Primary Progressive Aphasia Patients Research Articles

Explainable machine learning radiomics model for Primary Progressive Aphasia classification.

Primary Progressive Aphasia (PPA) is a neurodegenerative disease characterized by linguistic impairment. The two main clinical subtypes are semantic (svPPA) and non-fluent/agrammatic (nfvPPA) variants. Diagnosing and classifying PPA patients represents a complex challenge that requires the integration of multimodal information, including clinical, biological, and radiological features. Structural neuroimaging can play a crucial role in aiding the differential diagnosis of PPA and constructing diagnostic support systems. In this study, we conducted a white matter texture analysis on T1-weighted images, including 56 patients with PPA (31 svPPA and 25 nfvPPA), and 53 age- and sex-matched controls. We trained a tree-based algorithm over combined clinical/radiomics measures and used Shapley Additive Explanations (SHAP) model to extract the greater impactful measures in distinguishing svPPA and nfvPPA patients from controls and each other. Radiomics-integrated classification models demonstrated an accuracy of 95% in distinguishing svPPA patients from controls and of 93.7% in distinguishing svPPA from nfvPPA. An accuracy of 93.7% was observed in differentiating nfvPPA patients from controls. Moreover, Shapley values showed the strong involvement of the white matter near left entorhinal cortex in patients classification models. Our study provides new evidence for the usefulness of radiomics features in classifying patients with svPPA and nfvPPA, demonstrating the effectiveness of an explainable machine learning approach in extracting the most impactful features for assessing PPA.

Apraxia Patterns for the Differentiation between Alzheimer's Disease and Frontotemporal Dementia Variants.

Background and Objectives: Despite the increasing use of biomarkers, differentiation between Alzheimer's disease (AD), behavioral variant Frontotemporal Dementia (bvFTD), and Primary Progressive Aphasia (PPA) remains a challenge. Apraxia is a supportive feature for diagnosing AD but is underrepresented in other dementia types. Herein, we investigated the presence and characteristic profiles of limb, verbal, and non-verbal apraxia in three major dementia types. Materials and Methods: Test for Upper Limb Apraxia (TULIA) and Apraxia Battery for Adults-2 (ABA-2) were administered in patients with AD (n = 22), bvFTD (n = 41), and PPA (n = 22), with 20 individuals serving as healthy controls (HC). Composite and subdomain scores were compared between each patient group and the HC. Praxis profiles indicative of each dementia type and a possible predictive value were sought. Results: Apraxia provided high diagnostic accuracy for detecting dementia compared with HC (sensitivity: 63.6-100%, specificity: 79.2-100%). Patients with AD performed worse when imitating intransitive gestures as well as pantomiming transitive gestures (mean differences: 2.10 and 3.12, respectively), compared with bvFTD. PPA patients, compared with bvFTD, had comparable results in limb, verbal, and non-verbal praxis assessments, despite the greater deterioration in the outcome. Compared with patients with AD, PPA had increased pathological outcomes in verbal (86.4% vs. 40.9%) and non-verbal apraxia (31.8% vs. 0%), while bvFTD had increased pathological outcomes in verbal apraxia (85.4% vs. 44.5%). Finally, apraxia is correlated with cognitive decline. Conclusions: Apraxia profile evaluation could contribute to the differentiation between AD and Frontotemporal Dementia (FTD). Both TULIA and ABA-2 are reliable tools that can be performed as bed-side tests in clinical practice.

More than a piece of cake: Noun classifier processing in primary progressive aphasia.

