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Background: Primary progressive aphasia (PPA) is a clinical syndrome characterized by gradual loss of language skills. This study aimed to evaluate the diagnostic capacity of a connected speech task for the diagnosis of PPA and its variants, to determine the main components of spontaneous speech, and to examine their neural correlates., Methods: A total of 118 participants (31 patients with nfvPPA, 11 with svPPA, 45 with lvPPA, and 31 healthy controls) were evaluated with the Cookie Theft picture description task and a comprehensive language assessment protocol. Patients also underwent 18 F-fluorodeoxyglucose positron emission tomography and magnetic resonance imaging studies. Principal component analysis and machine learning were used to evaluate the main components of connected speech and the accuracy of connected speech parameters for diagnosing PPA. Voxel-based analyses were conducted to evaluate the correlation between spontaneous speech components and brain metabolism, brain volumes, and white matter microstructure., Results: Discrimination between patients with PPA and controls was 91.67%, with 77.78% discrimination between PPA variants. Parameters related to speech rate and lexical variables were the most discriminative for classification. Three main components were identified: lexical features, fluency, and syntax. The lexical component was associated with ventrolateral frontal regions, while the fluency component was associated with the medial superior prefrontal cortex. Number of pauses was more related with the left parietotemporal region, while pauses duration with the bilateral frontal lobe. The lexical component was correlated with several tracts in the language network (left frontal aslant tract, left superior longitudinal fasciculus I, II, and III, left arcuate fasciculus, and left uncinate fasciculus), and fluency was linked to the frontal aslant tract., Conclusion: Spontaneous speech assessment is a useful, brief approach for the diagnosis of PPA and its variants. Neuroimaging correlates suggested a subspecialization within the left frontal lobe, with ventrolateral regions being more associated with lexical production and the medial superior prefrontal cortex with speech rate., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Primary progressive aphasia (PPA) is a neurodegenerative syndrome for which no effective treatment is available., Objective: We aimed to assess the effect of repetitive transcranial magnetic stimulation (rTMS), using personalized targeting., Methods: We conducted a randomized, double-blind, pilot study of patients with PPA receiving rTMS, with a subgroup of patients receiving active- versus control-site rTMS in a cross-over design. Target for active TMS varied among the cases and was determined during a pre-treatment phase from a list of potential regions. The primary outcome was changes in spontaneous speech (word count). Secondary outcomes included changes in other language tasks, global cognition, global impression of change, neuropsychiatric symptoms, and brain metabolism using FDG-PET., Results: Twenty patients with PPA were enrolled (14 with nonfluent and 6 with semantic variant PPA). For statistical analyses, data for the two variants were combined. Compared to the control group (n = 7), the group receiving active-site rTMS (n = 20) showed improvements in spontaneous speech, other language tasks, patient and caregiver global impression of change, apathy, and depression. This group also showed improvement or stabilization of results obtained in the baseline examination. Increased metabolism was observed in several brain regions after the therapy, particularly in the left frontal and parieto-temporal lobes and in the precuneus and posterior cingulate bilaterally., Conclusion: We found an improvement in language, patient and caregiver perception of change, apathy, and depression using high frequency rTMS. The increase of regional brain metabolism suggests enhancement of synaptic activity with the treatment., Trial Registration: NCT03580954 (https://clinicaltrials.gov/ct2/show/NCT03580954).

