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AI-driven reclassification of multiple sclerosis progression.
Multiple sclerosis (MS) affects 2.9 million people. Traditional classification of MS into distinct subtypes poorly reflects its pathobiology and has limited value for prognosticating disease evolution and treatment response, thereby hampering drug discovery. Here we report a data-driven classification of MS disease evolution by analyzing a large clinical trial database (approximately 8,000 patients, 118,000 patient visits and more than 35,000 magnetic resonance imaging scans) using probabilistic machine learning. Four dimensions define MS disease states: physical disability, brain damage, relapse and subclinical disease activity. Early/mild/evolving (EME) MS and advanced MS represent two poles of a disease severity spectrum. Patients with EME MS show limited clinical impairment and minor brain damage. Transitions to advanced MS occur via brain damage accumulation through inflammatory states, with or without accompanying symptoms. Advanced MS is characterized by moderate to high disability levels, radiological disease burden and risk of disease progression independent of relapses, with little probability of returning to earlier MS states. We validated these results in an independent clinical trial database and a real-world cohort, totaling more than 4,000 patients with MS. Our findings support viewing MS as a disease continuum. We propose a streamlined disease classification to offer a unifying understanding of the disease, improve patient management and enhance drug discovery efficiency and precision.
Predicting Cognition and Affective Changes in Newly Diagnosed Parkinson’s Disease Through Longitudinal Data-Driven Clustering
Background: Although primarily characterised as a motor disorder, Parkinson’s Disease (PD) also presents with non-motor symptoms, including cognitive decline and affective dysfunction, which are major predictors of quality of life and mortality for individuals. However, factors associated with these non-motor symptom trajectories remain under-characterised. Purpose: This study aimed to investigate predictors of cognitive and affective function over a 5-year follow-up period using data from the Progressive Parkinson’s Marker Initiative. Results: Fuzzy C-means clustering analysis of year-5 cognitive and affective function scores showed two clusters. The second group (n = 96) were older and had worse cognition, affective, and motor functioning at year-5 follow-up compared to the first (n = 213). Predictors of cluster membership was assessed in n = 113 individuals for whom data on all variables of interest were available (cluster 1/2 = 79/34). Cluster membership at 5-year follow-up was significantly predicted by baseline cognitive and affective function, as well as decreased levels of CSF amyloid-beta and increased CSF concentrations of phosphorylated-tau at baseline. Alternative non-linear supervised machine learning model (support vector regressor) using the same predictors improved classification accuracy by 5%. Conclusion: Our analysis highlights that including established biomarkers of other neurocognitive disorders (namely, amyloid-beta and phosphorylated-tau) also has utility for predicting cognitive and affective trajectory in PD. This suggests that assessing a multi-modal panel of prognostic markers, beyond clinical symptom presentation alone, may have utility for informing prognosis of cognitive and affective outcomes in PD. This is significant, potentially allowing for the earlier development of personalised therapeutic interventions for those at highest risk of impairment within these non-motor domains.
TDP-43 pathology is associated with divergent protein profiles in ALS brain and spinal cord.
