Predictors of Care Home Admission and Survival Rate in Patients With Syndromes Associated With Frontotemporal Lobar Degeneration in Europe.

BACKGROUND AND OBJECTIVES: Data on care home admission and survival rates of patients with syndromes associated with frontotemporal lobar degeneration (FTLD) are limited. However, their estimation is essential to plan trials and assess the efficacy of intervention. Population-based registers provide unique samples for this estimate. The aim of this study was to assess care home admission rate, survival rate, and their predictors in incident patients with FTLD-associated syndromes from the European FRONTIERS register-based study. METHODS: We conducted a prospective longitudinal multinational observational registry study, considering incident patients with FTLD-associated syndromes diagnosed between June 1, 2018, and May 31, 2019, and followed for up to 5 years till May 31, 2023. We enrolled patients fulfilling diagnosis of the behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS), and FTD with motor neuron disease (FTD-MND). Kaplan-Meier analysis and Cox multivariable regression models were used to assess care home admission and survival rates. The survival probability score (SPS) was computed based on independent predictors of survivorship. RESULTS: A total of 266 incident patients with FTLD were included (mean age ± SD = 66.7 ± 9.0; female = 41.4%). The median care home admission rate was 97 months (95% CIs 86-98) from disease onset and 57 months (95% CIs 56-58) from diagnosis. The median survival was 90 months (95% CIs 77-97) from disease onset and 49 months (95% CIs 44-58) from diagnosis. Survival from diagnosis was shorter in FTD-MND (hazard ratio [HR] 4.59, 95% CIs 2.49-8.76, p < 0.001) and PSP/CBS (HR 1.56, 95% CIs 1.01-2.42, p = 0.044) compared with bvFTD; no differences between PPA and bvFTD were found. The SPS proved high accuracy in predicting 1-year survival probability (area under the receiver operating characteristic curve = 0.789, 95% CIs 0.69-0.87), when defined by age, European area of residency, extrapyramidal symptoms, and MND at diagnosis. DISCUSSION: In FTLD-associated syndromes, survival rates differ according to clinical features and geography. The SPS was able to predict prognosis at individual patient level with an accuracy of ∼80% and may help to improve patient stratification in clinical trials. Future confirmatory studies considering different populations are needed.

Study protocol for the Functional Communication Checklist for people living with primary progressive aphasia.

This study protocol describes the development of the first instrument of functional communication for people living with primary progressive aphasia (PPA), with future applications to other progressive conditions, with expert validation, item-level reliability analyses, input from partners in research, and outcomes. Progressive conditions like PPA require monitoring, and as such, re-assessment. Re-assessment poses the high risk of being burdensome, destructive, and of little use to the patient. As such, there is a significant need to establish a validated and reliable measure that (1) poses minimal patient burden and (2) captures communication ability in a strengths-based manner for both clinical and research purposes. A strengths-based approach to assessment is widely recognized as the optimal way to promote patient autonomy, minimize harm, and implement functional treatment protocols and strategies. To date, there are no strengths-based assessment tools that were developed for people living with PPA nor ways to efficiently document functional communication performance. This study protocol outlines our work to address this gap in clinical practice and research.

Automatic Speech Recognition in Primary Progressive Apraxia of Speech.

INTRODUCTION: Transcribing disordered speech can be useful when diagnosing motor speech disorders such as primary progressive apraxia of speech (PPAOS), who have sound additions, deletions, and substitutions, or distortions and/or slow, segmented speech. Since transcribing speech can be a laborious process and requires an experienced listener, using automatic speech recognition (ASR) systems for diagnosis and treatment monitoring is appealing. This study evaluated the efficacy of a readily available ASR system (wav2vec 2.0) in transcribing speech of PPAOS patients to determine if the word error rate (WER) output by the ASR can differentiate between healthy speech and PPAOS and/or among its subtypes, whether WER correlates with AOS severity, and how the ASR's errors compare to those noted in manual transcriptions. METHOD: Forty-five patients with PPAOS and 22 healthy controls were recorded repeating 13 words, 3 times each, which were transcribed manually and using wav2vec 2.0. The WER and phonetic and prosodic speech errors were compared between groups, and ASR results were compared against manual transcriptions. RESULTS: Mean overall WER was 0.88 for patients and 0.33 for controls. WER significantly correlated with AOS severity and accurately distinguished between patients and controls but not between AOS subtypes. The phonetic and prosodic errors from the ASR transcriptions were also unable to distinguish between subtypes, whereas errors calculated from human transcriptions were. There was poor agreement in the number of phonetic and prosodic errors between the ASR and human transcriptions. CONCLUSIONS: This study demonstrates that ASR can be useful in differentiating healthy from disordered speech and evaluating PPAOS severity but does not distinguish PPAOS subtypes. ASR transcriptions showed weak agreement with human transcriptions; thus, ASR may be a useful tool for the transcription of speech in PPAOS, but the research questions posed must be carefully considered within the context of its limitations. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.26359417.

