General cognitive ability in childhood has been linked to differences in brain structure and connectivity in numerous studies. However, longitudinal examinations of links between early cognitive ability and multimodal brain development are limited. Leveraging longitudinal data from 10,495 participants of the Adolescent Brain Cognitive Development study, we examined whether childhood cognitive ability was associated with differences in longitudinal development of gray and white matter structure and resting state functional connectivity (rsFC). Linear mixed-effects models tested associations between baseline cognition-matrix reasoning, fluid cognition, crystallized cognition-and trajectories of whole-brain and regional brain measures. Brain measures included cortical thickness, surface area, and volume, fractional anisotropy, mean diffusivity, and rsFC across four time points. Across modalities, higher baseline cognitive scores were associated with slower increases in measures that normatively increased over adolescence and faster decreases for those that were found to decline. Specifically, higher childhood fluid cognition was associated with faster contraction of gray matter area and volume, and higher matrix reasoning was related to slower increases in white matter fractional anisotropy. Meanwhile, lower values in all cognitive measures-early matrix reasoning, fluid cognition, and crystallized cognition-were associated with greater increases in between-network rsFC that were absent in those with higher baseline cognitive scores. Regionally, differences in gray matter structural trajectories by cognitive ability were most prominent in the frontal lobe, while effects for white matter and rsFC trajectories varied across distributed brain systems. Findings provide insight into theories of cognition and highlight possible neurobiological pathways linking early cognition to long-term outcomes.
Introduction: A vast body of cognitive research in psychosis has focused on auditory hallucinations, though more recent studies are turning towards other sensory modalities. This study aimed to compare the cognitive profile of persons experiencing uni- or multisensory versus multimodal hallucinations. Methods: Participants with primary diagnosis of a psychotic disorder were subdivided into those experiencing uni- or multisensory (UMS; n = 31) versus multimodal (MM; n = 28) hallucinations relative to non-clinical controls (NC; n = 32). Cognitive assessment comprised the MATRICS Consensus Cognitive Battery, supplemented by a Colour Word Interference Test. Analyses of variance (ANOVAs) and correlation analyses were performed. Results: The UMS and MM groups performed significantly worse than the NC group on some cognitive domains (i.e. speed of processing, attention/vigilance, working memory, verbal learning), but not others (i.e. reasoning and problem-solving, social cognition). For visual learning, the MM group performed significantly worse than the NC group only, whereas for inhibition, the UMS group performed significantly worse than the NC group only. Conclusion: A novel cognitive profile associated with multimodal hallucinations was documented. Dissociation between performance of the two clinical groups on visual learning and inhibition suggests these cognitive domains may be of relevance to hallucinations, pending further investigations.
Creatine monohydrate is one of the most widely used dietary supplements worldwide, and growing preclinical evidence suggests it may exert cognitive benefits beyond its established role in energy metabolism. However, the conditions under which these effects emerge, and the neurobiological mechanisms mediating them, remain incompletely characterised. A systematic review was conducted following PRISMA 2020 guidelines, searching Scopus, PubMed, and Web of Science for experimental studies published between 2015 and 2026. Studies were eligible if they evaluated the effects of creatine supplementation on cognitive performance in rodent models and reported behavioural and/or neurobiological outcomes. Risk of bias was assessed using SYRCLE's tool for animal studies. Nineteen studies were included, comprising experiments rodents across healthy animals and models of neurodegeneration, metabolic insult, perinatal stress, and creatine biosynthesis deficiency. Creatine improved learning and memory in the majority of studies. The magnitude of cognitive benefits was moderated by route of administration, with intranasal delivery showing superior brain uptake and cognitive effects relative to oral supplementation, treatment duration, and sex. Mechanistically, cognitive improvements were associated with enhanced mitochondrial respiratory capacity, upregulation of synaptic plasticity proteins (CaMKII, PSD-95, BDNF) via CaMKII/CREB and PI3K/AKT/mTOR signalling, attenuation of neuroinflammation through NF-κB suppression and STAT1 inhibition, and reduction of oxidative stress through CK-BB restoration. Preclinical evidence consistently supports a cognitive-enhancing role for creatine, mediated by a convergent set of energetic, synaptic, anti-inflammatory, and antioxidant mechanisms. Translating these findings to clinical applications will require brain-targeted delivery strategies, systematic consideration of sex as a biological variable, and mechanistically rigorous study designs.
