The nonfluent/agrammatic variant of primary progressive aphasia (nfav-PPA) and primary progressive apraxia of speech (PPAOS) are neurodegenerative syndromes that raise diagnostic challenges related to several issues. First, there are two divergent conceptions, one stipulating that (i) nfav-APP and PPAOS are distinct entities, and the other (ii) that PPAOS has to be integrated into the nfav-APP spectrum. A second related issue concerns the consideration of phonological dimensions, lying at the language interface with speech, which could potentially help overcome the nfva-PPA/PPAOS controversy. Third, there is a lack of internationally validated clinical tests assessing apraxia of speech and syntactic abilities with sufficient specificity and sensitivity. This narrative review discusses these issues taking into account clinical, neurocognitive and neurobiological dimensions. It proposes a conceptual-integrative framework conciliating competing nfav-APP/PPAOS accounts while suggesting a graded continuum with subdivisions, related to neurodegenerative expansion throughout language/speech production systems, ranging from syntactic to phonological to phonetic-articulatory impairments. A second controversy in the field of PPA arises from divergent conceptions of semantic PPA (sv-PPA), defined by primary damage to verbal semantics, and of semantic dementia (SD) characterized by multimodal semantic impairments. The current consensus criteria of PPA have deconstructed the initial SD conception by absorbing it into sv-PPA, hence leaving mixed and some non-verbal semantic phenotypes nosologically orphaned. Again, the article proposes a conceptual and integrative model, built on findings from clinical research and cognitive neuroscience, suggesting a graded continuum with subdivisions spanning from verbal to different non-verbal semantic impairments including social-semantic/behavioral phenotypes.

Les études ayant exploré la stimulation transcrânienne par courant direct (tDCS) comme approche thérapeutique ont généré des résultats encourageants dans les dégénérescences lobaires fronto-temporales. Toutefois, le niveau de preuve reste modeste puisque la plupart des investigations n’a pas adoptés des designs en double aveugle versus placebo.Nous avons appliqué 3 sessions de tDCS (20minutes, 1,59mA) dans un design crossover en double aveugle versus placebo dans 4 populations de patients : démence sémantique (DS, n=12), APP logopénique (APP-vl, n=12), démence fronto-temporale (DFT, n=12), paralysie supranucléaire progressive (PSP, n=12). Les cibles corticales correspondaient aux régions les plus atteintes (DS–pôles temporaux, APP-vl–jonctions temporo-pariétales, DFT et PSP–cortex préfrontal). Trois modalités de stimulation étaient utilisées : tDCS anodale-excitatoire sur la région cible gauche, tDCS cathodale-inhibitrice sur la cible homotopique droite (principe d’inhibition inter-hémisphérique), tDCS placebo. Les effets modulatoires étaient mesurés par différentes tâches de langage (fluence, matching sémantique, dénomination). Les champs électriques tDCS cérébraux étaient simulés par des modèles computationnels pour chaque population.Les résultats ont montré des effets de modulation/amélioration langagière pour la SD et la PSP. Aucun effet n’a été observé pour la DFT et APP-vl. Les modèles computationnels ont montré une diffusion du champ électrique centrée sur les cibles cérébrales, ainsi qu’une diminution de leur intensité dans des modèles implémentant une atrophie de la cible. Des analyses de corrélation sur des données individuelles ont montré des effets plus importants pour des patients avec des durées d’évolution les moins longues et avec des degrés d’aphasie les moins sévères.Ces données représentent des preuves-de-concept pour la DS et PSP et fournissent ainsi un rationnel pour des études de validation portant sur de plus larges cohortes avec des séances tDCS itératives promouvant la neuroplasticité et des effets thérapeutiques. L’hétérogénéité et l’absence d’effets dans la DFT et l’APP-vl incitent à explorer davantage les paramètres influençant le potentiel modulatoire de la tDCS, incluant le site et degré d’atrophie de la cible cérébral ainsi que la sévérité de l’aphasie.

