Brain Markers Research Articles

Multimodal dementia identification using lifestyle and brain lesions, a machine learning approach

Dementia diagnosis often relies on expensive and invasive neuroimaging techniques that limit access to early screening. This study proposes an innovative approach for facilitating early dementia screening by estimating diffusion tensor imaging (DTI) measures using accessible lifestyle and brain imaging factors. Conventional DTI analysis, though effective, is often hindered by high costs and limited accessibility. To address this challenge, fuzzy subtractive clustering identified 14 influential variables from the Lifestyle for Brain Health and Brain Atrophy and Lesion Index frameworks, encompassing demographics, medical conditions, lifestyle factors, and structural brain markers. A multilayer perceptron (MLP) neural network was developed using these selected variables to predict fractional anisotropy (FA), a DTI metric reflecting white matter integrity and cognitive function. The MLP model achieved promising results, with a mean squared error of 0.000 878 on the test set for FA prediction, demonstrating its potential for accurate DTI estimation without costly neuroimaging techniques. The FA values in the dataset ranged from 0 to 1, with higher values indicating greater white matter integrity. Thus, a mean squared error of 0.000 878 suggests that the model’s predictions were highly accurate compared to the observed FA values. This multifactorial approach aligns with the current understanding of dementia’s complex etiology influenced by various biological, environmental, and lifestyle factors. By integrating readily available data into a predictive model, this method enables widespread, cost-effective screening for early dementia risk assessment. The proposed accessible screening tool could facilitate timely interventions, preventive strategies, and efficient resource allocation in public health programs, ultimately improving patient outcomes and caregiver burden.

No association between peripheral serotonin-gene-related DNA methylation and brain serotonin neurotransmission in the healthy and depressed state.

Methylation of serotonin-related genes has been proposed as a plausible gene-by-environment link which may mediate environmental stress, depressive and anxiety symptoms. DNA methylation is often measured in blood cells, but little is known about the association between this peripheral epigenetic modification and brain serotonergic architecture. Here, we evaluated the association between whole-blood-derived methylation of four CpG sites in the serotonin transporter (SLC6A4) and six CpG sites of the tryptophan hydroxylase 2 (TPH2) gene and in-vivo brain levels of serotonin transporter (5-HTT) and serotonin 4 receptor (5-HT4) in a cohort of healthy individuals (N = 254) and, for 5-HT4, in a cohort of unmedicated patients with depression (N = 90). To do so, we quantified SLC6A4/TPH2 methylation using bisulfite pyrosequencing and estimated brain 5-HT4 and 5-HTT levels using positron emission tomography. In addition, we explored the association between SLC6A4 and TPH2 methylation and measures of early life and recent stress, depressive and anxiety symptoms on 297 healthy individuals. We found no statistically significant association between peripheral DNA methylation and brain markers of serotonergic neurotransmission in patients with depression or in healthy individuals. In addition, although SLC6A4 CpG2 (chr17:30,236,083) methylation was marginally associated with the parental bonding inventory overprotection score in the healthy cohort, statistical significance did not remain after accounting for blood cell heterogeneity. We suggest that findings on peripheral DNA methylation in the context of brain serotonin-related features should be interpreted with caution. More studies are needed to rule out a role of SLC6A4 and TPH2 methylation as biomarkers for environmental stress, depressive or anxiety symptoms.

Building diagnostic neuroimaging biomarkers for psychiatric disorders using reverse inference approaches: A viable route?

The advent of structural magnetic resonance imaging (sMRI) at the end of the 20th century opened the way toward a deeper understanding of the neurophysiology of psychiatric disorders, substantiating regional structural abnormalities underlying this group of clinical conditions. However, despite abundant and flourishing scientific research, sMRI methodologies are not currently integrated into daily diagnostic practice. One reason behind this failed translation may be the prevailing approach to logical reasoning in neuroimaging: The forward inference via frequentist-based statistics. This reasoning prevents clinicians from obtaining information about the selectivity of results, which are therefore of limited use regarding the definition of biomarkers and refinement of diagnostic processes. Recently, another type of inferential approach has started to emerge in the neuroimaging field: The reverse inference via Bayesian statistics. Here, we introduce the key concepts of this approach, with a particular emphasis on the clinical sMRI environment. We survey recent findings showing significant potential for clinical translation. Clinical opportunities and challenges for developing reverse inference-based neural markers for psychiatry are also discussed. We propose that a systematic sharing of imaging data across the human brain mapping community is an essential first step toward a paradigmatic clinical shift. We conclude that a defined synergy between forward-based and reverse-based sMRI research can illuminate current discussions on diagnostic brain markers, offering clarity on key issues and fostering new tailored diagnostic avenues.

