vascular

Cartilage targeting exosomes for OA gene therapy and pain treatment

Project Summary Gene therapy has the potential to facilitate targeted expression of therapeutic proteins to promote cartilage regeneration in osteoarthritis (OA). The dense, avascular, aggrecan-glycosaminoglycan rich negatively charged cartilage, however, hinders their transport to reach chondrocytes in effective doses. While viral vector mediated gene delivery has shown promise, concerns over immunogenicity and tumorigenic side-effects persist. To address this, we have developed surface-modified cartilage-targeting MSC exosomes as non-viral carriers for gene therapy. MSC derived exosomes have intrinsic therapeutic potential as they can induce cartilage repair and are non-immunogenic, making them desirable for gene delivery. We have engineered charge-reversed cationic exosomes by anchoring cartilage targeting optimally charged arginine-rich cationic peptide (CPC) motifs into the anionic exosome bilayer (Exo-CPC) by using buffer pH as a charge-reversal switch. Exo-CPC use charge interactions to penetrate through the full thickness of arthritic cartilage (close to tidemark) and deliver the packaged genetic material cargo to chondrocytes residing in the deep tissue layers while native anionic exosomes cannot. They can also bind within the synovial joint, making them effective for OA pain relief gene therapy. Here we will engineer charge-reversed Exo-CPC for delivery of IL-1RA (receptor antagonist of interleukin-1) mRNA and NaV1.8 (voltage gated sodium channel 1.8) inhibitor siRNA to stimulate both disease modifying response and long-term pain relief with a one-time intra-articular dose. IL-1RA mRNA targets are in the chondrocytes and synovium cells; Nav1.8 expressing nerves innervate into synovium and subchondral bone in OA – sites that Exo-CPC can readily target. Aim 1 will engineer cartilage targeting Exo-CPC for delivery of IL- 1RA mRNA and Nav1.8 inhibitor siRNA. Their ability to deliver IL-1RA mRNA to chondrocytes and IL-1RA protein translation efficiency will be evaluated in-vitro. Exo-CPC-Na v1.8’s ability to reduce NaV1.8 bioactivity of sensory nerves will also be evaluated. In Aim 2, their distribution intra-articular (proximity to NaV1.8-positive nerves), extra-articular, and DRG and spinal cord using partial meniscectomy NaV1.8-tdTomato reporter mice OA models will be evaluated. Additionally, their dose dependent reduction on MMP activity, neuronal excitability and pain- related behaviors, and any immunogenicity will be assessed. Aim 3 will use the determined functional doses to study the long-term disease modifying and pain-relief effects of mono and combination therapy with Exo-CPC- IL-1RA and Exo-CPC-Nav1.8 in rescuing injury induced tissue structural damage as well as in reducing pain (weight bearing asymmetry) for up to one month following IA administration in early vs. late stages (intervention at 2 vs 6 weeks) of MMT (medial meniscectomy) induced OA rats. The project paves way for utilizing the intrinsic therapeutic potential of MSC Exosomes as viral-free, non-immunogenic carriers for OA gene therapy by employing cartilage as a drug depot. Cationic exosomes can be used to deliver other OA gene targets, and can be widely used for targeting other negatively charged tissues like meniscus, ligaments, discs, fracture callus etc.

Neuroinflammation in Cerebral Small Vessel Disease

Project Summary/Abstract Cerebral small vessel disease (cSVD) is a leading cause of vascular contributions to cognitive impairment and dementia (VCID), which is the 2nd leading cause of dementia and a significant contributor to Alzheimer’s disease (AD). Thus far, the underlying pathogenesis of cSVD is poorly understood. Several lines of evidence, including animal models, postmortem human brain pathology, and systemic inflammatory markers, demonstrated the damaging role of chronic neuroinflammation in cSVD. Direct evidence of neuroinflammation at the tissue level in patients with cSVD is still critically needed. The sphingosine-1-phosphate receptor 1 (S1PR1) regulates neuroinflammation through microglial and astrocyte activation and trafficking and has emerged as a promising target for neuroinflammation. In postmortem brains of patients with cSVD, we observed elevated S1PR1 expression and colocalization of S1PR1 with astrocytes and microglia. A novel 11C-CS1P1 PET radiotracer with high affinity and specificity targeting S1PR1 has been recently developed and validated in animal models and post-mortem human specimens. Under an FDA-approved eIND (IND 146548), we have successfully completed the safety and dosimetry study in healthy participants and performed preliminary studies in patients with cSVD. We found that 11C-CS1P1 PET uptake is significantly associated with WMH lesion burden in patients with cSVD after controlling for age, sex, race, vascular risk factors, and amyloid deposition. We hypothesize that 11C-CS1P1 PET uptake is a tissue-level biomarker of neuroinflammation to provide insight into cSVD severity, progression, and prognosis. We will 1) evaluate the relationship between 11C-CS1P1 PET uptake and cSVD neuroimaging abnormalities and cognitive impairment, 2) evaluate the test-retest repeatability and longitudinal evolution, and 3) determine whether 11C-CS1P1 PET uptake at baseline predict cSVD progression. The successful completion of this study will establish 11C-CS1P1 PET as an neuroinflammation imaging biomarker and investigate the role of neuroinflammation in cSVD pathogenesis and progression. It will lay a foundation for developing future therapies in modulating neuroinflammation.

Cardiorespiratory and autonomic impacts of coolants in e-cigarette aerosols

PROJECT SUMMARY / ABSTRACT Coolants such as menthol, WS-3, and WS-23 are widely used in electronic cigarettes (e-cigs) to reduce irritation and enhance appeal—especially among youth. Despite their prevalence, the cardiopulmonary toxicity of these agents remains poorly characterized. Recent work shows that e-cig aerosols can disrupt autonomic nervous system regulation and cardiac electrophysiology, increasing catecholamine release, enhancing sympathetic regulation of cardiac rhythm, and provoking arrhythmias. Proof is also mounting that nicotine’s sympathomimetic traits mediate these pathogenic effects. Preliminary data from our laboratory show that coolants increase systemic nicotine levels, blunt respiratory reflexes, and potentiate arrhythmias upon exposures to e-cigarette aerosols, suggesting a paradoxical role for coolants in suppressing ventilatory responses while intensifying cardiovascular risk. These findings take on added significance in light of recent case reports of sudden cardiac arrest in young e-cigarette users, including some in otherwise healthy individuals. This project will elucidate how e-cigarette coolants alter exposure to harmful and potentially harmful constituents (HPHCs)—particularly nicotine and aldehydes—concurrent with their effects on cardiovascular and respiratory physiology. Using robust murine models with continuous ECG, blood pressure, and pleural pressure telemetry, we will assess how coolants alter the acute and chronic effects of e-cigarette aerosols on cardiac electrophysiology, autonomic tone, ventilatory function, hemodynamics, and toxicant exposure. We will also evaluate how coolant concentration and device power modulate these effects. In parallel, we will determine whether adolescent mice exhibit heightened susceptibility to these effects compared to adults, with attention to sex differences and the persistence of cardiotoxicity after exposure cessation. This comprehensive, multi-modal approach incorporates novel protocols for arrhythmia inducibility, high-resolution physiologic monitoring, and complementary analyses of biomarkers of exposure and effect. By clarifying how coolants interact with HPHCs—especially nicotine and aldehydes—to drive cardiopulmonary injury across age and sex, this work addresses high-priority research areas identified in RFA-OD-25-001, including the toxicological evaluation of e-cigarette constituents and their cardiopulmonary effects. The results will inform regulatory policy and public health strategies aimed at mitigating cardiovascular risk associated with e-cigarette use, particularly among vulnerable youth.

Administrative Core

CORE A: PROJECT SUMMARY/ABSTRACT Administrative Core The administrative core will be led by Dr. Jordan Pober, the overall PI of this P01 application. Dr. Pober has had past experience as PI of an NHLBI P01 focused on allograft vasculopathy. He also has administrative experience at Yale as the founder and director of two Yale interdepartmental programs: Vascular Biology and Therapeutics and Human and Translational Immunology. The co-leader of the Core is Dr. Marie Robert, a surgical pathologist with extensive expertise in celiac disease (CeD) who has served in the recent past as the head of the scientific advisory board to the Beyond Celiac organization. The principal task of the Core will be to facilitate interactions among Project, Core and Collaborating Site personnel to foster synergies to address the overall aims of the proposal. Specific tasks include (1) organizing an executive committee of all Project, Core and Site Leaders with advisory and review responsibilities; (2) organizing monthly review meetings, each meeting focused on an individual project and site and (sometimes) core activities involving all program personnel and our internal advisors; (3) organizing an external advisory committee of experts to participate in an annual review of the whole program; and (4) managing budgetary and regulatory functions of the program. The innovative aspects of Core A is its prioritization of team science, bringing together the insights and knowledge of clinical-based and laboratory-based investigators.

Biostatistics, Ethics, Data Management, Research Design and Community Engagement(BEDRoC) Core

Biostatistics, Ethics, Data Management, Research Design and Community Engagement (BEDRoC) Core Abstract The Biostatistics, Ethics, Data Management, Research Design and Community Engagement (BEDRoC) Core will promote and support aging with serious illness science for the Center for Aging with Serious Illness (CASI). BEDRoC will provide expertise in statistical design and analysis, research ethics, and community engagement for all components of CASI. The Core's services will support the Research Project Leaders (RPLs) and Pilot Project Leaders (PPLs) and build capacity for the broader Dartmouth Health aging research community to conduct rigorous, impactful research to inform and improve care delivery for older adults with serious illness. BEDRoC includes expertise in mixed methods approaches that feature both quantitative and qualitative research methods to provide a comprehensive understanding of the complex issues related to aging with serious illness, ethical approaches to consent in research trials, multidimensional quality of life measurement, and innovative modeling approaches to studying clinical decision making. BEDRoC faculty have actively collaborated in study planning with each RPL, serving as both mentors and experienced collaborators on the three different projects involving decision aids for patients considering carotid revascularization, a patient-reported outcome-directed referral intervention to improve referral rates to palliative care services, and a pilot trial for a virtual/home-based exercise and a weight management osteoarthritis treatment program in older patients with osteoarthritis and multimorbidity. The BEDRoC Core will further support CASI by establishing an innovative training curriculum with workshops, tutorials, resources, and services, offered locally to RPLs and PPLs and extended to regional and national investigators in the IDeA network. In addition to their primary individual project mentors, each RPL will receive training and guidance from BEDRoC leaders through co-mentoring and RPL-focused works-in-progress sessions. BEDRoC will also provide access to a comprehensive inventory of patient-reported outcomes instruments, which are crucial in geriatric research to provide validated measures of health status, quality of life and functional ability outcomes. BEDRoC will coordinate with the Administrative and Mentoring Core to integrate community advisors in guiding their activities in support of the RPLs. BEDRoC will also enable research collaboration with and within the larger Dartmouth and IDeA investigator communities. The BEDRoC Core will build capacity for aging research and disseminate new resources to RPLs and PPLs, including innovative solutions created through robust community engagement. These services, resources, and solutions will ensure all projects operate in a cohesive, complementary, and collaborative manner to study approaches to improving the health of older patients with serious illness.

