January 23, 2025

Saanvi Sharma

10th Grade

Williamsville East High School

Abstract

Multiple Sclerosis (MS) is an autoimmune disease that targets the central nervous system, causing the breakdown of the protective myelin sheath needed by nerve cells to function properly. Causing disability in over 1 million Americans, multiple sclerosis is the leading non-traumatic cause of disability in young individuals in the United States. Although this disease is idiopathic, there are many theories currently being researched, one being the disruption of the blood-brain barrier. The blood-brain barrier (BBB) is what keeps harmful components in blood out of the brain. Disruption of this barrier can cause inflammatory blood proteins, such as fibrinogen, to enter the brain. These proteins may cause inflammation, specifically an autoimmune response as frequently seen in MS patients. This ties into the primary focus of this research: the correlation between the blood-brain barrier, immune activation, and the neurodegeneration that takes place in multiple sclerosis.

Introduction

The blood-brain barrier is a highly selective semipermeable membrane that regulates transfer between the circulatory and central nervous systems. It is composed of endothelial cells, astrocyte end-feet that cover the capillary, pericytes, and a basement membrane. The proper function of this membrane is vital to the body, as it regulates what enters the brain. When the blood-brain barrier leaks, components of the blood that can cause brain damage enter the brain. They, therefore, can promote inflammation and neuronal degradation, such as the protein fibrinogen. Fibrinogen, a glycoprotein synthesized in the liver, plays a pivotal role in the coagulation cascade forming insoluble fibrin clots, crucial for hemostasis, and vital in the body's main clotting mechanism. Found abundantly in the blood, also known as Coagulation factor 1, fibrinogen is actively converted into fibrin by thrombin during clot formation. This protein is extremely important in the body, however it possesses inflammatory properties, especially in the brain. It has been shown that multiple sclerosis lesions form around those areas where the blood-brain barrier has been disrupted in the past where proteins as such have entered the CNS. 

Pathogenesis of MS

Multiple sclerosis is characterized by the demyelination of neurons in the CNS, and progressively the transmission of signals across the nervous system, which is impaired. The main signs of MS pathogenesis are lesions, scar tissues, myelin damage, axonal injury, and inflammation in the CNS. There are four main types of multiple sclerosis: Clinically Isolated Syndrome (CIS), Relapsing-Remitting Multiple Sclerosis (RRMS), Primary Progressive Multiple Sclerosis (PPMS), and Secondary Progressive Multiple Sclerosis(SPMS). All four of these have varied courses as they develop, but all cause neurodegeneration as they progress in a patient.

Obesity and Its Correlation to the Blood-Brain Barrier and MS

Although the cause of multiple sclerosis is not known, there are risk factors that have been shown to increase the risk of developing the disease and disease progression in many individuals. Some factors are genetics, obesity, and smoking. Interestingly, these are the same risk factors for blood-brain barrier leakage, this shows a tie between the barrier leakage and multiple sclerosis. Obesity can cause the oxidative stress in the body to increase, causing the leakage of the BBB to increase. Obesity and chronic HFD (high-fat diet) consumption, especially diets rich in saturated fat, have been linked to reduced cognitive function in both humans and animals. 

Cytoskeletal proteins are vital in the tight junctions of the blood-brain barrier and keep it tight. Obesity suppresses these proteins, allowing the integrity of this barrier to be breached. Two of these proteins are vimentin and tubulin. Vimentin provides resistance against cellular stress from obesity and helps maintain cellular integrity, at the same time, tubulins are the highly conserved subunit of microtubules, which are involved in various fundamental functions, including brain development. These microtubules help in neuronal proliferation, migration, differentiation, cargo transport along the axons, synapse formation, etc. Those with weaker blood-brain barriers due to obesity may also have higher chances of developing Multiple Sclerosis, this shows a link between these two syndromes. 

Fibrinogen Found in the Brain

As well as the similarities in risk factors, animal studies have found fibrinogen in the brain before any signs of demyelination or the presence of immune cells. Many postmortem studies have found blood-brain barrier leakage in active, chronic active, chronic inactive, and pre-active MS lesions. Fibrin is found in active and preactive white matter lesions but is slowly converted into diffuse tissue over time. This is because of fibrinolysis, a process that causes fibrinogen to degrade as soon as it forms. Deep gray matter has less inflammation compared to white matter, and this may be because it is composed of more neuronal cells than myelinated axons that are affected by MS and that are more present in white matter. Fibrinogen was also, interestingly, found in the cortex of the brain.

