Home-Based Transcranial Direct Current Stimulation in Primary Progressive Aphasia: A Pilot Study.

BACKGROUND: This study aims to determine (a) if home-based anodal transcranial direct current stimulation (a-tDCS) delivered to the left supramarginal gyrus (SMG) coupled with verbal short-term memory/working memory (vSTM/WM) treatment ("RAM", short for "Repeat After Me") is more effective than sham-tDCS in improving vSTM/WM in patients with primary progressive aphasia (PPA), and (b) whether tDCS effects generalize to other language and cognitive abilities. METHODS: Seven PPA participants received home-based a-tDCS and sham-tDCS coupled with RAM treatment in separate conditions in a double-blind design. The treatment task required participants to repeat word spans comprising semantically and phonologically unrelated words in the same and reverse order. The evaluation of treatment effects was carried out using the same tasks as in the treatment but with different items (near-transfer effects) and tasks that were not directly related to the treatment (far-transfer effects). RESULTS: A-tDCS showed (a) a significant effect in improving vSTM abilities, measured by word span backward, and (b) a generalization of this effect to other language abilities, namely, spelling (both real words and pseudowords) and learning (retention and delayed recall). CONCLUSIONS: These preliminary results indicate that vSTM/WM intervention can improve performance in trained vSTM/WM tasks in patients with PPA, especially when augmented with home-based tDCS over the left SMG.

Plasma membrane damage is a new trigger of cellular senescence.

By blocking proliferation and inducing a secretory phenotype, cellular senescence has beneficial and deleterious effects, the latter being linked to aging. Suda et al. recently reported that plasma membrane (PM) damage (PMD) triggers senescence, suggesting that PMD inducers promote senescence and that the PMD repair machinery can regulate it.

Preliminary validation of the Virtual Kitchen Challenge as an objective and sensitive measure of everyday function associated with cerebrovascular disease.

Preliminary validity of a computer-based test of everyday function (Virtual Kitchen Challenge [VKC]) was examined against brain-imaging markers of cerebrovascular disease and in contrast to conventional neuropsychological and self-report measures. Twenty community-dwelling older adults (n = 6 mild cognitive impairment) performed simulated breakfast and lunch tasks using a computer touchscreen (VKC). Automated measures (completion time, proportion time off screen, etc.) were computed during training and test conditions. White matter hyperintensity (WMH) volumes from brain magnetic resonance imaging and conventional measures of cognition and function also were obtained. VKC completion time and proportion time off screen improved significantly from training to test and were significantly associated with WMH volume (r > 0.573). VKC measures and WMH were not significantly correlated with conventional cognitive or self-report measures. The VKC holds promise as a valid measure of subtle functional difficulties in older adults that is sensitive to change and cerebrovascular pathology, highlighting its potential for clinical trials. Highlights: Virtual Kitchen Challenge (VKC) scores showed significant improvement from training to test conditions.VKC scores (completion time and proportion of time off screen) were associated with a neuroimaging biomarker of brain health (white matter hyperintensities).

Revisiting sensitivity of senescent cells to BH3 mimetics.

B cell leukemia/lymphoma 2 (BCL2) homology domain 3 (BH3) mimetics were reported to selectively kill senescent cells and improve age-related diseases. Defining why these cells show increased sensitivity to these molecules will help to identify new pharmacological compounds with senolytic activity. Here, we discuss how recent research findings provide new clues to understand this vulnerability.

Cholesterol biosynthetic pathway induces cellular senescence through ERRα.

Cellular senescence is a cell program induced by various stresses that leads to a stable proliferation arrest and to a senescence-associated secretory phenotype. Accumulation of senescent cells during age-related diseases participates in these pathologies and regulates healthy lifespan. Recent evidences point out a global dysregulated intracellular metabolism associated to senescence phenotype. Nonetheless, the functional contribution of metabolic homeostasis in regulating senescence is barely understood. In this work, we describe how the mevalonate pathway, an anabolic pathway leading to the endogenous biosynthesis of poly-isoprenoids, such as cholesterol, acts as a positive regulator of cellular senescence in normal human cells. Mechanistically, this mevalonate pathway-induced senescence is partly mediated by the downstream cholesterol biosynthetic pathway. This pathway promotes the transcriptional activity of ERRα that could lead to dysfunctional mitochondria, ROS production, DNA damage and a p53-dependent senescence. Supporting the relevance of these observations, increase of senescence in liver due to a high-fat diet regimen is abrogated in ERRα knockout mouse. Overall, this work unravels the role of cholesterol biosynthesis or level in the induction of an ERRα-dependent mitochondrial program leading to cellular senescence and related pathological alterations.

