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.

Elevated Plasma Phosphorylated Tau 181 in Amyotrophic Lateral Sclerosis.

OBJECTIVE: Plasma phosphorylated tau (p-tau181 ) is reliably elevated in Alzheimer's disease (AD), but less explored is its specificity relative to other neurodegenerative conditions. Here, we find novel evidence that plasma p-tau181 is elevated in amyotrophic lateral sclerosis (ALS), a neurodegenerative condition typically lacking tau pathology. We performed a detailed evaluation to identify the clinical correlates of elevated p-tau181 in ALS. METHODS: Patients were clinically or pathologically diagnosed with ALS (n = 130) or AD (n = 79), or were healthy non-impaired controls (n = 26). Receiver operating characteristic (ROC) curves were analyzed and area under the curve (AUC) was used to discriminate AD from ALS. Within ALS, Mann-Whitney-Wilcoxon tests compared analytes by presence/absence of upper motor neuron and lower motor neuron (LMN) signs. Spearman correlations tested associations between plasma p-tau181 and postmortem neuron loss. RESULTS: A Wilcoxon test showed plasma p-tau181 was higher in ALS than controls (W = 2,600, p = 0.000015), and ROC analyses showed plasma p-tau181 poorly discriminated AD and ALS (AUC = 0.60). In ALS, elevated plasma p-tau181 was associated with LMN signs in cervical (W = 827, p = 0.0072), thoracic (W = 469, p = 0.00025), and lumbosacral regions (W = 851, p = 0.0000029). In support of LMN findings, plasma p-tau181 was associated with neuron loss in the spinal cord (rho = 0.46, p = 0.017), but not in the motor cortex (p = 0.41). Cerebrospinal spinal fluid p-tau181 and plasma neurofilament light chain were included as reference analytes, and demonstrate specificity of findings. INTERPRETATION: We found strong evidence that plasma p-tau181 is elevated in ALS and may be a novel marker specific to LMN dysfunction. ANN NEUROL 2022;92:807-818.

Electrical impedance myography in the evaluation of the tongue musculature in amyotrophic lateral sclerosis.

INTRODUCTION: Electrical impedance myography (EIM) quantifies muscle health and is used as a biomarker of muscle abnormalities in neurogenic and myopathic diseases. EIM has yet to be evaluated in the tongue musculature in patients with amyotrophic lateral sclerosis (ALS), who often show clinical bulbar signs. METHODS: The lingual musculature of 19 subjects with motor neuron disease and 21 normal participants was assessed using EIM, strength and endurance testing, and clinical assessment. RESULTS: Tongue musculature in the ALS group was characterized by significantly smaller phase (Ph) and greater resistance (R) when compared with the healthy cohort. Ph and tongue endurance were correlated in the ALS group. CONCLUSIONS: EIM of tongue musculature could distinguish those with ALS from healthy controls. The demonstrated relationship between tongue function and Ph supports further testing of EIM of the tongue as a potential biomarker in ALS.

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.

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.

Quantifying articulatory impairments in neurodegenerative motor diseases: A scoping review and meta-analysis of interpretable acoustic features.

PURPOSE: Neurodegenerative motor diseases (NMDs) have devastating effects on the lives of patients and their loved ones, in part due to the impact of neurologic abnormalities on speech, which significantly limits functional communication. Clinical speech researchers have thus spent decades investigating speech features in populations suffering from NMDs. Features of impaired articulatory function are of particular interest given their detrimental impact on intelligibility, their ability to encode a variety of distinct movement disorders, and their potential as diagnostic indicators of neurodegenerative diseases. The objectives of this scoping review were to identify (1) which components of articulation (i.e. coordination, consistency, speed, precision, and repetition rate) are the most represented in the acoustic literature on NMDs; (2) which acoustic articulatory features demonstrate the most potential for detecting speech motor dysfunction in NMDs; and (3) which articulatory components are the most impaired within each NMD. METHOD: This review examined literature published between 1976 and 2020. Studies were identified from six electronic databases using predefined key search terms. The first research objective was addressed using a frequency count of studies investigating each articulatory component, while the second and third objectives were addressed using meta-analyses. RESULT: Findings from 126 studies revealed a considerable emphasis on articulatory precision. Of the 24 features included in the meta-analyses, vowel dispersion/distance and stop gap duration exhibited the largest effects when comparing the NMD population to controls. The meta-analyses also revealed divergent patterns of articulatory performance across disease types, providing evidence of unique profiles of articulatory impairment. CONCLUSION: This review illustrates the current state of the literature on acoustic articulatory features in NMDs. By highlighting the areas of need within each articulatory component and disease group, this work provides a foundation on which clinical researchers, speech scientists, neurologists, and computer science engineers can develop research questions that will both broaden and deepen the understanding of articulatory impairments in NMDs.

