proteins

2026-04-21 | Combined treatment for primary progressive aphasia (Schaffer Mendez et al., 2026)

Purpose: Individuals with primary progressive aphasia (PPA) face negative psychosocial repercussions, yet few studies have investigated counseling for this population. In a prior study, a novel intervention encompassing script training and aphasia-modified cognitive behavioral therapy was piloted with an individual with PPA, yielding promising results. The purpose of this study is to determine the acceptability and feasibility of this intervention for individuals with different PPA subtypes, with secondary aims of understanding preliminary treatment outcomes and evaluating the sensitivity of selected psychosocial measures.Method: Nine participants with PPA were recruited (three with nonfluent/agrammatic variant, three with logopenic variant, and three with semantic variant). Acceptability was measured using a posttreatment questionnaire. Feasibility was examined via intervention adherence, independent practice engagement, retention, assessment completion, interrater reliability, and fidelity ratings. Speech-language outcomes were evaluated via hypothesis testing using simulation analysis from pre- to posttreatment for all participants and from pretreatment to follow-up time points for six participants. Counseling outcomes at posttreatment were measured via psychosocial scales and analyzed using Wilcoxon signed-ranks tests.Results: Findings indicate that this treatment is acceptable and feasible. All participants demonstrated significant improvement in speech-language performance following treatment, with five participants demonstrating significant improvement up to 1 year posttreatment. Despite promising qualitative evidence regarding counseling outcomes, a sensitive quantitative measure of psychosocial functioning was not identified.Conclusions: Pairing tailored speech-language interventions with counseling for individuals with heterogeneous PPA phenotypes is acceptable and feasible. Preliminary outcomes indicate positive communication findings and that alternative psychosocial measures may be beneficial in a future efficacy trial.Supplemental Material S1. LRCT treatment steps.Supplemental Material S2. Comprehensive psychosocial assessment data.Schaffer Mendez, K., Evans, W. S., Wauters, L. D., Dutcher, C. D., Philburn, C., & Henry, M. L. (2026). A combined speech-language and counseling intervention for primary progressive aphasia: Acceptability, feasibility, and preliminary outcomes. Journal of Speech, Language, and Hearing Research, 69(6), 2549–2567. https://doi.org/10.1044/2026_JSLHR-25-00390

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2023-03-02 | Structural correlates of language processing in primary progressive aphasia

Abstract 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.

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2021-06-21 | Evaluating a Maintenance-Based Treatment Approach to Preventing Lexical Dropout in Progressive Anomia.

Purpose Primary progressive aphasia (PPA) and the amnestic variant of Alzheimer's disease (AD) are neurodegenerative conditions characterized by a profound loss of functional communication abilities. Communicative impairment in AD and PPA is especially apparent in the domain of naming common objects and familiar faces. We evaluated the effectiveness of a language intervention targeting maintenance of an individualized core vocabulary in a longitudinal cohort of older adults experiencing either PPA or AD. Method PPA (n = 9) and AD (n = 1) patients were administered a semantically based language treatment for up to 2 years. Patients repeatedly named and generated semantic features for a personalized lexicon consisting of 100 words. We evaluated naming accuracy and off-line neuropsychological measures at four successive timepoints. Naming accuracy was assessed in patients (n = 7) who completed at least three recurrent evaluations. Off-line neuropsychological performance was assessed across timepoints in all patients. Results Patients demonstrated relative preservation of naming trained words relative to a steep decline for untrained (control) words. The greatest decrements were observed for naming people relative to objects. Conclusion These results suggest that consistent training of a finite set of words can protect a core lexicon composed of crucial target concepts (e.g., a spouse's name). We discuss potential benefits and clinical implications of maintenance-based approaches to promoting language functioning in the context of neurodegeneration.

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2015-11-12 | The Application of Timing in Therapy of Children and Adults with Language Disorders

A number of evidence revealed a link between temporal information processing (TIP) and language. Both literature data and results of our studies indicated an overlapping of deficient TIP and disordered language, pointing to the existence of an association between these two functions. On this background the new approach is to apply such knowledge in therapy of patients suffering from language disorders. In two studies we asked the following questions: (1) can the temporal training reduce language deficits in aphasic patients (Study 1) or in children with specific language impairment (SLI, Study 2)? (2) can such training ameliorate also the other cognitive functions? Each of these studies employed pre-training assessment, training application, post-training and follow-up assessment. In Study 1 we tested 28 patients suffering from post-stroke aphasia. They were assigned either to the temporal training (Group A, n = 15) in milliseconds range, or to the non-temporal training (Group B, n = 13). Following the training we found only in Group A improved TIP, accompanied by a transfer of improvement to language and working memory functions. In Study 2 we tested 32 children aged from 5 to 8 years, affected by SLI who were classified into the temporal training (Group A, n = 17) or non-temporal training (Group B, n = 15). Group A underwent the multileveled audio-visual computer training Dr. Neuronowski (®), recently developed in our laboratory. Group B performed the computer speech therapy exercises extended by playing computer games. Similarly as in Study 1, in Group A we found significant improvements of TIP, auditory comprehension and working memory. These results indicated benefits of temporal training for amelioration of language and other cognitive functions in both aphasic patients and children with SLI. The novel powerful therapy tools provide evidence for future promising clinical applications.

