The Sant Pau Research Institute (IR Sant Pau) is actively participating in the CADASIMUS project, a collaborative initiative recently selected in the “Dr. Miguel Blanco” seed funding call of the RICORS-ICTUS thematic network (Research Network on Outcomes and Quality of Stroke Care), funded by the Carlos III Health Institute as part of the new program of Cooperative Health-Oriented Research Networks (RICORS)).

The project was one of those selected in this competitive call, which aims to support the development of innovative preclinical studies to test a new drug for CADASIL. Thanks to this grant, CADASIMUS will receive €15,000 in funding, intended to cover the study’s key experimental costs. This funding will allow the launch of planned activities during the first year, such as drug treatment in a CADASIL cell model, as well as the study of the proteomic profile of the cell model and patient plasma and will serve as a basis for future applications for larger national or international projects.

The project is coordinated by the Translational Stroke Group at the Health Research Institute of Santiago de Compostela (IDIS) and involves the participation of IR Sant Pau, the Institute of Biomedicine of Seville (IBiS), and Donostia University Hospital. The co–principal investigators are Ana Bugallo Casal, Paula Villatoro González (IR Sant Pau), Ana Domínguez, and Patricia de la Riva.

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a rare disease caused by genetic variants in the NOTCH3 gene and is considered the genetic model more than all others of cerebral small vessel disease. Currently, no specific treatment exists for this condition. The CADASIMUS project will explore the potential of a drug already approved for other indications to modulate altered cellular mechanisms in CADASIL, such as autophagy, using an approach based on patient-derived cell models and biomarker analysis in human samples.

According to Paula Villatoro, “This project has a significant social and economic impact by addressing CADASIL, a rare disease with no specific treatment that causes progressive disability, recurrent subcortical strokes, and early vascular dementia. Identifying an already approved drug as a potential treatment would accelerate its clinical application and reduce costs associated with developing new therapies. Moreover, implementing biomarkers would optimize clinical trials by reducing the need for large cohorts and shortening study durations.”

The use of advanced omics technologies (such as proteomics via Olink technology) will enable the identification of potential therapeutic targets and biomarkers that can be validated in future clinical trials. One of the project’s innovative elements is the stratified analysis by biological sex, aiming to advance toward more equitable precision medicine.

IR Sant Pau’s involvement also includes the CADAGENIA biobank, which houses samples from patients with CADASIL, and collaboration with the CADASIL Spain Association, which actively contributes to the dissemination and alignment of the project with real patient needs.

Paula Villatoro also highlights the importance of network collaboration: “Collaboration among centers like IDIS, Sant Pau, IBiS, and Donostia is essential to combine capabilities, share resources, and accelerate knowledge. The RICORS-ICTUS structure precisely facilitates this cooperation, with a shared goal: to improve the clinical and therapeutic management of cerebrovascular diseases.”

With this recognition, IR Sant Pau reinforces its commitment to research in rare neurological diseases and to network-based collaboration within RICORS-ICTUS—a key collaborative structure for advancing the quality of care and outcomes in stroke and related diseases.

Early detection of Alzheimer’s disease has undergone a shift recently with the incorporation of biomarkers that allow for the identification of brain changes even before the first symptoms appear. However, the application of these new diagnostic frameworks—focused exclusively on biological parameters—raises clinical, ethical, and social questions that remain unanswered.

In this context, the article “On the complexity of biomarker-driven diagnoses of Alzheimer’s disease”, recently published in the Journal of Neuropsychology, reflects on the challenges and risks of diagnosing the disease based solely on the presence of -amyloid or phosphorylated tau in the brain. This is especially true for individuals who show no cognitive impairment. The paper is authored by Dr. Miguel Ángel Santos-Santos, a researcher in the Neurobiology of Dementias group at the Sant Pau Research Institute (IR Sant Pau) and neurologist at the Memory Unit of Hospital de Sant Pau. Together with Dr. Stephanie Grasso and Dr. Alexandra Leigh Clark, both from the University of Texas at Austin.

“Biomarkers are a promising tool, but we cannot yet consider a positive result as a diagnosis in itself. In cognitively healthy individuals, it’s more responsible to interpret them as indicators of elevated risk,” says Dr. Santos-Santos. The article highlights that a significant portion of people with abnormal biomarkers never go on to develop dementia, likely thanks to mechanisms of cognitive reserve and brain resilience. This concept, influenced by factors such as educational level, life experiences, and sociocultural context, is key to understanding the progression of the disease.

However, as the authors warn, current diagnostic models are based on studies involving homogeneous populations, which limits their applicability to minority groups or people with different life trajectories. “Diagnostic models must take racial, cultural, and structural diversity into account if we want to move toward truly equitable precision medicine,” explains Dr. Santos-Santos.

The researchers propose an alternative approach based on multifactorial risk prediction models that integrate biological data, neuropsychological testing, and social determinants of health. These models would better identify those individuals who would truly benefit from monitoring or early intervention strategies, avoiding unnecessary diagnostic labeling.

In addition, the commentary emphasizes the importance of clearly and responsibly communicating biomarker findings to patients, to avoid misunderstandings and negative impacts on their psychological well-being. In this regard, the authors advocate for an interdisciplinary approach that combines scientific evidence with each individual’s personal context.

This work reinforces the commitment of IR Sant Pau and the Memory Unit at Hospital de Sant Pau to cutting-edge international research in brain aging and dementias. Their contribution to the global debate on how to ethically, equitably, and effectively use the diagnostic tools of the future.

Reference article:

Grasso SM, Santos-Santos MÁ, Clark AL. On the complexity of biomarker-driven diagnoses of Alzheimer’s disease. J Neuropsychol 2025. https://doi.org/10.1111/jnp.12428

On Thursday the 26th, the documentary A Journey to the Limits of Human Adaptation was presented at Girona Cinemas. Produced by Tarannà Viatges and the Sant Pau Research Institute (IR Sant Pau), this production blends science, adventure, and public outreach to explore how the human body responds to the most extreme conditions of altitude and oxygen deprivation. The film is based on the scientific project Sherpa Project 2017: Effects of Exposure to Extreme Environmental Hypoxia on the Human Body, led by Dr. José Manuel Soria, head of the Complex Disease Genomics Research Group at IR Sant Pau.

This groundbreaking project had a highly ambitious goal: to move the lab into the most extreme natural environment to study, in real time, how the human body reacts to severe environmental hypoxia, such as that found in the Himalayas above 5,000 meters of altitude. Hypoxia—a decrease in oxygen availability in body tissues—is a condition that can occur not only at high altitudes, but also in various respiratory and cardiovascular diseases. Understanding how the body adapts to it can provide valuable insights for medicine.

The documentary follows the expedition of mountaineer Ferran Latorre along the southern face of Everest in Nepal, and showcases the scientific logistics involved in such a hostile environment. Biological samples were collected from 52 participants—15 trekkers (individuals hiking to base camp without summiting), 15 elite climbers, and 22 Sherpas—at three different altitude points: at sea level (Barcelona), at 5,400 meters (Everest base camp, after the acclimatization trek), and beyond 8,000 meters, in the so-called “death zone,” where only Sherpas and elite climbers were able to reach. In addition to blood samples, physiological data such as oxygen saturation, heart rate, and respiratory response were recorded, allowing for in-depth analysis of adaptation mechanisms to extreme environments.

The study also aimed to compare adaptation among individuals with different levels of training and acclimatization: from occasional trekkers, to professional climbers, to Sherpas—an indigenous Himalayan population with a genetically inherited ability to adapt to high altitudes that makes them unique in the world. This comparison helps identify differences between adaptation gained through training and adaptation passed down genetically over generations.

The documentary offers a human and intimate look at the challenges of conducting science in extreme conditions, and highlights the collaborative effort between scientists, athletes, and the local population. It also reflects on the limits of the human body and how far we can adapt to seemingly impossible environmental conditions.

All proceeds from the documentary screening will go entirely to thrombosis research conducted by IR Sant Pau, through the Activa’TT Foundation for Health, thereby helping to advance knowledge and treatment of this vascular disease.

Physicians from the Intensive Care Medicine Department at Hospital Sant Pau, members of the Sant Pau Research Institute (IR Sant Pau), have participated in the international PROMIZING study. This is one of the most ambitious clinical trials to date aimed at optimizing the discontinuation of mechanical ventilation in patients with severe respiratory failure. Recently published in The New England Journal of Medicine, the study compares proportional-assist ventilation (PAV+) with pressure-support ventilation (PSV), with the goal of determining whether the former method could facilitate faster and less complicated weaning from the ventilator.