RSK3 switches cell fate: from stress-induced senescence to malignant progression.

BACKGROUND: TGFß induces several cell phenotypes including senescence, a stable cell cycle arrest accompanied by a secretory program, and epithelial-mesenchymal transition (EMT) in normal epithelial cells. During carcinogenesis cells lose the ability to undergo senescence in response to TGFß but they maintain an EMT, which can contribute to tumor progression. Our aim was to identify mechanisms promoting TGFß-induced senescence escape. METHODS: In vitro experiments were performed with primary human mammary epithelial cells (HMEC) immortalized by hTert. For kinase library screen and modulation of gene expression retroviral transduction was used. To characterize gene expression, RNA microarray with GSEA analysis and RT-qPCR were used. For protein level and localization, Western blot and immunofluorescence were performed. For senescence characterization crystal violet assay, Senescence Associated-ß-Galactosidase activity, EdU staining were conducted. To determine RSK3 partners FLAG-baited immunoprecipitation and mass spectrometry-based proteomic analyses were performed. Proteosome activity and proteasome enrichment assays were performed. To validate the role of RSK3 in human breast cancer, analysis of METABRIC database was performed. Murine intraductal xenografts using MCF10DCIS.com cells were carried out, with histological and immunofluorescence analysis of mouse tissue sections. RESULTS: A screen with active kinases in HMECs upon TGFß treatment identified that the serine threonine kinase RSK3, or RPS6KA2, a kinase mainly known to regulate cancer cell death including in breast cancer, reverted TGFß-induced senescence. Interestingly, RSK3 expression decreased in response to TGFß in a SMAD3-dependent manner, and its constitutive expression rescued SMAD3-induced senescence, indicating that a decrease in RSK3 itself contributes to TGFß-induced senescence. Using transcriptomic analyses and affinity purification coupled to mass spectrometry-based proteomics, we unveiled that RSK3 regulates senescence by inhibiting the NF-κΒ pathway through the decrease in proteasome-mediated IκBα degradation. Strikingly, senescent TGFß-treated HMECs display features of epithelial to mesenchymal transition (EMT) and during RSK3-induced senescence escaped HMECs conserve EMT features. Importantly, RSK3 expression is correlated with EMT and invasion, and inversely correlated with senescence and NF-κΒ in human claudin-low breast tumors and its expression enhances the formation of breast invasive tumors in the mouse mammary gland. CONCLUSIONS: We conclude that RSK3 switches cell fate from senescence to malignancy in response to TGFß signaling.

Expressive recall and recognition as complementary measures to assess novel word learning ability in aphasia.

Novel word learning ability has been associated with language treatment outcomes in people with aphasia (PWA), and its assessment could inform prognosis and rehabilitation. We used a brief experimental task to examine novel word learning in PWA, determine the value of phonological cueing in assessing learning outcomes, and identify factors that modulate learning ability. Twelve PWA and nineteen healthy controls completed the task, and recall and recognition tests of learning ability. Most PWA showed comparable learning outcomes to those of the healthy controls. Learning assessed via expressive recall was more clearly evidenced with phonological cues. Better single word processing abilities and phonological short-term memory and higher integrity of the left inferior frontal gyrus were related to better learning performance. Brief learning tasks like this one are clinically feasible and hold promise as screening tools of verbal learning in PWA once validated and evaluated for their capacity to predict treatment outcomes.

Integrity of input verbal short-term memory ability predicts naming accuracy in aphasia.

Background: Contemporary models of aphasia predominantly attribute lexical retrieval deficits to impaired access and/or maintenance of semantic, lexical, and phonological representations of words. A central hypothesis of language-emergent models of verbal short-term memory (STM) is that temporary storage and maintenance of verbal information arises from activation of linguistic representations in long-term memory. This close relationship between short-term retention and linguistic representations has prompted accounts of aphasia that include impairments to both these components. Aims: We investigated associations between measures of input semantic and phonological verbal STM and corresponding output processing measures. We hypothesised that both input and output functions of verbal STM rely on a common substrate (i.e., temporary activation and maintenance of long-term linguistic representations). Methods & Procedure: Twenty adults with aphasia completed a series of semantic and phonological probe spans. Results were compared with naming performance in immediate and delayed conditions. The data were analysed using correlations, principal components analysis and linear regressions. Results & Discussion: Input semantic and phonological verbal STM abilities were predictive of naming accuracy. Greater input semantic and phonological STM spans were associated with fewer semantic and phonological naming errors. Latent factors identified by principal components analysis of probe span data were consistent with a two-step interactive model of word retrieval. Probe spans measuring access to semantic and initial consonant-vowel representations aligned with lexical-semantic abilities (lexical-semantic factor). Probe spans assessing access to the rhyme component of a word measured lexical-phonological abilities (lexical-phonological factor). The principal components analysis indicated that stronger lexical-semantic abilities were associated with fewer semantic and nonword errors, and stronger lexical phonological abilities were associated with fewer formal and unrelated errors. In addition, our results were consistent with models that postulate serial access to phonology, proceeding from initial to final phonemes. The span measuring access to initial consonant-vowel was associated with lexical selection, while the span measuring access to rhyme information was associated with phonological selection. Conclusion: Performance on input semantic and phonological tasks predicts accuracy of picture naming performance and types of errors made by people with aphasia. These results indicate overlap in input and output semantic and phonological processing, which must be accounted for in models of lexical processing. These findings also have implications for approaches to diagnosis and treatments for lexical comprehension and production that capitalise on the overlap of input and output processing.