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2009-02-01 | Impairment‐ and activity/participation‐directed interventions in progressive language impairment: Clinical and theoretical issues

Abstract Background: There is a broad constellation of clinical syndromes in which the most prominent initial and ongoing symptom is deterioration in spoken or receptive language processing, reading, writing, or semantic knowledge. Despite the core language impairments, people with these disorders are likely to be under‐referred for speech pathology services (Taylor, Kingma, Croot, & Nickels, 2009 Taylor, C., Miles Kingma, R., Croot, K. and Nickels, L. 2009. Speech pathology services for primary progressive aphasia: Exploring an emerging area of practice.. Aphasiology, 22: 161–174. [Taylor & Francis Online] , [Google Scholar] this issue), and there is limited published research on speech pathology interventions in these disorders. Aims: This paper reviews the published impairment‐ and activity/participation‐directed interventions in semantic dementia and progressive aphasia to determine the current evidence base for clinical decisions about client suitability and selection of treatment goals, methods, and measures. We also identify questions that need to be addressed in future therapy research. Methods & Procedures: We reviewed 15 reports of impairment‐directed behavioural, pharmacological, and repeated transcranial magnetic stimulation treatments that implemented some level of experimental control. We reviewed a further 10 reports of interventions generally carried out without experimental control, targeting impairments, activity/participation limitations, education, carer training, or a mixture of these approaches. Outcomes & Results: In the impairment‐directed studies almost all participants showed improvement on treated items immediately post‐treatment. Improvement was specific to treated items in most word retrieval studies, but there is a possibility that greater generalisation to other items or other language tasks/contexts may have occurred in treatments not targeting naming, and/or for clients with articulatory impairments. Without ongoing practice of therapy activities, treatment gains declined for all participants over a period varying from 2 months to between 6 months and 1 year. There was only one experimentally controlled activity/participation‐directed intervention reported for people with progressive language impairments, although other reports of activity/participation‐directed interventions described increased communicativeness and communication effectiveness for participants following intervention. Consistent with the aims of activity/participation‐interventions, these interventions appear to have a greater impact on everyday communication outside the clinic than impairment‐directed interventions, but these impacts need to be investigated and documented. Conclusions: These studies highlight the need for rigorous research design to identify treatment, generalisation, and maintenance effects (Rapp & Glucroft, 2009 Rapp, B. and Glucroft, B. 2009. The benefits and protective effects of behavioural treatment for dysgraphia in a case of primary progressive aphasia.. Aphasiology, 22: 236–265. [Taylor & Francis Online] , [Google Scholar] this issue), and to identify outcomes that go beyond improvement in the clinic on targeted words, language structures, and behaviours. It is important to tailor interventions closely to individual client needs, involve the spouse/carer in intervention, and ensure that clients have appropriate expectations about therapy. The patterns of therapy gain, limited generalisation, and decline following cessation of therapy activities in impairment‐directed studies raise questions about the learning mechanism(s) involved. They also have implications for client suitability, and for choice of therapy items, and therapy delivery and duration. Keywords: Primary progressive aphasiaFrontotemporal dementiaSemantic dementiaTreatmenttherapy

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oligonucleotides

2022-09-09 | Exploring the effects of verb and noun treatment on verb phrase production in primary progressive aphasia: A series of single case experimental design studies.

Evidence of generalization to connected speech following lexical retrieval treatment in Primary Progressive Aphasia (PPA) is scarce. Consequently, this study systematically investigated changes in verb phrase production following lexical retrieval treatment in a series of single case experimental design studies. Four individuals with PPA (three semantic- and one logopenic variant PPA) who had previously demonstrated that they could integrate verbs and nouns into sentence structures in a cueing paradigm, undertook a sequence of verb and noun lexical retrieval treatments using Repetition and Reading in the Presence of a Picture. Production of treated nouns- and/or verbs-in-isolation significantly improved following treatment for three of the four participants. Verb phrase production did not improve for one of these participants (logopenic PPA), perhaps due to the relatively small treatment dose. Two participants (semantic variant PPA) did, however, demonstrate across-level generalization, with improvement in treated verbs and using those verbs in (untreated) verb phrases. Their verb phrase production improved most after lexical retrieval treatment for both nouns and verbs, suggesting this combined approach may benefit across-level generalization for some individuals in clinical practice.

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2022-05-04 | Tonal and orthographic analysis in a Cantonese-speaking individual with nonfluent/agrammatic variant primary progressive aphasia.

Clinical understanding of primary progressive aphasia (PPA) has been established based on English-speaking population. The lack of linguistic diversity in research hinders the diagnosis of PPA in non-English speaking patients. This case report describes the tonal and orthographic deficits of a multilingual native Cantonese-speaking woman with nonfluent/agrammatic variant PPA (nfvPPA) and progressive supranuclear palsy. Our findings suggest that Cantonese-speaking nfvPPA patients exhibit tone production impairments, tone perception deficits at the lexical selection processing, and linguistic dysgraphia errors unique to logographic script writer. These findings suggest that linguistic tailored approaches offer novel and effective tools in identifying non-English speaking PPA individuals.

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2022-04-05 | Modified script training for nonfluent/agrammatic primary progressive aphasia with significant hearing loss: A single-case experimental design.

Speech-language pathology caseloads often include individuals with hearing loss and a coexisting neurogenic communication disorder. However, specific treatment techniques and modifications designed to accommodate this population are understudied. Using a single-case experimental design, the current study investigated the utility of modified Video Implemented Script Training for Aphasia (VISTA) for an individual with nonfluent/agrammatic variant primary progressive aphasia and severe-to-profound, bilateral hearing loss. We analyzed the impact of this intervention, which incorporates orthographic input and rehearsal, on script production accuracy, speech intelligibility, grammatical complexity, mean length of utterance, and speech rate. Treatment resulted in comparable positive outcomes relative to a previous study evaluating script training in nonfluent/agrammatic primary progressive aphasia patients with functional hearing. Follow-up data obtained at three months, six months, and one year post-treatment confirmed maintenance of treatment effects for trained scripts. To our knowledge, this is the first study to investigate a modified speech-language intervention tailored to the needs of an individual with PPA and hearing loss, with findings confirming that simple treatment modifications may serve to broaden the range of treatment options available to those with concomitant sensory and communication impairments.