Effects of Modified Video-Implemented Script Training for Aphasia in the Three Variants of Primary Progressive Aphasia.

PURPOSE: Primary progressive aphasia (PPA) is a neurodegenerative disorder characterized by worsening of speech and/or language. Script training intervention promotes automatized speech production via repeated practice of scripted content. This study evaluated the acceptability, feasibility, and effects of a modified version of Video-Implemented Script Training for Aphasia (VISTA) in the three PPA variants and compared outcomes by intervention modality (teletherapy vs. in person). METHOD: Thirteen bilingual (Spanish-Catalan) participants were included (semantic variant, n = 5; logopenic variant, n = 5; nonfluent/agrammatic variant, n = 3; teletherapy, n = 7). Using a nonrandomized design, intervention was administered in participants' dominant language. Participants were trained on an individualized script twice per week, over 8 weeks. Performance on measures related to script accuracy, content, and subjective ratings of production quality was evaluated at baseline, immediately post, and at 3 and 6 months post-intervention. RESULTS: No significant differences were observed on the basis of intervention modality. Participants demonstrated significant improvements from pre- to post-intervention in script production, synonym production, keywords, and global quality on the trained script. Maintenance was observed when comparing performance at post-intervention relative to 3- and 6-month follow-up for script and synonym production. Significant improvement in production quality of the untrained topic was observed following intervention. Different patterns of benefit were observed by PPA variant. CONCLUSIONS: Modified VISTA was acceptable and effective across the three PPA variants, as evidenced by improvements on a broader array of outcome measures than those previously reported. Findings also provide further support for provision for teletherapy in individuals with PPA. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.26999326.

Clinical implications of head trauma in frontotemporal dementia and primary progressive aphasia.

BACKGROUND: Traumatic brain injury (TBI) and repetitive head impacts (RHI) have been linked to increased risk for multiple types of neurodegenerative disease, higher dementia risk, and earlier age of dementia symptom onset, suggesting transdiagnostic implications for later-life brain health. Frontotemporal dementia (FTD) and primary progressive aphasia (PPA) represent a spectrum of clinical phenotypes that are neuropathologically diverse. FTD/PPA diagnoses bring unique challenges due to complex cognitive and behavioral symptoms that disproportionately present as an early-onset dementia (before age 65). We performed a detailed characterization of lifetime head trauma exposure in individuals with FTD and PPA compared to healthy controls to examine frequency of lifetime TBI and RHI and associated clinical implications. METHODS: We studied 132 FTD/PPA (age 68.9 ± 8.1, 65% male) and 132 sex-matched healthy controls (HC; age 73.4 ± 7.6). We compared rates of prior TBI and RHI (contact/collision sports) between FTD/PPA and HC (chi-square, logistic regression, analysis of variance). Within FTD/PPA, we evaluated associations with age of symptom onset (analysis of variance). Within behavioral variant FTD, we evaluated associations with cognitive function and neuropsychiatric symptoms (linear regression controlling for age, sex, and years of education). RESULTS: Years of participation were greater in FTD/PPA than HC for any contact/collision sport (8.5 ± 6.7yrs vs. 5.3 ± 4.5yrs, p = .008) and for American football (6.2yrs ± 4.3yrs vs. 3.1 ± 2.4yrs; p = .003). Within FTD/PPA, there were dose-dependent associations with earlier age of symptom onset for TBI (0 TBI: 62.1 ± 8.1, 1 TBI: 59.9 ± 6.9, 2 + TBI: 57.3 ± 8.4; p = .03) and years of American football (0yrs: 62.2 ± 8.7, 1-4yrs: 59.7 ± 7.0, 5 + yrs: 55.9 ± 6.3; p = .009). Within bvFTD, those who played American football had worse memory (z-score: -2.4 ± 1.2 vs. -1.4 ± 1.6, p = .02, d = 1.1). CONCLUSIONS: Lifetime head trauma may represent a preventable environmental risk factor for FTD/PPA. Dose-dependent exposure to TBI or RHI influences FTD/PPA symptom onset and memory function in bvFTD. Clinico-pathological studies are needed to better understand the neuropathological correlates linking RHI or TBI to FTD/PPA onset and symptoms.

