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How Systemic Inflammation Affects Your Brain & Central Nervous System

Bodies are like well-oiled machines, with many systems that work together to keep things running smoothly. But when one system doesn’t work properly, that can cause problems throughout the body.

For people living with an inflammatory disease, such as Gaucher disease, a faulty immune system can wreak havoc on the body. Inflammation is one of the ways the immune system protects and heals the body. But constant immune activation can cause inflammation throughout the body, which may affect physical and mental function. This is especially true if the systemic inflammation throws the central nervous system (CNS) off-balance.

We spoke with Gregory Grabowski, MD, to understand how systemic inflammation affects the CNS. He is professor emeritus of Pediatrics and of Molecular Genetics, Biochemistry, and Microbiology at the University of Cincinnati College of Medicine. Dr. Grabowski is also a prolific Gaucher disease researcher. He founded of one of the world’s largest clinics for Gaucher disease and the first enzyme replacement therapy center. He is a member of the National Gaucher Foundation’s Medical Advisory Board.

Understanding Inflammation

Local inflammation is the immune system’s reaction to an injury or irritation. If you get a cut or sprain your ankle, your body’s inflammatory response may include redness and swelling at the injury site. This response might be short-lived (acute inflammation) or last for weeks or months (chronic inflammation).

What is systemic inflammation?

Systemic inflammation occurs when the immune system is constantly defending the body. Stress, infection, or chronic diseases can put the body in a proinflammatory state. When this happens, the immune system becomes primed and ready to create an inflammatory response. Immune cells increase production of proinflammatory proteins such as cytokines and chemokines. These agents serve as immune mediators that stimulate inflammatory responses throughout the body.

Systemic inflammation and Gaucher disease

People living with Gaucher disease are prone to systemic inflammation. Their macrophages (immune cells) secrete higher levels of proinflammatory cytokines than macrophages in people who don’t have Gaucher disease. Your doctor uses the levels of cytokines in your blood to understand the degree of systemic inflammation in your body.

“With untreated Gaucher disease, increased levels of cytokines create a chronic, ongoing stimulus that is always there,” Dr. Grabowski says. “If a patient with Gaucher disease gets pneumonia or some other kind of infection, the inflammatory response will likely be greater than in other patients who don’t have Gaucher and aren’t in a proinflammatory state. This is particularly true for untreated patients.”

Supporting the immune system can help manage chronic inflammation and reduce symptoms.  Learn more about natural ways to boost your immune system through diet, exercise, and mindfulness.

How Systemic Inflammation Interacts with the Brain

The immune system interacts with the CNS, which includes the brain and spinal cord. But the CNS relies on a blood-brain barrier to keep the systems separate and protect the balanced environment of the brain. The barrier is a network of blood vessels, passable only in certain circumstances. It allows entry of essential nutrients, locks out harmful substances, and limits the entry of immune cells and mediators into the CNS.

But the barrier can break down in response to systemic inflammation. This breakdown can allow the immune system to interact directly with the brain. Systemic inflammation’s effect on the blood-brain barrier can be:

  • Disruptive, with a visible change in the anatomy of the blood-brain barrier, or
  • Nondisruptive, characterized by a functional change to the barrier

Blood-brain barrier changes in Gaucher patients

In some Gaucher patients, systemic inflammation causes nondisruptive changes to the blood-brain barrier. This occurs more frequently in patients with Gaucher disease types 2 or 3 who have severe, untreated organ disease. Similar changes likely occur in Gaucher disease type 1 patients, but at lower levels.

The changes to the blood-brain barrier allow proinflammatory cytokines and chemokines to gain access to the brain and interfere with its balanced environment. As a result, the brain’s inflammatory response may kick in, causing cognitive and behavioral symptoms.

“This is an individual thing,” Dr. Grabowski says. “It varies from one patient to another, and it depends on each patient’s clinical severity, treatment status, and how the disease presents.”

Neurological effects of systemic inflammation

Systemic inflammation can lead to immune responses in the brain that show up in many ways. People may experience cognitive symptoms such as memory lapses or confusion. Other common symptoms, known as “sickness behavior,” may include:

  • Depression
  • Decreased physical activity
  • Fatigue
  • Lack of motivation
  • Loss or lack of appetite

“This systemic inflammation can affect cognitive function, it can create delirium, and it can create some serious problems especially for people with neuropathic disease,” Dr. Grabowski says. If systemic inflammation continues and goes untreated, the neurological changes can become permanent.

Systemic inflammation and neurodegenerative disease

In neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, immune cells within the brain tend to exist in a chronic inflammatory state. These microglial cells are primed and ready to over-respond to any stimulus that comes through the blood-brain barrier. When immune mediators stimulate those primed microglial cells, inflammatory responses may increase.

“Many neurologists note that they often see this type of response with Alzheimer’s disease and Parkinson’s disease,” Dr. Grabowski says. “Somebody gets inflammatory gout, for example, and then suddenly, they are much worse cognitively. Once treated, the systemic inflammation decreases, and cognition improves.”

How Enzyme Replacement and Substrate Reduction Therapies May Help

At this point, research into the effects of systemic inflammation on the brain has mostly focused on neurogenerative diseases. But Dr. Grabowski believes the findings may hold true for neuronopathic Gaucher disease (type 3) as well.

“In Gaucher disease type 3 patients treated with enzyme replacement therapy (ERT), we find that the systemic proinflammatory state is very much quelled,” Dr. Grabowski says. “It’s not eliminated, but it diminishes significantly, because the engorged Gaucher cells go away. This also occurs in type 1 patients treated with either ERT or substrate reduction therapy (SRT).”

Many patients with Gaucher disease who receive ERT are getting better, cognitively and physically. Dr. Grabowski’s type 3 patients report symptom improvements including restored appetites, increased energy levels, and fewer lapses in memory. But these changes aren’t the result of ERT directly treating the disease’s brain involvement. Dr. Grabowski attributes the improvements to the interaction between systemic inflammation and the brain, but this is an area of active research.

Researchers haven’t yet connected the cognitive effects of ERT or SRT to changes in systemic inflammation. But such studies could lead to additional therapies that directly target the systemic inflammatory reactions in Gaucher disease. That type of therapy could improve overall outcomes and quality of life for patients with Gaucher disease.

“We know that infused enzymes can’t get through the blood-brain barrier and into brain,” he says. “So, it’s very important that you treat the systemic effects of Gaucher disease, to be able to diminish the effects in the brain.”

Systemic Inflammation & Gaucher Disease: A Look Ahead

Researchers specializing in neurological disorders are studying the neurological effects of systemic inflammation. Dr. Grabowski expects that their research into Parkinson’s disease, multiple sclerosis, and Alzheimer’s disease will also provide answers for patients with Gaucher disease.

“More and more data is coming out, but this is still very much a work in progress,” he says. “We still need a lot more information. The good news is that several different foundations [associated with neurodegenerative diseases] are now putting enormous amounts of effort into this area.”

Currently, most of the research into the neurodegenerative effects of systemic inflammation focuses on how peripheral cytokines and chemokines, as well as other proinflammatory agents, affect the brain. “Over the last decade or so, the lysosome has become a major focus of research and clinical applications for Parkinson’s disease and Alzheimer’s disease,” Dr. Grabowski says. “Clearly, the fields of Gaucher disease and other lysosomal storage diseases could benefit from such research. There are and will continue to be collaborations between these fields of research.”

How the National Gaucher Foundation Can Help

If you or a loved one lives with Gaucher disease, the National Gaucher Foundation is here for your family. We offer resources to optimize your health with Gaucher disease and connect you with the support you need.

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