Neuronal and glial cytoplasmic inclusions positive for TAR DNA-binding protein 43 (TDP-43) are the defining pathological hallmark of 97% of amyotrophic lateral sclerosis (ALS) and 50% of frontotemporal dementia (FTD). The ALS-FTD clinicopathological spectrum variably involves cortical and spinal anterior horn cell pathology. The broader protein composition of these inclusions is of major importance to understanding pathogenesis, clinical heterogeneity and biomarker development. This study examined the proteome associated with TDP-43 inclusions in ALS, using mass spectrometry-based proteomic analysis of spinal cord and cerebral cortex from donors with phosphoTDP-43 positive ALS (n = 16), alpha-synuclein positive Parkinson's disease (PD, n = 8), phosphotau and beta-amyloid positive Alzheimer's disease (AD, n = 8) and age matched non-neurological controls (n = 8), comparing ALS with non-ALS conditions, spinal cord with cerebral cortex samples, and detergent-soluble with -insoluble fractions. Increased abundance of TDP-43 in the detergent-insoluble fraction of ALS cortex and spinal cord tissue confirmed disease-specific protein enrichment by serial fractionation. The most striking alterations between ALS and other conditions were found in the detergent-insoluble fraction of spinal cord, with predominant enrichment of endosomal and extracellular vesicle pathways. In the cortex mitochondrial membrane/envelope and ion transmembrane transport pathways were enriched in the detergent-insoluble fraction. RNA/DNA metabolic processes (in spinal cord) versus mitochondrial and synaptic protein pathways (in cortex) were upregulated in the detergent-soluble fraction of ALS cases and downregulated in the insoluble protein fraction. Whilst motor cortex and spinal cord may not optimally reflect disease-specific pathways in AD, in PD a significant enrichment of alpha-synuclein in the detergent-insoluble fraction of spinal cord was found. Among proteins concordantly elevated in the detergent-insoluble fractions of spinal cord and cortex, there was greater representation of proteins encoded by ALS-associated genes, specifically Cu/Zn superoxide dismutase 1, valosin containing protein and TDP-43 (odds ratio 16.34, p = 0.002). No significant increase in TDP-43 interacting proteins was observed in either detergent-soluble or -insoluble fractions. Together, this study shows a divergence in the composition of proteins associated with TDP-43 positive detergent-insoluble inclusions between spinal cord and cerebral cortex. A common upregulation of proteins encoded by ALS-causing genes implicates their role in the pathogenesis of the ALS-FTD spectrum of diseases beyond TDP-43. Data are available via ProteomeXchange with identifier PXD067060.
Design considerations for C9orf72 disease prevention trials
Abstract The idea that it might be possible to prevent some forms of amyotrophic lateral sclerosis and frontotemporal dementia has finally come of age. The hexanucleotide repeat expansion in the C9orf72 gene accounts for ∼10% of all amyotrophic lateral sclerosis and 10-15% of all frontotemporal dementia diagnoses, with the two clinical syndromes co-manifesting in a significant number of patients. As a result, clinically unaffected carriers of pathogenic C9orf72 repeat expansions are currently the largest identifiable population at significantly elevated risk for both amyotrophic lateral sclerosis and frontotemporal dementia, and in whom it might be possible to prevent the emergence of clinically manifest disease. Strategies for the design of disease prevention trials among clinically unaffected C9orf72 carriers have begun to emerge separately in the amyotrophic lateral sclerosis and frontotemporal dementia fields. However, recognition of the need to define neurodegenerative diseases based on biology underscores the need to consider all potential clinical manifestations of a C9orf72 repeat expansion together, rather than the traditional siloed approach of focusing on only amyotrophic lateral sclerosis or only frontotemporal dementia. Indeed, emerging clinical and biological markers that might be used to quantify pre-symptomatic disease progression and to predict the short-term risk of phenoconversion to clinically manifest disease are shared across the phenotypic spectrum. Given the anticipated progress in the development of therapeutic strategies to target the C9orf72 repeat expansion, and the enthusiasm for prevention trials among the unaffected C9orf72 repeat expansion carrier population, now is the time to begin work on the design of disease prevention trials. To this end, The Association for Frontotemporal Degeneration and the ALS Association supported a multi-stakeholder workshop (in Washington D.C., June 2024) to unify efforts to design a prevention trial for the population at elevated genetic risk for the phenotypic spectrum of C9orf72 disease. Here we describe recommendations emanating from this Workshop for the selection of outcome measures, delineation of eligibility criteria, optimal use of biomarkers and digital health technologies, potential analytic frameworks, and relevant regulatory considerations related to C9orf72 disease prevention trials. We also emphasize the importance of the amyotrophic lateral sclerosis and frontotemporal dementia communities working together in partnership with the C9orf72 repeat expansion carrier community, the regulatory authorities, and the broader drug development community.
Brain signatures of nociplastic pain: Fibromyalgia Index and descending modulation at population level.
