A study led by the Sant Pau Research Institute (IR Sant Pau), the Clinical Biochemistry Service at Hospital de Sant Pau, and the Spanish Biomedical Research Network in Diabetes and Associated Metabolic Diseases (CIBERDEM) has identified a key disruption in cholesterol transport to the brain in patients with Alzheimer’s disease. The findings suggest that the lipoproteins in the cerebrospinal fluid of patients with Alzheimer’s have a reduced ability to deliver cholesterol to neurons. This impairment may be linked to the presence of the APOE4 genetic variant, one of the main known risk factors for the disease. The study has been published in the Journal of Lipid Research.

According to Dr. Mireia Tondo, researcher in the Lipid Disorder Pathophysiology Group at IR Sant Pau and lead author of the project, “We’ve long known that people with the APOE4 variant—especially in the homozygous form—have a much higher risk of developing Alzheimer’s, but until now, the reasons for this weren’t well understood. Our study suggests that one contributing factor may be that neurons, in the presence of this variant, have a harder time absorbing cholesterol delivered through the cerebrospinal fluid.”

Cholesterol: Essential for Neuronal Viability

Cholesterol is a vital molecule for proper neuronal function. It plays a key role in membrane formation, synaptic transmission, and myelin production. Unlike other organs, the brain does not receive cholesterol from the bloodstream due to the protective blood–brain barrier. “All the cholesterol the brain needs is produced locally,” explains Dr. Tondo, “and it’s stored in specific lipoprotein particles that transport it from glial cells to neurons. If this process fails, the neuron may not receive the structural and functional resources it needs.”

The research team analyzed cerebrospinal fluid samples from 10 patients with Alzheimer’s disease and 10 individuals without the disease, all part of the Sant Pau Initiative on Neurodegeneration (SPIN) cohort. They evaluated two stages of cerebral lipid transport: first, the ability of astrocytes to release cholesterol into the cerebrospinal fluid, and second, the ability of neurons to absorb this cholesterol. The results indicated that astrocyte cholesterol release was similar in all participants, but neuronal uptake was clearly impaired in patients with Alzheimer’s.

Based on these findings, the team sought to determine whether this defect was related to genetics. “Most of the patients in our sample were heterozygous for the APOE4 variant, and we observed lower cholesterol uptake in them. So we decided to go further and create recombinant lipoprotein nanoparticles, identical except for containing either APOE3 or APOE4,” Dr. Tondo explains. “When we tested them in cultured neurons, those containing APOE4 delivered cholesterol much less efficiently. This led us to believe that this variant may directly contribute to the dysfunction we observed.”

Protein Alterations and Functional Implications

The researchers also performed a detailed proteomic analysis of the cerebrospinal fluid lipoproteins. They identified 239 proteins associated with these particles, of which 27 were altered in Alzheimer’s patients. Interestingly, none of these differences directly involved proteins related to cholesterol metabolism. “This finding tells us that the lipoprotein system is far more complex than we thought, and that other mechanisms—such as inflammation, cell adhesion, or protein degradation—may also influence disease progression,” adds Dr. Tondo.

“Efficient delivery of cholesterol to neurons is essential for their function and maintenance. Our results strongly suggest that this process is impaired in Alzheimer’s disease, particularly in the presence of the APOE4 variant,” says Carla Borràs, the study’s first author. “This may contribute to neuronal vulnerability and progressive degeneration.”

This research was made possible through collaboration between the lipid metabolism group and the Memory Unit at Sant Pau, an international reference center in the clinical and biomolecular study of dementias. Additional contributors included researchers from the Spanish Biomedical Research Network in Neurodegenerative Diseases (CIBERNED), the Spanish National Center for Cardiovascular Research (CNIC), the Biomedical Research Network in Cardiovascular Diseases (CIBERCV), and the Catalan Institute of Nanoscience and Nanotechnology (ICN2).

Dr. Tondo stresses the importance of cautious interpretation: “This study does not prove that cholesterol deficiency is the direct cause of the disease, but it may be one of the factors contributing to neuronal damage. In any case, it opens a very interesting line of research into cerebral lipid metabolism, especially in people with genetic risk.”

The research group is already working on a new study to see whether this mechanism is also impaired in people with Down syndrome, a population with genetic risk for developing Alzheimer’s. “We want to know whether the problem with neuronal cholesterol uptake also exists in this other genetic context. This could help us understand whether there are common mechanisms and whether improving lipid metabolism could be a way to delay neurodegeneration,” concludes Dr. Tondo.

Project Funding

This work was partially funded by the Instituto de Salud Carlos III (ISCIII), part of the Spanish Ministry of Economic Affairs and Digital Transformation, and by the European Regional Development Fund (FEDER) under the slogan “A way of making Europe,” through projects PI21/00140, PI23/00232, PI18/0035, PI22/00758, JR22/00003, INT21/00073, PI20/01473, and PI23/01786.

The study was also funded by the U.S. National Institutes of Health (NIH) through grants R01 AG056850, R21 AG056974, R01 AG061566, R01 AG081394, and R61 AG066543, as well as by the Tatiana Pérez de Guzmán el Bueno Foundation through grant IIBSP-DOW-2020-151, and the European Union’s Horizon 2020 Research and Innovation Framework Programme (H2020-SC1-BHC-2018-2020).

Article reference:

Borràs C, Canyelles M, Santos D, Rotllan N, Núñez E, Vázquez J, Maspoch D, Cano-Sarabia M, Zhao Q, Carmona-Iragui M, Sirisi S, Lleó A, Fortea J, Alcolea D, Blanco-Vaca F, Escolà-Gil JC, Tondo M. Cerebrospinal fluid lipoprotein-mediated cholesterol delivery to neurons is impaired in Alzheimer’s disease and involves APOE4. J Lipid Res 2025:100865. https://doi.org/10.1016/j.jlr.2025.100865

Lipoprotein(a), also known as Lp(a), is a lipid particle with pro-inflammatory properties whose blood concentration is determined mainly by genetic factors. Its involvement in the development of atherosclerotic cardiovascular disease is well documented, but one key question remains in the field of primary prevention: Does Lp(a) also pose a relevant risk in people without classic cardiovascular risk factors?

To address this question, a large international study published in the European Journal of Preventive Cardiology analyzed data from 66,495 individuals across eight European population cohorts, followed over a median of 9.7 years. All participants were free of coronary heart disease at the time of enrollment. The study included the participation of Dr. Teresa Padró, researcher in the Biomarkers of Cardiovascular Disease group at the Sant Pau Research Institute (IR Sant Pau) and member of CIBERCV.

Researchers stratified participants based on the number of modifiable cardiovascular risk factors they had at the start of the study: high blood pressure, diabetes mellitus, hypercholesterolemia, and smoking. A total of 41,770 individuals had none or only one of these risk factors, while 24,725 had two or more. Participants were also classified by their Lp(a) levels, using the 90th percentile of the distribution (43.2 mg/dL) as the cutoff.

Over the follow-up period, a total of 3,467 new cases of ischemic heart disease were recorded among the participants. This category includes myocardial infarction, coronary death, unstable angina, coronary revascularization procedures, and deaths of undetermined cause but with a possible cardiac origin. Of these, 1,191 occurred in individuals who, at the start of the study, had no cardiovascular risk factors or only one. The remaining 2,276 cases occurred in participants with two or more traditional risk factors.

What About Lp(a)?

The study results show that having elevated Lp(a) levels —above 43.2 mg/dL, which corresponds to the top 10% of the population—increases the risk of developing coronary heart disease, such as a heart attack, in both people with few cardiovascular risk factors and those with several. In fact, the increased risk was very similar in both groups: 38% higher in those with none or only one risk factor and 27% higher in those with two or more. This difference was not statistically significant, meaning that the impact of high Lp(a) on coronary risk is essentially the same, regardless of a person’s prior risk profile.

“This study indicates that people with elevated Lp(a) levels are at increased risk of coronary heart disease even if they don’t have high blood pressure, diabetes, high cholesterol, or a history of smoking,” explains Dr. Teresa Padró. “This poses a significant clinical challenge, since traditional prevention strategies based on risk factor reduction don’t apply in these cases.”