Plusieurs tests cliniques (p. ex., MMSE) permettent un screening et suivi rapide des atteintes cognitives dans le cadre des maladies neurodégénératives. En revanche, de tels tests rapides manquent dans le domaine des troubles du langage qui font partie d’un grand nombre de maladies neurodégénératives et plus particulièrement des aphasies primaires progressives (APP).Le ‘Mini Linguistic State Examination’ (MLSE), test rapide des capacités langagières, est en cours de développement dans une vingtaine de pays. Nous avons élaboré sa version franco-canadienne (MLSE-fc) qui a été appliquée à 219 sujets sains (validation/valeurs normatives), 57 patients APP (variante nonfluente/agrammatique [APPvnfa, n=8], variante logopénique [APPvl, n=26], variante sémantique [APPvs, n=10]), et 13 patients atteints de la maladie d’Alzheimer typique/amnésique (MA).Le MLSE-fc évalue, comme les autres versions du MLSE, 5 domaines langagiers (élocution, phonologie, sémantique, syntaxe, mémoire de travail verbale (MTV), à l’aide de 11 sous-tests. Les stimuli étaient appariés avec ceux de la version initiale/anglaise. Résultats La durée de passation était d’environ 12minutes pour les patients. La consistance inter-examinateur était élevée (kappa=92 %). Il n’y avait pas d’effet plafond chez les sujets sains et les scores variaient selon l’âge et le niveau socio-culturel (stratification). Les patients APP avaient des scores totaux inférieurs aux patients MA. Des scores aux sous-tests distinguaient les 3 variantes d’APP avec des scores les plus faibles dans les domaines ‘élocution’, ‘MTV’ et ‘sémantique’ respectivement dans l’APPvnfa, APPvl, et APPvs.En somme, le MLSE-fc est un outil rapide et examinateur-indépendant, validé/normé avec une large population de sujets sains. Il permet de distinguer les patients APP des patients MA, et de contribuer à classer les 3 variantes d’APP. Les versions MLSE en différentes langues représenteront un outil international de l’évaluation et du suivi des troubles du langage dans les APP et dans d’autres maladies neurologiques. Elles permettront également de fournir des ‘endpoints’ dans des essais cliniques/thérapeutiques.

Objectif Les ondes lentes (OL) du sommeil jouent un rôle clé dans la clairance des déchets cérébraux, influençant l’accumulation des lésions associées à la maladie d’Alzheimer (MA). De petites OL ont récemment été observées sur l’EEG d’éveil chez des rongeurs ou des jeunes adultes, et sont interprétées comme des intrusions locales de sommeil. Leur occurrence augmente lors de la privation de sommeil et prédit des erreurs comportementales. Cette étude visait à comparer les caractéristiques des OL d’éveil en fonction du statut amyloïde (A−/A+) et neurodégénératif (N−/N+) actuel, ainsi que des transitions vers A+ ou N+ dans les prochaines années. Méthodes Nous avons inclus 314 personnes âgées avec plaintes mnésiques issues de la cohorte INSIGHT-preAD (70–85 ans). Le statut amyloïde (A) et neurodégénératif (N) a été évalué à l’inclusion et deux ans plus tard par TEP au Florbetapir et au 18F-FDG. Les caractéristiques des OL (densité et amplitude dans les bandes de fréquence delta et thêta) ont été extraites à partir de 2minutes d’EEG de repos haute densité (256 électrodes). Des ANOVA ont été utilisé sur chaque électrode EEG pour comparer les OL selon le statut A/N et les transitions vers A+ ou N+. Les analyses ont été ajustées pour l’âge, le sexe et le niveau d’éducation, avec correction des comparaisons multiples par permutations basées sur des clusters. Résultats Par rapport aux participants A−N−, les groupes A+N−, A–N+ et A+N+ présentaient une densité d’OL delta plus faible (Fig. 1). Les individus A+N+ montraient également une amplitude des OL plus élevée dans les bandes delta et thêta. Les participants ayant évolué de A− vers A+ (n=16) présentaient une amplitude d’OL significativement plus élevée (delta et thêta) que ceux restés A− et ceux déjà A+. Les participants passant de N- à N+ (n=33) présentaient une densité d’OL delta plus faible que ceux restés N−. Conclusion Les caractéristiques des OL du sommeil local pourraient constituer des biomarqueurs EEG précoces de la déposition amyloïde et de la neurodégénérescence dans la MA. Facilement mesurables lors d’un court EEG de repos, elles pourraient permettre d’identifier les individus à risque dès les stades précliniques, avant tout déclin cognitif.

