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Ultra-High Resolution PET in Aging, Neurodegeneration and Psychotic Disorders

Conditions: Alzheimer Dementia (AD); ALS – Amyotrophic Lateral Sclerosis; Parkinson s Disease; REM Sleep Behavior Disorder (iRBD); PSP – Progressive Supranuclear Palsy; MSA – Multiple System Atrophy; Dementia With Lewy Bodies (DLB); ALS With Frontotemporal Dementia (ALS/FTD); Adult Onset Psychotic Disorder; Very Late Onset Psychotic Disorder

Interventions: Other: UHR PET/CT scan of the brain with ¹⁸F-FDG; Other: UHR PET/CT scan of the brain with ¹⁸F-PE2I; Other: UHR PET/CT scan of the brain with ¹⁸F-SynVesT-1; Other: UHR PET/CT scan of the brain with ¹⁸F-MK6240; Other: 3T MRI imaging of the brain

Sponsors: Universitaire Ziekenhuizen KU Leuven

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Low Birthweight Increases Risk of Early Stroke

Research led by the University of Gothenburg in Sweden suggests that low birthweight is a risk factor for having a stroke in younger adulthood.

In a study including just under 800,000 people, the investigators found that risk for early stroke events was 18-23% higher in men and women who had a birth weight under the median level than those with a higher birth weight.

Around 795,000 people in the U.S. have a stroke each year. Although it can affect people of any age, it is much more common in older individuals with estimates of prevalence suggesting that 0.9% of 18–44 year olds have strokes versus 3.8% of those in the 45–64 year age group and 7.7% of people aged 65 and over.

Low birth weight has been previously linked to an increased risk for stroke in several studies. Researchers think that low birth weight is an indicator of exposure to an adverse environment in the womb that may adversely affect the cardiovascular system of the fetus in a way that increases stroke risk—for example, by increasing the risk of high blood pressure.

Over the last 10-15 years, stroke prevalence has stayed the same in older adults but has gone up by 14-16% in 18-64 year-olds. Lina Lilja, a doctoral student at the University of Gothenburg, and colleagues aimed to investigate whether low birth weight increased the risk of stroke in younger adults.

They included 420,173 men and 348,758 women from Sweden who were born between 1973 and 1982 and followed up from birth until 2022. The researchers collected data on birth weight, gestational age, and body mass index in young adulthood, as well as information on first stroke and the type of stroke.

Overall, 2252 first stroke events were recorded at an average age of 36 years. Of these, 1624 were ischemic stroke (average age 37 years) and 588 were intracerebral hemorrhage (average age 33 years).

The results, which will be presented at the European Congress on Obesity in Istanbul later this year, showed that birth weight below the median (3.5kg) increased the risk for all stroke by 21%. The rates of stroke were slightly higher in men with a low birthweight at 23% versus women with a low birthweight at 18%.

Notably, gestational age at birth and young adult body mass index were not linked to stroke risk in this study.

The post Low Birthweight Increases Risk of Early Stroke appeared first on Inside Precision Medicine.

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Pancreatic Cancer Development Driven by NADPH Disruption

Researchers at the University of Michigan have uncovered metabolic pathways that explain how pancreatic cells transition from acinar-to-ductal metaplasia to pancreatic ductal adenocarcinoma (PDAC). The study, published in Nature Metabolism, detailed on how reduced production of a molecule central to biosynthesis and oxidative stress control called NADPH alters cellular conditions to favor cancer progression. By examining precancerous pancreatic lesions, the team found that disruptions in enzymes responsible for NADPH production increase oxidative stress, accelerating the formation of lesions and, in some cases, the progression to PDAC.

“We know a lot about how pancreatic tumors behave and look, but we don’t know how they become cancerous,” said lead author Megan Radyk, PhD, a former postdoc in the lab of Costas Lyssiotis, PhD, at the University of Michigan and now an assistant professor at Roswell Park Comprehensive Cancer Center. “We wanted to learn about what metabolic changes happen before you get an established tumor.”