Multiple Sclerosis (MS) is a common neuroinflammatory disorder in young adults. Disrupted neural connectivity due to demyelination and axonal degeneration contributes to cognitive impairment. The aim is to examine EEG functional connectivity (coherence and phase lag) in relapsing-remitting MS (RRMS) and explore its correlation with cognitive function. Thirty-five RRMS patients and 35 age- and sex-matched healthy controls (HC) were included. Neurological (Expanded Disability Status Scale), MRI, and cognitive (Paced Auditory Serial Addition Test) assessment were conducted, in addition to neurophysiological evaluation using quantitative EEG (coherence and phase lag) and P300 response. RRMS patients showed lower PASAT scores (30.2 ± 10 RRMS, 36.8 ± 9.6 HC (P = 0.024)) and significant disruption in resting-state EEG functional connectivity; lower coherence of alpha at inter-temporal (P = 0.001), inter-parietal (P = 0.005), and inter-temporal beta (P = 0.001). Phase lag of beta band was higher in patients at the left frontal-temporal (P = 0.002), left frontal-parietal (P = 0.007) and inter-temporal (P = 0.01) levels. This disruption correlated with disease severity markers. Phase lag alterations were linked to cognitive performance. (PASAT correlated with: left frontal-temporal beta phase lag (r = -0.626, P ≤ 0.001) and global theta phase lag (r = -0.398, P = 0.02) CONCLUSION: EEG functional connectivity measures provide valuable insights into cognitive impairment in RRMS. These findings are preliminary and require independent validation in future studies. Understanding the cognitive-connectivity inter-relation may help to tailor treatment and rehabilitation plans.
Obesity is associated with risk for chronic health problems and increased mortality. Weight stigma, which entails negative attitudes and behaviors directed at people based solely on their body size, is psychologically harmful and contributes to obesity and obesity-related health problems. Yet, weight stigma is pervasive in society and commonly experienced by patients in healthcare settings, which lowers the quality of patients' healthcare experiences. Healthcare providers and trainees report feeling underprepared to treat obesity, which may lead to overreliance on weight-management strategies that are not evidence-based and are susceptible to weight stigma, such as fad diets emphasizing unrealistic dietary restriction. In the current manuscript, we discuss current weight stigma interventions with other populations and the rationale for integrating training in evidence-based approaches to treat obesity with weight stigma interventions, specifically cognitive dissonance-based interventions. Current learning theories emphasize empathic perspective-taking, and current methods to reduce weight stigma use social-cognitive theories to raise awareness of stereotypes. However, current methods are insufficient because they create discomfort but fail to alter internalized bias nor advise providers on how to deliver non-stigmatizing, evidence-based obesity interventions. Cognitive dissonance theory posits that resolving tension between beliefs and behaviors will change future behaviors. Cognitive dissonance-based interventions have effectively reduced personal weight stigma and are promising to be similarly effective in reducing weight stigma among healthcare providers. In this manuscript, we highlight how cognitive dissonance theory can help improve interventions to reduce bias and support providers' efforts treating obesity.
There is a growing concern about the increasing number of young people who are not in employment, education or training (NEET) globally. This study investigates the impact of concurrent cognitive and socio-emotional development trajectories in childhood on NEET status in adolescence in a UK cohort. We analysed longitudinal data on 8368 children from the UK Millennium Cohort Study. Exposure trajectories of cognitive and socio-emotional development from age 3 to 14 years were characterised using group-based multi-trajectory models. We used Poisson regression to examine associations between developmental trajectories and NEET status at age 17, adjusting for confounders. Population-attributable fractions were estimated to quantify NEET proportions attributable to the developmental problems. At age 17, 3.5% of participants were NEET, of which about one-third (38%) were not economically active. Children with persistent cognitive and socio-emotional development problems had a fourfold increased risk of being NEET (adjusted risk ratio (ARR) 3.5; 95% CI 2.3 to 5.3), and those with late socio-emotional problems had a threefold increased risk (3.0; 95% CI 2.1 to 4.3), compared with children in the no problem group. Early and resolving socio-emotional and cognitive problems were not associated with being NEET. An estimated 28% (95% CI 18% to 36%) of NEET cases were attributable to cognitive and socio-emotional behaviour problems in childhood. Childhood cognitive and socio-emotional development plays a critical role in shaping pathways to education and employment in adolescence. Policies and strategies aiming to reduce NEET should target early social and emotional skills alongside efforts to support academic achievement.