Clinical understanding of primary progressive aphasia (PPA) has been primarily derived from Indo-European languages. Generalizing certain linguistic findings across languages is unfitting due to contrasting linguistic structures. While PPA patients showed noun classes impairments, Chinese languages lack noun classes. Instead, Chinese languages are classifier language, and how PPA patients manipulate classifiers is unknown. We included 74 native Chinese speakers (22 controls, 52 PPA). For classifier production task, participants were asked to produce the classifiers of high-frequency items. In a classifier recognition task, participants were asked to choose the correct classifier. Both semantic variant (sv) PPA and logopenic variant (lv) PPA scored significantly lower in classifier production task. In classifier recognition task, lvPPA patients outperformed svPPA patients. The classifier production scores were correlated to cortical volume over left temporal and visual association cortices. This study highlights noun classifiers as linguistic markers to discriminate PPA syndromes in Chinese speakers. Noun classifier processing varies in the different primary progressive aphasia (PPA) variants. Specifically, semantic variant PPA (svPPA) and logopenic variant PPA (lvPPA) patients showed significantly lower ability in producing specific classifiers. Compared to lvPPA, svPPA patients were less able to choose the accurate classifiers when presented with choices. In svPPA, classifier production score was positively correlated with gray matter volume over bilateral temporal and left visual association cortices in svPPA. Conversely, classifier production performance was correlated with volumetric changes over left ventral temporal and bilateral frontal regions in lvPPA. Comparable performance of mass and count classifier were noted in Chinese PPA patients, suggesting a common cognitive process between mass and count classifiers in Chinese languages.

Dyslexia phenotypes in Chinese‐speaking individuals with Primary Progressive Aphasia

AbstractBackgroundThere are more than 7,000 living languages worldwide with wide heterogeneities in their linguistic features. Varying dementia symptomatology has been noted across speakers of different languages. Chinese languages adopt logographic scripts that contrast greatly from Indo‐European languages with alphabetic writing systems. For instance, Chinese characters have weak grapheme‐phoneme correspondence, with only 19‐ 39% pronounced per their phonetic components. Chinese characters also have 20 different spatial configurations with varying visuospatial complexity and abundant heteronyms. Past literature has focused on the reading presentations of primary progressive aphasia (PPA) patients that adopt Indo‐European languages. This study outlined the reading presentations of Chinese‐speaking PPA patients.MethodThe CLAP (Chinese Language Assessment for PPA) battery is designed to characterize the neurolinguistics features of Chinese‐speaking PPA individuals. In CLAP character reading test, participants are tasked to read aloud 50 Chinese characters that vary in lexicality (pictographic, regular compound, and irregular compound characters), character frequency and concreteness. Voxel‐based morphometry(VBM) was performed to examine the neural basis of reading performance. Participants are also tasked with reading pairs of compound words with heteronyms (e.g., “bow tie” vs “bow down).ResultsA total of 15 Mandarin‐speaking controls and 38 PPA individuals [6 nonfluent variant (nfv) PPA, 9 semantic variant (sv) PPA and 23 logopenic variant (lv) PPA] completed CLAP reading task. In character reading test, svPPA scored significantly lower than controls and nfvPPA (pictographic: p = 0.026; regular compound: p = 0.007; irregular compound characters: p<0.001). Regardless of lexicality, the reading score significantly correlated with volumetric changes over left temporal pole. While over‐regularization errors/surface dyslexia was the most common reading error across control and PPA groups, it was not specific to svPPA (p = 0.109). Conversely, on heteronym word reading test, svPPA and lvPPA scored significantly lower in accuracy, with over‐regularization errors more frequently noted in svPPA group.ConclusionContrary to English svPPA patients that struggled specifically with irregular word reading and showed frequent surface dyslexia, Chinese PPA patients showed no variant‐specific differences across lexicality, and svPPA‐specific over‐regularization phenomenon were found at the lexical (i.e., heteronym‐reading) and not sub‐lexical reading. Diagnostic criteria for PPA syndrome vary with languages and should ideally be tailored linguistically.