Ventromedial frontoinsular connectivity is associated with long-term smoking behavior change in aging

Abstract A central question in the field of cognitive aging and behavioral neuroscience is what enables some individuals to successfully change their behavior more than others? Smoking is a significant risk factor for cognitive decline, particularly in vulnerable populations, including those who are at an elevated risk for Alzheimer’s disease (AD). Developing effective smoking reduction strategies is therefore a public health priority. The goal of the current study is to better understand the brain mechanisms underlying long-term smoking behavior change in cognitively normal, but at-risk, older adults. Neuroimaging and human lesion studies have implicated the insula and its functional network in subjective interoceptive awareness of cigarette craving and smoking-cue reactivity. We sought to characterize the extent to which anterior insular resting-state functional connectivity (RSFC) MRI predicted long-term smoking reduction (mean: 2.7 years, range 8 months–4 years) using a seed-to-voxel approach. Twenty-three (18 women; 26% APOE4 carriers; 61.5 years, SD = 3.7) cognitively unimpaired older individuals who smoked cigarettes at their baseline visit and have a first-degree family history of AD (at least one parent or multiple siblings affected) were included from a prospective longitudinal cohort, Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) in the current study. We found that reduced long-term smoking behavior was associated with enhanced antagonistic RSFC between bilateral anterior insula (aINS) and ventromedial prefrontal cortex (vmPFC). In a second pre-registered replication study within a larger, independent sample of 118 cognitively normal older adults who smoked cigarettes at baseline from the UK Biobank (73 women; 27.9% APOE4 carriers; 60.3 years, SD = 2.7), we found that baseline enhanced antagonistic RSFC between anterior insula and vmPFC predicted long-term smoking reduction (mean 5.2 years; ranging from 3 years to 7 years). To our knowledge, this is the largest study to examine the neural substrates of long-term smoking cessation in human aging. Our results suggest that antagonistic RSFC between aINS and vmPFC is a brain marker of future smoking reduction and disease prevention in older adults at risk for AD.

Qatar's National Mental Health Study-The World Mental Health Qatar.

We provide an overview of Qatar's first epidemiological study on prevalence, predictors, and treatment contact for mood and anxiety disorders. We highlight the importance of the three-pronged study, its aims, and its key components. The first component comprised a probability-based representative survey of Qatari and non-Qatari (Arab) adult males and females recruited from the general population and interviewed using the International Diagnostic Interview (CIDI version 3.3). The second component, a clinical reappraisal study, assessed concordance between diagnoses based on the CIDI and independent clinical assessments conducted by trained clinical interviewers. The third component comprised a resting-state functional magnetic resonance imaging study of healthy survey respondents who were matched to patients with psychosis. 5000 survey interviews provided data on prevalence and treatment of common mental disorders. Clinical re-interviews (N=485) provided important diagnostic validity data. Finally, state-of-the art structural and functional brain markers for psychosis were also collected (N=100). Descriptive epidemiological data were collected to inform future mental health priorities in Qatar and situates these within a global context. The study fills important gaps in regional and global estimates and establish necessary baseline to develop comprehensive risk estimates for mental health in Qatar's young population.

Feeding Status Transiently Alters the Phosphorylation of Enzymes in the PI3K/Akt/GSK3β Pathway but not Phosphorylated Tau in the Cortex of Male Obese Zucker Rats