Currently, there are no approved treatments specifically designed to lower Lp(a) levels, although many clinical trials are underway. According to the authors, until these drugs become available, the only option to mitigate the cardiovascular risk associated with Lp(a) remains intensive control of modifiable risk factors—a strategy that is not feasible in individuals who do not have any.

“These findings also reinforce the need to develop therapies that target Lp(a) in the context of primary prevention,” adds Dr. Padró. “They also highlight the importance of including Lp(a) in cardiovascular risk assessment, even in people who appear to be healthy.”

The study is part of the BiomarCaRE project (Biomarker for Cardiovascular Risk Assessment across Europe), funded by the European Union through the Seventh Framework Programme (FP7/2007–2013). Lp(a) levels were measured in a central laboratory using a standardized immunoturbidimetric method, ensuring the reliability of the data analyzed.

Reference Article:

Arnold N, Goßling A, Bay B, Weimann J, Blaum C, Brunner FJ, Ferrario MM, Brambilla P, Cesana G, Leoni V, Palmieri L, Donfrancesco C, Padró T, Andersson J, Jousilahti P, Ojeda F, Zeller T, Linneberg A, Söderberg S, Iacoviello L, Gianfagna F, Sans S, Veronesi G, Thorand B, Peters A, Tunstall-Pedoe H, Kee F, Salomaa V, Schnabel RB, Kuulasmaa K, Blankenberg S, Waldeyer C, Koenig W. Lipoprotein (a) and incident coronary heart disease in the community: Impact of traditional cardiovascular risk factors. Eur J Prev Cardiol 2025. https://doi.org/10.1093/eurjpc/zwaf340

A team led by Drs. Elba Pascual-Goñi and Luis Querol, researchers from the Neuromuscular Diseases Group at the Sant Pau Research Institute (IR Sant Pau), has published in the journal Journal of NeuroEngineering and Rehabilitation the results of a study validating the use of digital biomechanical sensors to assess gait in people with peripheral neuropathies. The study was carried out in collaboration with the startup Ephion Health and showed that this technology can provide objective, sensitive, and repeatable measurements of patients’ functional status.

Gait assessment is a fundamental tool for understanding the functional impact of peripheral neuropathies, a group of diseases that affect the nerves connecting the central nervous system to the limbs. These impairments can cause muscle weakness, imbalance, instability, and difficulty walking, with a direct impact on patients’ quality of life. However, the clinical evaluation of these changes is often based on subjective scales that may not capture the most subtle or early changes.

Wearable Technology to Identify Abnormal Gait Patterns

The study included data from 79 patients with various types of peripheral neuropathies—both autoimmune and hereditary—and 50 healthy volunteers as a control group. Using a system of inertial sensors placed on different parts of the body and plantar pressure insoles, researchers collected multiple biomechanical parameters during a two-minute walking test. This system allowed for detailed analysis of spatiotemporal variables (such as walking speed, step length, or cadence), joint angles, and pressure distribution on the soles of the feet.

The results indicate that this system can detect prototypical abnormal gait patterns associated with peripheral neuropathies, such as ataxia—an uncoordinated or unstable gait—and steppage gait—an exaggerated knee lift to prevent the foot from dragging. These patterns are common in many neuropathies, and the digital system made it possible to identify them with great precision.

In addition, many of the biomechanical parameters measured correlate with conventional clinical scales, such as the MRC (Medical Research Council) score and the i-RODS scale, which are commonly used to assess strength and disability in this patient population.

A Useful Tool for Follow-Up and Clinical Trials

One of the study’s key contributions is its longitudinal component. In a subgroup of patients who experienced clinically relevant changes over time, the system detected significant modifications in several biomechanical parameters, especially those related to knee, ankle, hip function, and plantar pressure. This demonstrates the system’s potential as a continuous monitoring tool and an objective functional biomarker for tracking the progression of peripheral neuropathies.

This study is particularly relevant in the current context, where the availability of new treatments for some peripheral neuropathies makes it more important than ever to have sensitive and objective tools to evaluate their effectiveness. Although conventional clinical scales are useful, they often have limited sensitivity and may fail to detect subtle but clinically meaningful changes. The use of biomechanical sensors helps overcome these limitations and paves the way for more accurate and personalized evaluation, both in clinical practice and in future therapeutic trials.

According to Dr. Pascual-Goñi, “The study shows that wearable technology based on inertial sensors and pressure insoles can provide an accurate and less subjective evaluation of gait, with applications in both clinical and research settings. It could facilitate early detection of changes, personalized patient monitoring, and the assessment of treatment efficacy in clinical trials.”

Reference article:

Tejada-Illa C, Pegueroles J, Claramunt-Molet M, Pi-Cervera A, Heras-Delgado A, Gascón-Fontal J, Idelsohn-Zielonka S, Rico M, Vidal N, Martín-Aguilar L, Caballero-Ávila M, Lleixà C, Collet-Vidiella R, Llansó L, Carbayo Á, Vesperinas A, Querol L, Pascual-Goñi E. Digital biomechanical assessment of gait in patients with peripheral neuropathies. J Neuroeng Rehabil 2025;22:159. https://doi.org/10.1186/s12984-025-01694-w

On Tuesday, July 29, the Sant Pau Research Institute (IR Sant Pau) welcomed Dr. Vladyslav Vyazovskiy, professor at the University of Oxford and one of the world’s most recognized voices in sleep research. Dr. Vyazovskiy chaired the dissertation committee for Diego del Castillo Berges, a predoctoral researcher in the Molecular Synapse Physiology group led by Dr. Àlex Bayés.

The dissertation, titled Alterations in NREM Sleep Accompany Dysregulation of Synaptic Proteome Dynamics in Syngap1 Heterozygous Mice, focuses on non-rapid eye movement (NREM) sleep, one of the two major phases of sleep characterized by slow and synchronized brain activity. This is essential for energy restoration and memory consolidation. The study specifically explores how deep sleep affects the molecular functioning of synapses in a mouse model carrying a mutation in the SYNGAP1 gene, one of the most common monogenic causes of intellectual disability and neurodevelopmental disorders.

Using proteomic and electroencephalographic analysis techniques, the study indicates that these mice exhibit significant alterations both in the molecular mechanisms regulating neuronal connections and in their sleep patterns. Under normal conditions, about 10% of the synaptic proteome follows rhythmic oscillations throughout the day. In the mutant mice, about half of these oscillations are lost, but a new set of cyclic proteins emerges, suggesting not just a loss of rhythmicity, but a pathological reorganization of synaptic function.

On a functional level, SYNGAP1 heterozygous mutant mice maintain a generally normal sleep architecture and circadian regulation of the sleep-wake cycle, but they show subtle changes in NREM sleep microarchitecture. They experience fewer microarousals and more stable periods of deep sleep, but with altered brain activity: there is an increase in delta power (associated with slow waves) and a decrease in sigma power, which reflects the activity of sleep spindles—brief, rapid oscillations typical of NREM sleep involved in memory consolidation and sensory disconnection during rest. While the mechanisms regulating brain activity during deep sleep and across the day are preserved, the pattern of sleep spindles is altered and no longer follows the usual slow rhythm. This change, together with the reduction in microarousals, suggests a possible dysfunction in the noradrenaline signaling system.

The dissertation proposes that this dysregulation of proteomic dynamics and brain oscillations during NREM sleep could be related to the cognitive and behavioral deficits observed in SYNGAP1-related disorders. Furthermore, it suggests that therapeutic strategies aimed at restoring the characteristic oscillations of NREM sleep may have beneficial effects.

Dr. Vyazovskiy’s presence as chair of the dissertation committee brought both scientific and symbolic value to the defense. His group, based in the Department of Physiology, Anatomy, and Genetics at the University of Oxford, investigates the synaptic, cellular, and neurophysiological mechanisms that regulate the sleep-wake cycle. It also studies how these processes are altered in neurological and psychiatric disorders, aging, and metabolism. He is particularly well known for his contributions to the synaptic homeostasis hypothesis, which posits that sleep plays a vital role in restoring the balance of brain plasticity accumulated during wakefulness.