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2019-01-30 | Primary progressive aphasia: a model for neurodegenerative disease

Purpose of review Knowledge on primary progressive aphasia (PPA) has expanded rapidly in the past few decades. Clinical characteristics, neuroimaging correlates, and neuropathological features of PPA are better delineated. This facilitates scientific studies on the disease pathophysiology and allows speech and language therapy to be more precisely targeted. This review article begins with a summary of the current understanding of PPA and discusses how PPA can serve as a model to promote scientific discovery in neurodegenerative diseases. Recent findings Studies on the different variants of PPA have demonstrated the high compatibility between clinical presentations and neuroimaging features, and in turn, enhances the understanding of speech and language neuroanatomy. In addition to the traditional approach of lesion-based or voxel-based mapping, scientists have also adopted functional connectivity and network topology approaches that permits a more multidimensional understanding of neuroanatomy. As a result, pharmacological and cognitive therapeutic strategies can now be better targeted towards specific pathological/molecular and cognitive subtypes. Summary Recent scientific advancement in PPA potentiates it to be an optimal model for studying brain network vulnerability, neurodevelopment influences and the effects of nonpharmacological intervention in neurodegenerative diseases.

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2018-03-28 | Retraining speech production and fluency in non-fluent/agrammatic primary progressive aphasia

The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) presents with a gradual decline in grammar and motor speech resulting from selective degeneration of speech-language regions in the brain. There has been considerable progress in identifying treatment approaches to remediate language deficits in other primary progressive aphasia variants; however, interventions for the core deficits in nfvPPA have yet to be systematically investigated. Further, the neural mechanisms that support behavioural restitution in the context of neurodegeneration are not well understood. We examined the immediate and long-term benefits of video implemented script training for aphasia (VISTA) in 10 individuals with nfvPPA. The treatment approach involved repeated rehearsal of individualized scripts via structured treatment with a clinician as well as intensive home practice with an audiovisual model using 'speech entrainment'. We evaluated accuracy of script production as well as overall intelligibility and grammaticality for trained and untrained scripts. These measures and standardized test scores were collected at post-treatment and 3-, 6-, and 12-month follow-up visits. Treatment resulted in significant improvement in production of correct, intelligible scripted words for trained topics, a reduction in grammatical errors for trained topics, and an overall increase in intelligibility for trained as well as untrained topics at post-treatment. Follow-up testing revealed maintenance of gains for trained scripts up to 1 year post-treatment on the primary outcome measure. Performance on untrained scripts and standardized tests remained relatively stable during the follow-up period, indicating that treatment helped to stabilize speech and language despite disease progression. To identify neural predictors of responsiveness to intervention, we examined treatment effect sizes relative to grey matter volumes in regions of interest derived from a previously identified speech production network. Regions of significant atrophy within this network included bilateral inferior frontal cortices and supplementary motor area as well as left striatum. Volumes in a left middle/inferior temporal region of interest were significantly correlated with the magnitude of treatment effects. This region, which was relatively spared anatomically in nfvPPA patients, has been implicated in syntactic production as well as visuo-motor facilitation of speech. This is the first group study to document the benefits of behavioural intervention that targets both linguistic and motoric deficits in nfvPPA. Findings indicate that behavioural intervention may result in lasting and generalized improvement of communicative function in individuals with neurodegenerative disease and that the integrity of spared regions within the speech-language network may be an important predictor of treatment response.

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small molecules

2026-09-10 | Where does the "ἀφημί" (speechless) in nfvPPA come from?: a case study on phonological retrieval and the potent effect of moraic assistance.

Diagnosing non-fluent/agrammatic variant primary progressive aphasia (nfvPPA) relies primarily on apraxia of speech (AOS) and agrammatism. However, differentiating phonetic-level (articulatory) from phonemic-level (phonological) impairments remains clinically challenging, especially in advanced stages. We report a 65-year-old Japanese male with nfvPPA who had become virtually speechless (ἀφημί). Leveraging the Kana writing system's one-to-one correspondence to morae, we designed a cross-modal experiment to isolate his underlying deficit. Speech production was evaluated across four conditions: picture naming, Kanji word reading, Kana word reading, and character-by-character Kana reading. Statistical analysis was performed using Fisher's exact test and adjusted residual analysis. Speech intelligibility significantly improved during character-by-character Kana reading compared to other modalities. Residual analysis confirmed that explicit moraic cues markedly reduced error rates. These findings indicate that our approach effectively unmasked superimposed phonemic-level retrieval deficits contributing to speechlessness in nfvPPA. This study highlights the utility of Japanese orthography in disentangling underlying mechanisms and demonstrates that moraic assistance can serve as a potent facilitation strategy in severe cases.

