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t was proposed that a reorganization of the relationships between cognitive functions occurs in dementia, a vision that surpasses the idea of a mere decline of specific domains. The complexity of cognitive structure, as assessed by neuropsychological tests, can be captured by exploratory graph analysis (EGA). EGA was applied to the neuropsychological assessment of people (humans) with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer’s disease (AD; total N = 638). Both sexes were included. In AD, memory scores detach from the other cognitive functions, and memory subdomains reduce their reciprocal relation. SCD showed a pattern of segregated neuropsychological domains, and MCI showed a noisy and less stable pattern. Results suggest that AD drives a reorganization of cognitive functions toward a less-fractionated architecture compared with preclinical conditions. Cognitive functions show a reorganization that goes beyond the performance decline. Results also have clinical implications in test interpretations and usage.

Evidence that Huntington's disease (HD) is characterized by impaired cholesterol biosynthesis in the brain has led to strategies to increase its level in the brain of the rapidly progressing R6/2 mouse model, with a positive therapeutic outcome. Here we tested the long-term efficacy of chronic administration of cholesterol to the brain of the slowly progressing zQ175DN knock-in HD mice in preventing (“early treatment”) or reversing (“late treatment”) HD symptoms. To do this we used the most advanced formulation of cholesterol loaded brain-permeable nanoparticles (NPs), termed hybrid-g7-NPs-chol, which were injected intraperitoneally. We show that one cycle of treatment with hybrid-g7-NPs-chol, administered in the presymptomatic (“early treatment”) or symptomatic (“late treatment”) stages is sufficient to normalize cognitive defects up to 5 months, as well as to improve other behavioral and neuropathological parameters. A multiple cycle treatment combining both early and late treatments (“2 cycle treatment”) lasting 6 months generates therapeutic effects for more than 11 months, without severe adverse reactions. Sustained cholesterol delivery to the brain of zQ175DN mice also reduces mutant Huntingtin aggregates in both the striatum and cortex and completely normalizes synaptic communication in the striatal medium spiny neurons compared to saline-treated HD mice. Furthermore, through a meta-analysis of published and current data, we demonstrated the power of hybrid-g7-NPs-chol and other strategies able to increase brain cholesterol biosynthesis, to reverse cognitive decline and counteract the formation of mutant Huntingtin aggregates. These results demonstrate that cholesterol delivery via brain-permeable NPs is a therapeutic option to sustainably reverse HD-related behavioral decline and neuropathological signs over time, highlighting the therapeutic potential of cholesterol-based strategies in HD patients. Data availability: This study does not include data deposit

Visuo-spatial working memory is one of the main domain-general cognitive mechanisms underlying mathematical abilities and their development in children. However, if visuo-spatial working memory involves different processes and components, then the term ‘mathematics’ refers to a broad concept that includes multiple domains and skills. The aim of this present study was to investigate the relationship between different visuo-spatial working memory components and several mathematical abilities in a sample of third- to fifth-grade Italian children. To assess the relationships between different visuo-spatial working memory components and different mathematical abilities, we relied on Network Analysis (NA). Results indicate that some but not all visuo-spatial working memory components are associated with some mathematical abilities.

The growing number of machine learning-based Cyber-Physical Systems (CPSs) and their ability to adapt and to learn is gaining research interest in several biomedical applications. The use of learning capabilities allows CPSs to interact and analyse their environment, learn from patterns, and perform highly complex prediction tasks. However, while on the one side the use of machine learning acts as a flywheel to the diffusion of those systems, on the other side exposes them to the problem of transparency and interpretability that affect any machine-learning-based systems. This, in critical fields like medicine, is just as important as models' performances, in order to understand their behaviour, errors, and to garner user trust. In this paper we investigate the role of state-of-the-art explainable AI techniques in the field of cyber-physical systems.

The current diagnostic criteria for the behavioural variant of frontotemporal dementia (bvFTD) foresee a relative sparing of long-term memory. Although bvFTD patients were thought to report secondary memory deficits associated with prefrontal dysfunctions, some studies indicated the presence of a “genuine memory deficit” related to mesial temporal lobe dysfunctions. Among various neuropsychological tests, the Free and Cue Selective Reminding Test (FCSRT) has been recommended to distinguish genuine from apparent amnesia. We conducted a systematic review and a random effect Bayesian meta-analysis to evaluate the nature and severity of memory deficit in bvFTD. Our objective was to determine whether the existing literature offers evidence of genuine or apparent amnesia in patients with bvFTD, as assessed via the FCSRT. On 06/19/2021, we conducted a search across four databases (PMC, Scopus, Web of Science, and PubMed). We included all studies that evaluated memory performance using the FCSRT in patients with bvFTD, as long as they also included either cognitively unimpaired participants or AD groups. We tested publication bias through the Funnel plot and Egger’s test. To assess the quality of studies, we used the Newcastle-Ottawa quality assessment scale adapted for cross-sectional studies. We included 16 studies in the meta-analysis. The results showed that bvFTD patients perform better than AD patients (pooled effects between 0.95 and 1.14), as their memory performance stands between AD and control groups (pooled effects between − 2.19 and − 1.25). Moreover, patients with bvFTD present both genuine and secondary memory disorders. As a major limitation of this study, due to our adoption of a rigorous methodology and stringent inclusion criteria, we ended up with just 16 studies. Nonetheless, our robust findings can contribute to the ongoing discussion on international consensus criteria for bvFTD and the selection of appropriate neuropsychological tools to facilitate t

