Virtual Reality Combined With Psychoeducation to Improve Emotional Well-Being in Informal Caregivers of Alzheimer's Disease Patients: Rationale and Study Design of a Randomized Controlled Trial.

OBJECTIVES: Care for community-dwelling people with dementia is frequently delegated to relatives, who find themselves in the role of informal caregivers with no practical management knowledge. This situation exposes caregivers to increased risk for emotional wellbeing. The current study aims to test whether the integration of the efficacy of an immersive virtual reality (VR) experience into an online psychoeducational program impacts caregiver empathy and therefore emotional wellbeing. METHODS: One-hundred informal caregivers of mild-to-moderate Alzheimer's disease (AD) patients will be enrolled and randomly assigned to (i) an online psychoeducational program (control arm); or (ii) an online psychoeducational program integrated with VR (experimental arm). VR will consist of 360-degree videos involving the caregivers to an immersive experience of dementia symptoms from the patient's perspective. Before, after the intervention and after 2 months, all participants will complete validated clinical scales for caregiver burden and anxiety (primary outcomes) and sense of competence and dispositional empathy (secondary outcomes). A subsample of 50 participants will also undergo MRI exam, including structural and functional (resting-state and task-functional MRI [fMRI]) sequences. The fMRI task paradigm will use emotional stimuli to evaluate the neural correlate of empathy, by stressing its cognitive and affective components. The main outcome will be the change in the clinical assessment; the secondary outcome will be the change in brain connectivity of networks subserving the empathic and emotional functioning. RESULTS: We expect that the psychoeducational program will decrease anxiety and stress, enabling caregivers to perceive themselves capable of managing AD patients at home, educating them on symptom handling and boosting their cognitive empathy. In the experimental intervention, the VR-based experience will act as an add-on to psychoeducation, leading to greater improvement in the assessed clinical dimensions. VR should, in fact, enable a deeper understanding of disease symptoms and improve caregivers' cognitive empathy. We expect that the experimental intervention will result in deeper comprehension of disease symptoms and further strengthen caregivers' cognitive empathy. At the neural level, we expect to observe increased activation in circuits subserving cognitive empathy and decreased activation in circuits underlying affective empathy. CONCLUSIONS: To the best of our knowledge, this will be the first randomized controlled trial assessing the effect of combining psychoeducational interventions with VR-based experience in caregivers, and assessing both clinical and imaging outcomes. TRIAL REGISTRATION: Registered in ClinicalTrials.gov (NCT05780476).

Citrus supplementation in subjective cognitive decline: results of a 36-week, randomized, placebo-controlled trial.

BACKGROUND: Developing interventions for older adults with subjective cognitive decline (SCD) has the potential to prevent dementia in this at-risk group. Preclinical models indicate that Citrus-derived phytochemicals could benefit cognition and inflammatory processes, but results from clinical trials are still preliminary. The aim of this study is to determine the effects of long-term supplementation with Citrus peel extract on cognitive performance and inflammation in individuals with SCD. METHODS: Eighty participants were randomly assigned to active treatment (400 mg of Citrus peel extract containing 3.0 mg of naringenin and 0.1 mg of auraptene) or placebo at 1:1 ratio for 36 weeks. The primary endpoint was the change in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score across the 36-week trial period. Other cognitive outcomes included tests and scales evaluating verbal memory, attention, executive and visuospatial functions, and memory concerns. The secondary endpoint was the change of interleukin-8 (IL-8) levels over the 36-week trial period in a subsample of 60 consecutive participants. An Intention-to-treat approach with generalized linear mixed models was used for data analysis. RESULTS: The RBANS total score showed significant improvement in both Citrus peel extract and placebo groups at 36 weeks (p for time < .001, d = 0.36, p time x treatment = .910). Significant time effects were also found in cognitive domains of short- and long-term verbal memory (p < .001) and scales of subjective memory (p < .01), with no significant time x treatment interaction. The largest effect sizes were observed in verbal memory in the placebo group (d = 0.69 in short-term, and d = 0.78 in long-term verbal memory). Increased IL-8 levels were found at 36-week follow-up in both Citrus peel extract and placebo groups (p for time = .010, d = 0.21, p time x treatment = .772). Adverse events were balanced between groups. CONCLUSIONS: In this randomized clinical trial, long-term Citrus peel extract supplementation did not show cognitive benefits over placebo in participants with SCD, possibly due to high placebo response. These findings might have specific implications for designing future nutraceutical trials in individuals experiencing SCD. TRIAL REGISTRATION: The trial has been registered at the United States National Library of Medicine at the National Institutes of Health Registry of Clinical Trials under the code NCT04744922 on February 9th, 2021 ( https://www. CLINICALTRIALS: gov/ct2/show/NCT04744922 ).