The auditory phenotype of behavioural variant frontotemporal dementia

AbstractBackgroundPatients with behavioural variant frontotemporal dementia commonly exhibit abnormal hedonic and other behavioural responses to sounds, however hearing dysfunction in this disorder is poorly characterised. Here we addressed this issue using the Queen Square Tests of Auditory Cognition (QSTAC) – a neuropsychological battery for the systematic assessment of central auditory functions (including pitch pattern perception, environmental sound recognition, sound localisation and emotion processing) in cognitively impaired people.MethodThe QSTAC was administered to 15 patients with behavioural variant frontotempoal dementia, 24 patients with comparator dementia syndromes (primary progressive aphasia and typical Alzheimer’s disease) and 15 healthy age‐matched individuals. Participants also had pure tone audiometry to assess peripheral hearing function and a comprehensive general neuropsychological assessment.ResultAfter accounting for nonverbal executive and peripheral hearing performance, patients with behavioural variant frontotemporal dementia showed deficits of environmental sound and auditory emotion recognition and sound localisation, compared both with healthy controls and patients with Alzheimer’s disease. Patients with behavioural variant frontotemporal dementia were further differentiated from primary progressive aphasia patients on their performance across QSTAC (sound recognition and localisation) subtests.ConclusionBehavioural variant frontotemporal dementia has a distinct phenotype of auditory cognitive dysfunction which likely contributes to the hearing alterations that many patients with this diagnosis experience in daily life. Our findings call attention to an under‐recognised issue in frontotemporal dementia that warrants further clinical interpretation and the development of management strategies tailored to real‐world acoustic environments.

EEG correlates in the three variants of Primary Progressive Aphasia

AbstractBackgroundThe 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.

Assessing processing speed and its neural correlates in the three variants of primary progressive aphasia with a non-verbal tablet-based task

Prior research has revealed distinctive patterns of impaired language abilities across the three variants of Primary Progressive Aphasia (PPA): nonfluent/agrammatic (nfvPPA), logopenic (lvPPA) and semantic (svPPA). However, little is known about whether, and to what extent, non-verbal cognitive abilities, such as processing speed, are impacted in PPA patients. This is because neuropsychological tests typically contain linguistic stimuli and require spoken output, being therefore sensitive to verbal deficits in aphasic patients. The aim of this study is to investigate potential differences in processing speed between PPA patients and healthy controls, and among the three PPA variants, using a brief non-verbal tablet-based task (Match) modeled after the WAIS-III digit symbol coding test, and to determine its neural correlates. Here, we compared performance on the Match task between PPA patients (n = 61) and healthy controls (n = 59) and across the three PPA variants. We correlated performance on Match with voxelwise gray and white matter volumes. We found that lvPPA and nfvPPA patients performed significantly worse on Match than healthy controls and svPPA patients. Worse performance on Match across PPA patients was associated with reduced gray matter volume in specific parts of the left middle frontal gyrus, superior parietal lobule, and precuneus, and reduced white matter volume in the left parietal lobe. To conclude, our behavioral findings reveal that processing speed is differentially impacted across the three PPA variants and provide support for the potential clinical utility of a tabled-based task (Match) to assess non-verbal cognition. In addition, our neuroimaging findings confirm the importance of a set of fronto-parietal regions that previous research has associated with processing speed and executive control. Finally, our behavioral and neuroimaging findings combined indicate that differences in processing speed are largely explained by the unequal distribution of atrophy in these fronto-parietal regions across the three PPA variants.

A cognitive marker for Alzheimer disease pathology in primary progressive aphasia? A validation study in the clinical setting

We validated in the clinical setting a putative clinical marker for a biological diagnosis of primary progressive aphasia (PPA) due to amyloid previously identified in an autopsy cohort and including impaired (score ≤4) digit span (DS) as index of phonological loop dysfunction and broadened criteria for logopenic PPA. In 29 PPA patients with an amyloid-positive (A+) biomarker and 28 PPA patients with an amyloid-negative (A−) biomarker, Receiver Operating Characteristics (ROC) curve analysis showed moderate specificity (71%) but insufficient sensitivity (41%) for the proposed marker. Specificity was particularly poor (58%) for the discrimination between A+ PPA and the A− subgroup with nonfluent PPA. DS may be compromised in both logopenic and nonfluent PPA, whose loci of neurodegeneration lie at the 2 ends of the left fronto-parieto-temporal system that underpins phonology. An Statistical Parametric Mapping (SPM) correlation analysis between DS score and metabolism on brain 18-fluoro-deoxy-glucose positron emission tomography also showed a major contribution of the left frontal cortex to impaired span.