PDAC is the most common form of pancreatic cancer and has a low five-year survival rate. The disease develops through a stepwise process that begins with acinar-to-ductal metaplasia (ADM), a reversible state in which pancreatic cells respond to injury or inflammation by adopting a duct-like phenotype. Under normal conditions, these cells can revert to their original state. However, in the presence of oncogenic KRAS mutations, this process is disrupted, leading to persistent ADM and progression to pancreatic intraepithelial neoplasia (PanIN), which can ultimately become PDAC.

NADPH’s normal role is in maintaining cellular homeostasis. It supports the synthesis of lipids, cholesterol, and nucleotides, and it aids antioxidant systems that regulate reactive oxygen species (ROS). Under normal conditions, NADPH helps neutralize ROS, preventing cellular damage. The current study, however, demonstrated that lower levels of NADPH impair antioxidant defenses, leading to increased ROS and lipid peroxidation, which in turn promote the formation of precancerous lesions.

The researchers identified two NADPH-producing enzymes for their work: glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1). Both enzymes support the production of the appropriate levels of NADPH needed for biosynthesis and ROS regulation.

Using a multimodal approach involving RNA sequencing, metabolomics, and mouse models with oncogenic KRAS mutations, the Michigan team studied how the loss of these two enzymes affects pancreatic tissue. They observed that deficiency in either G6PD or ME1 increased ROS levels and accelerated the formation of ADM and pancreatic intraepithelial neoplasia (PanIN) lesions. Antioxidant treatments, including glutathione and N-acetyl cysteine, reduced lesion formation, further bolstering the current understanding of the role of oxidative stress in early tumorigenesis. The team achieved similar results when these methods were applied to human pancreatic tissue samples.

But results from later in the study showed that the two enzymes played distinct roles in the later stages of PDAC. While they both contributed to early lesion formation, only the loss of ME1 promoted progression to PDAC. This suggests that although both enzymes regulate NADPH and oxidative stress, they have distinct roles in later metabolic demands of cancer cells.

The study builds on prior research showing that KRAS mutations drive metabolic reprogramming and ROS production in pancreatic cells. Previous work has also indicated that antioxidant pathways, including those regulated by NRF2, are activated during tumor initiation.

Clinically, these findings suggest that targeting metabolic pathways involved in NADPH production could provide a strategy to intercept pancreatic cancer before it fully develops. Measuring levels of G6PD, ME1, or related metabolites could also serve as biomarkers to identify patients at higher risk of lesions progressing to cancer.

“Our study can help the search for new biomarkers that can intercept pancreatic cancer before it progresses,” the researchers wrote.

Future research will focus on identifying additional enzymes that regulate NADPH levels and determining how these pathways can be targeted safely. The researchers also plan to study whether patients with mutations in G6PD, ME1, or related pathways have an increased risk of pancreatic disease.

The post Pancreatic Cancer Development Driven by NADPH Disruption appeared first on Inside Precision Medicine.

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Injectable Microgel Developed to Reduce Bleeding in Infants Undergoing Surgery

Biomedical researchers headed by a team at the Lampe Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill/North Carolina State University, have developed an injectable microgel to help reduce bleeding in infants who require surgical care. Tests in an animal model showed that the hemostatic microgels, known as B-knob-triggered microgels (BK-TriGs), reduced bleeding by at least 50%.

Research lead Ashley Brown, PhD, who is the Lampe Distinguished Professor of Biomedical Engineering, is co-corresponding author of the team’s published paper in Science Advances, titled “Hemostatic B-knob-triggered microgels (BK-TriGs) to address bleeding in neonates.” In their paper the team concluded “This study highlights the potential of BK-TriGs, designed for neonatal-specific clotting mechanisms, to address the heightened bleeding and thrombosis risks in neonates, who face 4.4 times higher postsurgery mortality … Our findings support BK-TriGs as a promising approach for improving hemostasis in neonates, offering a tailored, effective solution for this vulnerable patient population.”