Global perspectives on the management of primary progressive aphasia.

Speech-language therapists/pathologists (SLT/Ps) are key professionals in the management and treatment of primary progressive aphasia (PPA), however, there are gaps in education and training within the discipline, with implications for skills, confidence, and clinical decision-making. This survey aimed to explore the areas of need amongst SLT/Ps working with people living with PPA (PwPPA) internationally to upskill the current and future workforce working with progressive communication disorders. One hundred eighty-six SLT/Ps from 27 countries who work with PwPPA participated in an anonymous online survey about their educational and clinical experiences, clinical decision-making, and self-reported areas of need when working with this population. Best practice principles for SLT/Ps working with PwPPA were used to frame the latter two sections of this survey. Only 40.7% of respondents indicated that their university education prepared them for their current work with PwPPA. Competency areas of "knowing people deeply," "practical issues," "connectedness," and "preventing disasters" were identified as the basic areas of priority and need. Respondents identified instructional online courses (92.5%), sample tools and activities for interventions (64.8%), and concrete training on providing care for advanced stages and end of life (58.3%) as central areas of need in their current work. This is the first international survey to comprehensively explore the perspectives of SLT/Ps working with PwPPA. Based on survey outcomes, there is a pressing need to enhance current educational and ongoing training opportunities to better promote the well-being of PwPPA and their families, and to ensure appropriate preparation of the current and future SLT/P workforce.

Everyday Memory Disturbance in Primary Progressive Aphasia.

INTRODUCTION: Mounting evidence indicates distinct memory profiles among the primary progressive aphasia (PPA) variants. Neuropsychological tests reveal disproportionate memory impairments in the logopenic variant PPA (lv-PPA) relative to the non-fluent variant PPA (nfv-PPA) and semantic variant PPA (sv-PPA). The real-world experience of day-to-day memory disturbances in PPA, however, remains poorly understood. METHODS: Everyday expressions of memory in 26 lv-PPA, 24 nfv-PPA, and 40 sv-PPA patients, and 70 healthy controls were examined using the Cambridge Behavioural Inventory-Revised (CBI-R) carer questionnaire. Kruskal-Wallis tests compared CBI-R Memory items (1-8) across groups. Receiver operating characteristic curves evaluated the most discriminative items to distinguish lv-PPA from nfv-PPA. RESULTS: Compared to controls, lv-PPA and sv-PPA patients were reported to experience more day-to-day memory issues (item 1), increased repetition of questions (2), forgetting the names of familiar people and objects (4, 5), and poor concentration (6). lv-PPA patients were also reported to exhibit more occurrences of losing or misplacing items (3) and forgetting the day (7). All PPA groups experienced more confusion in unfamiliar environments (8) than controls. Direct comparisons among PPA groups revealed distinct profiles, with lv-PPA and sv-PPA patients exhibiting more frequent forgetting of names and objects (3, 4) than nfv-PPA, and sv-PPA demonstrating greater day-to-day memory impairment (1), repeated questions (2), and poor concentration (6) compared to nfv-PPA. Forgetting the names of familiar objects (5) was the most sensitive and specific item to distinguish lv-PPA from nfv-PPA. CONCLUSIONS: Our findings demonstrate distinct day-to-day memory profiles in PPA. Future research should explore the influence of language impairments on these profiles.

Speech-language within and between network disruptions in primary progressive aphasia variants.

Primary progressive aphasia (PPA) variants present with distinct disruptions in speech-language functions with little known about the interplay between affected and spared regions within the speech-language network and their interaction with other functional networks. The Neurodegenerative Research Group, Mayo Clinic, recruited 123 patients with PPA (55 logopenic (lvPPA), 44 non-fluent (nfvPPA) and 24 semantic (svPPA)) who were matched to 60 healthy controls. We investigated functional connectivity disruptions between regions within the left-speech-language network (Broca, Wernicke, anterior middle temporal gyrus (aMTG), supplementary motor area (SMA), planum temporale (PT) and parietal operculum (PO)), and disruptions to other networks (visual association, dorsal-attention, frontoparietal and default mode networks (DMN)). Within the speech-language network, multivariate linear regression models showed reduced aMTG-Broca connectivity in all variants, with lvPPA and nfvPPA findings remaining significant after Bonferroni correction. Additional loss in Wernicke-Broca connectivity in nfvPPA, Wernicke-PT connectivity in lvPPA and greater aMTG-PT connectivity in svPPA were also noted. Between-network connectivity findings in all variants showed reduced aMTG-DMN and increased aMTG-dorsal-attention connectivity, with additional disruptions between aMTG-visual association in both lvPPA and svPPA, aMTG-frontoparietal in lvPPA, and Wernicke-DMN breakdown in svPPA. These findings suggest that aMTG connectivity breakdown is a shared feature in all PPA variants, with lvPPA showing more extensive connectivity disruptions with other networks.