Metabolic syndrome (MetS) fosters pathological brain markers such as excess phosphorylated tau (ptau) to produce neuronal dysfunction. Activation of the PI3K/Akt/GSK3β pathway by increasing pAkt-Ser473 and pGSK3β-Tyr216 promotes phosphorylation of tau at residues such as Ser396. Insulin also increases pGSK3β-Ser9 to limit phosphorylation of tau. Deficient insulin signaling has been proposed to reduce pGSK3β-Ser9 and promote pathological excess ptau-Ser396. However, studies of these pathways in rodent models of MetS report both elevated and reduced expression of pAkt-Ser473 and pGSK3β-Ser9, raising the question of the predictive value and role of altered pGSK3β-Ser9 expression in producing excess ptau. Studies reporting reduced pGSK3β-Ser9 in insulin resistant and diabetic rodents often used fasted animals for tissue collection, but other studies without reported fasting showed increased pGSK3β-Ser9. However, elevated ptau was consistently observed under both conditions. Because short-term changes in insulin and glucose alter pAkt-Ser473 and pGSK3β-Ser9 expression, we hypothesized that phosphorylation was related to the feeding status at time of tissue collection rather than the chronic disease state, and excess ptau was resistant to these short-term changes. We examined whether fasting altered pAkt-Ser473, pGSK3β-Tyr216, and pGSK3β-Ser9, and ptau-Ser396 levels in 18-week-old male obese (OZR) and lean (LZR) Zucker rats. After measurement of blood glucose by tail sample in their home cage, fasted (16 hours) and non-fasted rats were euthanized for tissue collection. Though baseline glucose was higher in OZRs vs. LZRs in the fed state (202.4±21.9 vs. 115.9±2.7 mg/dl, t-test) and fasted state (169.4±5.8 vs. 95.3±3.8 mg/dl, t-test), fasting significantly reduced glucose in OZRs but not LZRs (2-way ANOVA with Tukey’s post hoc, P=0.023 for OZRs and P=0.143 for LZRs, n=5-8/group). Protein expression in the cerebral cortex was measured by Western blotting and normalized to actin (n=3-5 for all groups). Expression of ptau-Ser396/total tau was significantly elevated in OZRs vs. LZRs in both feeding conditions (p<0.001) and was not altered by fasting in either phenotype. Expression of pAkt-Ser476 was elevated in non-fasted OZRs vs. LZRs (p<0.001). Fasting greatly reduced pAkt-Ser476 in OZRs (p<0.001) but not LZRs (P=0.741), making expression in fasted OZRs and LZRs comparable (P=0.674). Expression of pGSK3β-Ser9 was significantly elevated in fed OZRs vs. LZRs (p<0.001). Fasting reduced expression of pGSK3β-Ser9 only in OZRs (p<0.001 in OZRs, P=0.952 in LZRs), but expression of was still elevated in fasted OZRs vs. LZRs (P=0.009). Expression of pGSK3β-Tyr216 was significantly elevated in fed OZRs vs. LZRs (p<0.001) but significantly lower in fasted OZRs vs. LZRs (p<0.001). These data show that feeding status does not alter the ptau-Ser396 in the cerebral cortex of OZRs vs. LZRs, but phosphorylation of the enzymes of the PI3K/Akt/GSK3β signaling pathway are greatly affected by MetS and feeding status at time of tissue collection. Thus, when OZRs have access to food, elevated pGSK3β-Tyr216 may contribute to the GSK3β-mediated rise in ptau-Ser396 despite elevated pGSK3β-Ser9. Supported by R01Hl132568S1, JES Edwards Foundation, and Summerfield G. Roberts Foundation. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Normative volumes and relaxation times at 3T during brain development

While research has unveiled and quantified brain markers of abnormal neurodevelopment, clinicians still work with qualitative metrics for MRI brain investigation. The purpose of the current article is to bridge the knowledge gap between case-control cohort studies and individual patient care. Here, we provide a unique dataset of seventy-three 3-to-17 years-old healthy subjects acquired with a 6-minute MRI protocol encompassing T1 and T2 relaxation quantitative sequence that can be readily implemented in the clinical setting; MP2RAGE for T1 mapping and the prototype sequence GRAPPATINI for T2 mapping. White matter and grey matter volumes were automatically quantified. We further provide normative developmental curves based on these two imaging sequences; T1, T2 and volume normative ranges with respect to age were computed, for each ROI of a pediatric brain atlas. This open-source dataset provides normative values allowing to position individual patients acquired with the same protocol on the brain maturation curve and as such provides potentially useful quantitative biomarkers facilitating precise and personalized care.

Brain structure and functional connectivity linking childhood cumulative trauma to COVID-19 vicarious traumatization.

The COVID-19 pandemic has caused some individuals to experience vicarious traumatization (VT), an adverse psychological reaction to those who are primarily traumatized, which may negatively impact one's mental health and well-being and has been demonstrated to vary with personal trauma history. The neural mechanism of VT and how past trauma history affects current VT remain largely unknown. This study aimed to identify neurobiological markers that track individual differences in VT and reveal the neural link between childhood cumulative trauma (CCT) and VT. We used structural and resting-state functional magnetic resonance imaging before the pandemic to identify prospective brain markers for COVID-related VT by correlating individuals' VT levels during the pandemic with the gray matter volume (GMV) and seed-based resting-state functional connectivity (RSFC) and examined how these brain markers linked CCT to VT in a sample of general young adults (N = 115/100). Whole-brain GMV-behavior correlation analysis showed that VT was positively associated with GMV in the right dorsolateral prefrontal gyrus (DLPFC). Using the cluster derived from the GMV-behavior correlation analysis as the seed region, we further revealed that the RSFC between the right DLPFC and right precuneus was negatively associated with VT. Importantly, the right DLPFC volume and DLPFC-precuneus RSFC mediated the effect of CCT on VT. These findings remained unaffected by factors such as family socioeconomic status, other stressful life events, and general mental health. Overall, our study presents structural and functional brain markers forVTand highlights these brain-based markers as a potential neural mechanism linking CCT to COVID-related VT,which has implications for treating and preventing the development of trauma-related mental disorders.