Improving Disease-Modifying Therapy Uptake among Patients with Multiple Sclerosis

Project Summary/Abstract Recent advances in the epidemiology of multiple sclerosis (MS) indicate that its prevalence is similar among White (238 per 100,000) and Black (226 per 100,000) populations. These data challenge historic assumptions about individuals with northern European heritage having higher risk and prevalence of MS. Evidence also suggests that MS incidence may be higher than previously recognized in the United States and increasing over time with more individuals identified and diagnosed year over year. MS continues to impose significant and growing burden on patients, healthcare systems and society. These health differences in the diagnosis, treatment and symptom management of MS in light of the increasing prevalence of MS in the US are an important public health issue that requires broader urgent research and policy attention to reduce the overall disease burden. In this study, we will use real-world data derived from the electronic health records (EHR) from four large academic medical centers (University of Kentucky, University of Virginia, Virginia Commonwealth University, and University of Southern California). Extracted EHR data from these four medical centers will be deidentified, combined, and harmonized. We will use this combined data set to examine (1) whether there are any differences in the timely treatment of disease modifying therapy (DMT) among different MS populations, (2) any disparities in the management of symptoms and comorbidities, (3) how non-medical factors of health such as income, education, and health insurance status (patientlevel), linguistically appropriate care provision (provider-level), and neighborhood factors (system-level) affect these outcomes and influence disparities across populations, and (4) assess whether disparities exist in the risks of cardiovascular disease CVD and mortality in MS subgroups and examine if these disparities can be reduced with improved treatment of MS and vascular comorbidities. In pursuing these objectives, we will identify clinical solutions (e.g., optimal DMT sequences) and non-medical factors such as neighborhood factors such as poverty, educational achievement, crime rates, civic participation, and housing quality, access to care factors, and cultural and linguistic match between providers and patients that substantially contribute to health disparities. For actionable solutions, we will rank-order these factors by their relative importance in addressing disparities, which will guide decision-making at the policy, system, and provider level. Our long-term objective is to develop public health strategies and scalable solutions to reduce overall burden in the management of MS. This project is expected to help policy makers and health system administrators in prioritizing interventions and to have implications for clinical practice in improving care of all patients with MS in neurology clinics, at the healthcare system level, and for national health policy.

Mechanisms and consequences of cerebrovascular dysfunction in preeclampsia

PROJECT SUMMARY/ABSTRACT Preeclampsia (PE) is a common hypertensive disorder of pregnancy that causes significant maternal and fetal morbidity and mortality worldwide. PE women are at a high risk of stroke, including intracerebral hemorrhage, during the peripartum period, suggesting the sequelae of PE adversely impacts the cerebral circulation to promote hemorrhage. In addition, women with severe early-onset PE are at an 85-fold increased risk of death from intracerebral hemorrhage, importantly suggesting severity of disease promotes greater vulnerability of the cerebral circulation to degradation and rupture. However, the consequences of PE extend far beyond pregnancy and are associated with excessive cardiovascular and cerebrovascular disease risk later in life. Women with previous pregnancy complicated by PE can develop cognitive impairment as early as in their 30’s and 40’s, suggesting PE predisposes the brain to early-onset cognitive impairment. Studies have shown that formerly PE women have changes in gray matter volume and increased white matter lesion burden that occurs as a function of time from pregnancy, suggesting that PE continues to progressively damage the brain long after the affected pregnancy. Thus, our overall goal is to elucidate mechanisms by which women with PE are at risk of intracerebral hemorrhage in pregnancy and cognitive decline later in life. Our preliminary studies found greater vascular degradation, hematoma and cerebral edema in a model of severe PE that was associated with vascular inflammation and microglia activation (neuroinflammation). In addition, we found endothelial dysfunction and diminished neurovascular coupling in PE rats that persisted 5 months postpartum. Impaired neurovascular coupling is well-recognized as an underlying contributor to cognitive decline. These effects in postpartum animals with previous exposure to PE were associated with memory impairment that was not present in the pregnant state, suggesting neurovascular dysfunction precedes cognitive decline. Our central hypothesis is that the sequela of PE accelerates hypertension-induced cerebrovascular dysfunction that predisposes to intracerebral hemorrhage during pregnancy and its persistence postpartum results in early-onset cognitive decline. We will therefore elucidate mechanisms by which PE accelerates vascular degradation and worsens outcome from hemorrhagic stroke, probing pathways involved in oxidative degradative processes using multi-omics and multivariate analysis (Aim 1). We will also determine underlying molecular mechanisms that cause persistent cerebral microvascular dysfunction and cognitive decline postpartum, including oxidative stress-induced BBB leakage and persistent neuroinflammation that drives potassium channel dysfunction, reduced neurovascular coupling and neurovascular uncoupling (Aim 2). We will also use machine learning approaches together with multi-omics and outcome measures to identify factors and cellular pathways that are most impactful for prediction of intracerebral hemorrhage and cognitive impairment. The ability to predict and prevent devasting neurovascular disorders associated with PE has the potential to have long-lasting impacts on the lives of women with PE.

Tbx4-Driven Pulmonary Hypertension: Mechanisms and Therapeutic Targets

Project Summary: Heterozygous rare variants in TBX4 are the second most common cause of heritable pulmonary arterial hypertension (PAH). Presentation of this form is commonly in children. Patients with mutations in TBX4 generally have alveolar simplification or hypoplasia in addition to elevated pulmonary vascular resistance. We have developed a set of three tools to help determine the molecular etiology of TBX4-induced PAH; (1) we identified the direct binding targets using a combination of ChIP-seq and RNA-seq; (2) we developed a mouse model with Tbx4 knockout after birth, that substantially phenocopies human disease; (3) we performed single-cell RNA-seq on these mice. By combining these three tools, we can develop a complete model for how loss of a transcription factor leads to the molecular and physiologic changes we see in our mice. The phenotype in mice appears to be dominated by defects in pericytes, resulting in impaired angiogenesis. Pericytes, which strongly express Tbx4, are cells located on the outside of capillaries and precapillary arterioles, and can either stabilize vessels (mesh pericytes), or drive angiogenesis (angiogenic pericytes). The pericytes in Tbx4 mutant mice are heavily skewed towards mesh and away from the angiogenic phenotype. Loss of Tbx4 results in derepression of Tbx4 binding target Rgs5 (10x induction), which directly results in inhibition of Pi3K, and the phenotypic switch in pericytes. We will test this hypothesis through pericyte-specific Tbx4 knockout (Aim 1) and pharmacologic induction of Pi3K in vivo in prevention and rescue models, as well as by siRNA to Rgs5 in precision-cut lung slices from Tbx4 KO mice (Aim 3). We will also test the role of Tbx4 in fibroblasts and smooth muscle using cell-specific knockouts – based on our mouse and single cell data, we expect they contribute somewhat, but primarily through increased stiffness (Aim 2). Finally, we will confirm relevance to human disease through spatial transcriptomics in lung sections explanted from patients with TBX4 mutation or rearrangement (Aim 1), and through determining whether defects in human patient iPSC-derived pericytes can be corrected through Rgs5 or Pi3K interventions (Aim 3). In combination, these aims determine the cellular and molecular mechanisms leading from mutation to physiology with loss of TBX4, and establish therapeutic targets.

Role of stress signals in the pathogenesis of pulmonary veno-occlusive disease

PROJECT SUMMARY/ABSTRACT Pulmonary veno-occlusive disease (PVOD) is a subclass of pulmonary hypertension characterized by preferential remodeling of the pulmonary venules and capillaries, and currently, there are no efficacious drug therapies. The clinical presentations and the radiographic findings of PVOD are indistinguishable from PAH, and therefore, it is often misclassified as PAH. However, the application of PAH therapeutics to PVOD patients leads to life-threatening pulmonary edema, thus, there is a critical need for diagnostic methods that accurately differentiate PVOD from PAH. Genetically, PVOD is associated with biallelic loss of function (LOF) mutations in the EIF2AK4 gene encoding GCN2. GCN2 phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2α), shuts down protein synthesis, and activates the integrated stress response (ISR). However, the molecular mechanisms connecting the loss of GCN2 with pulmonary vascular remodeling are poorly understood. Recent studies find that biallelic EIF2AK4 mutations are identified in ~9% of PAH patients. Conversely, heterozygous mutations in the BMPR2 gene, a leading cause of PAH, have been reported in PVOD patients. These results suggest that (i) PVOD and PAH share some of the pathophysiological mechanisms, and (ii) the presence of EIF2AK4 or BMPR2 mutations does not provide an accurate genetic diagnosis for PVOD. The long-term goal of this proposal is to elucidate the pathophysiological mechanisms involved in remodeling not only pulmonary arterioles but also venules and capillaries and develop those pathways as potential therapies for POVD. It has been observed that cancer patients administered with the chemotherapeutic agent mitomycin-C (MMC) rapidly develop PVOD. Rats administered with MMC develop PVOD-like phenotypes, including right ventricular (RV) hypertrophy, increased RV systolic pressure, and pulmonary vascular lesions in arteries and veins. We found that Rad51, an essential enzyme for double-strand DNA break repair, associates with VE-Cad in the vascular endothelium; however, upon MMC treatment, Rad51 and VE-Cad complex (VRC) were released into the circulation, resulting in increased vascular permeability and reduced barrier integrity. MMC treatment also mediates the depletion of GCN2, which recapitulates the genetic cause of PVOD (LOF EIF2AK4 mutations). Based on these data, this proposal will test the hypothesis that the vascular remodeling in PVOD involves (i) the release of VRC, (ii) the aberrant protein synthesis due to the activation of ISR, and (iii) the mechanism of maladaptive ISR activation. Finally, we will explore the potential application of the circulating VRC as a blood biomarker for PVOD.