Background: Primary progressive aphasia (PPA) is a clinical syndrome including a group of neurodegenerative disorders that present with language impairment. We hypothesised that impairment in reading prosody may be present in a subgroup of patients with PPA, and particularly non-fluent PPA (nfvPPA), because of the impairment of key brain regions involved in the pathophysiology of speech dysprosody and reading observed in these patients., Methods: Ninety-five participants were evaluated using a narrative text comprising several declarative, exclamatory, and interrogative sentences, as well as a comprehensive language protocol. Patients were also examined with 18 F-fluorodeoxyglucose positron emission tomography imaging., Results: Impairment was more frequent and more severe in patients with nfvPPA, especially in the subgroup of patients with Apraxia of Speech (AOS). Patients with nfvPPA, mainly those with AOS, showed lower values in several pitch variables. Statistically significant differences were also observed in sentence duration, reading times, and types of error. A regression model including mean length of utterances, time after full stops, number of pauses, and number of pitch variables below the mean, correctly classified 70-71.3% of patients. When combined with sentence repetition task, the percentage of patients correctly classified was 96.2% and 92.4%, respectively, for each classification. The left frontal lobe was the region most strongly correlated with reading prosody parameters. Specific tasks displayed additional correlations with the left parietal and occipital lobes; right frontal lobe, thalamus, and caudate; and right cerebellum., Conclusion: Reading prosody is relevant in PPA diagnosis and classification. Because reading prosody may be quantified, it is amenable to use in diagnosis and follow-up. We found neuroimaging correlation with metabolism in the left frontal lobe, as well as in other regions including the right frontal lobe, basal ganglia, and cerebellum, which suggests that these may be the main brain regions involved in prosodic control in patients with PPA., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Primary progressive aphasia (PPA) is a clinical syndrome of neurodegenerative origin with 3 main variants: non-fluent, semantic, and logopenic. However, there is some controversy about the existence of additional subtypes. Our aim was to study the language and cognitive features associated with a new proposed classification for PPA., Material and Methods: Sixty-eight patients with PPA in early stages of the disease and 20 healthy controls were assessed with a comprehensive language and cognitive protocol. They were also evaluated with 18 F-FDG positron emision tomography (PET). Patients were classified according to FDG PET regional metabolism, using our previously developed algorithm based on a hierarchical agglomerative cluster analysis with Ward's linkage method. Five variants were found, with both the non-fluent and logopenic variants being split into 2 subtypes. Machine learning techniques were used to predict each variant according to language assessment results., Results: Non-fluent type 1 was associated with poorer performance in repetition of sentences and reading of irregular words than non-fluent type 2. Conversely, the second group showed a higher degree of apraxia of speech. Patients with logopenic variant type 1 performed more poorly on action naming than patients with logopenic type 2. Language assessments were predictive of PET-based subtypes in 86%-89% of cases using clustering analysis and principal components analysis., Conclusions: Our study supports the existence of 5 variants of PPA. These variants show some differences in language and FDG PET imaging characteristics. Machine learning algorithms using language test data were able to predict each of the 5 PPA variants with a relatively high degree of accuracy, and enable the possibility of automated, machine-aided diagnosis of PPA variants., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Primary progressive aphasia (PPA) is a heterogeneous syndrome that is difficult to diagnose at early stages. Plasma neurofilament light chain (NFL) has been proposed as a potential biomarker for PPA., Objective: To examine the diagnostic properties of plasma NFL in PPA and to evaluate its association with clinical stages of the disease and brain metabolism., Methods: Our study included 80 participants (13 with non-fluent, 12 with semantic, and 16 with logopenic variant PPA; 13 with amnestic Alzheimer's disease [AD]; 13 with behavioral variant frontotemporal dementia; and 13 healthy controls). Plasma NFL concentration was measured using a high-sensitivity enzyme-linked immunosorbent assay (ELISA) kit. PET imaging was performed in a subgroup of patients., Results: NFL discriminated patients from controls with an area under the curve of 0.914 (95% CI, 0.843-0.984; p < 0.001) (cut-off: 76.46 pg/mL; 94% sensitivity, 76.9% specificity). There were no significant differences between clinical syndromes (PPA subtypes), the main clinical forms of dementia (frontotemporal dementia and AD), or the expected pathological groups (frontotemporal lobar degeneration-tau [FTLD-tau], FTLD-TDP43, and AD). NFL levels showed weak to moderate correlations with age and functional scale score. We found no significant correlation with the extent of hypometabolism observed on FDG-PET images., Conclusion: Plasma NFL is a non-specific marker of neurodegeneration, and may be helpful in the diagnosis of PPA. However, NFL does not permit differential diagnosis between PPA subtypes and is not correlated with the extent of neurodegeneration.

Reading impairment is an important feature in Primary Progressive Aphasia (PPA). The Spanish orthography entails completely regular spelling to sound correspondences, so reading disorders may be different to English. In the current study, reading, phonological and semantic abilities of 35 patients with the three variants of PPA, and 13 healthy volunteers were assessed. Brain metabolism was concomitantly obtained from each participant using 18 F-fluorodeoxyglucose positron emission tomography imaging. Two main patterns of impairment were identified: difficulties in nonwords reading with preservation of exception words in agrammatic and logopenic aphasia, and the inverse pattern in semantic dementia. Left frontal and left parietotemporal regions were associated to nonwords reading, while the anterior temporal lobe was related to reading of exception words. These results support the usefulness of examining reading abilities in the differential diagnosis of PPA variants, and suggest potential types of words that could be used in Spanish to assess these patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Primary progressive aphasia is a clinical syndrome caused by a neurodegeneration of areas and neural networks involved in language, usually in the left hemisphere. The term "crossed aphasia" denotes an acquired language dysfunction caused by a lesion in the hemisphere ipsilateral to the dominant hand. A case is presented on a 75-year-old right-handed woman with a logopenic variant of primary progressive aphasia with word-finding difficulties of 2 years onset. The 18 F-FDG PET/CT showed right temporoparietal hypometabolism. A functional MRI scan was performed during a verb naming task in order to characterise language lateralisation patterns. A similar activation pattern was observed in both hemispheres, with less activation than expected in bilateral inferior frontal gyrus. These findings support that logopenic variant of primary progressive aphasia should not be considered as a neurodegeneration starting in the left brain hemisphere, but as a syndrome characterised by asymmetric neurodegeneration of brain regions and neural networks involved in language., (Copyright © 2016 Elsevier España, S.L.U. y SEMNIM. All rights reserved.)