Sant Pau’s participation in the trial was significant thanks to the contribution of a team of intensivists with a strong track record in clinical research. The trial was designed and directly led by Dr. Jordi Mancebo, a leading figure in the field of mechanical ventilation and one of the driving forces behind the study from the beginning. Furthermore, by Dr. Juan Carlos Suárez, a close collaborator and also a physician in the Intensive Care Department. Sadly, both passed away before the final publication of the study and were honored by their colleagues with a special dedication at the end of the article. Also listed as coauthors of the paper are Dr. Indalecio Morán and Dr. Núria Rodríguez, active members of the hospital’s care and research team.

Knowledge to Improve Clinical Practice

PROMIZING (short for Proportional Assist Ventilation for Minimizing the Duration of Mechanical Ventilation) was a prospective, multicenter, randomized study conducted across 23 hospitals in 7 countries (Canada, France, Italy, Greece, Argentina, Saudi Arabia, and Spain). The study enrolled 722 patients admitted after an episode of severe acute respiratory failure, of whom 573 were randomized. All participants were adults who had been under invasive mechanical ventilation for at least 24 hours and had failed an initial spontaneous breathing trial. They were randomized to receive spontaneous mechanical ventilation in either PAV+ or PSV mode. The primary endpoint was the time to successful liberation from the ventilator, defined as definitive discontinuation of ventilation without the need for reintubation for at least seven days.

Using the method proposed in the study to compare both modes during the weaning phase, the authors found no significant differences between PAV+ and PSV regarding the time to successful ventilator liberation. Specifically, the average time to permanent disconnection was nearly identical in the PAV+ group (7.3 days) compared to the PSV group (6.8 days), with the small difference not being statistically significant. The probability of successful liberation at 28 days was also very similar between the two groups (83.3% with PAV+ and 85.2% with PSV). Likewise, the average number of ventilator-free days during this period was 20.4 for PAV+ and 21.3 for PSV.

Regarding 90-day mortality, the results showed a rate of 29.6% in the PAV+ group and 26.6% in the PSV group, with no statistically relevant differences.

Other Key Findings of the Study

In addition to findings on ventilation duration and mortality, the study also explored factors relevant to quality of care and patient safety, such as the incidence of delirium, the cumulative use of sedatives and opioids, tolerance to the assigned ventilatory mode, and complications associated with the weaning process.

The incidence of delirium was similar between the two groups, suggesting that the ventilatory mode alone is not a determining factor in patients’ acute cognitive state. However, the study did note that patients in the PAV+ group tended to require lower cumulative doses of sedatives during the early observation period, which could suggest better synchrony between the patient and the ventilator. Despite this trend, the difference was not statistically significant. Opioid use was also tracked and compared, with no substantial differences between groups.

On the other hand, patients in the PAV+ group were switched to controlled ventilation modes more frequently than those in the PSV group. According to the authors, this may reflect both the clinical management complexity and a lower level of familiarity among staff with this strategy. Specifically regarding tolerance to the assigned mode, most patients were able to complete the intervention period in their assigned mode. However, there was a slight increase in mode changes within the PAV+ group, often due to clinical decisions related to respiratory stability or patient adaptation to the ventilator.

There were also no differences between groups in terms of complications related to the weaning process or the ventilatory mode itself, reaffirming the safety of PAV+ use in centers experienced in mechanical ventilation. While the study did not show statistically significant differences between PAV+ and PSV, it provides valuable information for better understanding the practical implications and clinical acceptability of proportional-assist ventilation.

According to Dr. Indalecio Morán, “PROMIZING provides very robust knowledge to guide decision-making during mechanical ventilation withdrawal and to further study spontaneous ventilation modes during the weaning phases, while validating the safety of proportional ventilation in centers with excellence in mechanical ventilation management.” For her part, Dr. Núria Rodríguez noted, “This study shows us that what can truly make a difference is an individualized weaning strategy applied with rigor. The ventilatory mode is a tool, but the key is how we use it within a coherent, patient-centered clinical framework.”

Reference:

Bosma KJ, Burns KEA, Martin CM, Skrobik Y, Mancebo Cortés J, Mulligan S, Lafreniere-Roula M, Thorpe KE, Suárez Montero JC, Morán Chorro I, Rodríguez-Farré N, Butler R, Bentall T, Beduneau G, Enguerrand P, Santos M, Piraino T, Spadaro S, Montanaro F, Basmaji J, Campbell E, Mercat A, Beloncle FM, Carteaux G, Maraffi T, Charbonney E, Lecronier M, Dres M, Arabi YM, Amaral ACK, Marinoff N, Adhikari NKJ, Geagea A, Shin P, Vaporidi K, Kondili E, Shahin J, Campisi J, Rodriguez PO, Setten M, Goligher EC, Ferguson ND, Fanelli V, Ferreyra G, Lellouche F, Sibley S, Brochard L, PROMIZING Study Investigators, the Canadian Critical Care Trials Group, and the REVA Network. Proportional-assist ventilation for minimizing the duration of mechanical ventilation. N Engl J Med. 2025. https://doi.org/10.1056/NEJMoa2505708

A recent international multicenter study published in JAMA Otolaryngology–Head & Neck Surgery has shown that adding chemotherapy to adjuvant radiotherapy after surgery improves survival outcomes in patients with oral cavity squamous cell carcinoma. This is when there is major extranodal extension (ENE) of the disease. In contrast, in patients with minor ENE, chemotherapy does not appear to significantly improve clinical outcomes, which could prompt a reconsideration of current therapeutic recommendations.

The study, led by the Princess Margaret Cancer Centre in Toronto, included 755 patients treated between 2005 and 2018 at leading centers in Canada, the United States, and Australia. Among the authors is Dr. Cristina Valero, a researcher at the Sant Pau Research Institute (IR Sant Pau) and Memorial Sloan Kettering Cancer Center in New York, who was the only contributor affiliated with a Spanish institution.

What Is Extranodal Extension and Why It Matters

Extranodal extension (ENE) is a pathological feature indicating that the tumor has spread to lymph nodes and breached their capsule, infiltrating surrounding tissues. This extension can be classified as minor (≤2 mm) or major (>2 mm), and its presence is generally associated with a poorer prognosis, including higher risk of recurrence and reduced survival.

ENE has long been considered a high-risk criterion justifying the use of concurrent chemotherapy with adjuvant radiotherapy following surgery. However, the findings of this new study challenge the need to add chemotherapy in all ENE cases, particularly those with minor extension.

“Currently, any degree of ENE is an indication for chemotherapy in combination with adjuvant radiotherapy, regardless of the extent of extranodal spread,” explains Dr. Valero. “The results of this study suggest that this approach may not be necessary for patients with minor ENE, thus avoiding treatments that do not provide clinical benefit and may lead to significant toxicities. More studies are needed to validate our findings before clinical protocols can be reconsidered.”

Implications for Clinical Practice

The findings of this study have important translational value. In patients with major ENE, chemoradiotherapy significantly improved both disease-free survival and overall survival. However, in patients with minor ENE, these improvements were not statistically significant, even after adjusting for age, tumor stage, surgical margins, or radiotherapy.

This evidence supports the need for a more refined risk stratification approach in the treatment of advanced oral cancer, aiming to personalize therapeutic decisions and reduce exposure to unnecessary aggressive treatments.

“Collaborative research of this kind is essential for advancing personalized medicine and for generalizing findings,” adds Dr. Valero. “It allows us to critically evaluate our clinical practices and make decisions based on the best available evidence.”

Leadership and Excellence in International Research

The study involved a large multidisciplinary team of oncologists, pathologists, surgeons, epidemiologists, and biostatisticians from top-tier institutions, including Memorial Sloan Kettering Cancer Center (U.S.), University Health Network in Toronto (Canada), Chris O’Brien Lifehouse (Australia), and the Medical University of South Carolina (U.S.). Dr. Valero is among the co-authors who contributed to data acquisition, analysis, and interpretation.

Her involvement highlights IR Sant Pau’s commitment to high-quality international clinical research and its active role in studies that have the potential to change clinical practice for the benefit of patients.

Reference Article:

Manojlovic-Kolarski M, Su S, Weinreb I, Calvisi R, Perez-Ordonez B, Smith S, Patel S, Valero C, Xu B, Ghossein R, Katabi N, Clark J, Low T-HH, Gupta R, Graboyes E, Davies J, Richardson M, Goldstein D, Huang SH, O’Sullivan B, Xu W, Hansen A, de Almeida JR. Adjuvant chemoradiotherapy for oral cavity SCC with minor and major extranodal extension. JAMA Otolaryngol Head Neck Surg 2025. https://doi.org/10.1001/jamaoto.2025.1721.