Effects of Apolipoprotein A4 on Lipid Metabolism via Sympathetic Regulation

Obesity increases the risks and progression of hypertriglyceridemia, metabolic dysfunction- associated steatotic liver disease (MASLD), and cardiovascular diseases. Previous studies demonstrate that a single injection of apolipoprotein A4 (APOA4) elevates sympathetic neural activity and fatty acid β-oxidation in adipose tissues; and consistent infusion of APOA4 in obese mice fed a high-fat diet lowers fat mass, reduces hypertriglyceridemia, elevates brown adipose tissue thermogenesis, and attenuates steatosis and enhances sympathetic neural activity in the liver. This project hypothesizes that APOA4 reduces hypertriglyceridemia by regulating lipid metabolism through sympathetic stimulation in adipose tissues (Specific Aim 1) and sympathetic action in the liver (Specific Aim 2). The role of sympathetic action via the neurotransmitter norepinephrine and adrenergic receptor-mediated pathways will be investigated, and their necessity in APOA4-mediated lipid metabolism will be tested. A strength of this project is the interdisciplinary collaboration between investigators with established successful collaboration and publications. The project will provide physiological, molecular, and neurochemical mechanisms underlying how APOA4 differentially regulates metabolism through sympathetic activation in various types of adipose tissues and the liver in male and female obese mice. Findings would provide impetus to develop unique, novel, targeted therapeutic applications against hypertriglyceridemia and MASLD. Importantly, this project will expose undergraduates and graduate students to meritorious research, provide students with hands-on biomedical research experience, and strengthen research environment at R15 eligible institutions.

From Evidence to Scale: Implementation Science and Simulation Modeling to Transform HIV-Hypertension Care Integration

Project Summary As HIV programs mature, cardiovascular disease (CVD) is becoming a leading contributor to morbidity and mortality. Integration of HIV and CVD prevention, with a focus on hypertension–the most prevalent and impactful modifiable CVD risk factor, presents an opportunity to build more robust primary health systems that improve health outcomes and advance health system sustainability–a key priority for the U.S. PEPFAR program. Using an expanded version of the HIV Synthesis microsimulation model—which incorporates hypertension and CVD outcomes—and data from the NHLBI-funded HLB-SIMPLe consortium’s cluster randomized trials in six African countries, we will evaluate the health effects, cost-effectiveness, and scalability of implementation strategies to promote HIV-hypertension integration to improve health outcomes for people with and without HIV under a range of health system constraints. Our first aim is to develop and validate an additional layer to HIV Synthesis model that accounts for health system constraints and implementation strategies for integration of HIV and hypertension care. This will include parameterization using data from the WHO Health System Building Blocks framework and empiric data from trials in the HLB-SIMPLe consortium. Our second aim is to evaluate the health effects and cost-effectiveness of implementation strategies for HIV-hypertension integration to identify the most effective and scalable approaches for settings with varying health system constraints representative of conditions in west, east, and southern Africa. Analyses will include scenarios targeting people with HIV and scaling up to the broader population. Our third aim focuses on engaging policymakers and program managers to promote uptake of findings through dissemination workshops and interactive modeling tools, with tailored model outputs to specific health system contexts. Using qualitative interviews with policymakers, we will use the Weiss schema for conceptualizing research utilization to assess model impact on decision-making. We will use the Translational Science Benefits Model, to capture, classify and conceptualize the clinical, policy, economic, and operational impacts and identify barriers and facilitators to use in country programs focused on HIV, hypertension, and related NCDs. The overarching project goal is to inform evidence-based, cost-effective implementation strategies for integrating NCD care into HIV platforms, improving population health outcomes in Africa and advancing implementation science through generalizable knowledge about the intersection of implementation strategies, health system strength, and service integration.

Programming Offspring Metabolism: The Role of Milk Extracellular Vesicles in Fat Development

SUMMARY Obesity is a global health crisis, contributing significantly to the prevalence of metabolic disorders, cardiovascular diseases, and various chronic conditions. A growing body of evidence suggests that maternal obesity during pregnancy and lactation can predispose offspring to obesity and metabolic dysfunction later in life. However, the mechanisms by which maternal obesity programs these adverse outcomes in offspring remain poorly understood. Breast milk is not only a source of essential nutrients but also contains bioactive components, including extracellular vesicles (EVs), which play crucial roles in cellular communication and development. Recent studies have shown that EVs can survive digestion and enter the infant’s circulation, influencing immune and metabolic development. Despite the established link between maternal obesity and altered breast milk composition, no study has investigated the role of milk-derived EVs (mEVs) in programming offspring fat development and metabolism. Understanding this novel pathway could revolutionize our approach to preventing intergenerational transmission of obesity. Our preliminary studies using a mouse model of maternal high-fat diet-induced obesity revealed significant alterations in mEV biogenesis and cargo composition, including changes in specific miRNAs. Oral administration of mEVs from obese dams to neonatal mice increased adiposity and impaired lipid metabolism, indicating that mEVs are crucial in modulating fat development and metabolic pathways in offspring. Several key miRNAs found in mouse mEVs are conserved in human milk EVs, highlighting the potential translational relevance of our findings to human health. We hypothesize that mEVs are critical mediators of maternal obesity’s programming effects on offspring metabolism and adiposity. In specific aim 1, we will use mouse models and advanced molecular techniques (miRNA sequencing, proteomics, and lipidomics) to characterize how maternal obesity affects mEV biogenesis and the composition of their bioactive cargo. We will also evaluate how maternal dietary intake, independent of obesity, influences mEV composition. Specific aim 2 will define the programming effects of mEVs on offspring energy metabolism and obesity. In addition, we will explore whether human milk EVs from lean and obese mothers exert similar programming effects on fat development and metabolism in a mouse model. This R21 application embodies a high-risk, high-reward approach to obesity research. It ventures into uncharted territory by proposing that mEVs are novel regulators of metabolic programming, a concept that has not been explored in prior studies. The potential reward is substantial: discovering a new mechanism by which maternal obesity influences offspring health could fundamentally shift our understanding of early-life metabolic programming and lead to innovative strategies for obesity prevention. If successful, this research could open a new field of study with broad implications for maternal and child health.

Primary cilia protein IFT88 governs smooth muscle phenotype and vascular remodeling

Project Summary/Abstract Cardiovascular disease remains the leading cause of death in the United States, accounting for nearly 1 million deaths in 2022. Vascular diseases such as atherosclerosis, aneurysm, and coronary artery disease are regulated largely by smooth muscle cells (SMCs) residing in the blood vessel wall. The central dogma of vascular SMC biology is that differentiated cells can de-differentiate and give rise to a spectrum of alternative phenotypes promoting invasion, proliferation, fibrosis, and inflammation, but the mechanisms regulating SMC phenotypic transitions are poorly understood. Intraflagellar transport 88 (IFT88) is an essential protein for the formation of primary cilia, centriole-associated plasma membrane organelles that project into the extracellular milieu and regulate cell cycle reentry and responses to stimuli like growth factors and mechanical strain. Non- ciliary functions of IFT88 also include progression of the cell cycle checkpoint and polarized motility, both of which are functionally critical for SMC-mediated vascular remodeling. Little is known about the functional role of the primary cilia in SMCs and the role of the essential cilia protein IFT88 in regulating SMC phenotype. To address this gap in knowledge, my postdoctoral studies focus on the role of IFT88 in the context of intimal hyperplasia (K99). During the independent phase (R00), I will apply these findings to arteriovenous fistula (AVF) maturation, a surgical intervention often required for dialysis individuals with polycystic kidney disease (PKD), an IFT88 loss-of-function disease. I will test my central hypothesis that cilia are key regulators of SMC phenotype in three Specific Aims: 1) determine the role of IFT88-dependent SMC primary cilia in mechanotransduction of extracellular matrix (ECM) stiffness (K99), 2) determine the role of IFT88 in pathological intimal hyperplasia (K99), and 3) test whether SMC IFT88 expression is required for adaptive remodeling of grafted veins following AVF placement (R00). Overall, we propose that IFT88+ ciliated SMC represent an unidentified subclass of the SMC phenotype spectrum that is primarily responsible for vascular remodeling and is an attractive potential target for treatment of vascular diseases. Building on strong existing collaborations, we have formed a research and mentoring team with expertise in SMC pathophysiology, primary cilia biology, mechanobiology, AVF surgery, and PKD to complete the proposed aims. The additional training in cell-ECM interactions (Aim 1, K99), in vivo murine ligation injury and in vivo cilia imaging (Aim 2, K99), and AVF surgery and PKD pathology (Aim 3, R00) will be indispensable for preparing the PI, Dr. O’Brien, for his career as an independent investigator. Completion of the proposed aims will also contribute directly to an understanding of the function of IFT88-dependent primary cilia in SMCs and may likely identify novel therapeutic targets for treatment of vascular diseases.