When adults cut themselves, a multi-step process called hemostasis stops the bleeding from the injured blood vessel. But hemostasis in infants is different from hemostasis in adults. This difference can be problematic if infants require surgery to address significant medical problems. In surgeries, neonatal patients normally receive blood from adult donors to compensate for blood lost during the operation. “Current treatments rely on transfusing adult blood products, which may cause complications resulting from structural and functional differences between neonatal and adult fibrinogen,” the authors wrote. “… these transfusions pose serious safety concerns by increasing morbidity, prolonging intensive care unit stays, and elevating posttransfusion thrombosis risks in neonates.”

Brown noted, “… if you give adult blood to an infant, the difference in adult hemostasis versus infant hemostasis can lead to too much clotting. That can increase the likelihood of thrombosis, where blood clots form in the lungs or elsewhere and put the baby at risk … “My research team has done a lot of work on surgery-related bleeding in newborns, and we wanted to develop a therapeutic intervention that would reduce bleeding and—by extension—reduce the need for infants to receive adult blood transfusions during surgery.”

The scientists have now reported on their development of a material called B-knob triggered microgels (BK-TriGs). “Fibrin is the main clotting protein in human blood,” Brown explains. “There is a short amino acid sequence called a ‘B peptide’ that links together fibrin molecules to create blood clots where they are needed—and these B peptides play a particularly important role in hemostasis for infants. The BK-TriGs are engineered particles that are studded with those B peptides.”

The particles can absorb water and become squishy hydrogels, which mimic the mechanical properties of natural platelets in a way that maximizes the ability of the B peptides to create fibrin networks and stanch bleeding. “Functionalized with a fibrin hole b–specific peptide, BK-TriGs enhance clot density and resistance to degradation,” the team noted.

The researchers first tested the BK-TriGs by using microfluidic devices that allowed them to conduct in vitro testing to see how the microgels affected clotting in blood plasma from human adults and infants. “In vitro studies using neonatal platelet-poor plasma (PPP) showed that at an optimal concentration, BK-TriGs increased clot density by more than 100% and improved stability by reducing fibrinolysis,” they wrote in summary. “Under flow conditions BK-TriGs promoted robust clot formation compared to plasma-only controls.” Brown noted, “We found that BK-TriGs worked better at improving blood clotting in infant plasma than in adult plasma, which was what we expected to see.”

To further test the efficacy of the BK-TriGs, the researchers worked with lab mice that were genetically engineered to not make fibrinogen, the precursor to fibrin. This allowed the researchers to first introduce infant fibrinogen into the lab mice so that the mice exhibit a form of hemostasis similar to infants. “This innovative model enabled the evaluation of BK-TriGs in a setting that replicates key aspects of neonatal fibrinogen polymerization and fibrinolytic sensitivity, providing preliminary insights into their potential clinical utility.”

Brown added, “We found that the BK-TriGs outperformed any of the other options we tested at reducing blood loss. Specifically, the BK-TriGs reduced blood loss by 50-60% compared to the control group.”

The authors further stated, “The findings highlight the potential of BK-TriGs as a promising synthetic platelet-mimetic approach for enhancing clot density and stability, particularly in neonatal plasma where traditional blood products may pose risks … A fibrin-targeted approach like BK-TriGs, which enhances clot formation without introducing systemic thrombotic risk, may offer a safer alternative to adult fibrinogen transfusions.”

Next steps for the work are to see how BK-TriGs compare to other hemostatic therapeutics that are on the market, either on their own or when used in conjunction with BK-TriGs. “The results we’re reporting here are exciting, but we are still far removed from clinical use,” Brown, acknowledged. “We need to make sure there are no unforeseen risks associated with blood clotting.” The team also commented, “Expanding this research to include different clinical bleeding scenarios will be essential to advancing these materials toward therapeutic applications.”

“This is particularly relevant in neonates, where the most severe bleeding complications often arise in critical sites such as the gastrointestinal tract and the brain,” Brown continued, “But if we do find BK-TriGs are safe and effective, we’re optimistic this could be a cost-effective way to make surgery safer for infants. Manufacturing the BK-TriG particles would be relatively inexpensive—certainly in comparison to blood products.”