FDG-PET in the diagnosis of primary progressive aphasia: a systematic review.

Primary progressive aphasia (PPA) is a disease known to affect the frontal and temporal regions of the left hemisphere. PPA is often an indication of future development of dementia, specifically semantic dementia (SD) for frontotemporal dementia (FTD) and logopenic progressive aphasia (LPA) as an atypical presentation of Alzheimer's disease (AD). The purpose of this review is to clarify the value of 2-deoxy-2-[18F]fluoro-D-glucose (FDG)-positron emission tomography (PET) in the detection and diagnosis of PPA. A comprehensive review of literature was conducted using Web of Science, PubMed, and Google Scholar. The three PPA subtypes show distinct regions of hypometabolism in FDG-PET imaging with SD in the anterior temporal lobes, LPA in the left temporo-parietal junction, and nonfluent/agrammatic Variant PPA (nfvPPA) in the left inferior frontal gyrus and insula. Despite the distinct patterns, overlapping hypometabolic areas can complicate differential diagnosis, especially in patients with SD who are frequently diagnosed with AD. Integration with other diagnostic tools could refine the diagnostic process and lead to improved patient outcomes. Future research should focus on validating these findings in larger populations and exploring the therapeutic implications of early, accurate PPA diagnosis with more targeted therapeutic interventions.

Incidence of Primary Progressive Apraxia of Speech and Primary Progressive Aphasia in Olmsted County, MN, 2011-2022.

BACKGROUND AND OBJECTIVE: No epidemiologic studies have formally assessed the incidence of primary progressive aphasia (PPA) and primary progressive apraxia of speech (PPAOS). Thus, we decided to assess the incidence of these disorders in Olmsted County, MN, between 2011 and 2022, and to characterize clinical, radiographic, and pathologic characteristics of these patients. METHODS: This was a retrospective examination of data from a population-based cohort of patients with PPA and PPAOS prospectively identified in Olmsted County, MN, from 2011 to 2022. The incidence of PPA among adults (older than 18 years) was calculated for Olmsted County as the number of patients per 100,000 person-years during the study period. The adult population of Olmsted County was determined by the annual catchment population reported by the Rochester Epidemiological Project for each year 2011-2022. A behavioral neurologist verified the clinical diagnoses and determined subtypes. RESULTS: We identified 10 patients (60% female) within the study period (median age of symptoms onset: 70 years; range: 66-73), 8 with PPA and 2 with PPAOS. Of the 8 patients with PPA (6 female patients, 2 male patients), 2 met criteria for non-fluent variant PPA (nfvPPA), 3 for logopenic variant PPA (lvPPA), and 3 for semantic variant (svPPA). Speech evaluation confirmed the clinical diagnoses in all patients and all showed typical imaging findings consistent with their respective subtype. Six patients (2 PPAOS, 2 nfvPPA, 2 lvPPA) died and 3 underwent autopsy (2 PPAOS, 1 nfvPPA), confirming the pathologic diagnosis of progressive supranuclear palsy. The incidence of PPA + PPAOS was 0.70 persons per 100,000 person-years (95% CI 0.34-1.29 persons per 100,000) during the study period. The incidence of PPAOS was 0.14 persons per 100,000 person-years (95% CI 0.02-0.55 persons per 100,000), whereas for the 8 patients with PPA, the incidence was 0.56 persons per 100,000 person-years (95% CI 0.24-1.10 cases per 100,000). The incidence of nfvPPA was 0.14 persons per 100,000 person-years (95% CI 0.02-0.55), 0.21 persons per 100,000 person-years (95% CI 0.04-0.61) for lvPPA, and 0.21 persons per 100,000 person-years (95% CI 0.04-0.61) for svPPA. DISCUSSION: As a group, PPA and PPAOS are a relatively rare group of diseases. PPAOS has a slightly lower incidence than PPA as a group but similar incidence to the individual PPA variants.