Design, synthesis, and biological evaluation of some 2-(3-oxo-5,6-diphenyl-1,2,4-triazin-2(3H)-yl)-N-phenylacetamide hybrids as MTDLs for Alzheimer's disease therapy

Inspite of established symptomatic relief drug targets, a multi targeting approach is highly in demand to cure Alzheimer's disease (AD). Simultaneous inhibition of cholinesterase (ChE), β secretase-1 (BACE-1) and Dyrk1A could be promising in complete cure of AD. A series of 18 diaryl triazine based molecular hybrids were successfully designed, synthesized, and tested for their hChE, hBACE-1, Dyrk1A and Aβ aggregation inhibitory potentials. Compounds S-11 and S-12 were the representative molecules amongst the series with multi-targeted inhibitory effects. Compound S-12 showed hAChE inhibition (IC50 value = 0.486 ± 0.047 μM), BACE-1 inhibition (IC50 value = 0.542 ± 0.099 μM) along with good anti-Aβ aggregation effects in thioflavin-T assay. Only compound S-02 of the series has shown Dyrk1A inhibition (IC50 value = 2.000 ± 0.360 μM). Compound S-12 has also demonstrated no neurotoxic liabilities against SH-SY5Y as compared to donepezil. The in vivo behavioral studies of the compound S-12 in the scopolamine- and Aβ-induced animal models also demonstrated attanuation of learning and memory functions in rats models having AD-like characteristics. The ex vivo studies, on the rat hippocampal brain demonstrated reduction in certain biochemical markers of the AD brain with a significant increase in ACh level. The Western blot and Immunohistochemistry further revealed lower tau, APP and BACE-1 molecular levels. The drosophilla AD model also revealed improved eyephenotype after treatment with compound S-12. The molecular docking studies of the compounds suggested that compound S-12 was interacting with the ChE-PAS & CAS residues and catalytic dyad residues of the BACE-1 enzymes. The 100 ns molecular dynamics simulation studies of the ligand-protein complexed with hAChE and hBACE-1 also suggested stable ligand–protein confirmation throughout the simulation run.

Parental status and markers of brain and cellular age: A 3D convolutional network and classification study

Recent research shows prominent effects of pregnancy and the parenthood transition on structural brain characteristics in humans. Here, we present a comprehensive study of how parental status and number of children born/fathered links to markers of brain and cellular ageing in 36,323 UK Biobank participants (age range 44.57–82.06 years; 52% female). To assess global effects of parenting on the brain, we trained a 3D convolutional neural network on T1-weighted magnetic resonance images, and estimated brain age in a held-out test set. To investigate regional specificity, we extracted cortical and subcortical volumes using FreeSurfer, and ran hierarchical clustering to group regional volumes based on covariance. Leukocyte telomere length (LTL) derived from DNA was used as a marker of cellular ageing. We employed linear regression models to assess relationships between number of children, brain age, regional brain volumes, and LTL, and included interaction terms to probe sex differences in associations. Lastly, we used the brain measures and LTL as features in binary classification models, to determine if markers of brain and cellular ageing could predict parental status. The results showed associations between a greater number of children born/fathered and younger brain age in both females and males, with stronger effects observed in females. Volume-based analyses showed maternal effects in striatal and limbic regions, which were not evident in fathers. We found no evidence for associations between number of children and LTL. Classification of parental status showed an Area under the ROC Curve (AUC) of 0.57 for the brain age model, while the models using regional brain volumes and LTL as predictors showed AUCs of 0.52. Our findings align with previous population-based studies of middle- and older-aged parents, revealing subtle but significant associations between parental experience and neuroimaging-based surrogate markers of brain health. The findings further corroborate results from longitudinal cohort studies following parents across pregnancy and postpartum, potentially indicating that the parenthood transition is associated with long-term influences on brain health.