Kalyanaka Ghrita (KG) is a classical Ayurvedic polyherbal formulation traditionally indicated for disorders of memory, intellect, and mental well-being. Ayurveda emphasizes individualized therapeutic decision-making, which the N-of-1 trial design aligns with conceptually and methodologically, enabling systematic evaluation of traditional formulations at the single-patient level, where inter-individual variability is central. To assess the efficacy and safety of Kalyanaka Ghrita in a patient diagnosed with Mild Cognitive Impairment (MCI) using an N-of-1 trial design. A quasi-randomized N-of-1 trial was conducted to evaluate the effects of KG in a patient with MCI. The study comprised six alternating treatment and no-treatment periods of two months each, spanning a total of 14 months. Cognitive outcomes were assessed using the Hindi Mental State Examination (HMSE) and the Clinical Dementia Rating (CDR) scales. Functional abilities were measured with the Instrumental Activities of Daily Living (IADL) scale, and affective status was evaluated using the Geriatric Depression Scale (GDS)- short form. Bayesian modeling estimated posterior probabilities and 95% highest posterior density intervals (HPDI) for treatment effects. KG administration improved overall cognitive abilities, as indicated by global HMSE scores (posterior probability >97%, 95% HPDI excluding zero), with the most substantial gains in orientation (posterior probability >98%) and recall (posterior probability >93%) domains. Reduction in CDR-Sum of Boxes scores indicated strong improvement (posterior probability >98%; 95% HPDI excluded zero). Benefits were consistent in orientation and community affairs, with moderate effects on memory and judgment/problem-solving. Functional outcomes assessed using IADLs showed a probable benefit (posterior probability >80%, HPDI overlapping zero). Depressive symptoms, as measured by the GDS, decreased markedly (posterior probability = 100%; 95% HPDI -2.23 to -0.80). All safety lab parameters remained within physiological limits, confirming good tolerability of KG. KG produced measurable improvements across cognitive, functional, and affective domains in a patient with MCI, suggesting a potential role in the management of early cognitive decline. The formulation was well tolerated. The study also demonstrates the feasibility of applying an N-of-1 trial within Ayurveda. Despite limitations such as the single-patient, quasi-randomized, open-label design and absence of biomarker testing, the findings offer preliminary support for both the therapeutic potential of KG in MCI and the methodological value of N-of-1 trials in Ayurvedic research.
Cognitive reappraisal involves reinterpreting negative content to reduce its negative impact. Recent findings suggest that cognitive reappraisal can attenuate the link between emotions and eating-related measures. The level of regulatory engagement during the use of cognitive reappraisal can be assessed by physiological markers such as pupil dilation. The present study examined whether trial-by-trial within-person variations in pupil diameter while implementing reappraisal can predict subsequent desire to eat. Forty-three healthy females completed a computerized task combining a standard reappraisal task with a food-rating task. Participants viewed negative or neutral non-food-related images and were instructed to observe them passively or reappraise their content. Each image was followed by a picture of a food item, and participants rated their desire to eat the depicted food. Observing negative images led to an immediate reduction in the desire to eat compared to viewing emotionally neutral images. Importantly, applying reappraisal reduced the impact of negative emotions on the desire to eat. Moreover, greater pupil dilation during reappraisal, but not during passive viewing of negative or neutral images, predicted higher subsequent desire to eat. These findings suggest that regulatory engagement plays a key role in shaping the relationship between emotions and the desire to eat. The study offers insights relevant to understanding disorders involving both dysregulated eating and difficulties applying cognitive reappraisal.