Targeting the fibrogenic ECM as an alternative approach to treating IPF

Project Abstract Idiopathic pulmonary fibrosis and, more broadly, progressive pulmonary fibrosis are wound healing disorders whose hallmark is unorganized and unchecked extracellular matrix (ECM) deposition leading to scarring/stiffening of the lung interstitium. A highly complex, multicellular process, the generation of scar itself is primarily a function of activated fibroblasts with contributions from multiple subpopulations and non-fibroblastic cells. Myofibroblasts, the contractile cohort of activated fibroblasts, physically perturb (i.e. stretch) the local ECM microenvironment, which we have recently shown triggers site-specific, stretch-dependent conformational changes within the ECM protein fibronectin. We have previously demonstrated that a specific stretch-induced conformational change in the critical receptor binding domain of fibronectin triggers a cellular “integrin switch”, a stark change in the ECM receptors used by cells to engage fibronectin. This integrin switch is sufficient to drive activation of naïve lung fibroblasts, acquisition of mesenchymal characteristics in alveolar epithelial cells, and pathogenic remodeling of vascular structures. In this proposal we hypothesize that fibronectin displays a stretch- dependent conformational change specifically in regions of active lung fibrogenesis and that this conformational change disrupts homeostatic integrin binding dynamics in fibroblasts, leading to their acquisition of a pro-fibrogenic phenotype and transcriptional program. We address this hypothesis in a systematic way through three proposed aims. The first aim focuses on quantifying the presence and spatial localization of the stretch-induced conformational change within a cohort of lung fibrosis patient tissue samples, determining if it represents a consistent marker of active fibrogenic regions and elucidation of critical microenvironmental signatures that further expand our understanding of the impact of fibronectin's integrin switch in driving disease. In the second aim we will begin to unravel the molecular mechanism explaining how the integrin switch that emerges because of the stretch-induced conformational change drives fibroblast activation and fibrogenic gene programs using both idealized in vitro culture systems as well as ex vivo human disease tissue models. Finally, in the third aim we will explore the therapeutic potential of binding and blocking this specific stretch-induced conformation of fibronectin using a promising new and potential antibody drug in both in vivo and ex vivo models of disease.

Development of a multi-modal mouse model of cluster headache

PROJECT SUMMARY / ABSTRACT Cluster headache (CH), which affects about 1 in 1,000 people, is a severe and debilitating primary headache disorder characterized by repeated attacks occurring in clusters over weeks or months. CH has clearly defined features: severe pain (worse than childbirth), facial autonomic changes (such as a watery eye), restlessness, and a striking circadian pattern of attacks (at the same time each day like clockwork in approximately 70.5% of patients). CH also has a well-defined pathophysiology of 3 systems: the trigeminovascular pain system, the autonomic nervous system, and the hypothalamic system (in particular the posterior hypothalamus, the first brain area activated during an attack). Despite the well-known features and systems involved in CH, no disease- specific treatments are available: all CH treatments are repurposed medications from other diseases. This lack of CH-specific treatments is due in large part to the lack of a viable animal model that faithfully recapitulates the aforementioned CH features. To develop a specific animal model for CH, we previously studied a trigeminovascular headache model (repeated nitroglycerin injections), and discovered a circadian pattern of pain responses that reflects the clockwork-like pattern of attacks in CH patients. Furthermore, our analysis also identified a recently discovered CH modifier gene Mertk (MER proto-oncogene, tyrosine receptor kinase) to be highly rhythmically expressed in the trigeminal ganglion. Deletion of Mertk (Mertk-KO) altered the normal circadian rhythm of pain sensitivity by increasing pain sensitivity over 24 hours. Finally, activation of the posterior hypothalamus (via c-Fos staining) was observed after NTG administration in wild-type mice. Based on these exciting preliminary findings, we hypothesize that a combination of trigeminovascular (nitroglycerin), genetic (Mertk-KO), and hypothalamic (direct optogenetic activation of the posterior hypothalamus) manipulations will generate the first multi-modal animal model of CH. In Aim 1 (the R61 phase), we will determine the contributions of each aspect of our combined model, alone or in combination (a 4x2 grid of NTG or control, Mertk KO mouse or wild-type control, and optogenetic injection or control). Our milestone for progression to the R33 phase will be significant differences in at least two pain behaviors in our model compared to controls. In Aims 2 and 3 (the R33 phase), we will validate our model through face validity (lacrimation and restlessness), construct validity (CGRP, PACAP, and VIP in the trigeminal ganglion and hypothalamus), and predictive validity (ability of first-line and new treatments to ameliorate the pain behaviors of our model). This project is highly significant and innovative, addressing a profound need for a specific and comprehensive animal model for this devastating yet understudied disease. With the unique combination of complementary expertise in CH (laboratory and clinical), circadian biology, pharmacology, optogenetics and pain, we are ideally suited to generate this combined CH model with the goal of providing insights into CH pathophysiology and developing novel therapeutics.

Adventures in Spin Labeling: Clinical Perfusion Imaging and the Path to Technical Innovation

Arterial spin labeling (ASL) MRI has become a vital tool in clinical neuroimaging, enabling noninvasive assessment of cerebral perfusion across a range of conditions including stroke, vascular malformations, and brain tumors. With broader clinical adoption, its practical strengths — as well as important limitations — have become increasingly clear.

Neurosurgery & Consciousness: Bridging Science and Philosophy in the Age of AI

Overview of neurosurgery specialty interplay between neurology, psychiatry and neurosurgery. Discussion on benefits and disadvantages of classifications. Presentation of sub-specialties: trauma, oncology, functional, pediatric, vascular and spine. How does an ordinary day of a neurosurgeon look like; outpatient clinic, emergencies, pre/intra/post operative patient care. An ordinary operation. Myth-busting and practical insights of every day practice. An ordinary operation. Hint for research on clinical problems to be solved. The coming ethical frontiers of neuroprosthetics. In part two we will explore the explanatory gap and its significance. We will review the more than 200 theories of the hard problem of consciousness, from the prevailing to the unconventional. Finally, we are going to reflect on the AI advancements and the claims of LLMs becoming conscious

Impact of High Fat Diet on Central Cardiac Circuits: When The Wanderer is Lost

Cardiac vagal motor drive originates in the brainstem's cardiac vagal motor neurons (CVNs). Despite well-established cardioinhibitory functions in health, our understanding of CVNs in disease is limited. There is a clear connection of cardiovascular regulation with metabolic and energy expenditure systems. Using high fat diet as a model, this talk will explore how metabolic dysfunction impacts the regulation of cardiac tissue through robust inhibition of CVNs. Specifically, it will present an often overlooked modality of inhibition, tonic gamma-aminobuytric acid (GABA) A-type neurotransmission using an array of techniques from single cell patch clamp electrophysiology to transgenic in vivo whole animal physiology. It also will highlight a unique interaction with the delta isoform of protein kinase C to facilitate GABA A-type receptor expression.

How the brain barriers ensure CNSimmune privilege”

Britta Engelhard’s research is devoted to understanding thefunction of the different brain barriers in regulating CNS immunesurveillance and how their impaired function contributes toneuroinflammatory diseases such as Multiple Sclerosis (MS) orAlzheimer’s disease (AD). Her laboratory combines expertise invascular biology, neuroimmunology and live cell imaging and hasdeveloped sophisticated in vitro and in vivo approaches to studyimmune cell interactions with the brain barriers in health andneuroinflammation.

Brain-heart interactions at the edges of consciousness

Various clinical cases have provided evidence linking cardiovascular, neurological, and psychiatric disorders to changes in the brain-heart interaction. Our recent experimental evidence on patients with disorders of consciousness revealed that observing brain-heart interactions helps to detect residual consciousness, even in patients with absence of behavioral signs of consciousness. Those findings support hypotheses suggesting that visceral activity is involved in the neurobiology of consciousness and sum to the existing evidence in healthy participants in which the neural responses to heartbeats reveal perceptual and self-consciousness. Furthermore, the presence of non-linear, complex, and bidirectional communication between brain and heartbeat dynamics can provide further insights into the physiological state of the patient following severe brain injury. These developments on methodologies to analyze brain-heart interactions open new avenues for understanding neural functioning at a large-scale level, uncovering that peripheral bodily activity can influence brain homeostatic processes, cognition, and behavior.

Blood-brain barrier dysfunction in epilepsy: Time for translation

The neurovascular unit (NVU) consists of cerebral blood vessels, neurons, astrocytes, microglia, and pericytes. It plays a vital role in regulating blood flow and ensuring the proper functioning of neural circuits. Among other, this is made possible by the blood-brain barrier (BBB), which acts as both a physical and functional barrier. Previous studies have shown that dysfunction of the BBB is common in most neurological disorders and is associated with neural dysfunction. Our studies have demonstrated that BBB dysfunction results in the transformation of astrocytes through transforming growth factor beta (TGFβ) signaling. This leads to activation of the innate neuroinflammatory system, changes in the extracellular matrix, and pathological plasticity. These changes ultimately result in dysfunction of the cortical circuit, lower seizure threshold, and spontaneous seizures. Blocking TGFβ signaling and its associated pro-inflammatory pathway can prevent this cascade of events, reduces neuroinflammation, repairs BBB dysfunction, and prevents post-injury epilepsy, as shown in experimental rodents. To further understand and assess BBB integrity in human epilepsy, we developed a novel imaging technique that quantitatively measures BBB permeability. Our findings have confirmed that BBB dysfunction is common in patients with drug-resistant epilepsy and can assist in identifying the ictal-onset zone prior to surgery. Current clinical studies are ongoing to explore the potential of targeting BBB dysfunction as a novel treatment approach and investigate its role in drug resistance, the spread of seizures, and comorbidities associated with epilepsy.

