scholarly journals Redefining the multidimensional clinical phenotypes of frontotemporal lobar degeneration syndromes

2019 ◽  
Author(s):  
Alexander G. Murley ◽  
Ian Coyle-Gilchrist ◽  
Matthew Rouse ◽  
P Simon Jones ◽  
Win Li ◽  
...  
Keyword(s):  
Diagnostic Criteria ◽  
Clinical Features ◽  
Frontotemporal Lobar Degeneration ◽  
Clinical Phenotype ◽  
Principal Component ◽  
Primary Progressive Aphasia ◽  
Diagnostic Features ◽  
Cross Sectional ◽  
Progressive Aphasia ◽  
Primary Progressive

AbstractThe syndromes caused by frontotemporal lobar degeneration (FTLD) have highly heterogenous and overlapping clinical features. There has been great progress in the refinement of clinical diagnostic criteria in the last decade, but we propose that a better understanding of aetiology, pathophysiology and symptomatic treatments can arise from a transdiagnostic approach to clinical phenotype and brain morphometry. In a cross-sectional epidemiological study, we examined 310 patients with a syndrome likely to be caused by frontotemporal lobar degeneration, including behavioural variant frontotemporal dementia (bvFTD), the non-fluent (nfvPPA), semantic (svPPA) variants of primary progressive aphasia, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We also included patients with logopenic primary progressive aphasia (lvPPA) and those who met criteria for PPA but not one of the three subtypes. To date, forty-nine patients have a neuropathological diagnosis. A principal component analysis identified symptom dimensions that broadly recapitulated the core features of the main clinical syndromes. However, the subject-specific scores on these dimensions showed considerable overlap across the diagnostic groups. Sixty-two percent of participants had phenotypic features that met the diagnostic criteria for more than one syndrome. Behavioural disturbance was prevalent in all groups. Forty-four percent of patients with CBS had PSP-like features and thirty percent of patients with PSP had CBS-like features. Many patients with PSP and CBS had language impairments consistent with nfvPPA while patients with bvFTD often had semantic impairments. Using multivariate source-based morphometry on a subset of patients (n=133), we identified patterns of co-varying brain atrophy that were represented across the diagnostic groups. Canonical correlation analysis of clinical and imaging components found three key brain-behaviour relationships that revealed a continuous spectrum across the cohort rather than discrete diagnostic entities. In the forty-six patients with longitudinal follow up (mean 3.6 years) syndromic overlap increased with time. Together, these results show that syndromes associated with FTLD do not form discrete mutually exclusive categories from their clinical features or structural brain changes, but instead exist in a multidimensional spectrum. Patients often manifest diagnostic features of multiple disorders and deficits in behaviour, movement and language domains are not confined to specific diagnostic groups. It is important to recognise individual differences in clinical phenotype, both for clinical management and to understand pathogenic mechanisms. We suggest that the adoption of a transdiagnostic approach to the spectrum of FTLD syndromes provides a useful framework with which to understand disease progression, heterogeneity and treatment.

scholarly journals Redefining the multidimensional clinical phenotypes of frontotemporal lobar degeneration syndromes

Brain ◽  
2020 ◽  
Vol 143 (5) ◽  
pp. 1555-1571 ◽  
Author(s):  
Alexander G Murley ◽  
Ian Coyle-Gilchrist ◽  
Matthew A Rouse ◽  
P Simon Jones ◽  
Win Li ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Frontotemporal Dementia ◽  
Diagnostic Criteria ◽  
Clinical Features ◽  
Frontotemporal Lobar Degeneration ◽  
Clinical Phenotype ◽  
Principal Component ◽  
Corticobasal Syndrome ◽  
Diagnostic Features ◽  
Cross Sectional

Abstract The syndromes caused by frontotemporal lobar degeneration have highly heterogeneous and overlapping clinical features. There has been great progress in the refinement of clinical diagnostic criteria in the past decade, but we propose that a better understanding of aetiology, pathophysiology and symptomatic treatments can arise from a transdiagnostic approach to clinical phenotype and brain morphometry. In a cross-sectional epidemiological study, we examined 310 patients with a syndrome likely to be caused by frontotemporal lobar degeneration, including behavioural variant frontotemporal dementia, non-fluent, and semantic variants of primary progressive aphasia (PPA), progressive supranuclear palsy and corticobasal syndrome. We included patients with logopenic PPA and those who met criteria for PPA but not a specific subtype. To date, 49 patients have a neuropathological diagnosis. A principal component analysis identified symptom dimensions that broadly recapitulated the core features of the main clinical syndromes. However, the subject-specific scores on these dimensions showed considerable overlap across the diagnostic groups. Sixty-two per cent of participants had phenotypic features that met the diagnostic criteria for more than one syndrome. Behavioural disturbance was prevalent in all groups. Forty-four per cent of patients with corticobasal syndrome had progressive supranuclear palsy-like features and 30% of patients with progressive supranuclear palsy had corticobasal syndrome-like features. Many patients with progressive supranuclear palsy and corticobasal syndrome had language impairments consistent with non-fluent variant PPA while patients with behavioural variant frontotemporal dementia often had semantic impairments. Using multivariate source-based morphometry on a subset of patients (n = 133), we identified patterns of covarying brain atrophy that were represented across the diagnostic groups. Canonical correlation analysis of clinical and imaging components found three key brain-behaviour relationships, with a continuous spectrum across the cohort rather than discrete diagnostic entities. In the 46 patients with follow-up (mean 3.6 years) syndromic overlap increased with time. Together, these results show that syndromes associated with frontotemporal lobar degeneration do not form discrete mutually exclusive categories from their clinical features or structural brain changes, but instead exist in a multidimensional spectrum. Patients often manifest diagnostic features of multiple disorders while deficits in behaviour, movement and language domains are not confined to specific diagnostic groups. It is important to recognize individual differences in clinical phenotype, both for clinical management and to understand pathogenic mechanisms. We suggest that a transdiagnostic approach to the spectrum of frontotemporal lobar degeneration syndromes provides a useful framework with which to understand disease aetiology, progression, and heterogeneity and to target future treatments to a higher proportion of patients.