Searching Reproducible Brain Features using NeuroMark: Templates for Different Age Populations and Imaging Modalities

A primary challenge to the data-driven analysis is the balance between poor generalizability of population-based research and characterizing more subject-, study- and population-specific variability. We previously introduced a fully automated spatially constrained independent component analysis (ICA) framework called NeuroMark and its functional MRI (fMRI) template. NeuroMark has been successfully applied in numerous studies, identifying brain markers reproducible across datasets and disorders. The first NeuroMark template was constructed based on young adult cohorts. We recently expanded on this initiative by creating a standardized normative multi-spatial-scale functional template using over 100,000 subjects, aiming to improve generalizability and comparability across studies involving diverse cohorts. While a unified template across the lifespan is desirable, a comprehensive investigation of the similarities and differences between components from different age populations might help systematically transform our understanding of the human brain by revealing the most well-replicated and variable network features throughout the lifespan. In this work, we introduced two significant expansions of NeuroMark templates first by generating replicable fMRI templates for infants, adolescents, and aging cohorts, and second by incorporating structural MRI (sMRI) and diffusion MRI (dMRI) modalities. Specifically, we built spatiotemporal fMRI templates based on 6,000 resting-state scans from four datasets. This is the first attempt to create robust ICA templates covering dynamic brain development across the lifespan. For the sMRI and dMRI data, we used two large publicly available datasets including more than 30,000 scans to build reliable templates. We employed a spatial similarity analysis to identify replicable templates and investigate the degree to which unique and similar patterns are reflective in different age populations. Our results suggest remarkably high similarity of the resulting adapted components, even across extreme age differences. With the new templates, the NeuroMark framework allows us to perform age-specific adaptations and to capture features adaptable to each modality, therefore facilitating biomarker identification across brain disorders. In sum, the present work demonstrates the generalizability of NeuroMark templates and suggests the potential of new templates to boost accuracy in mental health research and advance our understanding of lifespan and cross-modal alterations.

The brain markers of creativity measured by divergent thinking in childhood: Hippocampal volume and functional connectivity

Creativity, a high-order cognitive ability, has received wide attention from researchers and educators who are dedicated to promoting its development throughout one's lifespan. Currently, creativity is commonly assessed with divergent thinking tasks, such as the Alternative Uses Task. Recent advancements in neuroimaging techniques have enabled the identification of brain markers for high-order cognitive abilities. One such brain structure of interest in this regard is the hippocampus, which has been found to play an important role in generating creative thoughts in adulthood. However, such role of the hippocampus in childhood is not clear. Thus, this study aimed to investigate the associations between creativity, as measured by divergent thinking, and both the volume of the hippocampus and its resting-state functional connectivity in 116 children aged 8–12 years. The results indicate significant relations between divergent thinking and the volume of the hippocampal head and the hippocampal tail, as well as the volume of a subfield comprising cornu ammonis 2–4 and dentate gyrus within the hippocampal body. Additionally, divergent thinking was significantly related to the differences between the anterior and the posterior hippocampus in their functional connectivity to other brain regions during rest. These results suggest that these two subregions may collaborate with different brain regions to support diverse cognitive processes involved in the generation of creative thoughts. In summary, these findings indicate that divergent thinking is significantly related to the structural and functional characteristics of the hippocampus, offering potential insights into the brain markers for creativity during the developmental stage.

Psilocybin enhances insightfulness in meditation: a perspective on the global topology of brain imaging during meditation

In this study, for the first time, we explored a dataset of functional magnetic resonance images collected during focused attention and open monitoring meditation before and after a five-day psilocybin-assisted meditation retreat using a recently established approach, based on the Mapper algorithm from topological data analysis. After generating subject-specific maps for two groups (psilocybin vs. placebo, 18 subjects/group) of experienced meditators, organizational principles were uncovered using graph topological tools, including the optimal transport (OT) distance, a geometrically rich measure of similarity between brain activity patterns. This revealed characteristics of the topology (i.e. shape) in space (i.e. abstract space of voxels) and time dimension of whole-brain activity patterns during different styles of meditation and psilocybin-induced alterations. Most interestingly, we found that (psilocybin-induced) positive derealization, which fosters insightfulness specifically when accompanied by enhanced open-monitoring meditation, was linked to the OT distance between open-monitoring and resting state. Our findings suggest that enhanced meta-awareness through meditation practice in experienced meditators combined with potential psilocybin-induced positive alterations in perception mediate insightfulness. Together, these findings provide a novel perspective on meditation and psychedelics that may reveal potential novel brain markers for positive synergistic effects between mindfulness practices and psilocybin.