Cognitive, psychological, and physiological effects of a web-based mindfulness intervention in older adults during the COVID-19 pandemic: an open study.

BACKGROUND: The development of effective strategies to maintain good mental health of older adults is a public health priority. Mindfulness-based interventions have the potential to improve psychological well-being and cognitive functions of older adults, but little is known about the effect of such interventions when delivered through internet. During the COVID-19 pandemic we evaluated short- and long-term cognitive, psychological, and physiological effects of a mindfulness-based intervention (MBI) delivered via web-based videoconference in healthy older adults. METHODS: Fifty older adults participated in an 8-week MBI, which comprised structured 2-h weekly group sessions. A comprehensive evaluation encompassing cognitive (verbal memory, attention and processing speed, executive functions) and psychological assessments (depression and anxiety symptoms, mindfulness, worries, emotion regulation strategies, well-being, interoceptive awareness and sleep) was conducted. Additionally, electroencephalography (EEG) data were recorded before and after the MBI and at the 6-month follow-up (T6). Data were analyzed using an intention-to-treat approach, using linear mixed models adjusted for age. The effect size for time was computed as omega squared. RESULTS: We observed significant improvements from pre-MBI to post-MBI and at the T6 across several measures. These improvements were notable in the areas of verbal memory (California Verbal Learning Test, p ≤ .007), attention and executive functions (Trail Making Test A and BA, p < .050), interoceptive awareness (Multidimensional Assessment of Interoceptive Awareness, p = .0002 for self-regulation and p < .05 for noticing, body listening, and trusting dimensions), and rumination (Heidelberg Form for Emotion Regulation Strategies, p = .018). These changes were associated with low to medium effect size. Moreover, we observed significant changes in EEG patterns, with a decrease in alpha1 (p = .004) and an increase in alpha2 (p < .0001) from pre-MBI to T6. Notably, improvements in TMTBA and rumination were correlated with the decrease in alpha1 (p < .050), while improvements in TMTA were linked to the increase in alpha2 (p = .025). CONCLUSIONS: The results of our study show that a web-based MBI in older adults leads to improvements in cognitive and psychological measures, with associated modulations in specific brain rhythms. While these findings are promising, further controlled studies are required to validate these preliminary results. TRIAL REGISTRATION: The trial has been registered with the United States National Library of Medicine at the National Institutes of Health Registry of Clinical Trials under the code NCT05941143 on July 12, 2023.

Unsupervised [18F]Flortaucipir cutoffs for tau positivity and staging in Alzheimer's disease.

PURPOSE: Several [18F]Flortaucipir cutoffs have been proposed for tau PET positivity (T+) in Alzheimer's disease (AD), but none were data-driven. The aim of this study was to establish and validate unsupervised T+ cutoffs by applying Gaussian mixture models (GMM). METHODS: Amyloid negative (A-) cognitively normal (CN) and amyloid positive (A+) AD-related dementia (ADRD) subjects from ADNI (n=269) were included. ADNI (n=475) and Geneva Memory Clinic (GMC) cohorts (n=98) were used for validation. GMM-based cutoffs were extracted for the temporal meta-ROI, and validated against previously published cutoffs and visual rating. RESULTS: GMM-based cutoffs classified less subjects as T+, mainly in the A- CN (<3.4% vs >28.5%) and A+ CN (<14.5% vs >42.9%) groups and showed higher agreement with visual rating (ICC=0.91 vs ICC<0.62) than published cutoffs. CONCLUSION: We provided reliable data-driven [18F]Flortaucipir cutoffs for in vivo T+ detection in AD. These cutoffs might be useful to select participants in clinical and research studies.

