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
To determine whether logopenic features of phonologic loop dysfunction reflect Alzheimer disease (AD) neuropathology in primary progressive aphasia (PPA).
We performed a retrospective case-control ...study of 34 patients with PPA with available autopsy tissue. We compared baseline and longitudinal clinical features in patients with primary AD neuropathology to those with primary non-AD pathologies. We analyzed regional neuroanatomic disease burden in pathology-defined groups using postmortem neuropathologic data.
A total of 19/34 patients had primary AD pathology and 15/34 had non-AD pathology (13 frontotemporal lobar degeneration, 2 Lewy body disease). A total of 16/19 (84%) patients with AD had a logopenic spectrum phenotype; 5 met published criteria for the logopenic variant (lvPPA), 8 had additional grammatical or semantic deficits (lvPPA+), and 3 had relatively preserved sentence repetition (lvPPA-). Sentence repetition was impaired in 68% of patients with PPA with AD pathology; forward digit span (DF) was impaired in 90%, substantially higher than in non-AD PPA (33%,
< 0.01). Lexical retrieval difficulty was common in all patients with PPA and did not discriminate between groups. Compared to non-AD, PPA with AD pathology had elevated microscopic neurodegenerative pathology in the superior/midtemporal gyrus, angular gyrus, and midfrontal cortex (
< 0.01). Low DF scores correlated with high microscopic pathologic burden in superior/midtemporal and angular gyri (
≤ 0.03).
Phonologic loop dysfunction is a central feature of AD-associated PPA and specifically correlates with temporoparietal neurodegeneration. Quantitative measures of phonologic loop function, combined with modified clinical lvPPA criteria, may help discriminate AD-associated PPA.
Abstract
Quantitative examinations of speech production in amyotrophic lateral sclerosis (ALS) are rare. To identify language features minimally confounded by a motor disorder, we investigated ...linguistic and motor sources of impaired sentence expression in ALS, and we related deficits to gray matter (GM) and white matter (WM) MRI abnormalities. We analyzed a semi-structured speech sample in 26 ALS patients and 19 healthy seniors for motor- and language-related deficits. Regression analyses related grammaticality to GM atrophy and reduced WM fractional anisotropy (FA). Results demonstrated that ALS patients were impaired relative to controls on quantity of speech, speech rate, speech articulation errors, and grammaticality. Speech rate and articulation errors were related to the patients' motor impairment, while grammatical difficulty was independent of motor difficulty. This was confirmed in subgroups without dysarthria and without executive deficits. Regressions related grammatical expression to GM atrophy in left inferior frontal and anterior temporal regions and to reduced FA in superior longitudinal and inferior frontal-occipital fasciculi. In conclusion, patients with ALS exhibit multifactorial deficits in sentence expression. They demonstrate a deficit in grammatical expression that is independent of their motor disorder. Impaired grammatical expression is related to disease in a network of brain regions associated with syntactic processing.
► We examined narrative discourse in patients with Lewy body spectrum disorder. ► Lewy body disease and PD with dementia patients show impaired narrative organization. ► Their narrative organization ...is correlated with deficits in executive functioning. ► Their impaired discourse cohesion is related to reduced frontal cortical volume. ► Narrative discourse includes both linguistic and non-linguistic components.
Narrative discourse is an essential component of day-to-day communication, but little is known about narrative in Lewy body spectrum disorder (LBSD), including Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), and dementia with Lewy bodies (DLB). We performed a detailed analysis of a semi-structured speech sample in 32 non-aphasic patients with LBSD, and we related their narrative impairments to gray matter (GM) atrophy using voxel-based morphometry. We found that patients with PDD and DLB have significant difficulty organizing their narrative speech. This was correlated with deficits on measures of executive functioning and speech fluency. Regression analyses associated this deficit with reduced cortical volume in inferior frontal and anterior cingulate regions. These findings are consistent with a model of narrative discourse that includes executive as well as language components and with an impairment of the organizational component of narrative discourse in patients with PDD and DLB.
We compared digital speech and language features of patients with amnestic Alzheimer 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.
We included patients with aAD or lvPPA with CSF (phosphorylated tau (p-tau/β-amyloid Aβ ≥0.09, and total tau/Aβ ≥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.
