTIVE: Investigate the full range of acoustic and lexical properties of speech to test the hypothesis that PSPS-CBS show a subset of speech impairments found in naPPA. METHODS: Acoustic and lexical measures, extracted from natural, digitized semi-structured speech samples using novel, automated methods, were compared in PSPS-CBS (n = 87), naPPA (n = 25), and healthy controls (HC, n = 41). We related these measures to grammatical performance and speech fluency, core features of naPPA, to neuropsychological measures of naming, executive, memory and visuoconstructional functioning, and to cerebrospinal fluid (CSF) phosphorylated tau (pTau) levels in patients with available biofluid analytes. RESULTS: Both naPPA and PSPS-CBS speech produced shorter speech segments, longer pauses, higher pause rates, reduced fundamental frequency (f0) pitch ranges, and slower speech rate compared to HC. naPPA speech was distinct from PSPS-CBS with shorter speech segments, more frequent pauses, slower speech rate, reduced verb production, and higher partial word production. In both groups, acoustic duration measures generally correlated with speech fluency, measured as words per minute, and grammatical performance. Speech measures did not correlate with standard neuropsychological measures. CSF pTau levels correlated with f0 range in PSPS-CBS and naPPA. CONCLUSION: Lexical and acoustic speech features of PSPS-CBS overlaps those of naPPA and are related to CSF pTau levels.

Automated analysis of lexical features in frontotemporal degeneration.

We implemented an automated analysis of lexical aspects of semi-structured speech produced by healthy elderly controls (n = 37) and three patient groups with frontotemporal degeneration (FTD): behavioral variant FTD (n = 74), semantic variant primary progressive aphasia (svPPA, n = 42), and nonfluent/agrammatic PPA (naPPA, n = 22). Based on previous findings, we hypothesized that the three patient groups and controls would differ in the counts of part-of-speech (POS) categories and several lexical measures. With a natural language processing program, we automatically tagged POS categories of all words produced during a picture description task. We further counted the number of wh-words, and we rated nouns for abstractness, ambiguity, frequency, familiarity, and age of acquisition. We also computed the cross-entropy estimation, where low cross-entropy indicates high predictability, and lexical diversity for each description. We validated a subset of the POS data that were automatically tagged with the Google Universal POS scheme using gold-standard POS data tagged by a linguist, and we found that the POS categories from our automated methods were more than 90% accurate. For svPPA patients, we found fewer unique nouns than in naPPA and more pronouns and wh-words than in the other groups. We also found high abstractness, ambiguity, frequency, and familiarity for nouns and the lowest cross-entropy estimation among all groups. These measures were associated with cortical thinning in the left temporal lobe. In naPPA patients, we found increased speech errors and partial words compared to controls, and these impairments were associated with cortical thinning in the left middle frontal gyrus. bvFTD patients' adjective production was decreased compared to controls and was correlated with their apathy scores. Their adjective production was associated with cortical thinning in the dorsolateral frontal and orbitofrontal gyri. Our results demonstrate distinct language profiles in subgroups of FTD patients and validate our automated method of analyzing FTD patients' speech.

Lexical and Acoustic Characteristics of Young and Older Healthy Adults.

Purpose This study examines the effect of age on language use with an automated analysis of digitized speech obtained from semistructured, narrative speech samples. Method We examined the Cookie Theft picture descriptions produced by 37 older and 76 young healthy participants. Using modern natural language processing and automatic speech recognition tools, we automatically annotated part-of-speech categories of all tokens, calculated the number of tense-inflected verbs, mean length of clause, and vocabulary diversity, and we rated nouns and verbs for five lexical features: word frequency, familiarity, concreteness, age of acquisition, and semantic ambiguity. We also segmented the speech signals into speech and silence and calculated acoustic features, such as total speech time, mean speech and pause segment durations, and pitch values. Results Older speakers produced significantly more fillers, pronouns, and verbs and fewer conjunctions, determiners, nouns, and prepositions than young participants. Older speakers' nouns and verbs were more familiar, more frequent (verbs only), and less ambiguous compared to those of young speakers. Older speakers produced shorter clauses with a lower vocabulary diversity than young participants. They also produced shorter speech segments and longer pauses with increased total speech time and total number of words. Lastly, we observed an interaction of age and sex in pitch ranges. Conclusions Our results suggest that older speakers' lexical content is less diverse, and these speakers produce shorter clauses than young participants in monologic, narrative speech. Our findings show that lexical and acoustic characteristics of semistructured speech samples can be examined with automated methods.