Comparison of category and letter fluency tasks through automated analysis.

Introduction: Category and letter fluency tasks are commonly used neuropsychological tasks to evaluate lexical retrieval. Methods: This study used validated automated methods, which allow for more expansive investigation, to analyze speech production of both category ("Animal") and letter ("F") fluency tasks produced by healthy participants (n = 36) on an online platform. Recordings were transcribed and analyzed through automated pipelines, which utilized natural language processing and automatic acoustic processing tools. Automated pipelines calculated overall performance scores, mean inter-word response time, and word start time; errors were excluded from analysis. Each word was rated for age of acquisition (AoA), ambiguity, concreteness, frequency, familiarity, word length, word duration, and phonetic and semantic distance from its previous word. Results: Participants produced significantly more words on the category fluency task relative to the letter fluency task (p < 0.001), which is in line with previous studies. Wilcoxon tests also showed tasks differed on several mean speech measures of words, and category fluency was associated with lower mean AoA (p<0.001), lower frequency (p < 0.001), lower semantic ambiguity (p < 0.001), lower semantic distance (p < 0.001), lower mean inter-word RT (p = 0.03), higher concreteness (p < 0.001), and higher familiarity (p = 0.02), compared to letter fluency. ANOVAs significant interactions for fluency task on total score and lexical measures showed that lower category fluency scores were significantly related to lower AoA and higher prevalence, and this was not observed for letter fluency scores. Finally, word-characteristics changed over time and significant interactions were noted between the tasks, including word familiarity (p = 0.019), semantic ambiguity (p = 0.002), semantic distance (p=0.001), and word duration (p<0.001). Discussion: These findings showed that certain lexical measures such as AoA, word familiarity, and semantic ambiguity were important for understanding how these tasks differ. Additionally, it found that acoustic measures such as inter-word RT and word duration are also imperative to analyze when comparing the two tasks. By implementing these automated techniques, which are reproducible and scalable, to analyze fluency tasks we were able to quickly detect these differences. In future clinical settings, we expect these methods to expand our knowledge on speech feature differences that impact not only total scores, but many other speech measures among clinical populations.

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.

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.

Natural speech markers of Alzheimer's disease co-pathology in Lewy body dementias.

INTRODUCTION: An estimated 50% of patients with Lewy body dementias (LBD), including Parkinson's disease dementia (PDD) and Dementia with Lewy bodies (DLB), have co-occurring Alzheimer's disease (AD) that is associated with worse prognosis. This study tests an automated analysis of natural speech as an inexpensive, non-invasive screening tool for AD co-pathology in biologically-confirmed cohorts of LBD patients with AD co-pathology (SYN + AD) and without (SYN-AD). METHODS: We analyzed lexical-semantic and acoustic features of picture descriptions using automated methods in 22 SYN + AD and 38 SYN-AD patients stratified using AD CSF biomarkers or autopsy diagnosis. Speech markers of AD co-pathology were identified using best subset regression, and their diagnostic discrimination was tested using receiver operating characteristic. ANCOVAs compared measures between groups covarying for demographic differences and cognitive disease severity. We tested relations with CSF tau levels, and compared speech measures between PDD and DLB clinical disorders in the same cohort. RESULTS: Age of acquisition of nouns (p = 0.034, |d| = 0.77) and lexical density (p = 0.0064, |d| = 0.72) were reduced in SYN + AD, and together showed excellent discrimination for SYN + AD vs. SYN-AD (95% sensitivity, 66% specificity; AUC = 0.82). Lower lexical density was related to higher CSF t-Tau levels (R = -0.41, p = 0.0021). Clinically-diagnosed PDD vs. DLB did not differ on any speech features. CONCLUSION: AD co-pathology may result in a deviant natural speech profile in LBD characterized by specific lexical-semantic impairments, not detectable by clinical disorder diagnosis. Our study demonstrates the potential of automated digital speech analytics as a screening tool for underlying AD co-pathology in LBD.

CSF Biomarkers of Alzheimer Disease in Patients With Concomitant α-Synuclein Pathology.