Nociplastic pain is defined by altered nociceptive processing in the absence of clear peripheral damage or somatosensory lesions. The Fibromyalgia Index (FMI), derived from the 2016 diagnostic criteria, is increasingly used as a marker of nociplastic pain severity in clinical studies, yet its neurobiological validity remains untested at scale. Using multimodal neuroimaging data from over 40,000 participants in UK Biobank, we examined whether FMI scores were associated with altered functional and structural connectivity within the descending pain modulatory system (DPMS), a brain network involved in endogenous pain control and implicated in nociplastic pain conditions. Functional connectivity was assessed using resting-state functional MRI (rfMRI), and structural connectivity using diffusion-weighted MRI (dMRI) tractography. Connectivity was quantified between seven DPMS regions: periaqueductal grey (PAG), rostral ventromedial medulla (RVM), hypothalamus, amygdala, rostral and subgenual anterior cingulate cortex (rACC, sgACC), and dorsolateral prefrontal cortex (dlPFC). Multi-group structural equation models (SEMs) tested associations between FMI scores and connectivity, stratified by chronic pain status. Mediation models evaluated which aspects of nociplastic pain accounted for the observed associations: widespread pain and SPACE symptoms (Sleep disturbance, Pain, Affect, Cognitive problems, and low Energy). To assess specificity, we repeated analyses using the Douleur Neuropathique 4 (DN4), a measure of neuropathic pain, and average pain intensity as comparison outcomes. In 22,139 individuals with chronic pain (58% female; mean age 64.8, SD 7.59) FMI scores were associated with altered structural connectivity between the PAG and amygdala (β=0.023, 95%CI: 0.0087 to 0.039; Pcorr=0.0125) and between the PAG and hypothalamus (β= -0.029, 95%CI: -0.043 to -0.015; Pcorr =0.0013). Functional connectivity in the same circuits showed smaller effects. These associations were not observed in individuals without chronic pain. Mediation analyses revealed that PAG-amygdala and PAG-hypothalamus connectivity were partially explained by fatigue, sleep duration, and widespread pain. DPMS connectivity was not significantly associated with neuropathic pain or average pain intensity. These findings suggest that FMI scores reflect biologically meaningful changes in brain connectivity, particularly in subcortical DPMS circuits implicated in affective and homeostatic dimensions of pain. Structural connectivity was more strongly associated with FMI than functional measures, possibly reflecting cumulative effects of chronic pain on white matter architecture. The absence of similar associations for other pain outcomes supports the specificity of FMI as a marker of nociplastic pain severity. These results provide a neurobiological basis for the FMI and support its use in population research and biomarker development for nociplastic pain.
A cross-species analysis of neuroanatomical covariance sex differences in humans and mice.
BACKGROUND: Structural covariance within the brain is thought to reflect inter-regional sharing of developmental influences. This hypothesis has proved difficult to test but can be informatively probed by the study of sex differences. Here, we use neuroimaging in humans and mice to study sex-differences in anatomical covariance- asking (1) are there sex differences in structural covariance and (2) do regions that share the same developmental influences, as exhibited by shared sex differences in volume, also show shared sex differences in volume covariance. This study design illuminates both the biology of sex-differences and theoretical models for anatomical covariance- benefitting from tests of inter-species convergence. METHODS: Brain volume correlations for males and females across 255 regions in mice (n = 423) and 378 regions in humans (n = 436) were calculated using volumetric measures obtained from structural MRI. Mean correlations for each sex were compared within species to determine whether covariance sex differences exist. Specific covariances with strong sex differences in each species were identified via permutation tests for statistical significance. Brain maps of regional average structural covariance sex-bias were generated for mice and humans. Regional average structural covariance sex-bias and volumetric sex-bias were correlated to identify whether these features align in their direction of sex-bias. RESULTS: We find that volumetric structural covariance is stronger in adult females than males for both wild-type mice and healthy human subjects: 98% of comparisons with statistically significant covariance sex differences in mice are female-biased, while 76% of such comparisons are female-biased in humans (q
Quadriceps Strength and Temporal Preparation in Elderly Adults: The Mediating Role of Beta Oscillation.
