Distinct [18F]THK5351 binding patterns in primary progressive aphasia variants

Predicting primary progressive aphasias with support vector machine approaches in structural MRI data

To determine patterns of hypometabolism on fluorodeoxyglucose F18 positron emission tomography (FDG-PET) in patients with progressive apraxia of speech (PAS) and primary progressive aphasia (PPA) variants and to use these patterns to further refine current classification. We identified all patients who had FDG-PET and PAS or PPA who were evaluated by an expert speech-language pathologist. Patterns of hypometabolism were independently classified by 2 raters blinded to clinical data. Three speech-language pathologists reclassified all patients into 1 of 7 operationally defined categories of PAS and PPA blinded to FDG-PET data. Tertiary care medical center. Twenty-four patients with PAS or PPA and FDG-PET. Fluorodeoxyglucose F18 PET hypometabolic pattern. Of the 24 patients in the study, 9 had nonfluent speech output; 14, fluent speech; and 1 was unclassifiable. Twenty-one patients showed FDG hypometabolism; the remaining 3 did not. Among the patients showing hypometabolism, 8 had a prerolandic pattern of which 7 had nonfluent speech including progressive nonfluent aphasia (n = 3), PAS (n = 1), and mixed nonfluent aphasia/apraxia of speech (n = 3); the other patient had PPA unclassifiable. The remaining 13 had a postrolandic pattern, all with fluent speech (P < .001), including logopenic progressive aphasia (n = 6), progressive fluent aphasia (n = 6), and semantic dementia (n = 1). Patterns of hypometabolism differed between the nonfluent variants and between the fluent variants, including progressive fluent aphasia. Patterns of FDG-PET hypometabolism support the clinical categorizations of fluency, the distinction of apraxia of speech from progressive nonfluent aphasia, and the designation of a progressive fluent aphasia category.

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.

To determine how well the consensus criteria could classify subjects with primary progressive aphasia (PPA) using a quantitative speech and language battery that matches the test descriptions provided by the consensus criteria. A total of 105 participants with a neurodegenerative speech and language disorder were prospectively recruited and underwent neurologic, neuropsychological, and speech and language testing and MRI in this case-control study. Twenty-one participants with apraxia of speech without aphasia served as controls. Select tests from the speech and language battery were chosen for application of consensus criteria and cutoffs were employed to determine syndromic classification. Hierarchical cluster analysis was used to examine participants who could not be classified. Of the 84 participants, 58 (69%) could be classified as agrammatic (27%), semantic (7%), or logopenic (35%) variants of PPA. The remaining 31% of participants could not be classified. Of the unclassifiable participants, 2 clusters were identified. The speech and language profile of the first cluster resembled mild logopenic PPA and the second cluster semantic PPA. Gray matter patterns of loss of these 2 clusters of unclassified participants also resembled mild logopenic and semantic variants. Quantitative application of consensus PPA criteria yields the 3 syndromic variants but leaves a large proportion unclassified. Therefore, the current consensus criteria need to be modified in order to improve sensitivity.

Background: The efficacy of telerehabilitation-based treatment for anomia has been demonstrated in post-stroke aphasia, but the efficacy of this method of anomia treatment delivery has not been established within the context of degenerative illness.Aims: The current study evaluated the feasibility and efficacy of a telerehabilitation-based approach to anomia treatment within the three subtypes of primary progressive aphasia (PPA).Methods & Procedures: Each of the three telerehabilitation participants represented a distinct subtype of PPA. Following a baseline evaluation of language and cognition, a phonological treatment and an orthographic treatment were administered to all participants over the course of 6 months. One month after the end of treatment, a post-treatment evaluation began. All treatment sessions and the majority of the evaluation sessions were administered via telerehabilitation. Treatment effects were examined within each subject, and treatment effects were also compared between each telerehabilitation participant and a group of in-person participants who had the same subtype of PPA.Outcomes & Results: All three telerehabilitation participants exhibited positive treatment effects. CGR (nonfluent/agrammatic variant PPA) and WCH (logopenic variant PPA) showed maintenance of naming for prophylaxis items under both treatment conditions, while ACR (semantic variant PPA) demonstrated increased naming of remediation items under the phonological treatment condition. Compared to in-person participants with the same subtype of PPA, each of the telerehabilitation participants typically showed effects that were either within the expected range or larger than expected.Conclusions: Telerehabilitation-based anomia treatment is feasible and effective in all three subtypes of PPA.

