Tracking Neuroinflammation in Development, Neurodegenerative Disease

One of the ways that the body responds to injury or infection is to set off a variety of inflammatory processes. The brain is no different; specific cell types called astrocytes and microglia release a variety of neurochemicals to help contain any insults and set the brain up for repair. Research presented at the Society for Neuroscience’s annual meeting this year in Washington, DC, suggests that neuroinflammation, once thought to be a simple clean-up process, is much more sophisticated. Our growing understanding is providing new insights into how neuroinflammation may influence brain development, neurodegenerative disease, and overall brain health.

A changing view of neuroinflammation

We’ve known for a long time that neuroinflammation, or the release of prostaglandins, cytokines, free radicals, and other growth factors in response to toxins, infection, or injury, was mediated by astrocytes and microglia, says Margaret McCarthy, a researcher at the University of Maryland School of Medicine. But, she argues, we’re only now learning that they have a role outside “the context of intrigue.”

“We used to think these cells would rush to the scene of an accident and they would clean up the dead bodies and carry them away. This is a very important process because if you don’t get rid of dead neurons, they leak all sorts of nasty neurochemicals, resulting in additional cell death,” she says. “But now we know these cells are important to normal brain functioning.”

Microglia spend a good bit of their time “surveying” the brain and making sure each neuron is functioning correctly, she says. “They are moving around all the time and literally touching a stable of neurons they are responsible for and saying, ‘Are you okay? Everybody okay?  You okay?’” she says. “It takes about two hours for the entire brain to be surveyed by microglia, and if they find a cell that’s not okay, they basically engulf it and consume it. We also now know they do a finer sort of nibbling where they are actually pruning synapses, too—which is a very important process in development.”

This more detailed understanding, McCarthy argues, suggests that neuroinflammation may play a more important role in overall brain health than previously imagined—and could offer scientists new insights into how neuroinflammation may influence brain development and disease.

Neuroinflammation, development, and psychiatric disease

Many neuropsychiatric conditions, including schizophrenia and depression, can be traced back to the womb—various in utero processes that result in changes to the brain’s connectivity and structure that ultimately lead to psychopathology. Claudia Buss, a researcher at Charité-University Medicine Berlin, and her colleagues wondered if, perhaps, neuroinflammation might be effecting some of those changes.

“Maternal infection and immune activation during pregnancy, particularly early pregnancy, are important predictors of offspring psychopathology. And we know that maternal inflammation can influence fetal inflammation via placental transport or placental inflammation,” says Buss.

To look more closely at the relationship between inflammation and brain development, the research team took blood samples from 58 pregnant women during early, mid- and late pregnancy to measure interleukin-6, a cytokine that is released in response to infection or stress. Once the mothers gave birth, researchers scanned the brains of the newborns as they slept using functional magnetic resonance imaging (fMRI). Buss and colleagues discovered that higher concentrations of interleukin-6 in mothers was linked to reduced network connectivity in offspring, with those infants’ brains showing weaker connections in the default mode network.

“We were really interested in the default mode network because alterations in the connectivity of that network has also been associated with psychiatric disorders in children and adults,” says Buss. “And what we saw was that default mode network connectivity right after birth was less mature in newborns with mothers who had elevated interleukin-6, a marker of inflammation, during early pregnancy. These findings have implications for early identification of individuals at risk for developing psychopathology—as well as help guide the development of intervention strategies to prevent or reduce the likelihood of developing that psychopathology in the future.”

Following the progression of neuroinflammation

Interleukin-6 is not the only neurochemical released as part of the neuroinflammatory process. Expression of the translocator protein (TSPO) increases dramatically in the brain with inflammation. Cynthia Lemere, an Alzheimer’s researcher at Harvard Medical School, is using that increased expression to track neuroinflammation in living animals using positron emission tomography.

“One of the big questions in Alzheimer’s disease is what the role of neuroinflammation actually is. Is it something that occurs early in the disease?  Or something secondarily, later in the disease?” she says. “So understanding inflammation and its role may be key to understanding the disease process—and potential therapies to prevent or treat Alzheimer’s.”

Lemere and her team used a new tracer called 18F-GE180 to track TSPO in animal models of Alzheimer’s disease as well as wild type control mice. They found much higher expression of TSPO in the Alzheimer’s animals—specific to brain areas like the hippocampus and cortex.

“This is an excellent tool to help us try and figure out where and when in the brain neuroinflammation starts to rise—and then correlate that back to the pathology and the behavior,” says Lemere. “In the past, we’ve had to rely on post-mortem studies but now we can do multiple PET scans longitudinally over time so we can track what’s happening.”

Moving forward

18F-GE180 is already being used in human test subjects in Europe—and soon will be in the US—to study disease progression and drug efficacy. But neuroinflammation is not specific to Alzheimer’s disease alone: This method could help researchers track, diagnose and treat any number of neurodegenerative and psychiatric disorders that have been linked to neuroinflammation, Lemere says. She hopes that it will help tease out whether neuroinflammation is initiating these diseases or simply a response to whatever biological mechanism is actually responsible for the disease state.

McCarthy is quick to caution that studies looking at the link between neuroinflammation and brain health, whether we are talking about fetal brain development or neurodegenerative disease, are still very preliminary. But, that said, she argues, they hold great promise.

“The new research is really shining a spotlight on where the field is headed—in some respects, we are identifying a lot more questions than answers,” she says. “But we’re learning that microglia are amazingly versatile cells. And they are very, very important to understanding neuroinflammation as well as overall brain function and health.”