Cortical white matter microstructural alterations underlying the impaired gamma-band auditory steady-state response in schizophrenia

The gamma-band auditory steady-state response (ASSR), primarily generated from the auditory cortex, has received substantial attention as a potential brain marker indicating the pathophysiology of schizophrenia. Previous studies have shown reduced gamma-band ASSR in patients with schizophrenia and demonstrated correlations with impaired neurocognition and psychosocial functioning. Recent studies in clinical and healthy populations have suggested that the neural substrates of reduced gamma-band ASSR may be distributed throughout the cortices surrounding the auditory cortex, especially in the right hemisphere. This study aimed to investigate associations between the gamma-band ASSR and white matter alterations in the bundles broadly connecting the right frontal, parietal and occipital cortices to clarify the networks underlying reduced gamma-band ASSR in patients with schizophrenia. We measured the 40 Hz ASSR using electroencephalography and diffusion tensor imaging in 42 patients with schizophrenia and 22 healthy comparison subjects. The results showed that the gamma-band ASSR was positively correlated with fractional anisotropy (an index of white matter integrity) in the regions connecting the right frontal, parietal and occipital cortices in healthy subjects (β = 0.41, corrected p = 0.075, uncorrected p = 0.038) but not in patients with schizophrenia (β = 0.17, corrected p = 0.46, uncorrected p = 0.23). These findings support our hypothesis that the generation of gamma-band ASSR is supported by white matter bundles that broadly connect the cortices and that these relationships may be disrupted in schizophrenia. Our study may help characterize and interpret reduced gamma-band ASSR as a useful brain marker of schizophrenia.

Abstract B007: Establishment of patient-derived brain metastasis initiating cells as a novel preclinical model of breast cancer metastatization

Abstract Brain metastasis from breast cancer (BCBM) are lethal tumors occurring in 10-15% of IV stage breast cancers against which only limited therapeutic options are available. A critical hindrance to the design of novel therapeutic approaches is the narrow set of preclinical models to study BCBM pathophysiology, chiefly those resembling the stem-like population which is thought be the main source of BCBM dissemination and progression. We aimed to isolate patient-derived metastasis-initiating cells (MICs) to furnish novel preclinical models of metastatization. MICs were cultured as stem-enriching tumorspheres, which we characterized in term of i) brain/breast/stem markers expression ii) tumorigenicity, iii) growth and in vitro/in vivo self-renewal, iv) adhesion to organ-specific endothelium, v) metastatic potential and vi) drug responsiveness. Further, we transcriptionally profiled MIC-driven organ-specific metastasis. Patient-derived MICs expressed epithelial markers while the expression of brain markers was poor, coherently with their epithelial origins. About 90% of MICs were positive to the expression of the putative stem cell markers CD15, CD24 and CD44, while CD133 and ALDH1A1 were less represented. MICs were grown indefinitely in stem cell medium and successfully formed spheres in serial clonogenic assays, suggesting their endowment with stem-like traits. Similarly, their ability to form tumors when orthotopically injected in mice brain was maintained upon serial transplantation and under in vivo limiting dilution conditions. The representative PR60 MICs showed metastatic potential to mice brain and bones upon either intracardiac or intranipple transplantation. Of note, independently of the route of injection, this metastatization pattern wholly mirrored the clinical course of the patient they had been derived from. PR60-driven brain metastasis also recapitulated patient tumor histology, cytoarchitecture and marker expression. Further confirming their brain-tropism, PR60 MICs preferentially adhered to human brain compared to non-brain endothelium under shear stress mimicking in vivo hemodynamic conditions. Transcriptomically, PR60 MICs displayed high correlation with the BCBM of origin but retain the ability to form intra-nipple tumors resembling patient primitive breast tumor. PR60-derived brain and bone metastasis reveal a distinct expression profile suggesting that PR60 MICs can colonize different organs rewiring their transcriptomic landscape. Compared to the whole tumor of origin, MICs revealed an up-regulation of drug resistance signatures, which are often linked with stem-like traits, and that were functionally validated by a high throughput drug screening. Altogether, we established a robust and versatile MIC model that reliably mirrors the brain metastasis of origin and mimics the different steps of brain metastatic dissemination for in vitro and in vivo studies. This model has the potential to provide further knowledge for future therapy development for BCBM management. Citation Format: Stefania Faletti, Cristina Richichi, Daniela Osti, Elena Ceccacci, Massimiliano Del Bene, Camilla Cerutti, Giovanni Bertalot, Monica Patanè, Bianca Pollo, Giuliana Pelicci. Establishment of patient-derived brain metastasis initiating cells as a novel preclinical model of breast cancer metastatization [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B007.