His research also explores innovative areas such as local sleep (in which different brain regions may be in different functional states), torpor and hibernation, the effects of psychedelic compounds such as 5-MeO-DMT, and the detailed analysis of circadian rhythms and brain oscillations across multiple timescales.

His visit to Sant Pau was a valuable opportunity to promote scientific exchange and strengthen ties with leading neuroscience groups on the international stage. It also represents recognition of the achievements of the Molecular Synapse Physiology group, a pioneer in the study of the human synaptic proteome and the molecular alterations involved in neurological and developmental disorders.

Vitamin D supplementation may have effects that go far beyond bone metabolism. In patients with decompensated cirrhosis, correcting vitamin D deficiency is associated with improvements in frailty, muscle strength, inflammation, and cognitive function—especially working memory. These findings are supported by two articles recently published in the scientific journals Medical Sciences and Nutrients as part of a multidisciplinary, international collaboration coordinated by Hospital Gregorio Marañón in Madrid and Hospital de Sant Pau in Barcelona.

The studies were led by the Departments of Digestive Diseases at Hospital Gregorio Marañón and Hospital de Sant Pau–Sant Pau Research Institute (IR Sant Pau), along with the Sant Pau University School of Nursing. They were conducted in collaboration with research groups from CIBERehd and CIBERSAM and the University of Melbourne (Australia). The work was supported by the European Commission and the Carlos III Health Institute.

Frailty and Muscle Strength

The first study, published in Medical Sciences, showed that vitamin D supplementation, as part of a multifactorial nutritional intervention, significantly improves frailty and muscle strength and mass in patients with decompensated cirrhosis and vitamin D deficiency.

The study included 39 patients who had recently been hospitalized for complications related to liver cirrhosis. Once low vitamin D levels were confirmed, treatment with supplements was initiated in accordance with current clinical guidelines, along with other micronutrients as needed. Over a 12-month period, researchers assessed the impact of this intervention on frailty (Fried index), handgrip strength, body composition, and quality of life.

“Our research group has been studying frailty in cirrhosis for years. We knew that vitamin D deficiency is very common in patients with advanced cirrhosis, but until now, there was no solid evidence on whether treating it had a real clinical impact on frailty.” This is explained by Dr. Germán Soriano, researcher in the Digestive Diseases group at IR Sant Pau and clinical lead at Hospital de Sant Pau. He is one of the corresponding authors of the study.

After six months, patients showed a significant improvement in the Fried frailty index and a sustained increase in muscle strength throughout the year-long follow-up. At 12 months, there was also an increase in lean and fat mass. “Most importantly, not only did biochemical and nutritional parameters improve, but so did clinical and functional variables such as grip strength, anxiety levels, and quality of life,” notes Dr. Soriano. “This has important implications for the well-being and independence of these patients.”

The observational study highlights a low-cost, easily implemented strategy to improve the functional status of individuals with advanced liver disease—a particularly vulnerable population. “Improving frailty may reduce the risk of further hospitalizations, falls, and mortality. Incorporating vitamin D deficiency screening and treatment into routine clinical management of these patients could make a meaningful difference,” Dr. Soriano concludes.

Improvements in Inflammation and Cognitive Function

The second study, published in Nutrients, showed that vitamin D supplementation can improve cognitive function and reduce inflammation in patients with decompensated cirrhosis. This is one of the most severe forms of chronic liver disease and is characterized by chronic inflammation, impaired immune response, and often, cognitive dysfunction. In this context, the researchers hypothesized that vitamin D deficiency—very common in these patients—could be contributing to these impairments.

“Our data suggest that vitamin D plays a key role in regulating inflammation and cognitive performance in patients with advanced cirrhosis,” says Dr. Rita García-Martínez of Hospital Gregorio Marañón, who led the project at that site.

The study included 39 patients with decompensated cirrhosis and vitamin D deficiency. Twenty-seven completed six months of follow-up, and 22 were evaluated at the 12-month mark. All patients received a daily oral vitamin D supplement aimed at restoring adequate blood levels of the vitamin.

Results indicated that patients with lower vitamin D levels had poorer cognitive function, particularly in tasks involving working memory and learning. Similarly, patients with higher levels of inflammatory markers such as the cytokine IL-1β also performed worse on tasks requiring processing speed and attention. After supplementation, not only was there a significant improvement in cognitive performance, but levels of certain proinflammatory cytokines, including IL-1β and IL-6, were also reduced. “These findings strengthen the link between systemic inflammation and cognitive impairment in cirrhosis, opening the door to possible therapeutic interventions,” notes Dr. Rafael Bañares, a physician in the Digestive Diseases Department at Hospital Gregorio Marañón. Along the same lines, Dr. García-Martínez points out that vitamin D “could become a safe, affordable, and easy-to-administer therapeutic tool to prevent common complications in patients with advanced liver disease.”

A Simple Intervention With Great Potential

The results of these two studies underscore the need not to underestimate vitamin deficiencies in patients with cirrhosis, especially in the decompensated stages of the disease. Vitamin D supplementation appears to be a low-cost, accessible, and safe strategy with potential impact on quality of life, functional autonomy, and clinical prognosis in these patients.

The researchers also included a gender-based analysis, identifying some differences in clinical response to supplementation. “It’s essential to consider sex and gender in clinical care. In this case, both women and men showed clear improvements in muscle strength, indicating that supplementation is beneficial across genders,” emphasizes Dr. Soriano.

The researchers advocate for the systematic screening and treatment of vitamin D deficiency in the follow-up protocols for patients with decompensated cirrhosis as a complementary tool to improve their functionality, well-being, and clinical outcomes. “Our results support incorporating this practice routinely as an additional and effective resource in the comprehensive care of these patients,” concludes Dr. García-Martínez.

Reference articles:

1. Díaz-Ruíz R, Poca M, Román E, Cuyàs B, Bañares I, Morales Á, Hernández Martínez-Esparza E, Panadero R, Velasco C, Rapado-Castro M, Bretón I, Bañares R, Soriano G, García-Martínez R. Treatment of vitamin D deficiency in decompensated patients with cirrhosis is associated with improvement in frailty. Med Sci (Basel) 2025;13. https://doi.org/10.3390/medsci13010030
2. Diaz-Ruiz R, Poca M, Roman E, Panadero-Gomez R, Cuyàs B, Bañares I, Morales A, Puerto M, Lopez-Esteban R, Blazquez E, Fernández-Castillo M, Correa-Rocha R, Rapado-Castro M, Breton I, Bañares R, Soriano G, Garcia-Martinez R. Vitamin D supplementation is associated with inflammation amelioration and cognitive improvement in decompensated patients with cirrhosis. Nutrients 2025;17:226. https://doi.org/10.3390/nu17020226

A new study has identified a promising therapeutic pathway to restore the ability of HDL lipoproteins to remove cholesterol from vascular smooth muscle cells (VSMCs), which are involved in the development of atherosclerosis. The research was led by scientists from the CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), the Sant Pau Research Institute (IR Sant Pau), and the Clinical Biochemistry Department of Sant Pau Hospital in Barcelona.

Vascular smooth muscle cells can transform into foam cells during the atherosclerotic process, making up as much as 70% of this cell type within the arterial plaque. These cells lose their ability to efficiently remove cholesterol, which contributes to the progression of cardiovascular disease.

The study, published in the journal Biomedicine & Pharmacotherapy and led by Joan Carles Escolà-Gil, Francisco Blanco-Vaca, and Marina Canyelles, demonstrates that pharmacological activation of the Liver X Receptor (LXR) allows the lost ability of VSMCs to release cholesterol to be restored. This promotes its transport to fecal excretion.

An Innovative Therapeutic Combination

The researchers used an experimental drug that activates the LXR receptor. When administered to cholesterol-loaded VSMCs, it significantly increased the transport of cholesterol to HDL in the blood, the liver, and finally to the feces.

Acyl-CoA cholesterol acyltransferase (known as ACAT) is an enzyme that converts free cholesterol into esterified cholesterol for storage within the cells. Under normal conditions, this prevents excessive accumulation of free cholesterol. However, in foam cells, this action contributes to the retention of cholesterol within the cell. Inhibiting this enzyme prevents cholesterol from being stored, facilitating its elimination from the body. In this study, the drug that activates LXR was combined with another drug that inhibits the ACAT enzyme, which further enhanced this process.