Automated analysis of lexical features in Frontotemporal Degeneration.

We implemented an automated analysis of lexical aspects of semi-structured speech produced by healthy elderly controls (n=37) and three patient groups with frontotemporal degeneration (FTD): behavioral variant FTD (n=74), semantic variant primary progressive aphasia (svPPA, n=42), and nonfluent/agrammatic PPA (naPPA, n=22). Based on previous findings, we hypothesized that the three patient groups and controls would differ in the counts of part-of-speech (POS) categories and several lexical measures. With a natural language processing program, we automatically tagged POS categories of all words produced during a picture description task. We further counted the number of wh -words, and we rated nouns for abstractness, ambiguity, frequency, familiarity, and age of acquisition. We also computed the cross-entropy estimation, which is a measure of word predictability, and lexical diversity for each description. We validated a subset of the POS data that were automatically tagged with the Google Universal POS scheme using gold-standard POS data tagged by a linguist, and we found that the POS categories from our automated methods were more than 90% accurate. For svPPA patients, we found fewer unique nouns than in naPPA and more pronouns and wh -words than in the other groups. We also found high abstractness, ambiguity, frequency, and familiarity for nouns and the lowest cross-entropy estimation among all groups. These measures were associated with cortical thinning in the left temporal lobe. In naPPA patients, we found increased speech errors and partial words compared to controls, and these impairments were associated with cortical thinning in the left middle frontal gyrus. bvFTD patients' adjective production was decreased compared to controls and was correlated with their apathy scores. Their adjective production was associated with cortical thinning in the dorsolateral frontal and orbitofrontal gyri. Our results demonstrate distinct language profiles in subgroups of FTD patients and validate our automated method of analyzing FTD patients' speech.

Automated analysis of natural speech in amyotrophic lateral sclerosis spectrum disorders.

OBJECTIVE: We implemented automated methods to analyze speech and evaluate the hypothesis that cognitive and motor factors impair prosody in partially distinct ways in patients with amyotrophic lateral sclerosis (ALS). METHODS: We recruited 213 participants, including 67 with ALS (44 with motor ALS, 23 with ALS and frontotemporal degeneration [FTD]), 33 healthy controls, and neurodegenerative reference groups with behavioral variant FTD (n = 90) and nonfluent/agrammatic primary progressive aphasia (n = 23). Digitized, semistructured speech samples obtained from picture descriptions were automatically segmented with a Speech Activity Detector; continuous speech segments were pitch-tracked; and duration measures for speech and silent pause segments were extracted. Acoustic measures were calculated, including fundamental frequency (f0) range, mean speech and pause segment durations, total speech duration, and pause rate (pause count per minute of speech). Group comparisons related performance on acoustic measures to clinical scales of cognitive and motor impairments and explored MRI cortical thinning in ALS and ALS-FTD. RESULTS: The f0 range was significantly impaired in ALS spectrum disorders and was related to bulbar motor disease, and regression analyses related this to cortical thickness in primary motor cortex and perisylvian regions. Impaired speech and pause duration measures were related to the degree of cognitive impairment in ALS spectrum disorders, and regressions related duration measures to bilateral frontal opercula and left anterior insula. CONCLUSION: Automated analyses of acoustic speech properties dissociate motor and cognitive components of speech deficits in ALS spectrum disorders.

A longitudinal study of speech production in primary progressive aphasia and behavioral variant frontotemporal dementia.

We examined longitudinal change in language expression during a semi-structured speech sample in 48 patients with primary progressive aphasia (PPA) or behavioral variant frontotemporal dementia (bvFTD) and related this to longitudinal neuroimaging of cortical thickness available in 25 of these patients. All patient groups declined significantly on measures of both speech fluency and grammar, although patients with nonfluent/agrammatic PPA (naPPA) declined to a greater extent than patients with the semantic variant, the logopenic variant, and bvFTD. These patient groups also declined on several neuropsychological measures, but there was no correlation between decline in speech expression and decline in neuropsychological performance. Longitudinal decline in grammaticality, assessed by the number of well-formed sentences produced, was associated with longitudinal progression of gray matter atrophy in left frontal operculum/insula and bilateral temporal cortex.

Divergent patterns of TDP-43 and tau pathologies in primary progressive aphasia.