The Sant Pau Research Institute (IR Sant Pau) held its annual Innovation Day 2025 this Tuesday, a flagship event that showcases the talent, creativity, and commitment of the center’s professionals to health innovation. During the event, and as part of the second edition of the INNOPAU program, this year’s winners were announced.

The project CUMADE received the first prize and will be awarded €50,000 to continue its development. The second prize, endowed with €15,000, went to project CHYMERA. Both awards were made possible through the support of the Private Foundation of the Hospital de la Santa Creu i Sant Pau. Projects CUMADE and CHYMERA also received special mentions as the most disruptive initiatives, with €8,000 each in funding provided by the ITEMAS platform of the Carlos III Health Institute (ISCIII). Finally, project RADAR was selected by Padcelona for the development of a Minimum Viable Product (MVP) in Digital Health.

During the event, the six finalist projects were presented, selected for their capacity to innovate from clinical knowledge and practice. All of them address real challenges identified within the hospital and propose concrete, applicable solutions with the potential to significantly impact patient quality of life and the efficiency of the healthcare system.

• MARPRESING
  Leads: Jessica Marin, Ana Marin, and Oliva Ros, from the Digestive Endoscopy Unit.
  A medical device that applies external abdominal pressure during colonoscopy. It improves procedure efficiency, enhances patient comfort, and reduces the risk of work-related injuries among healthcare staff.
• CUMADE
  Leads: Dabit Arzamendi, from the Hemodynamics Unit, and Abdel Hakim Moustafa, from the Dimensions Lab.
  An innovative solution that combines precision engineering and 3D printing to design customized devices that address complex issues like leaks in cardiovascular implants. It represents a new paradigm in personalized structural medicine.
• RADAR
  Leads: Carlen Reyes, Jara González, Elisabet Rayó, and Helena Serrano, from the Sardenya Primary Care Team (EAP Sardenya).
  A digital platform that analyzes clinical and pharmacological data to detect potential adverse drug reactions in real time in primary care. It aims to improve patient safety and optimize therapeutic decision-making.
• DAMMPIS
  Leads: Ariadna Bellès, Carles Subirà, Jaume Baldirà, Matias Flores, and Rosa Oms, from the Intensive Care Unit.
  An integrated sensor system that prevents the accidental removal of medical devices in critically ill patients. It provides real-time alerts and helps reduce serious complications, enhancing safety and efficiency in intensive care units.
• CHYMERA
  Leads: Josep Munuera, Daniel Caballero, Lydia Canales, and Lucía Borrego, from the Diagnostic Imaging Department.
  An AI-based tool that automates quality control of chest X-rays, reducing variability and preventing repeat imaging. It improves efficiency and safety in high-demand environments such as hospital emergency departments.
• AQUAFLOW
  Leads: Sandra Peña, Esther Franquet, Piedad Arias, and Mireia Plans, from the Nephrology Department of the Puigvert Foundation.
  A specialized water belt for people with peritoneal dialysis catheters, allowing safe and hygienic immersion in water. It addresses an unmet need and helps improve the autonomy and quality of life of kidney patients.

The projects were developed throughout the INNOPAU program, an incubator driven by IR Sant Pau that supports teams in transforming innovative care ideas into viable projects. During the program, participants take part in various training modules and receive specialized guidance in key areas such as intellectual property management, fundraising, healthcare regulations, business modeling, and strategic project development.

The culmination of the program is Innovation Day, held on June 17, where teams present their progress to the broader innovation ecosystem. The event also serves to connect professionals with strategic players such as representatives from the pharmaceutical industry, investment funds, technology centers, and other key stakeholders in the health sector.

The day also featured a roundtable discussion on “New Technologies and Transformation in Health,” with participation from professionals across clinical, research, tech, and business domains, as well as dedicated networking spaces to foster collaboration among ecosystem players.

A Strategic Commitment for Sant Pau

With strong support from the Foundation and IR Sant Pau, the institution is positioning innovation as a strategic pillar for transforming the healthcare system. Beyond research, innovation is a key tool for anticipating emerging social challenges, adopting new technologies, and improving the quality of care in tangible ways.

For Sant Pau, innovation means listening to professionals, identifying opportunities from clinical practice, and providing the support and tools to help their ideas grow. It means investing in a more efficient, personalized, and sustainable healthcare model. Ultimately, it means transforming knowledge into impact.

With events like Innovation Day, Sant Pau reaffirms its leadership as a pioneering institution in translational research and health innovation, positioning itself as a hub of excellence in the development of solutions that put people at the center.

Fetuses more exposed to certain air pollutants show changes in the size of specific brain structures, particularly during the second and third trimesters of pregnancy. This is the main finding of a new study led by the Barcelona Institute for Global Health (ISGlobal), a center supported by the “la Caixa” Foundation, in collaboration with the BCNatal center (Hospital Sant Joan de Déu, Hospital Clínic, and University of Barcelona) and the Hospital de Sant Pau. It is the first study to specifically examine the association of air pollution on fetal brain development during pregnancy.

The study, published in The Lancet Planetary Health, analyzed data collected between 2018 and 2021 from 754 mother-fetus pairs participating in the BiSC (Barcelona Life Study Cohort) project in Barcelona. This study aimed to understand the association of air pollution on child health and brain development, and is considered one of the most comprehensive studies in this field.

During the third trimester of pregnancy, participants underwent transvaginal neurosonography, a specialized ultrasound that allows the analysis of fetal brain shape and structures. Exposure to nitrogen dioxide (NO_₂), particulate matter (PM_2.5), and black carbon was estimated with hybrid models that combine data from real measurements with advanced statistical methods. The research considered three “microenvironments”: the participants’ homes, workplaces, and commuting routes. Data on activity patterns were collected via a geolocation app installed on the participants’ mobile phones.

The research team observed that prenatal exposure to NO_₂, PM_2.5, and black carbon in all aforementioned microenvironments combined was associated with an increase in the volume of various brain cavities that contain cerebrospinal fluid. Specifically, direct associations were identified between exposure to these pollutants and increased volume of the lateral ventricles, located in each brain hemisphere. There was also an enlargement of the cisterna magna, a cavity located in the lower part of the brain. An increase in the width of the cerebellar vermis —the central part of the cerebellum, essential for balance and motor coordination— was also detected.

The study results also showed an association between higher exposure to black carbon and a reduction in the depth of the lateral sulcus (also known as the Sylvian fissure), a deep groove that runs through the brain, which might suggest less maturation of the brain.

The associations between exposure to air pollution and changes in the morphology of these brain structures were stronger during the second and third trimesters of pregnancy. “During mid to late gestation, the fetal brain enters a key phase of its development, making it particularly vulnerable to external factors such as pollution,” explains Payam Dadvand, ISGlobal researcher and a senior author of the study.

“As clinicians, we are now seeing compelling evidence that even in pregnancies that appear healthy by all conventional measures, factors such as air pollution can subtly affect fetal brain development. These findings underline the importance of increased awareness and education, both within the health community and across society,” say Elisa Llurba and Lola Gómez-Roig, clinicians at the Hospital de Sant Pau and BCNatal-Hospital Sant Joan de Déu, respectively, and co-authors of the study.

Significant Differences at the Population Level

The observed effects do not imply that the children participating in the BiSC project have pathological brain alterations. In fact, all measurements of the participants’ brain structures are within the range considered normal. “The point is that these differences, although small at the individual level, are indeed relevant from a population perspective, as they inform us about how pollution impacts the fetal brain and its vulnerability to environmental exposures,” says Laura Gómez-Herrera, ISGlobal researcher and co-lead author of the study.

The research team emphasizes the need for further studies to confirm these findings and track their potential consequences over time. “At this stage, we can only report having observed differences in the brains of fetuses with higher exposure to pollution compared to those with lower exposure. Additional research is needed to determine whether these effects are reversible after birth or if they persist, and whether they have any implications for neurodevelopmental outcomes in later stages,” emphasizes Jordi Sunyer, a senior author of the study.

Despite the uncertainties that remain, this study could have significant implications for public health policy. “Our findings strengthen the evidence supporting the need to reduce pregnant women’s exposure to air pollution, particularly in urban settings,” says Yu Zhao, ISGlobal researcher and co-lead author of the study.