The post Injectable Microgel Developed to Reduce Bleeding in Infants Undergoing Surgery appeared first on GEN – Genetic Engineering and Biotechnology News.

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How an Alzheimer’s Risk Gene Rewires the Brain Decades Before Symptoms

For millions of people worldwide, carrying the APOE4 gene variant means a significantly higher risk of developing Alzheimer’s disease. Yet one of the biggest unanswered questions has been when, and how, that risk begins to take hold in the brain.

New research from the Gladstone Institutes, published in Nature Aging, suggests that the effects of APOE4 emerge far earlier than previously understood. The study shows that subtle but important changes in brain activity occur long before memory loss begins, offering a potential window for early intervention.

Early changes in a seemingly healthy brain

Alzheimer’s disease is typically diagnosed after cognitive symptoms appear, but growing evidence suggests that the disease process begins decades earlier. The new study adds to this picture by demonstrating that brain circuits in young individuals carrying APOE4 are already functioning differently.

We found fundamental changes in brain circuits occurring in young mice that still had normal learning and memory, and importantly, that those changes predicted the development of cognitive deficits at older ages, ” said Misha Zilberter, PhD, principal staff research scientist at Gladstone and senior author of the study.

The researchers observed increased neuronal activity in the hippocampus, a brain region essential for learning and memory. Similar patterns of hyperactivity have been reported in human APOE4 carriers, even before clinical symptoms arise.

According to the scientists, this suggests that Alzheimer’s risk is not simply a matter of late-stage degeneration, but may instead involve long-term changes in how brain circuits are wired and function.

Smaller neurons, stronger signals

To understand what drives this early hyperactivity, the team examined individual brain cells. They found that neurons in key regions of the hippocampus were physically smaller in APOE4 carriers compared to those with the more common, lower-risk APOE3 variant.

While this might seem like a minor structural difference, it has functional consequences. Smaller neurons are more easily activated, meaning they fire more readily in response to stimuli. This heightened sensitivity can lead to persistent hyperactivity within neural circuits.

Over time, this imbalance may place stress on the brain and contribute to the gradual decline seen in Alzheimer’s disease.

A surprising source of dysfunction

For years, researchers believed that APOE4’s effects were primarily driven by astrocytes, support cells in the brain that produce most of the APOE protein. However, the new findings challenge this assumption.

The team discovered that the disruptive effects on brain activity were instead linked to APOE4 produced directly by neurons themselves. When APOE4 was removed from neurons, their size and activity returned to normal. Removing it from astrocytes, by contrast, had little effect.

This shift in understanding refocuses attention on neurons as key drivers of early disease processes, rather than passive victims of surrounding dysfunction.

A reversible pathway—and a new target

Perhaps the most striking finding of the study is that these early changes may not be permanent.

The researchers identified a protein called Nell2 as a central player in the process. Levels of Nell2 were elevated in APOE4 neurons and appeared to drive both the reduction in cell size and the increase in neuronal activity.

By reducing Nell2 levels in adult mice, the team was able to restore normal neuron structure and function—even after the changes had already occurred.

“What’s exciting about Nell2 is that we were able to reverse the disease manifestations in adult mice by lowering its level,” said Yadong Huang, co-senior author of the study. “That tells us the damage is not irreversible […].”

This raises the possibility of developing therapies that target Nell2, potentially slowing or preventing disease progression in individuals at high genetic risk.

Implications for early intervention

APOE4 is present in roughly one in four people and in the majority of Alzheimer’s patients. Despite this, current treatments largely focus on late-stage symptoms rather than early prevention.

The new findings suggest that intervening earlier, before cognitive decline begins, could be key. If brain circuit changes can be detected and corrected at an early stage, it may be possible to delay or even prevent the onset of Alzheimer’s disease.

The study also highlights the importance of understanding how genetic risk translates into functional changes in the brain. Rather than acting as a simple risk marker, APOE4 appears to actively reshape neural activity over time.