Dysphagia in primary progressive aphasia: Clinical predictors and neuroanatomical basis.

BACKGROUND AND PURPOSE: Dysphagia is an important feature of neurodegenerative diseases and potentially life-threatening in primary progressive aphasia (PPA) but remains poorly characterized in these syndromes. We hypothesized that dysphagia would be more prevalent in nonfluent/agrammatic variant (nfv)PPA than other PPA syndromes, predicted by accompanying motor features, and associated with atrophy affecting regions implicated in swallowing control. METHODS: In a retrospective case-control study at our tertiary referral centre, we recruited 56 patients with PPA (21 nfvPPA, 22 semantic variant [sv]PPA, 13 logopenic variant [lv]PPA). Using a pro forma based on caregiver surveys and clinical records, we documented dysphagia (present/absent) and associated, potentially predictive clinical, cognitive, and behavioural features. These were used to train a machine learning model. Patients' brain magnetic resonance imaging scans were assessed using voxel-based morphometry and region-of-interest analyses comparing differential atrophy profiles associated with dysphagia presence/absence. RESULTS: Dysphagia was significantly more prevalent in nfvPPA (43% vs. 5% svPPA and no lvPPA). The machine learning model revealed a hierarchy of features predicting dysphagia in the nfvPPA group, with excellent classification accuracy (90.5%, 95% confidence interval = 77.9-100); the strongest predictor was orofacial apraxia, followed by older age, parkinsonism, more severe behavioural disturbance, and more severe cognitive impairment. Significant grey matter atrophy correlates of dysphagia in nfvPPA were identified in left middle frontal, right superior frontal, and right supramarginal gyri and right caudate. CONCLUSIONS: Dysphagia is a common feature of nfvPPA, linked to underlying corticosubcortical network dysfunction. Clinicians should anticipate this symptom particularly in the context of other motor features and more severe disease.

Applications of the R.A.I.S.E. Assessment Framework to Support the Process of Assessment in Primary Progressive Aphasia.

PURPOSE: To establish the extent to which person-centered processes are integrated in assessment procedures, the Relationship, Assessment, Inclusion, Support, Evolve (R.A.I.S.E.) Assessment framework was used to evaluate measures that are typically used when assessing people living with primary progressive aphasia (PPA). METHOD: Forty-five assessment tools were evaluated through the lens of the five R.A.I.S.E. principles: building the client-clinician Relationship, Assessment choices, Including the client and care partners, providing Support, and Evolving procedures to match client capability and progression. The principles were operationalized as questions for raters to evaluate whether a measure met this aspect of the R.A.I.S.E. Assessment framework. RESULTS: Ten measures commonly used in the assessment of people living with PPA met all R.A.I.S.E. principles. These measures centered upon the elicitation of naturalistic discourse, conversation, client self-report, and clinician ratings. Thirteen measures did not meet any of the criteria, and represented standardized evaluation procedures do not provide the opportunity to connect to the client, elicit or provide feedback or support, nor to adapt in response to need or performance. CONCLUSIONS: Whether using standardized or informal assessment tools, a relational and qualitative approach to providing assessment is paramount to promote client success and therapeutic engagement. We provide guidance through the R.A.I.S.E. framework on practices to cultivate person-centered processes of assessment in the care of people living with PPA.

Artificial intelligence classifies primary progressive aphasia from connected speech.

Neurodegenerative dementia syndromes, such as primary progressive aphasias (PPA), have traditionally been diagnosed based, in part, on verbal and non-verbal cognitive profiles. Debate continues about whether PPA is best divided into three variants and regarding the most distinctive linguistic features for classifying PPA variants. In this cross-sectional study, we initially harnessed the capabilities of artificial intelligence and natural language processing to perform unsupervised classification of short, connected speech samples from 78 pateints with PPA. We then used natural language processing to identify linguistic features that best dissociate the three PPA variants. Large language models discerned three distinct PPA clusters, with 88.5% agreement with independent clinical diagnoses. Patterns of cortical atrophy of three data-driven clusters corresponded to the localization in the clinical diagnostic criteria. In the subsequent supervised classification, 17 distinctive features emerged, including the observation that separating verbs into high- and low-frequency types significantly improved classification accuracy. Using these linguistic features derived from the analysis of short, connected speech samples, we developed a classifier that achieved 97.9% accuracy in classifying the four groups (three PPA variants and healthy controls). The data-driven section of this study showcases the ability of large language models to find natural partitioning in the speech of patients with PPA consistent with conventional variants. In addition, the work identifies a robust set of language features indicative of each PPA variant, emphasizing the significance of dividing verbs into high- and low-frequency categories. Beyond improving diagnostic accuracy, these findings enhance our understanding of the neurobiology of language processing.