Research indicates that the anterior temporal lobes (ATLs) in the left and right hemispheres constitute a supramodal hub for verbal and nonverbal semantic information. However, it remains unclear whether (1) left and right ATLs are respectively specialized for verbal and nonverbal semantic processing (functional specialization models) or (2) bilateral ATLs equally contribute to multimodal semantic processing (unitary "hub-and-spoke" models). The present study examined the question using repetitive transcranial magnetic stimulation (rTMS) with an implicit semantic priming paradigm minimizing top-down influences from cognitive control mechanisms. After receiving rTMS over the left ATL, right ATL or vertex, healthy human adults of either sex made real-versus-unreal judgments about visual words or objects each preceded by semantically related or unrelated primes. While a similar amount of semantic priming survived vertex stimulation for both words and objects, we found that left ATL stimulation, but not right ATL stimulation, eliminated semantic priming for words, suggesting that the verbal semantics is represented in the left ATL. In contrast, rTMS over the ATL eliminated semantic priming for objects irrespective of the side of stimulation. This latter finding suggests a twofold mechanism whereby semantic processing of visual objects depends on semantic computations in the right ATL as well as automatic activation of semantic word representations in the left ATL generating "verbal label" feedback. The observed functional asymmetry of the semantic ATL hub overall supports functional specialization models enriched by verbal label feedback accounts, unveiling that verbal semantic knowledge plays a guiding role in the semantic analysis of visual objects.

INTRODUCTION:Growing evidence supports a critical role of sleep slow waves (SW) in Alzheimer's disease (AD). However, wake SW (sleep-like SW potentially reflecting local intrusions of sleep) remain unexplored in AD. METHODS:A total of 274 older adults with subjective cognitive decline (SCD) (INSIGHT-preAD cohort, 76.6 ± 3.5 years) underwent (i) positron emission tomography (PET) scans for amyloid (A) and neurodegeneration (N), (ii) high-density resting-state electroencephalogram (EEG) recordings to detect wake SW, and (iii) cognitive assessments. PET biomarkers were reassessed 2 years later. We examined wake SW associations with (1) current A/N status, (2) cognition, and (3) amyloid conversion. RESULTS:A+N-, A-N+, and A+N+ individuals exhibited lower delta wake SW density than A-N- participants. Wake SW amplitude (1) was higher in A+N+ than A-N- individuals, (2) correlated with poorer memory, and (3) predicted A- to A+ conversion (n = 157 A- stable individuals, n = 16 convertors). DISCUSSION:Wake SW represent promising early EEG biomarkers for AD pathology and amyloid conversion, facilitating risk stratification before cognitive decline onset.

Abnormal brain accumulation of amyloid-β peptides, represents one of the earliest biological indicators of Alzheimer’s disease (AD) risk. Estimation on amyloid positivity (A+) prevalence among older adults without dementia are needed to assess the epidemiological impact of AD diagnosis solely through biological markers. We combined data from the French MEMENTO clinical cohort, where amyloid status was assessed through reference procedures, with the nationally representative SHARE-HCAP survey. Using stabilized inverse odds of selection weights, we adjusted the MEMENTO sample to estimate the prevalence of A+ in the French population aged 65–85 without dementia and their five-year risk of developing AD dementia. A+ prevalence was 21.4% (95% CI: 18.4–24.7) in French adults aged 65–85 without dementia i.e. approximately 2.5 million individuals, reaching 27.5% in the 80–85 age group. Over five years of follow-up, the cumulative incidence of AD dementia was 22.7% among A+ individuals, 8.0% among cognitively normal A+ adults and 62.3% among those with mild cognitive impairment. While A+ is common in older adults without dementia, most do not develop dementia within five years. Defining AD by A+ could substantially increase diagnoses, raising major public health, ethical, and health system challenges, especially as new anti-amyloid therapies emerge.

