An exciting new study by our research team has shown promise addressing the underlying mechanisms that can cause neurological disorders such as Parkinson’s disease and dementia with Lewy bodies.
Thanks to collaboration between researchers at the Mind Research Network (a division of Lovelace Biomedical), the New Mexico VA Healthcare System, and The Nene and Jamie Koch Comprehensive Movement Disorder Center, we’ve identified a unique way to stimulate the brain’s natural waste-clearing system.
About 1.1 million people in the U.S. are living with Parkinson’s disease (PD) and about 90,000 more are diagnosed each year. In patients with this and other neurodegenerative conditions, the brain’s internal plumbing system may be impaired. This allows toxic proteins that are the byproduct of brain function to build up. This accumulation of waste or unwanted proteins may contribute to the classic motor and cognitive symptoms of these diseases.
Our new research, conducted at the Mind Research Network, shows that providing patients with intermittent low levels of carbon dioxide in on/off cycles can cause blood vessels in the brain to expand and contract. This rhythmic movement may pump cerebrospinal fluid into the brain to clear away proteins and peptides.
Glymphatic Pathway: The Brain’s Waste Clearing System
The glymphatic pathway uses cerebrospinal fluid (CSF) to clear waste from the brain. This process is driven by vasomotion, the rhythmic widening and narrowing of blood vessels. As CSF flows along the perivascular spaces that surround blood vessels, the rhythmic pulses of vasomotion are thought to pump CSF into brain tissue to collect and clear waste.
This crucial pumping action happens most often, and most efficiently, while we’re asleep. Studies have shown that slow vasomotion rhythms during non-REM sleep are best for driving this system.
When everything’s working well, vasomotion clears potentially toxic proteins from the brain. This prevents them from building up, a hallmark of neurodegenerative conditions including PD. But the failure of the glymphatic pathway may be a major factor contributing to neurodegeneration.
Why the Clearance System Fails
In both PD and dementia with Lewy bodies (DLB), when the glymphatic system slows down, inflammation occurs and unwanted proteins can accumulate. Alpha-synuclein is one example, when this protein is upregulated, it can mis-fold and aggregate, ultimately forming clumps known as Lewy bodies that contribute to disease.
Previous research suggested that glymphatic function was impaired in patients with PD. We observed that even when awake, these patients’ blood vessels responded less to carbon dioxide compared to participants without PD.
We wrote a review paper to understand the implications of altered cerebrovascular dysfunction in PD. Dr. Henry Lin was instrumental in integrating the human and animal research, which suggested to us that altered cerebrovascular dysfunction may be one of the reasons why glymphatic function is impaired in PD.
Our most recent study confirmed this. Thanks to the support of Dr. Sarah Pirio Richardson at the Nene and Jamie Koch Comprehensive Movement Disorder Center at UNM Health Science Center, we compared a group of about 30 people with PD to a similar size group of people without the condition. We found that the CSF response to intermittent carbon dioxide was reduced in patients with PD. This suggests that impaired blood vessel movement could be a key part of the disease, but it’s just the beginning of what we found.
Research Breakthrough: Activating Waste Removal While Awake
The second goal of our study, published in NPJ Parkinson’s Disease, was to test whether the glymphatic pathway could be safely activated in a controlled way while patients were awake.
We employed an approach called intermittent hypercapnia. Participants were asked to breathe low levels of carbon dioxide, a potent vasodilator, through a specialized mask.
Carbon dioxide was administered in a cycle: 35 seconds on, then 35 seconds off. This pattern is important, because carbon dioxide causes blood vessels to dilate, and removing the carbon dioxide causes the blood vessels to constrict. We believe his creates the pumping action needed to push CSF into the brain to clear waste.
Proof of Clearance: Measuring Blood Proteins
Participants underwent three 10-minute sessions, totaling about 30 minutes. To find out if waste was being cleared from the brain, we took blood samples before and after the sessions. The results showed a significant increase in the concentrations of several key biomarkers, including total alpha synuclein, neurofilament light (NfL) and glial fibrillary acidic protein (GFAP).
We observed the most robust increases in concentrations soon after the intervention was completed, suggesting these proteins are being cleared from the brain. Specifically, we found:
- A strong indicator of nerve damage, NfL increased by an average of 25.1%
- GFAP, a marker of brain inflammation, went up by an average of 14.7%
What’s more, we observed clearance of biomarkers associated with Alzheimer’s disease, too. The procedure was found to be safe and feasible.
Path Toward a Potential New Therapy
While these results are exciting, this therapy has a long way to go before it could be considered for approval as a clinical treatment.
Our immediate challenge will be moving from short, limited therapy sessions to testing whether this method is safe for daily or long-term use. We’ll study how to properly “dose” carbon dioxide, determining the best concentration, duration and frequency to produce a clinical effect.
In other words, we’ll study whether it improves symptoms or slows the progression of disease.
This treatment is promising beyond Parkinson’s disease. Because it targets the fundamental mechanism of waste clearance, it could be effective for dementia with Lewy bodies and/or Alzheimer’s disease. In fact, we’re already working on a pilot study just for patients with Alzheimer’s.
Related: Read “Grassroots to Greatness: UNM HSC’s Nene and Jamie Koch Comprehensive Movement Disorder Center”
Movement Disorders Research at UNM Health Sciences Center
For prospective medical trainees, this is an excellent time to explore the field of moment disorders research here at UNM Health Sciences Center. There are many opportunities for trainees to get involved in our research related to carbon dioxide and glymphatic clearance, and other studies.
The Nene and Jamie Koch Comprehensive Movement Disorder Center collaborates closely with the Mind Research Network, which has state-of-the-art infrastructure for advanced imaging research.
UNM Health Sciences Center is also home to one of only 38 NIH-funded Alzheimer’s Disease Research Centers nationwide. The New Mexico Alzheimer’s Disease Research Center is dedicated to fostering the next generation of researchers interested in exploring PD, DLB, and related conditions.
Related: Read “Collaborative Research Aims to Crack the Gut-Brain Connection”
Research Improves Lives, Now and in the Future
UNM Health Sciences Center is dedicated to innovative research that aims to fundamentally improve the lives of our patients and their families. Successfully demonstrating that we can non-invasively activate the brain’s waste clearing system marks a major step forward in addressing the root cause of neurodegeneration.
This wouldn’t be possible without the generous participation of patients and caregivers. Working together with our research teams, they’re helping advance this promising science.
If you’re interested in taking part in this or other clinical trial opportunities, contact us at 505-803-5499.