Long-lasting improvements in episodic memory among subjects with mild cognitive impairment who received transcranial direct current stimulation combined with cognitive treatment and telerehabilitation: a multicentre, randomized, active-controlled study.

Background: In recent years, an increasing number of studies have examined the potential efficacy of cognitive training procedures in individuals with normal ageing and mild cognitive impairment (MCI). Objective: The aims of this study were to (i) evaluate the efficacy of the cognitive Virtual Reality Rehabilitation System (VRRS) combined with anodal transcranial direct current stimulation (tDCS) applied to the left dorsolateral prefrontal cortex compared to placebo tDCS stimulation combined with VRRS and (ii) to determine how to prolong the beneficial effects of the treatment. A total of 109 subjects with MCI were assigned to 1 of 5 study groups in a randomized controlled trial design: (a) face-to-face (FTF) VRRS during anodal tDCS followed by cognitive telerehabilitation (TR) (clinic-atDCS-VRRS+Tele@H-VRRS); (b) FTF VRRS during placebo tDCS followed by TR (clinic-ptDCS-VRRS+Tele@H-VRRS); (c) FTF VRRS followed by cognitive TR (clinic-VRRS+Tele@H-VRRS); (d) FTF VRRS followed by at-home unstructured cognitive stimulation (clinic-VRRS+@H-UCS); and (e) FTF cognitive treatment as usual (clinic-TAU). Results: An improvement in episodic memory was observed after the end of clinic-atDCS-VRRS (p < 0.001). We found no enhancement in episodic memory after clinic-ptDCS-VRRS or after clinic-TAU.Moreover, the combined treatment led to prolonged beneficial effects (clinic-atDCS-VRRS+Tele@H-VRRS vs. clinic-ptDCS-VRRS+Tele@H-VRRS: p = 0.047; clinic-atDCS-VRRS+Tele@H-VRRS vs. clinic-VRRS+Tele@H-VRRS: p = 0.06). Discussion: The present study provides preliminary evidence supporting the use of individualized VRRS combined with anodal tDCS and cognitive telerehabilitation for cognitive rehabilitation. Clinical trial registration: https://clinicaltrials.gov/study/NCT03486704?term=NCT03486704&rank=1, NCT03486704.

Sharing brain imaging data in the Open Science era: how and why?

The sharing of human neuroimaging data has great potential to accelerate the development of imaging biomarkers in neurological and psychiatric disorders; however, major obstacles remain in terms of how and why to share data in the Open Science context. In this Health Policy by the European Cluster for Imaging Biomarkers, we outline the current main opportunities and challenges based on the results of an online survey disseminated among senior scientists in the field. Although the scientific community fully recognises the importance of data sharing, technical, legal, and motivational aspects often prevent active adoption. Therefore, we provide practical advice on how to overcome the technical barriers. We also call for a harmonised application of the General Data Protection Regulation across EU countries. Finally, we suggest the development of a system that makes data count by recognising the generation and sharing of data as a highly valuable contribution to the community.

Clinical validity of the Italian adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB) in Mild Cognitive Impairment and Alzheimer's Disease.

BACKGROUND: The identification and staging of Alzheimer's Disease (AD) represent a challenge, especially in the prodromal stage of Mild Cognitive Impairment (MCI), when cognitive changes can be subtle. Worldwide efforts were dedicated to select and harmonize available neuropsychological instruments. In Italy, the Italian Network of Neuroscience and Neuro-Rehabilitation has promoted the adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB), collecting normative data from 433 healthy controls (HC). Here, we aimed to explore the ability of I-UDSNB to differentiate between a) MCI and HC, b) AD and HC, c) MCI and AD. METHODS: One hundred thirty-seven patients (65 MCI, 72 AD) diagnosed after clinical-neuropsychological assessment, and 137 HC were included. We compared the I-UDSNB scores between a) MCI and HC, b) AD and HC, c) MCI and AD, with t-tests. To identify the test(s) most capable of differentiating between groups, significant scores were entered in binary logistic and in stepwise regressions, and then in Receiver Operating Characteristic curve analyses. RESULTS: Two episodic memory tests (Craft Story and Five Words test) differentiated MCI from HC subjects; Five Words test, Semantic Fluency (vegetables), and TMT-part B differentiated AD from, respectively, HC and MCI. CONCLUSIONS: Our findings indicate that the I-UDSNB is a suitable tool for the harmonized and concise assessment of patients with cognitive decline, showing high sensitivity and specificity for the diagnosis of MCI and AD.