Neurovascular Interactions: Mechanisms, Imaging, Therapeutics

Astrocyte reprogramming / activation and brain homeostasis

Astrocytes are multifunctional glial cells, implicated in neurogenesis and synaptogenesis, supporting and fine-tuning neuronal activity and maintaining brain homeostasis by controlling blood-brain barrier permeability. During the last years a number of studies have shown that astrocytes can also be converted into neurons if they force-express neurogenic transcription factors or miRNAs. Direct astrocytic reprogramming to induced-neurons (iNs) is a powerful approach for manipulating cell fate, as it takes advantage of the intrinsic neural stem cell (NSC) potential of brain resident reactive astrocytes. To this end, astrocytic cell fate conversion to iNs has been well-established in vitro and in vivo using combinations of transcription factors (TFs) or chemical cocktails. Challenging the expression of lineage-specific TFs is accompanied by changes in the expression of miRNAs, that post-transcriptionally modulate high numbers of neurogenesis-promoting factors and have therefore been introduced, supplementary or alternatively to TFs, to instruct direct neuronal reprogramming. The neurogenic miRNA miR-124 has been employed in direct reprogramming protocols supplementary to neurogenic TFs and other miRNAs to enhance direct neurogenic conversion by suppressing multiple non-neuronal targets. In our group we aimed to investigate whether miR-124 is sufficient to drive direct reprogramming of astrocytes to induced-neurons (iNs) on its own both in vitro and in vivo and elucidate its independent mechanism of reprogramming action. Our in vitro data indicate that miR-124 is a potent driver of the reprogramming switch of astrocytes towards an immature neuronal fate. Elucidation of the molecular pathways being triggered by miR-124 by RNA-seq analysis revealed that miR-124 is sufficient to instruct reprogramming of cortical astrocytes to immature induced-neurons (iNs) in vitro by down-regulating genes with important regulatory roles in astrocytic function. Among these, the RNA binding protein Zfp36l1, implicated in ARE-mediated mRNA decay, was found to be a direct target of miR-124, that be its turn targets neuronal-specific proteins participating in cortical development, which get de-repressed in miR-124-iNs. Furthermore, miR-124 is potent to guide direct neuronal reprogramming of reactive astrocytes to iNs of cortical identity following cortical trauma, a novel finding confirming its robust reprogramming action within the cortical microenvironment under neuroinflammatory conditions. In parallel to their reprogramming properties, astrocytes also participate in the maintenance of blood-brain barrier integrity, which ensures the physiological functioning of the central nervous system and gets affected contributing to the pathology of several neurodegenerative diseases. To study in real time the dynamic physical interactions of astrocytes with brain vasculature under homeostatic and pathological conditions, we performed 2-photon brain intravital imaging in a mouse model of systemic neuroinflammation, known to trigger astrogliosis and microgliosis and to evoke changes in astrocytic contact with brain vasculature. Our in vivo findings indicate that following neuroinflammation the endfeet of activated perivascular astrocytes lose their close proximity and physiological cross-talk with vasculature, however this event is at compensated by the cross-talk of astrocytes with activated microglia, safeguarding blood vessel coverage and maintenance of blood-brain integrity.

Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer's disease

Obesity and Brain – Bidirectional Influences

The regulation of body weight relies on homeostatic mechanisms that use a combination of internal signals and external cues to initiate and terminate food intake. Homeostasis depends on intricate communication between the body and the hypothalamus involving numerous neural and hormonal signals. However, there is growing evidence that higher-level cognitive function may also influence energy balance. For instance, research has shown that BMI is consistently linked to various brain, cognitive, and personality measures, implicating executive, reward, and attentional systems. Moreover, the rise in obesity rates over the past half-century is attributed to the affordability and widespread availability of highly processed foods, a phenomenon that contradicts the idea that food intake is solely regulated by homeostasis. I will suggest that prefrontal systems involved in value computation and motivation act to limit food overconsumption when food is scarce or expensive, but promote over-eating when food is abundant, an optimum strategy from an economic standpoint. I will review the genetic and neuroscience literature on the CNS control of body weight. I will present recent studies supporting a role of prefrontal systems in weight control. I will also present contradictory evidence showing that frontal executive and cognitive findings in obesity may be a consequence not a cause of increased hunger. Finally I will review the effects of obesity on brain anatomy and function. Chronic adiposity leads to cerebrovascular dysfunction, cortical thinning, and cognitive impairment. As the most common preventable risk factor for dementia, obesity poses a significant threat to brain health. I will conclude by reviewing evidence for treatment of obesity in adults to prevent brain disease.

Taking the pulse of ageing: the role of cerebrovascular risk factors in ageing and dementia

Cerebrovascular support is critical for healthy cognitive ageing. Reduced cerebral blood flow in ageing is caused, among other things, by hypertension, arteriosclerosis (i.e. stiffening of the arteries) and plaque formation. Arterial stiffness is predictive of cognitive decline, is a critical risk factor for cerebrovascular accidents, and has been linked to heightened risks for Alzheimer’s Disease and other forms of dementia. The elasticity of cerebral arteries is influenced by lifestyle factors, including cardiorespiratory fitness. Monica will discuss data obtained in their laboratory with new noninvasive measures of cerebrovascular health (pulse-DOT, a diffuse optical tomographic method for studying cerebral arteriosclerosis), in conjunction with structural and functional brain measures and cognitive assessments. These findings support a model in which localised changes in arteriosclerosis lead to specific profiles of structural, functional, and cognitive declines, paving a way to individualised interventions.

MBI Webinar on preclinical research into brain tumours and neurodegenerative disorders

WEBINAR 1 Breaking the barrier: Using focused ultrasound for the development of targeted therapies for brain tumours presented by Dr Ekaterina (Caty) Salimova, Monash Biomedical Imaging Glioblastoma multiforme (GBM) - brain cancer - is aggressive and difficult to treat as systemic therapies are hindered by the blood-brain barrier (BBB). Focused ultrasound (FUS) - a non-invasive technique that can induce targeted temporary disruption of the BBB – is a promising tool to improve GBM treatments. In this webinar, Dr Ekaterina Salimova will discuss the MRI-guided FUS modality at MBI and her research to develop novel targeted therapies for brain tumours. Dr Ekaterina (Caty) Salimova is a Research Fellow in the Preclinical Team at Monash Biomedical Imaging. Her research interests include imaging cardiovascular disease and MRI-guided focused ultrasound for investigating new therapeutic targets in neuro-oncology. - WEBINAR 2 Disposition of the Kv1.3 inhibitory peptide HsTX1[R14A], a novel attenuator of neuroinflammation presented by Sanjeevini Babu Reddiar, Monash Institute of Pharmaceutical Sciences The voltage-gated potassium channel (Kv1.3) in microglia regulates membrane potential and pro-inflammatory functions, and non-selective blockade of Kv1.3 has shown anti-inflammatory and disease improvement in animal models of Alzheimer’s and Parkinson’s diseases. Therefore, specific inhibitors of pro-inflammatory microglial processes with CNS bioavailability are urgently needed, as disease-modifying treatments for neurodegenerative disorders are lacking. In this webinar, PhD candidate Ms Sanju Reddiar will discuss the synthesis and biodistribution of a Kv1.3-inhibitory peptide using a [64Cu]Cu-DOTA labelled conjugate. Sanjeevini Babu Reddiar is a PhD student at the Monash Institute of Pharmaceutical Sciences. She is working on a project identifying the factors governing the brain disposition and blood-brain barrier permeability of a Kv1.3-blocking peptide.

Lifestyle, cardiovascular health, and the brain

Lifestyle factors such as sleep, diet, stress, and exercise, profoundly influence cardiovascular health. Seeking to understand how lifestyle affects our biology is important for at least two reasons. First, it can expose a particular lifestyle’s biological impact, which can be leveraged for adopting specific public health policies. Second, such work may identify crucial molecular mechanisms central to how the body adapts to our environments. These insights can then be used to improve our lives. In this talk, I will focus on recent work in the lab exploring how lifestyle factors influence cardiovascular health. I will show how combining tools of neuroscience, hematology, immunology, and vascular biology helps us better understand how the brain shapes leukocytes in response to environmental perturbations. By “connecting the dots” from the brain to the vessel wall, we can begin to elucidate how lifestyle can both maintain and perturb salutogenesis.

The Role of Cerebrovascular Pathology in Aging and Neurodegenerative Disease Populations

Late-life cognitive impairment and dementia are heterogeneous and multifactorial conditions driven by a combination of genetic, vascular, and lifestyle-related factors. More than 75% of patients with dementia have evidence of cerebrovascular pathology at autopsy. Cerebrovascular disease lesions can be detected on structural MRI and used as biomarkers to determine the extent of cerebrovascular pathology. These biomarkers are associated with cognitive difficulties and increase the risk of dementia for the same level of neurodegenerative pathology. Given that some of the risk factors for cerebrovascular disease are potentially modifiable, identifying the role of cerebrovascular pathology in aging and neurodegenerative disease populations opens a window for prevention of cognitive decline and dementia.

Dissecting the neural circuits underlying prefrontal regulation of reward and threat responsivity in a primate

Gaining insight into the overlapping neural circuits that regulate positive and negative emotion is an important step towards understanding the heterogeneity in the aetiology of anxiety and depression and developing new treatment targets. Determining the core contributions of the functionally heterogenous prefrontal cortex to these circuits is especially illuminating given its marked dysregulation in affective disorders. This presentation will review a series of studies in a new world monkey, the common marmoset, employing pathway-specific chemogenetics, neuroimaging, neuropharmacology and behavioural and cardiovascular analysis to dissect out prefrontal involvement in the regulation of both positive and negative emotion. Highlights will include the profound shift of sensitivity away from reward and towards threat induced by localised activations within distinct regions of vmPFC, namely areas 25 and 14 as well as the opposing contributions of this region, compared to orbitofrontal and dorsolateral prefrontal cortex, in the overall responsivity to threat. Ongoing follow-up studies are identifying the distinct downstream pathways that mediate some of these effects as well as their differential sensitivity to rapidly acting anti-depressants.

Why is the suprachiasmatic nucleus such a brilliant circadian time-keeper?

Circadian clocks dominate our lives. By creating and distributing an internal representation of 24-hour solar time, they prepare us, and thereby adapt us, to the daily and seasonal world. Jet-lag is an obvious indicator of what can go wrong when such adaptation is disrupted acutely. More seriously, the growing prevalence of rotational shift-work which runs counter to our circadian life, is a significant chronic challenge to health, presenting as increased incidence of systemic conditions such as metabolic and cardiovascular disease. Added to this, circadian and sleep disturbances are a recognised feature of various neurological and psychiatric conditions, and in some cases may contribute to disease progression. The “head ganglion” of the circadian system is the suprachiasmatic nucleus (SCN) of the hypothalamus. It synchronises the, literally, innumerable cellular clocks across the body, to each other and to solar time. Isolated in organotypic slice culture, it can maintain precise, high-amplitude circadian cycles of neural activity, effectively, indefinitely, just as it does in vivo. How is this achieved: how does this clock in a dish work? This presentation will consider SCN time-keeping at the level of molecular feedback loops, neuropeptidergic networks and neuron-astrocyte interactions.

