Q&A: Environmental Interventions for Neuroinflammation with Dr. Austin Perlmutter

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In his 2024 Integrative Healthcare Symposium presentation, Austin Perlmutter, MD, discussed the role of environmental factors in neuroinflammation and how lifestyle interventions can reduce the risk of conditions like Alzheimer's disease and depression.

We interviewed Dr. Perlmutter in a podcast episode leading up to the symposium about the relationship between the brain and the immune system and how everyday choices impact cognition in the long-term.

Avery St. Onge: What are the key pathways involved in immune state and imbalance?

Austin Perlmutter, MD: There are very few areas of medicine and research that are even comparable to what we're seeing with the breakthroughs in immunity. We have often thought about the immune system, and many people still do, as a very basic thing that defends us against microbes and can be boosted by vitamin C. But the truth is, we have trillions of immune cells within us, which respond in real-time to what's happening in our environment. So, immunity is distributed throughout the body. Immune cells are found in basically every tissue in the body, most of which are located in the gut. 

What's interesting is we know there are specialized immune populations in the liver, for example, or in the skin. Regarding the brain, we know that about 15 percent of our brain cells are immune cells called microglia. We need to reconceptualize the immune system as something that’s just designed to defend us against the environment and instead look at it as an interconnected web of data collection and modification throughout all our organ systems. And that gives us an incredible opportunity to understand where our health goes wrong and where our health can go. 

St. Onge: Can you tell me more about the role of environmental and lifestyle factors in brain inflammation and immunity?

Dr. Perlmutter: Sure. What happens when we have inflammation in a joint? It gets ready to get swollen. It gets painful. But what happens when we get inflammation in the brain? That's where things get interesting because we don't necessarily experience pain in our brains. I mean, you might have a headache, but more likely, we're going to be talking about things like depression, worse cognition, and higher risk for Alzheimer's disease. So, inflammation in the brain turns out to be represented in a very different way than inflammation in other tissues. 

Now, how does inflammation get into the brain? It's an important question. And then, what does it look like when it gets there? We now know that when we have inflammation outside the brain, meaning in our periphery, it can get access to the brain if our blood-brain barrier is leaky.

We also know that the blood-brain barrier has receptors for inflammatory cytokines. We also know there are parts of the blood-brain barrier that, even without any sort of disease, may allow various immune markers and signals to get into the brain. So, experiencing stress, even watching something stressful on TV, can activate the brain's immune system because those stress signals get translated through nerves and into our brain's immune system. 

So, then, what does inflammation look like within the brain? Researchers have isolated a couple of major metrics we'd look at. One is the activation of our microglial cells. These brain immune cells comprise billions of cells within our brain. Microglial cells can become more activated toward an inflammatory state, and that seems to be critical to understanding brain inflammation.

We also know brain inflammation is associated with a migration of peripheral immune cells into the brain. Usually, the brain shouldn't have a whole lot of blood cells, specifically immune cells from the bloodstream getting into the brain. But when there's inflammation, that may change.

We also know that it's associated with damage to the brain itself, as well as damage to the blood-brain barrier. These are some of the ways that inflammation can get into the brain and why inflammation in the brain may map onto certain outcomes that we really should be caring about.

St. Onge: Now, are certain people more susceptible to these environmental and lifestyle factors impacting their brain and causing that inflammation?

Dr. Perlmutter: I think the answer is yes. If you ask any person how they experience life, and if it’s different depending on their genes or various aspects of their physiology, the answer will always be yes. Every person has a unique experience. When we think about environmental impacts on our brains, what we now recognize is that everything we do each day is going to be translated into data that is going to reach and influence our brains.

If you think about what the brain does, it's the central driver computer of our lives; it needs to be able to respond in real-time to data coming in from our bodies. We often think about this in the context of the stress response. Say I experienced something scary, and obviously, I had a brain response, meaning I froze, I had to run away, or I decided to fight. That's the classic response to a stressor. What we now know, though, is that the brain is incredibly responsive to data and not just what comes in through our eyes and through our ears.

