The missing link in the pathophysiology of vascular cognitive impairment design of the… – europe pmc article – europe pmc severe anoxic brain injury

Hemodynamic balance in the heart-brain axis is increasingly recognized as a crucial factor in maintaining functional and structural integrity of the brain and thereby cognitive functioning. Patients with heart failure (HF), carotid occlusive disease (COD), and vascular cognitive impairment (VCI) present themselves with complaints attributed to specific parts of the heart-brain axis, but hemodynamic changes often go beyond the part of the axis for which they primarily seek medical advice. The heart-brain study hypothesizes that the hemodynamic status of the heart and the brain is an important but underestimated cause of VCI. We investigate this by studying to what extent hemodynamic changes contribute to VCI and what the mechanisms involved are.Severe anoxic brain injury here, we provide an overview of the design and protocol.The heart-brain study is a multicenter cohort study with a follow-up measurement after 2 years among 645 participants (175 VCI, 175 COD, 175 HF, and 120 controls). Enrollment criteria are the following: 1 of the 3 diseases diagnosed according to current guidelines, age ≥50 years, no magnetic resonance contraindications, ability to undergo cognitive testing, and independence in daily life. A core clinical dataset is collected including sociodemographic factors, cardiovascular risk factors, detailed neurologic, cardiac, and medical history, medication, and a physical examination. In addition, we perform standardized neuropsychological testing, cardiac, vascular and brain MRI, and blood sampling.Severe anoxic brain injury in subsets of participants we assess alz-heimer biomarkers in cerebrospinal fluid, and assess echocardiography and 24-hour blood pressure monitoring. Follow-up measurements after 2 years include neuropsychological testing, brain MRI, and blood samples for all participants. We use centralized state-of-the-art storage platforms for clinical and imaging data. Imaging data are processed centrally with automated standardized pipelines.The heart-brain study investigates relationships between (cardio-)vascular factors, the hemodynamic status of the heart and the brain, and cognitive impairment. By studying the complete heart-brain axis in patient groups that represent components of this axis, we have the opportunity to assess a combination of clinical and subclinical manifestations of disorders of the heart, vascular system and brain, with hemodynamic status as a possible binding factor.Severe anoxic brain injury

Methods

The heart-brain study is a multicenter cohort study with a follow-up measurement after 2 years among 645 participants (175 VCI, 175 COD, 175 HF, and 120 controls). Enrollment criteria are the following: 1 of the 3 diseases diagnosed according to current guidelines, age ≥50 years, no magnetic resonance contraindications, ability to undergo cognitive testing, and independence in daily life. A core clinical dataset is collected including sociodemographic factors, cardiovascular risk factors, detailed neurologic, cardiac, and medical history, medication, and a physical examination. In addition, we perform standardized neuropsychological testing, cardiac, vascular and brain MRI, and blood sampling.Severe anoxic brain injury in subsets of participants we assess alz­heimer biomarkers in cerebrospinal fluid, and assess echocardiography and 24-hour blood pressure monitoring. Follow-up measurements after 2 years include neuropsychological testing, brain MRI, and blood samples for all participants. We use centralized state-of-the-art storage platforms for clinical and imaging data. Imaging data are processed centrally with automated standardized pipelines.

Introduction

With the rapid aging of the population, the prevalence of cognitive decline and dementia increases [ 1, 2, 3, 4]. Although alzheimer disease is the most common cause of dementia, vascular disease is increasingly recognized as an independent contributor to cognitive impairment [ 1].Severe anoxic brain injury the term vascular cognitive impairment (VCI) has been introduced to describe the complete spectrum of cognitive disorders (mild and major) associated with and due to cerebrovascular disease [ 1, 5, 6, 7, 8]. VCI can be the result of irreversible structural damage to the vascular system in the brain [ 9]. Based on that view, treatment for VCI is often restricted to secondary prevention by treating risk factors, such as high blood pressure [ 10]. Recent findings suggest that cerebral hypoperfusion can also hinder the function of the brain before structural damage occurs [ 9]. The latter is supported by the finding that nondemented patients with cardiovascular disease show cognitive decline [ 11] and that in patients with heart failure (HF) cognitive functioning can be enhanced by improving cardiac function [ 12, 13, 14].Severe anoxic brain injury furthermore, the observation of cognitive impairment in carotid occlusive disease (COD) suggests a relationship between reduced cerebral blood flow (CBF) and cognitive functioning [ 15]. Thus, cardiac and (cerebro-)vascular pathology affecting CBF might influence cellular functions in the brain before structures are altered. Exploring the contribution of cardiac and (cerebro-)vascular pathology to brain alterations is important, because it could identify treatment targets for patients with cognitive impairment due to this type of pathology in the foreseeable future. Medication that improves hemodynamics, such as antihypertensive medication, is available at this moment. However, trials assessing the efficacy of such therapies in VCI are currently lacking.Severe anoxic brain injury this is due to an incomplete understanding of the mechanisms involved and to the lack of research that identifies patients who will benefit most [ 1, 16, 17]. Since health care and research are usually organized in a monodisciplinary way, cardiovascular status tends to be neglected in patients presenting with cognitive impairment in memory clinics and, vice versa, cognitive disorders are often neglected in patients presenting with cardiovascular disease in cardiology or vascular medicine departments. Moreover, guidelines for diagnostic protocols that provide a combined comprehensive assessment of the cardiovascular and cerebral structure and function are lacking. The heart-brain study is part of a larger heart-brain connection consortium ( www.Heart-brain.Nl) [ 18], covering preclinical, experimental, and clinical trial research (textbox 1).Severe anoxic brain injury the heart-brain study hypothesizes that the hemodynamic status of the heart and the brain is an important, but underestimated cause of VCI. We aim to assess the association between (cardio-)vascular and hemodynamic factors in the heart and the brain in relation to cognitive function. Our objectives are to assess (1) the association between cardiovascular parameters and cognitive function, (2) the association between cardiovascular parameters and brain structure and perfusion, and (3) the association between brain structure and perfusion and cognitive function. We study these objectives in patients with HF, COD, and VCI, both cross-sectionally as well as longitudinally. By studying the complete heart-brain axis in patient groups that present themselves with complaints attributed to specific parts of the heart-brain axis, we have the opportunity to assess a combination of clinical and subclinical manifestations of disorders of the heart, vascular system, and brain, with hemodynamic status as a possible binding factor.Severe anoxic brain injury here, we describe the design and study protocol of this multidisciplinary study, in which cardiologists, epidemiologists, neurologists, neuropsychologists, radiologists, image processing experts, and MR physicists work together to study the hemodynamic status of the heart and the brain as an important, but underestimated determinant of VCI.