A shift in perspective

More broadly, the work reflects a growing shift in Alzheimer’s research, from focusing solely on hallmark features such as amyloid plaques and tau tangles to examining earlier, subtler changes in brain function.

By identifying a concrete pathway linking genetic risk to altered brain activity, the study provides a clearer framework for understanding how the disease develops.

“This study is a big breakthrough for the field of Alzheimer’s research,” Huang said. “It opens the door to a better understanding of how APOE4 alters the function of neurons at a young age to increase risk of cognitive decline, and to the development of therapies that could block the detrimental effects of APOE4 early on.”

While the findings are based on mouse models, they align closely with observations in humans and offer a strong foundation for future research. The next steps will involve determining whether targeting Nell2 or similar pathways can produce similar benefits in human patients.

If successful, such approaches could transform how Alzheimer’s disease is treated, not as an inevitable consequence of aging, but as a process that can be detected early and potentially reversed.

The post How an Alzheimer’s Risk Gene Rewires the Brain Decades Before Symptoms appeared first on Inside Precision Medicine.

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Epigenetic Strategy Restores Tumor Suppressor in Acute Myeloid Leukemia Models

Scientists from The Jackson Laboratory (JAX) and their collaborators elsewhere have found a potential way to treat cases of acute myeloid leukemia that involves turning a key cancer fighting gene back on. Besides potentially treating AML without harsh chemotherapy regimens, their work also highlights a promising strategy for studying gene-silencing mechanisms in other diseases. Full details of the study, which was done in mice, are available in a paper published in Science Translational Medicine titled “Epigenetic reactivation of the tumor suppressor ZBTB7A by KDM4 inhibition in human acute myeloid leukemia.”

Normally, tumor suppressor genes work to prevent cells from becoming cancerous. But in cancers like AML, some of these genes are switched off epigenetically. These changes to gene activity are difficult to track because standard DNA sequencing technologies are designed to find mutated DNA. “If we can identify which genes have been silenced and understand how to turn them back on, that could open up entirely new therapeutic possibilities,” said Eric Wang, PhD, an assistant professor JAX who led the research. “Instead of only trying to kill these cells, we may be able to restore the mechanisms that normally keep them under control.”

Though scientists have made great strides in developing therapies for AML, prognosis for the disease is still relatively poor. Part of the challenge is that AML cells remain in an immature, stem cell-like state. According to the paper, Wang and his team developed a tool that combines fluorescence in situ hybridization and flow cytometry with CRISPR gene editing technology to map gene activity in cells. They used the tool, called FISHnCRISP, to identify a tumor-suppressing gene called ZBTB7A that is silenced in AML patients. By restoring ZBTB7A expression, the scientists forced the cancer cells into a state where they grew less aggressively.

Digging into the details, AML cells produce a longer version of ZBTB7A’s regulatory tail, that contains sites that attract a protein called ZFP36L2, which reduces the gene’s activity. Additionally, a family of enzymes known as KDM4 modify how DNA is packaged inside AML cells, which effectively silences ZBTB7A expression. Data from experiments in mice with AML showed that when KDM4 enzymes were blocked, ZBTB7A regained its expression, reducing leukemia burden while leaving normal blood formation largely unaffected.

Importantly, “there are drug candidates out there to inhibit KDM4, and in our study we just repurposed one of them to treat AML cells,” Wang said. “We won’t know unless we test it in clinical trials, but this approach could be better than chemotherapy, because we showed it’s not toxic at all to normal blood cells.” 

Future studies will focus on refining the approach and determining whether it might be combined with existing treatments. The team plans to test an experimental drug that targets KDM4, which is currently being tested in a clinical trial for solid tumors. 

“We demonstrated that downregulating ZBTB7A causes this hyperinflammatory state that promotes cancer growth” and “now, we’re proposing this epigenetic approach to force AML cells to differentiate into white blood cells that eventually undergo cell death,” Wang said. “We could potentially translate our research into an early phase clinical trial more readily than developing a whole new compound from scratch.” 

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