The logopenic variant of primary progressive aphasia (lvPPA) has been associated with Alzheimer disease, although this relationship is still subject to debate. The purpose of this study is to determine the frequency of amyloid biomarkers in patients with lvPPA, and record any potential clinical or topographic differences between patients with and without amyloid deposits. We conducted cognitive examination and positron-emission tomography studies with fluorodeoxyglucose ((18)F) and florbetapir ((18)F) in a cohort of 16 patients diagnosed with lvPPA. We evaluated the prevalence of amyloid deposits as well as any clinical and metabolic differences between the groups with and without significant presence of amyloid deposits. Eleven patients (69 %) were considered amyloid-positive. The amyloid-positive group displayed less metabolic activity in the left temporoparietal region than the control group, while the amyloid-negative group showed lower metabolism in the left temporoparietal region extending to the anterior temporal and basal frontal regions. The percentage of change in patients with clinical and FDG-PET follow-up did not differ between the amyloid-positive and amyloid-negative subgroups. The frequency of amyloid-positive cases confirms that lvPPA is frequently associated with Alzheimer disease. Amyloid-negative patients show a different cerebral metabolic pattern. These findings show the relevance of using amyloid PET to study lvPPA, and also suggest that the logopenic variant may not be specific to Alzheimer disease in certain cases.

Purpose: Diagnosing progressive primary aphasia (PPA) and its variants is of great clinical importance, and fluorodeoxyglucose (FDG) positron emission tomography (PET) may be a useful diagnostic technique. The purpose of this study was to evaluate interobserver variability in the interpretation of FDG PET images in PPA as well as the diagnostic sensitivity and specificity of the technique. We also aimed to compare visual and statistical analyses of these images., Methods: There were 10 raters who analysed 44 FDG PET scans from 33 PPA patients and 11 controls. Five raters analysed the images visually, while the other five used maps created using Statistical Parametric Mapping software. Two spatial normalization procedures were performed: global mean normalization and cerebellar normalization. Clinical diagnosis was considered the gold standard., Results: Inter-rater concordance was moderate for visual analysis (Fleiss' kappa 0.568) and substantial for statistical analysis (kappa 0.756-0.881). Agreement was good for all three variants of PPA except for the nonfluent/agrammatic variant studied with visual analysis. The sensitivity and specificity of each rater's diagnosis of PPA was high, averaging 87.8 and 89.9% for visual analysis and 96.9 and 90.9% for statistical analysis using global mean normalization, respectively. In cerebellar normalization, sensitivity was 88.9% and specificity 100%., Conclusion: FDG PET demonstrated high diagnostic accuracy for the diagnosis of PPA and its variants. Inter-rater concordance was higher for statistical analysis, especially for the nonfluent/agrammatic variant. These data support the use of FDG PET to evaluate patients with PPA and show that statistical analysis methods are particularly useful for identifying the nonfluent/agrammatic variant of PPA.

Primary progressive aphasia (PPA) may be the onset of several neurodegenerative diseases. This study evaluates a cohort of patients with PPA to assess their progression to different clinical syndromes, associated factors that modulate this progression, and patterns of cerebral metabolism linked to different clinical evolutionary forms. Thirty-five patients meeting PPA criteria underwent a clinical and neuroimaging (18)F-Fluorodeoxyglucose PET evaluation. Survival analysis was performed using time from clinical onset to the development of a non-language symptom or deficit (PPA-plus). Cerebral metabolism was analyzed using Statistical Parametric Mapping. Patients classified into three PPA variants evolved to atypical parkinsonism, behavioral disorder and motor neuron disease in the agrammatic variant; to behavioral disorder in the semantic; and to memory impairment in the logopenic. Median time from the onset of symptoms to PPA-plus was 36 months (31-40, 95 % confidence interval). Right laterality, and years of education were associated to a lower risk of progression, while logopenic variant to a higher risk. Different regions of hypometabolism were identified in agrammatic PPA with parkinsonism, motor neuron disease and logopenic PPA-plus. Clinical course of PPA differs according to each variant. Left anterior temporal and frontal medial hypometabolism in agrammatic variant is linked to motor neuron disease and atypical parkinsonism, respectively. PPA variant, laterality and education may be associated to the risk of progression. These results suggest the possibility that clinical and imaging data could help to predict the clinical course of PPA.

Background: New consensus criteria have been proposed to classify primary progressive aphasia (PPA) into three variants: agrammatic, semantic, and logopenic. Some studies have subsequently addressed the usefulness of these criteria, with controversial results. We aimed to determine the correlation between the clinical diagnosis according to the new criteria and brain topography in (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET)., Methods: Patients meeting the PPA criteria were prospectively recruited in a single center during a period of 18 months. They were clinically classified according to the new criteria and underwent FDG-PET. The cerebral metabolism of each patient was compared to a healthy control group using statistical parametric mapping. The expected variant according to the analysis of PET imaging was compared with the clinical diagnosis using the consensus criteria., Results: 32 patients were included. 90% of them fulfilled the consensus criteria and could be classified into one of the three clinical variants. The correlation with the cerebral metabolism was high: the kappa index was 0.91 in the agrammatic variant, 0.71 in the semantic variant, and 0.74 in the logopenic variant., Conclusions: A high correlation with the diagnosis obtained using FDG-PET was found. However, an overdiagnosis of the logopenic variant was observed. These results support the use of the new criteria, but some modifications or complementary studies may still be necessary., (© 2014 S. Karger AG, Basel.)