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2025-12-01 | Impaired Treg function and activation of the CXCL10/CXCR3 inflammatory pathway in Non‐Fluent Variant Primary Progressive Aphasia

BACKGROUND: Despite growing evidence supporting the role of inflammation in neurodegenerative processes, a detailed molecular understanding of the peripheral immune system's status and its mechanistic implications in the pathology of frontotemporal dementia (FTD) remains limited. In this study, we investigate (a) the suppressive function of regulatory T cells (Tregs), (b) the inflammatory profile of peripheral monocytes, and (c) the levels of inflammatory markers in the plasma of individuals with non-fluent variant primary progressive aphasia (nfvPPA), a subtype of FTD. METHOD: Plasma and peripheral blood mononuclear cells (PBMCs) were obtained from 17 nfvPPA and 34 age-matched HC recruited by the Houston Methodist Nantz National Alzheimer's Center. The suppressive function of Tregs was assessed using proliferation assays. RNA from peripheral monocytes was analyzed via Nanostring chips and qRT-PCR to determine the inflammatory profiles. Plasma cytokine levels were measured using the Olink® Target 48 Cytokine panel. Time-of-flight mass cytometry (CyTOF) was employed to evaluate PBMCs immunoprofiles and the activation of signaling pathways at single-cell resolution. RESULT: Tregs from nfvPPA individuals demonstrated a compromised ability to suppress responder T cell proliferation compared to HC. Additionally, peripheral monocytes in the nfvPPA cohort exhibited significantly increased expression of pro-inflammatory genes, including C1q, NLRP3, PRG3, and CXCL10. Elevated levels of CXCL10 were also detected in the plasma of nfvPPA patients. By integrating both transcriptomic and proteomic data, we identified the activation of the CXCL10/CXCR3 cascade in nfvPPA individuals. Proteomic analysis by CyTOF revealed that CXCL10 was predominantly expressed by CD14 monocytes, while its receptor, CXCR3, was highly expressed on CD4 and CD8T cells. Our in vitro studies demonstrated that CXCL10 exerted pro-inflammatory effects on CXCR3-positive T cells, effects that were mitigated by the addition of the selective CXCR3 blocker AMG487. CONCLUSION: Individuals with nfvPPA exhibit impaired immunosuppressive function of Tregs, accompanied by systemic activation of the CXCL10/CXCR3 pathway, which is involved in the homing of T cells into the brain. Our findings highlight the potential clinical impact of (i) restoring Treg suppressive function and (ii) targeting the CXCL10/CXCR3 axis to mitigate neurodegeneration by limiting neuroinflammation and the infiltration of cytotoxic T cells to the brain.

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2025-08-20 | Longitudinal evaluation of common and unique brain-networks in variants of primary progressive aphasia.

The two variants of primary progressive aphasia (PPA) with Frontotemporal dementia pathology- semantic (svPPA) and non-fluent (nfvPPA) exhibit both shared and distinct features. The phenotypic heterogeneity stems from alterations in underlying brain networks. Investigating the common network (CN) and variant-specific unique network (UN) is critical to understanding the pathology of these conditions. Additionally, examining the evolution of these networks is key to elucidating disease progression. We applied algebraic-topology to explore the CN and UN using individualised resting-state fMRI data from 31 patients with nfvPPA, 32 with svPPA, and 38 age- and sex-matched controls (scanned at first visit). Using persistent homology, we identified the networks that differentiated (p < 0.01) each patient group from healthy controls. Since the subset of these subjects was scanned at the 6th and 12th months, the longitudinal changes in the rsfMRI networks were evaluated at each interval. Network features were correlated with clinical behaviours, and the longitudinal impact of the changes in these networks on behaviours was evaluated over the 12-month period. To validate the rsfMRI networks and the longitudinal changes, we evaluated the grey matter (GM) volume, GM atrophy and the rate-of-atrophy of the brain areas. To corroborate the findings, we applied persistent homology on the structural networks derived from diffusion tensor images. We found the existence of a left lateralised functional network identical in both PPA groups. This CN, comprising regions associated with language and cognition, remained stable over time (12 months period) and was associated with the severity of dementia. Conversely, the right-dominant UN in both variants showed progressive disintegration annually. In svPPA, cerebellar disassociation led to a decline in daily life activities, while parietal lobe degradation in nfvPPA impaired naming abilities. The CN and UN with similar regions were also found in the structural connectivity and the longitudinal changes in UN aligned with accelerated GM atrophy in the affected regions. Given the limited availability of pharmacological treatments, rehabilitation in PPA has primarily focused on modulating the left hemisphere using brain stimulation techniques. However, our findings indicate that while the disintegrated left hemispheric CN remained relatively stable, dysconnectivity progressed in the right hemisphere. These observations, along with the phylogenetic organization of brain networks and the variant-specific patterns of progression, highlight the need to incorporate right hemispheric rehabilitation strategies alongside the conventional left-hemispheric approaches in PPA.

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2024-09-11 | Efficacy of Acetylcholinesterase Inhibitors in the Logopenic Variant of Primary Progressive Aphasia.