This study investigated the relationship between lower limb muscle strength and temporal preparation in older adults using an electroencephalogram to assess neural oscillations during cognitive processes. Forty older adults were divided into higher (HSG, 70.40 ± 5.15 years) and lower muscle strength (LSG, 71.43 ± 4.86 years) groups based on quadriceps strength estimated via a manual muscle test. Functional mobility was assessed using the Timed Up and Go (TUG) test, while temporal preparation was evaluated using a choice response time (RT) task with randomly varying foreperiods (FPs) that required lower limb motor responses. The HSG outperformed the LSG on both the TUG test (HSG: 6.07 ± 1.14 vs. LSG: 6.79 ± 0.88, p = 0.031) and the cognitive task (HSG: 462.97 ± 51.06 ms vs. LSG: 525.86 ± 73.69 ms, p = 0.002), despite no clear FP effect in either group. Additionally, the HSG demonstrated a more pronounced modulation of oscillatory beta power during the late phase of longer FP trials (qs
Exploring the influence of a 4-week aerobic exercise intervention on cognitive control processes in young adults: An SFT and DDM study
Prior research has highlighted the potential impact of aerobic exercise on cognitive functioning, particularly in situations demanding heightened cognitive control. However, the mechanism underlying this cognitive enhancement has remained unknown. To address this issue, this study examined the impact of a 4-week aerobic exercise program on cognitive control processes in young male adults (aerobic exercise group: n = 36, aged 21.42 ± 1.13 years) in comparison to a control group that received no treatment (n = 33, aged 21.82 ± 1.76 years). We employed the redundant-target Stroop task to investigate inhibition processes at both perceptual and semantic stages. Utilizing systems factorial technology and the drift diffusion model, we assessed changes in resilience capacity and the underlying cognitive mechanisms. Our primary findings revealed a significant reduction in mean response times (RTs) in the aerobic exercise group, accompanied by a decrease in RT variability when inhibiting semantic processing. Resilience capacity significantly declined in both groups at similar levels. Notably, the aerobic exercise group exhibited an enhanced drift rate during automatic response inhibition and reduced non-decision time in the condition involving the inhibition of perceptual information. This study deepens our understanding of how a 4-week aerobic exercise program enhances cognitive control, affecting distinct cognitive processes, including processing speed, information accumulation during automatic response inhibition, and sensory and motor processes in perceptual conflicts. Our research underscores the potential of aerobic exercise as a means to boost cognitive control among young adults.
Application of Brain-Computer Interface and Virtual Reality in Advancing Cultural Experience
Virtual reality (VR), a computer-generated interactive environment, is provided to a user by projecting a peripheral image onto environmental surfaces. VR has an advantage of enhancing the immersive experience. Nowadays, VR has been widely applied in tourism and cultural experience. On the other hand, a recent integration of electroencephalography-based (EEG-based) brain-computer interface (BCI) and VR is capable of promoting the immersive virtual experience. Therefore, our study aims to propose an integrative framework to implement EEG-based BCI in a VR game to advance the cultural experience. A room escape game in a Tainan temple is created. EEG signals arc recorded while users arc playing the game. The online analyses of EEG signals arc used to interact with the VR display. This integrative framework can result in a better experience than the conventional setup.
Layer-specific changes in sensory cortex across the lifespan in mice and humans.
The segregation of processes into cortical layers is a convergent feature in animal evolution. However, how changes in the cortical layer architecture interact with sensory system function and dysfunction remains unclear. Here we conducted functional and structural layer-specific in vivo 7T magnetic resonance imaging of the primary somatosensory cortex in two cohorts of healthy younger and older adults. Input layer IV is enlarged and more myelinated in older adults and is associated with extended sensory input signals. Age-related cortical thinning is driven by deep layers and accompanied by increased myelination, but there is no clear evidence for reduced inhibition. Calcium imaging and histology in younger and older mice revealed increased sensory-evoked neuronal activity accompanied by increased parvalbumin expression as a potential inhibitory balance, with dynamic changes in layer-specific myelination across age groups. Using multimodal imaging, we demonstrate that middle and deep layers show specific sensitivity to aging across species.