“The results indicate that the transition of VSMCs into foam cells significantly impairs their ability to expel cholesterol. However, this function can be restored by activating the LXR receptor, which opens new opportunities to reduce cholesterol buildup in the arterial wall,” highlights Dr. Carla Borràs, first author of the study and researcher at IR Sant Pau and CIBERDEM.

For his part, Dr. Joan Carles Escolà, one of the study’s directors, points out that “the combination of drugs that activate the LXR receptor with ACAT inhibitors could represent a new synergistic therapeutic strategy to slow the progression of atherosclerosis, although it will be necessary to develop delivery vehicles that can specifically target these treatments to foam cells.”

Researchers from the CIBER of Cardiovascular Diseases (CIBERCV), the Institute of Biomedical Research of Barcelona, and the CSIC also participated in the study.

Article Reference:

Carla Borràs, Noemí Rotllan, Raquel Griñán, David Santos, Arnau Solé, Chen Dong, Qi Zhao, Vicenta Llorente-Cortes, Marta Mourín, Begoña Soto, Mercedes Camacho, Mireia Tondo, Marina Canyelles, Francisco Blanco-Vaca, Joan Carles Escolà-Gil. Restoring cholesterol efflux in vascular smooth muscle cells transitioning into foam cells through Liver X receptor activation. Biomedicine & Pharmacotherapy, 2025, Volume 188, 118178, https://doi.org/10.1016/j.biopha.2025.118178

A team of researchers from the Sant Pau Research Institute (IR Sant Pau) and the Spanish National Research Council (CSIC) has identified a new protein in the blood, EPAC1, as a sensitive and specific marker of severe coronary artery disease (CAD). The findings, published in the international journal Journal of Translational Medicine, pave the way for new tools to improve early diagnosis and risk stratification of this disease, which remains one of the leading causes of death in the Western world.

The study, led by Dr. Vicenta Llorente-Cortés from the Lipids and Cardiovascular Pathology Group at the Institute of Biomedical Research of Barcelona (IIBB-CSIC), IR Sant Pau, and CIBERCV, focused on the search for circulating proteins directly related to the cellular processes occurring in the coronary arteries during the progression of atherosclerosis. In particular, the researchers analyzed the behavior of vascular smooth muscle cells (VSMCs), which in advanced stages of the disease transform into foam cells within arterial plaques.

A New Marker Derived From Hypoxic Arterial Cells

Using high-resolution proteomic techniques, the team identified that the protein EPAC1 (Exchange Protein directly Activated by cAMP 1) is secreted in lower amounts by these cells when they are exposed to hypoxic conditions, as occurs around advanced atherosclerotic plaques. They subsequently measured blood EPAC1 levels in a cohort of 202 patients with suspected CAD and demonstrated that lower levels of this protein were significantly associated with more extensive and severe disease.

“What’s most relevant is that EPAC1 reflects a very specific mechanism of advanced stages of coronary artery disease—not just a nonspecific inflammatory process,” explains Dr. Eduardo García, IR Sant Pau researcher and first author of the study. “This gives us a potential diagnostic tool with greater accuracy and specificity than currently available biomarkers.”

Better Diagnostic Performance Than Commonly Used Markers

In statistical analyses, EPAC1 showed superior predictive capability compared to widely used biomarkers such as high-sensitivity troponin T (hs-TnT) and high-sensitivity C-reactive protein (hs-CRP). A cutoff value of 9.16 ng/mL allowed for accurate sensitivity and specificity in distinguishing patients with severe coronary involvement, as measured by the Segment Involvement Score (SIS) through computed tomography.

In addition, the researchers confirmed in cellular studies that hypoxia reduces EPAC1 expression both at the messenger RNA and protein levels in smooth muscle cells transformed into foam cells, providing biological support for the clinical finding.

Clinical Implications and Future Applications

“The discovery of EPAC1 as a biomarker is not only diagnostically valuable but also helps us better understand the pathological processes occurring in the arteries during the development of atherosclerosis,” says Dr. Vicenta Llorente-Cortés. “In the near future, we could incorporate its measurement into clinical algorithms that help identify patients with more advanced disease who require earlier or more intensive intervention.”

The authors emphasize that it will be necessary to validate these findings in multicenter studies and larger populations. They also would like to explore whether blood levels of EPAC1 correlate with long-term cardiovascular events, such as myocardial infarction or sudden cardiac death.

Funding

The development of this project was funded by the FIS projects PI21/01523 and PI24/00618 from the Instituto de Salud Carlos III (ISCIII) and co-financed by the European Regional Development Fund (ERDF). The group also participates in the Research Networks (Metabolic Diseases and Cancer RED2018-102799-T), a project funded by MINECO. Additionally, the group is recognized by the Generalitat de Catalunya (2021 SGR 00834).

Article Reference:

García E, Claudi L, La Chica Lhoëst MT, Polishchuk A, Samouillan V, Benítez Amaro A, Piñero J, Escolà-Gil JC, Sabidó E, Leta R, Vilades D, Llorente-Cortés V. Reduced blood EPAC1 protein levels as a marker of severe coronary artery disease: the role of hypoxic foam cell-transformed smooth muscle cells. Journal of Translational Medicine. 2025;23:523. https://doi.org/10.1186/s12967-025-06513-3

Treatment with durvalumab, a PD-L1 inhibitor monoclonal antibody, has become established recently as the standard therapy for patients with unresectable stage III non-small cell lung cancer (NSCLC) who do not show progression after concurrent chemoradiotherapy (cCRT). This is based on the results of the PACIFIC trial. However, in a significant percentage of cases, the disease eventually progresses, which has driven the search for new therapeutic strategies to expand the effectiveness of immunologic consolidation treatment.

The COAST study falls within this context, with its final results recently published in JAMA Network Open. This is an international phase 2 clinical trial that evaluated the efficacy and safety of durvalumab administered as monotherapy or in combination with two new monoclonal antibodies—oleclumab (anti-CD73) and monalizumab (anti-NKG2A)—as consolidation treatment after cCRT in patients with locally advanced, unresectable NSCLC. The study involved 73 centers worldwide, including Hospital de Sant Pau, through medical oncologist and researcher at the Institut de Recerca Sant Pau (IR Sant Pau), Dr. Margarita Majem.

“The participation in this study has allowed us to contribute to the development of immunotherapeutic combinations that have the potential to improve the prognosis of patients with a disease that is still difficult to treat in locally advanced stages,” notes Dr. Majem. “Consolidation treatment with durvalumab has represented a significant advance lately, but we know there is still room for improvement, and combinations with oleclumab or monalizumab point in that direction.”

Clinical Benefit in Response and Progression Rates

The study included 189 patients with stage III NSCLC who had not experienced progression after completing cCRT. Participants were randomized into three treatment groups for up to 12 months: durvalumab monotherapy, durvalumab with oleclumab, and durvalumab with monalizumab.

The results indicated that the two investigated combinations provided an added clinical benefit compared to durvalumab alone. Although the differences did not reach statistical significance, the researchers observed a higher objective response rate (ORR) and longer progression-free survival (PFS) in the combination arms. The median PFS was 21.1 months in the group treated with durvalumab and oleclumab and 19.8 months in the group with durvalumab and monalizumab, compared to 7.3 months observed with durvalumab monotherapy. Overall survival also appeared to improve with the combinations, although the data do not yet allow definitive conclusions in this regard due to the limited maturity of follow-up. Regarding safety, all three treatments showed comparable profiles with no new toxicity signals.

Complementary Immunologic Mechanisms

Mechanistically, oleclumab acts by blocking CD73, an enzyme that contributes to tumor immunosuppression through the production of adenosine, while monalizumab inhibits NKG2A, a receptor that suppresses the activity of NK cells and cytotoxic T lymphocytes. Both targets are involved in immune evasion that can occur after radiotherapy, which justifies their use as immunologic consolidation in this clinical context.

“The rational combination of immunotherapies with complementary mechanisms could become a key pathway for advancing the treatment of locally advanced lung cancer,” adds Dr. Majem. “These results reinforce the need to continue research along these lines, and indeed, they are already being evaluated in a phase 3 trial, PACIFIC-9, in which we hope to confirm their clinical benefit.”