Differentiating between primary progressive aphasia (PPA) variants based on the profile of language deficits can be difficult in a proportion of patients. Further, little is presently know about the pattern of longitudinal changes in behavior in PPA variants. To determine the presence of behavioral changes in the main variants of PPA: semantic (sv-PPA), nonfluent/agrammatic (nfv-PPA), and logopenic (lv-PPA), and establish the course of these changes over time. We measured behavioral changes in 73 prospectively recruited PPA (30 sv-PPA, 22 nfv-PPA, and 21 lv-PPA), as well as 33 behavioral variant frontotemporal dementia (bv-FTD) and 31 Alzheimer's disease (AD) patients, at baseline and after 1 year, using the Cambridge Behavioural Inventory Revised. All included patients had mild dementia severity at baseline. Both at baseline and follow-up, sv-PPA exhibited significantly more behavioral disturbances of the type characteristic of bv-FTD compared with other PPA variants. 74% of sv-PPA patients with mild dementia severity exhibited at least one behavior disturbance at baseline, which increased to 84% during follow-up. Behavioral symptoms did not differ between nfv-PPA and lv-PPA groups at baseline. At follow-up, however, empathy loss was significantly more pronounced in nfv-PPA. The prevalence and course of behavioral symptoms in lv-PPA was similar to that found in AD. sv-PPA show more prominent FTD-like behavioral disturbances compared with other PPA variants which typically emerge already early in the disease course. Empathy loss may be an important factor that helps differentiating nfv-PPA from lv-PPA. Our results may allow improved prediction of likely progression in behavioral symptoms across the PPA variants.

The inability to name objects (anomia) is one of the most common findings in the neurologic examination of primary progressive aphasia (PPA). In the semantic variant of PPA, the anomia is profound and reflects a combination of object naming and word comprehension deficits. In contrast, nonsemantic variants of PPA display a more selective impairment of object naming, without corresponding impairments of word comprehension. The aim of the present study was to explore the nature of the anomia in nonsemantic variants of PPA with a sensitive chronometric test of covert word/picture association. We tested priming effects in 12 patients with nonsemantic variant of PPA and 18 controls. Stimuli consisted of written words and line pictures of concrete objects. Within-format (word-word and picture-picture) and cross-format (word-picture and picture-word) priming effects were assessed by measuring the shortening of response times to the second versus initial presentation of corresponding stimulus pairs. In addition to the expected impairment of picture-to-word priming, a condition simulating object naming, the nonsemantic PPA patients also showed unexpected impairments of word-to-picture and word-to-word priming. Picture-to-picture priming was preserved, demonstrating the selectivity of the deficit for lexical processing. These findings show that the information processing bottleneck in patients with nonsemantic variants of PPA is not confined to the stage of lexical access but that it also extends into the prior levels of lexical semantics. The boundaries between the semantic and nonsemantic variants are therefore far from rigid.

Primary progressive aphasias (PPA) are neurodegenerative diseases clinically characterized by an early and relatively isolated language impairment. Three main clinical variants, namely the nonfluent/agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA) have been described, each with specific linguistic/cognitive deficits, corresponding anatomical and most probable pathological features. Since the discovery and the development of diagnostic criteria for the PPA variants by the experts in the field, significant progress has been made in the understanding of these diseases. This review aims to provide an overview of the literature on each of the PPA variant in terms of their clinical, anatomical and pathological features, with a specific focus on recent findings. In terms of clinical advancements, recent studies have allowed a better characterization and differentiation of PPA patients based on both their linguistic and non-linguistic profiles. In terms of neuroimaging, techniques such as diffusion imaging and resting-state fMRI have allowed a deeper understanding of the impact of PPA on structural and functional connectivity alterations beyond the well-defined pattern of regional gray matter atrophy. Finally, in terms of pathology, despite significant advances, clinico-pathological correspondence in PPA remains far from absolute. Nonetheless, the improved characterization of PPA has the potential to have a positive impact on the management of patients. Improved reliability of diagnoses and the development of reliable in vivo biomarkers for underlying neuropathology will also be increasingly important in the future as trials for etiology-specific treatments become available.