Reference

Laura Gómez-Herrera, Yu Zhao, Ioar Rivas, Elisenda Eixarch, Carla Domínguez-Gallardo, Toni Galmes, Marta Muniesa, Maria Julia Zanini, Alan Domínguez, Marta Cirach, Mark Nieuwenhuijsen, Xavier Basagaña, Xavier Querol, Maria Foraster, Mariona Bustamante, Jesus Pujol, Mireia Gascon, Elisa Llurba, María Dolores Gómez-Roig, Payam Dadvand, Jordi Sunyer. Air pollution and foetal brain morphological development: a prospective study. The Lancet Planetary Health, Vol 9, June 2025. https://doi.org/10.1016/S2542-5196(25)00093-2

A study led by the Sant Pau Research Institute (IR Sant Pau) has succeeded in describing, for the first time in detail, the structural evolution of the medial temporal lobe (MTL) regions across the clinical stages of Alzheimer’s disease in people with Down syndrome. The results, published in the journal Brain, reveal that volume and cortical thickness loss in these regions can begin 13 to 15 years before the onset of symptoms, marking a significant advance in early diagnosis and the design of preventive clinical trials.

The study is based on a large cohort of 259 adults with Down syndrome and 138 euploid controls (individuals without Down syndrome), all of whom underwent high-resolution magnetic resonance imaging (MRI), cerebrospinal fluid biomarker analysis, and detailed clinical and neuropsychological characterization. It is the first study to systematically map the trajectory of MTL subregions—including the anterior and posterior hippocampus, entorhinal cortex, parahippocampus, and Brodmann areas 35 and 36—in relation to cognitive decline and biological markers of the disease.

“We chose to focus on the medial temporal lobe because it is one of the first regions affected by the accumulation of tau neurofibrillary tangles, one of the two key pathologies of Alzheimer’s disease,” explains Dr. Alexandre Bejanin, from the Neurobiology of Dementias group at IR Sant Pau and coordinator of the study. “These regions are also involved in functions such as episodic memory and spatial orientation, which are altered early in the disease.”

An Ideal Model for Studying the Onset of Alzheimer’s Disease

People with Down syndrome have a unique genetic predisposition: overexpression of the APP gene due to trisomy of chromosome 21 leads to overproduction of beta-amyloid (Aβ) protein, making them a natural genetic model of Alzheimer’s. It is estimated that over 90% of this population will develop the disease during their lifetime.

This genetic singularity allowed the researchers to use participants’ age as an estimate of the time to symptom onset (Estimated Years to Onset, EYO), providing an objective temporal framework to study brain changes before dementia. According to their calculations, the inflection point in structural degeneration occurs between 15 and 9 years before the average age of symptom onset.

“This approach allowed us to observe that the entorhinal cortex and posterior hippocampus are the first regions to show structural loss, even before symptoms appear,” notes Alejandra Morcillo-Nieto, also a researcher in the Neurobiology of Dementias group and first co-author of the study. “Moreover, some regions like the parahippocampus initially show cortical thickening, possibly reflecting inflammatory or compensatory processes, before entering a phase of atrophy—although this is a hypothesis that should be confirmed in future studies.”

High-Precision Neuroimaging and Biomarkers

The work is part of the Down-Alzheimer Barcelona Neuroimaging Initiative (DABNI) and used MRI images acquired at two hospitals in Barcelona: Hospital de Sant Pau and Hospital Clínic. For automated segmentation of MTL subregions, the study used ASHS-T1 software, previously validated in Alzheimer’s populations. This system enables segmentation not only of the anterior and posterior hippocampus, but also key cortical structures such as the entorhinal cortex, Brodmann areas 35 and 36 (including the transentorhinal cortex), and the parahippocampus. In addition, a complementary algorithm (CRASHS) was used to model cortical thickness with greater surface precision.

“We didn’t use novel images per se, but advanced analytical techniques applied to standard images typically obtained in clinical practice,” emphasizes Dr. Alexandre Bejanin. “What we did was apply a specific segmentation software that allows very precise quantification of these medial temporal lobe regions—something that had not been done before in the context of Down syndrome.”

The researchers normalized volumes and thicknesses using scores adjusted for age, sex, and intracranial volume, and harmonized data from different scanners using the ComBat method. Image quality was verified through automatic analysis (CAT12) and visual evaluation by experts.

In parallel, cerebrospinal fluid samples from 243 participants with Down syndrome were analyzed to determine levels of Aβ42/40, phosphorylated tau at position 181 (pTau181), and neurofilament light chain (NfL). The researchers correlated these biomarkers with the structural measures obtained through imaging.

Topographic Progression and Predictive Value

The analysis revealed an orderly anatomical progression of atrophy, consistent with the classical pattern of tau propagation. The entorhinal cortex was the first region to show a cortical thickness inflection point (EYO = -15.7 years), followed by the posterior hippocampus (EYO = -13.5), Brodmann 35 (-13), the anterior hippocampus (-11.5), the parahippocampus (-9.8), and Brodmann 36 (-9).

Posterior hippocampal volume showed particularly strong correlations with all cerebrospinal fluid biomarkers: positive with Aβ42/40 and negative with pTau181 and NfL. Among all structures studied, this region was also the most effective in distinguishing asymptomatic individuals from those with clinical symptoms, with an accuracy of 86.3%. When included in a multivariate model with age, pTau181, and parahippocampal thickness, diagnostic accuracy rose to 96.4%.

“Our data indicate that structural MRI not only enables early detection of changes, but can effectively complement fluid biomarkers in predicting clinical status,” says Benjamin Buehner, first co-author of the study. “This is especially relevant in Down syndrome, where cognitive testing may be limited by baseline intellectual disability.”

Implications for Research and Clinical Trials

This study provides, for the first time, a detailed map of how the medial temporal lobe is affected by Alzheimer’s disease in Down syndrome and places the onset of structural changes more than a decade before clinical symptoms appear. This information is critical for designing future therapeutic trials aimed at intervening during preclinical stages to prevent neurodegeneration.

The authors emphasize that while the cross-sectional design limits the establishment of a causal temporal sequence, the genetic homogeneity of Down syndrome and the reliability of the EYO model provide exceptional robustness to the findings.

The study involved collaboration from more than twenty national and international centers and institutions, including Hospital Clínic de Barcelona, the University of Barcelona, the Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), the University of Pennsylvania, and the French INSERM.

Reference Article:

Buehner BJ, Morcillo-Nieto AO, Zsadanyi SE, Rozalem Aranha M, Arriola-Infante JE, Vaqué-Alcázar L, Arranz J, Rodríguez-Baz Í, Maure Blesa L, Videla L, Barroeta I, Del Hoyo Soriano L, Benejam B, Fernández S, Sanjuan Hernandez A, Bargalló N, González-Ortiz S, Giménez S, de Flores R, Yushkevich PA, Alcolea D, Belbin O, Lleó A, Carmona-Iragui M, Fortea J, Bejanin A. Medial Temporal Lobe Atrophy in Down Syndrome Along the Alzheimer’s Disease Continuum. Brain. 2025. https://doi.org/10.1093/brain/awaf133

A scientific review by Dr. Anna Aulinas, coordinator of the Functional Unit for Pituitary Diseases at Hospital de Sant Pau and researcher with the Pituitary Diseases group at the Sant Pau Research Institute (IR Sant Pau), together with Dr. Elizabeth Lawson, professor at Harvard Medical School, offers a new perspective on hypopituitarism. The review focuses on an aspect that has so far received little attention: the potential oxytocin deficiency in these patients.

The review, titled “The Oxytocin System and Implications for Oxytocin Deficiency in Hypothalamic-Pituitary Disease”, was published in Endocrine Reviews, one of the most prestigious international journals in the field of endocrinology. In addition to being pioneering in its subject, the review was highlighted by the journal itself as the “Featured Article of the Week,” a distinction reserved for the most relevant and potentially impactful contributions within the scientific community.

A Key Hormone Beyond Labor and Lactation

Oxytocin is a hormone produced in the hypothalamus and secreted by the posterior pituitary gland, traditionally known for its role in childbirth and lactation. However, recent studies have proved that it also plays a central role in regulating food intake, body composition, bone health, cardiovascular activity, emotions, and social bonding.

The review compiles, for the first time in a comprehensive way, data pointing to a potential oxytocin deficiency in individuals with hypothalamic and/or pituitary damage—caused by tumors, surgery, radiotherapy, or inflammatory diseases. This could contribute to some persistent symptoms these patients experience, despite conventional hormone replacement therapy.