OBJECTIVE: To measure postmortem burden of frontotemporal lobar degeneration (FTLD) with TDP-43 (FTLD-TDP) or tau (FTLD-Tau) proteinopathy across hemispheres in primary progressive aphasia (PPA) using digital histopathology and to identify clinicopathological correlates of these distinct proteinopathies. METHODS: In an autopsy cohort of PPA (FTLD-TDP = 13, FTLD-Tau = 14), we analyzed laterality and regional distribution of postmortem pathology, quantified using a validated digital histopathological approach, in available brain tissue from up to 8 cortical regions bilaterally. We related digital pathology to antemortem structural neuroimaging and specific clinical language features. RESULTS: Postmortem cortical pathology was left-lateralized in both FTLD-TDP (beta = -0.15, standard error [SE] = 0.05, p = 0.007) and FTLD-Tau (beta = -0.09, SE = 0.04, p = 0.015), but the degree of lateralization decreased with greater overall dementia severity before death (beta = -8.18, SE = 3.22, p = 0.015). Among 5 core pathology regions sampled, we found greatest pathology in left orbitofrontal cortex (OFC) in FTLD-TDP, which was greater than in FTLD-Tau (F = 47.07, df = 1,17, p < 0.001), and in left midfrontal cortex (MFC) in FTLD-Tau, which was greater than in FTLD-TDP (F = 19.34, df = 1,16, p < 0.001). Postmortem pathology was inversely associated with antemortem magnetic resonance imaging cortical thickness (beta = -0.04, SE = 0.01, p = 0.007) in regions matching autopsy sampling. Irrespective of PPA syndromic variant, single-word comprehension impairment was associated with greater left OFC pathology (t = -3.72, df = 10.72, p = 0.004) and nonfluent speech with greater left MFC pathology (t = -3.62, df = 12.00, p = 0.004) among the 5 core pathology regions. INTERPRETATION: In PPA, FTLD-TDP and FTLD-Tau have divergent anatomic distributions of left-lateralized postmortem pathology that relate to antemortem structural imaging and distinct language deficits. Although other brain regions may be implicated in neural networks supporting these complex language measures, our observations may eventually help to improve antemortem diagnosis of neuropathology in PPA. Ann Neurol 2019;85:630-643.

Validated automatic speech biomarkers in primary progressive aphasia.

Objective: To automatically extract and quantify specific disease biomarkers of prosody from the acoustic properties of speech in patients with primary progressive aphasia. Methods: We analyzed speech samples from 59 progressive aphasic patients (non-fluent/agrammatic = 15, semantic = 21, logopenic = 23; ages 50-85 years) and 31 matched healthy controls (ages 54-89 years). Using a novel, automated speech analysis protocol, we extracted acoustic measurements of prosody, including fundamental frequency and speech and silent pause durations, and compared these between groups. We then examined their relationships with clinical tests, gray matter atrophy, and cerebrospinal fluid analytes. Results: We found a narrowed range of fundamental frequency in patients with non-fluent/agrammatic variant aphasia (mean 3.86 ± 1.15 semitones) compared with healthy controls (6.06 ± 1.95 semitones; P < 0.001) and patients with semantic variant aphasia (6.12 ± 1.77 semitones; P = 0.001). Mean pause rate was significantly increased in the non-fluent/agrammatic group (mean 61.4 ± 20.8 pauses per minute) and the logopenic group (58.7 ± 16.4 pauses per minute) compared to controls. In an exploratory analysis, narrowed fundamental frequency range was associated with atrophy in the left inferior frontal cortex. Cerebrospinal level of phosphorylated tau was associated with an acoustic classifier combining fundamental frequency range and pause rate (r = 0.58, P = 0.007). Receiver operating characteristic analysis with this combined classifier distinguished non-fluent/agrammatic speakers from healthy controls (AUC = 0.94) and from semantic variant patients (AUC = 0.86). Interpretation: Restricted fundamental frequency range and increased pause rate are characteristic markers of speech in non-fluent/agrammatic primary progressive aphasia. These can be extracted with automated speech analysis and are associated with left inferior frontal atrophy and cerebrospinal phosphorylated tau level.

Evaluation of Linguistic Markers of Word-Finding Difficulty and Cognition in Parkinson's Disease.

