Variant Primary Progressive Aphasia Research Articles

Atypical forms of Alzheimer's disease: patients not to forget.

The aim of this paper is to summarize the latest work on neuroimaging in atypical Alzheimer's disease (AD) patients and to emphasize innovative aspects in the clinic and research. The paper will mostly cover language (logopenic variant of primary progressive aphasia; lvPPA), visual (posterior cortical atrophy; PCA), behavioral (bvAD) and dysexecutive (dAD) variants of AD. MRI and PET can detect and differentiate typical and atypical AD variants, and novel imaging markers like brain iron deposition, white matter hyperintensities (WMH), cortical mean diffusivity, and brain total creatine can also contribute. Together, these approaches have helped to characterize variant-specific distinct imaging profiles. Even within each variant, various subtypes that capture the heterogeneity of cases have been revealed. Finally, in-vivo pathology markers have led to significant advances in the atypical AD neuroimaging field. Overall, the recent neuroimaging literature on atypical AD variants contribute to increase knowledge of these lesser-known AD variants and are key to generate atypical variant-specific clinical trial endpoints, which are required for inclusion of these patients in clinical trials assessing treatments. In return, studying these patients can inform the neurobiology of various cognitive functions, such as language, executive, memory, and visuospatial abilities.

Network anatomy in logopenic variant of primary progressive aphasia.

The logopenic variant of primary progressive aphasia (lvPPA) is a neurodegenerative syndrome characterized linguistically by gradual loss of repetition and naming skills resulting from left posterior temporal and inferior parietal atrophy. Here, we sought to identify which specific cortical loci are initially targeted by the disease (epicenters) and investigate whether atrophy spreads through predetermined networks. First, we used cross-sectional structural MRI data from individuals with lvPPA to define putative disease epicenters using a surface-based approach paired with an anatomically fine-grained parcellation of the cortical surface (i.e., HCP-MMP1.0 atlas). Second, we combined cross-sectional functional MRI data from healthy controls and longitudinal structural MRI data from individuals with lvPPA to derive the epicenter-seeded resting-state networks most relevant to lvPPA symptomatology and ascertain whether functional connectivity in these networks predicts longitudinal atrophy spread in lvPPA. Our results show that two partially distinct brain networks anchored to the left anterior angular and posterior superior temporal gyri epicenters were preferentially associated with sentence repetition and naming skills in lvPPA. Critically, the strength of connectivity within these two networks in the neurologically-intact brain significantly predicted longitudinal atrophy progression in lvPPA. Taken together, our findings indicate that atrophy progression in lvPPA, starting from inferior parietal and temporoparietal junction regions, predominantly follows at least two partially nonoverlapping pathways, which may influence the heterogeneity in clinical presentation and prognosis.

Predicting Confrontation Naming in the Logopenic Variant of Primary Progressive Aphasia

ABSTRACT Background Naming difficulties are prominent and pervasive in the logopenic variant of primary progressive aphasia (lvPPA) and may reflect its underlying deficits in phonological processing. Importantly, some words appear to be more vulnerable to deterioration than others. We hypothesize that these differences can be explained, in part, by the unique psycholinguistic properties of words. Aims Our study investigated the role of psycholinguistic properties of words, along with their underlying psycholinguistic factors, in predicting confrontation naming performance in individuals with lvPPA. Methods & Procedures Naming accuracy data were collected from 14 individuals with lvPPA using the Boston Naming Test (BNT). For each test item, values were extracted for frequency, age of acquisition (AoA), familiarity, word length, phonological neighborhood density (PND), semantic neighborhood density (SND), arousal, and valence. We examined the effects of these psycholinguistic properties on naming accuracy using logistic regression analyses at the individual level and multiple linear regression analysis at the group level. Further, we performed mediation analyses to examine the mediating contributions of related psycholinguistic properties on naming accuracy. Finally, principal component analysis (PCA) was performed to extract fundamental factors of the psycholinguistic properties. These factor scores were entered into regression analyses to investigate their relative contribution to naming accuracy in lvPPA. Outcomes & Results Age of acquisition emerged as the strongest psycholinguistic predictor of naming accuracy in lvPPA at both the individual and group levels. The influence of AoA on naming accuracy was only partially mediated by frequency. Three principal psycholinguistic factors were extracted from the PCA. These were interpreted as “lexical-semantic usage”, “phonological complexity”, and “emotional intensity”. Results indicated that “lexical-semantic usage” and “emotional intensity” predicted naming performance at both the individual and group levels. Conclusions Age of acquisition has been associated with the phonological level in models of word naming. The observed psycholinguistic effects on naming accuracy are discussed in the context of phonological deficits in lvPPA and models of word naming.