scholarly journals Predicting loss of independence and mortality in frontotemporal lobar degeneration syndromes

2020 ◽  
Author(s):  
Alexander G. Murley ◽  
Matthew A. Rouse ◽  
Ian Coyle-Gilchrist ◽  
P Simon Jones ◽  
Win Li ◽  
...  
Keyword(s):  
Survival Time ◽  
Clinical Features ◽  
Frontotemporal Lobar Degeneration ◽  
Proportional Hazards ◽  
Care Home ◽  
Primary Progressive Aphasia ◽  
Functional Independence ◽  
Cox Proportional Hazards ◽  
Progressive Aphasia ◽  
Primary Progressive

AbstractObjectiveTo test the hypothesis that in syndromes associated with frontotemporal lobar degeneration, behavioural impairment predicts loss of functional independence and motor clinical features predict mortality, irrespective of syndrome subtype.MethodWe used a transdiagnostic approach to survival in an epidemiological cohort, testing the association between clinical features, independence and survival in patients with clinical diagnoses of behavioural variant frontotemporal dementia (n=64), non-fluent variant primary progressive aphasia (n=36), semantic variant primary progressive aphasia (n=25), progressive supranuclear palsy (n=101) and corticobasal syndrome (n=68). A principal components analysis identified six dimensions of clinical features. Using Cox proportional hazards and logistic regression we identified the association between each of these dimensions and functionally independent survival (time from clinical assessment to care home admission), and absolute survival (time to death). Analyses adjusted for the covariates of age, gender and diagnostic group. Secondary analysis excluded specific diagnostic groups.ResultsBehavioural disturbance, including impulsivity and apathy, was associated with reduced functionally independent survival (OR 2.46, p<0.001), even if patients with bvFTD were removed from the analysis. Motor impairments were associated with reduced absolute survival, even if patients with PSP and CBS were removed from the analysis.ConclusionOur results may help individualised prognostication and planning of disease-modifying trials and support a transdiagnostic approach to symptomatic treatment trials in patients with clinical syndromes associated with frontotemporal lobar degeneration.

scholarly journals Predicting loss of independence and mortality in frontotemporal lobar degeneration syndromes

2021 ◽  
pp. jnnp-2020-324903 ◽  
Author(s):  
Alexander G Murley ◽  
Matthew A Rouse ◽  
Ian T S Coyle-Gilchrist ◽  
P Simon Jones ◽  
Win Li ◽  
...  
Keyword(s):  
Survival Time ◽  
Clinical Features ◽  
Frontotemporal Lobar Degeneration ◽  
Care Home ◽  
Primary Progressive Aphasia ◽  
Functional Independence ◽  
Cox Proportional Hazards ◽  
Diagnostic Group ◽  
Progressive Aphasia ◽  
Primary Progressive

ObjectiveTo test the hypothesis that in syndromes associated with frontotemporal lobar degeneration, behavioural impairment predicts loss of functional independence and motor clinical features predict mortality, irrespective of diagnostic group.MethodsWe used a transdiagnostic approach to survival in an epidemiological cohort in the UK, testing the association between clinical features, independence and survival in patients with clinical diagnoses of behavioural variant frontotemporal dementia (bvFTD n=64), non-fluent variant primary progressive aphasia (nfvPPA n=36), semantic variant primary progressive aphasia (svPPA n=25), progressive supranuclear palsy (PSP n=101) and corticobasal syndrome (CBS n=68). A principal components analysis identified six dimensions of clinical features. Using Cox proportional hazards and logistic regression, we identified the association between each of these dimensions and both functionally independent survival (time from clinical assessment to care home admission) and absolute survival (time to death). Analyses adjusted for the covariates of age, gender and diagnostic group. Secondary analysis excluded specific diagnostic groups.ResultsBehavioural disturbance, including impulsivity and apathy, was associated with reduced functionally independent survival (OR 2.46, p<0.001), even if patients with bvFTD were removed from the analysis. Motor impairments were associated with reduced absolute survival, even if patients with PSP and CBS were removed from the analysis.ConclusionOur results can assist individualised prognostication and planning of disease-modifying trials, and they support a transdiagnostic approach to symptomatic treatment trials in patients with clinical syndromes associated with frontotemporal lobar degeneration.