Results and conclusion

The heart-brain study hypothesizes that the hemodynamic status of the heart and the brain are important, but underestimated determinants of VCI. Previous studies have investigated components of the heart-brain axis in (prospective cohorts of) healthy people [ 28, 29, 30, 31, 32, 33], patients with HF [ 12, 13, 34, 35, 36, 37, 38, 39], and COD [ 40, 41, 42, 43].Severe anoxic brain injury these studies have found circumstantial evidence that cardiac and cardiovascular pathology affecting CBF and perfusion in the brain may influence brain function before structures are irreversibly damaged. It is currently unknown how often hemodynamic changes based on cardiovascular pathology occur in patients with cognitive impairment. Various cardiovascular factors, such as cardiac output, blood pressure, pulse wave velocity, and aortic and carotid stiffness, may influence CBF. On the other hand, in VCI a lower CBF could also be related to a decreased need of blood by an already affected brain. Little is known about how these factors, separate or in concert, influence cognitive performance.Severe anoxic brain injury the heart-brain study is unique because of the integrated approach that we use to investigate relationships between (cardio-)vascular factors, the hemodynamic status of the heart and the brain, and cognitive impairment, in three patient groups that represent components of the heart-brain axis. While zooming in on one component of the heart-brain axis we assess the other components and how they are interconnected. This way, we assess both clinical and subclinical manifestations of disorders of the heart, vascular system, and brain, with hemodynamic status as a possible binding factor along the heart-brain axis. This integrated approach may show light on the mechanisms involved in these relationships.Severe anoxic brain injury to study the relationships as clearly as possible we chose to exclude patients with current atrial fibrillation at the time of inclusion, since atrial fibrillation may lead to unpredictable hemodynamic changes. This exclusion might lead to limited generalizability of this study. However, the patient groups mainly function as a model of specific parts of the heart-brain axis, i.E., hemodynamic components possibly leading to chronic cerebral hypoperfusion.

We perform extensive phenotyping using a comprehensive and standardized MRI protocol that has been developed to measure structure and function of both the heart and the brain. Alongside, a platform for data storage and image processing is developed in which both automatic and manual quality assessment procedures are implemented.Severe anoxic brain injury quantification of imaging biomarkers of the heart, brain, and cerebropetal arteries is performed with existing and newly developed automated software. With this study, we provide a foundation for an interdisciplinary collaborative network for the study of the heart-brain axis that will lead to a true multidisciplinary and consensus-based approach of clinical management of cognitive impairment in patients with HF, COD, and VCI. The close collaboration between departments of cardiology and neurology opens possibilities for future heart-brain clinics, through which implementation of newly developed diagnostic tools and treatment options can be optimized. With this approach we meet the clinical and research need for centers of excellence with transdisciplinary programs within and between centers [ 1, 16, 17].Severe anoxic brain injury

In addition to the heart-brain study, in the heart-brain connection consortium [ 18] we perform preclinical, experimental, and clinical trial studies that further increase the understanding of the mechanisms underlying the relationship between hemodynamic status and cognitive functioning (textbox 1).

We conduct a randomized controlled trial aimed at improving cerebral perfusion (as measured with MRI-based arterial spin labeling) in elderly patients with VCI through aerobic exercise, while taking into account a potential modulatory effect of cardiac output [ 63]. This proof-of-principle RCT may show that improvement of the cerebral perfusion can lead to improved cognitive functioning in patients with VCI.Severe anoxic brain injury

MRI, magnetic resonance imaging; RCT, randomized, controlled trial; SAMP8, senescence accelerated mouse; VCI, vascular cognitive impairment.

In conclusion, in the heart-brain study we test the hypothesis that the hemodynamic status of the heart and the brain is an important, but underestimated cause of VCI offering promising opportunity for treatment. Moreover, we develop a novel, clinically feasible diagnostic protocol including a comprehensive MRI protocol that assesses the heart, the vascular system, and the brain. This protocol can be used for identifying patients suitable for future trials as well as monitoring treatment effects. Finally, we provide a foundation for an interdisciplinary collaboration for the study of VCI that will lead to a true multidisciplinary and consensus-based approach of the clinical management of VCI.Severe anoxic brain injury