Semantic variant Primary Progressive Aphasia: Additional semantic features in Chinese language users

AbstractBackgroundTo date, most literature on Primary Progressive Aphasia (PPA) has been based on English language users. Yet, there are more than 7,000 living languages worldwide with vast heterogeneities in their linguistic features. Contrary to English language, Chinese language is a classifier language in which it is grammatically mandatory to have classifiers present between numerals and nouns. In addition, Chinese characters typically have an abundance of homophones (i.e., words with same pronunciation but vary in orthography and meaning) and heteronyms (i.e., words with same orthography but vary in meaning and pronunciation). Chinese language users rely on semantic knowledge to identify the accurate classifiers, homophones, and heteronym pronunciations. Thus, we hypothesize that Chinese‐speaking semantic variant (sv) PPA patients have difficulties producing classifiers, homophones, and heteronyms.MethodTo assess classifier production, participants are presented with pictures of nouns. Participants are first tasked with producing noun‐specific classifiers spontaneously. If failed, they are presented with four classifiers to select. To evaluate homophone selection skills, participants are shown short sentences with one character/word removed. They are then tasked to complete the sentences by choosing one of the four homophones presented. For heteronym reading, participants are asked to read out loud Chinese compound words with heteronyms (e.g., “windmill” and “wind up”).ResultWe recruited 22 controls and 47 PPA individuals (12 svPPA, 10 nonfluent variant (nfv) PPA and 25 logopenic variant (lv) PPA). In classifier production test, svPPA and lvPPA patients produce fewer accurate classifiers (p<0.0001, p = 0.001), with svPPA showing least improvement when presented with multiple choices (p = 0.003). In homophone selection test, svPPA and lvPPA scored lower than controls (p<0.0001 and p = 0.007). For heteronym reading test, svPPA showed the lowest performance when tasked with reading heteronym characters (p = 0.001). Using voxel‐based morphometry, we noted that the ability to produce classifiers, read heteronyms and identify heteronyms are correlated with grey matter volumetric changes over the anterior portion of the left temporal lobe and fusiform gyri, brain regions associated with language semantic functions.ConclusionPPA symptomatology may vary across languages. Thus, studying PPA symptoms via a linguistically diverse approach potentially provides a more comprehensive understanding to the syndrome.

Quantifying three types of abnormal language in semantic variant primary progressive aphasia

AbstractBackgroundPatients with the semantic variant of Primary Progressive Aphasia (svPPA) experience a gradual loss of semantic memory, impairing word retrieval and word comprehension. As such, svPPA patients often use superordinate, vague, and empty words. These patients often use language that refers to one’s own experience (“self‐referential”), one’s language impairments (“inability”), and/or contains tangents (“tangential”). These forms of aberrant language were identified previously as distinguishing svPPA from the other canonical variants of PPA (Gallee et al., 2021).MethodSpeech samples of the WAB picnic scene from 15 svPPA patients were analyzed by counting words and categorizing three forms of aberrant language at two timepoints (30 samples total), baseline and follow‐up (at least 12 months post baseline). Words were identified as self‐referential, inability, or tangential. Quantitative analyses were conducted to look for relationships between total word count and each of the three forms of aberrant language.ResultPreliminary results showed a strong correlation (r = .97) between the total number of aberrant words and the total number of words in the picture description transcriptions. At T1, 40% (6/15) used self‐referential words, 87% (13/15) used inability words, and 53% (8/15) used tangential words. At T2, 67% (10/15) used self‐referential words, 100% (15/15) used inability words, and 67% (10/15) used tangential words. Inability is the most prominent type of aberrant language. Longitudinal analyses are ongoing to investigate consistency or inconsistency within patients and relationship to aphasia severity.ConclusionPreliminary findings suggest patients with svPPA produce distinct types of aberrant language in a picture description task. The prominent use of inability words may be due to its scripted nature in that svPPA patients use these phrases repeatedly and may be related to disinhibition. Further, it is notable that several components of language not analyzed in this study, including grammar, syntax, and content units, are potentially informative. Using this method provides an efficient way to characterize speech of svPPA patients, which may lead to early subtyping, prognostication, and targeted treatment goals.Reference: Gallée,J.;Cordella,C.; Fedorenko, E.; Hochberg, D.; Touroutoglou, A.; Quimby, M.; Dickerson, B.C. Breakdowns in Informativeness of Naturalistic Speech Production in Primary Progressive Aphasia. Brain Sci. 2021,11, 130.