Diabetes-associated cognitive impairment (DACI) is a prevalent and debilitating complication of type 2 diabetes, yet the mechanisms linking metabolic dysregulation to neuroinflammation and cognitive decline remain incompletely understood. In this study, we identify astrocytic SCAP (SREBP cleavage-activating protein) as a crucial regulator of glial metabolic-inflammatory crosstalk in DACI. Using a high-fat diet-induced mouse model of diabetes, we demonstrate that astrocytic SCAP expression is significantly upregulated, whereas astrocyte-specific SCAP deletion alleviates cognitive deficits, reduces microglial activation, and attenuates lipid droplet accumulation in the hippocampus. Transcriptomic analysis of SCAP-deficient mice identified lipocalin-2 (LCN2) as a prominent downstream candidate associated with inflammatory regulation. Mechanistically, astrocytic SCAP promotes NF-κB-dependent LCN2 expression, leading to LCN2-dependent paracrine activation of microglial 24p3R-mTOR signaling and consequent microglial inflammatory activation and lipid droplet accumulation. Consistently, pharmacological inhibition of mTOR or antibody-mediated blockade of LCN2 in vivo significantly ameliorated hippocampal neuroinflammation, neuronal injury, and cognitive decline in diabetic mice. These findings reveal a novel SCAP-LCN2-24p3R-mTOR signaling axis that links astrocytic lipid sensing to microglial inflammatory and metabolic dysfunction, providing a mechanistic framework for metabolic-inflammatory coupling in DACI and highlighting this pathway as a potential therapeutic target for DACI.
People with HIV (PWH) exhibit persistent immune activation despite suppressive antiretroviral therapy, contributing to neurocognitive vulnerability. Marijuana use is common among PWH and may influence inflammatory pathways, but its in vivo immunologic effects in treated HIV remain unclear. In this cross-sectional study (Durham, NC; 2021-2023), 238 adults with and without HIV were grouped by chronic marijuana use. Soluble immune biomarkers were measured in plasma/serum, and log-transformed outcomes were analyzed using hierarchical multivariable regression. Seven biomarkers showed significant model fit: sCD163, IFN-γ, TNF-α, TNF-RII, CXCL10, CCL4, and VCAM-1. Among HIV-negative participants, marijuana use was linked to reduced CXCL10, suggesting disruption of IFN-γ-dependent chemotactic signaling. In contrast, HIV infection in the absence of marijuana use was associated with a broad, multi-pathway inflammatory profile, including TNF signaling, interferon activation, monocyte/macrophage activation, and endothelial recruitment. Among PWH, marijuana use did not modulate these effects, although CCL4 and VCAM-1 were not significantly elevated in this group compared to controls. However, these markers did not differ between marijuana-using and non-using PWH, suggesting a potential divergence from the broader inflammatory profile rather than a clear marijuana-associated attenuation. Cognitive analyses demonstrated a modest inverse association between memory performance and TNF-related markers, indicating that HIV-associated inflammatory signaling may relate to memory function, whereas marijuana-related cognitive effects require further study.
Brain health disorders (BHDs) remain a concern for people with HIV (PWH) despite antiretroviral therapy access and viral suppression. The contribution of HIV to brain health is often obscured by comorbidities in high-income settings which are less prevalent in sub-Saharan Africa. Neurofilament light chain (NfL), a biomarker of axonal injury, may offer insight into underlying mechanisms. 338 virally-suppressed PWH and 250 people without HIV (PWoH) completed a Research Domain Criteria-informed battery assessing cognitive, sensorimotor, and social processing systems. Demographically-adjusted norms were derived from PWoH. Serostatus differences in impairment (≥ 1SD below the mean) were examined using multivariable logistic regression. Additional models examined associations between NfL (plasma, cerebrospinal fluid [CSF]) and task performance. PWH were similar to PWoH in age (43.9 vs. 43.5yrs), sex (female, 54 vs. 46%), and education (6.1 vs. 5.8yrs). PWH had higher odds of impairment in the cognitive control and attention (Color Trails, Symbol Digit) and sensorimotor (Grooved Pegboard) domains. Plasma NfL was associated with sensorimotor impairment in both groups. Similar trends held in CSF NfL but did not reach statistical significance, likely due to sample size (n = 85). Cognitive and sensorimotor difficulties are common in PWH in Rakai, independent of typical Western confounders. The profile of impairment differs from reports in high-income settings where declarative memory deficits are often observed. NfL was associated with sensorimotor impairment, suggesting that NfL may capture ongoing axonal injury and motor system vulnerability in PWH and PWoH. These findings suggest NfL's potential as a biomarker of sensorimotor impairment in sub-Saharan Africa.