A New Clinical Entity Under Study

The concept of oxytocin deficiency in hypopituitarism is not yet fully recognized but is emerging as a clinical entity with its own distinct features. Through analysis of existing literature, the review identifies evidence linking this deficiency to poorer quality of life, psychosocial disturbances, a tendency toward obesity, and bone fragility, among other issues.

Although some patients have begun to receive oxytocin as an experimental therapy in highly controlled clinical settings, the authors emphasize that further research is needed before it can be recommended for widespread use. In particular, there is an urgent need to develop specific diagnostic tests to detect oxytocin deficiency, as well as to assess the safety and efficacy of treatments in well-designed clinical trials.

A Step Toward a More Comprehensive View of Hypopituitarism

The review concludes that incorporating oxytocin into the set of hormones considered in the management of hypopituitarism could represent a paradigm shift in patient care. The proposal is clear: when symptoms persist despite standard hormone replacement therapy, it may be necessary to look beyond and also consider the function of the neurohypophysis.

According to Dr. Aulinas, “Oxytocin deficiency could explain part of the invisible suffering experienced by these patients. Recognizing it opens the door to a new research path and, in the future, to a more comprehensive and humane approach to their medical care.” This work marks a turning point in the understanding of “non-classical” hormonal deficits associated with hypopituitarism and invites a reevaluation of how these complex disorders are diagnosed and treated.

Reference article:

Aulinas A, Lawson EA. The oxytocin system and implications for oxytocin deficiency in hypothalamic-pituitary disease. Endocr Rev 2025. https://doi.org/10.1210/endrev/bnaf008

This past weekend, the Born Centre for Culture and Memory was the venue for the 18th Science Festival, a large gathering for all audiences to engage with science and knowledge. The Sant Pau Research Institute was one of the participating entities, offering three workshops that captivated numerous families.

On Saturday afternoon, visitors were able to enjoy a dynamic and educational activity to find out what the brain, heart and blood look like and how they work through life-size 3D models and interactive posters. Children had to connect the parts of the organs and identify their functions in order to better understand these three fundamental pillars of the human body. The activity, led by Jorge Clusa, outreach coordinator at the Sant Pau Research Institute, was very popular among children.

On Sunday morning, Marta Cano and Romina Miranda, researchers from the mental health group at the Sant Pau Research Institute, also invited the youngsters to explore the structures of the brain and its functions by assembling a 3D paper puzzle of this organ. The attendees also had a lot of fun participating in an original brain bingo game in which each move revealed a curiosity about the human brain.

To close the Festival, on Sunday afternoon, Dr. Robert Belvís, Dr. Noemí Morollón, Dr. Juan Aibar, professionals of the Headache and Neuralgia Unit of the Hospital de Sant Pau, with the support of Iago Andreu, a clinical engineer from the hospital’s Dimension Lab, explored the complexity of neurosurgery. The attendees who joined us discovered how technology helps to plan operations with more precision and safety, and were able to live an immersive experience by trying on virtual reality glasses.

The Sant Pau Research Institute thanks everyone who made this success possible, both the organizers and the participants, who contributed to making this Science Festival a memorable edition.

Researchers at the Sant Pau Research Institute (IR Sant Pau) have published a study in Epilepsy & Behavior documenting a high frequency of neuropsychiatric symptoms in adults with tuberous sclerosis complex (TSC), a rare, multisystem genetic disorder with highly variable clinical expression. While the condition primarily affects the nervous system, it can also impact other organs such as the kidneys, heart, skin, and lungs.

The study provides an in-depth analysis of the cognitive and emotional profiles of 28 adult patients with confirmed TSC and no severe intellectual disability, highlighting an unmet clinical need. Although most participants exhibited significant emotional, cognitive, or behavioral alterations, only a minority had received specialized mental health care.

The most common symptoms included mood swings (reported in 80% of cases), excessive shyness (70%), and sleep and attention disorders (60%). Additionally, half of the patients reported low self-esteem. Despite this symptom burden, only four individuals—14% of the sample—had received psychiatric or psychological care. “Our patients have many problems in these neuropsychiatric domains, but they don’t seek help for them. And unfortunately, we don’t have the resources to monitor them more closely either because there are so many gaps in mental health care that this ends up being an unmet need,” explains Dr. Alba Sierra, researcher in the Epilepsy Group at IR Sant Pau, neurologist at Hospital Sant Pau, and corresponding author of the study.

Genetic Origin and Variable Manifestations

TSC is caused by mutations in the TSC1 or TSC2 genes, which lead to abnormal activation of the mTOR pathway and the formation of hamartomas—benign masses made up of normal but disorganized cells. These can develop in different organs. When they affect the central nervous system, they may cause epilepsy, intellectual disability, and neuropsychiatric disorders.

While the impact of epilepsy in TSC has been widely studied, emotional and cognitive symptoms—collectively known as TAND (TSC-Associated Neuropsychiatric Disorders)—have received less attention, especially in adults. “Disease severity is highly variable: some people have mild symptoms and are diagnosed by chance in adulthood, while others experience severe epilepsy, intellectual disability, and multi-organ involvement. That’s why we included a wide age range, from 18 to 65 years. This disease can manifest at any point in life,” notes Dr. Sierra.

Comprehensive Clinical and Neuropsychological Assessment

The study combined a clinical evaluation with an extensive neuropsychological battery. All patients underwent standardized intelligence testing (WAIS-IV) and cognitive screening (MoCA), along with specific scales to assess anxiety, depression, quality of life, and subjective health perception. The researchers also used the TAND-L checklist to detect symptoms across different domains, from behavior to academic skills. Clinically, the study considered epilepsy history, infantile spasms, findings from MRI and EEG, and genetic profile when available.

Beyond Epilepsy: Factors Linked to Greater Impact

Results showed a clear link between epilepsy severity and duration and poorer cognitive performance. Significant associations were also observed with other clinical factors. For example, patients with a history of infantile spasms or mutations in the TSC2 gene had more impaired cognitive profiles and greater emotional and academic difficulties. Additionally, the presence of hamartomas in the frontal and parietal lobes was associated with behavioral, learning, and other specific cognitive impairments.

“We found that epilepsy isn’t the only factor driving these symptoms. Genetics and the location of brain hamartomas also play a role. The impact is multifactorial,” emphasizes Dr. Sierra.

Cross-Specialty Coordination: A Structural Need

Beyond the clinical findings, the study encourages reflection on the current care model for TSC patients. Traditionally, neurology appointments have focused on controlling epileptic seizures, without systematically addressing neuropsychiatric symptoms. “We tend to focus heavily on purely neurological symptoms, and perhaps haven’t explored these other issues—ones that directly affect quality of life—as much. This study draws attention to the need to look beyond the seizures,” adds Dr. Sierra.

In line with this more holistic perspective, the team underscores the need for multidisciplinary care. TSC doesn’t just impact the brain—it can lead to serious complications in vital organs, including kidney failure, cardiac issues, or lung disease. “Follow-up has to be comprehensive. A systemically involved disease like this requires joint work among specialists. It’s the only way to ensure high-quality care,” concludes Dr. Sierra.

Future Outlook: Toward Longitudinal Follow-Up

The study opens the door to future research aimed at tracking the progression of these symptoms over time. Longitudinal studies could provide more in-depth insight into how neuropsychiatric alterations evolve with age and help develop more effective, personalized intervention strategies.

Reference Article:

Toscano-Prat C, García-Sánchez C, Ros-Castelló V, Barguilla-Arribas A, Saladich IG, Rodríguez-Clifford K, Torra-Balcells R, Boronat S, Sierra-Marcos A. Cognitive and neuro-psychiatric profile in adult patients with epilepsy secondary to Tuberous Sclerosis Complex. Epilepsy Behav. 2025;166:110380. https://doi.org/10.1016/j.yebeh.2025.110380

The Sant Pau Research Institute and The Hospital de Sant Pau, who have once again participated together in the BCN Salut Games— the solidarity olympics of the health and research sector— have been crowned champions of this year’s edition, which gathered a total of 5,435 participants from 51 different centers.

More than 400 professionals from Hospital de Sant Pau took part in this sports event, where Sant Pau finished in first place, followed by Hospital Clínic and Sant Joan de Déu, in second and third place respectively.

The aim of this solidarity olympics is to encourage physical activity and healthy habits in the healthcare field, while also fostering cohesion, togetherness, and motivation within institutions and among participating organizations.