The use of biomarkers has recently supported the association between Alzheimer disease (AD) pathology and the logopenic variant of primary progressive aphasia (PPA). We aim to investigate possible differences in cerebrospinal fluid (CSF) biomarker concentrations in the three PPA variants, and to assess any agreement between CSF biomarkers and (18)F-florbetapir PET. A group of 10 PPA were retrospectively enrolled. Patients with logopenic variant (lvPPA) showed different levels of Aβ1-42 and p-tau compared to nonfluent/agrammatic and semantic variants (nfv/svPPA). All nfv/svPPA patients had negative amyloid PET. Among the lvPPA group, a negative amyloid PET was found only in one patient, who was also the only one to display a normal CSF. Thus, this small cohort appeared to display an excellent agreement between CSF and (18)F-florbetapir PET and suggest that these examinations may have the same validity in detecting in vivo evidence of AD pathology in PPA clinical variants.

Background: Primary progressive aphasia (PPA) is a disorder in which language impairment is the initial and predominant symptom. Three main phenotypes are described, the nonfluent variant (nfvPPA), the semantic variant (svPPA) and the logopenic variant (lvPPA). Although PPA is most commonly a sporadic disorder, recent studies have shown an association of PPA with mutations in a number of genes.Aims: To understand the extent to which PPA may be inherited, which genetic mutations may cause it, and whether the phenotypes of genetic PPA differ from sporadic PPA.Main Contribution: In around 20–30% of patients with PPA, a family history is present although nfvPPA is more heritable than svPPA and lvPPA which are both usually sporadic disorders. Mutations in the progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72), genes are the major causes of genetic PPA.Conclusions: Key pointers that may suggest testing for a GRN mutation in PPA are a family history of one of the disorders within the frontotemporal dementia spectrum, a nfvPPA phenotype, particularly if presenting with a prominent anomia and asymmetrical fronto-temporo-parietal atrophy. In someone with nfvPPA and a family history, GRN should be tested initially but a search for hexanucleotide repeat expansions in the C9orf72 gene should be performed if negative, particularly if there are features of motor neurone disease, or a family history of someone with motor neurone disease. Mutations in other genes are only very rare causes of PPA but if GRN and C9orf72 are both negative, testing for mutations in the microtubule-associated protein tau (MAPT), valosin-containing protein (VCP) and presenilin 1 (PSEN1) should be considered.

ObjectiveThe prognostic value of cerebrospinal fluid neurofilament light chain, total tau, phosphorylated tau181, and amyloid beta1‐42 was examined in frontotemporal dementia subtypes.MethodsWe compared baseline biomarkers between 49 controls, 40 patients with behavioral variant frontotemporal dementia, 24 with semantic variant primary progressive aphasia, and 26 with nonfluent variant primary progressive aphasia. Linear mixed effect models were used to assess the value of baseline biomarkers in predicting clinical and radiographic change in patient cohorts over multiple yearly follow up visits.ResultsNeurofilament light chain concentrations were lowest in controls. Elevated baseline neurofilament light chain predicted faster worsening in clinical severity, frontotemporal volume and frontotemporal fractional anisotropy in patients with behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. High total tau similarly predicted faster progression in nonfluent variant primary progressive aphasia. In behavioral variant frontotemporal dementia, higher phosphorylated tau181 predicted faster clinical progression whereas lower amyloid beta1‐42 predicted faster volumetric and fractional anisotropy reduction. Neurofilament light chain and phosphorylated tau181 were of greater predictive value in patients with tau pathology as compared to TDP‐43 pathology. Baseline neurofilament light chain correlated with baseline clinical severity and frontotemporal volume in behavioral variant frontotemporal dementia. Baseline total tau correlated with baseline clinical severity in semantic variant primary progressive aphasia.InterpretationHigh cerebrospinal fluid neurofilament light chain predicts more aggressive disease in behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. Total tau, phosphorylated tau181, and amyloid beta1‐42 also predict some measures of disease aggressiveness in frontotemporal dementia.

