Primary Progressive Aphasia Associated With GRN Mutations: New Insights Into the Non-amyloid Logopenic Variant

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012174
Author(s):  
Dario Saracino ◽  
Sophie Ferrieux ◽  
Marie Noguès-Lassiaille ◽  
Marion Houot ◽  
Aurélie Funkiewiez ◽  
...  
Keyword(s):  
Primary Progressive Aphasia ◽  
Cross Sectional Study ◽  
Csf Biomarkers ◽  
Cognitive Profiles ◽  
Apraxia Of Speech ◽  
Cross Sectional ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Left Posterior ◽  
Language Network

Objective.To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with progranulin (GRN) mutations, and study their neuroanatomical correlates.Methods.PPA patients carrying GRN mutations (PPA-GRN) were selected amongst a national prospective research cohort of 1,696 frontotemporal dementia (FTD) patients, including 235 patients with PPA. All PPA patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and grey matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls, and sporadic PPA patients.Results.Among the overall population of 235 patients, 45 (19%) carried GRN mutations. We studied 32 of these and showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (13, 41%), followed by non-fluent/agrammatic (nfvPPA: 9, 28%) and mixed forms (8, 25%). Semantic variant was rather rare (2, 6%). LvPPA patients, qualified as non-amyloid-lvPPA, presented canonical logopenic deficit. Seven out of 13 had a pure form, six showed subtle additional linguistic deficits not fitting criteria for mixed PPA, hence labelled as “logopenic-spectrum variant”. GM atrophy primarily involved left posterior temporal gyrus, mirroring neuroanatomical changes of amyloid-positive-lvPPA. NfvPPA patients presented agrammatism (89%) rather than apraxia of speech (11%).Conclusions.This study shows that most frequent PPA variant associated with GRN mutations is non-amyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that language network may be affected at different levels. GRN testing is indicated for PPA patients, whether familial or sporadic. This finding is important for upcoming GRN gene-specific therapies.

scholarly journals Speech production differences in English and Italian speakers with nonfluent variant PPA

Neurology ◽  
2020 ◽  
Vol 94 (10) ◽  
pp. e1062-e1072 ◽  
Author(s):  
Elisa Canu ◽  
Federica Agosta ◽  
Giovanni Battistella ◽  
Edoardo G. Spinelli ◽  
Jessica DeLeon ◽  
...  
Keyword(s):  
Gray Matter Volume ◽  
Primary Progressive Aphasia ◽  
Cross Sectional Study ◽  
Speech Impairment ◽  
Neuropsychological Battery ◽  
Connected Speech ◽  
Cross Sectional ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Language Measures

ObjectiveTo understand whether the clinical phenotype of nonfluent/agrammatic primary progressive aphasia (nfvPPA) could present differences depending on the patient’s native language.MethodsIn this cross-sectional study, we analyzed connected speech samples in monolingual English (nfvPPA-E) and Italian speakers (nfvPPA-I) who were diagnosed with nfvPPA and matched for age, sex, and Mini-Mental State Examination scores. Patients also received a comprehensive neuropsychological battery. All patients and 2 groups of age-matched healthy controls underwent an MRI scan with 3D T1-weighted sequences. Connected speech measures and the other cognitive features were compared between patient groups. MRI variables, in terms of gray matter volume, were compared between each patient group and the corresponding controls.ResultsCompared to nfvPPA-E, nfvPPA-I had fewer years of education and shorter reported disease duration. The 2 groups showed similar regional atrophy compatible with clinical diagnosis. Patients did not differ in nonlanguage domains, comprising executive scores. Connected speech sample analysis showed that nfvPPA-E had significantly more distortions than nfvPPA-I, while nfvPPA-I showed reduced scores in some measures of syntactic complexity. On language measures, Italian speakers performed more poorly on syntactic comprehension.ConclusionsnfvPPA-E showed greater motor speech impairment than nfvPPA-I despite higher level of education and comparable disease severity and atrophy changes. The data also suggest greater grammatical impairment in nfvPPA-I. This study illustrates the need to take into account the possible effect of the individual's spoken language on the phenotype and clinical presentation of primary progressive aphasia variants.

scholarly journals The Course of Primary Progressive Aphasia Diagnosis : A Cross-Sectional Study.