In addition, Sant Pau raised a total of €2,597 this year in solidarity donations from participating professionals. These funds will go to the Kàlida Foundation, a support center for people affected by cancer, offering care and guidance to individuals going through or having gone through cancer, as well as to their close circle of family, caregivers, and friends.

Soon, the BCN Salut Games organization will present Sant Pau’s management team with the trophy recognizing them as champions of the 2025 edition. The Kàlida Foundation will also receive the solidarity check with the funds raised, handed over by Sant Pau’s management.

An international study involving researchers from the Sant Pau Research Institute (IR Sant Pau) has demonstrated that women who are carriers of genetic mutations causing frontotemporal dementia (FTD) show a greater capacity to compensate for brain damage than men, at least in the early stages of the disease. The discovery suggests that sex is a key biological factor in the evolution of this hereditary form of dementia and opens the door to more gender-sensitive precision medicine.

The article was published in the journal Alzheimer’s & Dementia, the official publication of the Alzheimer’s Association, and is part of a series of three scientific papers on sex differences in the clinical and biological manifestations of genetic FTD. The research is part of the North American ALLFTD consortium and included collaboration from leading neuroscience and neuroimaging centers in San Francisco (UCSF) and Toronto (University of Toronto).

“What we observed is that, for the same degree of brain damage, women with FTD performed better than men in executive function and social cognition tests. This indicates they have greater cognitive and behavioral reserve,” explains Dr. Jesús García Castro, neurologist and researcher in the team led by Dr. Ignacio Illán-Gala at the Sant Pau Memory Unit and Sant Pau Research Institute (IR Sant Pau), and first author of the study.

FTD is a neurodegenerative disease still not well known to the general public, but which has gained recent attention following the diagnosis of actor Bruce Willis. Unlike Alzheimer’s, which primarily affects memory, FTD presents as personality changes, social behavior disturbances, and language or speech difficulties. It typically begins at an earlier age—between 45 and 65 years—and may lead to a progressive loss of executive functions such as judgment, empathy, or impulse control. For this reason, the study of behavioral changes is key to early detection.

A longitudinal look at brain resilience

Frontotemporal dementia is a rare neurodegenerative disease that usually appears between 45 and 65 years of age and severely affects personality, social behavior, and language. In about 30% of cases, it is caused by mutations in genes such as C9orf72, GRN, or MAPT, which lead to abnormal protein accumulation and progressive loss of brain tissue, especially in the frontal and temporal lobes.

Thanks to the systematic follow-up of the ALLFTD consortium, the researchers were able to analyze over 670 brain MRIs and clinical data from 394 carriers of pathogenic mutations and 279 non-carrier relatives over several years. They studied both asymptomatic individuals (presymptomatic phase) and those already diagnosed with mild cognitive impairment or dementia.

“This longitudinal design allowed us to observe how the disease evolves even before the first symptoms appear. And this is where we saw the female advantage: women showed better cognitive performance despite having greater degrees of frontal brain atrophy,” highlights Dr. García Castro.

The team used an innovative methodology known as the residual approach, which quantifies cognitive reserve: the discrepancy between a person’s actual performance and what would be expected based on their degree of neurodegeneration. This approach revealed that women, especially those carrying the C9orf72 expansion, maintained better executive and social functioning despite cortical thinning.

An advantage that fades with disease progression

Statistical models also showed that this female advantage is not permanent. As the disease progresses and brain damage extends, compensatory capacity decreases, and deterioration trajectories equalize between men and women in advanced stages.

“It’s as if the female brain has more capacity to resist the disease for a time, but once a certain threshold is reached, the decline accelerates,” summarizes Dr. García Castro. “This matches what has been observed in Alzheimer’s: greater initial resilience in women, followed by faster deterioration when symptoms emerge.”

Indeed, the study observed a trend towards later symptom onset in women (up to 6.5 years on average), although this result did not reach statistical significance due to sample size.

Clinical implications and future research directions

The work has important implications for the design of clinical trials and progression prediction models in hereditary dementias. Until now, most studies had not considered sex as a differentiating variable, which may have obscured important patterns in treatment response or clinical evolution.

“Our findings reinforce the need to integrate sex and gender perspectives into precision medicine, especially in diseases like FTD, where variability is enormous even within the same genetic mutation,” notes Dr. García Castro.

The Sant Pau group, in collaboration with international partners of the ALLFTD consortium, continues to analyze other modulators of progression in genetic FTD, including immunological, hormonal, and structural markers.

Study funding

The research was conducted as part of the North American ALLFTD (Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects) consortium, funded by the U.S. National Institute on Aging (NIA) and the U.S. National Institute of Neurological Disorders and Stroke (NINDS).

In addition, the work was supported by the Carlos III Health Institute through multiple projects (PI20/01473, PI23/01786, PI18/00435, PI20/01330, PI21/01395, PI21/00791, CP20/00038, PI22/00307, INT21/00073, CM21/00243 and CM23/00176), co-financed by the European Union. It also received funding from the Biomedical Research Network Centre on Neurodegenerative Diseases (CIBERNED) and the European Regional Development Fund (ERDF) under the slogan “A way to make Europe”.

At the international level, the study was supported by the Alzheimer’s Association (grants AARG-22-923680, AARF-22-924456 and GBHI ALZ UK-21-720973), the Alzheimer Society (UK), and the Global Brain Health Institute (GBHI). It also received support from the Tatiana Pérez de Guzmán el Bueno Foundation, and from the Horizon 2020 programme of the European Union.

In Catalonia, the research was promoted by the Department of Health of the Generalitat through the Strategic Plan for Health Research and Innovation (PERIS), and was supported by clinical talent contracts such as Juan Rodés and Río Hortega.

This institutional support has made it possible to carry out a large-scale multicenter study with participation from 18 centers in the United States and Canada, and consolidates Sant Pau’s leadership in advancing precision medicine in the field of neurodegenerative diseases.

Reference article:

Garcia Castro J, Rubio-Guerra S, Casaletto KB, Selma González J, Memel M, Vaqué-Alcázar L, Morcillo-Nieto A, Arriola-Infante J, Dols-Icardo O, Bejanin A, Belbin O, Fortea J, Alcolea D, Carmona-Iragui M, Barroeta I, Santos-Santos M, Sánchez Saudinós MB, Sala Matavera I, Heuer HW, Forsberg LK, Kantarci K, Staffaroni AM, Tartaglia C, Rankin KP, Boeve B, Boxer A, Rosen HJ, Lleó A, Illán-Gala I, ALLFTD Consortium. Sex differences in the executive and behavioral reserve of autosomal dominant frontotemporal dementia. Alzheimers Dement 2025;21:e70070. https://doi.org/10.1002/alz.70070

A team of researchers from the Sant Pau Research Institute (IR Sant Pau) has received the 2025 Best Communication Award from the Catalan Resuscitation Council (Consell Català de Ressuscitació, CCR), in recognition of the scientific and translational impact of their work.

The winning study, titled “Region-Specific Vulnerability to Brain Damage Following Cardiac Arrest and Cardiopulmonary Resuscitation: Preclinical Studies in Pigs,” was led by Dr. Gemma Vilahur, head of the Molecular Pathology and Therapeutics of Atherothrombotic and Ischemic Diseases Research Group at IR Sant Pau and a member of CIBERCV.

The research offers a comprehensive and holistic understanding of the pathophysiological mechanisms that occur in the brain following a five-minute cardiac arrest and subsequent resuscitation. Using a preclinical model, the study analyzes markers related to glial activation, apoptosis, and the deregulation of cellular survival pathways. It reveals a differential neuronal response across brain regions, with more intense inflammatory reactions and greater vulnerability to neuronal loss in the cerebral cortex, caudate nucleus, and hippocampus. While further exploration of these findings is underway, the results may have important implications for the development and implementation of targeted neuroprotective strategies in patients who have suffered cardiac arrest.

The award was presented on Tuesday, May 20, during the closing ceremony for the awards and grants hosted by the Academy of Medical Sciences of Catalonia in Barcelona. Representing the team, María Ángeles Cánovas—who has been involved in the research project since its inception—accepted the award.

This recognition highlights the scientific excellence of the work being conducted at IR Sant Pau, particularly in the field of cardiovascular research and its connection to brain health. It also underscores the importance of cross-disciplinary and cross-institutional collaboration in advancing the understanding of complex conditions such as those resulting from cardiac arrest. The study involved researchers from Hospital Clínic de Barcelona, the Liverpool Centre for Cardiovascular Science (United Kingdom), and CIBERCV (Carlos III Health Institute).