Multimodal cross-examination of progressive apraxia of speech by diffusion tensor imaging-based tractography and Tau-PET scans.

Progressive apraxia of speech (PAOS) is a 4R tauopathy characterized by difficulties with motor speech planning. Neurodegeneration in PAOS targets the premotor cortex, particularly the supplementary motor area (SMA), with degeneration of white matter (WM) tracts connecting premotor and motor cortices and Broca's area observed on diffusion tensor imaging (DTI). We aimed to assess flortaucipir uptake across speech-language-related WM tracts identified using DTI tractography in PAOS. Twenty-two patients with PAOS and 26 matched healthy controls were recruited by the Neurodegenerative Research Group (NRG) and underwent MRI and flortaucipir-PET. The patient population included patients with primary progressive apraxia of speech (PPAOS) and non-fluent variant/agrammatic primary progressive aphasia (agPPA). Flortaucipir PET scans and DTI were coregistered using rigid registration with a mutual information cost function in subject space. Alignments between DTI and flortaucipir PET were inspected in all cases. Whole-brain tractography was calculated using deterministic algorithms by a tractography reconstruction tool (DSI-studio) and specific tracts were identified using an automatic fiber tracking atlas-based method. Fractional anisotropy (FA) and flortaucipir standardized uptake value ratios (SUVRs) were averaged across the frontal aslant tract, arcuate fasciculi, inferior frontal-occipital fasciculus, inferior and middle longitudinal fasciculi, as well as the SMA commissural fibers. Reduced FA (p < .0001) and elevated flortaucipir SUVR (p = .0012) were observed in PAOS cases compared to controls across all combined WM tracts. For flortaucipir SUVR, the greatest differentiation of PAOS from controls was achieved with the SMA commissural fibers (area under the receiver operator characteristic curve [AUROC] = 0.83), followed by the left arcuate fasciculus (AUROC = 0.75) and left frontal aslant tract (AUROC = 0.71). Our findings demonstrate that flortaucipir uptake is increased across WM tracts related to speech/language difficulties in PAOS.

The yes-no reversal phenomenon in patients with primary progressive apraxia of speech.

Patients who have a yes-no reversal respond "yes" when they mean no and vice versa. The unintentional response can be made both verbally and with gestures (e.g., head shake or nod, thumbs up or down). Preliminary reports associate this phenomenon with 4-repeat tauopathies including primary progressive apraxia of speech (PPAOS), nonfluent/agrammatic primary progressive aphasia, and corticobasal syndrome; however, the significance and timing of this symptom relative to others are not well understood. Whereas some accounts associate yes-no reversals with other binary reversals (e.g., up/down, hot/cold) and attribute the reversals to disturbances of selection within the language system, others implicate more general inhibitory control processes. Here, we compared clinical and neuroimaging findings across 30 patients with PPAOS (apraxia of speech in the absence of aphasia), 15 of whom had a yes-no reversal complaint and 15 who did not. The two groups did not differ on any of the language or motor speech measures; however, patients who had the yes-no reversal received lower scores on the Frontal Assessment Battery and motor assessments. They also had greater hypometabolism in the left supplementary motor area and bilateral caudate nuclei on [18F]-fluorodeoxyglucose PET, but only the right caudate nucleus cluster survived correction for multiple comparisons. We interpret these results to suggest that the yes-no reversal phenomenon is associated with cognitive abilities that are supported by the frontostriatal network; more specifically, impaired response inhibition.

A Critical Review of Noninvasive Brain Stimulation Technologies in Alzheimer's Dementia and Primary Progressive Aphasia.