Monash Biomedical Imaging highlights from 2021 and looking ahead to 2022

Despite the challenges COVID-19 has continued to present, Monash Biomedical Imaging (MBI) has had another outstanding year in terms of publications and scientific output. In this webinar, Professor Gary Egan, Director of MBI, will present an overview of MBI’s achievements during 2021 and outline the biomedical imaging research programs and partnerships in 2022. His presentation will cover: • MBI operational and research achievements during 2021 • Biomedical imaging technology developments and research outcomes during 2021 • Linked laboratories and research teams at MBI • Progress on the development of a cyclotron and precision radiopharmaceutical facility at Clayton • Emerging research opportunities at the Monash Heart Hospital in cardiology and cardiovascular disease. Professor Gary Egan is Director of Monash Biomedical Imaging, Director of the ARC Centre of Excellence for Integrative Brain Function and a Distinguished Professor at the Turner Institute for Brain and Mental Health, Monash University. He is also lead investigator of the Victorian Biomedical Imaging Capability, and Deputy Director of the Australian National Imaging Facility. His substantive body of published work has made a significant impact on the neuroimaging and neuroscience fields. He has sustained success in obtaining significant grants to support his own research and the development of facilities to advance biomedical imaging.

​Improving the identification of cardiometabolic risk in early psychosis

People with chronic schizophrenia die on average 10-15 years sooner than the general population, mostly due to physical comorbidity. While sociodemographic, chronic lifestyle and iatrogenic factors are important contributors to this comorbidity, a growing body of research is beginning to suggest that early signs of cardiometabolic dysfunction may be present from the onset of psychosis in some young adults, and may even be detectable before the onset of psychosis. Given that primary prevention is the best means to prevent the onset of more chronic and severe cardiometabolic phenotypes such as CVD, there is clear need to be able to identify young adults with psychosis who are most at risk of future adverse cardiometabolic outcomes, such that the most intensive interventions can be directed in an informed way to attenuate the risk or even prevent those adverse outcomes from occurring.In this talk, Ben will first outline some recent advances in our understanding of the association between cardiometabolic and schizophrenia spectrum disorders. He will then introduce the field of cardiometabolic risk prediction, and highlight how existing tools developed for older general population adults are unlikely to be suitable for young people with psychosis. Finally, he will discuss the current state of play and the future of the Psychosis Metabolic Risk Calculator (PsyMetRiC), a novel clinically useful cardiometabolic risk prediction algorithm tailored for young people with psychosis, which has been developed and externally validated using data from three psychosis early intervention services in the UK.

Neurovascular signaling pathways in the mammalian retina

As a developmental outpocket of the brain, the retina exhibits features commonly found in most brain areas, including neurovascular interactions. In this presentation I will discuss various pathways that contribute to neurovascular interactions in the mammalian retina and present newly uncovered elements that likely participate in these pathways. Information obtained from retina could improve our understanding of neurovascular coupling pathways throughout the brain.

Identification and treatment of advanced, rupture-prone plaques to reduce cardiovascular mortality

Atherosclerosis is the underlying cause of major cardiovascular events, including heart attack and stroke. The build-up of plaque in coronary arteries can be a major risk for events, but risk is significantly higher in patients with vulnerable rather than stable plaque. Diagnostic imaging of vulnerable plaque is extremely useful for both stratifying patient risk and for determining effectiveness of experimental intervention in reducing cardiovascular risk. In the preclinical setting, being able to distinguish between stable and vulnerable plaque development and pair this with biochemical measures is critical for identification of new experimental candidates. In this webinar, Professor Stephen Nicholls and Dr Kristen Bubb from the Victorian Heart Institute will discuss the benefits of being able to visualise vulnerable plaque for both clinical and preclinical research. Professor Stephen Nicholls is a clinician-researcher and the Head of the Victorian Heart Institute. He is the lead investigator on multiple large, international, cardiovascular outcomes trials. He has attracted over $100 million in direct research funding and published more than 400 peer-reviewed manuscripts. He is focused on both therapeutic intervention to reduce vascular inflammation and lipid accumulation and precision medicine approaches to prevent cardiovascular mortality. Dr Kristen Bubb is a biomedical researcher and Group Leader within the Monash Biomedicine Discovery Institute Cardiovascular Program and Victorian Heart Institute. She focuses on preclinical/translational research into mechanisms underlying vascular pathologies including atherosclerosis and endothelium-driven hypertension within specific vascular systems, including pulmonary and pregnancy-induced. She has published >30 high impact papers in leading cardiovascular journals and attracted category 1&2 funding of >$750,000.

The influence of menstrual cycle on the indices of cortical excitability

Menstruation is a normal physiological process in women occurring as a result of changes in two ovarian produced hormones – estrogen and progesterone. As a result of these fluctuations, women experience different symptoms in their bodies – their immune system changes (Sekigawa et al, 2004), there are changes in their cardiovascular and digestive system (Millikan, 2006), as well as skin (Hall and Phillips, 2005). But these hormone fluctuations produce major changes in their behavioral pattern as well causing: anxiety, sadness, heightened irritability and anger (Severino and Moline, 1995) which is usually classified as premenstrual syndrome (PMS). In some cases these symptoms severely impair women’s lives and professional help is required. The official diagnosis according to DSM-5 (2013) is premenstrual dysphoric disorder (PMDD). Despite its ubiquitous presence the origins of PMS and PMDD are poorly understood. Some efforts to understand the underlying brain state during the menstruation cycle were performed by using TMS (Smith et al, 1999; 2002; 2003; Inghilleri et al, 2004; Hausmann et al, 2006). But all of these experiments suffer from major shortcomings - no control groups and small number of subjects. Our plan is to address all of these shortcomings and make this the biggest (to our knowledge) experiment of its kind which will, hopefully, provide us with some much needed answers.

Evidence for the role of glymphatic dysfunction in the development of Alzheimer’s disease

Glymphatic perivascular exchange is supported by the astroglial water channel aquaporin-4 (AQP4), which localizes to perivascular astrocytic endfeet surrounding the cerebral vasculature. In aging mice, impairment of glymphatic function is associated with reduced perivascular AQP4 localization, yet whether these changes contribute to the development of neurodegenerative disease, such as Alzheimer’s disease (AD), remains unknown. Using post mortem human tissue, we evaluated perivascular AQP4 localization in the frontal cortical gray matter, white matter, and hippocampus of cognitively normal subjects and those with AD. Loss of perivascular and increasing cellular localization of AQP4 in the frontal gray matter was specifically associated with AD status, amyloid β (Aβ) and tau pathology, and cognitive decline in the early stages of disease. Using AAV-PHP.B to drive expression on non-perivascular AQP4 in wild type and Tg2576 (APPSwe, mouse model of Aβ deposition) mice, increased cellular AQP4 localization did not slow glymphatic function or change Aβ deposition. Using the Snta1 knockout line (which lacks perivascular AQP4 localization), we observed that loss AQP4 from perivascular endfeet slowed glymphatic function in wild type mice and accelerated Aβ plaque deposition in Tg2576 mice. These findings demonstrate that loss of perivascular AQP4 localization, and not increased cellular AQP4 localization, slows glymphatic function and promotes the development of AD pathology. To evaluate whether naturally occurring variation in the human AQP4 gene, or the alpha syntrophin (SNTA1), dystrobrevin (DTNA) or dystroglycan (DAG1) genes (whose products maintain perivascular AQP4 localization) confer risk for or protection from AD pathology or clinical progression, we evaluated 56 tag single nucleotide polymorphisms (SNPs) across these genes for association with CSF AD biomarkers, MRI measures of cortical and hippocampal atrophy, and longitudinal cognitive decline in the Alzheimer’s Disease Neuroimaging Initiative I (ADNI I) cohort. We identify 25 different significant associations between AQP4, SNTA1, DTNA, and DAG1 tag SNPs and phenotypic measures of AD pathology and progression. These findings provide complimentary human genetic evidence for the contribution of perivascular glymphatic dysfunction to the development of AD in human populations.

Metabolic and functional connectivity relate to distinct aspects of cognition

A major challenge of cognitive neuroscience is to understand how the brain as a network gives rise to our cognition. Simultaneous [18F]-fluorodeoxyglucose positron emission tomography functional magnetic resonance imaging (FDG-PET/fMRI) provides the opportunity to investigate brain connectivity not only via spatially distant, synchronous cerebrovascular hemodynamic responses (functional connectivity), but also glucose metabolism (metabolic connectivity). However, how these two modalities of brain connectivity differ in their relation to cognition is unknown. In this webinar, Dr Katharina Voigt will discuss recent findings demonstrating the advantage of simultaneous FDG-PET/fMRI in providing a more complete picture of the neural mechanisms underlying cognition, that calls for a combination of both modalities in future cognitive neuroscience. Dr Katharina Voigt is a Research Fellow within the Turner Institute for Brain and Mental Health, Monash University. Her research interests include systems neuroscience, simultaneous PET-MRI, and decision-making.

From Vulnerable Plaque to Vulnerable Brain: Understanding the Role of Inflammation in Vascular Health, Stroke, and Cerebrovascular Disease

Every year around 100,000 people in the UK will have a stroke. Stroke is a leading cause of adult disability, and cerebrovascular disease more broadly is a major cause of dementia. Understanding these diseases – both acute and chronic manifestations of cerebrovascular disease – requires consideration not only of the brain itself, but also the blood vessels supplying it. Atherosclerosis – the hardening of arteries as we age – may predispose to stroke by triggering the formation of blood clots that block the blood supply to the brain, but also involves inflammation that may cause chronic damage to the brain and prime both the brain and body for injury. Understanding this interaction between systemic disease and brain health may have important implications for our understanding of healthy ageing and provide novel therapeutic approaches for reducing the burden of cerebrovascular disease. This talk will consider how advances in imaging may facilitate our understanding of the processes underlying atherosclerosis and how it affects the brain in stroke, as well as work currently underway to translate this understanding into improving treatments for stroke.

Untitled Seminar

Isabelle Brunet (France) – Neurovascular development Debby Silver (USA) - Dynamic post-transcriptional control of cortical development Robin Vigouroux (France) – Evolution of binocular vision Patricia Garcez (Brazil) – Beyond microcephaly: how Zika virus impacts brain development

Migraine Headache: the revolution and its evolution

This seminar will focus on the extraordinary shift in migraine research during the last 4 decades with the discovery of the trigeminovascular system (TVS) and it’s major impact on pathophysiology and treatment.  Compelling evidence supporting the importance of TVS, cortical spreading depression and parameningeal inflammation will be explored as will the implications of newly discovered microvascular channels within the meninges on an attack.