2021 ◽  
Author(s):  
Aurélie Mouton ◽  
Alexandra PLONKA ◽  
Roxane FABRE ◽  
Maï Tran ◽  
Philippe ROBERT ◽  
...  
Keyword(s):  
Primary Progressive Aphasia ◽  
Data Bank ◽  
Cross Sectional Study ◽  
Diagnosis Delay ◽  
Sectional Study ◽  
Pharmacological Treatments ◽  
Cross Sectional ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
First Diagnosis

Abstract BackgroundThe Primary Progressive Aphasia (PPA) diagnosis trajectory is debated, as several changes in diagnosis occur during PPA course, due to phenotype evolution from isolated language alterations to global cognitive impairment.The goal of the present study, based on a French cohort was to describe the demographics and the evolution of subjects with (PPA) in comparison with Alzheimer Disease (AD) on a period of seven years. MethodsWe conducted a repeated cross-sectional study. The study population comprised individuals with PPA and AD diagnosis (N=167191) from 2010 to 2016 in the French National data Bank (BNA). Demographic variables, MMSE scores, diagnosis status at each visit and prescribed treatments were considered.ResultsFrom 2010 to 2016, 5186 patients were initially diagnosed with PPA, 162005 with AD. Compared to AD subjects, significant differences were found concerning: age (younger at first diagnosis for PPA), gender (more balanced in PPA), education level (higher in PPA) and MMSE score (higher in PPA). Percentage of pending diagnosis, delay between first consultation and first diagnosis and the number of different diagnoses before the diagnosis of interest were significantly higher in PPA group compared to AD group. Pharmacological and non-pharmacological treatments were significatively more recommended following PPA than AD diagnosis.ConclusionThis study improves the knowledge of PPA epidemiology and has the potential to help adopting appropriate public health service policies. It supports the hypothesis that PPA is diagnosed later than AD. The PPA diagnosis increases the prescription of non-pharmacological treatments, especially speech and language therapy (SLT) that is the main treatment available and most effective when at the initial stage.Trial registrationClinicalTrials.gov identifier NCT03687112

scholarly journals MODULARITY and granularity ACROSS the language network-A primary progressive aphasia perspective

Cortex ◽  
2021 ◽  
Author(s):  
M.-Marsel Mesulam ◽  
Christina A. Coventry ◽  
Benjamin M. Rader ◽  
Alan Kuang ◽  
Jaiashre Sridhar ◽  
...  
Keyword(s):  
Primary Progressive Aphasia ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Language Network

Spanish Version of the Mini-Linguistic State Examination for the Diagnosis of Primary Progressive Aphasia

2021 ◽  
pp. 1-8
Author(s):  
Jordi A. Matias-Guiu ◽  
Vanesa Pytel ◽  
Laura Hernández-Lorenzo ◽  
Nikil Patel ◽  
Katie A. Peterson ◽  
...  
Keyword(s):  
Primary Progressive Aphasia ◽  
Spanish Version ◽  
Classification Model ◽  
Healthy Controls ◽  
Language Test ◽  
Cross Sectional ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Clinical Variants ◽  
State Examination

Background: Primary progressive aphasia (PPA) is a neurodegenerative syndrome with three main clinical variants: non-fluent, semantic, and logopenic. Clinical diagnosis and accurate classification are challenging and often time-consuming. The Mini-Linguistic State Examination (MLSE) has been recently developed as a short language test to specifically assess language in neurodegenerative disorders. Objective: Our aim was to adapt and validate the Spanish version of MLSE for PPA diagnosis. Methods: Cross-sectional study involving 70 patients with PPA and 42 healthy controls evaluated with the MLSE. Patients were independently diagnosed and classified according to comprehensive cognitive evaluation and advanced neuroimaging. Results: Internal consistency was 0.758. The influence of age and education was very low. The area under the curve for discriminating PPA patients and healthy controls was 0.99. Effect sizes were moderate-large for the discrimination between PPA and healthy controls. Motor speech, phonology, and semantic subscores discriminated between the three clinical variants. A random forest classification model obtained an F1-score of 81%for the three PPA variants. Conclusion: Our study provides a brief and useful language test for PPA diagnosis, with excellent properties for both clinical routine assessment and research purposes.