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.

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.

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).

Asymmetry of radiomics features in the white matter of patients with Primary Progressive Aphasia (P6-12.005)

<h3>Objective:</h3> Primary Progressive Aphasia (PPA) is a neurological disease characterized by linguistic deficits. Semantic (svPPA) and non-fluent/agrammatic (nfvPPA) variants are the two main subtypes of PPA. <h3>Background:</h3> Several studies have investigated brain morphometric changes in PPA patients documenting patterns of asymmetry in gray and white matter (WM) properties. We applied a novel radiomics framework to investigate WM asymmetry. Moreover, we examined whether WM asymmetry in specific brain regions could be associated with verbal fluency impairments. <h3>Design/Methods:</h3> Analyses were performed on 3 Tesla T1-MRI. We included 31 svPPA, 25 nfvPPA and 53 age- and sex-matched controls. Asymmetry Index (AI) was computed for 86 radiomics features in 34 WM regions. Between-group comparisons in AIs were performed using analysis of variance. Correlation analyses investigated the relationships between performance at verbal fluency tasks (semantic and phonemic) and at Boston Naming Test and AIs. <h3>Results:</h3> Relative to controls, WM asymmetry in svPPA patients involved regions adjacent to middle temporal cortex as part of the inferior longitudinal (ILF), fronto-occipital (IFOF) and superior longitudinal (SLF) fasciculi. Conversely, nfvPPA patients showed an asymmetry of WM in lateral occipital brain regions (ILF/IFOF). A higher lateralization of radiomics features involving IFOF, cingulum and forceps minor was found in nfvPPA compared to svPPA patients. Correlation analysis highlighted a positive relationship between semantic fluency and AI in WM adjacent to the lateral occipital gyrus in nfvPPA patients. Performances at Boston Naming Test were significantly associated with AI in WM regions located close to the middle temporal and parahippocampal gyri in svPPA patients. <h3>Conclusions:</h3> Radiomics depicted distinct pathways of WM asymmetry in svPPA and nfvPPA involving damage of fiber tracts associated to linguistic functions. Assessing asymmetry of radiomics in PPA allows achieving a deeper insight into the neuroanatomical damage and a possible marker to evaluate the language severity changes related to drug therapy or rehabilitation speech treatments. <b>Disclosure:</b> Dr. Tafuri has nothing to disclose. Dr. Filardi has nothing to disclose. Dr. Urso has nothing to disclose. Dr. Gnoni has nothing to disclose. Dr. DE BLASI has nothing to disclose. Dr. Nigro has nothing to disclose. Dr. Logroscino has nothing to disclose.

Structural correlates of language processing in primary progressive aphasia.