Researchers from the Sant Pau Research Institute (IR Sant Pau) and CIBER-BBN have led an exhaustive scientific review of therapies aimed at the CXCR4 receptor, a key target in more than 20 types of cancer. The article, published in Biomarker Research, provides a comprehensive overview of the most advanced therapeutic and diagnostic approaches under development to act on this receptor, considered a poor-prognosis biomarker and a characteristic signature of tumor stem cells.

The CXCR4 receptor (C-X-C chemokine receptor type 4) is a membrane protein belonging to the family of G-protein-coupled receptors whose normal role is to guide cell migration, especially in the immune system and during embryonic development. Under physiological conditions it regulates processes such as hematopoiesis, tissue regeneration, and the inflammatory response, acting as a cellular docking site for its natural ligand, the chemokine CXCL12. However, this essential function becomes corrupted in pathological contexts such as cancer, where CXCR4 overexpression in tumor cells gives them advantages such as the ability to invade tissues, evade the immune system, and resist treatments.

Beyond its physiological role, CXCR4 has for decades been an object of interest in HIV research because the virus uses it as a co-receptor to enter certain immune cells. This intense work in the context of HIV infection made it possible to characterize its structure, develop multiple antagonists, and deepen our understanding of its activation mechanisms—knowledge that is now being repurposed in oncology.

“The CXCR4 receptor has proved to be an extraordinary molecular target for precision oncology. Its overexpression in many tumor types makes it a strategic target both for blocking cancer progression and for accurately delivering drugs to the most aggressive tumor cells,” emphasizes Dr. Ugutz Unzueta, researcher in the Oncogenesis and Antitumor Drugs group and coordinator of the review.

The IR Sant Pau group has been at the forefront of this line of research for the past fifteen years, with more than one hundred publications focused on developing nanomedicine based on protein nanoparticles that selectively recognize and attack CXCR4⁺ cells. Their approach has contributed significantly to expanding the therapeutic arsenal available against resistant tumors or those with a high risk of metastasis. This accumulated experience was decisive in leading a review that summarizes current knowledge and outlines future directions in the clinical development of this strategy.

New therapeutic horizons for a key molecular target

CXCR4 has been extensively validated as a therapeutic target. Developing new strategies therefore faces the challenge of improving efficacy without increasing toxicity, giving prominence to approaches that allow targeted, selective drug delivery. Designing functionalized nanoparticles, antibody-drug conjugates, photothermal molecules, or interfering RNA’s specifically aimed at CXCR4-positive cells opens new avenues to increase specificity and reduce adverse effects.

Looking ahead, prospects point to closer integration of diagnosis, patient selection, and treatment. Precision cancer medicine is moving toward combination therapies able to simultaneously recognize multiple tumor markers—such as CXCR4 together with others typical of tumor stem cells—helping overcome one of today’s main challenges: tumor plasticity and heterogeneity within the same tumor.

The review also argues for redesigning clinical trials. Instead of traditional models focused on specific tumor types, the authors highlight the value of so-called basket trials, which group patients by shared biomarkers—such as high CXCR4 expression—regardless of the tumor’s organ of origin. This approach would enable better patient selection and higher therapeutic response rates.

Meanwhile, molecular imaging technologies such as positron emission tomography (PET) with specific tracers are poised to play a fundamental role in patient detection, stratification, and monitoring. Agents like [68Ga]-Pentixafor allow non-invasive visualization of CXCR4 expression in tumors and target organs, facilitating both the selection of candidates for targeted therapies and real-time monitoring of response.

“Progress in personalized medicine for cancer treatment demands combining imaging technologies, molecular markers, and targeted therapies. CXCR4 is a paradigmatic example of how basic and applied research can converge to change clinical practice,” notes Ariana Rueda, first author of the study.

Reference article

Rueda A, Serna N, Mangues R, Villaverde A, Unzueta U. Targeting the chemokine receptor CXCR4 for cancer therapies. Biomarker Research. 2025;13:68. https://doi.org/10.1186/s40364-025-00778-y.

The Sant Pau Research Institute (IR Sant Pau) has secured funding for the creation of the Network for the Integrative Study of Synaptic Circuits and Their Role in Disease. This network will be coordinated by Dr. Àlex Bayés, head of the Molecular Synapse Physiology research group at IR Sant Pau. This thematic network, part of the State Program for Knowledge Transfer and Collaboration within the 2024–2027 State Plan for Scientific, Technical, and Innovation Research, is one of only two networks funded in the area of nervous system diseases. It was funded in a highly competitive call for proposals.

According to Dr. Bayés, “this network aims to foster scientific collaboration among basic and translational research groups working on synaptic circuits from very different, yet complementary, methodological approaches. The goal is to share knowledge and generate synergies to better understand the function of neuronal circuits and their dysfunction in neurodevelopmental disorders and neurodegenerative diseases.”

This is the third network of this kind led by Dr. Bayés from IR Sant Pau, following those established in 2015 and 2019. “We already have a solid track record in coordinating research networks. These initiatives not only help strengthen interdisciplinary research, but also increase the national and international visibility of our work and of IR Sant Pau.”

The network will consist of twelve research groups from different institutions across Spain, with experts in molecular biology, neuroscience, optical and electron microscopy, animal behavior, and optogenetics, among others. Network activities will include regular meetings, mobility programs for early-career researchers, and science outreach initiatives to bring research closer to the public. In addition, the network will promote data sharing, participation in collaborative research projects, and the application for new funding opportunities. The funding granted totals €28,000, to be distributed over two years.

With this initiative, IR Sant Pau reaffirms its commitment to high-quality basic and translational research, “which is essential for the later development of applied research,” says Dr. Bayés, as well as to building knowledge networks that contribute to scientific progress and the improvement of disease treatment. This new project further strengthens the institute’s position as a leader in synaptic circuit research and their role in brain health. It supports both the development of new research lines and the training of young scientists in a highly collaborative and innovative environment.

A recently published letter in The Lancet, signed by Dr. Juan Fortea and leading European experts in Alzheimer’s disease, celebrates the European Commission’s approval of lecanemab as a key milestone in transforming the diagnostic and therapeutic approach to the disease. The authors highlight that this decision finally enables a long-awaited paradigm shift in Europe: moving from symptom-based diagnosis in later stages to early biological diagnosis, opening the door to more precise, personalized, and effective care.

This advance, they emphasize, will benefit not only those who receive treatment with lecanemab, but also a much larger number of people with cognitive impairment, by fostering structural improvements in diagnostic, prognostic, and clinical follow-up systems. The introduction of this treatment requires a reorganization of care that may have broad positive effects beyond the drug itself.

However, the letter also delivers strong criticism of the European regulatory process. The authors express disappointment that the European Medicines Agency (EMA) has rejected the approval of donanemab, despite the scientific evidence and the fact that this treatment is already being used in many other countries around the world. This decision, along with the accumulated delays in the process, has led to a nearly two-year setback in access to disease-modifying therapies in Europe, with direct consequences for patients and their families.

The signatories call for deep reflection on the consistency and agility of regulatory evaluation processes in Europe and urge greater openness to emerging data and a more flexible, nuanced assessment of risk-benefit ratios that allows for informed decisions based on the most up-to-date evidence.

The letter concludes with a clear message: while regulatory caution is necessary, so too is therapeutic urgency in the face of a progressive and fatal disease like Alzheimer’s. Europe cannot afford to continue falling behind.

Reference:

Fortea J, Boban M, Engelborghs S, Frederiksen KS, Hort J, Kennelly S, Kramberger MG, Mehrabian S, Plantone D, Paquet C, Santana I, Scarmeas N, Solje E, Spiru L, Šutovský S, Vijverberg EGB, Winblad B, Jessen F. Regulatory asymmetry in Alzheimer’s disease care. Lancet. 2025. https://doi.org/10.1016/s0140-6736(25)00907-9.

An international team of researchers has discovered how cholesterol can disrupt the internal functioning of the heart by accumulating in the mitochondria of cardiomyocytes. They have also developed an experimental immunotherapy capable of reversing this process and restoring cellular energy production.

The study, recently published in the Journal of Lipid Research, was led by Dr. Vicenta Llorente-Cortés, researcher at the Lipids and Cardiovascular Pathology group of the Institute of Biomedical Research of Barcelona (IIBB-CSIC), part of the Spanish National Research Council (CSIC), the Sant Pau Biomedical Research Institute (IR Sant Pau), and the CIBERCV.