Transcranial direct current stimulation (tDCS) has generated some promising outcomes in primary progressive aphasia (PPA). The logopenic variant (lv-PPA), one of the most frequent PPA phenotypes, erodes the temporal-parietal junction (TPJ) generating impaired lexical processing, rapidly extending to semantic deficits. Positive tDCS effects have been reported in several small-cohort studies but there is need for rigorous sham-controlled double-blind investigations to substantiate, or not, beneficial effects.We used a sham-controlled double-blind counter-balanced crossover design with 12 clinically and imaging-characterized lv-PPA patients applying, according to the principle of interhemispheric rivalry, anodal and cathodal tDCS over the left and right TPJ, respectively, as compared to sham. A letter fluency (lexical access), a picture-naming (lexical/semantic access), and a semantic-matching task (semantic access) were applied before and after tDCS. Computational modeling was used to characterize predicted cortical tDCS current distribution.Comparisons of post/pre-tDCS results did not show language improvement in any task. Finite element models showed impact for both tDCS modalities on the TPJ, but with lower radial field-strength when atrophy was implemented in the model. Correlation analyses on individual data, uncorrected for multiples comparisons, suggested that lesser aphasia severity and shorter disease duration are associated with more efficient tDCS effects.Our results showing the absence of significant tDCS outcomes in lv-PPA mitigate previous reports of positive tDCS effects with similar or smaller patient sample sizes, and they demonstrate the need for exploring factors influencing stimulation effects. Findings from computational modelling combined with our uncorrected correlation results suggest that tDCS use might be most appropriate in PPA patients having slight atrophy and aphasia severity. Future studies on larger patient populations are required for robust proof-of-concept regarding therapy use of tDCS in PPA.

BACKGROUND AND OBJECTIVES:Primary care is often the first point of contact for patients with cognitive complaints, making initial cognitive screening an essential step to avoid delays in diagnosing Alzheimer's disease (AD) at an early stage. We developed MemScreen, a self-administered smartphone application that assesses overall cognition and verbal memory, and evaluated its ability to detect mild cognitive impairment (MCI) in both general and clinical populations. METHODS:We conducted two validation cohort studies: (1) UK-based Whitehall II cohort study (13th wave, 2018-2022) involving a general population (MCI defined by poor performance on a global cognitive score), and (2) five French memory clinics involving patients without dementia (amnestic MCI defined by the Free and Cued Selective Reminding Test). MemScreen, MMSE, and TMT-A effectiveness was assessed using Area Under the Curve (AUC) values from unadjusted and adjusted logistic regression models. RESULTS:In Whitehall II (n = 2118, mean age 75.9 years, 23.9 % women, 14.5 % MCI), median MemScreen completion time was 4 min 18 s. MemScreen had the highest AUC (0.87; 95 % CI: 0.82-0.89) for distinguishing MCI, outperforming MMSE (AUC = 0.79; 0.76-0.82; p = 0.018) and TMT-A (AUC = 0.77; 0.74-0.80; p = 0.023). MemScreen sensitivity and specificity were 78.6 % and 78.7 %, respectively. In memory clinics (n = 303, mean age 70.5 years, 53 % women, 46.9 % amnestic MCI), median completion time was 5 min 17 s. MemScreen showed superior performance (AUC = 0.87; 0.83-0.91) compared to MMSE (AUC = 0.72; 0.67-0.78; p < 0.001) and TMT-A (AUC = 0.63; 0.56-0.69; p < 0.001), with 93.0 % sensitivity and 54.0 % specificity for amnestic MCI. DISCUSSION:MemScreen outperformed traditional tests in identifying MCI in both general and clinical populations. Its self-administration and short completion time suggest potential as an effective screening tool to optimize memory clinic referrals for AD diagnosis and treatment.