Reactive astrocytes as imaged with 11C‐DED in patients with different dementia disorders

AbstractBackgroundNeuroinflammation, which receives ever increasing interest in neurodegenerative diseases, comprises a heterogeneous cascade of events that are thought to be related to the downstream neurodegeneration. The aim of this study was to evaluate the binding of 11C‐Deuterium‐L‐Deprenyl PET (DED) as a measure of reactive astrocytes in patients with different dementia disorders, and to assess its association with other disease biomarkers.MethodEleven patients with a clinical diagnosis of semantic variant of primary progressive aphasia (svPPA, n = 5) and behavioral variant of frontotemporal dementia (bvFTD, n = 6) were recruited. All patients had a cerebrospinal fluid biomarker profile that was inconsistent with Alzheimer’s disease (AD) or a negative amyloid‐β PET scan. The imaging protocol included 11C‐DED‐PET, 18F‐FDG‐PET, and a 3D T1 MRI. A group of amyloid‐beta positive patients with AD (n = 20) that underwent similar investigations were used for comparison. Z‐scores were created for 11C‐DED binding (Patlak slopes) and tracer relative delivery (R1 parameter) relative to that of healthy controls (HC; n = 20), for assessing the load of reactive astrocytes and cerebral perfusion, respectively.ResultThe patients with svPPA and bvFTD showed significantly higher 11C‐DED binding in frontotemporal areas, compared to HC. Patients with AD showed significantly higher 11C‐DED binding in temporo‐occipital areas, compared to HC. The regional distribution of 11C‐DED binding in the patients with svPPA and bvFTD was consistent with the expected underlying pattern of neurodegeneration in those disorders, although the load of binding was heterogeneous across patients with the same clinical diagnosis.ConclusionReactive astrocytes appear to be a common feature of different dementia disorders, although the regional pattern of reactivity differs. Ongoing work evaluates the relationship between patterns of reactive astrocyte activation, cerebral perfusion, glucose metabolism, atrophy, and cognitive performance.

Unique combinations of shape morphometric features improves discriminability of ftld phenotypes

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) is associated with diverse clinical phenotypes underlain by multiple disease pathologies and genetic mutations. As such, traditional structural MRI analyses lack sensitivity and specificity for discriminating FTLD syndromes. Here, we use data‐driven methods to extract a concise set of MRI‐derived shape morphometric features and examine the discriminatory capability of their unique combinations in four FTLD clinical phenotypes.Method190 patients with sporadic or familial FTLD spectrum disorders (i.e., behavioral variant (bvFTD, n = 107), non‐fluent variant primary progressive aphasia (nfvPPA, n = 27), semantic variant primary progressive aphasia (svPPA, n = 12) and progressive supranuclear palsy (PSP, n = 44)) and 27 controls without pathogenic mutations from the ALLFTD cohort were evaluated. MRI data were preprocessed with FreeSurfer software and four cortical measures were extracted and indexed to a normalized surface atlas: cortical thickness (CT), surface area (SA), surface curvature (SC) and jacobian white matter surface metric distortion (JW). For all phenotypes, each shape feature was contrasted with controls using linear models adjusted for age and gender. Principal component analysis (PCA) was then applied to each individual structural measure and the discriminatory power based on individual and combined measures was assessed using logistic regression and 10‐fold cross‐validation.ResultFigure 1 displays FDR‐corrected T‐scores of differences from controls in each morphometric feature in bvFTD. Results reveal complementary patterns of CT, SA, SC and JW for each phenotype, with greatest differences observed in CT across groups. In Figure 2, we display the features derived from the PCA, weighted by eigenvector coefficients, in bvFTD. In Figures 3‐6, receiver operating characteristic curves for individual and combined measures alongside areas under the curve (AUCs) are shown for each phenotype. In bvFTD, nfvPPA and PSP, the superior model included CT and SC at AUCs of 88.3, 87, and 78.6, respectively. For svPPA, the superior model included CT, SC and JW at an AUC of 85.6.ConclusionIntegrating additional MRI‐derived surface morphometric features improved classification performance in all FTLD phenotypes. The principal component analysis‐based approach indicated distinct brain regions contribute to discrimination for each shape feature, suggesting they may reflect unique aspects of neurodegeneration across groups.

