Groundbreaking discoveries at UVA Health are shifting how we think of neuroinflammation’s role in disease, and UVA Health’s John Lukens, PhD, associate professor in the Department of Neuroscience, is helping shed new light on the role of this inflammation in concussions. This has important implications for new avenues of research that could improve diagnosis and treatment of diseases like Alzheimer’s, Parkinson’s, cerebrovascular disease, and more.
Concussions are often misunderstood in clinical settings, which leads to misinterpretation of the severity of brain injury, misaligned treatment — such as holding patients back from normal activities for too long — and inaccurate or missed diagnosis of other disorders.
“Dr. Lukens’ research is critical to inform questions on if there are ways to identify who experiences neuroinflammation, what severity of injury causes neuroinflammation, and when it remits,” says Donna Broshek, PhD, a clinical neuropsychologist and professor in the Department of Psychiatry and Neurobehavioral Sciences. “We’re now asking questions like what is the role of neuroinflammation? Is it a protective thing? Is it a damaging thing? And is there a way to treat it?”
How Lymphatic Drainage Impacts Concussion Recovery
Key to Lukens’ research were novel discoveries about the lymphatic drainage pathway in the brain. Previously, experts believed the brain didn’t have lymphatic drainage pathways to clear out debris and communicate with the immune system, which led physicians and researchers to think the brain was “immune privileged.” Research from UVA Health in 2016, however, found there are lymphatic vessels close to the skull, which debunked this prevailing thinking.
Lukens’ research built on that foundation and found that impairment of these drainage pathways contributed to the risk of severe cognitive dysfunction in mouse models.
“This is a new pathway, and there’s still a lot we don’t know,” says Lukens. “But we found that even a mild head injury — one that didn’t cause extensive tissue damage or impact mouse behavior — caused impacts to efficient drainage of the lymphatic system immediately post-injury.”
In some cases, the lymphatic system in the brain completely shut down and took up to two months post-injury to get to a steady state, leading to evidence that traumatic brain injury (TBI) could impair the drainage pathway.
Paradigm Shifts on Inflammation
For decades, the paradigm was that any immune response in the brain and spinal cord was bad for the patient. But now, with emerging data, clinicians recognize it’s a balance. In other words, just as in cases of influenza or COVID-19, too little or too much inflammation or immune response can be problematic. For TBI, the immune system plays an important role — in this case, cytokines produce growth factors that enable wound healing.
“Inflammation can play negative or beneficial roles depending on what response is involved,” says Lukens. “That’s why we want to be selective in how we target the immune response in the central nervous system, focusing on enhancing the pathways that are good and blocking those that are harmful.”
The lymphatic system provides a critical pathway to cleanse the brain of neurotoxic aggregates. Recently, this pathway has proven to be important in draining proteins like Tau proteins, amyloid beta, and alpha synuclein, which are drivers of Alzheimer’s and Parkinson’s diseases. And unfortunately, when things don’t drain appropriately, they continue to trigger inflammation and damage.
A Gold Rush for Knowledge
Neuroinflammation is important to understand, including for neurodegenerative disorders. For example, contributors to dementia include cerebrovascular disease in patients with high cholesterol, diabetes that’s not well managed, and hypertension.
“Now that we’ve moved on from this idea that the brain is immune privileged, the field has changed. And now it’s a gold rush to understand neurological disorders in this new context,” says Lukens. “We became interested in understanding why people with repetitive brain injury may later develop severe clinical consequences, such as mental illness and Alzheimer’s. A connection between the history of concussions and these disorders is strong — and accepted — but no one understands why.”
This research has the potential to benefit many patients, including those living with Parkinson’s and Alzheimer’s. “There is such a dire need for disease-modifying treatments for these conditions,” says Lukens. “A lot of these diseases are progressive and terminal, so translating this research to support treatments for neurodegenerative disorders will hopefully be an early use case.”
While it’s still early, the implications for further research on neuroinflammation and its downstream impacts are vast.
“We suspect neuroinflammation could interact with cerebrovascular risk,” says Broshek. “Dr. Lukens’ research helps us understand the process happening in some brains in animal models and gives clues as to what triggers that process in humans. And it’s important for human brain health to understand neuroinflammation.”
Translating Concussion Research to Diagnostics in the Clinic
Concussion and TBI are highly interdisciplinary, with numerous researchers and clinicians collaborating to translate the latest research into patient care, including Lukens’ research.
“We’re thrilled that the research we do can make a difference in people’s lives,” says Lukens. “Hopefully, we will get to a point where people are going in for their physicals, and we can track lymphatic function and know their risk of neurodegenerative disease.”
There are still steps to take, including finding ways to study this challenging lymphatic system in humans, which will rely on advanced imaging capabilities and identification of novel biomarkers.
“Dr. Lukens’ work is phenomenal, and these results are very intriguing,” says Broshek. “The next step will be translating these learnings from animal models to understanding what happens in people. We want to learn more about how neuroinflammation might affect individuals with recurring impacts and multiple exposures to high-impact forces that lead to concussions.”
Bringing the Latest Breakthroughs to Support Patient Care
Concussions are extremely common injuries, especially for amateur and professional athletes and individuals in certain career fields. Unfortunately, concussion tests used in the diagnosis of concussion are not fool proof, and patients, such as athletes, may minimize their symptoms if they’re motivated to get back to playing.
“One thing we can envision from our results is that we’ll have a measurable way to say when patients should return to high-risk activities based on when their lymphatics are functioning properly,” says Lukens.
The implications from this research may lead not only to improved diagnostic tools but to concussion treatment in the clinic as well, where neurologists, neuropsychologists, sports medicine physicians, physical medicine and rehabilitation specialists, physical and occupational therapists, athletic trainers, and other medical professionals can reap the benefits.
“At this point, we don’t really know the role of neuroinflammation in humans or how to treat it,” says Broshek. “That’s why this research is so important for all patients. After all, we’re all at risk, unfortunately, for TBI. We’re hoping this research in animal models helps to identify treatments that can reduce neuroinflammation, minimize the effects of impact forces to the brain, and track recovery.”
Fortunately, this research can continue to expand for the benefit of patients around the world — and in our backyard.
“I’m proud to have this community where I have really good neuroscientists and neuroimmunologists surrounding me,” says Lukens. “These are two of the most complicated fields in action today, and we get to bring them together at UVA Health to grow our expertise.”