Psychobiological effects of an eHealth psychoeducational intervention to informal caregivers of persons with dementia: a pilot study during the COVID-19 pandemic in Italy.

BACKGROUND: The workload associated with caring for a person with dementia (PwD) could negatively affect informal caregivers' physical and mental health. According to the recent literature, there is a need for studies testing the implementation of affordable and accessible interventions for improving caregivers' well-being. AIMS: This study aimed to explore the feasibility and effectiveness of an 8 week eHealth psychoeducation intervention held during the COVID-19 pandemic in Italy in reducing the psychological burden and neuroendocrine markers of stress in caregivers of PwD. METHODS: Forty-one informal caregivers of PwD completed the eHealth psychoeducation intervention. Self-reported (i.e., caregiver burden, anxiety symptoms, depressive symptoms, and caregiver self-efficacy) and cortisol measurements were collected before and after the intervention. RESULTS: Following the intervention, the caregivers' self-efficacy regarding the ability to respond to disruptive behaviours improved (t = - 2.817, p = 0.007), anxiety and burden levels decreased (state anxiety: t = 3.170, p = 0.003; trait anxiety: t = 2.327, p = 0.025; caregiver burden: t = 2.290, p = 0.027), while depressive symptoms and cortisol levels did not change significantly. Correlation analyses showed that the increase in self-efficacy was positively associated with the improvement of caregiver burden from pre- to post-intervention (r = 0.386, p = 0.014). The intervention had a low rate of dropout (n = 1, due to the patient's death) and high levels of appreciation. DISCUSSION: The positive evidence and participation rate support the feasibility and effectiveness of the proposed eHealth psychoeducational intervention to meet the need for knowledge of disease management and possibly reduce detrimental effects on caregivers' psychological well-being. CONCLUSION: Further placebo-controlled trials are needed to test the generalizability and specificity of our results.

Cognitive and biological effects of citrus phytochemicals in subjective cognitive decline: a 36-week, randomized, placebo-controlled trial.

BACKGROUND: Auraptene (AUR) and naringenin (NAR) are citrus-derived phytochemicals that influence several biological mechanisms associated with cognitive decline, including neuronal damage, oxidative stress and inflammation. Clinical evidence of the efficacy of a nutraceutical with the potential to enhance cognitive function in cohorts at risk of cognitive decline would be of great value from a preventive perspective. The primary aim of this study is to determine the cognitive effects of a 36-week treatment with citrus peel extract standardized in levels of AUR and NAR in older adults experiencing subjective cognitive decline (SCD). The secondary aim is to determine the effects of these phytochemicals on blood-based biomarkers indicative of neuronal damage, oxidative stress, and inflammation. METHODS: Eighty older persons with SCD will be recruited and randomly assigned to receive the active treatment (400 mg of citrus peel extract containing 0.1 mg of AUR and 3 mg of NAR) or the placebo at a 1:1 ratio for 36 weeks. The primary endpoint is a change in the Repeatable Battery for the Assessment of Neuropsychological Status score from baseline to weeks 18 and 36. Other cognitive outcomes will include changes in verbal and nonverbal memory, attention, executive and visuospatial functions. Blood samples will be collected from a consecutive subsample of 60 participants. The secondary endpoint is a change in interleukin-8 levels over the 36-week period. Other biological outcomes include changes in markers of neuronal damage, oxidative stress, and pro- and anti-inflammatory cytokines. CONCLUSION: This study will evaluate whether an intervention with citrus peel extract standardized in levels of AUR and NAR has cognitive and biological effects in older adults with SCD, facilitating the establishment of nutrition intervention in people at risk of cognitive decline. TRIAL REGISTRATION: The trial is registered with the United States National Library of Medicine at the National Institutes of Health Registry of Clinical Trials under the code NCT04744922 on February 9th, 2021 ( https://www. CLINICALTRIALS: gov/ct2/show/NCT04744922 ).