With the publication of these results, the COAST study lays the foundation for a new generation of immunotherapeutic strategies that, if confirmed in larger trials, could expand the available arsenal against unresectable NSCLC and improve survival in this patient population.

Reference article:

Aggarwal C, Martinez-Marti A, Majem M, Barlesi F, Carcereny E, Chu Q, Monnet I, Sánchez-Hernández A, Dakhil S, Camidge DR, Pillet M, Brown M, Paliompeis C, Dowson A, Cooper ZA, Kumar R, Herbst RS. Durvalumab alone or combined with novel agents for unresectable stage III non-small cell lung cancer: Update from the COAST randomized clinical trial: Update from the COAST randomized clinical trial. JAMA Netw Open 2025;8:e2518440. https://doi.org/10.1001/jamanetworkopen.2025.18440

The Research Institute and Hospital de Sant Pau took part once again in Festival Cruïlla, with the aim of bringing scientific and health knowledge closer to the public in a playful, participatory, and engaging environment. Under the slogan “The music that could save your life”, Sant Pau offered two outreach activities that were very well received by attendees.

Over the course of three days, Sant Pau professionals shared knowledge and practices around health and well-being, showing that music can not only move us emotionally but also have a real impact on people’s health.

One of the activities focused on cardiopulmonary resuscitation (CPR) training, led by Lluïsa Vilageliu and Alicia Belmonte, nurses from the Emergency Department and ICU respectively, and anesthesiologist Guillermo Martin. Through short educational sessions, they taught participants how to react in the event of a cardiac arrest—essential training that can help save lives.

The other proposal was a participatory music therapy session led by music therapist Inés Cardoso, where attendees experienced how body percussion and music can enhance physical and emotional well-being.

With initiatives like this, Sant Pau is committed to innovating in the way it communicates science and healthcare, reaching new audiences and highlighting the transformative value of research beyond the usual settings.

The Sant Pau Research Institute (IR Sant Pau) and Hospital de Sant Pau have participated in a major international study that evaluated the efficacy and safety of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer in a real-world clinical practice setting.

The study, recently published in the journal JAMA Oncology, included 1,585 patients treated outside the context of clinical trials between September 2012 and December 2023. It involved 61 hospitals across 21 countries, reflecting both its global reach and the strength of its findings. Results were also presented at the latest Congress on Gastrointestinal Tumors of the European Society for Medical Oncology (ESMO GI), held in Barcelona from July 2 to 5, 2025. They confirm that TNT provides solid clinical benefits even in real-world healthcare conditions, beyond the standardized protocols of clinical trials.

A Strategy to Advance Treatment and Avoid Surgery in Some Cases

Total neoadjuvant therapy consists of delivering radiotherapy and non-radiosensitizing chemotherapy before surgery, with the goal of reducing tumor size, improving local disease control, and, in some cases, avoiding surgical intervention. In patients who achieve a complete response to treatment, whether clinical or pathological, a strategy called watch and wait may be applied, involving close monitoring of the patient without immediate surgery. This approach, increasingly adopted by specialized centers managing this condition, aims to preserve rectal function and avoid the sequelae of major surgery, provided there are sufficient guarantees of proper oncologic control.

In this study, 79.5% of patients presented with at least one high-risk feature—such as extensive nodal involvement, extramural venous invasion, or threatened mesorectal fascia—and were treated with different TNT regimens, reflecting the diversity of real-world clinical practice.

Patients received one of the following treatment types: the PRODIGE 23 regimen (intensive chemotherapy with FOLFIRINOX or FOLFOXIRI followed by long-course radiotherapy, 17.7%), the RAPIDO regimen (short-course radiotherapy followed by consolidation chemotherapy with FOLFOX or CAPOX, 33.4%), an induction OPRA regimen (initial chemotherapy followed by long-course radiotherapy, 12%), a consolidation OPRA regimen (long-course radiotherapy followed by chemotherapy, 16.2%) or other regimens (22.7%).

More Than 23% Complete Response Rate and Notable Survival Outcomes

Clinical outcomes were consistent with those observed in controlled studies. 23.2% of patients achieved a complete response to treatment. Among them, 192 patients (12.1%) were managed with the watch-and-wait approach, and 30 patients (1.9%) underwent local excision. At three years, event-free survival was 68%, and overall survival at five years was 79%, validating the effectiveness of TNT in routine clinical settings. Regarding disease progression, 8.5% of cases showed local progression and 16.4% distant progression.

In the overall analysis, patients treated with the PRODIGE 23 regimen achieved better local control and survival outcomes than those treated with RAPIDO, OPRA-induction, or OPRA-consolidation regimens, although they also experienced a higher incidence of serious adverse events. However, after applying an adjustment analysis using propensity score matching to balance clinical characteristics across groups, no significant differences in survival outcomes were observed between the various TNT regimens. This reinforces the idea that all of them may be valid options in routine clinical practice.

Dr. David Páez, medical oncologist at Hospital de Sant Pau and co-investigator in the study, highlighted the importance of these findings.
“This study confirms that total neoadjuvant therapy is also effective outside the controlled environment of clinical trials, reinforcing its role as a standard treatment in patients with locally advanced rectal cancer. It is especially valuable to see that different regimens can offer similar outcomes, which provides flexibility to tailor treatment to each clinical case.”

A New Functional Unit to Advance Quality and Research

Sant Pau’s participation in this study comes at a time of strategic advancement in the management of rectal cancer at the hospital. A functional rectal cancer unit has recently been established, a multidisciplinary team comprising professionals from Medical Oncology, General Surgery, Radiation Oncology, Radiology, Gastroenterology, Pathology, and other involved specialties.

This unit aims to improve coordination among departments, apply uniform treatment criteria, and promote applied clinical research. In Dr. Páez’s words, “The creation of this functional unit allows us to work more integratively and efficiently and facilitates participation in international projects like this one, which generate evidence with a real impact on patient care.”

Through the combination of specialized care, teamwork, and active participation in international studies, IR Sant Pau and Hospital de Sant Pau reaffirm their commitment to continuous improvement in colorectal cancer treatment and to clinical research in service of healthcare practice.

Reference Article:

Audisio A, Gallio C, Velenik V, Meillat H, Ruiz-Garcia E, Riesco MC, Alecha JS, Rasschaert G, Carvalho C, Randrian V, Kirac I, Hernando J, Artaç M, O’Connor JM, Waldhorn I, Braam PM, Shamseddine A, Moretto R, De la Pinta C, De Felice F, Dulskas A, Páez López-Bravo D, Vanden Bulcke A, Bock F, Deleporte A, Van Den Eynde M, Geboes KP, Loi M, Messina M, Houlzé-Laroye C, Puccini A, Pastorino A, Papamichael D, Fiore M, Sur D, Eid M, Antoun C, Salati M, Garajovà I, Jakubauskas M, Tomášek J, Sousa Pinto CM, Schwingel J, Morano F, Adams RA, Dermine A, Chau A, Javed MA, Ghidini M, Fiorica F, Montenegro P, Petrillo A, Spolverato G, Mulet Margalef N, Diaz M, Baratelli C, Puleo F, Karampeazis A, Sert F, Gilliaux Q, De Stefano A, Liberale G, Moretti L, Martinive P, Deltuvaite Thomas V, Staggs V, Saad ED, Van Laethem J-L, Sclafani F, International Real-World TNT Study Consortium. Total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncol 2025. https://doi.org/10.1001/jamaoncol.2025.2026

A multicenter study led by researchers from the Sant Pau Research Institute (IR Sant Pau) and the Department of Obstetrics and Gynecology at Hospital de Sant Pau has shown that the NT-proBNP biomarker—commonly used to rule out heart failure in non-pregnant patients—can reliably predict the onset of early-onset preeclampsia (before 34 weeks of gestation), with a sensitivity of 90.9% and a specificity of 94.3%. These results are comparable to those of the currently used test (the sFlt-1/PlGF ratio), but with the advantage of being more affordable and widely available. The study was conducted in a group of 316 pregnant women with clinical suspicion of preeclampsia between 24 and 40 weeks of gestation.