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.

scholarly journals Primary progressive aphasia: Classification of variants in 100 consecutive Brazilian cases

2013 ◽  
Vol 7 (1) ◽  
pp. 110-121 ◽  
Author(s):  
Mirna Lie Hosogi Senaha ◽  
Paulo Caramelli ◽  
Sonia M.D. Brucki ◽  
Jerusa Smid ◽  
Leonel T. Takada ◽  
...  
Keyword(s):  
Diagnostic Criteria ◽  
Language Impairment ◽  
Demographic Data ◽  
Primary Progressive Aphasia ◽  
Clinical Syndrome ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Diagnosis And Classification ◽  
Consensus Classification

ABSTRACT Primary progressive aphasia (PPA) is a neurodegenerative clinical syndrome characterized primarily by progressive language impairment. Recently, consensus diagnostic criteria were published for the diagnosis and classification of variants of PPA. The currently recognized variants are nonfluent/agrammatic (PPA-G), logopenic (PPA-L) and semantic (PPA-S). Objective: To analyze the demographic data and the clinical classification of 100 PPA cases. Methods: Data from 100 PPA patients who were consecutively evaluated between 1999 and 2012 were analyzed. The patients underwent neurological, cognitive and language evaluation. The cases were classified according to the proposed variants, using predominantly the guidelines proposed in the consensus diagnostic criteria from 2011. Results: The sample consisted of 57 women and 43 men, aged at onset 67.2±8.1 years (range of between 53 and 83 years). Thirty-five patients presented PPA-S, 29 PPA-G and 16 PPA-L. It was not possible to classify 20% of the cases into any one of the proposed variants. Conclusion: It was possible to classify 80% of the sample into one of the three PPA variants proposed. Perhaps the consensus classification requires some adjustments to accommodate cases that do not fit into any of the variants and to avoid overlap where cases fit more than one variant. Nonetheless, the established current guidelines are a useful tool to address the classification and diagnosis of PPA and are also of great value in standardizing terminologies to improve consistency across studies from different research centers.

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 natural history of primary progressive aphasia: beyond aphasia

2021 ◽  
Author(s):  
Hulya Ulugut ◽  
Simone Stek ◽  
Lianne E. E. Wagemans ◽  
Roos J. Jutten ◽  
Maria Antoinette Keulen ◽  
...  
Keyword(s):  
Diagnostic Criteria ◽  
Primary Progressive Aphasia ◽  
Cognitive Test ◽  
Motor Deficits ◽  
Behavioral Disturbances ◽  
Progressive Aphasia ◽  
Clinical Criteria ◽  
Primary Progressive ◽  
Clinical Onset ◽  
History Of

Abstract Introduction Primary progressive aphasia (PPA) is divided into three prototypical subtypes that are all characterized by their single core symptom of aphasia. Although later in their course, other cognitive, behavioral, and motor domains may become involved, little is known about the progression profile of each subtype relative to the other subtypes. Methods In this longitudinal retrospective cohort study, based on the recent biomarker-supported diagnostic criteria, 24 subjects diagnosed with semantic variant (svPPA), 22 with non-fluent variant (nfvPPA), and 18 with logopenic variant (lvPPA) were collected and followed up for 1–6 years. Symptom distribution, cognitive test and neuropsychiatric inventory scores, and progression into another syndrome were assessed. Results Over time, lvPPA progressed with broader language problems (PPA-extended) and nfvPPA progressed to mutism, whereas semantic impairment remained the major problem in svPPA. Apart from linguistic problems, svPPA developed pronounced behavioral disturbances, whereas lvPPA exhibited a greater cognitive decline. By contrast, in nfvPPA motor deficits were more common. Furthermore, within 5 years (IQR = 2.5) after clinical onset, 65.6% of the patients additionally fulfilled the clinical criteria for another neurodegenerative syndrome (PPA-plus). Fourteen out of 24 (58%) svPPA patients additionally met the diagnostic criteria of behavioral variant frontotemporal dementia (5.1 years, IQR = 1.1), whereas the clinical features of 15/18 (83%) lvPPA patients were consistent with Alzheimer disease dementia (4.5 years IQR = 3.4). Furthermore, 12/22 (54%) of the subjects with the nfvPPA progressed to meet the diagnostic criteria of corticobasal syndrome, progressive supranuclear palsy, or motor neuron disease (5.1 years IQR = 3.4). Discussion Despite aphasia being the initial and unique hallmark of the syndrome, our longitudinal results showed that PPA is not a language limited disorder and progression differs widely for each subtype, both with respect to the nature of symptoms and disease duration.

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