Deletions/duplications in GRN and MAPT genes is not common in frontotemporal dementia

AbstractBackgroundFrontotemporal dementia (FTD) is an umbrella term for several syndromes with behavioural and/or language symptoms. Mutations in GRN and MAPT genes are the most frequent genetic cause of FTD in different populations. Our previous data indicate that the frequency of mutations in GRN gene is up to 12.5% in familial FTD cases in Russian cohort of patients. Mutations in MAPT gene were absent in the same cohort. According to the literature, not only point mutation in these genes, but also deletions/duplications can be the genetic cause of FTD.MethodWe analyzed DNA from 50 patients with clinical diagnosis of behavioural variant of FTD, bvFTD (N = 33) and primary progressive aphasia, PPA (N = 17), picture 1. There were 26 familial and 24 sporadic FTD cases. Exon rearrangements were analyzed by MLPA method (SALSA MLPA P275‐C3, MRC‐Holland, Netherlands) using standard protocol. PCR products were separated by size with capillary electrophoresis using genetic analyzer Nanofor 5 (Syntol, Russia). The analysis of result was performed with GeneMarker V3.0.1.ResultWe did not find any deletion or duplication of exons in the GRN and MAPT genes. The results may indicate that this type of mutation is not common in Russian patients with FTD.ConclusionIn 2017‐2021, we identified several point mutations in GRN in Russian patients with FTD; here we show that exon rearrangements in GRN and MAPT genes are not frequent in Russia. According to the literature, only 1.5% of individuals with GRN‐associated forms have deletion or duplication in GRN gene. The data about exon rearrangements in MAPT gene are absent. However, in the case of typical clinical phenotype of GRN‐ or MAPT‐associated form of FTD, MLPA analysis can be recommended.

Subcortical atrophy imaging biomarker performance across the sporadic and genetic frontotemporal dementias

AbstractBackgroundFrontotemporal dementia (FTD) is a common cause of young‐onset dementia, with promising disease‐modifying candidates. Cortical signatures are well established; however, comprehensive longitudinal investigations of subcortical atrophy are limited and sample size estimates to inform imaging biomarker choice are lacking. Therefore, the current study investigated the relative utility of automated subcortical atrophy measures to detect putative disease‐modifying treatment effects in clinical, genetic and pathologically‐confirmed FTD.MethodLongitudinal registration and segmentation algorithms were applied to a cohort of 262 people, 184 of whom were diagnosed with FTD, to measure atrophy in the amygdala, hippocampus, caudate and thalamus. Clinical diagnoses were behavioural variant FTD (n = 66) and primary progressive aphasia (PPA, n = 118), comprising semantic variant PPA (n = 45), non‐fluent variant PPA (n = 45), logopenic variant PPA (n = 21), and PPA‐not otherwise specified (n = 7). Fifty‐three patients had either a known pathogenic mutation (in the MAPT, C9orf72 or GRN genes) and/or underlying tau or TDP‐43 pathology confirmed at post‐mortem. Seventy‐eight cognitively normal controls were included for comparison. Sample size estimates were computed to explore the relative feasibility of subcortical atrophy measures to track disease progression and detect treatment‐related effects across the different subgroups.ResultRelatively distinct patterns of significantly increased atrophy across the amygdala, hippocampus, caudate and/or thalamus were detected (p < 0.001) for all sporadic, genetic, and pathology‐confirmed FTD subgroups, with a strong left‐dominant pattern evident for PPA‐NOS and GRN patients. The best performing marker (as determined by lowest sample size required to detect a treatment effect) varied by subgroup supporting the importance of informed regional biomarker choice based on the population enrolled. Measures of the caudate and thalamus performed particularly well across all the subgroups, producing estimates well below 100 patients per treatment arm. The left hippocampal BSI (boundary shift integral) measure produced the lowest estimate overall in PPA‐NOS, with 12 individuals required to detect a 30% reduction in atrophy.ConclusionThis work confirms the relative utility of subcortical atrophy measures across the FTD spectrum and provides valuable sample size information to inform non‐invasive biomarker choice for sporadic and genetic FTD trials.

Tau‐PET imaging with 18F‐PI‐2620 reveals lateralized distribution of tau pathology in critical language regions in patients with early onset of Alzheimer’s Disease and patients with primary progressive aphasia