Purpose: Early cognitive symptoms such as word-finding difficulty (WFD) in daily conversation are common in Parkinson's disease (PD), but studies have been limited by a lack of feasible, quantitative measures. Linguistic analysis, focused on pauses in speech, may yield markers of impairment of cognition and communication in PD. The objective of this study was to evaluate the relationship of linguistic markers in semistructured speech to WFD symptoms and cognitive function in PD. Method: Speech recordings of description of the Cookie Theft picture in 53 patients with PD without dementia and 23 elderly controls were analyzed with Praat software. Montreal Cognitive Assessment (MoCA; Nasreddine et al., 2005), category naming fluency, and confrontation naming tests were administered. Questionnaires rating WFD symptoms and cognitive instrumental activities of daily living were completed. We determined the relationships between (a) pause length and location, (b) MoCA score, and (c) WFD symptoms, using Pearson's correlations and multivariate regression models. Results: Compared with controls, patients with PD had more pauses within utterances as well as fewer words per minute and a lower percentage of well-formed sentences. Pauses within utterances differed significantly between PD-mild cognitive impairment and normal cognition (p < .001). Words per minute and percentage of well-formed sentences were predictive of MoCA in multivariate regression models. Pauses before verbs were associated with patient-reported severity of WFD symptoms (p = .006). Conclusions: Linguistic markers including pauses within utterances distinguish patients with PD with mild cognitive symptoms from elderly controls. These markers are associated with global cognitive function before the onset of dementia. Pauses before verbs and grammatical markers may index early cognitive symptoms such as WFD that may interfere with functional communication. Supplemental Material: https://doi.org/10.23641/asha.6615401.

Production of verbs related to body movement in amyotrophic lateral sclerosis (ALS) and Parkinson's Disease (PD).

Theories of grounded cognition propose that action verb knowledge relies in part on motor processing regions, including premotor cortex. Accordingly, impaired action verb knowledge in patients with amyotrophic lateral sclerosis (ALS) and Parkinson's Disease (PD) is thought to be due to motor system degeneration. Upper motor neuron disease in ALS degrades the motor cortex and related pyramidal motor system, while disease in PD is centered in the basal ganglia and can spread to frontostriatal areas that are important to language functioning. These anatomical distinctions in disease may yield subtle differences in the action verb impairment between patient groups. Here we compare verbs where the body is the agent of the action to verbs where the body is the theme. To examine the role of motor functioning in body verb production, we split patient groups into patients with high motor impairment (HMI) and those with low motor impairment (LMI), using disease-specific measures of motor impairment. Regression analyses assessed how verb production in ALS and PD was related to motor system atrophy. We find a dissociation between agent- and theme-body verbs in ALS: ALS HMI were impaired for agent body verbs but not theme verbs, compared to ALS LMI. This dissociation was not present in PD patients, who instead show depressed production for all body verbs. Although patients with cognitive impairment were excluded from this study, cognitive performance significantly correlated with the production of theme verbs in ALS and cognitive/stative verbs in PD. Finally, regression analyses related the agent-theme dissociation in ALS to grey matter atrophy of premotor cortex. These findings support the view that motor dysfunction and disease in premotor cortex contributes to the agent body verb deficit in ALS, and begin to identify some distinct characteristics of impairment for verbs in ALS and PD.

Longitudinal Changes in Semantic Concreteness in Semantic Variant Primary Progressive Aphasia (svPPA).

This study examines longitudinal changes in the concreteness of nouns produced by human patients with semantic variant primary progressive aphasia (svPPA). Cross-sectional studies show that patients with svPPA demonstrate severe loss of concrete noun knowledge linked to atrophy of the left ventral temporal lobe. It is unknown how disease spread and duration affect the magnitude of the concreteness impairment in svPPA. We evaluate longitudinal spoken production of concrete nouns in svPPA, and relate this to changes in longitudinal MRI measures of gray matter (GM). Noun concreteness in svPPA is compared to that of behavioral variant frontotemporal dementia (bvFTD) patients, who typically demonstrate highly concrete speech. We elicited naturalistic speech samples at two time points (time 1 and time 2) in patients with svPPA (n = 11) and bvFTD (n = 15) through descriptions of the Cookie Theft picture and evaluated each spoken noun for concreteness. Compared to bvFTD patients whose noun production remained highly concrete throughout the testing period, mixed-effects models revealed that noun concreteness significantly decreased as disease progressed in svPPA. We also measured longitudinal changes to GM in a subset of svPPA patients (n = 7), who showed significant decline in the left and right temporal and frontal regions. Regression analyses revealed that longitudinal GM atrophy in the right fusiform and parahippocampal gyri and the left superior temporal gyrus was related to decreasing noun concreteness. These results suggest that progressive atrophy of the ventral temporal lobe in svPPA contributes to declining concrete noun production over time.