Is noxious stimulus-evoked electroencephalography response a reliable, valid, and interpretable outcome measure to assess analgesic efficacy in neonates? A systematic review and individual participant data (IPD) meta-analysis protocol.
BACKGROUND: There are several major challenges limiting our ability to test analgesic efficacy for treatment of neonatal pain, and progress in analgesic drug studies in neonates has stalled. One significant issue is the reliance of clinical pain assessments on traditional behavioural and vital signs-based measures and the exclusion of novel brain-based biomarkers. In this review protocol, we outline our strategy to assess the reliability, validity, and interpretability of an electroencephalography (EEG)-based response biomarker for assessment of acute somatic nociceptive pain in neonates. METHODS: To standardise EEG analysis and generate the outcome of interest, we will perform an individual participant data (IPD) meta-analysis using data from neonates aged 34-44-week postmenstrual age that have had EEG recorded during acute somatic nociceptive skin-breaking procedures. Relevant data from both published and grey literature will be identified by searching six databases (MEDLINE, Embase, CINAHL, Web of Science, Scopus, Google Scholar), two clinical trial registry platforms (ClinicalTrials.gov, WHO ICTRP), and by consulting expert opinion. We will assess availability bias, data accuracy, and data quality by cross-referencing provided data with data descriptions in the literature, identifying duplicates and nonsensical values, and extracting quality control metrics. Data will be synthesised via a two-stage IPD meta-analysis using a random effects modelling approach grouped by site. Reliability (inter- and intra-rater) outcomes will be measured as Gwet's AC1 coefficient. Validity (known-groups and known-stimuli) outcomes will be measured as EEG response magnitude differences between clinically meaningfully different stimuli. Interpretability will be addressed by providing normative values, in both original and standardised units. DISCUSSION: The purpose of this study is to establish the reliability, validity, and interpretability of a specific EEG-based response biomarker for assessing acute somatic nociceptive pain in neonates. It will provide an overview of available data and how EEG is being used globally to assess acute neonatal pain. If sufficient IPD are made available and the outcome is reliable, valid, and interpretable, this work will support the use of EEG-based outcome measures as primary endpoints in clinical trials assessing analgesic efficacy in neonates. SYSTEMATIC REVIEW REGISTRATION: The protocol was registered with PROSPERO on 14 July 2023: CRD42023444809.
Characterising ongoing brain aging and baseline effects from cross-sectional data
“Brain age delta” is the difference between age estimated from brain imaging data and actual age. Positive delta in adults is normally interpreted as implying that an individual is aging (or has aged) faster than the population norm, an indicator of unhealthy aging. Unfortunately, from cross-sectional (single timepoint) imaging data, it is impossible to know whether a single individual’s positive delta reflects a state of faster ongoing aging, or an unvarying trait (in other words, a “historical baseline effect” in the context of the population being studied). However, for a cross-sectional dataset comprising many individuals, one could attempt to disambiguate varying aging rates from fixed baseline effects. We present a method for doing this, and show that for the common approach of estimating a single delta per subject, baseline effects are likely to dominate. If instead one estimates multiple biologically distinct modes of brain aging, we find that some modes do reflect aging rates varying strongly across subjects. We demonstrate this, and verify our modelling, using longitudinal (two timepoint) data from 4,400 participants in UK Biobank. In addition, whereas previous work found incompatibility between cross-sectional and longitudinal brain aging, we show that careful data processing does show consistency between cross-sectional and longitudinal results.
The effects of lacosamide, pregabalin, and tapentadol on peripheral nerve excitability: A randomized, double-blind, placebo-controlled, crossover, multi-center trial in healthy subjects.