AbstractBackgroundLanguage disorders are frequent in patients in advanced and early stages of dementia (Goth & Strøm, 2018) together with the deterioration of other cognitive domains (e.g., memory) (Taler & Phillips, 2008). The first complaint in people with dementia often is language impairment, even preceding other cognitive declines (Ferris & Farlow, 2013). Logopenic variant primary progressive aphasia (lvPPA) and non‐fluent/agrammatic variant PPA (nf/avPPA) are rare neurodegenerative disorders being language impairment the main feature (Gono‐Tempini, 2011). Both β‐amyloid (Aβ) and tau appear to occur in Alzheimer disease (AD). Moreover, Aβ and tau aggregates also represent the underlying pathology in lvPPA (Montembeault et al. 2018) while nf/avPPA resembles a pure tau‐pathology. The purpose of this study is to explore the distribution of tau‐pathology in critical language regions in patients with early‐onset AD (EOAD) and patients diagnosed with primary progressive aphasia (PPA).MethodEight participants (55‐77y): 4 with EOAD, 3 with lvPPA (these first seven patients additionally had a positive 18F‐Florbetaben Amyloid PET), 1 with nf/avPPA, and 14 healthy controls (HC) (age range 54‐76y) underwent dynamic PET scans with 18F‐PI‐2620 to examine the distribution of tau‐pathology in the following cortical language regions: inferior frontal gyrus (IFG), superior temporal gyrus (STG), supramarginal and angular gyrus (PL). Group differences in language regions were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum.ResultCompared to HC, 3/4 patients with EOAD showed elevated levels of 18F‐PI‐2620 binding, mainly in the right IFG and IPL and left STG, while 3/4 patients with PPA (2 lvPPA and 1 nf/avPPA) showed left lateralized elevated uptake of 18F‐PI‐2620 in all language regions. All PPA patients showed increased binding of 18F‐PI‐2620 predominantly in the left parietal regions.ConclusionOur preliminary results reveal a lateralized distribution pattern of 18F‐PI‐2620 in language regions in patients with EOAD and particularly in those with PPA. These findings suggest that 18F‐PI‐2620 PET imaging is a promising tool to visualize tau aggregations in patients with EOAD and PPA. However, further studies are needed to confirm these preliminary results.

Multifocal Transcranial Direct Current Stimulation in Primary Progressive Aphasia Does Not Provide a Clinical Benefit Over Speech Therapy.

Primary progressive aphasia (PPA) is a group of neurodegenerative disorders including Alzheimer's disease and frontotemporal dementia characterized by language deterioration. Transcranial direct current stimulation (tDCS) is a non-invasive intervention for brain dysfunction. To evaluate the tolerability and efficacy of tDCS combined with speech therapy in the three variants of PPA. We evaluate changes in fMRI activity in a subset of patients. Double-blinded, randomized, cross-over, and sham-controlled tDCS study. 15 patients with PPA were included. Each patient underwent two interventions: a) speech therapy + active tDCS and b) speech therapy + sham tDCS stimulation. A multifocal strategy with anodes placed in the left frontal and parietal regions was used to stimulate the entire language network. Efficacy was evaluated by comparing the results of two independent sets of neuropsychological assessments administered at baseline, immediately after the intervention, and at 1 month and 3 months after the intervention. In a subsample, fMRI scanning was performed before and after each intervention. The interventions were well tolerated. Participants in both arms showed clinical improvement, but no differences were found between active and sham tDCS interventions in any of the evaluations. There were trends toward better outcomes in the active tDCS group for semantic association and reading skills. fMRI identified an activity increase in the right frontal medial cortex and the bilateral paracingulate gyrus after the active tDCS intervention. We did not find differences between active and sham tDCS stimulation in clinical scores of language function in PPA patients.

Comparing two picture naming tasks in primary progressive aphasia: Insights from behavioural and neural results

Picture naming tests are widely used to evaluate language impairments in neurodegenerative diseases, especially in Primary Progressive Aphasia (PPA). The available tests differ for many factors affecting the performance, e.g. format of stimuli and their psycholinguistic properties. We aim to identify the most appropriate naming test to be used on PPA according to the clinical and research demands. We investigated the behavioural characteristics, i.e. proportion of correct responses and error type, and their neural correlates in two Italian naming tests, CaGi naming (CaGi) and naming subtest of the Screening for Aphasia in NeuroDegeneration battery (SAND), administered to 52 PPA patients who underwent an FDG-PET scan. We analysed the effectiveness of the tests in distinguishing PPA versus controls and among PPA variants, considering the psycholinguistic variables affecting performance. We explored the brain metabolic correlates of behavioural performance in the tests. SAND, differently from CaGi, has time limits for the response and its items are less frequent and acquired later. SAND and CaGi differed in terms of number of correct responses and error profile, suggesting a higher difficulty to name SAND items compared to CaGi. Semantic errors predominated in CaGi, while anomic and semantic errors were equally frequent in SAND. Both tests distinguished PPA from controls, but SAND outperformed CaGi in discriminating among PPA variants. FDG-PET imaging revealed a shared metabolic involvement of temporal areas associated with lexico-semantic processing, encompassing anterior fusiform, temporal pole, and extending to posterior fusiform in sv-PPA. Concluding, a picture naming test with response time limit and items which are less frequent and acquired later in life, as SAND, may be effective at highlighting subtle distinctions between PPA variants, improving the diagnosis. Conversely, a naming test without time limit for the response, as CaGi, may be useful for a better characterization of the nature of the naming impairment at the behavioural level, eliciting more naming errors than anomia, possibly helping in the development of rehabilitation protocols.