For over 25 years, cholinesterase inhibitors (ChEIs) have been the main symptomatic treatment for Alzheimer's disease (AD). Several meta-analyses have supported their effectiveness in various neurocognitive, functional, and behavioral aspects of amnestic AD. Over 86% of cases of the logopenic variant of primary progressive aphasia (lvPPA), also named language variant AD, are caused by a similar pathologic process than AD, yet no study has examined the efficacy of ChEIs in this AD variant. We aimed to explore the efficacy of ChEIs in the treatment of lvPPA by comparing their evolution on the MMSE, and other functional and behavioral parameters, to that of treated amnestic AD patients. A retrospective chart review was performed in 45 patients with lvPPA and 52 patients with amnestic AD. Both groups were similar in terms of age, level of education, and onset of symptoms. Drug history and MMSE scores, as well as functional (activities of daily living [ADLs] and instrumental activities of daily living [IADLs]), neurocognitive and neuropsychiatric symptoms were collected on several time points before and after the introduction of ChEIs. Data were analyzed using ANOVA and a generalized linear mixed model. Patients with lvPPA showed a similar trajectory of decline than amnestic AD patients on serial MMSEs up to 12-24 months after the introduction of ChEIs. There was a significant impact on ADLs but not IADLs and neuropsychiatric symptoms remained stable over time. This study provides preliminary evidence for efficacy of ChEIs in patients with lvPPA and suggests similar benefits to those seen in amnestic AD patients, hence reassuring patients and their physicians. For over 25 years, cholinesterase inhibitors (ChEIs) have been the main symptomatic treatment for Alzheimer's disease (AD). Several meta-analyses have supported their effectiveness in various neurocognitive, functional, and behavioral aspects of amnestic AD. Over 86% of cases of the logopenic variant of primary progressive aphasia (lvPPA), also named language variant AD, are caused by a similar pathologic process than AD, yet no study has examined the efficacy of ChEIs in this AD variant. We aimed to explore the efficacy of ChEIs in the treatment of lvPPA by comparing their evolution on the MMSE, and other functional and behavioral parameters, to that of treated amnestic AD patients. A retrospective chart review was performed in 45 patients with lvPPA and 52 patients with amnestic AD. Both groups were similar in terms of age, level of education, and onset of symptoms. Drug history and MMSE scores, as well as functional (activities of daily living [ADLs] and instrumental activities of daily living [IADLs]), neurocognitive and neuropsychiatric symptoms were collected on several time points before and after the introduction of ChEIs. Data were analyzed using ANOVA and a generalized linear mixed model. Patients with lvPPA showed a similar trajectory of decline than amnestic AD patients on serial MMSEs up to 12-24 months after the introduction of ChEIs. There was a significant impact on ADLs but not IADLs and neuropsychiatric symptoms remained stable over time. This study provides preliminary evidence for efficacy of ChEIs in patients with lvPPA and suggests similar benefits to those seen in amnestic AD patients, hence reassuring patients and their physicians.

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2023-04-03 | Point-light display: a new tool to improve verb recovery in patients with aphasia? A pilot study

Some studies have demonstrated that Action Observation (AO) could help patients with aphasia to recover use of verbs. However, the role of kinematics in this effect has remained unknown. The main aim was to assess the effectiveness of a complementary intervention based on the observation of action kinematics in patients with aphasia. Seven aphasic patients (3 males, 4 females) aged between 55 and 88 years participated in the studies. All patients received a classical intervention and an additional, specific intervention based on action observation. This consisted in visualizing a static image or a point-light sequence representing a human action and in trying to name the verb representing the action. In each session, 57 actions were visualized: 19 represented by a static drawing, 19 by a non-focalized point-light sequence, i.e., a point-light display with all dots in white, and 19 by a focalized point-light sequence, i.e., a point-light display (PLD) with the dots corresponding to the main limbs in yellow. Before (pre-test) and after (post-test) the intervention, each patient performed the same denomination task, in which all actions were presented in photographs. The results showed a significant improvement in performance between pre and post-test, but only when the actions were presented in focalized and non-focalized point-light sequences during the intervention. The presentation of action kinematics seems crucial in the recovery of verbs in patients with aphasia. This should be considered by speech therapists in their interventions.

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gene therapies

2026-03-09 | Behavioural rigidity as a transdiagnostic marker of nucleus accumbens dysfunction in dementia.

Behavioural rigidity, the tendency to persist with inflexible patterns of thoughts or actions, is increasingly recognised as a transdiagnostic symptom across psychiatric, neurodevelopmental, and neurodegenerative disorders. Empirical studies exploring the prevalence and underlying neural mechanisms of behavioural rigidity in dementia, however, are lacking. This cross-sectional study sought to delineate the structural and functional neural correlates of behavioural rigidity using a transdiagnostic approach looking across the frontotemporal lobar degeneration (FTLD) spectrum and Alzheimer's disease. A total of 204 participants were recruited, including 110 frontotemporal dementia (FTD), 53 Alzheimer's disease (AD), and 41 healthy older control participants. Within the FTD group, 66 cases were diagnosed with clinically probable behavioural variant FTD (bvFTD), 26 presented with semantic dementia (SD), and 18 cases had progressive non-fluent aphasia (PNFA). Behavioural rigidity was assessed using the Stereotypical and Motor Behaviour subscale of the Cambridge Behavioural Inventory-Revised. Voxel-based morphometry (VBM) was performed to identify grey matter regions associated with behavioural rigidity transdiagnostically, the results of which informed subsequent seed-based voxel-wise functional connectivity analyses. All imaging analyses were adjusted for relevant demographic and technical covariates. Statistical thresholds were set at voxel-level p < 0.001 (uncorrected) and cluster-level p < 0.05 (FDR-corrected). Our main finding was that behavioural rigidity is pervasive across dementia subtypes, ranging from most pronounced in bvFTD to milder/relatively absent in PNFA, relative to Controls. Whole-brain VBM across the entire patient sample revealed a significant negative association between behavioural rigidity and grey matter intensity exclusively in the bilateral nucleus accumbens. Using the bilateral nucleus accumbens as seeds, resting-state functional connectivity analysis showed that higher levels of behavioural rigidity were associated with stronger connectivity between the left nucleus accumbens and the left supplementary motor area, paracentral lobule, and precuneus. This is the first study, to our knowledge, to examine the neural substrates of behavioural rigidity across FTLD syndromes transdiagnostically using structural and functional neuroimaging approaches. Our findings reveal a gradation of rigid and repetitive behaviours, most apparent in bvFTD, which in turn reflects pathological disruption of the nucleus accumbens. Taken together, our findings highlight the need to consider repetitive and rigid behaviours as a transdiagnostic feature in neurodegenerative disorders, and one which indexes underlying nucleus accumbens pathology. More broadly, this study underscores the importance of screening for rigid and repetitive behaviours in the clinic and identifies the nucleus accumbens as a promising neural target to ameliorate these symptoms.