Amygdalar nuclei and hippocampal subfields on MRI: Test-retest reliability of automated volumetry across different MRI sites and vendors.

BACKGROUND: The amygdala and the hippocampus are two limbic structures that play a critical role in cognition and behavior, however their manual segmentation and that of their smaller nuclei/subfields in multicenter datasets is time consuming and difficult due to the low contrast of standard MRI. Here, we assessed the reliability of the automated segmentation of amygdalar nuclei and hippocampal subfields across sites and vendors using FreeSurfer in two independent cohorts of older and younger healthy adults. METHODS: Sixty-five healthy older (cohort 1) and 68 younger subjects (cohort 2), from the PharmaCog and CoRR consortia, underwent repeated 3D-T1 MRI (interval 1-90 days). Segmentation was performed using FreeSurfer v6.0. Reliability was assessed using volume reproducibility error (ε) and spatial overlapping coefficient (DICE) between test and retest session. RESULTS: Significant MRI site and vendor effects (p â€‹< â€‹.05) were found in a few subfields/nuclei for the ε, while extensive effects were found for the DICE score of most subfields/nuclei. Reliability was strongly influenced by volume, as ε correlated negatively and DICE correlated positively with volume size of structures (absolute value of Spearman's r correlations >0.43, p â€‹< â€‹1.39E-36). In particular, volumes larger than 200 â€‹mm3 (for amygdalar nuclei) and 300 â€‹mm3 (for hippocampal subfields, except for molecular layer) had the best test-retest reproducibility (ε â€‹< â€‹5% and DICE â€‹> â€‹0.80). CONCLUSION: Our results support the use of volumetric measures of larger amygdalar nuclei and hippocampal subfields in multisite MRI studies. These measures could be useful for disease tracking and assessment of efficacy in drug trials.

Evolutionary modifications in human brain connectivity associated with schizophrenia.

The genetic basis and human-specific character of schizophrenia has led to the hypothesis that human brain evolution may have played a role in the development of the disorder. We examined schizophrenia-related changes in brain connectivity in the context of evolutionary changes in human brain wiring by comparing in vivo neuroimaging data from humans and chimpanzees, one of our closest living evolutionary relatives and a species with which we share a very recent common ancestor. We contrasted the connectome layout between the chimpanzee and human brain and compared differences with the pattern of schizophrenia-related changes in brain connectivity as observed in patients. We show evidence of evolutionary modifications of human brain connectivity to significantly overlap with the cortical pattern of schizophrenia-related dysconnectivity (P < 0.001, permutation testing). We validated these effects in three additional, independent schizophrenia datasets. We further assessed the specificity of effects by examining brain dysconnectivity patterns in seven other psychiatric and neurological brain disorders (including, among others, major depressive disorder and obsessive-compulsive disorder, arguably characterized by behavioural symptoms that are less specific to humans), which showed no such associations with modifications of human brain connectivity. Comparisons of brain connectivity across humans, chimpanzee and macaques further suggest that features of connectivity that evolved in the human lineage showed the strongest association to the disorder, that is, brain circuits potentially related to human evolutionary specializations. Taken together, our findings suggest that human-specific features of connectome organization may be enriched for changes in brain connectivity related to schizophrenia. Modifications in human brain connectivity in service of higher order brain functions may have potentially also rendered the brain vulnerable to brain dysfunction.

Neurobiological and clinical effect of metacognitive interpersonal therapy vs structured clinical model: study protocol for a randomized controlled trial.