BACKGROUND:There is a need for internationally applicable screening tests assessing language in neurodegenerative conditions, allowing for homogenized diagnosis/classification of primary progressive aphasias (PPA), monitoring language decline, and providing endpoints in clinical/therapy trials. The 'Mini-Linguistic State Examination' (MLSE) is currently developed within a worldwide network including 22 countries, and our Paris-Québec collaboration aimed at developing the French/Canadian MLSE (fc-MLSE), validating it with healthy controls and clinical populations. METHOD:The fc-MLSE was adapted from the English version using stimuli of similar linguistic complexity. As the English version, the fc-MLSE included 11 sub-tests assessing 5 linguistic domains (motor-speech, phonology, semantics, syntax, verbal working-memory), providing a total score (/100) and 5 sub-scores. The test was administered to 182 healthy controls to generate normative scores, and subsequently to 36 patients with PPA [(nonfluent/agrammatic variant (nfvPPA, n = 8), logopenic variant (lvPPA, n = 20), semantic PPA (svPPA, n = 8)], and 6 patients with Alzheimer's disease (AD). RESULT:Testing durations were approximately 8 and 12 minutes for controls and patients, respectively, and the inter-rater consistency was of 92%. In controls, no ceiling effects were observed. The total score and the 5 sub-scores were similar for women/men, and led to stratifications according to age-ranges and educational levels. In clinical populations, the fc-MLSE was able to distinguish AD and PPA patients from controls, and PPA had lower total MLSE scores than AD patients. Sub-scores also distinguished the three PPA variants, showing highest error-rates for motor speech in nfvPPA, verbal working-memory in lvPPA, and semantics in svPPA. CONCLUSION:The fc-MLSE is a rapid and examiner-consistent language test, validated with a large population of healthy controls. It can be helpful for clinical classification of PPA variants, and might represent a valuable tool for follow-up trial monitoring in PPA, AD and other neurodegenerative diseases affecting language. More generally, the use of MLSE versions developed in 22 countries will improve the consistency/uniformity of language assessments at the international level.

The identification of biomarkers for Alzheimer's disease (AD) remains a significant challenge, particularly for the clinical severity of the disease. Recent studies have shown that plasma brain-derived-tau (BD-Tau) could be a promising biomarker for the identification of AD-type neurodegeneration. This study aimed to investigate the potential of BD-Tau in differentiating various clinical stages of AD, ranging from cognitively unimpaired AD to severe dementia AD. Additionally, the study intended to examine the association of BD-Tau with clinical severity and elucidate its dynamic behavior throughout the natural course of AD. Cross-sectional and longitudinal EDTA plasma data, along with clinical information, were utilized from the Pitié-Salpêtrière hospital INSIGHT (cognitively unimpaired individuals with amyloid PET) and SOCRATES cohorts (AD and non-AD symptomatic neurodegenerative disease according to up-to-date international criteria). Plasma BD-Tau was analyzed using the Gothenburg University homebrew Quanterix Simoa immunoassay. The results revealed that BD-Tau is only elevated in individuals with symptomatic AD, whether the primary or secondary neurodegenerative disease, and not in other neurodegenerative conditions. Additionally, BD-Tau follows the clinical dynamics of AD, as it is only elevated in symptomatic AD patients, while individuals with AD biological changes but no symptoms have normal levels of BD-Tau. BD-Tau levels were also found to be significantly correlated with episodic memory scores and global cognitive performance across a wide range of AD severity. Longitudinal analyses further support BD-Tau's potential as an AD-type neurodegeneration biomarker, as it was found to increase over time only in the symptomatic AD group and not in other groups. These results support the notion that plasma BD-Tau could be a promising specific biomarker for AD staging, as it follows the AD clinical severity spectrum and is not elevated in asymptomatic amyloidosis.

There is a need for internationally applicable screening tests assessing language in neurodegenerative conditions, allowing for homogenized diagnosis/classification of primary progressive aphasias (PPA), monitoring language decline, and providing endpoints in clinical/therapy trials. The ‘Mini-Linguistic State Examination’ (MLSE) is currently developed within a worldwide network including 22 countries, and our Paris-Québec collaboration aimed at developing the French/Canadian MLSE (fc-MLSE), validating it with healthy controls and clinical populations. The fc-MLSE was adapted from the English version using stimuli of similar linguistic complexity. As the English version, the fc-MLSE included 11 sub-tests assessing 5 linguistic domains (motor-speech, phonology, semantics, syntax, verbal working-memory), providing a total score (/100) and 5 sub-scores. The test was administered to 182 healthy controls to generate normative scores, and subsequently to 36 patients with PPA [(nonfluent/agrammatic variant (nfvPPA, n  = 8), logopenic variant (lvPPA, n  = 20), semantic PPA (svPPA, n  = 8)], and 6 patients with Alzheimer's disease (AD). Testing durations were approximately 8 and 12 minutes for controls and patients, respectively, and the inter-rater consistency was of 92%. In controls, no ceiling effects were observed. The total score and the 5 sub-scores were similar for women/men, and led to stratifications according to age-ranges and educational levels. In clinical populations, the fc-MLSE was able to distinguish AD and PPA patients from controls, and PPA had lower total MLSE scores than AD patients. Sub-scores also distinguished the three PPA variants, showing highest error-rates for motor speech in nfvPPA, verbal working-memory in lvPPA, and semantics in svPPA. The fc-MLSE is a rapid and examiner-consistent language test, validated with a large population of healthy controls. It can be helpful for clinical classification of PPA variants, and might represent a valuable tool for follow-up trial monitoring in PPA, AD and other neurodegenerative diseases affecting language. More generally, the use of MLSE versions developed in 22 countries will improve the consistency/uniformity of language assessments at the international level.