Multiple pharmacologic agents now have been approved in the United States and other countries as treatment to slow disease and clinical progression for Alzheimer's disease. Given these treatments have not been proven to lessen the cognitive deficits already manifested in the Alzheimer's Clinical Syndrome (ACS), and none are aimed for another debilitating dementia syndrome identified as primary progressive aphasia (PPA), there is an urgent need for new, safe, tolerable, and efficacious treatments to mitigate the cognitive deficits experienced in ACS and PPA. Noninvasive brain stimulation has shown promise for enhancing cognitive functioning, and there has been interest in its potential therapeutic value in ACS and PPA. This review critically examines the evidence of five technologies in ACS and PPA: transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), transcranial random noise stimulation (tRNS), repetitive transcranial magnetic stimulation (rTMS), and noninvasive vagus nerve stimulation (nVNS). Many randomized controlled trials of tDCS and rTMS report positive treatment effects on cognition in ACS and PPA that persist out to at least 8 weeks, whereas there are few trials for tACS and none for tRNS and nVNS. However, most positive trials did not identify clinically meaningful changes, underscoring that clinical efficacy has yet to be established in ACS and PPA. Much is still to be learned about noninvasive brain stimulation in ACS and PPA, and shifting the focus to prioritize clinical significance in addition to statistical significance in trials could yield greater success in understanding its potential cognitive effects and optimal parameters.

Non-pharmacological interventions for improving language and communication in people with primary progressive aphasia.

BACKGROUND: Primary progressive aphasia (PPA) accounts for approximately 43% of frontotemporal dementias and is mainly characterised by a progressive impairment of speech and communication abilities. Three clinical variants have been identified: (a) non-fluent/agrammatic, (b) semantic, and (c) logopenic/phonological PPA variants. There is currently no curative treatment for PPA, and the disease progresses inexorably over time, with devastating effects on speech and communication ability, functional status, and quality of life. Several non-pharmacological interventions that may improve symptoms (e.g. different forms of language training and non-invasive brain stimulation) have been investigated in people with PPA. OBJECTIVES: To assess the effects of non-pharmacological interventions for people with PPA on word retrieval (our primary outcome), global language functions, cognition, quality of life, and adverse events. SEARCH METHODS: We searched the Cochrane Dementia and Cognitive Improvement Group's trial register, MEDLINE (Ovid SP), Embase (Ovid SP), four other databases and two other trial registers. The latest searches were run on 26 January 2024. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating the effects of non-pharmacological interventions in people with PPA. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: There were insufficient data available to conduct the network meta-analyses that we had originally planned (due to trial data being insufficiently reported or not reported at all, as well as the heterogeneous content of the included interventions). Therefore, we provide a descriptive summary of the included studies and results. We included 10 studies, with a total of 132 participants, evaluating non-pharmacological interventions. These were: transcranial direct current stimulation (tDCS) or repetitive transcranial magnetic stimulation (rTMS) as stand-alone treatments (used by two and one studies, respectively); tDCS combined with semantic and phonological word-retrieval training (five studies); tDCS combined with semantic word-retrieval training (one study); and tDCS combined with phonological word-retrieval training (one study). Results for our primary outcome of word retrieval were mixed. For the two studies that investigated the effects of tDCS as stand-alone treatment compared to placebo ("sham") tDCS, we rated the results as having very low-certainty evidence. One study found a significant beneficial effect on word retrieval after active tDCS; one study did not report any significant effects in favour of the active tDCS group. Five studies investigated tDCS administered to the dorsolateral prefrontal cortex, inferior frontal cortex, left frontotemporal region, or the temporoparietal cortex, combined with semantic and phonological word-retrieval training. The most consistent finding was enhancement of word-retrieval ability for trained items immediately after the intervention, when behavioural training was combined with active tDCS compared to behavioural training plus sham tDCS. We found mixed effects for untrained items and maintenance of treatment effects during follow-up assessments. We rated the certainty of the evidence as very low in all studies. One study investigated tDCS combined with semantic word-retrieval training. Training was provided across 15 sessions with a frequency of three to five sessions per week, depending on the personal preferences of the participants. tDCS targeted the left frontotemporal region. The study included three participants: two received 1 mA stimulation and one received 2 mA stimulation. The study showed mixed results. We rated it as very low-certainty evidence. One study investigated tDCS combined with phonological word-retrieval training. Training was again provided across 15 sessions over a period of three weeks. tDCS targeted the left inferior frontal gyrus. This study showed a significantly more pronounced improvement for trained and untrained words in favour of the group that had received active tDCS, but we rated the certainty of the evidence as very low. One study compared active rTMS applied to an individually determined target site to active rTMS applied to a control site (vertex) for effects on participants' word retrieval. This study demonstrated better word retrieval for active rTMS administered to individually determined target brain regions than in the control intervention, but we rated the results as having a very low certainty of evidence. Four studies assessed overall language ability, three studies assessed cognition, five studies assessed potential adverse effects of brain stimulation, and one study investigated quality of life. AUTHORS' CONCLUSIONS: There is currently no high-certainty evidence to inform clinical decision-making regarding non-pharmacological treatment selection for people with PPA. Preliminary evidence suggests that the combination of active tDCS with specific language therapy may improve impaired word retrieval for specifically trained items beyond the effects of behavioural treatment alone. However, more research is needed, including high-quality RCTs with detailed descriptions of participants and methods, and consideration of outcomes such as quality of life, depressive symptoms, and overall cognitive functioning. Moreover, studies assessing optimal treatments (i.e. behavioural interventions, brain stimulation interventions, and their combinations) for individual patients and PPA subtypes are needed. We were not able to conduct the planned (network) meta-analyses due to missing data that could not be obtained from most of the authors, a general lack of RCTs in the field, and heterogeneous interventions in eligible trials. Journals should implement a mandatory data-sharing requirement to assure transparency and accessibility of data from clinical trials.