Comprehension of acoustically degraded speech in Alzheimer's disease and primary progressive aphasia.

Successful communication in daily life depends on accurate decoding of speech signals that are acoustically degraded by challenging listening conditions. This process presents the brain with a demanding computational task that is vulnerable to neurodegenerative pathologies. However, despite recent intense interest in the link between hearing impairment and dementia, comprehension of acoustically degraded speech in these diseases has been little studied. Here we addressed this issue in a cohort of 19 patients with typical Alzheimer's disease and 30 patients representing the three canonical syndromes of primary progressive aphasia (non-fluent/agrammatic variant primary progressive aphasia; semantic variant primary progressive aphasia; logopenic variant primary progressive aphasia), compared to 25 healthy age-matched controls. As a paradigm for the acoustically degraded speech signals of daily life, we used noise-vocoding: synthetic division of the speech signal into frequency channels constituted from amplitude-modulated white noise, such that fewer channels convey less spectrotemporal detail thereby reducing intelligibility. We investigated the impact of noise-vocoding on recognition of spoken three-digit numbers and used psychometric modelling to ascertain the threshold number of noise-vocoding channels required for 50% intelligibility by each participant. Associations of noise-vocoded speech intelligibility threshold with general demographic, clinical and neuropsychological characteristics and regional grey matter volume (defined by voxel-based morphometry of patients' brain images) were also assessed. Mean noise-vocoded speech intelligibility threshold was significantly higher in all patient groups than healthy controls, and significantly higher in Alzheimer's disease and logopenic variant primary progressive aphasia than semantic variant primary progressive aphasia (all P < 0.05). In a receiver operating characteristic analysis, vocoded intelligibility threshold discriminated Alzheimer's disease, non-fluent variant and logopenic variant primary progressive aphasia patients very well from healthy controls. Further, this central hearing measure correlated with overall disease severity but not with peripheral hearing or clear speech perception. Neuroanatomically, after correcting for multiple voxel-wise comparisons in predefined regions of interest, impaired noise-vocoded speech comprehension across syndromes was significantly associated (P < 0.05) with atrophy of left planum temporale, angular gyrus and anterior cingulate gyrus: a cortical network that has previously been widely implicated in processing degraded speech signals. Our findings suggest that the comprehension of acoustically altered speech captures an auditory brain process relevant to daily hearing and communication in major dementia syndromes, with novel diagnostic and therapeutic implications.

The Dynamic Interplay between Loss of Semantic Memory and Semantic Learning Capacity: Insight from Neologisms Learning in Semantic Variant Primary Progressive Aphasia.

Semantic Variant of Primary Progressive Aphasia (svPPA) has often been considered as a loss of knowledge stored in semantic memory, but might also be due to a general disruption of mechanisms allowing the acquisition, storage, and retrieval of semantic memories. In order to assess any parallelism in svPPA patients between loss of semantic knowledge and inability to acquire new semantic information, we administered a battery of semantic learning tasks to healthy individuals and svPPA patients, where they were requested to learn new conceptual representations and new word forms, and to associate the former with the latter. A strong relation was found between loss of semantic knowledge and disruption of semantic learning: (a) patients with severe svPPA had the lowest scores in the semantic learning tasks; (b) significant correlations were found between scores obtained in semantic learning tasks and scores obtained in semantic memory disorders in svPPA patients.

Concrete and Abstract Concepts in Primary Progressive Aphasia and Alzheimer's Disease: A Scoping Review.

The concreteness effect (CE), namely a better performance with concrete compared to abstract concepts, is a constant feature in healthy people, and it usually increases in persons with aphasia (PWA). However, a reversal of the CE has been reported in patients affected by the semantic variant of Primary Progressive Aphasia (svPPA), a neurodegenerative disease characterized by anterior temporal lobe (ATL) atrophy. The present scoping review aims at identifying the extent of evidence regarding the abstract/concrete contrast in Alzheimer's disease (AD) and svPPA and associated brain atrophy. Five online databases were searched up to January 2023 to identify papers where both concrete and abstract concepts were investigated. Thirty-one papers were selected and showed that while in patients with AD, concrete words were better processes than abstract ones, in most svPPA patients, there was a reversal of the CE, with five studies correlating the size of this effect with ATL atrophy. Furthermore, the reversal of CE was associated with category-specific impairments (living things) and with a selective deficit of social words. Future work is needed to disentangle the role of specific portions of the ATL in concept representation.