BACKGROUND AND OBJECTIVES: Cerebrospinal fluid (CSF) biomarkers amyloid-ß42 (Aß42), phosphorylated tau (p-tau181), total tau (t-tau) and neurogranin (Ng) can diagnose Alzheimer's disease (AD) in life. However, it is unknown if CSF concentrations, and thus their accuracies, are affected by concomitant pathologies common in AD, such as α-synuclein (αSyn). Our primary goal was to test if biomarkers in patients with AD are altered by concomitant αSyn. We compared CSF Aß42, p-tau181, t-tau and Ng levels across autopsy-confirmed AD and concomitant AD and αSyn (AD+αSyn). Antemortem CSF levels were related to postmortem accumulations of αSyn. Finally, we tested how concommitant AD+αSyn affected diagnostic accuracy of two CSF-based strategies: the ATN framework and the t-tau/Aß42 ratio. METHODS: Inclusion criteria were neuropathologic diagnoses of AD, mixed AD+αSyn, and αSyn. A convenience sample of non-impaired controls were selected with available CSF and a mini mental state exam (MMSE)≥27. αSyn without AD and controls were included as reference groups. Analyses of covariance (ANCOVAs) tested planned comparisons were CSF Aß42, p-tau181, t-tau, and Ng differences across AD and AD+αSyn. Linear models tested how biomarkers were altered by αSyn accumulation in AD, accounting for pathologic amyloid-ß and tau. Receiver operating characteristic and area under the curve (AUC), including 95% confidence intervals (CI), evaluated diagnostic accuracy. RESULTS: Participants were 61 AD, 39 mixed AD+αSyn, 20 αSyn, and 61 Controls. AD had similar median age (73 [IQR=12]), MMSE (23 [IQR=9]), and sex distribution (Male=49%) compared to AD+αSyn age (70 [IQR=13]; p=0.3), MMSE (25 [IQR=9.5]; p=0.19), and sex distribution (Male=69%; p=0.077). ANCOVAs showed AD+αSyn had lower p-tau181 (F(1,94)=17, p=0), t-tau (F(1,93)=11, p=0.0004), and Ng levels (F(1,50)=12, p=0.0004) than AD; there was no difference in Aß42 (p=0.44). Models showed increasing αSyn related to lower p-tau181 (ß=-0.26, SE=0.092, p=0.0065), t-tau (ß=-0.19, SE=0.092, p=0.041), and Ng levels (ß=-0.2, SE=0.066, p=0.0046); αSyn was not a significant factor for Aß42 (p=1). T-tau/Aß42 had the highest accuracy when detecting AD, including mixed AD+αSyn cases (AUC=0.95; CI=0.92 to 0.98). DISCUSSION: Findings demonstrate that concomitant αSyn pathology in AD is associated with lower CSF p-tau181, t-tau, and Ng levels, and can affect diagnositic accuracy in AD patients.

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.

Psychometric Properties of Rapid Word-Based Rate Measures in the Assessment of Bulbar Amyotrophic Lateral Sclerosis: Comparisons With Syllable-Based Rate Tasks.

Purpose Rapid maximum performance repetition tasks have increasingly demonstrated their utility as clinimetric markers supporting diagnosis and monitoring of bulbar disease in amyotrophic lateral sclerosis (ALS). A recently developed protocol uses novel real-word repetitions instead of traditional nonword/syllable sequences in hopes of improving sensitivity to motor speech impairments by adding a phonological target constraint that would activate a greater expanse of the motor speech neuroanatomy. This study established the psychometric properties of this novel clinimetric protocol in its assessment of bulbar ALS and compared performance to traditional syllable sequence dysdiadochokinetic (DDK) tasks. Specific objectives were to (a) compare rates between controls and speakers with symptomatic versus presymptomatic bulbar disease, (b) characterize their discriminatory ability in detecting presymptomatic bulbar disease compared to healthy speech, (c) determine their articulatory movement underpinnings, and (d) establish within-individual longitudinal changes. Method DDK and novel tongue ("ticker"-TAR) and labial ("pepper"-LAR) articulatory rates were compared between n = 18 speakers with presymptomatic bulbar disease, n = 10 speakers with symptomatic bulbar disease, and n = 13 healthy controls. Bulbar disease groups were determined by a previously validated speaking rate cutoff. Discriminatory ability was determined using receiver operating characteristic analysis. Within-individual change over time was characterized in a subset of 16 participants with available longitudinal data using linear mixed-effects models. Real-time articulatory movements of the tongue front, tongue dorsum, jaw, and lips were captured using 3-D electromagnetic articulography; effects of movement displacement and speed on clinimetric rates were determined using stepwise linear regressions. Results All clinimetric rates (traditional DDK tasks and novel tasks) were reduced in speakers with symptomatic bulbar disease; only TAR was reduced in speakers with presymptomatic bulbar disease and was able to detect this group with an excellent discrimination ability (area under the curve = 0.83). Kinematic analyses revealed associations with expected articulators, greater motor complexity, and differential articulatory patterns for the novel real-word repetitions than their DDK counterparts. Only LAR significantly declined longitudinally over the disease course. Conclusion Novel real-word clinimetric rate tasks evaluating tongue and labial articulatory dysfunction are valid and effective markers for early detection and tracking of bulbar disease in ALS.

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.

Validation of Articulatory Rate and Imprecision Judgments in Speech of Individuals With Amyotrophic Lateral Sclerosis.