Understanding the relationships between brain structure and language behaviour in primary progressive aphasia provides crucial information about these diseases' pathomechanisms. However, previous investigations have been limited from providing a statistically reliable view of broad language abilities by sample size, variant focus and task focus. In this study, the authors aimed to determine the relationship between brain structure and language behaviour in primary progressive aphasia, to determine the degree to which task-associated regions were atrophied across disease variants and to determine the degree to which task-related atrophy overlaps across disease variants. Participants were 118 primary progressive aphasia patients and 61 healthy, age-matched controls tested from 2011 to 2018 in the German Consortium for Frontotemporal Lobar Degeneration cohort. Diagnosis of primary progressive aphasia required progressive deterioration of mainly speech and language for ≥ 2 years, and variant was diagnosed by the criteria of Gorno-Tempini et al. (Classification of primary progressive aphasia and its variants. Neurology. 2011;76(11):1006-1014). Twenty-one participants not fulfilling a specific subtype were classified as mixed-variant and excluded. Language tasks of interest included the Boston naming test, a German adaptation of the Repeat and Point task, phonemic and category fluency tasks and the reading/writing subtest of the Aachen Aphasia Test. Brain structure was measured by cortical thickness. We observed networks of language task-associated temporal, frontal and parietal cortex. Overlapping task-associated atrophy was observed in the left lateral, ventral and medial temporal lobes, middle and superior frontal gyri, supramarginal gyrus and insula. Some regions, primarily in the perisylvian region, were associated with language behaviour despite showing no significant atrophy. The results crucially extend less powerful studies associating brain and language measures in primary progressive aphasia. Cross-variant atrophy in task-associated regions suggests partially shared underlying deficits, whereas unique atrophy reinforces variant-specific deficits. Language task-related regions that are not obviously atrophied suggest regions of future network disruption and encourage understanding of task deficits beyond clearly atrophied cortex. These results may pave the way for new treatment approaches.

Spared speech fluency is associated with increased functional connectivity in the speech production network in semantic variant primary progressive aphasia.

Semantic variant primary progressive aphasia is a clinical syndrome characterized by marked semantic deficits, anterior temporal lobe atrophy and reduced connectivity within a distributed set of regions belonging to the functional network associated with semantic processing. However, to fully depict the clinical signature of semantic variant primary progressive aphasia, it is necessary to also characterize preserved neural networks and linguistic abilities, such as those subserving speech production. In this case-control observational study, we employed whole-brain seed-based connectivity on task-free MRI data of 32 semantic variant primary progressive aphasia patients and 46 healthy controls to investigate the functional connectivity of the speech production network and its relationship with the underlying grey matter. We investigated brain-behaviour correlations with speech fluency measures collected through clinical tests (verbal agility) and connected speech (speech rate and articulation rate). As a control network, we also investigated functional connectivity within the affected semantic network. Patients presented with increased connectivity in the speech production network between left inferior frontal and supramarginal regions, independent of underlying grey matter volume. In semantic variant primary progressive aphasia patients, preserved (verbal agility) and increased (articulation rate) speech fluency measures correlated with increased connectivity between inferior frontal and supramarginal regions. As expected, patients demonstrated decreased functional connectivity in the semantic network (dependent on the underlying grey matter atrophy) associated with average nouns' age of acquisition during connected speech. Collectively, these results provide a compelling model for studying compensation mechanisms in response to disease that might inform the design of future rehabilitation strategies in semantic variant primary progressive aphasia.

Unravelling neurotransmitters impairment in primary progressive aphasias.

Primary progressive aphasias (PPAs) are a group of neurodegenerative diseases mainly characterized by language impairment, and with variably presence of dysexecutive syndrome, behavioural disturbances and parkinsonism. Detailed knowledge of neurotransmitters impairment and its association with clinical features hold the potential to develop new tailored therapeutic approaches. In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of magnetic resonance imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission. We included 103 PPA patients and 80 age-matched healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in PPA patients (relative to HC) are correlated with specific neurotransmitter systems. As compared to HC, voxel-based brain changes in PPA were significantly associated with spatial distribution of serotonin, dopamine, and glutamatergic pathways (p< .05, False Discovery Rate corrected-corrected). Disease severity was negatively correlated with the strength of GMV colocalization of D1 receptors (p= .035) and serotonin transporter (p= .020). Moreover, we observed a significant negative correlation between positive behavioural symptoms, as measured with Frontal Behavioural Inventory, and GMV colocalization of D1 receptors (p= .007) and serotonin transporter (p< .001). This pilot study suggests that JuSpace is a helpful tool to indirectly assess neurotransmitter deficits in neurodegenerative dementias and may provide novel insight into disease mechanisms and associated clinical features.

