Role of Gut Microbiome, Alpha Synuclein in the Prodromal Stage of Parkinson Disease

Virginia Gao, PhD

The prodromal phase of Parkinson disease (PD) can last up to 20 years and is characterized by a range of nonmotor symptoms that can predate the onset of the classical motor symptoms. These symptoms include constipation, hyposmia, possible REM-sleep behavior disorder, depression, anxiety disorder, and cognitive impairment. Lewy bodies and Lewy neurites, considered neuropathological hallmarks of the disease, spread throughout the brain following a predetermined pattern.

Targeting the prodromal phase of neurodegenerative disorders is not a new concept, theoretically providing an opportunity for early neuroprotective treatment and limit the spreading of disease-specific pathology and subsequent neuronal death. At the recently concluded 2023 American Neurological Association (ANA) Annual Meeting, held September 9-12, in Philadelphia, Pennsylvania, Virginia Gao, PhD, participated in a session covering prodromal neurologic diseases and the opportunities for early detection and treatment.

Gao, a movement disorders fellow at Weill Cornell Medicine, is currently conducting research in the laboratory of Jacqueline Burré on the biochemical changes underling PD pathology in the central and enteric nervous system. At the meeting, Gao sat down with NeurologyLive® to discuss her presentation, and how certain biomarkers predate neurodegenerative disease. She spoke on the role of the gut microbiome and how it can be thought of as a “second brain,” as well as why alpha synuclein represents such a promising avenue for research.

NeurologyLive®: Can you provide an overview of your presentation and explain why this topic interests you?

Virginia Gao, PhD: I'm currently studying Parkinson disease, specifically focusing on the connection between the gut and the brain in Parkinson. Lewy Body pathology, which is a hallmark of Parkinson's, is often found in both the brain and the gut. Interestingly, some individuals experience prodromal symptoms related to the gut, such as constipation and early satiety, many years before they exhibit motor symptoms, which are required for a formal diagnosis. Our research approach has two main objectives. First, we aim to understand the disease better by studying its pathophysiology in the gut. Second, we explore whether the gut can be a potential avenue for early diagnosis and targeted treatment. Our primary focus is on alpha synuclein, a protein associated with Parkinson's. It plays a critical role because it's a major component of Lewy bodies and, in rare cases, is linked to familial forms of the disease. We're particularly interested in the less-studied physiological function of Alpha synuclein, which is expressed in all presynaptic neurons and plays a crucial role in neurotransmission. Our research investigates the earliest changes in Alpha synuclein and whether these changes occur in both the gut and the brain, potentially mirroring each other. Preliminary results suggest that we can detect these early changes.

How can alpha synuclein become more commonly used in the clinical diagnosis of Parkinson's Disease?

Currently, Parkinson's Disease is diagnosed clinically, but there is growing interest in developing a biological definition using biomarkers, similar to what has been done in Alzheimer's research. While Alpha synuclein biomarkers are not yet integrated into clinical practice, they are invaluable for advancing research. We anticipate that with time, the role of Alpha synuclein biomarkers in Parkinson's diagnosis will evolve.

In what ways can biomarkers enhance the diagnosis of patients?

Numerous peripheral biomarkers for Alpha synuclein are emerging, including those from cerebrospinal fluid, skin, and even blood samples. However, what we truly need are predictive biomarkers and biomarkers of disease progression. The sensitivity and specificity of these biomarkers will improve, and new candidates are showing promise. Currently, these biomarkers are not widely used for Parkinson's, but they hold significant potential.

What is the feasibility of using Alpha synuclein as a reliable biomarker for Parkinson's Disease?

Several factors must align for Alpha synuclein to become a reliable biomarker for Parkinson's Disease. Scientific advancements, validation of biomarkers for both research and clinical purposes, and policy changes are all part of the equation. Progress is being made, and barriers are gradually coming down, but there is still much work to be done.

How do we determine the effectiveness of biomarkers?

Identifying effective biomarkers is crucial. We require biomarkers that predict who is at risk of developing the disease, biomarkers that can accurately measure treatment responses in clinical trials, and ultimately, these biomarkers need validation for potential disease-modifying treatments. The effectiveness of biomarkers will depend on their ability to fulfill these roles.

What is the significance of identifying and treating patients in the prodromal stage?

Recognizing prodromal symptoms of Parkinson's, such as non-motor symptoms like loss of smell, REM sleep behavior, and various GI and autonomic issues, is vital. These symptoms can manifest years before motor symptoms and can serve as early indicators of the disease. Identifying and treating individuals in the prodromal stage is essential for advancing our understanding and management of Parkinson's Disease.

Article was edited for clarity by artificial intelligence.