Purpose: To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD). Methods: We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) <= 65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92). Results: Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees. Conclusion: We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BackgroundCarriers of small cytosine-adenine-guanine (CAG) repeats below 39 in the HTT gene are traditionally associated with milder Huntington's disease, but their clinical profile has not been extensively studied. ObjectiveTo study the phenotype of CAG(36-38) repeat carriers. MethodsWe included 35 patients and premanifest carriers of CAG(36-38) repeats. We compared clinical and neuropsychological profiles of 11 CAG(36-38) patients with 11 matched CAG(40-42) patients. In addition, we analyzed 243 CAG(36-38) individuals from the ENROLL study to complete the phenotype description. ResultsGlobal cognitive efficiency and performance in different cognitive subdomains were similar in small CAG(36-38) and typically CAG(40-42) expanded individuals. Chorea as the first symptom was significantly less frequent for CAG(36-38) patients (P = 0.04) despite similar total motor scores at first visit. Total motor score at last visit was significantly lower in CAG(36-38) carriers (P = 0.003). The similar cognitive and different motor profile of CAG(36-38) (n = 243) and CAG(40-42) (n = 4675) carriers was confirmed in the ENROLL database. Additionally, clinicians were significantly less confident in diagnosing Huntington's disease (P = 2.4e-8) and diagnosis happened significantly later in CAG(36-38) (P = 2.2e-6) despite a similar age at symptom onset (P = 0.29). ConclusionsWe showed that small CAG(36-38) expansion carriers had a similar cognitive profile to those with the more common CAG(40-42) expansions. These individuals may evade molecular diagnosis because of the absence of chorea rather than because of a low penetrance of symptoms. This finding should encourage neurologists to consider Huntington's disease in cognitively impaired elderly patients without typical chorea and anticipate consequences for genetic counseling in their offspring. (c) 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Progressive primary aphasia (PPA) designates a group of neurodegenerative diseases affecting language processing for which no pharmacologically effective treatment exists. PPA presents in three different variants with distinct language and brain damage areas: logopenic PPA, non-fluent/agrammatic PPA and semantic PPA (PPA-sv). We here present an interim analysis of a sham-controlled randomized double-blind protocol STIM SD assessing the therapeutic effects of direct current stimulation (tDCS) on a cohort of PPA-sv patients. This clinical condition affects the semantic system in anterior temporal lobes (ATL) predominating in the left (dominant) hemisphere, leading to profound word finding and comprehension impairments. To this end, a group of n=27 patients was randomized to a 2 week (10 day) regime of anodal stimulation on the left ATL, cathodal stimulation over the right ATL (following interhemispheric inhibition principles) compared to sham tDCS. Language tasks, including semantic associations (SA) and category fluency (FLU) were performed before the onset of treatment (baseline), and 3 days, 2 weeks, and 4 months thereafter. A group of matched healthy participants (n=20) were assessed to estimate normative task performance and to rate the severity of patient language/semantic deficits. The assessment of baseline symptom severity revealed severe impairment of PPA-sv patients in the AS and FLU tasks compared to the healthy controls. Regarding the effects of tDCS, an intermediate analysis (n=9 patients/group) failed to show statistically significant effects for any of the active stimulation conditions compared to sham tDCS. Nonetheless, individual improvement effects were noted for some patients of the cohort treated with active stimulation. At this stage, our observations confirm the feasibility of the implemented experimental design and patient’s tolerance to the stimulation protocol. Currently available datasets will be completed by recruiting the planned number of patients (n=20 condition) to be finally included. Research Category and Technology and Methods Clinical Research: 9. Transcranial Direct Current Stimulation (tDCS) Keywords: Noninvasive brain stimulation, Primary progressive aphasia, Semantic dementia, Language rehabilitation