According to Dr. Carmen Garrido, Head of Obstetrics at Hospital Sant Pau and collaborating researcher with the Perinatal and Women’s Medicine group at IR Sant Pau, “Preeclampsia is a disease that affects the cardiovascular system and is often associated with subclinical heart dysfunction during pregnancy. We knew from the literature that women with preeclampsia tend to have elevated levels of this biomarker. That led us to consider that NT-proBNP might be useful in predicting short-term complications, especially in settings without access to the sFlt-1/PlGF test.”

Dr. Madalina Nicoleta Nan, also a researcher with the Perinatal and Women’s Medicine group, adds: “The study suggests NT-proBNP is a valuable biomarker for ruling out the onset of preeclampsia at the time of suspicion and up to a week after assessment, especially in cases where the currently recommended test is unavailable.”

A Cardiovascular Marker With Obstetric Potential

This prospective study, published in Ultrasound in Obstetrics & Gynecology, was conducted between March 2018 and December 2020. It provides a practical and reliable tool to support personalized prediction and management of pregnant women with suspected preeclampsia in the second or third trimester, after first-trimester screening. In this context, NT-proBNP can help rule out short-term preeclampsia—within one week—particularly in resource-limited settings.

NT-proBNP, a protein associated with cardiac stress, is already routinely used to diagnose heart failure in the general population. In pregnancy, this biomarker reflects cardiovascular changes in women with preeclampsia and correlates with disease severity.

According to the study, NT-proBNP levels rise significantly days before symptom onset, making it an early warning marker. This predictive capability opens the door to enhanced clinical monitoring in at-risk women and the implementation of preventive measures, such as corticosteroids for fetal lung maturation or hospital admission if needed.

Dr. Garrido explains, “the main advantage of NT-proBNP is that it allows for objective and rapid assessment in settings where the sFlt-1/PlGF ratio is unavailable. This could help avoid unnecessary referrals to specialized centers and promote greater equity in care.”

A Step Forward in Identifying Complicated Cases

Although the sFlt-1/PlGF test is very effective for ruling out the disease (a low value excludes preeclampsia with 99% reliability), its positive predictive value is more uncertain, which can complicate clinical decision-making. The study suggests that NT-proBNP may offer improved precision in this scenario. “Our aim was to determine whether this biomarker could refine our predictions and support more conservative clinical decisions as pregnancy nears term,” adds Dr. Nan.

Beyond predicting early-onset preeclampsia, NT-proBNP also proved useful for identifying complicated cases associated with fetal growth restriction, placental abruption, or fetal death. Its predictive performance in this regard was similar to that of the current test.

Its sensitivity for predicting these serious complications was 84.2%, with a specificity of 91.4%—results comparable to the sFlt-1/PlGF test. This opens the door to broader clinical use. An integrated approach could be especially relevant in obstetric pathology or intermediate care units, where anticipating complications can significantly affect maternal and fetal outcomes.

Clinical Impact and Accessibility

This study provides the first evidence that NT-proBNP can predict disease before symptoms appear, paving the way for a new line of research already underway. The same team is now conducting a follow-up study to see whether combining this biomarker with the sFlt-1/PlGF ratio could further enhance predictive performance.

Even so, the researchers emphasize the need for larger, randomized studies before any changes are made to standard clinical practice. For now, the use of NT-proBNP should be limited to cases with clinical suspicion of preeclampsia, and results should always be interpreted in the context of specialized medical assessment. “This discovery allows us to move toward more equitable medicine, by offering a highly reliable diagnostic tool that does not require specialized technology,” says Dr. Garrido. “Moreover, its use could be particularly relevant in international settings with limited healthcare systems, helping reduce maternal morbidity and mortality in countries with less access to advanced diagnostic tools.”

Reference article:

M. N. Nan; C. Garrido-Giménez; A. Garcia-Osuna; P. Garcia Manau; J. Ullmo; J. Mora; O. Sánchez-Garcia; J. Platero; M. Cruz-Lemini; E. Llurba; on behalf of the EuroPE working group. N-terminal pro B-type natriuretic peptide as biomarker to predict pre-eclampsia and maternal-fetal complications. Ultrasound Obstet Gynecol 2025; 65(4):447–455. DOI: 10.1002/uog.29202

A team from Hospital de Sant Pau has analyzed sex-based differences in emergency department visits caused by medication-related health problems. The study, published in the journal Emergencias, reveals that women present more frequently with urgent consultations linked to certain adverse effects and types of medications.

The article, titled “Comprehensive Approach to Medication-Related Problems Leading to Emergency Department Visits From a Gender Perspective,” is part of the doctoral thesis of Connie Marin, a PhD candidate in Pharmacology at the Universitat Autònoma de Barcelona, under the supervision of Dr. Mireia Puig and Dr. Ana Juanes from Hospital de Sant Pau.

The research analyzed a cohort of 1,611 adult patients who visited the emergency department at Hospital de Sant Pau between 2021 and 2022 and were treated under the Código Medicamento (Medication Code) program. The results show that more than 55% of these visits involved women, with a significant increase in this proportion as age increased.

The researchers found significant differences between men and women in both the associated diagnoses and the types of medications involved in medication-related health problems. In the case of women, the most frequent consultations were related to:

• Diarrhea and decreased intestinal motility
• Unintentional medication poisoning
• Hypertension
• Hyponatremia
• Hypokalemia

The study also highlights a greater impact on women from medications acting on the nervous system, the cardiovascular system, and anti-infective agents.

The study was led by Dr. Mireia Puig, Dr. Jesús Ruíz, and Dr. Ana Juanes, with participation from the Código Medicamento Care Group at Hospital de Sant Pau, composed of professionals from various clinical fields.

“These findings reinforce the importance of integrating a gender perspective into pharmacological care to reduce inequalities and improve treatment safety,” the authors state.

Reference article:
Marín-Barcena C, Puig-Campmany M, Ruiz-Ramos J, Carazo-Díaz C, Vicente-Romero J, Juanes-Borrego A, Código Medicamento Group at Hospital de la Santa Creu i Sant Pau. Comprehensive approach to medication-related problems leading to emergency department visits from a gender perspective. Emergencias 2025;37:186–95. https://doi.org/10.55633/s3me/026.2025.

The Sant Pau Research Institute (IR Sant Pau) is leading the new multicenter clinical trial FTAA (Fast Track in Acute Appendicitis), aimed at improving the postoperative management of complicated appendicitis in children. The study proposes an innovative antibiotic treatment strategy that could reduce hospitalization time without compromising the safety or efficacy of the therapeutic approach.

The trial was recently presented at the European Association for Clinical Pharmacology and Therapeutics Congress (EACPT 2025), held in Helsinki, Finland, from June 28 to July 1. This is the first randomized clinical trial in a pediatric population comparing two antibiotic treatment duration strategies following surgery for complicated appendicitis, one of the most common surgical emergencies in childhood.

The project is coordinated by Dr. María José Martínez Zapata from the Clinical Epidemiology and Healthcare Services Research Group at IR Sant Pau, together with Dr. Carlos Leganés, a pediatric surgeon at Hospital Sant Pau. Also participating are Drs. Rosa María Antonijoan and Claudia Erika Delgado-Espinoza from the Clinical Pharmacology Department and Dr. José María Valle from the Pediatrics Department of the same hospital.

In addition to Hospital Sant Pau, the trial involves collaboration with six other leading hospitals: Hospital Sant Joan de Déu and Hospital del Mar in Barcelona, Hospital Germans Trias i Pujol in Badalona, Hospital Joan XXIII in Tarragona, Hospital Clínico Universitario in Santiago de Compostela, and Hospital Universitario Dr. Josep Trueta in Girona. This broad participation will provide representative and nationally applicable results.

The study has received funding from the 2023 Independent Clinical Research call by the Instituto de Salud Carlos III (ICI23/00070) and is supported by the Spanish Clinical Research Network (SCReN), aimed at facilitating clinical trials of interest to the National Health System.

The primary objective of the FTAA trial is to evaluate whether a shorter antibiotic regimen—three days of intravenous antibiotics in the hospital followed by two days of oral outpatient treatment with amoxicillin-clavulanate—is as effective as the standard five-day in-hospital antibiotic treatment in preventing complications within 30 days of surgery. A total of 772 pediatric patients are planned for recruitment.