Decision-making Approach in Late-onset Bilateral Semantic Variant Primary Progressive Aphasia with Coexisting Asymmetric Regional Amyloid Deposition

Semantic variant primary progressive aphasia (svPPA), a well-known subtype of the frontotemporal dementia often shows peculiar clinical features and structural neuroimage findings. To strengthen the accuracy of a clinical diagnosis, amyloid positron emission tomography-computed tomography (PET-CT) might be helpful. However, in patients with late-onset svPPA, an admixture of the various neuropathology would interfere with diagnostic approach. Herein, we report a case of late-onset bilateral svPPA showing a regional amyloid deposition on PET-CT scan.

Speech Motor Profiles in Primary Progressive Aphasia.

Previous research on motor speech disorders (MSDs) in primary progressive aphasia (PPA) has largely focused on patients with the nonfluent/agrammatic variant of PPA (nfvPPA), with few systematic descriptions of MSDs in variants other than nfvPPA. There has also been an emphasis on studying apraxia of speech, whereas less is known about dysarthria or other forms of MSDs. This study aimed to examine the qualitative and quantitative characteristics of MSDs in a prospective sample of individuals with PPA independent of subtype. We included 38 participants with a root diagnosis of PPA according to current consensus criteria, including one case with primary progressive apraxia of speech. Speech tasks comprised various speech modalities and levels of complexity. Expert raters used a novel protocol for auditory speech analyses covering all major dimensions of speech. Of the participants, 47.4% presented with some form of MSD. Individual speech motor profiles varied widely with respect to the different speech dimensions. Besides apraxia of speech, we observed different dysarthria syndromes, special forms of MSDs (e.g., neurogenic stuttering), and mixed forms. Degrees of severity ranged from mild to severe. We also observed MSDs in patients whose speech and language profiles were incompatible with nfvPPA. The results confirm that MSDs are common in PPA and can manifest in different syndromes. The findings emphasize that future studies of MSDs in PPA should be extended to all clinical variants and should take into account the qualitative characteristics of motor speech dysfunction across speech dimensions. https://doi.org/10.23641/asha.22555534.

Beyond impairment of language: empathy deficit in logopenic variant of Primary Progressive Aphasia (P5-6.002)

<h3>Objective:</h3> The aim of this study is to assess possible empathy deficits and their neural basis in lv-PPA compared to amnesic AD. <h3>Background:</h3> Empathy is the ability to understand (cognitive empathy) and to feel (affective empathy) what others feel. Evidence about empathy in logopenic variant of Primary Progressive Aphasia (lv-PPA) are rare and not conclusive. <h3>Design/Methods:</h3> We included 18 lv-PPA and 38 amnesic AD patients. Informer-rated Interpersonal Reactivity Index (IRI) was used to explore cognitive (Perspective Taking-PT and Fantasy-F subscales) and affective (Empathic Concern-EC and Personal Distress-PD subscales) empathy, before (T0) and after (T1) cognitive symptoms’ onset. Emotion recognition was tested through Ekman-60 Faces Test. Eighteen lv-PPA and 30 amnesic AD patients underwent Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and amyloid biomarker analysis. SPM analysis on FDG-PET was performed in 16 lv-PPA and 26 amnesic AD patients. <h3>Results:</h3> From T0 to T1, PT scores decreased, and PD scores increased in both lv-PPA (PT z=−3.43, <i>p</i>=0.001; PD z=−3.62, <i>p</i>&lt;0.001) and in amnesic AD (PT z=−4.57, <i>p</i>&lt;0.001; PD z=−5.20, <i>p</i>&lt;0.001). Lv-PPA performed poorer than amnesic AD in happiness recognition (7.54±2.18 vs 8.94±1.04, <i>p</i>=0.001). Delta-PT(T0–T1) negatively correlated with metabolic disfunction of left superior and middle frontal gyri, inferior parietal lobule and insula in lv-PPA, and of right superior temporal gyrus and middle frontal gyrus in amnesic AD (<i>p</i>&lt;0.005). Delta-PD(T0–T1) positively correlated with metabolic disfunction of left insula, inferior parietal lobule and superior frontal gyrus in lv-PPA (<i>p</i>&lt;0.005) and of right inferior frontal gyrus in amnesic AD (<i>p</i>&lt;0.001). <h3>Conclusions:</h3> Beyond language impairment, lv-PPA patients seems to present empathy changes and difficulties in emotion recognition. Lv-PPA and amnesic AD share the same empathic changes, with a damage of cognitive empathy and a heightening of person distress along time. Differences of neural correlates of empathy impairment might be due to the different vulnerability of specific brain regions in the two AD phenotypes. <b>Disclosure:</b> Ms. Giacomucci has nothing to disclose. Cristina Polito has nothing to disclose. Valentina Berti has nothing to disclose. Sonia Padiglioni has nothing to disclose. Dr. Galdo has nothing to disclose. Mr. Mazzeo has nothing to disclose. Dr. Bergamin has nothing to disclose. Miss Moschini has nothing to disclose. Miss Morinelli has nothing to disclose. Miss Nuti has nothing to disclose. Dr. De Cristofaro has nothing to disclose. Dr. Bagnoli has nothing to disclose. Benedetta Nacmias has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Sandro Sorbi has nothing to disclose. Valentina Bessi has nothing to disclose.