We examined patients with aAD (n = 44; age 62 ± 8 years; 24 women; Mini-Mental State Examination MMSE score 21.1 ± 4.8) or lvPPA (n = 21; age 64.1 ± 8.2 years; 11 women; MMSE score 23.0 ± 4.2) and HC (n = 28; age 65.9 ± 5.9 years, 15 women; MMSE score 29 ± 1). Patients with lvPPA produced fewer verbs (10.5 ± 2.3;
= 0.001) and adjectives (2.7 ± 1.3,
= 0.019) and more fillers (7.4 ± 3.9;
= 0.022) with lower lexical diversity (0.84 ± 0.1;
= 0.05) and higher pause rate (54.2 ± 19.2;
= 0.015) than individuals with 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 score: β = -1.6,
= 0.009; Boston Naming Test BNT score: β = -4.36,
< 0.001), adverbs (MMSE score: β = -1.9,
= 0.003; BNT score: β = -2.41,
= 0.041), pause rate (MMSE score: β = -1.21,
= 0.041; BNT score: β = -2.09,
= 0.041), and word length (MMSE score: β = 1.75,
= 0.001; BNT score: β = 2.94,
= 0.003) were significantly correlated with both MMSE and BNT scores, but other measures were not correlated with MMSE and/or BNT score. Prepositions (
= -0.36,
= 0.019), nouns (
= -0.31,
= 0.047), speech segment duration (
= -0.33,
= 0.032), word frequency (
= 0.33,
= 0.036), and pause rate (
= 0.34,
= 0.026) were correlated with patients' CSF p-tau levels.
Our measures captured language and speech differences between the 2 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.
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.
We used natural speech samples produced in a picture description task by younger (
= 76, ages 18-22 years) and older (
= 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.
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).
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.
https://doi.org/10.23641/asha.24964179.
To help understand speech changes in behavioral variant frontotemporal dementia (bvFTD), we developed and implemented automatic methods of speech analysis for quantification of prosody, and evaluated ...clinical and anatomical correlations.
We analyzed semi-structured, digitized speech samples from 32 patients with bvFTD (21 male, mean age 63 ± 8.5, mean disease duration 4 ± 3.1 years) and 17 matched healthy controls (HC). We automatically extracted fundamental frequency (f0, the physical property of sound most closely correlating with perceived pitch) and computed pitch range on a logarithmic scale (semitone) that controls for individual and sex differences. We correlated f0 range with neuropsychiatric tests, and related f0 range to gray matter (GM) atrophy using 3T T1 MRI.
We found significantly reduced f0 range in patients with bvFTD (mean 4.3 ± 1.8 ST) compared to HC (5.8 ± 2.1 ST;
= 0.03). Regression related reduced f0 range in bvFTD to GM atrophy in bilateral inferior and dorsomedial frontal as well as left anterior cingulate and anterior insular regions.
Reduced f0 range reflects impaired prosody in bvFTD. This is associated with neuroanatomic networks implicated in language production and social disorders centered in the frontal lobe. These findings support the feasibility of automated speech analysis in frontotemporal dementia and other disorders.
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 < 0.001). 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.
A brief speech expression protocol that can be administered and scored without special training would aid in the differential diagnosis of the 3 principal forms of primary progressive aphasia (PPA): ...nonfluent/agrammatic PPA, logopenic variant PPA, and semantic variant PPA.
We used a picture-description task to elicit a short speech sample, and we evaluated impairments in speech-sound production, speech rate, lexical retrieval, and grammaticality. We compared the results with those obtained by a longer, previously validated protocol and further validated performance with multimodal imaging to assess the neuroanatomical basis of the deficits.
We found different patterns of impaired grammar in each PPA variant, and additional language production features were impaired in each: nonfluent/agrammatic PPA was characterized by speech-sound errors; logopenic variant PPA by dysfluencies (false starts and hesitations); and semantic variant PPA by poor retrieval of nouns. Strong correlations were found between this brief speech sample and a lengthier narrative speech sample. A composite measure of grammaticality and other measures of speech production were correlated with distinct regions of gray matter atrophy and reduced white matter fractional anisotropy in each PPA variant.
These findings provide evidence that large-scale networks are required for fluent, grammatical expression; that these networks can be selectively disrupted in PPA syndromes; and that quantitative analysis of a brief speech sample can reveal the corresponding distinct speech characteristics.
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