BACKGROUND: Borderline Personality Disorder (BPD) is a complex and debilitating disorder, characterized by deficits in metacognition and emotion dysregulation. The "gold standard" treatment for this disorder is psychotherapy with pharmacotherapy as an adjunctive treatment to target state symptoms. The present randomized clinical trial aims to assess the clinical and neurobiological changes following Metacognitive Interpersonal Therapy (MIT) compared with Structured Clinical Management (SCM) derived from specific recommendations in APA (American Psychiatric Association) guidelines for BPD. METHODS: The study design is a randomized parallel controlled clinical trial and will include 80 BPD outpatients, aged 18-45 enrolled at 2 recruitment centers. Primary outcome will be the clinical change in emotion regulation capacities assessed with the Difficulties in Emotion Regulation Scale (DERS). We will also investigated the effect of psychotherapy on metacognitive abilities and several clinical features such as BPD symptomatology, general psychopathology, depression, personal functioning, and trait dimensions (anger, impulsivity, alexithymia). We will evaluate changes in brain connectivity patterns and during the view of emotional pictures. A multidimensional assessment will be performed at the baseline, at 6, 12, 18 months. We will obtain structural and functional Magnetic Resonance Images (MRIs) in MIT-Treated BPD (N = 30) and SCM-treated BPD (N = 30) at baseline and after treatment, as well as in a group of 30 healthy and unrelated volunteers that will be scanned once for comparison. DISCUSSION: The present study could contribute to elucidate the neurobiological mechanisms underlying psychotherapy efficacy. The inclusion of a multidisciplinary study protocol will allow to study BPD considering different features that can affect the treatment response and their reciprocal relationships. TRIAL REGISTRATION: NCT02370316 . Registered 02/24/2015.

Non-Invasive Brain Stimulation in Dementia: A Complex Network Story.

Non-invasive brain stimulation (NIBS) is emerging as a promising rehabilitation tool for a number of neurodegenerative diseases. However, the therapeutic mechanisms of NIBS are not completely understood. In this review, we will summarize NIBS results in the context of brain imaging studies of functional connectivity and metabolites to gain insight into the possible mechanisms underlying recovery. We will briefly discuss how the clinical manifestations of common neurodegenerative disorders may be related with aberrant connectivity within large-scale neural networks. We will then focus on recent studies combining resting-state functional magnetic resonance imaging with NIBS to delineate how stimulation of different brain regions induce complex network modifications, both at the local and distal level. Moreover, we will review studies combining magnetic resonance spectroscopy and NIBS to investigate how microscale changes are related to modifications of large-scale networks. Finally, we will re-examine previous NIBS studies in dementia in light of this network perspective. A better understanding of NIBS impact on the functionality of large-scale brain networks may be useful to design beneficial treatments for neurodegenerative disorders.

The European DTI Study on Dementia - A multicenter DTI and MRI study on Alzheimer's disease and Mild Cognitive Impairment.

The European DTI Study on Dementia (EDSD) is a multicenter framework created to study the diagnostic accuracy and inter-site variability of DTI-derived markers in patients with manifest and prodromal Alzheimer's disease (AD). The dynamically growing database presently includes 493 DTI, 512 T1-weighted MRI, and 300 FLAIR scans from patients with AD dementia, patients with Mild Cognitive Impairment (MCI) and matched Healthy Controls, acquired on 13 different scanner platforms. The imaging data is publicly available, along with the subjects' demographic and clinical characterization. Detailed neuropsychological information, cerebrospinal fluid information on biomarkers and clinical follow-up diagnoses are included for a subset of subjects. This paper describes the rationale and structure of the EDSD, summarizes the available data, and explains how to gain access to the database. The EDSD is a useful database for researchers seeking to investigate the contribution of DTI to dementia diagnostics.

Brain networks stimulation in dementia: insights from functional imaging.

PURPOSE OF REVIEW: Noninvasive brain stimulation (NIBS) is increasingly used in the field of dementia as a therapeutic option; however, evidence of clinical efficacy is limited, and the mechanism of action remains unknown. This review summarizes how functional imaging could contribute to the design of targeted and effective NIBS interventions for dementia. RECENT FINDINGS: Resting-state functional magnetic resonance imaging (fMRI) has largely contributed to understanding brain dysfunction in dementia by identifying disease-specific networks. Resting-state fMRI might inform on a number of factors critical for the conduction of effective NIBS trials, such as definition of stimulation paradigms and choice of the stimulation target. In addition, fMRI may contribute to the understanding of the mechanisms of action of NIBS, and provide a tool to monitor treatment efficacy. SUMMARY: Functional imaging is a promising approach for the development of hypothesis-driven, targeted stimulation approaches in the field of dementia.