TACO: A Turkish database for abstract concepts.

The organization of abstract concepts reflects different dimensions, grounded in the brain regions coding for the corresponding experience. Normative measures of linguistic stimuli offer noteworthy insights into the organization of conceptual knowledge, but studies differ in the dimensions and classes of concepts considered. Additionally, most of the available information has been collected in English, without considering possible linguistic and cultural differences. Here, we aimed to create a comprehensive Turkish database for abstract concepts (TACO), including rarely investigated classes such as political concepts. We included 503 words-78 concrete (fruits, animals, tools) and 425 abstract (emotions, social, mental states, theoretical, quantity, space, political)-rated by 134 Turkish speakers for familiarity, imageability, age of acquisition, valence, arousal, quantity, space, theoretical, social, mental state, and political dimensions. We calculated dominance and exclusivity, indicating the dimension receiving the highest mean score for each word, and the position of the word along the unidimensional-multidimensional continuum, respectively. A principal component analysis (PCA) was conducted on the semantic dimensions. The results showed that mental state was the dominant dimension for most concepts. Moderate to low levels of exclusivity indicated that the concepts were multidimensional. PCA revealed three components: Component 1 captured the juxtaposition between social/mental state and magnitude polarities, Component 2 highlighted affective components, and Component 3 grouped together political and theoretical dimensions. The introduction of political concepts provided insights into the multidimensional nature of this unexplored class, closely intertwined with the theoretical dimension. TACO constitutes the first comprehensive Turkish database covering several abstract dimensions, paving the way for cross-linguistic and cross-cultural studies of semantic representations.

Heterogeneity and overlap in the continuum of linguistic profile of logopenic and semantic variants of primary progressive aphasia: a Profile Analysis based on Multidimensional Scaling study.

BACKGROUND: Primary progressive aphasia (PPA) diagnostic criteria underestimate the complex presentation of semantic (sv) and logopenic (lv) variants, in which symptoms partially overlap, and mixed clinical presentation (mixed-PPA) and heterogenous profile (lvPPA +) are frequent. Conceptualization of similarities and differences of these clinical conditions is still scarce. METHODS: Lexical, semantic, phonological, and working memory errors from nine language tasks of sixty-seven PPA were analyzed using Profile Analysis based on Multidimensional Scaling, which allowed us to create a distributed representation of patients' linguistic performance in a shared space. Patients had been studied with [18F] FDG-PET. Correlations were performed between metabolic and behavioral data. RESULTS: Patients' profiles were distributed across a continuum. All PPA, but two, presented a lexical retrieval impairment, in terms of reduced production of verbs and nouns. svPPA patients occupied a fairly clumped space along the continuum, showing a preponderant semantic deficit, which correlated to fusiform gyrus hypometabolism, while only few presented working memory deficits. Adjacently, lvPPA + presented a semantic impairment combined with phonological deficits, which correlated with metabolism in the anterior fusiform gyrus and posterior middle temporal gyrus. Starting from the shared phonological deficit side, a large portion of the space was occupied by all lvPPA, showing a combination of phonological, lexical, and working memory deficits, with the latter correlating with posterior temporo-parietal hypometabolism. Mixed PPA did not show unique profile, distributing across the space. DISCUSSION: Different clinical PPA entities exist but overlaps are frequent. Identifying shared and unique clinical markers is critical for research and clinical practice. Further research is needed to identify the role of genetic and pathological factors in such distribution, including also higher sample size of less represented groups.

A digital teleneuropsychology platform for the diagnosis of mild cognitive impairment: from concept to certification as a medical device.