EEG correlates in the three variants of Primary Progressive Aphasia (P13-6.002)

<h3>Objective:</h3> The aim of this study is to explore the value of EEG analysis in the characterization of the three clinical presentations of primary progressive aphasia (PPA). <h3>Background:</h3> The analysis of EEG cortical sources is promising for the investigation of neurodegenerative disorders. <h3>Design/Methods:</h3> A 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. Applying seed-based analysis on 3T fMRI data of an independent group of young healthy controls (n.40), we built the maps of three networks belonging to the left perisylvian language network (nodes: middle temporal gyrus–MTG, inferior frontal gyrus–IFG, anterior temporal lobe–ATL) and the maps of default-mode network (DMN) and salience network (SN). Using eLORETA, EEG current source density (CSD) and linear-lagged connectivity (LLC) values were estimated and compared. CSD and LLC analysis were performed at whole-brain level and at network level, respectively. <h3>Results:</h3> Patients showed a low-to-moderate cognitive impairment. At CSD analysis lv-PPA patients showed a higher delta density than nfvPPA, svPPA and healthy subjects. They also showed a higher theta density relative to controls. Level of statistical significance showed a pronounced descending posterior-to-anterior and left-to-right gradient over the brain cortex at theta band. Also nfvPPA patients deviated from healthy subjects in terms of widespread higher theta density. LLC analysis pointed out a significantly higher connectivity at delta and theta frequency bands characterizing all three groups of patients relative to controls in language networks. Connectivity disruption was also evident in non-language networks. <h3>Conclusions:</h3> 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 in lvPPA patients, detectable by EEG. EEG might thus help in the differential diagnosis between AD-related and FTD-related PPA variants. <b>Disclosure:</b> Giordano Cecchetti has nothing to disclose. Federica Agosta has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Philips. Federica Agosta has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier INC. Silvia Basaia has nothing to disclose. Dr. Spinelli has nothing to disclose. Ms. Cividini has nothing to disclose. Marco Cursi has nothing to disclose. The institution of Elisa Canu has received research support from Italian Ministry of Health . Dr. Leocadi has nothing to disclose. Roberto Santangelo, 4503 has nothing to disclose. Dr. Caso has nothing to disclose. Dr. Fanelli has nothing to disclose. Dr. Minicucci has nothing to disclose. Giuseppe Magnani has nothing to disclose. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Less is more in language production: an information-theoretic analysis of agrammatism in primary progressive aphasia.

Agrammatism is a disorder of language production characterized by short, simplified sentences, the omission of function words, an increased use of nouns over verbs and a higher use of heavy verbs. Despite observing these phenomena for decades, the accounts of agrammatism have not converged. Here, we propose and test the hypothesis that the lexical profile of agrammatism results from a process that opts for words with a lower frequency of occurrence to increase lexical information. Furthermore, we hypothesize that this process is a compensatory response to patients' core deficit in producing long, complex sentences. In this cross-sectional study, we analysed speech samples of patients with primary progressive aphasia (n = 100) and healthy speakers (n = 65) as they described a picture. The patient cohort included 34 individuals with the non-fluent variant, 41 with the logopenic variant and 25 with the semantic variant of primary progressive aphasia. We first analysed a large corpus of spoken language and found that the word types preferred by patients with agrammatism tend to have lower frequencies of occurrence than less preferred words. We then conducted a computational simulation to examine the impact of word frequency on lexical information as measured by entropy. We found that strings of words that exclude highly frequent words have a more uniform word distribution, thereby increasing lexical entropy. To test whether the lexical profile of agrammatism results from their inability to produce long sentences, we asked healthy speakers to produce short sentences during the picture description task. We found that, under this constrained condition, a similar lexical profile of agrammatism emerged in the short sentences of healthy individuals, including fewer function words, more nouns than verbs and more heavy verbs than light verbs. This lexical profile of short sentences resulted in their lower average word frequency than unconstrained sentences. We extended this finding by showing that, in general, shorter sentences get packaged with lower-frequency words as a basic property of efficient language production, evident in the language of healthy speakers and all primary progressive aphasia variants.