Do Beliefs about the Pathogenetic Role of Amyloid Affect the Interpretation of Amyloid PET in the Clinic.

BACKGROUND: Beliefs of dementia experts about the pathogenic role of amyloid in Alzheimer's disease (AD) may affect the use of amyloid positron emission tomography (PET). OBJECTIVE: To assess the role attributed to amyloid in AD pathogenesis by Italian dementia experts, and whether this modulates the impact of amyloid PET results in their diagnostic workup. METHODS: 22 dementia experts rated their beliefs about the pathogenic role of amyloid. Then, we asked them to rate the probability of change in diagnosis based on the result of amyloid PET for 7 case vignettes, depicting patients who initially received a diagnosis based on a comprehensive workup and later received amyloid PET results consistent or inconsistent with the clinical picture. RESULTS: 55% of the experts assigned a dominant role to amyloid, and 32% attributed a similar role to amyloid and tau in AD pathogenesis. The probability of change in diagnosis ranged from 17% (SD = 21.6) for cases with consistent to 51% (SD = 34) for cases with inconsistent PET versus clinical data. Diagnostic change was not biased by the clinicians' beliefs about AD pathogenesis. CONCLUSIONS: This work supports an unbiased interpretation of amyloid PET across different beliefs about the pathogenic role of amyloid, and a belief-independent reluctance to change diagnosis in cases where change is expected and recommended.

Training labels for hippocampal segmentation based on the EADC-ADNI harmonized hippocampal protocol.

BACKGROUND: The European Alzheimer's Disease Consortium and Alzheimer's Disease Neuroimaging Initiative (ADNI) Harmonized Protocol (HarP) is a Delphi definition of manual hippocampal segmentation from magnetic resonance imaging (MRI) that can be used as the standard of truth to train new tracers, and to validate automated segmentation algorithms. Training requires large and representative data sets of segmented hippocampi. This work aims to produce a set of HarP labels for the proper training and certification of tracers and algorithms. METHODS: Sixty-eight 1.5 T and 67 3 T volumetric structural ADNI scans from different subjects, balanced by age, medial temporal atrophy, and scanner manufacturer, were segmented by five qualified HarP tracers whose absolute interrater intraclass correlation coefficients were 0.953 and 0.975 (left and right). Labels were validated as HarP compliant through centralized quality check and correction. RESULTS: Hippocampal volumes (mm(3)) were as follows: controls: left = 3060 (standard deviation [SD], 502), right = 3120 (SD, 897); mild cognitive impairment (MCI): left = 2596 (SD, 447), right = 2686 (SD, 473); and Alzheimer's disease (AD): left = 2301 (SD, 492), right = 2445 (SD, 525). Volumes significantly correlated with atrophy severity at Scheltens' scale (Spearman's ρ = <-0.468, P = <.0005). Cerebrospinal fluid spaces (mm(3)) were as follows: controls: left = 23 (32), right = 25 (25); MCI: left = 15 (13), right = 22 (16); and AD: left = 11 (13), right = 20 (25). Five subjects (3.7%) presented with unusual anatomy. CONCLUSIONS: This work provides reference hippocampal labels for the training and certification of automated segmentation algorithms. The publicly released labels will allow the widespread implementation of the standard segmentation protocol.

Hippocampal atrophy in people with memory deficits: results from the population-based IPREA study.

BACKGROUND: Clinical studies have shown that hippocampal atrophy is present before dementia in people with memory deficits and can predict dementia development. The question remains whether this association holds in the general population. This is of interest for the possible use of hippocampal atrophy to screen population for preventive interventions. The aim of this study was to assess hippocampal volume and shape abnormalities in elderly adults with memory deficits in a cross-sectional population-based study. METHODS: We included individuals participating in the Italian Project on the Epidemiology of Alzheimer Disease (IPREA) study: 75 cognitively normal individuals (HC), 31 individuals with memory deficits (MEM), and 31 individuals with memory deficits not otherwise specified (MEMnos). Hippocampal volumes and shape were extracted through manual tracing and the growing and adaptive meshes (GAMEs) shape-modeling algorithm. We investigated between-group differences in hippocampal volume and shape, and correlations with memory deficits. RESULTS: In MEM participants, hippocampal volumes were significantly smaller than in HC and were mildly associated with worse memory scores. Memory-associated shape changes mapped to the anterior hippocampus. Shape-based analysis detected no significant difference between MEM and HC, while MEMnos showed shape changes in the posterior hippocampus compared with HC and MEM groups. CONCLUSIONS: These findings support the discriminant validity of hippocampal volumetry as a biomarker of memory impairment in the general population. The detection of shape changes in MEMnos but not in MEM participants suggests that shape-based biomarkers might lack sensitivity to detect Alzheimer's-like pathology in the general population.