Cognitive reserve (CR) allows individuals to maintain cognitive functionality even in the presence of pathologies. The compensation hypothesis suggests that CR plays an indirect role between age and cognitive decline, contrasting the negative effect of ageing on cognition. We test this hypothesis in an unselected and consecutively enrolled sample of memory clinic attendees (n = 134) who completed the CR Index questionnaire and three neuropsychological tests assessing global cognition (MMSE, FAB, CDT). Participants were divided into two groups based on standard diagnostic criteria (DSM-5): those who were cognitively impaired (n = 92) and those who were preserved (n = 42). A principal component analysis was used to extract a composite measure of global cognitive functioning from the three neuropsychological tests, and mediation analysis was used to examine the relationship between CR, age and global cognitive functioning in the two groups. Results revealed that: (i) age had a significant direct negative effect on the global cognitive score in both groups; (ii) the three socio-behavioural proxies of CR together suppress the direct negative relationship between age and global cognitive score in cognitively impaired patients but not in cognitively preserved participants. This study confirms the association between CR, age and cognition and allows us to validate its role in a population with cognitive impairment and extend findings to a low-to-middle educated population. These results hold important implications for public health and wellness promotion, emphasising the beneficial role of maintaining healthy and active physical, cognitive and social lifestyles.

Introduction: Scientific evidence of the effectiveness of the tumor necrosis factor inhibitor adalimumab (ADA) in pediatric patients with non-infectious non-anterior uveitis is still limited. The aim of this study is to investigate the therapeutic role of ADA in a cohort of pediatric patients with non-anterior uveitis. MethodsThis is an international multicenter study analyzing real-life data referred to pediatric patients treated with ADA for intermediate uveitis/pars planitis, posterior uveitis and panuveitis. Data were drawn from the AutoInflammatory Disease Alliance (AIDA) registry for patients with uveitis. ResultsTwenty-one patients (36 affected eyes) were enrolled, and all patients benefited from ADA administration. In detail, 11 patients (19 affected eyes) did not experience further ocular inflammation after ADA introduction; 10 cases (17 affected eyes) showed a significant clinical improvement consisting of a decrease in severity and/or frequency of ocular relapses. The number of ocular flares dropped from 3.91 to 1.1 events/patient/year after ADA introduction (p = 0.0009); macular edema and retinal vasculitis were respectively observed in 18 eyes and 20 eyes at the start of ADA and in 4 eyes and 2 eyes at the last assessment. The mean daily glucocorticoid dosage significantly decreased from 26.8 +/- 16.8 mg/day at the start of ADA to 6.25 +/- 6.35 mg/day at the last assessment (p = 0.002). Intermediate uveitis/pars planitis (p = 0.01) and posterior uveitis (p = 0.03) were more frequently observed in patients with full response to ADA; panuveitis (p = 0.001) was significantly more frequent among patients continuing to experience uveitic flares. This could be related to a higher use of systemic glucocorticoids (p = 0.002) and conventional immunosuppressants (p = 0.007) at the start of ADA when treating intermediate uveitis/pars planitis. Regarding the safety profile, only one adverse event was reported during ADA treatment, consisting of the development of g

Neuropsychological testing aims to measure individuals' cognitive abilities (e.g. memory, attention), analysing their performance on specific behavioural tasks. Most neuropsychological tests are administered in the so-called ‘paper-and-pencil’ modality or via computerised protocols. The adequacy of these procedures has been recently questioned, with more specific concerns about their ecological validity, i.e. the relation between test scores observed in the laboratory setting and the actual everyday cognitive functioning. In developing more ecological tasks, researchers started to implement virtual reality (VR) technology as an administration technique focused on exposing individuals to simulated but realistic stimuli and environments, maintaining at the same time a controlled laboratory setting and collecting advanced measures of cognitive functioning. This systematic review aims to present how VR procedures for neuropsychological testing have been implemented in the last years. We initially explain the rationale for supporting VR as an advanced assessment tool, but we also discuss the challenges and risks that can limit the widespread implementation of this technology. Then, we systematised the large body of studies adopting VR for neuropsychological testing, describing the VR tools' distribution amongst different cognitive functions through a PRISMA-guided systematic review. The systematic review highlighted that only very few instruments are ready for clinical use, reporting psychometric proprieties (e.g. validity) and providing normative data. Most of the tools still need to be standardised on large cohorts of participants, having published only limited data on small samples up to now. Finally, we discussed the possible future directions of the VR neuropsychological test development linked to technological advances.