BACKGROUND: Chronic pain is a leading cause of disability globally, with limited treatment options and frequent adverse effects. The IMI-PainCare-BioPain project aimed to enhance analgesic drug development by standardizing biomarkers. This study, IMI2-PainCare-BioPain-RCT1, evaluated the effects of lacosamide, pregabalin, and tapentadol on peripheral nerve excitability in healthy subjects through a randomized, double-blind, placebo-controlled crossover trial. METHODS: The study included 43 healthy participants aged 18-45 years. Participants underwent four treatment periods where they received single doses of lacosamide (200 mg), pregabalin (150 mg), tapentadol (100 mg), or placebo. High-frequency stimulation was applied to induce hyperalgesia. The two primary endpoints were changes in Strength Duration Time Constant (SDTC) in large sensory and motor fibers between lacosamide and placebo periods at the first post-dose timepoint compared to baseline (60 min). Other predefined endpoints included recovery cycle, threshold electrotonus (TEd), and S2 accommodation as well as effects of pregabalin and tapentadol. RESULTS: Lacosamide statistically significantly reduced SDTC in large sensory fibers (mean reduction 0.04 (95% CI 0.01-0.08), p = 0.012) and in motor fibers (mean reduction 0.04 (95% CI 0.00-0.07), p = 0.039) but had no effect on small sensory fibers at the first timepoint compared to placebo. There were no effects of pregabalin and tapentadol on SDTC. Of other predefined endpoints, lacosamide produced statistically significant changes in subexcitability, S2 accommodation TEd(peak), and TEd40(Accom) in large sensory fibers. No statistically significant changes were observed in refractoriness, relative refractory period, or accommodation half-time at the first timepoint compared to placebo. CONCLUSIONS: This study demonstrates that nerve excitability testing can detect pharmacodynamic effects on large myelinated fibers in healthy subjects. Lacosamide statistically significantly reduced peripheral nerve excitability, particularly in large sensory fibers.
The lifetime accumulation of multimorbidity and its influence on dementia risk: a UK Biobank study.
The number of people living with dementia worldwide is projected to reach 150 million by 2050, making prevention a crucial priority for health services. The co-occurrence of two or more chronic health conditions, termed multimorbidity, occurs in up to 80% of dementia patients, making multimorbidity an important risk factor for dementia. However, we lack an understanding of the specific health conditions, and their age of onset, that drive the link between multimorbidity and dementia. Using data from 282 712 participants of the UK Biobank, we defined the sequential patterns of accumulation of 46 chronic conditions over the life course. By grouping individuals based on their life history of chronic illness, we show here that the risk of incident dementia can be stratified by both the type and timing of their accumulated chronic conditions. We identified several distinct clusters of multimorbidity throughout the lifespan (cardiometabolic, mental health, neurovascular, peripheral vascular, eye diseases and low/no multimorbidity). We observed that the odds of developing dementia varied based on when these comorbidities were diagnosed. Until midlife (age 55), the accumulation of cardiometabolic conditions, such as coronary heart disease, atrial fibrillation, and diabetes, was most strongly associated with dementia risk. However, from 55 to 70 years, the accumulation of mental health conditions, such as anxiety and depression, as well as neurovascular conditions, such as stroke and transient ischaemic attack, was associated with an over 2-fold increase in dementia risk compared with low multimorbidity. Importantly, individuals who continuously and sequentially accumulate cardiometabolic, mental health, and neurovascular conditions were at greatest risk. The age-dependent role of multimorbidity in predicting dementia risk could be used for early stratification of individuals into high- and low-risk groups and could inform targeted prevention strategies based on a person's prior history of chronic disease.
The mouse motor system contains multiple premotor areas and partially follows human organizational principles.