The Challenge and Opportunities of Mapping Cortical Layer Activity and Connectivity with fMRI

In this talk I outline the technical challenges and current solutions to layer fMRI. Specifically, I describe our acquisition strategies for maximizing resolution, spatial coverage, time efficiency as well as, perhaps most importantly, vascular specificity. Novel applications from our group, including mapping feedforward and feedback connections to M1 during task and sensory input modulation and S1 during a sensory prediction task are be shown. Layer specific activity in dorsal lateral prefrontal cortex during a working memory task is also demonstrated. Additionally, I’ll show preliminary work on mapping whole brain layer-specific resting state connectivity and hierarchy.

Developing metal-based radiopharmaceuticals for imaging and therapy

Personalised medicine will be greatly enhanced with the introduction of new radiopharmaceuticals for the diagnosis and treatment of various cancers, as well as cardiovascular disease and brain disorders. The unprecedented interest in developing theranostic radiopharmaceuticals is mainly due to the recent clinical successes of radiometal-based products including: • 177LuDOTA-TATE (trade name Lutathera, FDA approved in 2018), a peptide-based tracer that is used for treating metastatic neuroendocrine tumours • Ga 68 PSMA-11 (FDA approved in 2020), a positron emission tomography agent for imaging prostate-specific membrane antigen positive lesions in men with prostate cancer. In this webinar, Dr Brett Paterson and PhD candidate Mr Cormac Kelderman will present their research on developing the chemistry and radiochemistry to produce new radiometal-based imaging and therapy agents. They will discuss the synthesis of new molecules, the optimisation of the radiochemistry, and results from preclinical evaluations. Dr Brett Paterson is a National Imaging Facility Fellow at Monash Biomedical Imaging and academic group leader in the School of Chemistry, Monash University. His research focuses on the development of radiochemistry and new radiopharmaceuticals. Cormac Kelderman is a PhD candidate under the supervision of Dr Brett Paterson in the School of Chemistry, Monash University. His research focuses on developing new bis(thiosemicarbazone) chelators for technetium-99m SPECT imaging.

Multimorbidity in the ageing human brain: lessons from neuropathological assessment

Age-associated dementias are neuropathologically characterized by the identification of hallmark intracellular and extracellular deposition of proteins, i.e., hyperphosphorylated-tau, amyloid-β, and α-synuclein, or cerebrovascular lesions. The neuropathological assessment and staging of these pathologies allows for a diagnosis of a distinct disease, e.g., amyloid-β plaques and hyperphosphorylated tau pathology in Alzheimer's disease. Neuropathological assessment in large scale cohorts, such as the UK’s Brains for Dementia Research (BDR) programme, has made it increasingly clear that the ageing brain is characterized by the presence of multiple age-associated pathologies rather than just the ‘pure’ hallmark lesion as commonly perceived. These additional pathologies can range from low/intermediate levels, that are assumed to have little if any clinical significance, to a full-blown mixed disease where there is the presence of two distinct diseases. In our recent paper (McAleese et al. 2021 Concomitant neurodegenerative pathologies contribute to the transition from mild cognitive impairment to dementia, https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.12291, Alzheimer's & Dementia), using the BDR cohort, we investigated the frequency of multimorbidity and specifically investigated the impact of additional low-level pathology on cognition. In this study, of 670 donated post-mortem brains, we found that almost 70% of cases exhibited multimorbidity and only 22% were considered a pure diagnosis. Importantly, no case of Lewy Body dementia or vascular dementia was considered pure. A key finding is that the presence of low levels of additional pathology increased the likelihood of having mild dementia vs mild cognitive impairment by almost 20-fold, indicating low levels of additional pathology do impact the clinical progression of a distinct disease. Given the high prevalence and the potential clinical impact, cerebral multimorbidity should be at the forefront of consideration in dementia research.

Neuronal and Vascular Dysfunction in Optic Neuropathies: New Insights from Live Imaging Studies

Magnetic Resonance Measures of Brain Blood Vessels, Metabolic Activity, and Pathology in Multiple Sclerosis

The normally functioning blood-brain barrier (BBB) regulates the transfer of material between blood and brain. BBB dysfunction has long been recognized in multiple sclerosis (MS), and there is considerable interest in quantifying functional aspects of brain blood vessels and their role in disease progression. Parenchymal water content and its association with volume regulation is important for proper brain function, and is one of the key roles of the BBB. There is convincing evidence that the astrocyte is critical in establishing and maintaining a functional BBB and providing metabolic support to neurons. Increasing evidence suggests that functional interactions between endothelia, pericytes, astrocytes, and neurons, collectively known as the neurovascular unit, contribute to brain water regulation, capillary blood volume and flow, BBB permeability, and are responsive to metabolic demands. Increasing evidence suggests altered metabolism in MS brain which may contribute to reduced neuro-repair and increased neurodegeneration. Metabolically relevant biomarkers may provide sensitive readouts of brain tissue at risk of degeneration, and magnetic resonance offers substantial promise in this regard. Dynamic contrast enhanced MRI combined with appropriate pharmacokinetic modeling allows quantification of distinct features of BBB including permeabilities to contrast agent and water, with rate constants that differ by six orders of magnitude. Mapping of these rate constants provides unique biological aspects of brain vasculature relevant to MS.

Neuroimmune interactions in Cardiovascular Diseases

The nervous system and the immune system share the common ability to exert gatekeeper roles at the interfaces between internal and external environment. Although interaction between these two evolutionarily highly conserved systems is long recognized, the pathophysiological mechanisms regulating their reciprocal crosstalk in cardiovascular diseases became object of investigation only more recently. In the last years, our group elucidated how the autonomic nervous system controls the splenic immunity recruited by hypertensive challenges. In my talk, I will focus on the molecular mechanisms that regulate the neuro-immune crosstalk in hypertension. I will elaborate on the mechanistic insights into this brain-spleen axis led us uncover a new molecular pathway mediating the neuroimmune interaction established by noradrenergic-mediated release in the spleen of placental growth factor (PlGF), an angiogenic growth factor potentially targetable with pharmacological approaches.

Untitled Seminar

Mapping early brain network changes in neurodegenerative and cerebrovascular disorders: a longitudinal perspective

The spatial patterning of each neurodegenerative disease relates closely to a distinct structural and functional network in the human brain. This talk will mainly describe how brain network-sensitive neuroimaging methods such as resting-state fMRI and diffusion MRI can shed light on brain network dysfunctions associated with pathology and cognitive decline from preclinical to clinical dementia. I will first present our findings from two independent datasets on how amyloid and cerebrovascular pathology influence brain functional networks cross-sectionally and longitudinally in individuals with mild cognitive impairment and dementia. Evidence on longitudinal functional network organizational changes in healthy older adults and the influence of APOE genotype will be presented. In the second part, I will describe our work on how different pathology influences brain structural network and white matter microstructure. I will also touch on some new data on how brain network integrity contributes to behavior and disease progression using multivariate or machine learning approaches. These findings underscore the importance of studying selective brain network vulnerability instead of individual region and longitudinal design. Further developed with machine learning approaches, multimodal network-specific imaging signatures will help reveal disease mechanisms and facilitate early detection, prognosis and treatment search of neuropsychiatric disorders.

Phospholipid regulation in cognitive impairment and vascular dementia

An imbalance in lipid metabolism in neurodegeneration is still poorly understood. Phospholipids (PLs) have multifactorial participation in vascular dementia as Alzheimer, post-stroke dementia, CADASIL between others. Which include the hyperactivation of phospholipases, mitochondrial stress, peroxisomal dysfunction and irregular fatty acid composition triggering proinflammation in a very early stage of cognitive impairment. The reestablishment of physiological conditions of cholesterol, sphingolipids, phospholipids and others are an interesting therapeutic target to reduce the progression of AD. We propose the positive effect of BACE1 silencing produces a balance of phospholipid profile in desaturase enzymes-depending mode to reduce the inflammation response, and recover the cognitive function in an Alzheimer´s animal and brain stroke models. Pointing out there is a great need for new well-designed research focused in preventing phospholipids imbalance, and their consequent energy metabolism impairment, pro-inflammation and enzymatic over-processing, which would help to prevent unhealthy aging and AD progression.

Neurological consequences of COVID-19

The speakers will outline how neurologists in Bristol have been research-active during the COVID-19 pandemic including our contribution to national and international surveillance programmes as well as initiating research studies such as an evaluation of the impact of COVID anxiety on sleep and neurodegeneration and determining whether vascular changes in the eye predict COVID-19 severity.

The immunopathology of advanced multiple sclerosis

We recently analyzed a large cohort of multiple sclerosis (MS) autopsy cases of the Netherlands Brain Bank (NBB) and showed that 57% of the lesion in advanced MS is active (containing activated microglia/macrophages). These active lesions correlated with disease severity and differed between males and female MS patients.1 Already in normal appearing white matter microglia show early signs of demyelination.5 T cells are also frequently present in advanced stages of MS and have a tissue resident memory (Trm) phenotype, are more frequently CD8+ then CD4+, are located perivascular, enriched in active and mixed active/inactive MS lesions and correlated with lesion activity, lesion load and disease severity.2-4 Like Trm cells, B cells are located perivascular and were also enriched in active MS lesions but in lower numbers and a proportion of the MS patients had almost no detectable B cells in the regions analyzed. MS patients with limited presence of B cells had less severe MS, and less active and mixed active /inactive lesions. We conclude that advanced MS is characterize by a high innate and adaptive immune activity which is heterogeneous and relates to the clinical disease course.