BACKGROUND: Innovative digital solutions are shaping a new concept of dementia care, opening additional venues for prevention, diagnosis, monitoring and treatment. Hereby, we report the development of a tablet-based teleneuropsychology platform (Tenèpsia®), from concept to certification as Medical Device (MD) Class IIA, as per new MD regulation 745/2017. METHODS: The platform was designed for the remote cognitive evaluation and created thanks to the effort of a collaborative working group including experts from three Italian scientific societies and Biogen Italia S.r.l. (hereafter "Biogen"), and developers from Xenia Reply and Inside AI. The development strategy was guided by converting traditional paper-and-pencil tests into digital versions while maintaining comparable neuropsychological features and optimizing patient accessibility and user experience. The experts focused on the choice and adaptation of traditional neuropsychology measures for a 45-min teleneuropsychology assessment. RESULTS: The developers created a web and a mobile interface, respectively, for the professional (neuropsychologist) and non-professional (patient and caregiver) use. Recording of voice, drawing and typing information was enabled. Instant dashboards provide a quick overview of the patient's condition. Simulation activities were performed to obtain MD certification, valid across Europe. CONCLUSION: Neuropsychology services will benefit from the implementation in clinics of harmonized digital tools with adequate scientific and technological standards. The use of digital cognitive testing for the diagnosis of mild cognitive impairment is expected to enhance patient and clinician outcomes through simplified, digital objective data collection, sparing of time and resources, with a positive impact on healthcare costs and access to treatments, reducing inequalities and delays in diagnosis and cure.

European intersocietal recommendations for the biomarker-based diagnosis of neurocognitive disorders.

The recent commercialisation of the first disease-modifying drugs for Alzheimer's disease emphasises the need for consensus recommendations on the rational use of biomarkers to diagnose people with suspected neurocognitive disorders in memory clinics. Most available recommendations and guidelines are either disease-centred or biomarker-centred. A European multidisciplinary taskforce consisting of 22 experts from 11 European scientific societies set out to define the first patient-centred diagnostic workflow that aims to prioritise testing for available biomarkers in individuals attending memory clinics. After an extensive literature review, we used a Delphi consensus procedure to identify 11 clinical syndromes, based on clinical history and examination, neuropsychology, blood tests, structural imaging, and, in some cases, EEG. We recommend first-line and, if needed, second-line testing for biomarkers according to the patient's clinical profile and the results of previous biomarker findings. This diagnostic workflow will promote consistency in the diagnosis of neurocognitive disorders across European countries.

Insights into attention and memory difficulties in post-COVID syndrome using standardized neuropsychological tests and experimental cognitive tasks.

The COVID-19 pandemic has given rise to post-acute cognitive symptoms, often described as 'brain fog'. To comprehensively grasp the extent of these issues, we conducted a study integrating traditional neuropsychological assessments with experimental cognitive tasks targeting attention control, working memory, and long-term memory, three cognitive domains most commonly associated with 'brain fog'. We enrolled 33 post-COVID patients, all self-reporting cognitive difficulties, and a matched control group (N = 27) for cognitive and psychological assessments. Our findings revealed significant attention deficits in post-COVID patients across both neuropsychological measurements and experimental cognitive tasks, evidencing reduced performance in tasks involving interference resolution and selective and sustained attention. Mild executive function and naming impairments also emerged from the neuropsychological assessment. Notably, 61% of patients reported significant prospective memory failures in daily life, aligning with our recruitment focus. Furthermore, our patient group showed significant alterations in the psycho-affective domain, indicating a complex interplay between cognitive and psychological factors, which could point to a non-cognitive determinant of subjectively experienced cognitive changes following COVID-19. In summary, our study offers valuable insights into attention challenges faced by individuals recovering from COVID-19, stressing the importance of comprehensive cognitive and psycho-affective evaluations for supporting post-COVID individuals.

The science of micronutrients in clinical practice - Report on the ESPEN symposium.

