Summary Background and objectives Observational studies have linked elevated blood pressure (BP) to impaired cognitive function. However, the functional and structural changes in the brain that mediate the relationship between BP elevation and cognitive decline remain unknown. Using observational and genetic data from large consortia, this study aimed to identify brain structures potentially associated with BP values and cognitive function. Methods and results Blood pressure data were integrated with 3935 phenotypes derived from brain MRI and cognitive function defined by the fluid intelligence score. Observational analyzes were performed in the UK Biobank and in a prospective validation cohort. Mendelian randomization (MR) analyzes used genetic data derived from the UK Biobank, the International Blood Pressure Consortium, and the COGENT consortium. Mendelian randomization analysis identified a potentially adverse causal effect of higher systolic BP on cognitive function [-0.044 standard deviation (SD); 95% confidence interval (CI −0.066, −0.021) with strengthening of the MR estimate (−0.087 SD; 95% CI −0.132, −0.042), when further adjusted for diastolic BP. Mendelian randomization analysis found 242, 168, and 68 IDPs showing a significant association (false discovery rate P < 0.05) with systolic BP, diastolic BP, and pulse pressure, respectively. Most of these IDPs were inversely associated with cognitive function in the observational analysis in the UK Biobank and showed concordant effects in the validation cohort. Mendelian randomization analysis identified relationships between cognitive function and all nine PDIs associated with systolic BP, including anterior thalamic radiation, anterior corona radiata, or external capsule. Conclusion Complementary Mendelian randomization (MR) and observational analyzes identify brain structures associated with BP, which may be responsible for the adverse effects of hypertension on cognitive performance. |
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Genetic analyzes identify brain structures linked to cognitive decline associated with high blood pressure
For the first time, researchers have identified specific regions of the brain that are damaged by high blood pressure and may contribute to decreased mental processes and the development of dementia.
High blood pressure is known to be involved in causing dementia and damage to brain function. The study, which is published in the European Heart Journal [1] today (Tuesday), shows how this happens. It compiled information from a combination of magnetic resonance imaging (MRI) of brains, genetic analysis and observational data from thousands of patients to look at the effect of high blood pressure on cognitive function. The researchers then verified their findings in a separate large group of patients in Italy.
Tomasz Guzik, professor of Cardiovascular Medicine at the University of Edinburgh (UK) and Jagiellonian University School of Medicine in Krakow (Poland), who led the research, said: "Using this combination of imaging, genetic and observationally, we have identified specific parts of the brain that are affected by increases in blood pressure, including areas called putamen and specific white matter regions. We think these areas could be where high blood pressure affects cognitive function, such as loss of memory, thinking skills and dementia When we verified our findings by studying a group of patients in Italy who had high blood pressure, we found that the parts of the brain we had identified were indeed affected.
“We hope that our findings can help us develop new ways to treat cognitive decline in people with high blood pressure. Studying the genes and proteins in these brain structures could help us understand how high blood pressure affects the brain and causes cognitive problems. Additionally, by looking at these specific brain regions, we can predict who will develop memory loss and dementia faster in the context of high blood pressure. “This could help with precision medicine, so we can target more intensive therapies to prevent the development of cognitive decline in patients at higher risk.”
High blood pressure is common, occurring in 30% of people worldwide, with an additional 30% showing the early stages of the disease. Studies have shown that it affects brain function and can cause long-term changes. However, until now it was not known exactly how high blood pressure damages the brain and which specific regions are affected.
In research co-funded by the European Research Council, the British Heart Foundation and the Italian Ministry of Health, Prof. Guzik and an international team of researchers used brain MRI data from more than 30,000 participants in the UK Biobank study, genetic information genome wide association studies (GWAS) from the UK Biobank and two other international groups (COGENT and the International Blood Pressure Consortium), and a technique called Mendelian randomization, to see if the High blood pressure was actually the cause of changes in specific parts of the brain rather than simply being associated with these changes.
“Mendelian randomization is a way of using genetic information to understand how one thing affects another,” Professor Guzik said. “In particular, it tests whether something is potentially causing a certain effect, or whether the effect is just a coincidence. It works by using a person’s genetic information to see if there is a relationship between genes that predispose to higher blood pressure and outcomes. If there is a relationship, then it is more likely that high blood pressure is causing the result. This is because the genes are passed randomly from the parents, so they are not influenced by other factors that could confound the results. In our study, if a gene that causes high blood pressure is also linked to certain brain structures and their function, it suggests that high blood pressure could actually be causing brain dysfunction there, leading to problems with memory, “thought and dementia.”
The researchers found that changes in nine parts of the brain were linked to higher blood pressure and worse cognitive function. These included the putamen, which is a round structure at the base of the front part of the brain, responsible for regulating movement and influencing various types of learning. Other areas affected were the anterior thalamic radiation, the anterior corona radiata, and the anterior limb of the internal capsule, which are regions of white matter that connect and allow signaling between different parts of the brain. The anterior thalamic radiation is involved in executive functions, such as planning simple and complex daily tasks, while the other two regions are involved in decision making and managing emotions.
Changes in these areas included decreases in brain volume and the amount of surface area in the cerebral cortex, changes in connections between different parts of the brain, and changes in measures of brain activity.
Image: 3D reconstruction shows how high systolic blood pressure has affected major tracts of white matter in the brain. Red shows the areas most affected by high blood pressure, while yellow areas are also affected but to a lesser extent. The study shows that high systolic blood pressure causes damage to the white matter and its connections with other parts of the brain and this is linked to worse cognitive functions in the people analyzed. For the first time, specific areas of the brain are identified that are to blame for this disease. Credit Image is under copyright. If you use it, please credit Dr. Lorenzo Carnevale, IRCCS INM Neuromed, Pozzilli, Italy.
First author of the study, Associate Professor Mateusz Siedlinski, also a researcher at the Jagiellonian University Faculty of Medicine, said: "Our study, for the first time, identified specific locations in the brain that are potentially causally associated with blood pressure. high blood pressure and cognitive function. “This was uniquely made possible by the availability of data from the UK Biobank, including MRI brain images, and by previous research that identified genetic variants affecting the structure and function of more than 3,000 areas of the brain.”
Study co-author Professor Joanna Wardlaw, Head of Neuroimaging Sciences at the University of Edinburgh, said: "High blood pressure has long been known to be a risk factor for cognitive decline, but how does blood pressure High blood pressure damages the brain was unclear. This study shows that specific regions of the brain are at particularly high risk of blood pressure damage, which may help identify people at risk of cognitive decline in the early stages and potentially help guide therapies more effectively in the future.”
Limitations of the study include that participants in the UK Biobank study are mainly white and middle-aged, so it may not be possible to extrapolate the findings to older people.
An accompanying editorial is written by Dr. Ernesto Schiffrin, of Sir Mortimer B. Davis-Jewish General Hospital and McGill University, Montreal, Canada, and Dr. James Engert, of the University Health Center Research Institute. McGill University, Montreal. They note that "further mechanistic studies of the effects of BP [blood pressure] on cognitive function are required to determine the precise causal pathways and relevant brain regions."
They highlight one of the findings of the study on systolic and diastolic blood pressure (SBP and DBP). “Perhaps one of the most interesting results of this study is the possible different causal effects of SBP versus DBP. The authors observed some overlapping results for SBP and DBP on cognitive function when analyzed in isolation. However, when each parameter is analyzed after adjusting for the other, or in multivariable models, intriguing findings begin to emerge. DBP alone does not predict a decline in cognitive function, but is in fact protective when adjusted for SBP. “This result was true both in observation and when Mendelian randomization was used.” They continue to discuss possible reasons for this.