Distinct Topological Properties of the Reward Anticipation Network in Preadolescent Children With Binge Eating Disorder Symptoms

Few studies have considered the neural underpinnings of binge eating disorder (BED) in children, despite clinical and subclinical symptom presentation occurring in this age group. Symptom presentation at this age is of clinical relevance, as early onset of binge eating is linked to negative health outcomes. Studies in adults have highlighted dysfunction in the frontostriatal reward system as a potential candidate for binge eating pathophysiology, although the exact nature of such dysfunction is currently unclear. Data from 83 children (mean age 9.9 years, SD= 0.60) with symptoms of BED (57% girls) and 123 control participants (mean age 10.0 years, SD= 0.60) (52% girls) were acquired from the 4.0 baseline release of the Adolescent Brain Cognitive Development Study. Task-based graph theoretic techniques were used to analyze data from anticipation trials of the monetary incentive delay task. Network and nodal properties were compared between groups. The BED-S group showed alterations in topological properties associated with the frontostriatal subnetwork, such as reduced nodal efficiency in the superior frontal gyrus, nucleus accumbens, putamen, and in normal sex-difference patterns of these properties, such as diminished girls-greater-than-boys pattern of betweenness-centrality in nucleus accumbens observed in controls. Distinct network properties and sex-difference patterns in preadolescent children with BED-S suggest dysregulation in the reward system compared to those of matched controls. For the first time, these results quantify this dysregulation in terms of systems-level properties during anticipation of monetary reward and significantly inform the early and sex-related brain markers of BED symptoms.

Language brain responses and neurodevelopmental outcome in preschoolers with congenital heart disease: A fNIRS study

Neurodevelopmental disabilities affect up to 50% of survivors of congenital heart disease (CHD). Language difficulties are frequently identified during preschool period and can lead to academic, social, behavioral, and emotional difficulties. Structural brain alterations are associated with poorer neurodevelopmental outcomes in patients with CHD during infancy, childhood, and adolescence. However, evidence is lacking about the functional brain activity in children with CHD and its relationship with neurodevelopment. This study therefore aimed to characterize brain responses during a passive story-listening task in 3-year-old children with CHD, and to investigate the relationship between functional brain patterns of language processing and neurodevelopmental outcomes. To do so, we assessed hemodynamic concentration changes, using functional near-infrared spectroscopy (fNIRS), and neurodevelopmental outcomes, using the Wechsler Preschool and Primary Scale of Intelligence – 4th Edition (WPPSI-IV), in children with CHD (n = 19) and healthy controls (n = 23). Compared to their healthy peers, children with CHD had significantly lower scores on the Verbal comprehension index (VCI), the Vocabulary acquisition index (VAI), the General ability index (GAI), and the Information and the Picture Naming subtests of the WPPSI-IV. During the passive story-listening task, healthy controls showed significant hemodynamic brain responses in the temporal and the temporal posterior regions, with stronger activation in the temporal posterior than in the temporal regions. In contrast, children with CHD showed reduced activation in the temporal posterior regions compared to controls, with no difference of activation between regions. Reduced brain responses in the temporal posterior regions were also correlated with lower neurodevelopmental outcomes in both groups. This is the first study that reveals reduced brain functional responses in preschoolers with CHD during a receptive language task. It also suggests that the temporal posterior activation could be a potential brain marker of cognitive development. These findings provide support for the feasibility of identifying brain correlates of neurodevelopmental vulnerabilities in children with CHD.

Diosgenin alleviates alcohol-mediated escalation of social defeat stress and the neurobiological sequalae.

Emerging evidence indicates that persistent alcohol consumption escalates psychosocial trauma achieved by social defeat stress (SDS)-induced neurobiological changes and behavioral outcomes. Treatment with compounds with neuroprotective functions is believed to reverse ethanol (EtOH)-aggravated SDS-induced behavioral impairments. We investigated the outcomes of diosgenin treatment, a phytosteroidal sapogenin in mice co-exposed to repeated SDS and EtOH administration. During a period of 14days, SDS male mice were repeatedly administered EtOH (20%, 10mL/kg) orally from days 8-14 (n = 9). Within days 1-14, SDS mice fed with EtOH were simultaneously treated with diosgenin (25 and 50mg/kg) or fluoxetine (10mg/kg) by oral gavage. Locomotor, cognitive-, depressive-, and anxiety-like behaviors were assessed. Adrenal weight, serum glucose, and corticosterone levels were assayed. Brain markers of oxido-inflammatory, neurochemical levels, monoamine oxidase-B, and acetylcholinesterase activities were measured in the striatum, prefrontal cortex, and hippocampus. The anxiety-like behavior, depression, low stress resilience, social, and spatial/non-spatial memory decline exhibited by SDS mice exposed to repeated EtOH administration were alleviated by diosgenin (25 and 50mg/kg) and fluoxetine, illustrated by increased dopamine and serotonin concentrations and reduced monoamine oxidase-B and acetylcholinesterase activities in the prefrontal cortex, hippocampus, and striatum. Diosgenin attenuated SDS + EtOH interaction induced corticosterone release and adrenal hypertrophy, accompanied by reduced TNF-α, IL-6, malondialdehyde, and nitrite levels in the striatum, prefrontal cortex, and hippocampus. Diosgenin increased glutathione, superoxide dismutase, and catalase levels in SDS + EtOH-exposed mice. Our data suggest that diosgenin reverses SDS + EtOH interaction-induced behavioral changes via normalization of hypothalamic-pituitary-adrenal axis, neurochemical neurotransmissions, and inhibition of oxidative and inflammatory mediators in mice brains.