Pattern of structural and functional brain abnormalities in asymptomatic granulin mutation carriers.

BACKGROUND: To investigate the patterns of brain atrophy, white matter (WM) tract changes, and functional connectivity (FC) abnormalities in asymptomatic granulin (GRN) mutation carriers. METHODS: Ten cognitively normal subjects (five mutation carriers, GRN+; years to estimated disease onset: 12±7; five mutation noncarriers, GRN-) underwent a clinical and imaging (structural, diffusion tensor, and resting-state functional magnetic resonance imaging) assessment. Brain atrophy was measured with cortical thickness analysis, WM abnormalities with tract-based spatial statistics, and FC with independent component analysis. RESULTS: GRN+ showed smaller cortical thickness than GRN- in the right orbitofrontal and precentral gyrus and left rostral middle frontal gyrus. WM tracts abnormalities were limited to increased axial diffusivity in the right cingulum, superior longitudinal fasciculus, and corticospinal tract. There were no differences in FC of resting-state networks. CONCLUSION: Brain atrophy and WM tract abnormalities in frontal-parietal circuits can be detected at least a decade before the estimated symptom onset in asymptomatic mutation carriers.

Virtual Reality-Based Psychoeducation for Dementia Caregivers: The Link between Caregivers' Characteristics and Their Sense of Presence.

In neuropsychology and clinical psychology, the efficacy of virtual reality (VR) experiences for knowledge acquisition and the potential for modifying conduct are well documented. Consequently, the scope of VR experiences for educational purposes has expanded in the health field in recent years. In this study, we sought to assess the effectiveness of ViveDe in a psychoeducational caregiver program. ViveDe is a VR application that presents users with possible daily life situations from the perspective of individuals with dementia. These situations can be experienced in immersive mode through 360° video. This research aimed to ascertain the associations between the sense of presence that can be achieved in VR and some users' psychological characteristics, such as distress and empathetic disposition. The study involved 36 informal caregivers of individuals with Alzheimer's disease. These participants were assessed using scales of anxiety and depression, perceived stress, empathy, and emotional regulation. They were asked to participate in a six-session psychoeducation program conducted online on dementia topics, in addition to experiencing the ViveDe application. The immersive VR sessions enabled the caregivers to directly experience the symptoms of dementia (e.g., spatial disorientation, agnosia, difficulty in problem-solving, and anomia) in everyday and social settings. The results indicated that although the experience in ViveDe (evaluated using the XRPS scale and five questions about emotional attunement) showed efficacy in producing a sense of first-person participation in the symptoms of dementia, further research is needed to confirm this. The structural equation model provided evidence that the characteristics of individuals who enjoy the VR experience play a determining role in the perceived sense of presence, which in turn affects the efficacy of the VR experience as a psychoeducational tool. Further research will be conducted to ascertain the potential role of these elements in conveying change in the caregivers of people with dementia. This will help us study the long-term effectiveness of a large-scale psychoeducation program in VR.

Microstructural alterations in the locus coeruleus-entorhinal cortex pathway in Alzheimer's disease and frontotemporal dementia.