Subjective cognitive complaints are heterogeneous and may occur with normal, subtle, or objectively abnormal cognitive testing. Fluorodeoxyglucose (FDG) PET can help explore their metabolic substrate, particularly in subjective cognitive decline within the Alzheimer's disease continuum. In mild traumatic brain injury and long coronavirus disease (COVID), available studies suggest possible metabolic-network abnormalities but involve more heterogeneous populations and should be interpreted cautiously within multimodal, clinically characterized frameworks.
Selective isolation and analysis of brain-derived exosomes are essential for understanding and clinical management of neurodegeneration diseases. Herein, inspired by the unique lipidomic features of the central nervous system and lipid packing signature of exosomal membranes, we report a high-performance exosome capture platform, Exo-RTrap, developed through screening of the molecular interactions between an arginine-rich peptide (R9) and main lipids. Different from conventional view of nonspecific electrostatic association, we demonstrate highly selective and high-affinity binding of R9 toward phosphatidylserine (PS) over other anionic lipids, accompanied by spontaneous assembly into nanoscale vesicular complexes. Notably, R9 exhibits 370-fold stronger affinity for PS-containing liposomes than PS-free ones and recognizes membrane curvature in a PS-dependent manner, with sensitivity regulated by PS lateral density. Guided by these mechanistic insights, Exo-RTrap with dual-mode recognition coupling PS targeting with curvature responsiveness enabled rapid and selective isolation of exosomes from complex medium and biofluids, with purity and antifouling ability exceeding ultracentrifugation and precipitation methods. The capability of Exo-RTrap to selectively enrich disease-relevant neuronal exosomes was demonstrated by its accurate discrimination of serum samples from patients with Alzheimer's disease and mild cognitive impairment, whereas exosomes isolated by ultracentrifugation failed to achieve comparable performance. Moreover, integration with mass spectrometry-based proteomics further identified differentially expressed proteins as potential biomarkers for staging cognitive impairment. By defining the molecular rules governing R9-lipid interactions, this work presents a promising peptide-based exosome isolation platform for early detection and monitoring of neurodegenerative disorders.
Sandtray therapy is a non-pharmacological expressive intervention that enables individuals to communicate inner experiences through symbolic and metaphorical representation. Unlike traditional non-directive sandplay therapy, sandtray therapy is more structured and may include facilitator prompts. It has been associated with psychosocial benefits across diverse age groups experiencing psychological or behavioral challenges. This study examined the effects of sandtray therapy on cognition, mood, self-efficacy, life satisfaction, and gerotranscendence among community-dwelling older adults in Taiwan, and further explored participants' lived experiences. A mixed-methods design was employed. A total of 140 participants were randomly assigned to an intervention or control group. The intervention group attended weekly 30-40-minute sandtray sessions for four weeks, while the control group received no intervention. Outcomes were assessed pre- and post-intervention using the Mini-Mental State Examination (MMSE), Geriatric Depression Scale-Short Form (GDS-SF), General Self-Efficacy Scale (GSES), Satisfaction with Life Scale (SWLS), and Gerotranscendence Scale (GS). Semi-structured interviews were conducted following the intervention. A one-way analysis of covariance analyses revealed significant between-group differences in self-efficacy (p < .001), life satisfaction (p < .001), and gerotranscendence (p < .001). No significant effects were observed for cognitive function or depressive symptoms. Qualitative analysis identified three overarching themes: building social connectedness, the essential role of play in later life, and engagement in cognitively demanding processes. Sandtray therapy appeared feasible and well-tolerated within this study sample. The findings suggest that sandtray therapy may serve as a beneficial non-pharmacological intervention for promoting positive aging, particularly through improvements in self-efficacy, life satisfaction, and psychosocial growth among older adults.