For example, the gut-brain connection is emerging as a major pathway, translating data from our food to our brain, from our microbiome to our brain; that data is now understood to influence the brain's immune system.

So, coming back to your original question, is it true that individuals have different impacts of environmental factors on their brains and immune systems? Absolutely, because the microbiome is different depending on who you are. That will change the data that your brain gets; the tone of your vagus nerve will be different depending on your life experiences, which will change how your brain works. How you appreciate stress and how you experience what goes on each day will be different, depending on where you started. But what may be the most impactful part of all this is we have the opportunity to change all of those variables each day.

Suppose we want a healthier gut-brain connection to program a healthier immune system within the brain. In that case, we know that dietary changes are playing probably the biggest role in the makeup of our microbiome. If we want to have healthier signals coming in to program our stress pathways in the brain, which program our brain's immune system, we can make choices in the context of what we decide to consume each day.

So yes, it's different depending on who we are, and the environment has differential effects. But importantly, these are all things within our control to make changes to better support a brain immune system that works for us.

St. Onge: And, of course, brain inflammation is related to problems like Alzheimer's and depression, but that's obviously when it's gotten to a significant extent. Are there signs of mild brain inflammation that someone should be keyed into so they can start to begin these lifestyle modifications?

Dr. Perlmutter: Right, it's a good question. If we think about conditions like Alzheimer's and depression, these are states in which things have progressed pretty far. While we certainly know that inflammation is correlated with depression and Alzheimer's disease, there's a fallacy in this belief that because you have reached the end result, which is a diagnosis of Alzheimer's or depression, and you have higher levels of inflammation, that nothing was happening in the decades beforehand. And I believe that we need to destroy this idea.

What we really need to focus on is immune balance each day, including immune balance within our brains. So, what are some data points that we may not be having good immune balance, which includes higher risk for inflammation in a given day? Well, there are many of them.

For example, suppose a person has a higher BMI, specifically if they have more visceral fat; these are fat cells that tend to promote inflammation. In that case, that's a good signal that there may be issues with inflammation in the body, and by extension, that might be affecting the brain if we have evidence of poor metabolic health. That might mean a higher fasting insulin level, a higher hemoglobin A1C, an elevated fasting glucose, and even things like a higher uric acid level. These are indicators that there may be metabolic imbalance, which correlates with higher rates of inflammation. 

Similarly, if we're experiencing high levels of stress consistently if we feel like we're having trouble sleeping if we feel anxious all the time, this is an indication that our HPA Axis may be out of whack. Now, that's an entirely separate conversation as it relates to why that is the case and what goes wrong with our stress pathways. However, the important piece to understand here is chronic dysregulation. Stress pathways correlate with a higher rate of inflammation, which may include inflammation in the brain. 

There are other things that we can think about as far as just general exposures. If we tend to eat a diet that is high and ultra processed food, that is an indicator that we may be promoting inflammation in our bodies and brain. So, ask yourself on a given day, are you eating mostly foods that are real foods? Or are you eating mostly foods that your great-great-grandparents wouldn't have recognized? That's an indicator that there may be issues with inflammation. 

Similarly, if you're a sedentary person, if you don't move your body, that’s an indication that there may be higher levels of inflammation. One of the specific data points I'll be talking about in my presentation is that the air we breathe is a major risk factor for immune imbalance, including immune imbalance in the brain.

Do you live somewhere where wildfires are a big issue? Do you regularly use scented candles and air fresheners in your home? Do you cook on a stove that isn't ventilated? These are all indicators that you may be exposed to higher levels of air pollutants linked with higher levels of inflammation. 

There are many things that we can think about, but the bottom line is we need to be paying attention. It isn't something where we say, 'Oh, well, only certain populations need to be worried about brain inflammation; only people who have experienced symptoms of low mood or cognitive decline need to be worried about brain inflammation.’ This isn't a binary thing. It's something that we need to be paying attention to over the course of our lifespan. So again, everybody really needs to be thinking about this stuff.

Editor's Note: This interview has been edited and condensed. Listen to full podcast interview here.