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2026-02-05 | Primary progressive aphasia with mixed features: diagnostic challenges in overlapping syndromes

Presentation: I.A.M., 62-year-old female, university degree in psychology, hypertension, dyslipidemia and essential tremor. Symptoms began in 2021 with depression, anhedonia and emotional lability. In March 2022, she developed word-finding difficulties and circumlocutions. Progressive speech fluency reduction and slowed speech. By 2023, she presented with phonemic paraphasias and anomia, though semantic knowledge was preserved. She could semantically associate objects and gesture their use. Repetition of simple words was intact, but sentence repetition was impaired. Apraxia of speech and orobuccolingual apraxia became evident. Her husband reported new behavioral changes, disinhibition and increased tendency to approach and touch strangers, especially men. Brain MRI showed asymmetric temporal lobe atrophy, more pronounced on the left. FDG-PET revealed hypometabolism in the left precuneus and posterior cingulate, bilateral posterior temporoparietal cortices (worse on the left), basal ganglia and left frontal cortex. Amyloid-PET (PIB-PET) was negative for cortical β-amyloid deposition. Discussion: The case is consistent with Primary Progressive Aphasia (PPA) associated with Frontotemporal Lobar Degeneration (FTLD), displaying mixed features of logopenic PPA (anomia, word-finding difficulties, circumlocutions, repetition deficits) and non-fluent/agrammatic PPA (reduced fluency, apraxia of speech and orobuccolingual apraxia), alongside behavioral changes. Structural and metabolic imaging did not help differentiating the pathologies, making it necessary to use a specific biomarker for Alzheimer’s disease to exclude the diagnosis. Conclusion: Differentiating canonical PPA variants can be challenging, often requiring biomarker studies for accurate diagnosis. Etiological clarification is essential for patient management, treatment decisions, and prognostic counseling.

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2026-02-05 | Writing proficiency in different subtypes of primary progressive aphasia and its correlation with neuroimaging and demographic data

Background: Primary Progressive Aphasia (PPA) is a neurodegenerative syndrome that primarily affects language function. Three recognized variants include the semantic (PPA-s), non-fluent (PPA-nf), and logopenic (PPA-l) types. Mixed cases are classified as PPA-nc. Objective: To assess the performance of PPA subtypes in the HFSP dictation test and correlate results with neuroimaging and demographic data. Methods: This observational, descriptive cross-sectional study was conducted at a university cognitive and behavioral neurology clinic. Thirty-three patients (aged 52–77, education 4–21 years) participated after signing Ethics Committee–approved consent forms. The HFSP test was used to assess and classify writing errors, followed by analysis of correlations with gender, age, education, and neuroimaging data. Results: No correlation was found between number of errors, age, or education. Most frequent errors were graphemic substitutions (M=4.8) in PPA-s, lexicalization (M=9.0) in PPA-nf, and omissions (M=4.5) in PPA-l. In the PPA-nc group, graphemic substitutions (M=3.5) were most frequent, along with 42 cases of task incompletion (words not written). All patients showed impairment in at least one hemisphere: 16 had left hemisphere (LH) lesions only, 13 had bilateral lesions, 0 had right-only lesions, and 4 had unspecified encephalic damage. In LH lesion cases, lesion sites did not correlate with error type. Discussion: Findings support the literature associating PPA, regardless of subtype, with LH impairment mostly. Conclusion: Preliminary results suggest no significant correlations among the variables analyzed.

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2025-12-24 | A Case of Nonfluent/Agrammatic Variant Primary Progressive Aphasia With Dictating Difficulties in Monosyllables and Words

症例は非流暢性 / 失文法型原発性進行性失語の50歳代女性。発症初期から高度の発語失行を伴い，経過中に自発話は消失した。徐々に書字障害も進行し，特にひらがなでの単語の書き取りで，単語の後半になるほど文字の想起困難や錯書が目立った。書き取り障害の要因を明らかにするため，語音聴取能力，文字や線画が持つ音韻情報の強弱による音韻との照合能力の差異，単語の音韻情報の把持能力について検討した。その結果，語音聴取能力の低下が軽度出現していること，ひらがな文字，漢字文字，線画の順に音韻との照合が不良であること，入力されたもしくは聴覚的記憶から想起された音韻列の後半を把持できないことが示された。非流暢性 / 失文法型原発性進行性失語においても，前頭葉後方下部を含めた領域での機能障害が進行すると，音韻と形態・意味情報の照合や，音韻レベルでの言語性短期記憶障害を生じる可能性が示唆された。

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2025-12-01 | Natural Language Processing differentiates between Italian individuals with Nonfluent/Agrammatic from Logopenic variants of PPA