BACKGROUND & AIMS: The European Society for Clinical Nutrition and Metabolism published its first clinical guidelines for use of micronutrients (MNs) in 2022. A two-day web symposium was organized in November 2022 discussing how to apply the guidelines in clinical practice. The present paper reports the main findings of this symposium. METHODS: Current evidence was discussed, the first day being devoted to clarifying the biology underlying the guidelines, especially regarding the definition of deficiency, the impact of inflammation, and the roles in antioxidant defences and immunity. The second day focused on clinical situations with high prevalence of MN depletion and deficiency. RESULTS: The importance of the determination of MN status in patients at risk and diagnosis of deficiencies is still insufficiently perceived, considering the essential role of MNs in immune and antioxidant defences. Epidemiological data show that deficiencies of several MNs (iron, iodine, vitamin D) are a global problem that affects human health and well-being including immune responses such as to vaccination. Clinical conditions frequently associated with MN deficiencies were discussed including cancer, obesity with impact of bariatric surgery, diseases of the gastrointestinal tract, critical illness, and aging. In all these conditions, MN deficiency is associated with worsening of outcomes. The recurrent problem of shortage of MN products, but also lack of individual MN-products is a worldwide problem. CONCLUSION: Despite important progress in epidemiology and clinical nutrition, numerous gaps in practice persist. MN depletion and deficiency are frequently insufficiently searched for in clinical conditions, leading to inadequate treatment. The symposium concluded that more research and continued education are required to improve patient outcome.

The neural substrates of transdiagnostic cognitive-linguistic heterogeneity in primary progressive aphasia.

BACKGROUND: Clinical variants of primary progressive aphasia (PPA) are diagnosed based on characteristic patterns of language deficits, supported by corresponding neural changes on brain imaging. However, there is (i) considerable phenotypic variability within and between each diagnostic category with partially overlapping profiles of language performance between variants and (ii) accompanying non-linguistic cognitive impairments that may be independent of aphasia magnitude and disease severity. The neurobiological basis of this cognitive-linguistic heterogeneity remains unclear. Understanding the relationship between these variables would improve PPA clinical/research characterisation and strengthen clinical trial and symptomatic treatment design. We address these knowledge gaps using a data-driven transdiagnostic approach to chart cognitive-linguistic differences and their associations with grey/white matter degeneration across multiple PPA variants. METHODS: Forty-seven patients (13 semantic, 15 non-fluent, and 19 logopenic variant PPA) underwent assessment of general cognition, errors on language performance, and structural and diffusion magnetic resonance imaging to index whole-brain grey and white matter changes. Behavioural data were entered into varimax-rotated principal component analyses to derive orthogonal dimensions explaining the majority of cognitive variance. To uncover neural correlates of cognitive heterogeneity, derived components were used as covariates in neuroimaging analyses of grey matter (voxel-based morphometry) and white matter (network-based statistics of structural connectomes). RESULTS: Four behavioural components emerged: general cognition, semantic memory, working memory, and motor speech/phonology. Performance patterns on the latter three principal components were in keeping with each variant's characteristic profile, but with a spectrum rather than categorical distribution across the cohort. General cognitive changes were most marked in logopenic variant PPA. Regardless of clinical diagnosis, general cognitive impairment was associated with inferior/posterior parietal grey/white matter involvement, semantic memory deficits with bilateral anterior temporal grey/white matter changes, working memory impairment with temporoparietal and frontostriatal grey/white matter involvement, and motor speech/phonology deficits with inferior/middle frontal grey matter alterations. CONCLUSIONS: Cognitive-linguistic heterogeneity in PPA closely relates to individual-level variations on multiple behavioural dimensions and grey/white matter degeneration of regions within and beyond the language network. We further show that employment of transdiagnostic approaches may help to understand clinical symptom boundaries and reveal clinical and neural profiles that are shared across categorically defined variants of PPA.

In person versus remote cognitive rehabilitation in patients with subjective cognitive decline or neurocognitive disorders: what factors drive patient's preference?