If the outpatient strategy proves non-inferior, the study could represent a significant change in clinical practice, reducing children’s hospital stays and promoting quicker recovery in the home environment. This optimization of treatment would not only benefit the quality of life for patients and their families but also contribute to greater efficiency in healthcare resource utilization and decreased exposure to risks associated with prolonged hospitalization.

IR Sant Pau thus reaffirms its commitment to clinical research aimed at improving healthcare, especially in high-impact areas such as pediatric surgery and the rational use of antibiotics.

The CIBEREHD group from the Digestive Diseases Department at Hospital de Sant Pau has participated in an international clinical trial recently published in JAMA (Journal of the American Medical Association), one of the most prestigious medical journals worldwide. The study, conducted within the framework of the LIVERHOPE Consortium and led by Dr. Elisa Pose and Dr. Pere Ginès from Hospital Clínic de Barcelona, evaluated whether the combined administration of simvastatin and rifaximin, added to standard treatment, could reduce clinical complications and mortality in patients with decompensated cirrhosis—one of the most severe and complex stages of liver disease. The study was funded through a Horizon 2020 grant with European funds.

The study was conducted between January 2019 and December 2022 and included a total of 237 patients with decompensated cirrhosis recruited from 14 European centers, including Hospital de Sant Pau. It was a double-blind, randomized, placebo-controlled trial in which participants received either the combination of simvastatin (20 mg/day) and rifaximin (1,200 mg/day) or a placebo for one year, in addition to standard medical therapy.

The scientific rationale behind this combination lies in their complementary mechanisms of action. Simvastatin not only lowers blood cholesterol levels but is also known for its anti-inflammatory and antifibrotic properties, as well as its ability to reduce hepatic portal pressure—effects that, in a previous clinical study, appeared to reduce mortality. Rifaximin, on the other hand, is an antibiotic with very low systemic absorption that modulates the gut microbiome and likely inhibits bacterial translocation, endotoxemia, and inflammation, helping to reduce hepatic encephalopathy. Based on this, the project set out to determine whether this combined strategy could prevent the development of the severe condition known as acute-on-chronic liver failure (ACLF), other cirrhosis-related complications, and mortality.

However, the results were unexpected. The study showed no significant differences between the treated group and the placebo group in terms of ACLF incidence, liver transplant rates, or mortality. There were also no differences in the occurrence of typical cirrhosis complications such as ascites, hepatic encephalopathy, esophageal variceal bleeding, acute kidney injury, or infections.

As for safety, the therapeutic combination was generally well tolerated, although a few cases of rhabdomyolysis—a muscle-related complication—were reported in the treatment group. This underscores the need for caution when using statins in this patient population. This trial was based on previous phase II studies that had shown a good safety profile with low doses of simvastatin, like those used in the current study, although higher doses had occasionally been linked to liver and muscle toxicity.

Although the results were not positive, the researchers emphasized the importance of publishing this kind of evidence. In the words of Dr. Germán Soriano, physician in the Digestive Diseases Department at Hospital de Sant Pau and one of the authors of the article, “This study is a clear example that in clinical research, negative results are also valuable. They help us rule out approaches that seemed promising and better focus our efforts on strategies that are truly effective for our patients.” Dr. Soriano also highlighted the significance of participating in a multicenter study of this caliber: “It is important for Sant Pau to be part of international alliances that allow us to tackle global clinical challenges with a collaborative and rigorous approach.”

Reference article:

Pose E, Jiménez C, Zaccherini G, Campion D, Piano S, Uschner FE, de Wit K, Roux O, Gananandan K, Laleman W, Solé C, Alonso S, Cuyàs B, Ariza X, Juanola A, Ma AT, Napoleone L, Gratacós-Ginès J, Tonon M, Pompili E, Sánchez-Delgado J, Allegretti AS, Morales-Ruiz M, Carol M, Pérez-Guasch M, Fabrellas N, Pich J, Martell C, Joyera M, Domenech G, Ríos J, Torres F, Serra-Burriel M, Hernáez R, Solà E, Graupera I, Watson H, Soriano G, Bañares R, Mookerjee RP, Francoz C, Beuers U, Trebicka J, Angeli P, Alessandria C, Caraceni P, Vargas VM, Abraldes JG, Kamath PS, Ginès P, LIVERHOPE Consortium. Simvastatin and rifaximin in decompensated cirrhosis: A randomized clinical trial. JAMA 2025;333:864–74. https://doi.org/10.1001/jama.2024.27441

The Neuromodulation in Movement Disorders Group at Hospital de Sant Pau has received the Best Oral Presentation Award at the 2025 Congress of the Spanish Society of Neurosurgery (SENEC), recently held in Zaragoza. The award recognizes a pioneering study focused on deep brain stimulation (DBS) in Parkinson’s disease, one of the most advanced therapies for managing this neurodegenerative condition.

The winning study developed a functional three-dimensional map of the subthalamic nucleus (STN)—a key brain structure involved in movement control—based on the analysis of local field potentials (LFPs) recorded during surgery in patients with advanced Parkinson’s. These LFPs reflect the brain’s electrical activity and enable a more precise understanding of how its internal networks function in real time.

One of the study’s most relevant findings is that brain oscillations—especially those in the beta band, which are associated with the rigidity and slowness of movement characteristic of Parkinson’s—are not always confined within the classical anatomical boundaries of the STN. This suggests that traditional targeting based solely on anatomical criteria may not be sufficient to achieve optimal therapeutic outcomes.

A New Way to Personalize Deep Brain Stimulation

Thanks to advanced neuroimaging tools, spectral analysis, and computational modeling, the team has shown that the closer the electrode is placed to areas of high beta activity, the better the motor outcomes after surgery. This approach strengthens the case for “functional targeting,” a surgical strategy that considers both the anatomy and the brain physiology of each patient.

“Every brain is different, and in a complex disease like Parkinson’s, knowing the precise location of pathological activity allows us to personalize the therapy more effectively,” explains Dr. Juan Aibar, one of the researchers behind the study, together with Dr. Ignacio Aracil, Dr. Rodrigo Rodríguez, Dr. Berta Pascual, Dr. Alex Gironell, and Antonia Campolongo. “Our goal is to move toward precision neuromodulation, based on brain biomarkers that can guide us before, during, and after the procedure.”

Deep brain stimulation is a surgical technique that has transformed the treatment of advanced Parkinson’s disease. It involves implanting electrodes in specific brain regions to modulate their activity through electrical impulses. When applied correctly, DBS can significantly improve motor symptoms and quality of life, while reducing the need for medication.

This new study from Sant Pau not only enhances the scientific understanding of brain function in Parkinson’s disease but also provides concrete tools to improve surgical planning and maximize the benefits of deep brain stimulation.

A Consolidated and Expanding Line of Research

Sant Pau’s Neuromodulation in Movement Disorders Group has a long-standing track record in translational DBS research, combining neurosurgery, neurology, biomedical engineering, and data analysis. This award provides renewed momentum for the team’s commitment to translating scientific knowledge into tangible benefits for people affected by neurological disorders.

A team of researchers at the Sant Pau Research Institute (IR Sant Pau) has demonstrated that the plasma biomarker p-tau217, obtained through a simple blood test, can predict the clinical progression of Alzheimer’s disease even in its earliest stages. This is when symptoms are not yet evident. The study, published in the journal Neurology, reinforces the role of blood tests in the future of diagnosing and monitoring dementias.

The study, conducted within the framework of the SPIN cohort (Sant Pau Initiative on Neurodegeneration), included 731 individuals with and without cognitive impairment who were followed for an average of up to 10 years. The researchers analyzed levels of p-tau217—a specific form of the tau protein associated with neurodegeneration—and observed that this marker not only correlates with the presence of Alzheimer’s disease but also enables prediction of the rate of cognitive decline and progression to more advanced stages of the disease. This includes dementia.

“This marker has enormous potential as a clinical tool. It not only accurately identifies Alzheimer’s disease, but also allows us to estimate how fast it will progress—an essential factor in making therapeutic decisions,” says Dr. Ignacio Illán, researcher in the Neurobiology of Dementia group and neurologist at Sant Pau Hospital, who led the study.