The research was conducted in collaboration with scientists from CIBERdem, the Institute of Molecular Biology of Barcelona (IBMB-CSIC), the University of Barcelona (UB), the Autonomous University of Barcelona (UAB), the University of California (USA), and the University of Toulouse (France).

The Heart, Vulnerable to Lipid Damage

The heart requires a high and constant energy supply and depends on the efficiency of its mitochondria to sustain continuous contraction of the cardiac muscle. In fact, cardiomyocytes (heart muscle cells) are among the most mitochondria-rich human cells—nearly a third of their volume consists of mitochondria. These organelles convert nutrients into energy through a process called oxidative phosphorylation, which is essential for heart function.

Several studies have indicated that under altered metabolic conditions—such as obesity, diabetes, or hypercholesterolemia—progressive mitochondrial dysfunction occurs, which worsens heart failure. This study identifies, for the first time, a precise cellular mechanism through which cholesterol esters, transported by lipoproteins, penetrate cardiomyocytes and accumulate inside their mitochondria, causing structural and functional impairments.

The LRP1 Receptor and Mitochondrial Cholesterol: A Direct Link

The researchers demonstrated that the LRP1 receptor, a protein located on the cell membrane of cardiomyocytes, is the main factor responsible for transporting esterified cholesterol from lipoproteins into cardiomyocytes. Under lipotoxic conditions, this cholesterol accumulates in mitochondrial membranes and interiors. The result is disruption of mitochondrial architecture, impairment of the respiratory chain, and a significant loss in energy production capacity.

“We have revealed a previously unknown mechanism: the cholesterol carried by lipoproteins doesn’t just affect blood vessels or accumulate in plaques—it actually penetrates the mitochondria of the heart. The accumulation of cholesterol esters in mitochondria compromises cellular respiration and, consequently, the function of the heart itself,” explains Dr. Vicenta Llorente-Cortés, CSIC researcher, lead author of the study, and coordinator of the CIBERCV and CIBERdem groups at IIBB-CSIC and IR Sant Pau.

To counter this harmful mechanism, the team developed an experimental immunotherapy based on monoclonal antibodies specifically targeting the P3 domain of the LRP1 receptor. This strategy achieves selective blockade that prevents the LRP1 receptor from transferring cholesterol esters—carried in the bloodstream by lipoproteins—into the cell interior.

A Multitechnic and Multiorganic Approach to Uncover a Hidden Mechanism

To conduct this research, the scientists used a combination of advanced bioenergetics techniques (University of California), mass spectrometry (University of Toulouse), and confocal and electron microscopy (IR Sant Pau and University of Barcelona). They used a rabbit model with a lipid profile similar to that of humans to simulate dyslipidemic conditions associated with cardiovascular disease (CSIC).

The researchers performed subcellular fractionation analyses to isolate mitochondria and quantify their lipid content, and used high-precision respirometry techniques to assess mitochondrial respiratory chain efficiency in the presence and absence of cholesterol accumulation in the hearts of the experimental model.

Anti-P3 Antibodies: An Experimental Solution with Great Potential

Trials conducted in the rabbit model—with a lipid and lipoprotein profile similar to that of humans—showed that this immunotherapy significantly reduces mitochondrial lipid load, particularly the content of cholesterol esters involved in cellular respiration. As a direct consequence, restoration of mitochondrial architecture was observed, including the recovery of mitochondrial aristae—key structures for cellular respiration. Furthermore, the therapy improves the efficiency of oxidative phosphorylation and normalizes ATP production, the energy molecule that powers heart contraction.

Another significant effect observed following treatment with anti-P3 antibodies was the improvement in the interaction dynamics between mitochondria and cytoplasmic lipid droplets, indicating a functional reorganization of cellular metabolism.

This therapeutic approach, both innovative and highly targeted, not only halts the damage caused by cholesterol accumulation but also reverses the effects on the heart’s energy machinery. According to the researchers, this strategy could potentially be applied in the future to treat various cardiovascular conditions where altered lipid profiles promote intracellular cholesterol deposition, such as in obesity, myocardial ischemia, or chronic hypercholesterolemia.

“Our experimental treatment allows us to act on the heart at a level that had not been targeted before: inside the cell, inside the mitochondria, where the vital energy of the cardiac muscle is generated,” emphasizes Dr. Vicenta Llorente-Cortés.

Responding to an Unmet Clinical Need

Cardiovascular diseases are responsible for one in three deaths worldwide. While current treatments have made significant advances in controlling traditional risk factors such as hypertension or plasma cholesterol, there is still no effective strategy to address intracellular metabolic damage in the heart, particularly mitochondrial damage.

This study proposes an entirely new approach: to intervene directly in the process that leads cholesterol to accumulate in the energy machinery of cardiac cells, thereby preventing the bioenergetic dysfunction that precedes heart failure.

“This discovery has clear clinical implications: it enables us to envision new therapies aimed at preserving mitochondrial function in patients with high cardiovascular risk. This is especially relevant in contexts where circulating cholesterol remains persistently elevated, and lowering it externally is no longer enough—we need to protect the heart from within,” concludes Dr. Llorente-Cortés.

Study Funding

This study was supported by the Carlos III Health Institute (ISCIII) through the cooperative research programs of the Biomedical Research Networking Centers in Cardiovascular Diseases (CIBERCV) and in Diabetes and Associated Metabolic Diseases (CIBERdem), as well as by funding from the European Regional Development Fund (ERDF). Additional funding came from the Spanish Ministry of Science, Innovation, and Universities, and from the Government of Catalonia through the Agency for Management of University and Research Grants (AGAUR). International collaborations were co-funded by research agencies in the United States and France, including the National Institutes of Health (NIH) and the Centre National de la Recherche Scientifique (CNRS).

Reference Article:

Benitez-Amaro A, Garcia E, LaChica Lhoëst MT, Polishchuk A, Zegri-Reiriz I, Vilades D, Guerra JM, Fernández-Del-Rio L, Mirabet S, Samouillan V, Shirihai O, Liesa M, Enrich C, Llorente-Cortés V. LRP1 immunotherapy enhances cardiomyocyte respiration by restricting cholesteryl ester accumulation in mitochondria. J Lipid Res 2025:100783. https://doi.org/10.1016/j.jlr.2025.100783

https://www.youtube.com/watch?v=1v9ONbGySCc&t=29s

A recent study has identified specific alterations in lipid metabolism associated with subclinical atherosclerosis in individuals with type 2 diabetes. This silent condition, known as atherosclerosis, occurs before cardiovascular events and causes a gradual narrowing of the arteries due to the buildup of fatty plaques. It is one of the main causes of complications in patients with diabetes.

The study, published in Cardiovascular Diabetology, was led by Dr. Dídac Mauricio, scientific director of the Diabetes and Metabolic Diseases area at CIBER (CIBERDEM) and researcher at Sant Pau Research Institute (IR Sant Pau), and Maria Barranco-Altirriba, first author of the article and researcher in the Bioengineering, Biomaterials and Nanomedicine area at CIBER (CIBER-BBN), also at the same institute. The study also involved other teams from CIBERDEM, CIBER-BBN, and the Obesity and Nutrition Physiopathology area (CIBEROBN) across different institutions.

The research analyzed more than 500 individuals, including patients with type 1 and type 2 diabetes and individuals without diabetes. It employed advanced lipid analysis technologies along with ultrasound imaging of the carotid arteries. Results indicated that nearly half of the participants displayed signs of subclinical atherosclerosis.

Lipid alterations in type 2 diabetes

“In patients with type 2 diabetes, we identified 27 distinct lipid species associated with the presence of atherosclerotic plaques in the arteries. Among the most implicated lipids were phosphatidylcholines and diacylglycerols, which showed both increases and decreases. Interestingly, the most marked changes were observed in people with type 2 diabetes who smoked or were not receiving treatment to control cholesterol,” explained Dr. Dídac Mauricio.

“These findings point to a significant alteration in lipid metabolism in type 2 diabetes, which could help identify high cardiovascular risk patients at an early stage. Furthermore, this opens the door to new studies aimed at finding more personalized prevention and treatment strategies based on each individual’s lipid profile,” the research team concluded.

Article reference:

Barranco-Altirriba M, Rossell J, Alonso N, Weber RJM, Ortega E, Lloyd GR, et al. Lipidomic analysis reveals metabolism alteration associated with subclinical carotid atherosclerosis in type 2 diabetes. Cardiovasc Diabetol. 2025;24(1):152. doi:10.1186/s12933-025-02701-z.