The right uncinate fasciculus supports verbal short-term memory in aphasia.

Verbal short-term memory (STM) deficits are associated with language processing impairments in people with aphasia. Importantly, the integrity of STM can predict word learning ability and anomia therapy gains in aphasia. While the recruitment of perilesional and contralesional homologous brain regions has been proposed as a possible mechanism for aphasia recovery, little is known about the white-matter pathways that support verbal STM in post-stroke aphasia. Here, we investigated the relationships between the language-related white matter tracts and verbal STM ability in aphasia. Nineteen participants with post-stroke chronic aphasia completed a subset of verbal STM subtests of the TALSA battery including nonword repetition (phonological STM), pointing span (lexical-semantic STM without language output) and repetition span tasks (lexical-semantic STM with language output). Using a manual deterministic tractography approach, we investigated the micro- and macrostructural properties of the structural language network. Next, we assessed the relationships between individually extracted tract values and verbal STM scores. We found significant correlations between volume measures of the right Uncinate Fasciculus and all three verbal STM scores, with the association between the right UF volume and nonword repetition being the strongest one. These findings suggest that the integrity of the right UF is associated with phonological and lexical-semantic verbal STM ability in aphasia and highlight the potential compensatory role of right-sided ventral white matter language tracts in supporting verbal STM after aphasia-inducing left hemisphere insult.

Regulation and role of calcium in cellular senescence.

Cellular senescence is a state of stable cell proliferation arrest accompanied by a distinct secretory program impacting the senescent cell microenvironment. This phenotype can be induced by many stresses, including telomere shortening, oncogene activation, oxidative or genotoxic stress. Cellular senescence plays a key role in the organism throughout life, with beneficial effects at a young age for instance in embryonic development and wound healing, and deleterious effects during aging and in aging-related diseases. In the last decade calcium and calcium signaling have been established as critical factors in the implementation and regulation of cellular senescence. In this review we will present and discuss the main discoveries in this field, from the observation of an increased intracellular calcium concentration in senescent cells to the identification of calcium-binding proteins, calcium channels (TRP, ITPR, …) and MERCs (mitochondria-endoplasmic reticulum contact sites) as key players in this context.

Efficacy of a randomized controlled trial of integrative couple treatment for pathological gambling (ICT-PG): 10-month follow-up.

OBJECTIVE: Assess the efficacy of integrative couple treatment for pathological gambling (ICT-PG) in comparison to treatment provided in an individual approach. METHOD: Eighty couples were assigned randomly to ICT-PG (n = 44, Mage = 42.2, SD [13.4], n male gamblers = 29) or individual treatment (n = 36, Mage = 39.9 SD [13.0], n male gamblers = 31) with follow-ups at 4- and 10-months postadmission regarding the severity of gambling, the individual and couple's well-being. Linear mixed and generalized estimating equation models for repeated measures were applied to take into account the dependency of observations. Protocol was preregistered at www. CLINICALTRIALS: gov (ID: NCT02240485). RESULTS: Participants in both treatments generally improved over time with reductions on gambling expanses from an initial $4,000-$600 in a 90-day period following treatment, without difference across treatment conditions in money spent on gambling or frequency of gambling. However, on different indices of gambling severity, the participants in ICT-PG showed more improvement at follow-ups, with better control capacity (OR = 2.57, p < .0129) and greater reduction in gambling craving (OR = 5.83, p < .0001) and erroneous cognitions (OR = 2.63, p < .0063). The couple treatment was associated with a better individual well-being (e.g., less depression for partners, OR = 5.53; p < .0351, and gamblers, OR = 2.37; p < .0334) and couple well-being (e.g., better dyadic satisfaction for partners, OR = 2.02; p < .0057, and gamblers, OR = 3.07; p < .0212). CONCLUSIONS: The results underline the necessity to provide a greater diversity of treatment for gamblers and their partner. Further research should focus on identifying active components of ICT-PG and widen its provision to gamblers with concurrent addiction disorders. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

[Substance use among older residents in residential and long-term care facilities: A scoping review on intervention practices]. / Consommation de substances psychoactives chez les résident(e)s fréquentant des milieux d'hébergement et de soins de longue durée pour personnes âgées en perte d'autonomie : une revue de la portée sur les pratiques d'intervention.