Word Fluency Test Performance in Primary Progressive Aphasia and Primary Progressive Apraxia of Speech

2021 ◽  
pp. 1-8
Author(s):  
Lucia Scheffel ◽  
Joseph R. Duffy ◽  
Edythe A. Strand ◽  
Keith A. Josephs
Keyword(s):  
Test Performance ◽  
Primary Progressive Aphasia ◽  
High Sensitivity ◽  
Clinical Group ◽  
Apraxia Of Speech ◽  
Word Fluency ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
The Relationship ◽  
Fluency Task

Purpose This study compared performance on three-word fluency measures among individuals with primary progressive aphasia (PPA) and primary progressive apraxia of speech (PPAOS), and examined the relationship between word fluency and other measures of language and speech. Method This study included 106 adults with PPA and 30 adults with PPAOS. PPA participants were divided into three clinical subgroups: semantic (svPPA), logopenic (lvPPA), and nonfluent/agrammatic with or without apraxia of speech (nfPPA). Category fluency, letter fluency, and action/verb fluency tasks were administered to all participants. Results The four clinical groups performed abnormally on the word fluency measures, although not to a degree that represented high sensitivity to their PPA or PPAOS diagnosis. All PPA subgroups produced fewer words compared to individuals with PPAOS on all word fluency measures. Moderate correlations were found between word fluency and aphasia severity and naming performance in some of the clinical groups. Conclusions Word fluency measures are often challenging for individuals with PPA and PPAOS, but they are not of equal difficulty, with letter fluency being the most difficult. Differences among word fluency tests also vary to some degree as a function of the clinical group in question, with least impairment in PPAOS. However, the findings of this study do not support statistically significant differences in word fluency task performance among the PPA subgroups. Correlations suggest that word fluency performance in PPA is at least partly related to aphasia severity.

scholarly journals Electroencephalography in primary progressive aphasia and apraxia of speech

Aphasiology ◽  
2018 ◽  
Vol 33 (11) ◽  
pp. 1410-1417 ◽  
Author(s):  
Rene L. Utianski ◽  
John N. Caviness ◽  
Gregory A. Worrell ◽  
Joseph R. Duffy ◽  
Heather M. Clark ◽  
...  
Keyword(s):  
Primary Progressive Aphasia ◽  
Apraxia Of Speech ◽  
Progressive Aphasia ◽  
Primary Progressive

scholarly journals Primary progressive aphasia and the evolving neurology of the language network

2014 ◽  
Vol 10 (10) ◽  
pp. 554-569 ◽  
Author(s):  
M.-Marsel Mesulam ◽  
Emily J. Rogalski ◽  
Christina Wieneke ◽  
Robert S. Hurley ◽  
Changiz Geula ◽  
...  
Keyword(s):  
Primary Progressive Aphasia ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Language Network

scholarly journals Tau uptake in agrammatic primary progressive aphasia with and without apraxia of speech

2018 ◽  
Vol 25 (11) ◽  
pp. 1352-1357 ◽  
Author(s):  
R. L. Utianski ◽  
J. L. Whitwell ◽  
C. G. Schwarz ◽  
J. R. Duffy ◽  
H. Botha ◽  
...  
Keyword(s):  
Primary Progressive Aphasia ◽  
Apraxia Of Speech ◽  
Progressive Aphasia ◽  
Primary Progressive

scholarly journals Lack of Frank Agrammatism in the Nonfluent Agrammatic Variant of Primary Progressive Aphasia