Access, referral, service provision and management of individuals with primary progressive aphasia: A survey of speech-language therapists in Italy.

In Italy, approximately 650 individuals receive a diagnosis of primary progressive aphasia (PPA) every year. Unfortunately, the frequency with which patients are referred to speech-language services is suboptimal, likely due to skepticism regarding the value of speech-language therapy in the context of neurodegeneration. We conducted a virtual survey of speech and language therapists (SLTs) across Italy, to collect information about the assessment, intervention and management of patients with PPA. To ensure that as many SLTs as possible received the survey, the Italian Federation of SLTs (Federazione Logopedisti Italiani, FLI) aided in disseminating the survey. In total, 336 respondents participated in the online survey, 140 of whom had previous experience with PPA patients. Respondents indicated having seen a total of 428 PPA patients in the previous 24 months (three patients on average, range: 0-40). SLTs who reported never working with PPA identified underdiagnoses, low referral rates and the rarity of the clinical syndrome as major reasons for their lack of experience with PPA. SLTs with experience working with PPA indicated that patients may not have accessed services because of service dysfunction and geographical barriers. Respondents reported using informal interviews during assessments and tests developed for post-stroke aphasia, while impairment-based/restitutive interventions were utilised most often. Findings may serve to inform health policy organisations regarding the current shortcomings and needed recommendations for improving the care of individuals with PPA in Italy. Improving awareness of the utility of rehabilitation among SLTs and other clinical service providers may serve to facilitate access to intervention, which in turn will serve to better support individuals living with PPA. What is already known on the subject Speech and language therapists (SLTs) play a crucial role in the assessment, diagnosis and treatment of people with primary progressive aphasia (PPA). However, the frequency with which individuals with PPA are referred for speech and language services is suboptimal due to skepticism regarding the value of speech and language therapy in the context of neurodegeneration, the scarcity of SLTs with expertise in the treatment of PPA and the lack of awareness of the SLT role amongst referrers. What this paper adds to existing knowledge In recognition of the lack of published information on the provision of speech and language therapy services and clinicians' approaches to the assessment and treatment of individuals with PPA in Italy, we conducted an online survey to evaluate the current referral patterns for speech and language therapy services and to examine the current barriers to access these services for individuals with PPA in Italy. What are the potential or actual clinical implications of this work? The data presented here support that SLTs view treatment as useful for individuals with PPA and other professional figures and may serve to improve access to intervention, which in turn will serve to better support individuals living with PPA. The results highlight the need to inform health policy organisations about current gaps and aid in developing recommendations for improving the care of individuals with PPA, in order to understand how SLTs can best support individuals with PPA and their families.

Sex differences in effects of tDCS and language treatments on brain functional connectivity in primary progressive aphasia

Primary Progressive Aphasia (PPA) is a neurodegenerative disorder primarily affecting language functions. Neuromodulatory techniques (e.g., transcranial direct current stimulation, active-tDCS) and behavioral (speech-language) therapy have shown promising results in treating speech and language deficits in PPA patients. One mechanism of active-tDCS efficacy is through modulation of network functional connectivity (FC). It remains unknown how biological sex influences FC and active-tDCS or language treatment(s). In the current study, we compared sex differences, induced by active-tDCS and language therapy alone, in the default mode and language networks, acquired during resting-state fMRI in 36 PPA patients. Using a novel statistical method, the covariate-assisted-principal-regression (CAPs) technique, we found sex and age differences in FC changes following active-tDCS. In the default mode network (DMN): (1) men (in both conditions) showed greater FC in DMN than women. (2) men who received active-tDCS showed greater FC in the DMN than men who received language-treatment only. In the language network: (1) women who received active-tDCS showed significantly greater FC across the language network than women who received sham-tDCS. As age increases, regardless of sex and treatment condition, FC in language regions decreases. The current findings suggest active-tDCS treatment in PPA alters network-specific FC in a sex-dependent manner.