Fibrinogen Impact on the Brain

Unlike most blood factors, fibrinogen not only enters the CNS but is rapidly converted to fibrin by the perivascular tissue factor present. This leads to lesion formation inside the brain and CNS which can cause the fibrin and other immune factors to be drawn to the area. This positive feedback loop eventually leads to demyelination, at the spot of the blood-brain barrier leakage. This conversion to fibrin triggers immune cells such as microglia, the resident macrophages, or immune cells, in the brain that serve as the first line of immune defense in case of damage. The fibrin attaches to the CD11b/CD18 receptors and causes them to begin to attack the myelin sheath of neurons around them, as well as call for more immune cells. Even though the brain has a way to remyelinate or repair the myelin damage that occurs in multiple sclerosis, which is very helpful for patients to recover, this cascade is blocked in MS. Oligodendrocyte precursor cells in the CNS are responsible for remyelination and immune function, however in diseases such as multiple sclerosis, this process is often incomplete. The differentiation of these cells is suppressed by fibrinogen and other factors, and they are unable to efficiently remyelinate the neurons of the brain. Therefore, an MS patient cannot recover as greatly from any damage that has occurred, like a normal person would be able to. 

Early Onset MS

Pediatric-onset multiple sclerosis (POMS) accounts for about 10% of all MS cases, presenting unique opportunities for understanding the disease better. While multiple sclerosis (MS) is predominantly diagnosed in adults, the occurrence of MS in children and adolescents provides a different perspective of the disease, one that doesn't take the factor of aging into account.

In general, younger patients tend to have a more intact blood-brain barrier compared to adults due to less aging. This could allow for more study on other factors present that cause deterioration of the blood-brain barrier at a young age.

Obesity is one such factor that has been linked to an increased risk of developing MS, particularly in childhood and adolescence. Studies suggest that children with obesity have greater chances of developing MS later in life, possibly due to the inflammation associated with excess body fat. This connection highlights the importance of addressing lifestyle factors early on, building awareness especially those who have a family history of the disease. 

When it comes to disease progression, pediatric MS tends to differ from adult-onset MS in several ways. While young patients may experience more frequent relapses, they often recover quicker and experience less disability. However early diagnosis and treatment are essential to prevent long-term disability. This can help manage symptoms, reduce relapses, and slow the progression of the disease.

Overall, POMS offers a unique opportunity to study MS outside of the typical aging context. It also highlights the importance of early diagnosis and treatment, which could greatly affect a young child’s future living quality. 

How Can We Use This Information? 

Fibrinogen as well as other blood factors leaking into the blood-brain barrier are a known cause of multiple sclerosis progression and pathogenesis, but how can we use this information to create new treatments or diagnostic options for patients? Testing for blood-brain barrier leakage would be ideal to know who is at risk for multiple sclerosis and to allow for earlier testing and treatment. Most damage to the myelin sheath and inflammation that occurs during multiple sclerosis happens in the early stages of the disease. Therefore, being aware early and taking medications earlier can reduce the impact of this disease to a great extent. The second thing would be prevention, which would consist of diet control and raising awareness of the importance of the blood-brain barrier to those who aren't aware. Those who have a family history of MS, or are at high risk, could be taught about the steps they could take to strengthen their blood-brain barrier to prevent MS. Lastly, an option would be to remove these inflammatory proteins from the blood entirely. Anticoagulants that target the protein fibrinogen have been shown to slow down inflammation in animal studies; however, completely inhibiting a clotting factor may lead to excess bleeding and could pose unwanted risks. However, a way to target only the inflammatory part of fibrinogen but keep clotting function could be a promising discovery that might be able to reduce MS rates across the globe.

Concluding Thoughts

Multiple sclerosis is a disease that affects millions of people, and as of right now, there is no known cause. Research has shown that the blood-brain barrier integrity being breached can lead to inflammatory factors, the main one being fibrinogen, entering the brain and leading to neuronal damage. This coagulation factor, which is vital for the proper function of the body, causes not only the damage of neurons but also the inhibition of the cells that repair this damage. A better understanding of how we can stop the infiltration of these proteins into the BBB as well as test for leakage may have a great impact on new treatments and diagnoses for patients in the future.