Objectives Residential and long-term care facilities struggle to support older residents who experience a loss of autonomy, use psychoactive substances and face issues related to their consumption. Substance use can interact negatively with other physical, mental health or social conditions (e.g., homelessness) to create particularly complex profiles. In Quebec, as in many other countries around the world, there are often no clear guidelines for the care of elderly residents using psychoactive substances. The purpose of this study is to document the characteristics of existing interventions and practices towards older people who use psychoactive substances in residential and long-term care facilities in order to support decision makers with improvement of services and quality of care. Methods We carried out a scoping review of the scientific literature. We consulted 7 scientific databases (MEDLINE, EmBASE, PsychINFO, CINAHL, SocIndex, Ageline, Érudit). To identify the relevant grey literature, we explored the websites of governmental, non-governmental organizations and professional associations in the fields of addiction and aging in a selection of OECD countries. In addition, 31 experts were solicited to enhance the documentary research process. We conducted a thematic analysis on 65 documents. Results The philosophies underlying practices related to substance use reflect a hard balance to strike between priorities to be given to health, safety, and respect for human rights in residential and long-term-care settings. These philosophies, and the practices that stem from them, are distributed along a continuum ranging from the demand for abstinence to a total "laissez-faire" approach to substance use. Services offered are varied and involve complementary expertise in the health and social fields to meet the complex needs of this population. Finally, a diversity of organizational dynamics is observed: proposed interventions regarding substance use can be structured programs, informal interventions, internal substance use management policies, or specific settings for older adults who use substances, such as wet eldercare facilities. Conclusion This portrait of the interventions that target the use of psychoactive substances in residential and long-term care settings may assist care workers and service managers in Quebec and internationally, with clinical practice improvements. This may ultimately support both seniors-dedicated and addiction services. In view of population aging and the complex needs of older populations, clear guidelines are crucial to ensure the quality of care and services in these settings.

[The Challenges of Victimization in the Treatment of Substance Addiction: What Do Clinicians Say About It?] / Les enjeux liés à la victimisation dans le traitement de la dépendance aux substances : qu'en disent les cliniciens en dépendance ?

Literature seems to establish a two-way relationship between psychoactive substance use and the presence of victimization. Indeed, substance can be used by a victim to overcome the different impacts lived because of the criminal acts experienced. On the other side, psychoactive substance use may increase the risks of a person being victim of criminal acts. It is therefore no wonder that an important proportion of people who consult for a problem of consumption/addiction to psychoactive substances have already been victims of criminal acts. Since the clinical profiles of these individuals is severe and complex, it appears important that the clinicians working with this person be aware of the presence of victimization in their life in order to help them. The objective of this project is to document the difficulties and the challenges encountered by the addiction clinicians in their interventions with people having already been victims of criminal acts and to present possible solutions to help improve interventions and promote their recovery. Thirty-two addiction clinicians (N = 9 Men) have taken part in individual meetings of about 60 minutes. Once transcribed in verbatim form, the interviews have been analyzed under a continuous theming method following the steps put forward by Braun and Clarke (2006). The results of the qualitative analysis highlighted the four following aspects: (1) Perception of clinicians regarding the portrait of people consulting in a public intervention center specializing in addiction; (2) Perception of addiction clinicians regarding the possible interactions between substance use and victimization; (3) The stakes of substance abuse intervention with the victims of a criminal act and (4) Suggestions to improve services for people with substance addiction and being criminal act victims. The results put forward the complexity of intervention with people with a problem of consumption/addiction and who were victims of criminal act victims. The results highlight the complexity of the intervention with people with a problem of consumption/addiction and who were victims of criminal acts, as well as the need for training addiction clinicians about victimization.

3-deazaadenosine (3DA) alleviates senescence to promote cellular fitness and cell therapy efficiency in mice.