Abstract Background Differentiating between logopenic (lvPPA) and nonfluent/agrammatic (nfvPPA) variants of Primary Progressive Aphasia relies on expert evaluations of speech and language production. The dichotomy fluency/non‐fluency is not enough to support the clinical diagnosis as an effortful production of sentences (including morphosyntactic and phonological errors) can be present in both variants for different reasons. Connected speech analysis greatly supports the phenotypical classification of PPA, targeting abnormal language production. Method In this cross‐sectional study, 19 Italian patients with PPA (nfvPPA=9; lvPPA=10) underwent an audio‐recorded picture description task from the SAND battery. The speech data were analyzed using computational methods with the Computerized Language ANalysis (CLAN) software, allowing the extraction of linguistic features. Using a Mann‐Whitney non‐parametric test corrected for false discovery rate (FDR), we analyzed 45 linguistic features belonging to four linguistic levels. A machine‐learning (ML) model was trained to classify nfvPPA vs lvPPA. Result We identified ten features belonging to 4 linguistic levels differentiating nfvPPA from lvPPA. These included, at the phonetic and phonological level: silent pause ratio; at the lexico‐semantic level: noun, adverb, article, and determiner ratios; at the morphosyntactic level: total number of utterances and utterance error ratio; and at the pragmatic/discourse level: total words, total morphemes, and idea density. The ML model reached a sensitivity and specificity> 90%. Conclusion We implemented natural language processing to perform a machine‐learning classification based on connected speech samples of Italian‐speaking subjects. This approach has been applied for the first time to Italian PPA and demonstrated that key linguistic markers can be identified and compared across the two variants.

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2026-04-21 | A Combined Speech-Language and Counseling Intervention for Primary Progressive Aphasia: Acceptability, Feasibility, and Preliminary Outcomes.

Individuals with primary progressive aphasia (PPA) face negative psychosocial repercussions, yet few studies have investigated counseling for this population. In a prior study, a novel intervention encompassing script training and aphasia-modified cognitive behavioral therapy was piloted with an individual with PPA, yielding promising results. The purpose of this study is to determine the acceptability and feasibility of this intervention for individuals with different PPA subtypes, with secondary aims of understanding preliminary treatment outcomes and evaluating the sensitivity of selected psychosocial measures. Nine participants with PPA were recruited (three with nonfluent/agrammatic variant, three with logopenic variant, and three with semantic variant). Acceptability was measured using a posttreatment questionnaire. Feasibility was examined via intervention adherence, independent practice engagement, retention, assessment completion, interrater reliability, and fidelity ratings. Speech-language outcomes were evaluated via hypothesis testing using simulation analysis from pre- to posttreatment for all participants and from pretreatment to follow-up time points for six participants. Counseling outcomes at posttreatment were measured via psychosocial scales and analyzed using Wilcoxon signed-ranks tests. Findings indicate that this treatment is acceptable and feasible. All participants demonstrated significant improvement in speech-language performance following treatment, with five participants demonstrating significant improvement up to 1 year posttreatment. Despite promising qualitative evidence regarding counseling outcomes, a sensitive quantitative measure of psychosocial functioning was not identified. Pairing tailored speech-language interventions with counseling for individuals with heterogeneous PPA phenotypes is acceptable and feasible. Preliminary outcomes indicate positive communication findings and that alternative psychosocial measures may be beneficial in a future efficacy trial. https://doi.org/10.23641/asha.31836103.

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2026-04-02 | Peripheral immune profiling in frontotemporal dementia.

Frontotemporal dementia (FTD) encompasses a heterogenous and clinically diverse group of disorders, including the behavioural variant frontotemporal dementia, the non-fluent and the semantic variants of primary progressive aphasia. While these subtypes present with distinct clinical features, emerging evidence implicates neuroinflammation as a shared pathogenic mechanism. Nevertheless, little is known regarding the status of the peripheral immune system in the pathogenesis of FTD. Blood samples were obtained from 27 individuals with a clinical diagnosis of FTD (7 behavioural variants FTD, 10 non-fluent and 10 semantic variants of primary progressive aphasia) and 25 age-matched healthy controls. The immunophenotypes of peripheral immune cell populations were assessed with multicolour flow cytometry. Regulatory T cells were isolated and co-cultured with responder T cells and proliferation was determined by 3H-thymidine incorporation. The immune-related transcriptomic profile of isolated monocytes was analysed using the NanoString Human Inflammation Panel. Plasma levels of inflammatory cytokines and chemokines were quantified using the Olink® Target 48 Cytokine panel. Our analysis demonstrated that the suppressive function of regulatory T cells on responder T cells proliferation was significantly compromised in FTD individuals compared to healthy controls (P < 0.05). Transcriptomic profiling of FTD monocytes revealed a potential dysregulation of 153 immune-related genes. Enrichment analysis showed that these genes were mainly involved in chemokine-mediated signalling pathway, monocyte and lymphocyte chemotaxis, response to interferon-gamma and positive regulation of ERK1 and ERK2 cascades. Proteomic analysis of plasma inflammatory mediators showed a significant increase in the pro-inflammatory cytokine TNFa (P < 0.05) and the chemokines CXCL10, CCL3, CCL19, CSF1 (P < 0.05) and CXCL12 (P < 0.01) in FTD individuals compared to healthy controls. These findings provide the first evidence that the immunomodulatory function of regulatory T cells is compromised in individuals with FTD. In addition, there is a dysregulation of inflammation-related gene expression in peripheral monocytes and an increase of plasma inflammatory chemokines and cytokines in FTD individuals. Further investigation is warranted to assess the therapeutic potential of restoring dysfunctional regulatory T cells and modulating the inflammatory profile in the clinical setting of FTD.

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2026-02-02 | "Doing the Best I Can": Qualitative Outcomes and Participant Feedback From a Combined Communication and Counselling Treatment for Primary Progressive Aphasia.