Purpose Perceptual judgments of articulatory function are commonly used by speech-language pathologists to evaluate articulatory performance in individuals with amyotrophic lateral sclerosis (ALS). The goal of this study was to evaluate the psychometric properties (e.g., reliability, validity) of these perceptual measures to inform their application as part of a comprehensive bulbar assessment tool in ALS. Method Preexisting data from 51 individuals with ALS were obtained from a larger longitudinal study. Five independent raters provided perceptual judgments of articulatory rate and imprecision in a sentence task. Inter- and intrarater reliability of these judgments were assessed. Perceptual ratings were correlated with an acoustic measure of articulatory rate, in syllables per second, obtained from passage-reading recordings. Both perceptual and acoustic measures were correlated with gold-standard kinematic tongue and jaw movement measures, recorded from sentences using electromagnetic articulography. Results The results revealed good inter- and intrarater reliability of perceptual judgments of articulatory function. Strong correlations were observed between perceptual ratings of articulatory rate and imprecision and acoustic measures of articulatory rate and kinematic measures of tongue speed. Conclusions These findings support the clinical application of perceptual judgments of articulatory function as valid and reliable measures of underlying articulatory changes in bulbar ALS. Additional research is needed to understand the responsiveness of these measures to clinical changes in articulatory function in ALS.

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.

Cognitive Profile and Markers of Alzheimer Disease-Type Pathology in Patients With Lewy Body Dementias.

OBJECTIVE: To determine whether patients with Lewy body dementia (LBD) with likely Alzheimer disease (AD)-type copathology are more impaired on confrontation naming than those without likely AD-type copathology. METHODS: We selected 57 patients with LBD (dementia with Lewy bodies [DLB], n = 38; Parkinson disease dementia [PDD], n = 19) with available AD CSF biomarkers and neuropsychological data. CSF ß-amyloid1-42 (Aß42), phosphorylated-tau (p-tau), and total-tau (t-tau) concentrations were measured. We used an autopsy-validated CSF cut point (t-tau:Aß42 ratio > 0.3, n = 43), or autopsy data when available (n = 14), to categorize patients as having LBD with (LBD + AD, n = 26) and without (LBD - AD, n = 31) likely AD-type copathology. Analysis of covariance tested between-group comparisons across biologically defined groups (LBD + AD, LBD - AD) and clinical phenotypes (DLB, PDD) on confrontation naming (30-item Boston Naming Test [BNT]), executive abilities (letter fluency [LF], reverse digit span [RDS]), and global cognition (Mini-Mental State Examination [MMSE]), with adjustment for age at dementia onset, time from dementia onset to test date, and time from CSF to test date. Spearman correlation related cognitive performance to CSF analytes. RESULTS: Patients with LBD + AD performed worse on BNT than patients with LBD - AD (F = 4.80, p = 0.03); both groups performed similarly on LF, RDS, and MMSE (all p > 0.1). Clinically defined PDD and DLB groups did not differ in performance on any of these measures (all p > 0.05). A correlation across all patients showed that BNT score was negatively associated with CSF t-tau (ρ = -0.28, p < 0.05) and p-tau (ρ = -0.26, p = 0.05) but not Aß42 (p > 0.1). CONCLUSION: Markers of AD-type copathology are implicated in impaired language performance in LBD. Biologically based classification of LBD may be advantageous over clinically defined syndromes to elucidate clinical heterogeneity.

Neuropathology of Speech Network Distinguishes Bulbar From Nonbulbar Amyotrophic Lateral Sclerosis.

Bulbar amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative subtype affecting speech and swallowing motor functions as well as associated with the burden of cognitive deficits. The neuroanatomical underpinnings of bulbar ALS are not well understood. The aim of this study was to compare neuropathology of the speech network (SpN) between 3 cases of bulbar-onset ALS (bALS), 3 cases of spinal-onset ALS (sALS) with antemortem bulbar ALS (sALSwB) against 3 sALS without antemortem bulbar ALS (sALSnoB) and 3 controls. Regional distribution and severity of neuronal loss, TDP-43 (transactive response DNA-binding protein of 43 kDa), and tau proteinopathy were examined. All 3 bALS cases showed marked neuronal loss and severe proteinopathy across most SpN regions; sALSwB cases showed no neuronal loss but mild and variable TDP-43 pathology in focal regions; sALSnoB cases demonstrated an absence of pathology. Two bALS cases had coexisting tauopathy in SpN regions, which was not noted in any sALS cases. The findings suggested that bALS may have a distinct neuropathological signature characterized by marked neuronal loss and polypathology in the SpN. Milder TDP-43 pathology in the SpN for sALSwB cases suggested a link between severity of bulbar ALS and SpN damage. Findings support a clinicopathologic link between bulbar symptoms and pathology in the SpN.