Abstract WP135: Coexistence of Enlarged Perivascular Spaces and Other MRI Markers of Cerebral Small Vessel Diseases

Objective: Enlarged Perivascular Spaces (EPVS) have gained recognition as potential indicators of cerebrovascular pathologies. In this study, we investigated the association between the presence and severity of EPVS and other MRI Markers of cerebral small vessel diseases. Method: Our study was conducted on a subset of the Geisinger DiscovEHR Initiative Cohort. A predefined protocol was employed to evaluate each brain magnetic resonance imaging (MRI) data by two trained reviewers. The total numbers of EPVS were categorized into five grades (0-4) in centrum semiovale and basal ganglia regions. We compared patients with EPVS and an age-, gender-, body mass index-, and hypertension-propensity-score-matched cohort lacking EPVS. Results: Out of 3054 (mean age of 67.5 years, 97% white of Caucasian descent) randomly selected participants, 1465 (47.9%, mean age 69.9 years) showed evidence of EPVS in their imaging. Propensity score matching resulted in 1310 participants in each group. The presence of EPVS in basal ganglia was linked to higher white matter hyperintensity according to the Fazekas scale in deep white matter (OR, 1.4; 95% CI, 1.2-1.6), as well as global cortical atrophy (OR, 1.22; 95% CI, 1.1-1.4) on MRI scans. Other factors, such as cerebral aneurysm (OR, 2.3; 95% CI, 1.4-3.8), heart failure (OR, 1.85; 95% CI, 1.3-2.6), smoking (OR, 1.43; 95% CI, 1.1-1.8) exhibited associations. Moreover, an increased burden of EPVS correlated with higher Fazekas scales in periventricular and deep white matter. Conclusion: The presence and severity of EPVS exhibited are associated with MRI markers of white matter hyperintensity and global cortical atrophy. EPVS may be a marker of an aging brain and cerebral small vessel diseases. It might be associated with cerebrovascular risk factors.

Experimental Type 2 diabetes and lipotoxicity-associated neuroinflammation involve mitochondrial DNA-mediated cGAS/STING axis: implication of Type-1 interferon response in cognitive impairment.

Type-1 IFN (interferon)-associated innate immune response is increasingly getting attention in neurodegenerative and metabolic diseases like type 2 diabetes (T2DM). However, its significance in T2DM/lipotoxicity-induced neuroglia changes and cognitive impairment is missing. The present study aims to evaluate the involvement of cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon gene), IRF3 (interferon regulatory factor-3), TBK (TANK binding kinase)-mediated Type-1 IFN response in the diabetic brain, and lipotoxicity (palmitate-bovine serum albumin conjugate/PA-BSA)-induced changes in cells (neuro2a and BV2). T2DM was induced in C57/BL6 mice by feeding on a high-fat diet (HFD, 60% Kcal) for 16weeks and injecting a single dose of streptozotocin (100mg/kg, i.p) in the 12th week. Plasma biochemical parameter analysis, neurobehavioral assessment, protein expression, and quantitative polymerase chain reaction study were carried out to decipher the hypothesis. T2DM-associated metabolic and lipotoxic stress led to mitochondrial impairment causing leakage of mtDNA to the cytoplasm further commencing cGAS activation and its downstream signaling. The diseased hippocampus and cortex showed decreased expression of synaptophysin (p < 0.01) and PSD-95 (p < 0.01, p < 0.05) with increased expression of cGAS (p < 0.001), p-STING (p < 0.001), p-STAT1 (signal transducer and activator of transcription) (p < 0.01), and IFN-β (p < 0.001) compared to normal control. The IFN-β/p-STAT1-mediated microglia activation was executed employing a conditioned media approach. C-176, a selective STING inhibitor, alleviated cGAS/p-STING/IFN-β expression and proinflammatory microglia/M1-associated markers (CD16 expression, CXCL10, TNF-α, IL-1β mRNA fold change) in the diabetic brain. The present study suggests Type-1IFN response may result in neuroglia dyshomeostasis affecting normal brain function. Alleviating STING signaling has the potential to protect T2DM-associated central ailment.