There is a growing evidence base supporting the utility of restitutive speech-language treatments for individuals with primary progressive aphasia (PPA). In contrast, there is limited research investigating treatment approaches that offer counselling to this population. Given that people with PPA are susceptible to negative impacts on their psychosocial well-being, research is needed to address this underrepresented area of inquiry. This paper provides qualitative research findings from a pilot and feasibility study in which individuals with PPA completed a novel, telehealth-based treatment program comprising both tailored speech-language treatment and counselling (via aphasia-modified cognitive behavioural therapy). Nine participants with PPA (three with nonfluent/agrammatic variant; three with logopenic variant; three with semantic variant) completed the novel treatment program. A phenomenological analysis was used at pre- and post-treatment timepoints to analyse qualitative treatment outcomes and participant-derived feedback regarding the intervention. Following treatment, group-level themes identified across both timepoints included Communication Difficulties, Loss, Communication Strategy Usage, and Value of Support Systems. Themes identified only at pre-treatment included Negative Emotions and Social Disconnection, while those observed only at post-treatment were Acceptance, Gratitude, and Counselling and Coping Strategy Usage. Participant-generated feedback regarding the intervention resulted in themes of Positive Life Impact of Treatment, Satisfaction with Treatment Framework, and Satisfaction with Telerehabilitation. Qualitative results from this pilot study indicate positive/adaptive themes surrounding psychosocial functioning following treatment for participants with each PPA subtype. Furthermore, participant-generated feedback reflects overall satisfaction with this holistic communication and counselling-focused treatment approach, indicating treatment acceptability. What is already known on this subject People with primary progressive aphasia (PPA) often experience a negative impact on their emotional well-being and quality of life. While preliminary research indicates that these individuals may benefit from personal-adjustment counselling, research is limited pertaining to psychosocial approaches in PPA. Thus, additional research is warranted to investigate the benefit, acceptability and feasibility of these interventions. What this paper adds to existing knowledge Preliminary qualitative results provide evidence that a novel treatment approach comprising communication-focused intervention and aphasia-modified cognitive-behavioural therapy (CBT) results in positive psychosocial outcomes amongst nine individuals with heterogeneous PPA presentations. Participant-generated feedback following treatment supports the acceptability of this combined intervention. Individuals reported satisfaction with the intervention overall and recognized the value of engaging in a program that aims to optimize both communication and emotional well-being. What are the potential or actual clinical implications of this work? Speech-language therapists/pathologists may consider incorporating counselling approaches to optimize a person with PPA's emotional health and holistically meet patient needs. Aphasia-modified CBT, provided by a speech-language therapist/pathologist, requires further investigation to ultimately determine the clinical utility of this approach.

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2024-03-21 | Distinctive whole-brain cell types predict tissue damage patterns in thirteen neurodegenerative conditions

For over a century, brain research narrative has mainly centered on neuron cells. Accordingly, most neurodegenerative studies focus on neuronal dysfunction and their selective vulnerability, while we lack comprehensive analyses of other major cell types’ contribution. By unifying spatial gene expression, structural MRI, and cell deconvolution, here we describe how the human brain distribution of canonical cell types extensively predicts tissue damage in 13 neurodegenerative conditions, including early- and late-onset Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, mutations in presenilin-1, and 3 clinical variants of frontotemporal lobar degeneration (behavioral variant, semantic and non-fluent primary progressive aphasia) along with associated three-repeat and four-repeat tauopathies and TDP43 proteinopathies types A and C. We reconstructed comprehensive whole-brain reference maps of cellular abundance for six major cell types and identified characteristic axes of spatial overlapping with atrophy. Our results support the strong mediating role of non-neuronal cells, primarily microglia and astrocytes, in spatial vulnerability to tissue loss in neurodegeneration, with distinct and shared across-disorder pathomechanisms. These observations provide critical insights into the multicellular pathophysiology underlying spatiotemporal advance in neurodegeneration. Notably, they also emphasize the need to exceed the current neuro-centric view of brain diseases, supporting the imperative for cell-specific therapeutic targets in neurodegeneration.

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2024-02-26 | Reviewer #1 (Public Review): Distinctive Whole-brain Cell-Types Predict Tissue Damage Patterns in Thirteen Neurodegenerative Conditions

For over a century, brain research narrative has mainly centered on neuron cells. Accordingly, most whole-brain neurodegenerative studies focus on neuronal dysfunction and their selective vulnerability, while we lack comprehensive analyses of other major cell-types’ contribution. By unifying spatial gene expression, structural MRI, and cell deconvolution, here we describe how the human brain distribution of canonical cell-types extensively predicts tissue damage in thirteen neurodegenerative conditions, including early- and late-onset Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, mutations in presenilin-1, and three clinical variants of frontotemporal lobar degeneration (behavioural variant, semantic and non-fluent primary progressive aphasia) along with associated 3-repeat and 4-repeat tauopathies and TDP43 proteinopathies types A and C. We reconstructed comprehensive whole-brain reference maps of cellular abundance for six major cell-types and identified characteristic axes of spatial overlapping with atrophy. Our results support the strong mediating role of non-neuronal cells, primarily microglia and astrocytes, in spatial vulnerability to tissue loss in neurodegeneration, with distinct and shared across-disorders pathomechanisms. These observations provide critical insights into the multicellular pathophysiology underlying spatiotemporal advance in neurodegeneration. Notably, they also emphasize the need to exceed the current neuro-centric view of brain diseases, supporting the imperative for cell-specific therapeutic targets in neurodegeneration.

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