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The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) play a pivotal role in neurotransmission and neuronal function. However, the effects of age and sex on AMPAR distribution in the living human brain and their associations with cognitive function remain unclear. The purpose of this study was to characterize age- and sex-dependent changes in brain AMPAR density and their relationships with cognitive performance in healthy individuals. Using a positron emission tomography tracer for AMPAR, [11C]K-2, we imaged 143 healthy participants aged 20-79 years. AMPAR density was evaluated using standard uptake value ratios with white matter as a reference. Age- and sex-related changes in AMPAR density were assessed across the brain, hierarchical clustering was used to characterize sex-dependent regional patterns of age-related change, and associations with cognitive performance were examined using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Age-dependent differences in cell-surface AMPAR density was observed across most brain regions. Females in their 50 s showed a surge in the upregulation of AMPAR density across brain. Hierarchical clustering revealed five distinct age-related trajectories, featuring marked sex-dependent regional patterns. AMPAR density was positively associated with cognitive performance; delayed memory correlated with whole-brain AMPAR density in both sexes, whereas other cognitive domains showed sex-specific regional associations. These findings demonstrated age- and sex-related alteration of AMPAR distribution and propose a model of AMPAR related synaptic aging in the living human brain over the life span. Furthermore, they may help to elucidate the pathophysiology of neurodegenerative disorders.
Although standard chelation therapy effectively controls copper load, many patients with Wilson's disease (WD) suffer from persistent, refractory residual neuropsychiatric symptoms. This study evaluated the real-world efficacy of a structured multimodal psychosocial rehabilitation program on neurological, cognitive, and functional outcomes in adult patients with WD. We retrospectively analyzed adults with neurologic or mixed-phenotype WD who retained symptoms despite ≥12 months of standard anti-copper therapy. The intervention group underwent an 8 to 12 weeks multimodal rehabilitation program (integrating fine motor, cognitive, and psychosocial training), while controls received standard care. We employed 1:1 propensity score matching (PSM) to rigorously control for confounders. The primary outcome was the Global Assessment Scale for Wilson's Disease (GAS for WD) Tier 2 score at 6 months. After PSM, 68 patients (34 per group) with well-balanced baseline characteristics were analyzed. Analysis of covariance (ANCOVA) revealed that rehabilitation significantly improved the primary outcome compared to controls (adjusted mean difference in GAS Tier 2: -3.90; 95% CI: -4.51 to -3.30; P < 0.001). The rehabilitation group also achieved significant gains in cognition (Montreal Cognitive Assessment difference: 2.15; P < 0.001) and activities of daily living (difference: 8.60; P < 0.001). Adjunctive multimodal psychosocial rehabilitation safely and significantly ameliorates residual neurological, cognitive, and functional deficits in adult WD patients. These findings support integrating non-pharmacological interventions into comprehensive WD management to maximize functional recovery.