COS-PPA: protocol to develop a core outcome set for primary progressive aphasia.

INTRODUCTION: The term primary progressive aphasia (PPA) describes a group of language-led dementias. Disease-modifying treatments that delay, slow or reverse progression of PPA are currently lacking, though a number of interventions to manage the symptoms of PPA have been developed in recent years. Unfortunately, studies exploring the effectiveness of these interventions have used a variety of different outcome measures, limiting comparability. There are more constructs, apart from word retrieval, that are important for people with PPA that have not received much attention in the research literature. Existing core outcome sets (COS) for dementia and non-progressive aphasia do not meet the needs of people with PPA, highlighting a need to develop a specific COS for PPA. METHODS AND ANALYSIS: This protocol describes a three-stage study to identify a COS for PPA interventions in research and clinical practice. The stage 1 systematic review will identify existing speech, language and communication measures used to examine the effectiveness of interventions for PPA in the research literature. Employing a nominal group technique, stage 2 will identify the most important outcomes for people with PPA and their families. The data collected in stages 1 and 2 will be jointly analysed with the project PPI group and will inform the stage 2 modified Delphi consensus study to identify a core outcome measurement set for PPA among a range of research disciplines undertaking intervention studies for people with PPA. ETHICS AND DISSEMINATION: Ethical approval for stage 2 of the study has been sought individually in each country at collaborating institutions and is stated in detail in the manuscript. Stage 3 has been granted ethical approval by the Chairs of UCL Language and Cognition Department Ethics, Project ID LCD-2023-06. Work undertaken at stages 1, 2 and 3 will be published in open-access peer-reviewed journal articles and presented at international scientific conferences. PROSPERO REGISTRATION NUMBER: CRD42022367565.

MEM&SO protocol: understanding the determinants of social learning in neurodegenerative diseases.

BACKGROUND: People with neurodegenerative diseases may have difficulty learning new information, owing to their cognitive impairments. Teaching them techniques for learning in social contexts could alleviate this difficulty. The present study will examine the performances of patients with Alzheimer's disease and patients with the semantic variant of primary progressive aphasia on a memory test administered in three social contexts. The protocol will make it possible to identify determinants of social interactions, social abilities, cognition, and personality that can explain the potentially beneficial effect of social context on learning in these patients. METHODS: Thirty dyads (patient with primary memory impairment who meets criteria for Alzheimer's disease paired with caregiver), 16 dyads (patient meeting criteria for semantic variant of primary progressive aphasia paired with caregiver), and 46 dyads (healthy controls with no cognitive complaints) will be recruited. A nonverbal memory test (social memory task) will be administered to each dyad in three different social contexts (presence-only, observation, collaboration). Patients and healthy controls will also undergo a neuropsychological assessment to measure social (interactions and abilities), cognitive and personality aspects. Patients will be compared with controls on differential social scores calculated between the presence-only and collaboration contexts, and between the presence-only and observation contexts. A multiple comparative case study will be conducted to identify social, cognitive and personality variables that potentially explain the differential scores in the collaboration and observation contexts. DISCUSSION: For the first time, memory will be assessed in patients with Alzheimer's disease and patients with the semantic variant of primary progressive aphasia in three different contexts (presence-only, observation, collaboration). The multiple comparative case study will make it possible to identify the determinants of memory performance in the social context, in order to create the most beneficial learning context for individual patients, according to their profile. TRIAL REGISTRATION: This study was approved by the Ile de France XI institutional review board (2022-A00198-35), and registered on ClinicalTrials.gov (no. NCT05800028), on April 27, 2023.