2016 ◽  
Vol 6 (3) ◽  
pp. 407-423 ◽  
Author(s):  
Naida L. Graham ◽  
Carol Leonard ◽  
David F. Tang-Wai ◽  
Sandra Black ◽  
Tiffany W. Chow ◽  
...  
Keyword(s):  
Primary Progressive Aphasia ◽  
Diagnostic Feature ◽  
Apraxia Of Speech ◽  
Volumetric Mri ◽  
Motor Speech ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Grammatical Morphemes ◽  
Grammatical Errors ◽  
Diagnosis Method

Background/Aims: Frank agrammatism, defined as the omission and/or substitution of grammatical morphemes with associated grammatical errors, is variably reported in patients with nonfluent variant primary progressive aphasia (nfPPA). This study addressed whether frank agrammatism is typical in agrammatic nfPPA patients when this feature is not required for diagnosis. Method: We assessed grammatical production in 9 patients who satisfied current diagnostic criteria. Although the focus was agrammatism, motor speech skills were also evaluated to determine whether dysfluency arose primarily from apraxia of speech (AOS), instead of, or in addition to, agrammatism. Volumetric MRI analyses provided impartial imaging-supported diagnosis. Results: The majority of cases exhibited neither frank agrammatism nor AOS. Conclusion: There are nfPPA patients with imaging-supported diagnosis and preserved motor speech skills who do not exhibit frank agrammatism, and this may persist beyond the earliest stages of the illness. Because absence of frank agrammatism is a subsidiary diagnostic feature in the logopenic variant of PPA, this result has implications for differentiation of the nonfluent and logopenic variants, and indicates that PPA patients with nonfluent speech in the absence of frank agrammatism or AOS do not necessarily have the logopenic variant.

scholarly journals Speech Metrics and Samples That Differentiate Between Nonfluent/Agrammatic and Logopenic Variants of Primary Progressive Aphasia

2021 ◽  
pp. 1-22
Author(s):  
Katarina L. Haley ◽  
Adam Jacks ◽  
Jordan Jarrett ◽  
Taylor Ray ◽  
Kevin T. Cunningham ◽  
...  
Keyword(s):  
Large Scale ◽  
Primary Progressive Aphasia ◽  
Diagnostic Tools ◽  
Future Research ◽  
Apraxia Of Speech ◽  
Connected Speech ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Syllable Duration ◽  
Semantic Variant

Purpose Of the three currently recognized variants of primary progressive aphasia, behavioral differentiation between the nonfluent/agrammatic (nfvPPA) and logopenic (lvPPA) variants is particularly difficult. The challenge includes uncertainty regarding diagnosis of apraxia of speech, which is subsumed within criteria for variant classification. The purpose of this study was to determine the extent to which a variety of speech articulation and prosody metrics for apraxia of speech differentiate between nfvPPA and lvPPA across diverse speech samples. Method The study involved 25 participants with progressive aphasia (10 with nfvPPA, 10 with lvPPA, and five with the semantic variant). Speech samples included a word repetition task, a picture description task, and a story narrative task. We completed acoustic analyses of temporal prosody and quantitative perceptual analyses based on narrow phonetic transcription and then evaluated the degree of differentiation between nfvPPA and lvPPA participants (with the semantic variant serving as a reference point for minimal speech production impairment). Results Most, but not all, articulatory and prosodic metrics differentiated statistically between the nfvPPA and lvPPA groups. Measures of distortion frequency, syllable duration, syllable scanning, and—to a limited extent—syllable stress and phonemic accuracy showed greater impairment in the nfvPPA group. Contrary to expectations, classification was most accurate in connected speech samples. A customized connected speech metric—the narrative syllable duration—yielded excellent to perfect classification accuracy. Discussion Measures of average syllable duration in multisyllabic utterances are useful diagnostic tools for differentiating between nfvPPA and lvPPA, particularly when based on connected speech samples. As such, they are suitable candidates for automatization, large-scale study, and application to clinical practice. The observation that both speech rate and distortion frequency differentiated more effectively in connected speech than on a motor speech examination suggests that it will be important to evaluate interactions between speech and discourse production in future research.

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