“Functional communication” refers to an individual’s ability to communicate effectively in his or her everyday environment, and thus is a paramount skill to monitor and target therapeutically in people with aphasia. However, traditional controlled-paradigm assessments commonly used in both research and clinical settings often fail to adequately capture this ability. In the current study, facets of functional communication were measured from picture-elicited speech samples from 70 individuals with mild primary progressive aphasia (PPA), including the three variants, and 31 age-matched controls. Building upon methods recently used by Berube et al. (2019), we measured the informativeness of speech by quantifying the content of each patient’s description that was relevant to a picture relative to the total amount of speech they produced. Importantly, form-based errors, such as mispronunciations of words, unusual word choices, or grammatical mistakes are not penalized in this approach. We found that the relative informativeness, or efficiency, of speech was preserved in non-fluent variant PPA patients as compared with controls, whereas the logopenic and semantic variant PPA patients produced significantly less informative output. Furthermore, reduced informativeness in the semantic variant is attributable to a lower production of content units and a propensity for self-referential tangents, whereas for the logopenic variant, a lower production of content units and relatively ”empty” speech and false starts contribute to this reduction. These findings demonstrate that functional communication impairment does not uniformly affect all the PPA variants and highlight the utility of naturalistic speech analysis for measuring the breakdown of functional communication in PPA.

ABSTRACTBackground: Individuals with primary progressive aphasia (PPA) and their caregivers want to know what to expect so that they can plan support appropriately. The ability to predict decline in naming and semantic knowledge, and advise individuals with PPA and their caregivers regarding future planning, would be invaluable clinically.Aims: The aims of this study were to investigate patterns of decline in naming and semantic knowledge in each of the clinical variants of PPA (logopenic variant PPA, lvPPA; nonfluent agrammatic PPA, nfaPPA; and semantic variant PPA, svPPA) and to examine the effects of other variables on rate of decline. We hypothesized that speech-language rehabilitation, higher education, and higher baseline test scores would be associated with slower decline, and older age with faster decline.Methods and Procedures: A total of 94 participants with PPA underwent language testing, including 36 participants with lvPPA, 31 participants with nfaPPA, and 27 participants with svPPA. All participant groups were similar in age and education. We focused on decline on three tests: the short form of the Boston Naming Test (BNT), the Hopkins Assessment of Naming Actions (HANA), and the short form of the Pyramids and Palm Trees Test (PPTT).Outcome and Results: Across language tests, the most precipitous rates of decline (loss of points per month) occurred in nfaPPA, followed by svPPA, then lvPPA. Female sex, longer symptom duration, higher baseline test score, and speech-language rehabilitation were associated with slower decline.Conclusions: PPA variants were distinguishable by rapidity of decline, with nfaPPA having the most precipitous decline. As hypothesized, higher baseline test scores and speech-language rehabilitation were associated with slower decline. Surprisingly, age and education were not important prognostically for individuals in this study. Further study of prognostically-relevant variables in PPA is indicated in this population.

BackgroundThe analysis of EEG cortical sources is promising for the investigation of neurodegenerative disorders. The aim of this study is to explore its value in the characterization of the three clinical presentations of primary progressive aphasia (PPA).MethodA resting‐state 19‐channel EEG was obtained in 48 patients diagnosed with PPA (21 nonfluent/agrammatic variant PPA [nfv‐PPA], 18 logopenic variant PPA [lv‐PPA], 9 semantic variant PPA [sv‐PPA]) and in 21 matched healthy controls. Using eLORETA, EEG current source density (CSD) values were estimated at voxel‐level and compared among groups of patients and controls.ResultPatients showed a low‐to‐moderate cognitive impairment. Lv‐PPA cases showed a higher delta density over the left frontal and temporal regions when compared to sv‐PPA subjects, and in left precuneus and posterior cingulate when compared to nfv‐PPA patients. They also displayed a higher delta density in left frontal, parietal and temporal regions than healthy subjects, and lower alpha1 density in left occipital regions compared with other patient groups. Lv‐PPA patients also showed reduced alpha2, beta1 and beta2 density over the left occipital regions when compared to healthy subjects. No significant differences were found in terms of CSD among sv‐PPA, nfv‐PPA and healthy subjects.ConclusionConsistently with our previous studies, findings in PPA patients suggest that Alzheimer’s disease (AD), but not fronto‐temporal degeneration (FTD), might induce a characteristic disruption of the cortical electrical activity, detectable by EEG. EEG might thus help in the differential diagnosis between AD‐related and FTD‐related PPA variants.

Northwestern Anagram Test-Italian (Nat-I) for primary progressive aphasia