When spontaneous waves meet angiogenesis: a case study from the neonatal retina

By continuously producing electrical signals, neurones are amongst the most energy-demanding cells in the organism. Resting ionic levels are restored via metabolic pumps that receive the necessary energy from oxygen supplied by blood vessels. Intense spontaneous neural activity is omnipresent in the developing CNS. It occurs during short, well-defined periods that coincide precisely with the timing of angiogenesis. Such coincidence cannot be random; there must be a universal mechanism triggering spontaneous activity concurrently with blood vessels invading neural territories for the first time. However, surprisingly little is known about the role of neural activity per se in guiding angiogenesis. Part of the reason is that it is challenging to study developing neurovascular networks in tri-dimensional space in the brain. We investigate these questions in the neonatal mouse retina, where blood vessels are much easier to visualise because they initially grow in a plane, while waves of spontaneous neural activity (spreading via cholinergic starburst amacrine cells) sweep across the retinal ganglion cell layer, in close juxtaposition with the growing vasculature. Blood vessels reach the periphery by postnatal day (P) 7-8, shortly before the cholinergic waves disappear (at P10). We discovered transient clusters of auto-fluorescent cells that form an annulus around the optic disc, gradually expanding to the periphery, which they reach at the same time as the growing blood vessels. Remarkably, these cells appear locked to the frontline of the growing vasculature. Moreover, by recording waves with a large-scale multielectrode array that enables us to visualise them at pan-retinal level, we found that their initiation points are not random; they follow a developmental centre-to-periphery pattern similar to the clusters and blood vessels. The density of growing blood vessels is higher in cluster areas than in-between clusters at matching eccentricity. The cluster cells appear to be phagocytosed by microglia. Blocking Pannexin1 (PANX1) hemichannels activity with probenecid completely blocks the spontaneous waves and results in the disappearance of the fluorescent cell clusters. We suggest that these transient cells are specialised, hyperactive neurones that form spontaneous activity hotspots, thereby triggering retinal waves through the release of ATP via PANX1 hemichannels. These activity hotspots attract new blood vessels to enhance local oxygen supply. Signalling through PANX1 attracts microglia that establish contact with these cells, eventually eliminating them once blood vessels have reached their vicinity. The auto-fluorescence that characterises the cell clusters may develop only once the process of microglial phagocytosis is initiated.

Carnosine negatively modulates pro-oxidant activities of M1 peripheral macrophages and prevents neuroinflammation induced by amyloid-β in microglial cells

Carnosine is a natural dipeptide widely distributed in mammalian tissues and exists at particularly high concentrations in skeletal and cardiac muscles and brain. A growing body of evidence shows that carnosine is involved in many cellular defense mechanisms against oxidative stress, including inhibition of amyloid-β (Aβ) aggregation, modulation of nitric oxide (NO) metabolism, and scavenging both reactive nitrogen and oxygen species. Different types of cells are involved in the innate immune response, with macrophage cells representing those primarily activated, especially under different diseases characterized by oxidative stress and systemic inflammation such as depression and cardiovascular disorders. Microglia, the tissue-resident macrophages of the brain, are emerging as a central player in regulating key pathways in central nervous system inflammation; with specific regard to Alzheimer’s disease (AD) these cells exert a dual role: on one hand promoting the clearance of Aβ via phagocytosis, on the other hand increasing neuroinflammation through the secretion of inflammatory mediators and free radicals. The activity of carnosine was tested in an in vitro model of macrophage activation (M1) (RAW 264.7 cells stimulated with LPS + IFN-γ) and in a well-validated model of Aβ-induced neuroinflammation (BV-2 microglia treated with Aβ oligomers). An ample set of techniques/assays including MTT assay, trypan blue exclusion test, high performance liquid chromatography, high-throughput real-time PCR, western blot, atomic force microscopy, microchip electrophoresis coupled to laser-induced fluorescence, and ELISA aimed to evaluate the antioxidant and anti-inflammatory activities of carnosine was employed. In our experimental model of macrophage activation (M1), therapeutic concentrations of carnosine exerted the following effects: 1) an increased degradation rate of NO into its non-toxic end-products nitrite and nitrate; 2) the amelioration of the macrophage energy state, by restoring nucleoside triphosphates and counterbalancing the changes in ATP/ADP, NAD+/NADH and NADP+/NADPH ratio obtained by LPS + IFN-γ induction; 3) a reduced expression of pro-oxidant enzymes (NADPH oxidase, Cyclooxygenase-2) and of the lipid peroxidation product malondialdehyde; 4) the rescue of antioxidant enzymes expression (Glutathione peroxidase 1, Superoxide dismutase 2, Catalase); 5) an increased synthesis of transforming growth factor-β1 (TGF-β1) combined with the negative modulation of interleukines 1β and 6 (IL-1β and IL-6), and 6) the induction of nuclear factor erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1). In our experimental model of Aβ-induced neuroinflammation, carnosine: 1) prevented cell death in BV-2 cells challenged with Aβ oligomers; 2) lowered oxidative stress by decreasing the expression of inducible nitric oxide synthase and NADPH oxidase, and the concentrations of nitric oxide and superoxide anion; 3) decreased the secretion of pro-inflammatory cytokines such as IL-1β simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-β1; 4) prevented Aβ-induced neurodegeneration in primary mixed neuronal cultures challenged with Aβ oligomers and these neuroprotective effects was completely abolished by SB431542, a selective inhibitor of type-1 TGF-β receptor. Overall, our data suggest a novel multimodal mechanism of action of carnosine underlying its protective effects in macrophages and microglia and the therapeutic potential of this dipeptide in counteracting pro-oxidant and pro-inflammatory phenomena observed in different disorders characterized by elevated levels of oxidative stress and inflammation such as depression, cardiovascular disorders, and Alzheimer’s disease.

Epigenetics and Dementia: Lessons From the 20-Year Indianapolis-Ibadan Dementia Study

Dementia is of global interest because of the rapid increase in both the number of individuals affected and the population at risk. It is essential that the risk factors be carefully delineated for the formulation of preventive strategies. Epigenetics refers to external modifications that turn genes "on" or "off”, and cross-cultural studies of migrant populations provide information on the interplay of environmental factors on genetic predisposition. The Indianapolis-Ibadan Dementia Study compared the prevalence, incidence and risk factors of dementia in African Americans and Yoruba to tease out the role of epigenetics in dementia. The presentation will provide details on biomarkers of dementia, vascular risk factors and the association with apolipoprotein E in the Yoruba. The purpose will be to inspire early career researchers on possibilities and research strategies applicable in African populations

Computational modeling of neurovascular coupling at the gliovascular unit

COSYNE 2025

Assessment of vascularization and neurogenesis in an iPSC-derived 16p11.2 deletion organoid model

Astrocyte-derived HMGB1 regulates gliovascular maturation in the postnatal mouse brain

Astrocytic Ca2+ signals partake in inhibitory neurovascular coupling in a brain state-dependent manner

Bidirectional control of neurovascular coupling by pyramidal neurons

Cerebral 3D Doppler image registration based on vascular landmark automatic localization with deep neural network

Cerebrovascular reactivity to hypercapnia and neurovascular coupling explore different vascular beds

Drug lipid nano-carriers enter the injured brain at microvascular occlusions

Effect of white matter hyperintensities of vascular origin on brain power spectra profiles: a MEG study

Exposing microvascular endothelial cells to low energy accelerated protons and its relevance for hadrontherapy applications

Fibrinogen Regulates Lesion Border-Forming Reactive Astrocyte Properties after Vascular Damage

Generation of a Blood-Brain Barrier Model using Cryopreserved Human iPSC-derived Brain Microvascular Endothelial Cells, Pericytes, and Astrocytes

Heterogeneity and developmental dynamics of LYVE-1 perivascular macrophages distribution in the mouse brain

H-FABP as a biomarker of vascular brain damage in Transient Ischemic Attack

Hippocampal neurovascular coupling and spatial working memory impairment in a rodent model of type 2 diabetes: impact of dietary nitrate intervention

Identification of pro-angiogenic factors for in vitro vascularization of hiPSC-derived brain organoids

Imagery evaluation of cerebrovascular inflammation and functional consequences induced by sublethal doses of sarin surrogate: non-invasive imaging methods to predict long-term deficits

Impact of ferritin levels on outcomes after endovascular thrombectomy

Impaired dynamics of brain precapillary sphincters and pericytes at first order capillaries explains reduced neurovascular functions in aging

Improved neurocognitive outcome in the short-term following primary gamma knife radiosurgery (GKRS) for intracranial vascular anomalies

The influence of cardiovascular health in middle-aged adult populations on cognitive health in later life: a systematic review and meta-analysis

Influence of white matter hyperintensities of vascular origin on brain functional connectivity measured with MEG

Lack of abnormal cerebrovascular function in 5xFAD model of Alzheimer’s disease?

Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit

In mice and humans, brain vascular barrier homeostasis and contractility are acquired postnatally

Migration-promoting vascular scaffold in the postnatal neurogenic region: a comparison of mice and rats

A mouse model for the study of pain, affective disorders and cardiovascular comorbidity

Neurovascular dysfunction and cognitive impairment in a model of heart failure with preserved ejection fraction

Use of pCASL MRI sequence to study brain perfusion and vascular permeability after Blood Brain Barrier opening: limitations and perspectives

Preclinical study of the therapeutic efficacy on functional recovery of the adipose stromal vascular fraction after spinal contusion in the rat

Prevalence of cardiovascular disease risk factors among professional rugby union athletes: Linking cardiovascular and cognitive health in professional rugby

The protective actions of DHEA/S and BDNF against oxidative stress in an in vitro model of vascular dementia

Retinal vascular dysregulation in altitudinal visual field defects in glaucoma

The role of microvascular changes during development and progression of Parkinson’s Disease in a human alpha-synuclein overexpression mouse model (line 61)

TEM and SBF-SEM analyses of ependymal cells in spinal cord of adult rats revealed their substantial contacts to vascular basal lamina and to fractone bulbs

Spreading depolarization disrupts neurovascular coupling after global cerebral ischemia in mice

Tight junction proteins expression and cytoskeleton rearrangement are associated with brain microvascular endothelium permeabilisation in epileptogenesis

Transfer of a pharmacological neurovascular uncoupling model from mice to rats

Type 1 diabetes mediated microvascular dysfunction and impaired behavioral performance in mice

Ultrafast Doppler imaging and Ultrasound Localization Microscopy reveal vascular rearrangement's complexity in chronic spinal lesion lesion