While humans are known to have several premotor cortical areas, secondary motor cortex (M2) is often considered to be the only higher-order motor area of the mouse brain and is thought to combine properties of various human premotor cortices. Here, we show that axonal tracer, functional connectivity, myelin mapping, gene expression, and optogenetics data contradict this notion. Our analyses reveal three premotor areas in the mouse, anterior-lateral motor cortex (ALM), anterior-lateral M2 (aM2), and posterior-medial M2 (pM2), with distinct structural, functional, and behavioral properties. By using the same techniques across mice and humans, we show that ALM has strikingly similar functional and microstructural properties to human anterior ventral premotor areas and that aM2 and pM2 amalgamate properties of human pre-SMA and cingulate cortex. These results provide evidence for the existence of multiple premotor areas in the mouse and chart a comparative map between the motor systems of humans and mice.
Incidental Encoding of Objects during Search Is Stronger Than Intentional Memorization due to Increased Recollection Rather Than Familiarity
Abstract Most memory is not formed deliberately but as a by-product of natural behavior. These incidental representations, when generated during visual search, can be stronger than intentionally memorized content (search superiority effect). However, it is unknown if the search superiority effect is purely quantitative (stronger memory) or also driven by differences in the degree of recollection and familiarity, two hallmark processes supporting recognition memory. Here, we use signal detection modeling, introspective judgments, event-related EEG potentials, and eye tracking measures to answer this question. In a preregistered study, 30 participants searched for objects in scenes and intentionally memorized others before completing a surprise recognition memory test. Behavioral data from remember–know judgments and receiver operating characteristics indicate that search targets were more often recollected compared with intentionally memorized objects, whereas the two tasks did not lead to differences in familiarity. Surprisingly, the neural signatures did not fully align with the behavioral findings regarding recollection and familiarity. That is, both search targets and intentionally memorized objects elicited a more positive-going mid-frontal negativity peaking at around 400 msec post stimulus onset (FN400), which is associated with familiarity, as well as a more positive-going parietal late component (LPC), indicative of recollection. Both components showed no differences between tasks, indicating equal contributions of recollection and familiarity to remembering searched and memorized objects. Furthermore, the LPC was, as expected, sensitive to differences between recollected and familiar objects when these were intentionally memorized, but it was not affected by these differences for searched objects. Overall, our findings indicate that search superiority relies predominantly on increased recollection. The fact that established neural markers of recollection (LPC) behaved as anticipated for intentionally memorized objects but carried no predictive power for incidentally memorized objects implies that memories established in more ecologically valid tasks might involve neural processes different from those activated in commonly used settings that are more reductionist.
Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
CTNNB1 neurodevelopmental syndrome is a rare disorder caused by de novo heterozygous variants in the CTNNB1 gene encoding β-catenin. This study aims to characterize genetic variants in individuals with CTNNB1 neurodevelopmental syndrome, systematically assess the spectrum of clinical phenotypes using standardized measures and explore potential genotype-phenotype correlations. In this cross-sectional cohort study, individuals diagnosed with CTNNB1 neurodevelopmental syndrome underwent structured interviews using standardized scales to evaluate motor skills, speech, communication, feeding abilities, visual function, neurodevelopment, and psychopathology. Genetic variants were analyzed, and in a subset of cases, the impact of β-catenin variants on the Wnt/β-catenin signaling pathway was assessed. Across the 127 included participants (mean age: 70 months; range: 7-242 months) from 20 countries, we identified 88 different variants of the CTNNB1 gene, 87 of which were predicted to lead to loss of CTNNB1 function. Functional assays demonstrated reduced Wnt signaling activity, including 11 variants that also exhibited a dominant-negative effect. One missense variant demonstrated a gain-of-function effect. Dominant-negative variants were not clearly associated with a distinct phenotype, however, those with missense variants presented a milder phenotype, including earlier achievement of independent walking, fewer motor impairments, better conceptual and social skills, improved communication, and fewer feeding difficulties. This study describes genetic, functional, and phenotypic characteristics in individuals with CTNNB1 neurodevelopmental syndrome. Further investigation into the genotypic and phenotypic characteristics of this syndrome and their interrelationships is essential to deepen our understanding of the disorder and inform the development of targeted therapies.