Cellular senescence is a stable type of cell cycle arrest triggered by different stresses. As such, senescence drives age-related diseases and curbs cellular replicative potential. Here, we show that 3-deazaadenosine (3DA), an S-adenosyl homocysteinase (AHCY) inhibitor, alleviates replicative and oncogene-induced senescence. 3DA-treated senescent cells showed reduced global Histone H3 Lysine 36 trimethylation (H3K36me3), an epigenetic modification that marks the bodies of actively transcribed genes. By integrating transcriptome and epigenome data, we demonstrate that 3DA treatment affects key factors of the senescence transcriptional program. Remarkably, 3DA treatment alleviated senescence and increased the proliferative and regenerative potential of muscle stem cells from very old mice in vitro and in vivo. Moreover, ex vivo 3DA treatment was sufficient to enhance the engraftment of human umbilical cord blood (UCB) cells in immunocompromised mice. Together, our results identify 3DA as a promising drug enhancing the efficiency of cellular therapies by restraining senescence.

Treatment of the Linguistic and Temporal Components of Lexical Activation to Improve Word Retrieval in Aphasia.

Current approaches to treatments for word processing impairments in aphasia emphasize two components to target, the linguistic content, semantic or phonological representations of words, and the processing component, access to and retrieval of those representations. In this study, we explore these two components of a treatment to improve lexical activation that supports access and retrieval of word representations. Five people with aphasia participated. The treatment task was repetition of concrete word pairs after a 5-s response delay which was intended to provide practice in maintaining activation of the words for that 5-s period before reproducing them. Two of the five participants demonstrated a difficulty in maintaining activation of single words in repetition, with accuracy decreasing significantly after the 5-s interval. The treatment was applied to all participants, however, to determine if its benefit was specific to those with the activation maintenance impairment. Results confirmed that the activation maintenance treatment in the context of this repetition task led to more treatment gains for the two participants who demonstrated this specific impairment. They made gains on four of the nine measures compared to improvements on one to two measures for the other participants. A second question addressed in this study was the relative importance of the item component (linguistic content) of the treatment and the processing component, maintenance of activation. To that end, there were two conditions of treatment probes, (1) repeated content for all treatment, immediate post-treatment and 3-month maintenance probes and (2) novel content for probes in these three phases of treatment. Only one participant showed significant improvement in treatment when items were novel for all probes. We discuss the possibility that this outcome reflects a more specific deficit in the temporal processing component of lexical activation compared to the two other participants who showed better performance on probes with repeated items in treatment and post-treatment phases. Clinical implications of this study and directions of future research are discussed.

Expression of the Calcium-Binding Protein CALB1 Is Induced and Controls Intracellular Ca2+ Levels in Senescent Cells.

In response to many stresses, such as oncogene activation or DNA damage, cells can enter cellular senescence, a state of proliferation arrest accompanied by a senescence-associated secretory phenotype (SASP). Cellular senescence plays a key role in many physiopathological contexts, including cancer, aging and aging-associated diseases, therefore, it is critical to understand how senescence is regulated. Calcium ions (Ca2+) recently emerged as pivotal regulators of cellular senescence. However, how Ca2+ levels are controlled during this process is barely known. Here, we report that intracellular Ca2+ contents increase in response to many senescence inducers in immortalized human mammary epithelial cells (HMECs) and that expression of calbindin 1 (CALB1), a Ca2+-binding protein, is upregulated in this context, through the Ca2+-dependent calcineurin/NFAT pathway. We further show that overexpression of CALB1 buffers the rise in intracellular Ca2+ levels observed in senescent cells. Finally, we suggest that increased expression of Ca2+-binding proteins calbindins is a frequent mark of senescent cells. This work thus supports that, together with Ca2+channels, Ca2+-binding proteins modulate Ca2+ levels and flux during cellular senescence. This opens potential avenues of research to better understand the role of Ca2+ and of Ca2+-binding proteins in regulating cellular senescence.

Language learning in aphasia: A narrative review and critical analysis of the literature with implications for language therapy.

People with aphasia (PWA) present with language deficits including word retrieval difficulties after brain damage. Language learning is an essential life-long human capacity that may support treatment-induced language recovery after brain insult. This prospect has motivated a growing interest in the study of language learning in PWA during the last few decades. Here, we critically review the current literature on language learning ability in aphasia. The existing studies in this area indicate that (i) language learning can remain functional in some PWA, (ii) inter-individual variability in learning performance is large in PWA, (iii) language processing, short-term memory and lesion site are associated with learning ability, (iv) preliminary evidence suggests a relationship between learning ability and treatment outcomes in this population. Based on the reviewed evidence, we propose a potential account for the interplay between language and memory/learning systems to explain spared/impaired language learning and its relationship to language therapy in PWA. Finally, we indicate potential avenues for future research that may promote more cross-talk between cognitive neuroscience and aphasia rehabilitation.