INTRODUCTION: We investigated in vivo the microstructural integrity of the pathway connecting the locus coeruleus to the transentorhinal cortex (LC-TEC) in patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD). METHODS: Diffusion-weighted MRI scans were collected for 21 AD, 20 behavioral variants of FTD (bvFTD), and 20 controls. Fractional anisotropy (FA), mean, axial, and radial diffusivities (MD, AxD, RD) were computed in the LC-TEC pathway using a normative atlas. Atrophy was assessed using cortical thickness and correlated with microstructural measures. RESULTS: We found (i) higher RD in AD than controls; (ii) higher MD, RD, and AxD, and lower FA in bvFTD than controls and AD; and (iii) a negative association between LC-TEC MD, RD, and AxD, and entorhinal cortex (EC) thickness in bvFTD (all p < 0.050). DISCUSSION: LC-TEC microstructural alterations are more pronounced in bvFTD than AD, possibly reflecting neurodegeneration secondary to EC atrophy. Highlights: Microstructural integrity of LC-TEC pathway is understudied in AD and bvFTD.LC-TEC microstructural alterations are present in both AD and bvFTD.Greater LC-TEC microstructural alterations in bvFTD than AD.LC-TEC microstructural alterations in bvFTD are associated to EC neurodegeneration.

Heart rate variability and perinatal depressive symptoms: A scoping review protocol.

Objective: An emerging marker of depression in the perinatal period is represented by a reduction in the autonomic nervous system (ANS) activity, reflected by heart rate variability (HRV). This scoping review aims to map the association between HRV and depression during the perinatal period and to understand its potential clinical implications. Introduction: Previous evidence associated ANS dysfunction and depressive symptomatology in the general population. Few observational and intervention studies investigated how HRV could be related to both pre- and post-partum depressive symptoms. However, high heterogeneity in the study designs and methods has been reported. Therefore, this scoping review plans to combine all these findings to build a starting point for future research. Inclusion criteria: This scoping review will consider articles focusing on the association between HRV and depression in the peripartum and - when available - on the impact of interventions on HRV and how this correlates with changes in depressive symptoms. Studies will be included with no restrictions on participants' age, peripartum time points for the assessment, and HRV parameters collected. Methods: We will perform a systematic search using the Medline (PubMed), PsychInfo, and Web of Science (WoS) databases. Two authors will independently screen titles, abstracts, and then full-text articles that meet the inclusion criteria. The review will include only journal articles published in English, with no time limitations. Data will be extracted and presented in tables and/or graphical representations to summarise and describe the results. Extracted data will be reported in a comprehensive summary.

Effect of metacognitive interpersonal therapy on brain structural connectivity in borderline personality disorder: Results from the CLIMAMITHE randomized clinical trial.

BACKGROUND: Recently, we showed that Metacognitive Interpersonal Therapy (MIT) is effective in improving clinical symptoms in borderline personality disorder (BPD). Here, we investigated whether the effect of MIT on clinical features is associated to microstructural changes in brain circuits supporting core BPD symptoms. METHODS: Forty-seven BPD were randomized to MIT or structured clinical management, and underwent a clinical assessment and diffusion-weighted imaging before and after the intervention. Fractional anisotropy (FA), mean, radial, and axial diffusivities maps were computed using FSL toolbox. Microstructural changes were assessed (i) voxel-wise, with tract based spatial statistics (TBSS) and (ii) ROI-wise, in the triple network system (default mode, salience, and executive control networks). The effect of MIT on brain microstructure was assessed with paired tests using FSL PALM (voxel-wise), Linear Mixed-Effect Models or Generalized Linear Mixed Models (ROI-wise). Associations between microstructural and clinical changes were explored with linear regression (voxel-wise) and correlations (ROI-wise). RESULTS: The voxel-wise analysis showed that MIT was associated with increased FA in the bilateral thalamic radiation and left associative tracts (p < .050, family-wise error rate corrected). At network system level, MIT increased FA and both interventions reduced AD in the executive control network (p = .05, uncorrected). LIMITATIONS: The DTI metrics can't clarify the nature of axonal changes. CONCLUSIONS: Our results indicate that MIT modulates brain structural connectivity in circuits related to associative and executive control functions. These microstructural changes may denote activity-dependent plasticity, possibly representing a neurobiological mechanism underlying MIT effects. TRIAL REGISTRATION: ClinicalTrials.govNCT02370316 (https://clinicaltrials.gov/study/NCT02370316).