In the rubber hand illusion (RHI), participants see a fake hand touched synchronously with their real hand, which is hidden from view. The three-way interaction between vision, touch, and proprioception induces the sensation that the dummy hand belongs to oneself (i.e., subjective embodiment) and the illusory displacement of the real hand towards the fake one (i.e., proprioceptive drift). In the literature, there are mixed results (some positive and some null) regarding the existence of a relationship between subjective embodiment and proprioceptive drift. We conducted a Bayesian meta-analysis to tackle this issue quantitatively. Evidence strongly favours the presence of a correlation between subjective embodiment and proprioceptive drift, supporting the model proposed by Botvinick and Cohen in 1998. However, the correlation is around.35, a value suggesting that the two indices capture different facets of the RHI. This result clarifies the association between the illusory effects produced by the RHI and may be helpful for designing studies having appropriate statistical power.

Introduction: Body illusions are designed to temporarily alter body representation by embodying fake bodies or part of them. Despite their large use, the embodiment questionnaires have been validated only for the embodiment of fake hands in the rubber hand illusion (RHI). Methods: With the current study, we aimed at (1) extending the validation of embodiment questionnaires to a different illusory situation e.g., the full-body illusion (FBI); (2) comparing two methods to explore the questionnaires structures: a classic exploratory factor analysis (EFA) and a modern exploratory graph analysis (EGA). 118 healthy participants completed an FBI procedure where the subjective experience of embodiment was measured with a standard questionnaire. Results: The EFA results in two-factor structures. However, the confirmatory factor analysis (CFA) fit indices do not show a good fit with the data. Conversely, the EGA identified four communities: ownership, agency, co-location and disembodiment; the solution was confirmed by a CFA. Conlcusions: Overall, the EGA seems to be the best fitting method for the present data. Our results confirm the EGA as a suitable substitute for a more classical EFA. Moreover, the emerged structure suggests that the FBI induces similar effects to the RHI, implying that the embodiment sensations are common to different illusory methods.

Objectives: A novel method of rehabilitation for ideomotor apraxia (IMA), using a modified version of the mirror box (MB), is proposed. The rationale is based on the theory that disrupted body representation occurs in IMA and that MB training may improve body representation. In the present MB training, patients observed and reproduced movements made by the experimenter in a mirror. The visual perspective gave the illusory sensation of seeing one's own affected hand in the mirror. Methods: Thirteen patients were included in the study; apraxia was measured four times: i) at baseline; ii) after a week of unspecific poststroke rehabilitation (rest); iii) after a week of imitation training for apraxia, used as a control; and iv) after a week of MB training. Imitation and mirror box training were presented in counterbalanced order between participants. The effect of the mirror box on a measure of body representation was also assessed. Results: The results show that MB training improved apraxia when compared to the outcomes in both the imitation and rest conditions. The improvement correlates with the impact of the mirror box on the body representation (i.e., the degree of embodiment). Conclusions: MB training shows promising effects in promoting recovery from apraxia. The hypothesis is that the mirror box triggers a quickly generated sense of embodiment of the reflected moving arm into the observer's body representation. This embodiment of the visuomotor features of the observed movements would positively affect motor programming, promoting motor improvement. Crucially, this effect seems to extend to actions performed outside the mirror box setup, enhancing patients' performance on an apraxia test.

Supplementing brain cholesterol is emerging as a potential treatment for Huntington's disease (HD), a genetic neurodegenerative disorder characterized, among other abnormalities, by inefficient brain cholesterol biosynthesis. However, delivering cholesterol to the brain is challenging due to the blood-brain barrier (BBB), which prevents it from reaching the striatum, especially, with therapeutically relevant doses. Here we describe the distribution, kinetics, release, and safety of novel hybrid polymeric nanoparticles made of PLGA and cholesterol which were modified with an heptapeptide (g7) for BBB transit (hybrid-g7-NPs-chol). We show that these NPs rapidly reach the brain and target neural cells. Moreover, deuterium-labeled cholesterol from hybrid-g7-NPs-chol is released in a controlled manner within the brain and accumulates over time, while being rapidly removed from peripheral tissues and plasma. We confirm that systemic and repeated injections of the new hybrid-g7-NPs-chol enhanced endogenous cholesterol biosynthesis, prevented cognitive decline, and ameliorated motor defects in HD animals, without any inflammatory reaction. In summary, this study provides insights about the benefits and safety of cholesterol delivery through advanced brain-permeable nanoparticles for HD treatment.