“Tip-of-the-Iceberg” Opportunities in Parkinson’s Disease
From a treatment standpoint, Parkinson’s disease (PD) presents a distinct problem. Most patients are diagnosed when classic motor symptoms, like a resting tremor appear, but these symptoms don’t manifest until much of the dopamine-producing neuron function in the brain has already been lost. This means that the degeneration in the brain has been progressing for a long time, sometimes decades, before the disease is diagnosed and treatment can begin. It’s a “tip-of-the-iceberg” problem, where we’re only treating the advanced stage of the disease that we can see. To complicate matters further, our current treatments for PD mitigate the symptoms but don’t stop the actual disease progression. While there are therapies, medications, and activities that can greatly improve quality of life for people with Parkinson’s (PwP), we are still left with a situation in which we don’t know for sure what initially causes the degeneration to start, we don’t start treating it until much of the damage has already been done, and we don’t know how to stop the progression of neurodegeneration once it’s underway.
On one hand, this “tip-of-the-iceberg” problem is frustrating, but on the other, it provides an incredible opportunity for developing different and better ways to treat Parkinson’s. If the motor symptoms are only one manifestation of the disease, and a late one at that, that means there are a lot of other aspects of it that could serve as alternative and hopefully early warning signs and could also potentially offer researchers clues as to what is driving the disease pathology. Some of the non-motor manifestations of PD, such as constipation, changes in intestinal bacterial populations, and indicators of inflammation measured in the blood have led researchers to speculate that PD may not actually begin in the brain at all, but may progress from the gut or other peripheral systems to the brain. If this is true, it could mean that effective treatments for the earliest stages of PD would not necessarily need to target the brain, eliminating one technical challenge of PD treatment. Furthermore, if some disease processes begin decades before motor symptoms start, then this provides doctors and researchers with an enormous window of time in which to detect early indicators of PD and intervene. If we can find a way to do this reliably, then it is very possible that we could keep PD from ever progressing to the point that motor function is impaired.
This is a direction for PD research that is gaining traction in the field. Our lab, for instance, works on the neuroinflammation aspects of PD. There is a great deal of evidence suggesting that the immune system is chronically activated in PD and that this inflammation could be a major driver of neurodegeneration. The body’s immune system fights infections and keeps us from getting sick, but it is an incredibly powerful weapon, and if it is not regulated correctly, it can damage our own tissues, including neurons in our brains. Our lab is looking, for instance, to see if we can identify immune-related markers in the blood that distinguish PwP in the earliest stages of PD and trying to figure out how these immunological changes contribute to PD-related neuropathology. We are also exploring the possibility that PD pathology could originate in the intestine and progress to the brain as a result of chronic inflammation. We are identifying indicators of intestinal inflammation in stool from PwP and using animal models to investigate whether dysregulated intestinal immune activity could drive parkinsonian neuropathology. We hope that one day, a routine blood or stool test could be used to identify early indicators of PD, and that interventions to control dysregulated peripheral inflammation could protect the brain from PD-related degeneration.
Malú G. Tansey, PhD is a member of the WPC 2019 Program Committee, and also served as a committee member for the WPC 2016. She is a tenured Associate Professor at Emory University School of Medicine in Atlanta.
Madelyn C. Houser is a Ph.D. student in Emory's Immunology and Molecular Pathogenesis program.
Ideas and opinions expressed in this post reflect that of the authors solely. They do not reflect the opinions or positions of the World Parkinson Coalition®.