Background: To date, there is still a lack of consensus for identifying the ideal candidate for cognitive telerehabilitation (TR). The main goal of the present study is to identify the factors associated to the preference for either TR or in-person cognitive training (CT) programs in older adults at risk of dementia or with early cognitive impairment. Methods: A sample of 56 participants with subjective cognitive decline or neurocognitive disorders eligible for CT were enrolled at the Dementia Research Center and Neurorehabilitation Unit of IRCCS Mondino Foundation. All individuals underwent a baseline assessment to capture their complete profile, including cognitive reserve and lifestyle habits, sociodemographic characteristics, cognitive functioning, and mental health. Patients were then asked their preference for TR or in-person CT, before being randomized to either treatment as per protocol procedures. Statistical analyses included explorative descriptive approach, logistic regression, and non-parametric models to explore the overall contribution of each variable. Results: The two (TR and in-person) preference groups were similar for cognitive functioning and mental health status. Socio-demographic and lifestyle profiles seem to be the most important factors to influence the preference in terms of the area under the curve (AUC) of the models. The two preference groups differed in terms of socio-demographic characteristics (e.g., level of technological skills, age, and distance from the clinic). Furthermore, participants who selected the TR modality of CT had significantly higher levels of cognitive reserve and adopted more protective lifestyle habits (e.g., regular physical activity, Mediterranean diet) when compared to those who preferred in-person CT. Discussion: These findings highlight that the preference to receive CT delivered by TR or in person is a complex issue and is influenced by a variety of factors, mostly related to lifestyle habits and sociodemographic characteristics. Availability of profiles of patients that may be more attracted to one or the other modality of TR may help promote shared decision-making to enhance patient experience and outcomes.

Large languages, impossible languages and human brains.

We aim at offering a contribution to highlight the essential differences between Large Language Models (LLM) and the human language faculty. More explicitly, we claim that the existence of impossible languages for humans does not have any equivalent for LLM making them unsuitable models of the human language faculty, especially for a neurobiological point of view. The core part is preceded by two premises bearing on the distinction between machines and humans and the distinction between competence and performance.

Virtual brain simulations reveal network-specific parameters in neurodegenerative dementias.

Introduction: Neural circuit alterations lay at the core of brain physiopathology, and yet are hard to unveil in living subjects. The Virtual Brain (TVB) modeling, by exploiting structural and functional magnetic resonance imaging (MRI), yields mesoscopic parameters of connectivity and synaptic transmission. Methods: We used TVB to simulate brain networks, which are key for human brain function, in Alzheimer's disease (AD) and frontotemporal dementia (FTD) patients, whose connectivity and synaptic parameters remain largely unknown; we then compared them to healthy controls, to reveal novel in vivo pathological hallmarks. Results: The pattern of simulated parameter differed between AD and FTD, shedding light on disease-specific alterations in brain networks. Individual subjects displayed subtle differences in network parameter patterns that significantly correlated with their individual neuropsychological, clinical, and pharmacological profiles. Discussion: These TVB simulations, by informing about a new personalized set of networks parameters, open new perspectives for understanding dementias mechanisms and design personalized therapeutic approaches.

A Multimodal Approach for Clinical Diagnosis and Treatment of Primary Progressive Aphasia (MAINSTREAM): A Study Protocol.

Primary Progressive Aphasia (PPA) is a syndrome due to different neurodegenerative disorders selectively disrupting language functions. PPA specialist care is underdeveloped. There are very few specialists (neurologists, psychiatrists, neuropsychologists, and speech therapists) and few hospital- or community-based services dedicated to the diagnosis and continuing care of people with PPA. Currently, healthcare systems struggle to provide adequate coverage of care that is too often fragmented, uncoordinated, and unresponsive to the needs of people with PPA and their families. Recently, attention has been gained by non-invasive brain stimulation techniques that allow a personalized treatment approach, such as transcranial Direct Current Stimulation (tDCS). The MAINSTREAM trial looks forward to introducing and evaluating therapeutic innovations such as tDCS coupled with language therapy in rehabilitation settings. A Multimodal Approach for Clinical Diagnosis and Treatment of Primary Progressive Aphasia, MAINSTREAM (ID: 3430931) was registered in the clinicaltrials.gov database (identifier: NCT05730023) on 15 February 2023.

Comparing two picture naming tasks in primary progressive aphasia: Insights from behavioural and neural results.