Aerobic exercise is beneficial in managing Parkinson disease (PD), yet its potential remains less clear in early stages. This study investigates the impact of long-term aerobic exercise habits in individuals with early-stage PD compared with healthy controls. Cross-sectional study. To evaluate whether long-term exposure to moderate- to high-intensity exercise was associated with more favorable physical, cognitive, and patient-reported outcomes in early PD, by comparing "highly active" individuals (self-reported moderate- to high-intensity aerobic exercise ≥ twice weekly for >3 months) with "low-active" individuals (self-reported moderate- to high-intensity aerobic exercise ≤ twice weekly for >3 months) and healthy controls. University. Seventy low-active individuals with PD, 35 highly active individuals with PD, and 35 healthy controls were included. Not applicable. Assessments included Timed Up and Go Test, Six Spot Step Test, 6-Minute Walk Test, Mini Balance Evaluation Systems Test, Lower Extremity Muscle Peak Power, Aerobic Capacity, Physical Activity, Montreal Cognitive Assessment, Symbol Digit Modalities Test, Parkinson's Disease Questionnaire, Non-Motor Symptoms Questionnaire, Falls Efficacy Scale-International, European Quality of Life Questionnaire, Beck Depression Inventory-II, and Movement Disorders Society-sponsored revision of the Unified Parkinson's Disease Rating Scale. Highly active individuals with PD outperformed low-active individuals with PD (p < .05) in physical function outcomes, motor symptom severity, physical activity levels, and nonmotor symptoms, while showing comparable results to healthy controls across several tests covering physical and cognitive function and physical activity level. Low-active participants showed impairments in several physical function and activity outcomes relative to healthy controls (p < .05). Cognitive function outcomes were comparable across the PD groups, but healthy controls performed better in processing speed (p < .05). No significant differences were found between participant groups in quality of life or depressive symptoms. Regular engagement in moderate- to high-intensity aerobic exercise in early PD may preserve physical function, suggesting a potential role in limiting disease-related motor decline. These findings support the consideration of early, high-intensity aerobic exercise interventions as part of a comprehensive management strategy for PD.
Negative self-referential bias (NSB) is a hallmark of depression, yet its neural signature and link to relapse vulnerability remain unclear. We investigated whether NSB and its associated neural activity predict relapse and depressive symptoms following prophylactic psychotherapy. This is a two-year prospective neuroimaging study nested within a randomized controlled trial of Mindfulness-Based Cognitive Therapy and Cognitive Behavior Therapy with a Well-Being focus. Remitted depressed outpatients (N = 81) completed the Self-Referential Encoding Task during fMRI pre- and post-treatment and were followed bi-monthly. Study preregistration: https://osf.io/s4n8j. NSB predicted higher depressive symptoms (b = 0.10; 95% CI, 0.06 to 0.14; p ≤0.001) but not relapse. Greater NSB neural activity within frontal DMN and SN was associated with relapse status (DMN: b = 0.32; 95% CI, 0.09 to 0.55; SN: b = 0.36, 95% CI, 0.09 to 0.63), whereas DMN-SN connectivity was not. Static whole brain relapse biomarkers included elevated prefrontal activation and somatosensory deactivation. In non-relapsers, treatment-related attenuation of somatosensory deactivation predicted lower risk. Subgenual reactivity was the best prefrontal relapse indicator (Hazard Ratio = 1.84, 95% CI, 1.23 to 2.77), but somatosensory deactivation was the best overall relapse indicator (Hazard Ratio = 0.16; 95% CI, 0.05 to 0.52). Relapse vulnerability reflects not only heightened prefrontal negative self-processing but also insufficient recruitment of somatosensory systems supporting embodied self-experience, providing a more comprehensive model of depression relapse vulnerability. ClinicalTrials.gov Identifier: NCT01178424.
By 2050, two-thirds of people with dementia will live in low-and-middle-income countries (LMICs). However, multimodal prevention lifestyle interventions for people at risk are being developed predominantly in higher-income countries. We systematically reviewed randomised controlled trials (RCTs) evaluating non-pharmacological interventions in individuals with mild cognitive impairment and subjective cognitive decline in LMICs. We assessed quality using the Mixed Methods Assessment Tool, meta-analysed and synthesised evidence. We included 25 RCTs from six countries (most in China, n=17), involving 1304 participants. In the 15 studies with sufficient data to meta-analyse, we found significant positive effects on cognition favouring interventions (1.49 (standardised mean difference, 95% CI 1.06 to 1.93)). There was significant publication bias. We classified interventions into exercise, multidomain and arts/creative expression. Exercise (1.67, 95% CI 1.24 to 2.11, n=8) and multidomain (1.22, 95% CI 0.22 to 2.21, n=5) had replicated evidence of effectiveness. There was insufficient data to meta-analyse the arts/creative category. We propose greater consideration and investment in the development of interventions accounting for specific LMIC contexts from the outset, so they are acceptable and used by local services. CRD42023403908.