For her part, Judit Selma-González, first author and research neuropsychologist, also from the Neurobiology of Dementia group, highlights that “one of the most relevant findings is that p-tau217 allows us to identify people who do not yet have cognitive symptoms but are at higher risk of developing the disease in the short or medium term. This can help us better select patients eligible to participate in clinical trials of disease-modifying treatments.”

An Accessible Alternative

Until now, the most reliable biomarkers for detecting and monitoring Alzheimer’s disease have required invasive techniques such as lumbar puncture (to analyze cerebrospinal fluid) or costly procedures such as positron emission tomography (PET). The use of plasma p-tau217 offers a non-invasive, more accessible, and affordable alternative with both clinical and research applications.

The study indicated that p-tau217 levels increased progressively from the preclinical stages to the advanced stages of dementia, and were independently associated with a higher risk of cognitive decline (measured, among other tools, with the Mini-Mental State Examination) and conversion to dementia. In fact, the marker showed better prognostic ability than its cerebrospinal fluid equivalent, p-tau181, which is widely used today.

Clinical Applications and a Promising Future

This advance is particularly relevant in the current context, where disease-modifying treatments—such as anti-amyloid antibodies—are already being approved, and their use depends on the stage of Alzheimer’s disease progression. The possibility of using a blood test to determine this clinical stage and monitor its progression represents a major step toward more personalized and precise medicine. “In a memory clinic, having access to this information through a blood test opens up possibilities that were previously limited to highly specialized centers,” notes Dr. Ignacio Illán.

Funding and International Collaboration

This study was funded by the Instituto de Salud Carlos III (ISCIII) through projects PI14/01126, PI17/01019, PI18/00335, PI19/00882, PI18/00435, PI22/00611, INT19/00016, INT23/00048, PI17/01896, PI22/00307, PI20/01473, PI23/01786, PI21/00791, and PI24/00598, and co-funded by the European Union. It was also supported by research programs of the Spanish Biomedical Research Network Center on Neurodegenerative Diseases (CIBERNED) and the La Marató de 3cat Foundation (projects 20141210, 044412, and 20142610), as well as by the “la Caixa” Foundation (DABNI project), the Catalan Down Syndrome Foundation, the Víctor Grífols i Lucas Foundation, and the Government of Catalonia (2017-SGR-547, SLT006/17/125, SLT006/17/119, SLT002/16/408).

Several researchers were supported by competitive contracts, including Río Hortega and Sara Borrell fellowships from ISCIII in collaboration with the European Social Fund Plus. In addition, various authors are affiliated with the Global Brain Health Institute (GBHI) as fellows of the Atlantic Fellow for Equity in Brain Health program, with additional funding from the Alzheimer’s Association, the Alzheimer Society, and the Jérôme Lejeune Foundation. International collaboration was strengthened through the participation of the Institute of Neuroscience and Physiology at the University of Gothenburg (Sweden), the Banner Alzheimer’s Institute (United States), and the Barcelona Down Medical Center.

Reference Article:

Selma-Gonzalez J, Rubio-Guerra S, García-Castro J, Vera-Campuzano E, Sala I, Sánchez-Saudinós MB, Zhu N, Arranz J, Arriola-Infante JE, Rodríguez-Baz Í, Maure-Blesa L, Dols-Icardo O, Videla L, Valldeneu S, Barroeta I, Santos-Santos M, Carmona-Iragui M, Vaqué-Alcázar L, Alvarez-Sanchez E, Lorente O, Carreras M, Belbin O, Arslan B, Ashton NJ, Zetterberg H, Blennow K, Montoliu-Gaya L, Bejanin A, Lleó A, Fortea J, Alcolea D, Illan-Gala I. Association of plasma phosphorylated tau 217 with clinical deterioration across Alzheimer disease stages. Neurology. 2025;105:e213769. https://doi.org/10.1212/WNL.0000000000213769.

The prestigious journal Trends in Neurosciences recently published a scientific commentary authored by Dr. Oriol Dols-Icardo, a researcher with the Neurobiology of Dementias group at the Sant Pau Research Institute (IR Sant Pau) and the Memory Unit at Hospital de Sant Pau. The article provides a critical and contextualized analysis of recent advances in the genetics of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), a neurodegenerative disease that ranks among the most common causes of dementia after Alzheimer’s disease.

The commentary focuses on a study by Pottier and colleagues published in Nature Communications, which represents the most extensive whole-genome sequencing analysis conducted to date in patients with FTLD-TDP. The study included nearly 1,000 patients diagnosed with FTLD-TDP and its pathological subtypes A, B, and C, as well as more than 3,000 control individuals, and identified multiple genetic variants—both common and rare—specifically associated with each subtype. Some of these risk factors have also been linked to other diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and hippocampal sclerosis, all of which are associated to varying degrees with the presence of TDP-43 inclusions.

As corresponding author, Dr. Dols-Icardo led the writing of the commentary and invited two prominent international researchers to contribute: Dr. Lianne M. Reus from Vrije Universiteit Amsterdam in the Netherlands, and Dr. Alfredo Ramírez from the University of Cologne and the German Center for Neurodegenerative Diseases – DZNE. All three experts emphasize the importance of these findings for advancing the understanding of the biological and clinical heterogeneity of FTLD-TDP.

“Our commentary highlights that the different subtypes of FTLD-TDP may be driven by distinct genetic mechanisms, which supports the notion that they represent separate biological entities,” explains Dr. Oriol Dols-Icardo. Furthermore, TDP-43 is the primary aggregated protein in FTLD-TDP, ALS, and hippocampal sclerosis, but it is also present in 60% of individuals with Alzheimer’s disease. Dr. Dols-Icardo points out that “some of the identified genetic factors also play a key role in these diseases. This approach brings us closer to earlier and more accurate diagnosis and more personalized risk stratification, with clear implications for the development of targeted therapies.”

The article also underscores the need to replicate the findings in independent cohorts, as well as the importance of having in vivo biomarkers capable of distinguishing between the pathological subtypes of FTLD-TDP. In addition, it highlights how next-generation sequencing technologies—particularly long-read techniques—can reveal structural variants, alternative isoforms, and complex splicing variations associated with TDP-43 dysfunction, a key protein not only in FTLD but also in other neurodegenerative disorders.

This commentary is a significant contribution to the current scientific discussion on neurodegenerative diseases associated with TDP-43 protein inclusions and reinforces Sant Pau’s leadership—and that of its research team—in the field of neurodegenerative diseases.

Reference article:

Dols-Icardo O, Reus LM, Ramirez A. Genetic architecture of FTLD-TDP pathological subtypes. Trends Neurosci 2025. https://doi.org/10.1016/j.tins.2025.06.005

The Technology Transfer and Innovation Unit (UTI) at the Sant Pau Research Institute (IR Sant Pau) has obtained ISO 56001 certification, an international standard that sets out the requirements for implementing, maintaining, and continuously improving an innovation management system. This accreditation recognizes organizations that integrate innovation as a strategic and cross-cutting component of their activity, promoting an innovation-driven culture aligned with their goals and expected social impact.

ISO 56001 provides a framework that helps systematize the processes of ideation, development, and transfer of innovative solutions. In this regard, the certification marks a step forward in consolidating an ecosystem that fosters the generation of new ideas, interdisciplinary collaboration, and the practical application of research results.

The UTI at IR Sant Pau plays a key role in promoting a culture of innovation, protecting and leveraging research outcomes, and encouraging collaboration with the business sector and other stakeholders in the surrounding ecosystem. With the attainment of ISO 56001, the institution strengthens its commitment to excellence and reinforces a path focused on creating added value through knowledge.

This new milestone adds to the UNE 166002 certification obtained in 2022, which certifies a solid and effective R&D&I management system. Together, these certifications position IR Sant Pau as one of the pioneering centers in Catalonia in the implementation of advanced innovation management mechanisms. In fact, it becomes the third research institute in Catalonia to receive ISO 56001 accreditation.

IR Sant Pau will continue working to transform scientific knowledge into real-world solutions that improve people’s health and quality of life, through high-quality research committed to innovation, knowledge transfer, and social progress.

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.