Picture naming tests are widely used to evaluate language impairments in neurodegenerative diseases, especially in Primary Progressive Aphasia (PPA). The available tests differ for many factors affecting the performance, e.g. format of stimuli and their psycholinguistic properties. We aim to identify the most appropriate naming test to be used on PPA according to the clinical and research demands. We investigated the behavioural characteristics, i.e. proportion of correct responses and error type, and their neural correlates in two Italian naming tests, CaGi naming (CaGi) and naming subtest of the Screening for Aphasia in NeuroDegeneration battery (SAND), administered to 52 PPA patients who underwent an FDG-PET scan. We analysed the effectiveness of the tests in distinguishing PPA versus controls and among PPA variants, considering the psycholinguistic variables affecting performance. We explored the brain metabolic correlates of behavioural performance in the tests. SAND, differently from CaGi, has time limits for the response and its items are less frequent and acquired later. SAND and CaGi differed in terms of number of correct responses and error profile, suggesting a higher difficulty to name SAND items compared to CaGi. Semantic errors predominated in CaGi, while anomic and semantic errors were equally frequent in SAND. Both tests distinguished PPA from controls, but SAND outperformed CaGi in discriminating among PPA variants. FDG-PET imaging revealed a shared metabolic involvement of temporal areas associated with lexico-semantic processing, encompassing anterior fusiform, temporal pole, and extending to posterior fusiform in sv-PPA. Concluding, a picture naming test with response time limit and items which are less frequent and acquired later in life, as SAND, may be effective at highlighting subtle distinctions between PPA variants, improving the diagnosis. Conversely, a naming test without time limit for the response, as CaGi, may be useful for a better characterization of the nature of the naming impairment at the behavioural level, eliciting more naming errors than anomia, possibly helping in the development of rehabilitation protocols.

Event-related causality in stereo-EEG discriminates syntactic processing of noun phrases and verb phrases.

Objective.Syntax involves complex neurobiological mechanisms, which are difficult to disentangle for multiple reasons. Using a protocol able to separate syntactic information from sound information we investigated the neural causal connections evoked by the processing of homophonous phrases, i.e. with the same acoustic information but with different syntactic content. These could be either verb phrases (VP) or noun phrases.Approach. We used event-related causality from stereo-electroencephalographic recordings in ten epileptic patients in multiple cortical and subcortical areas, including language areas and their homologous in the non-dominant hemisphere. The recordings were made while the subjects were listening to the homophonous phrases.Main results.We identified the different networks involved in the processing of these syntactic operations (faster in the dominant hemisphere) showing that VPs engage a wider cortical and subcortical network. We also present a proof-of-concept for the decoding of the syntactic category of a perceived phrase based on causality measures.Significance. Our findings help unravel the neural correlates of syntactic elaboration and show how a decoding based on multiple cortical and subcortical areas could contribute to the development of speech prostheses for speech impairment mitigation.

HomeCoRe system for telerehabilitation in individuals at risk of dementia: A usability and user experience study.

Background: Telerehabilitation has enabled a broader application of cognitive rehabilitation programs. We have recently developed HomeCoRe, a system for supporting cognitive intervention remotely with the assistance of a family member. The main goal of the present study was to determine usability and user experience of HomeCoRe in individuals at risk of dementia and in their family members. The association between subjects' technological skills and main outcome measures was evaluated as well. Methods: Fourteen individuals with subjective cognitive decline (SCD) or mild neurocognitive disorder (mNCD) were recruited to participate in this pilot study. All participants received a touch-screen laptop implemented with the HomeCoRe software. The intervention consisted of 18 sessions and included a patient-tailored adaptive protocol of cognitive exercises. Usability was assessed in terms of treatment adherence and participants' performance across sessions; user experience via self-reported questionnaires and a descriptive diary. Results: Usability and user experience were overall satisfactory and suggested usability, pleasantness, and high motivation while using HomeCoRe. Technological skills correlated only with the perceived ability to start and/or perform exercises autonomously. Discussion: These results, although preliminary, suggest that the usability and user experience of HomeCoRe are satisfactory and independent of technological skills. These findings encourage wider and more systematic use of HomeCoRe to overcome the current limitations of in-person cognitive rehabilitation programs and to reach more individuals at risk of dementia.